The Firsthand Results Of A Nanofat Treatment Using Stem Cells And PRP Forbes
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Eat These 5 Underrated Foods To Boost Metabolism, Says An MD mindbodygreen
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BioRestorative Therapies IFATS 2024 Presentation to GlobeNewswire
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Fasting may help improve immune system; 3 reasons why one should fast at least once a week or a month - Times Now
Alpilean Weight Loss Reviews (Legit Or Fake) Dont Try Alpine Ice Hack Diet Before You See This! Outlook India
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Alpilean Weight Loss Reviews (Legit Or Fake) Dont Try Alpine Ice Hack Diet Before You See This! - Outlook India
Stevens Institute of Technology Professors Use Interdisciplinary Collaboration to Enhance the Field of 3D-Printed Tissues India Education Diary
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Stevens Institute of Technology Professors Use Interdisciplinary Collaboration to Enhance the Field of 3D-Printed Tissues - India Education Diary
Scientists at Weill Cornell Medicine in New York say that stress-induced circadian clock disruptions may influence weight gain.
A study published in June showed that mice with artificially increased stress levels and interrupted hormone releases experienced an increase in fat cell growth. Its results appear in Cell Reports.
The second study, published in August, found that fat cell precursors commit to becoming fat cells only within a few hours at night. This work appears in the Proceedings of the National Academies of Sciences (PNAS).
Mary Teruel, PhD, associate professor of biochemistry at Weill Cornell Medicine, was the senior author of both studies.
A lot of forces are working against a healthy metabolism when we are out of circadian rhythm, Dr. Teruel said in a press release. The more we understand, the more likely we will be able to do something about it.
In the Cell Reports study, Dr. Teruel and her team implanted pellets with glucocorticoids, a type of stress-related hormone, in mice. This was to mimic the effects of chronic stress or Cushings disease.
Cushings disease triggers elevated levels of cortisol, the bodys stress hormone.
The pellets released glucocorticoids under the skin of the mice at a steady rate over three weeks. The researchers also observed control mice with typical daily stress hormone fluctuations.
Although all the mice ate the same healthy diet, the mice with pellets ended up weighing over 9% more than the control mice.
The researchers observed whether the weight gain was from fat expansion and found that the brown and white fat of the pellet mice had more than doubled. Their insulin levels spiked as well.
To the teams surprise, the metabolic disturbances kept blood glucose levels low. Further, the disruptions prevented fat from accumulating in the blood or liver.
When the researchers removed the pellets, these changes reversed immediately.
Dr. Teruel explained to MNT: We saw this in our paper, basically, once we stopped flattening the corticoids, [the mice] started reversing [the fat mass gain] and the hyperinsulinemia went away so that increased insulin that seems to be causing the fat mass gains that went away when the restored rhythm.
She added that this study indicates that chronic stress can make weight gain more likely, even with a healthy, low fat diet.
If you stress the animals at the wrong time, it has a dramatic effect. The mice arent eating differently, but a big shift in metabolism causes weight gain, Dr. Teruel said in the release.
Dr. Teruels research team hopes that their findings lead to developing drugs that could help reset circadian rhythms to help people with obesity.
We dont know enough [yet], but one would think cortisol receptor antagonists or [] things that restore the cortisol rhythms would probably help a lot.
Dr. Mary Teruel
Experts understand that flaws in circadian clock genes can alter cell differentiation in fat, immune, skin, and muscle cells.
The PNAS study revealed that even though differentiation happens over a few days, differentiation commitment happens within only a few hours. The findings also show that daily bursts of cell differentiation seem to be limited to evening phases when people are normally resting.
The decision to become a fat cell happens rapidly over 4 hours. It is like a switch, Dr. Teruel said.
Medical News Today discussed this with Dr. Mir Ali, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California.
Dr. Ali explained how fat cells come to be: Fat cells form from [an] adipocyte progenitor cell or a type of cell that has not differentiated into its final form. The form it takes [to become] a fat cell depends on the hormonal and chemical stimulation it receives.
In the study, Dr. Teruel and her partners used fluorescent markers to observe daily fluctuations of fat cell production.
The researchers attached a red fluorescent protein to a protein that regulates circadian clock genes. They also attached a yellow fluorescent protein to peroxisome proliferator-activated receptor gamma (PPARG), a protein that controls fat cell production.
They discovered that during the rest period of the day, a certain circadian protein CCAAT enhancer binding protein alpha induces a rapid increase in the protein that regulates fat cell production.
The researchers also found that when PPARG levels hit a certain threshold, individual fat precursor cells irreversibly commit to differentiate within only a few hours, which is much faster than the rest phase and the overall multiday differentiation process.
Dr. Teruel and her team believe that working with this time window may open therapeutic strategies to use timed treatment relative to the [circadian] clock to promote tissue regeneration.
Dr. Ali said: These studies are interesting in that they show the timing and length of stimulation affect the formation and growth of fat cells. The implications of this are that if we can find a way to safely influence the cell to grow or not grow, it may affect obesity in humans.
However, he believed that more extensive research is needed to make the studies findings applicable to humans.
Dr. Teruel told MNT that she and her co-authors were just trying to work on basic mechanisms [] Right now, we need to show this is really a mechanism that happens []
The researchers do plan to replicate the studies with people. We are looking at protein ribbons and humans using saliva samples, Dr. Teruel shared with MNT. Were planning to do those kinds of experiments.
Their main objective, she said, is to figure out ways to restore circadian [rhythms].
Dr. Teruel mentioned that currently known strategies, such as meditation and regular sleep in the dark may help.
She expressed hope that there could be some pharmacological ways [to] fix this in the future as well.
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Stress can throw off circadian rhythms and lead to weight gain - Medical News Today
This story was originally published by the Guardianandis reproduced here as part of theClimate Deskcollaboration. The colorized thylacine footage was created by Australias National Film and Sound Archive
Scientists in Australia and the US have launched an ambitious multimillion-dollar project to bring back the thylacine, a marsupial that died out in the 1930s, and reintroduce it to its nativeTasmania.
The thylacine, also known as the Tasmanian tiger, is the second undertaking by Colossal, a Texas-based biotechnology de-extinction company that last year announced it planned to use genetic engineering techniques tore-create the woolly mammoth and return it to the Arctic tundra.
Its new project is a partnership with the University of Melbourne, which earlier this yearreceived a $5m philanthropic giftto open a thylacine genetic restoration lab. The labs team has previouslysequenced the genome of a juvenile specimenheld by Museums Victoria, providing what its leader, Prof Andrew Pask, called a complete blueprint on how to essentially build a thylacine.
The thylacine was Australias only marsupial apex predator. It once lived across the continent, but was restricted to Tasmania about 3,000 years ago. Dog-like in appearance and with stripes across its back, it was extensively hunted after European colonization. The last known survivor died in captivity in 1936. Despite hundreds of reported sightings in the decades that followed, andsome quixotic attempts to prove its ongoing existence, it was officially declared extinct in the 1980s.
The scientists aim to reverse this by taking stem cells from a living species with similar DNA, thefat-tailed dunnart, and turning them into thylacine cellsor the closest approximation possibleusing gene editing expertise developed by George Church, a professor of genetics at Harvard Medical School and Colossals co-founder. New marsupial-specific assisted reproductive technologies will be needed to use the stem cells to make an embryo, which would be transferred into either an artificial womb or a dunnart surrogate to gestate.
Pask said the partnership was the most significant contribution ever made to marsupial conservation in Australia as more than 30 scientists worked to accelerate the massive grand challenge of bringing the thylacine back from the dead. He believed the first joeys could be born in 10 years.
Colossals chief executive and other co-founder, the tech and software entrepreneur Ben Lamm, was more bullish, believing it was possible in less than six years, the timeframe that the company had set itself to produce the first set of mammoth calves. I think its highly probable this could be the first animal we de-extinct, Lamm told the Guardian.
The challenges faced by the project are significant, and the scientists acknowledge several breakthrough steps will have to land for it to succeed. On reproductive technology, Pask said: We are pursuing growing marsupials from conception to birth in a test-tube without a surrogate, which is conceivable given infant marsupials short gestation period and their small size.
If successful, the plan would be to introduce the animal in a controlled setting on Tasmanian private land with an eventual goal of returning it to the wild. The researchers said returning an apex predator could help rebalance the states ecosystem. But Pask said they also hoped that their work could have a wider impact in helping to addressan extinction crisis.
He said the world was changing too rapidly for existing conservation techniques to save many threatened species, pointing to the catastrophic impact on Australian wildlife from bushfires. We have to look at other technologies and novel ways to do that if we want to stop this biodiversity loss, he said. We have no choice. I mean, it will lead to our own extinction if we lose 50 percent of biodiversity on Earth in the next 50 to 100 years.
He said the team hoped to address concerns about the genetic health of the speciesan issue with the now extinct populationby sequencing the genomes of between 80 and 100 individuals, and that dealing with genetic diversity was relatively straightforward compared with other challenges the research faced.
The announcement has received a mixed response from conservation biologists. Corey Bradshaw, a professor in global ecology at Flinders University, believed it was unlikely to be successful. Even if you can do it [in the lab]and I have my doubts about thathow do you create the thousands of individuals of sufficient genetic variation you need to create a healthy population?
Euan Ritchie, a professor in wildlife ecology and conservation at Deakin University, said other outstanding questions included whether the project could do more to help threatened species than existing conservation genetics. He said turning a lab-created animal into a wild population would be an enormous challenge, but the financial support for de-extinction research should not be seen as a zero sum game.
Obviously we want to, as much as possible, save the current species we have, but if someone wants to fund bringing back the thylacine and they dont want to fund something else, then why not? If we do learn more about genetics that can be used to protect existing species, then all the better.
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Scientists Aim to Bring the Tasmanian Tiger Back From Extinction Mother Jones - Mother Jones
Ozone therapy is considered to be one of the most effective treatments to relieve pain, joints and contractures. Dr. Mariella Alvarenga, an expert in Aesthetic and Orthomolecular Medicine, shares her experience and the benefits of this technique.
It is the administration of medical ozone into the body for the treatment of various diseases. Through a set of techniques, ozone is used as a therapeutic agent in a large number of pathologies, such as osteoarthritis and arthritis, primarily inflammation. It consists of injections into pain points, that is, they are of direct action in local application.
What type of deformity is it recommended for?
It is used not only in medicine but also in beauty treatments. In beauty I can treat acne, cellulite, flaccidity, localized fat. When what is the drug, it improves circulation in general, it is indicated for hypertension, diabetics; in those chronic diseases which are degenerative and have impaired circulationDr. Alvarenga said.
On the other hand, ozone also works to improve the immune system as it stimulates the production of stem cells and the treatment consists of removing blood that will be ozonated and then reapplied intramuscularly. This treatment is called ozonized autovaccine or auto hemotherapy.
Also, it has another advantage that is important to me, which is the issue of price. Orthomolecular formulas became quite expensive, this is a fact. So, this gives me an opportunity to improve the package because it is a complete combination deserves, he said.
Those who want to know more about this serum therapy and improve their quality of life can contact her on Instagram or Facebook as @dramarielaalvarenga or call on 3764 527871.
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Benefits Of Ozone Therapy In Pain Medicine - Nation World News
Introduction
Obesity has become a global epidemic, which is spiraling out of control. With the prevalence of obesity, obesity-related problems such as T2DM, are also rapidly increasing. To discover the pathophysiological mechanisms between obesity and T2DM becomes particularly important for preventing and alleviating obesity related diabetes. Studies have found that adipose tissue can not only store fat, but also be an endocrine organ,1 secreting a variety of bioactive factors, collectively known as adipokines. As early as 1987, adipose tissue was identified as a main site for metabolism of sex steroids2 and production of adipsin,3 an endocrine factor that is markedly down-regulated in rodent obesity. The subsequent identification and characterization of leptin4 in 1994 firmly established adipose tissue as an endocrine organ. Adipokines secreted by adipose tissue have been identified that either promote inflammatory responses or contribute to the resolution of inflammation. An imbalance of pro- and anti-inflammatory adipokines leads to obesity-linked metabolic dysfunction.5 Restoring the balance would be the method for treating obesity and its complications. Our review focuses on describing a few newly discovered adipokines in chronological order of being identified as an adipokine. Their functions in metabolism have been proved in past studies, but some are disputable or the specific action pathway is still unclear. A summary of researches progress so far seems necessary to provide the basis for further exploration on their potentials as biomarkers for diagnosis, treatment, and prognosis in obesity and T2DM (Table 1).
Table 1 Newly Discovered Adipokines Effect on the Pathogenesis of Obesity and T2DM
The upregulated adipokines in the state of obesity and insulin resistance (IR) generally have pro-inflammatory effects, leading to the form of a chronic inflammatory state and contributing to metabolic dysfunction.
Follistatin like 1 (FSTL1) was originally cloned from an osteoblast cell line as transforming growth factor- (TGF-) stimulated clone 36 (TSC-36) in 1993.6 Later, it was reported as a pro-inflammatory molecule in 2006, which led to severe paw swelling and arthritis in mouse paws.7 FSTL1 expression was increased in adipose tissues of obese mice.8 During the switch from chow diet to high fat diet (HFD), FSTL1 deletion mice gained less body weight, fat mass, and glucose level than the control group. FSTL1 promoted adipogenesis by inhibiting the conversion of PPAR to p-PPAR through the integrin/FAK/ERK signaling pathway,9 and could activate NFB and JNK signaling pathways, critical in obesity-induced inflammation and IR, in adipocytes and macrophages.8 Insulin-stimulated phosphorylation of both Akt and IRS-1 was markedly reduced by FSTL1 treatment, which impaired insulin signal transduction in 3T3-L1 adipocytes.8 Further, FSTL1 expression in adipose tissue10 and circulation11 rose dramatically in response to acute physical activity in rodents.
Serum levels of FSTL1 were significantly higher in patients with overweight/obese8,10 or newly diagnosed T2DM10 than in control subjects. Furthermore, a positive correlation between FSTL1 levels and body mass index (BMI), waist-to-hip ratio (WHR), fasting blood glucose (FBG), 2-hour postglucose load blood glucose (2h-BG), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), and HOMA-IR was observed. On the other hand, morbid and super obesity were potentially associated with a decline in plasma FSTL1 levels.12 In the intervention study, acute physical activity was found to significantly increase the circulating FSTL1 concentration in young, healthy participants.10,13
Together, FSTL1 is a potential mediator of adipogenesis, inflammation and IR. Prospective cohort studies are warranted to gain more evidence of the causality between FSTL1 and metabolic disorders. In addition, adenovirus mediated overexpression of FSTL1 or blocking its actions through neutralizing antibodies in animals will directly elucidate the role of FSTL1 in the pathogenesis.
Wingless-type inducible signaling pathway protein 1 (WISP1, also known as CCN4), a target gene of the canonical Wnt signaling pathway and a member of the CCN family of extracellular matrix proteins,14,15 has been confirmed as a proinflammatory adipokine in 2015.16 HFD-fed mice demonstrated upregulated WISP1 expression in epididymal adipose tissue.16 Knockdown of WISP1 in HFD-fed mice significantly attenuated hepatic steatosis and skeletal muscle IR via reversing inflammation-associated JNK phosphorylation. Treatment with WISP1 significantly increased lipogenesis-associated gene expression and TG accumulation in hepatocytes and suppressed insulin signaling in C2C12 skeletal muscle cells, which was abrogated after NFB-, JNK-, and TLR4-knockdown.17 In vitro studies on primary human skeletal muscle cells (hSkMCs) and murine AML12 hepatocytes also showed that recombinant WISP1 directly impaired insulin action by inhibiting the Akt signaling pathway.18 Meanwhile, WISP1 promoted endogenous and transplanted adult mice pancreatic cell proliferation depending on Akt signaling, exhibiting potential therapeutic use to prevent or delay the appearance of diabetes.19
WISP1 mRNA expression was elevated in visceral adipose tissue (VAT) rather than in subcutaneous adipose tissue (SAT) in human subjects, correlated positively with fasting insulin and negatively with insulin sensitivity. Reduction of WISP1 mRNA expression in SAT was observed after the weight loss with a low-calorie diet.16 Both mRNA expression in VAT and serum levels of WISP1 were increased in obese men.18 Patients with T2DM had higher levels of circulating WISP1, associated with central abdominal fat mass.20 A conflicting study reported no difference in WISP1 concentrations between individuals with normal glucose tolerance (NGT) and with T2DM but revealing the positive correlations between circulating WISP1 with BMI, body fat percentage, TG, hip circumference and fatty liver index.21
More prospective clinical studies would be valuable to establish the causal relationship of WISP1 on obesity and T2DM. Further cell or molecule studies are needed to precisely determine the role of this promising adipokine in the pathogenesis of diseases.
Asprosin, the C-terminal cleavage product of profibrillin, was found as a novel adipokine in patients with Neonatal Progeroid Syndrome (NPS) in 2016.22 It performs two critical fasting-related functions (hepatic glucose production and appetite stimulation) using the same cAMP second messenger system, although using different spatiotemporal mechanisms at two distinct organs. Upon secretion by white adipose, Asprosin travels to the liver, stimulating the release of glucose by binding to the OLFR734 receptor.22,23 It also crosses the blood-brain barrier to hypothalamus, where it stimulates appetite by activating orexigenic AgRP neurons and inhibiting anorexigenic POMC neurons.24 Animal experiments demonstrated that Asprosin could induce islet cell inflammation, dysfunction and apoptosis through TLR4/JNK-mediated signaling25 and promote cell apoptosis by inhibiting the autophagy of cell via AMPKmTOR pathway.26 The administration of Asprosin increased blood glucose level in healthy mice while there was no change in diabetic ones.27 On the other hand, intraperitoneal injection of Asprosin-specific monoclonal antibody could drop plasma Asprosin levels, lower appetite and body weight and reduce blood glucose in mouse models.22,28 Asprosin-neutralizing antibody is a kind of dual-effect pharmacologic therapy that targets at both overnutrition and hyperglycemia.
Decreased levels of plasma Asprosin have been observed in NPS patients associated with reduced appetite and extreme leanness22,24 and in anorexia patients,29 whereas pathological increase in circulating Asprosin is related to obesity30,31 and T2DM.3234 Asprosin is also expressed in human placenta and elevated in the plasma of pregnant women with gestational diabetes (GDM) and their offspring.35 The postprandial Asprosin level is apparently lower than the fasting in individuals with NGT, but not in T2DM patients. In another word, the alteration of meal-related circadian oscillation of Asprosin may be affected by T2DM.36,37 Clinical trials have explored the influences of diet, exercise, drugs and surgery on circulating Asprosin. A trial showed that rapid coffee consumption led to lower energy, fat intake and circulatory Asprosin. Rapid caffeine metabolizers were more likely to benefit from the consumption of more than two cups of coffee per day (15cpw) by reducing their BMI.38 An 8-week Nordic Walking training at maximal fat oxidation intensity decreased the concentration of Asprosin in the blood as well as visceral obesity in young women with metabolic disorders.39 Blood samples of 10 men and 10 women who performed a single 20-s bicycle sprint were collected before exercise, in the 3s, 15s, 30s, and 60s of recovery, and 24h after competition. Whereas the single anaerobic effort induced an increase in Asprosin secretion only in women.40 Metformin or SGLT2 inhibitors treatment could lower circulating Asprosin levels in patients with newly diagnosed T2DM.41,42 Blood Asprosin levels decreased significantly 6 months after bariatric surgery, and Asprosin concentrations before bariatric surgery were associated with the weight reduction magnitude.31
Despite advances in the understanding of Asprosins function, the reproducibility of some data produced in this field is waiting for proof. The secretion and action mechanism and the regulating factors are unclear.
In addition to the pro-inflammatory adipokines described above, adipose tissues also secrete a number of anti-inflammatory factors, which have shown beneficial effects on adiposity and insulin action.
Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine discovered in 2010.43 Its expression was reduced in white adipose tissue of obese HFD mice. SFRP5-deficient mice fed with HFD exhibited elevated F4/80 and CD68, macrophage-mediated inflammation markers, in epididymal adipose tissue and impaired glucose clearance and insulin sensitivity compared with the wildtype mice, which was significantly improved after two weeks intravenous injection of SFRP5. In vitro, upregulation expression of SFRP5 in 3T3-L1 adipocytes prevented the inflammatory and insulin-resistant state by binding with Wnt5a and neutralizing JNK activation in macrophages and adipocytes via paracrine and autocrine mechanisms.43 However, a report provided contradictory findings that elevated hyperglycemia and glucose intolerance was observed by overexpressing SFRP5 in obese, prediabetic mice. Conversely, anti-SFRP5 monoclonal antibody (mAb) therapy improved these phenotypes in vivo.44 In addition, SFRP5 was downregulated in pancreatic islets from obese rodents and humans, correlated with activated canonical Wnt signaling, promoting proliferation in primary islet cells and in the cell line INS1E. Its expression in cells could be positively modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue.45
In human studies, individuals with obesity,4648 T2DM,4750 metabolic syndrome (Mets),51 or Polycystic ovary syndrome (PCOS)47 generally exhibited lower SFRP5 levels in blood than normal controls. Circulating SFRP5 levels were positively associated with insulin sensitivity, high density lipoprotein cholesterol (HDL-C) and adiponectin, but negatively with BMI, WHR, HbA1c, FBG, 2h-BG and HOMA-IR. Another study showed that increasing concentrations of SFRP5 were independently and significantly associated with T2DM.52 After treated with metformin53 for 3 months, serum SFRP5 of PCOS patients significantly increased than that before administration. 16 weeks treatment with liraglutide47 rose plasma SFRP5 levels and reduced HOMA-IR and BMI moderately, suggesting increases in insulin secretion and sensitivity and decreases in weight.
SFRP5 is an adipokine which acts as an inhibitor of Wnt signaling pathway. It has been suggested to exert anti-inflammatory and insulin-sensitizing effects, however, contradictory data has also been reported. Prospective studies will improve our understanding of its functions in metabolism. Further exploration of the biological mechanisms may pave the way for SFRP5 to serve as a potential novel treatment option for obesity and T2DM.
Meteorin-Like (Metrnl/Subfatin) was identified as a novel adipokine in 2014, dramatically expressed in subcutaneous fat of both rodents and humans.54 It can be induced in muscle after exercise and adipose tissue upon cold exposure, and is present in the blood. Increasing circulating levels of Metrnl stimulated energy expenditure and the gene expression associated with anti-inflammatory cytokines and improved glucose tolerance in obese/diabetic mice.55 An intraperitoneal injection of recombinant Metrnl improved glucose tolerance in mice with HFD-induced obesity or T2DM via a Ca2+-CAMKK2-AMPK-HDAC5-GLUT4-p38-TBC1D1 signaling pathway.56 Metrnl could also ameliorate cell function by inhibiting apoptosis and promoting proliferation of it through activating the Wnt/-catenin pathway in T2DM mice.57 Global Metrnl knockout increased blood TG by 14% and decreased TC by 16% and HDL-C by 24%, reflecting Metrnl s beneficial aspect on the regulation of lipid metabolism.58
The clinical evidences regarding its circulating levels in obesity and T2DM are conflicting. Some studies showed less circulatory Metrnl levels in obese or T2DM patients compared with the control group,5962 correlated with higher FBG, 2h-BG, fasting insulin, HOMA-IR, HbA1c, high-sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a). Others demonstrated either an increase6365 or no significant change.66,67 Clinical trials have revealed that the weight loss via low calorie diet (LCD), combined training (CT) or bariatric surgery (BS) could rise Metrnl levels, in correlation to the improvement in glucose and lipid homeostasis. In LCD and BS patients, serum Metrnl concentrations significantly increased after 3 months, but returned to baseline after 12 months.68 Besides, another study reported remarkably enhanced circulatory Metrnl levels 12 months after BS.69 CT for 16 weeks increased brown adipose tissue (BAT) thermogenic activity as well as serum Metrnl levels.70 Metformin treatment did not increase the serum Metrnl levels after 12weeks.60
Although Metrnl has shown emerging effects in obesity, T2DM and dyslipidemia, there are conflicts in the clinical results. Besides, a myriad of work still needs to be done to explore its structure-function relationship and regulatory mechanism with various signaling pathways in related diseases.
Neuregulin-4 (NRG4), a member of the ErbB ligand family, was firstly described in 1999.71 Then it was identified as a previously unknown BAT-enriched secreted factor attenuating hepatic lipogenic signaling and preserving glucose and lipid homeostasis in obesity in 2014.72 NRG4-deficient mice upon HFD gained more body weight, higher plasma TG concentrations, pronounced hepatic steatosis and exacerbated glucose intolerance and insulin resistance compared with controls.72 Similarly, mice with ErbB4 deletion developed into Mets when fed with a medium-fat diet (MFD).73 On the contrary, transgenic expression of NRG4 resulted in the prevention of HFD-induced adiposity and fatty liver, and the improvement of insulin sensitivity.72,74,75 In vitro experiments, NRG4 gave a pronounced effect on insulin secretion in the rat insulinoma cell line.76 The promotion of adipocyte browning by n-3 polyunsaturated fatty acids was accompanied by an elevation of NRG4 expression via the PPARG pathway. NRG4 directly prevented lipid accumulation in HepG2 cells.77 Collectively, these findings provided the evidence in support of the potential health benefits of NRG4 in managing obesity and obesity-associated diseases. On the other hand, NRG4 knockdown in liver attenuated hepatic gluconeogenesis via suppressing PEPCK, G6Pase and PGC-1 expression in diabetic mice, reminding that NRG4 specific-silencing in liver will provide a potential therapeutic strategy for T2DM.78
Several observational studies have showed that circulating NRG4 concentrations were inversely associated with the risk of obesity,79 T2DM72,80 or Mets.81,82 Subjects with lower NRG4 levels had higher FBG, fasting insulin, HOMA-IR, HbA1c, TC, TG, and hs-CRP. Controversially, other researchers found that serum NRG4 level was elevated in T2DM.8385 Serum NRG4 increased significantly in response to a 3-week -3 polyunsaturated fatty acids dietary protocol.86 Plasma levels of NRG4 were improved in three training protocols: high-intensity interval training (HIIT), circuit resistance training (CRT), and moderate intensity continuous training (MICT) compared with the control group. What is more, the increase was greater in HIIT and CRT compared with the MICT.87 After 24 weeks, metformin therapy resulted in a significant increase of NRG4 levels compared with the baseline and the placebo group.88
The phenotype of mice with either a gain or loss of NRG4 function suggestthat reduced NRG4 may be causally linked to obesity-related impaired glucose metabolism. Prospective cohort studies are warranted to gain more evidence in humans. In addition, the exact mechanisms of how NRG4 exerts these beneficial effects are not entirely clear.
In 2004, a small secretory protein family was found in humans and mice, which is composed of five highly homologous genes, called TAFA1-5. TAFA mRNAs are highly expressed in specific brain regions, but rarely in other tissues.89 In 2018, researchers found that family with sequence similarity 19 member A5 (FAM19A5/TAFA5) was a new type of protective factor, highly expressed in human and mouse adipose tissue. It significantly inhibited the proliferation and migration of vascular smooth muscle cells and the proliferation of carotid intima after balloon injury via the binding receptor S1PR2 in mice. HFD could induce the downregulation of FAM19A5 expression in adipose tissue.90
Plasma FAM19A5 in patients with nonalcoholic fatty liver was significantly lower than that in the control group, and there was a significant negative correlation between FAM19A5 and BMI, visceral fat, alanine aminotransferase, aspartate aminotransferase, liver hardness and carotid intima-media thickness.91 The latest research showed that serum FAM19A5 levels were apparently decreased in the obese children compared with healthy controls. Negative correlations were detected between FAM19A5 and BMI as well as FBG and fasting insulin.92 Inversely, it was found that serum FAM19A5 concentrations in T2DM patients were higher than that in non-diabetic subjects, and positively correlated with WC, WHR, FBG and HbA1c.93
What we can see is that FAM19A5 is so novel that there are few researches about it. Whether and how FAM19A5 participates in obesity, IR and T2DM are waiting for our attention in the future.
Taken together, adipokines act as the promising candidates which have been shown to possess properties of mediating glycolipid metabolism. Generally, overexpression of pro-inflammatory adipokines or lack of anti-inflammatory adipokines in rodent experiments are causally linked to the occurrence and development of obesity and T2DM. The pro-inflammatory adipokines increase whereas the anti-inflammatory adipokines decrease in obese rodents and humans, associated with corresponding metabolic indicators of adiposity and T2DM. It is worth discussing that, as previously reviewed,94 adipokines, such as, IFN- and IL-10, can be raised in T2D patients, but not generally favor pro-inflammation. The impaired Th1/Th2 ratios were implicated with a delicate balance existing within diverse metabolic conditions. Consistent with this view, our review provides controversial human studies about the four anti-inflammatory adipokines, proving that their circulating levels are abnormally elevated in patients with T2DM. Based on this point, maybe we should pay more attention to the relationship between the balance of multiple adipokines and metabolic diseases in the future, rather than just focusing on one factor. There is still a lot waiting to be explored. For example, some contradictory data need to be corroborated in large sample sizes. Clinical cohort studies to demonstrate the causal relationship between adipokines and metabolic diseases are required to carry out. Few preclinical studies about the pathophysiological molecular mechanisms by which adipokines act have been conducted. There will be a long way to go before adipokines can be put into clinical trials and applied in humans.
The authors report no conflicts of interest in this work.
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New Discovered Adipokines Associated with the Pathogenesis of Obesity | DMSO - Dove Medical Press
Have you seen all the glossy slimvance reviews? We did too. So we decided to decipher how this hyped fat burner really works,
We recently bumped into some Slimvance reviews that call it the next best thing in fat burners. We were intrigued because almost every day, a new fat burner comes along and promises to help you lose body weight without having to diet or exercise.
It's time we started to take an objective look at it without getting swayed by fancy marketing claims, isn't it?
Slimvance, on the face of it, looks like a promising product. After all, it is from a well-known company, Bodydynamix, and comes an aggressive marketing team behind it. There are Slimvance reviews all over the internet, some of which look too glossy.
They are also on social media. Facebook seems to be one of their preferred playgrounds.
The question is whether you should believe the hype and give this fat burner a try or not. Is Slimvance really as effective as it claims to be? We take an in-depth look at it in this Slimvance review.
Top 3 Alternatives to Slimvance
Leanbean Best Alternative for Women
PhenQ Best Alternative for Men
PhenGold Best Appetite Suppressant
What is Slimvance?
Slimvance is a range of fat burners from Bodydynamix that's aimed to fill the void in the industry forno-stimulant weight loss supplements. And it's a large one too.
After all, almost all fat burners have some form of stimulant in them. Caffeine is the most common one but there are others like synephrine and yohimbine as well.
While these can work for athletes and seasoned fitness buffs, the average joe looking to lose a few pounds before an upcoming holiday may find it too hot to handle with the constant jitters and tremors.
Slimvance does away with all of these and instead relies on three natural ingredients for its fat-burning properties - Slimvance Core Slimming Complex. We will talk more about this in the ingredients.
But when you log on to the official website, you are greeted with a claim that Slimvance can help you lose up to 6-times more weight than what you can do with a healthy diet and exercise.
Now that's a claim we have seen before and it's one that we tend to treat with a lot of skepticism. But if Bodydynamix can back this up with some solid evidence, Slimvance could very well be the next best thing in fat burners - stimulant-free or otherwise.
Of course, the onus is on us to find out if that's the case. So without further ado, let's take an in-depth look at this fat burner starting with the claims.
What are the different products in the Slimvance range?
The Slimvance range comprises four products.
Bodydynamix Slimvance XP - Bodydynamics Slimvance XP is the flagship product in the range and claims to help you lower your BMI in just four weeks. It's supposed to be athermogenic fat burner. Hence they call it the Metabolism Igniter.
Bodydynamix Slimvance Core Slimming Complex - As implied by the name, this is their fat burner that supposedly targets the core area or belly fat. They claim that you can achieve transformational weight loss in 16 weeks with this.
Bodydynamix core slimming complex stick packs - This is the same as the above-mentioned fat burner but in a convenient stick pack.
How does Slimvance work? Claims
Slimvance makes some tall claims about its weight loss benefits for what it brings to the table. We are not new to exaggerated claims from the health and wellness industry. So we take all these with a grain of salt.
6-Times more body weight
The first claim is that it can help you lose up to 6-times more weight than just diet and exercise. That's a huge claim. We would have been impressed if it was double or even triple the amount. But six times?
To run some math, if you cut7500 caloriesfrom your diet a week, you lose 1 lb of fat in healthy weight loss. Do they mean that they can increase this to 6 lbs. a week? Even if you calculate the total fat mass you lose over a 6-12 month period, you can notice instantly why Slimvance seems inflated.
Burning belly fat and waist fat
We all have our problem areas that seem to cling to body fat no matter what we do. For most of us, it's the stubborn belly and waist fat.
Slimvance claims that it can help you target these problem areas and lose more body fat than dieting and exercising alone. It does this by supposedly activating your body's natural ability to burn fat which can stem fat tissue growth.
Again, we cannot help but be skeptical about these claims. But we will put that aside for now and what else they claim.
Lowering BMI in four weeks
One of the claims made by Bodydynamix for Slimvance XP is that it can help you lower your BMI in four weeks. This is the flagship product in their range and claims to be a thermogenic fat burner.
A reduction in BMI is a broad phrase and can simply imply a reduction in weight. But we are not sure if that's what they mean here.
If they do mean a reduction in weight, the question is how much? Even a drop of 1-2 BMI points is considered significant for asupplement that can promote weight loss. So it will be interesting to see what the ingredients are.
Slimvance ingredients
As we mentioned earlier, Slimvance uses a 3-ingredient formula for its fat-burning properties - Core Slimming Complex.
This includes:
Turmeric
Turmeric, also called the Golden spice has been used in Indian Ayurvedic medicine for centuries. It is a powerful antioxidant and has anti-inflammatory properties.
There is some evidence to show that it can help with weight loss. A study done on rats showed that those given curcuminoids (found in turmeric) were able to lose more weight than the control group.
However, the study was done on rats and the sample size was small. So we need more research to say for certain if turmeric can help with weight loss in humans. As of now, it can be a beneficial ingredient. But with inconclusive research, we cannot vouch for it.
Moringa
Moringa Olifera or simply Moringa is a tree that is native to India. It is also known as the Drumstick tree. Every part of the tree - leaves, flowers, fruits, and seeds - can be used for medicinal purposes.
It has been traditionally used to treat various ailments like anemia, diarrhea, and indigestion. It is considered to be one of the most nutritious natural foods in the world.
Moringa leaves are rich in vitamins, minerals, and antioxidants. It also has a high protein content. Studies have shown that it can help reduce inflammation and boost immunity.
There is some evidence to show that Moringa can help with weight loss as well. But it's clearly not enough to make any significant claims.
Curry Leaves
Curry Leaves or Murraya Koenigii is a plant that is native to India. It is commonly used as an ingredient in Indian curries.
Curry leaves are rich in antioxidants, vitamins, and minerals. They have traditionally been used for their medicinal properties.
Curry leaves are known toboost metabolismand aid in digestion. They are also thought to help regulate blood sugar levels. But considering that this is one of the three primary ingredients that's intended to help you lose weight, the research is lacking.
A study done on rats showed that curry leaves can help reduce weight gain and improve insulin sensitivity. But the sample size was small and more research is needed to confirm these findings in humans.
Does Slimvance work?
Based on our detailed Slimvance review, we do not think that Slimvance will help you lose a significant amount of weight.
The ingredients are not strong enough on their own to make any claims about weight loss. And the research that has been done is mostly inconclusive to back up these claims.
Here are our thoughts.
Slimvance uses a proprietary blend
The biggest issue we have with Slimvance is that it uses a proprietary blend. This means that the exact amount of each ingredient is not disclosed.
All we know is that the Core Slimming Complex contains 450 mg of the three ingredients, which is not enough to make any significant impact.
Proprietary blends are often used to hide the ineffective or low doses of ingredients. So we would have liked to see more transparency from the company.
The research is inconclusive
As we mentioned earlier, the majority of the research that has been done on the Slimvance ingredients is either inconclusive or done on animals.
There is some evidence to show that Moringa and Curry leaves can help with weight loss. But the sample sizes are small and more research is needed to confirm these findings in humans.
As for Turmeric, there is not enough evidence to show that it can help with weight loss in humans, on its own. Maybe if it was blended with caffeine and other potent ingredients, it could have a more significant impact on your weight loss journey.
Slimvance is not a very strong
We are all for low stimulant fat burners. But the three primary ingredients in Slimvance are not very strong on their own. And considering that they are only present in small doses, we do not think that Slimvance will help you lose weight.
Slimvance Cost
Slimvance's range is priced at approximately $59.99 for a 1-month supply.
This puts it on the higher end of the spectrum, considering that it's not very strong and there are other fat burners on the market that are more effective, contain clinically proven ingredients and cost almost the same or even less.
Slimvance Reviews - Our thoughts
All in all, we do not think that Slimvance is an effective weight loss supplement. The ingredients are not strong enough on their own to make any claims about weight loss. And the research that has been done is mostly inconclusive to back up these claims.
So, if you're looking for a fat burner that can help you lose weight sustainably, we can recommend three top options instead.
#1 - Leanbean - No Stimulant Weight loss supplement
You do not need copious amounts of stimulants for body weight loss andLeanbeanis the prime example of that. It is a natural weight loss supplement that works great for women.
The thermogenic effects are very mild, but it does not cause any jitters or tremors, which is the case with many other non-stimulant fat burners. In fact, Leanbean works primarily by helping you control calories.
Why Leanbean is better than Slimvance
Every popular weight loss supplement talks about burning more calories. But what about the number of calories that you consume in the first place? If you are not able to control your calorie intake, then all the fat burning in the world will not help.
This is where Leanbean shines.
Curb calories without stress
Leanbean contains Glucomannan, which is adietary fiberthat swells in your stomach and makes you feel full. This means that you will not be reaching out for unhealthy snacks between meals. In other words, it reduces stress eating.
There'schromium too, which is a mineral that helps to regulate blood sugar levels. When blood sugar levels are balanced, you will not have cravings for sugary snacks.
Breaks down stored fat
If your diet in the past has been sketchy, then Leanbean has Choline, which is an essential nutrient for fat metabolism. So, not only does it help you control calories, but it also helps you break down stored body fat.
Leanbean is very popular with fitness models and athletes because it gets the job done without using any stimulants. This makes it ideal for people who are sensitive to caffeine or have a heart condition.
Stay energetic even with fewer calories
Leanbean's final ingredient is Vitamin B6, which is essential for energy production. So, even if you are taking in fewer calories, you will not feel fatigued during the day.
This makes it easier to hit the gym and stay active, both of which are critical for sustainable weight loss.
Leanbean Cost
Here's what's surprising. Despite having such high-quality ingredients and being so popular, Leanbean is very affordable.
A month's supply will cost you only $59.99. So, it is the same price as Slimvance. But it's clearly a lot more effective. You can buy a three month pack and get the fourth month's supply for free.
Click here for the Lowest Price on Leanbean
Conclusion - Is Leanbean Effective?
Leanbean is our top recommendation for a non-stimulant weight loss supplement because it helps you control calories without using any stimulants. It is also very popular and very affordable.
If you are looking for an alternative to Slimvance, then Leanbean is the way to go.
#2 - PhenQ - The all-in-one weight loss solution
PhenQis a weight loss supplement that takes a different approach from most other products. It is not just a thermogenic or a fat burner. It is an all-in-one solution that helps you with every aspect of weight loss.
The reason PhenQ is so popular is because it works on multiple fronts to help you lose weight.
Why PhenQ is better than Slimvance
You cannot rely on one working mechanism to help you with weight loss. Weight loss is a complex process and each one of us faces unique challenges. That's why PhenQ has been designed to tick off the most common boxes.
See the original post here:
Slimvance Reviews - Does This Fat Burner Really Work? - Outlook India
Stem cells have two features: the ability to differentiate along different lineages and the ability of self-renewal. Two major types of stem cells have been described, namely, embryonic stem cells and adult stem cells. Embryonic stem cells (ESC) are obtained from the inner cell mass of the blastocyst and are associated with tumorigenesis, and the use of human ESCs involves ethical and legal considerations. The use of adult mesenchymal stem cells is less problematic with regard to these issues. Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as umbilical cord, endometrial polyps, menses blood, bone marrow, adipose tissue, etc. This is because the ease of harvest and quantity obtained make these sources most practical for experimental and possible clinical applications. Recently, MSCs have been found in new sources, such as menstrual blood and endometrium. There are likely more sources of MSCs waiting to be discovered, and MSCs may be a good candidate for future experimental or clinical applications. One of the major challenges is to elucidate the mechanisms of differentiation, mobilization, and homing of MSCs, which are highly complex. The multipotent properties of MSCs make them an attractive choice for possible development of clinical applications. Future studies should explore the role of MSCs in differentiation, transplantation, and immune response in various diseases.
Original post:
Mesenchymal stem cells - PubMed
Cells in the body have specific purposes, but stem cells are cells that do not yet have a specific role and can become almost any cell that is required.
Stem cells are undifferentiated cells that can turn into specific cells, as the body needs them.
Scientists and doctors are interested in stem cells as they help to explain how some functions of the body work, and how they sometimes go wrong.
Stem cells also show promise for treating some diseases that currently have no cure.
Stem cells originate from two main sources: adult body tissues and embryos. Scientists are also working on ways to develop stem cells from other cells, using genetic reprogramming techniques.
A persons body contains stem cells throughout their life. The body can use these stem cells whenever it needs them.
Also called tissue-specific or somatic stem cells, adult stem cells exist throughout the body from the time an embryo develops.
The cells are in a non-specific state, but they are more specialized than embryonic stem cells. They remain in this state until the body needs them for a specific purpose, say, as skin or muscle cells.
Day-to-day living means the body is constantly renewing its tissues. In some parts of the body, such as the gut and bone marrow, stem cells regularly divide to produce new body tissues for maintenance and repair.
Stem cells are present inside different types of tissue. Scientists have found stem cells in tissues, including:
However, stem cells can be difficult to find. They can stay non-dividing and non-specific for years until the body summons them to repair or grow new tissue.
Adult stem cells can divide or self-renew indefinitely. This means they can generate various cell types from the originating organ or even regenerate the original organ, entirely.
This division and regeneration are how a skin wound heals, or how an organ such as the liver, for example, can repair itself after damage.
In the past, scientists believed adult stem cells could only differentiate based on their tissue of origin. However, some evidence now suggests that they can differentiate to become other cell types, as well.
From the very earliest stage of pregnancy, after the sperm fertilizes the egg, an embryo forms.
Around 35 days after a sperm fertilizes an egg, the embryo takes the form of a blastocyst or ball of cells.
The blastocyst contains stem cells and will later implant in the womb. Embryonic stem cells come from a blastocyst that is 45 days old.
When scientists take stem cells from embryos, these are usually extra embryos that result from in vitro fertilization (IVF).
In IVF clinics, the doctors fertilize several eggs in a test tube, to ensure that at least one survives. They will then implant a limited number of eggs to start a pregnancy.
When a sperm fertilizes an egg, these cells combine to form a single cell called a zygote.
This single-celled zygote then starts to divide, forming 2, 4, 8, 16 cells, and so on. Now it is an embryo.
Soon, and before the embryo implants in the uterus, this mass of around 150200 cells is the blastocyst. The blastocyst consists of two parts:
The inner cell mass is where embryonic stem cells are found. Scientists call these totipotent cells. The term totipotent refer to the fact that they have total potential to develop into any cell in the body.
With the right stimulation, the cells can become blood cells, skin cells, and all the other cell types that a body needs.
In early pregnancy, the blastocyst stage continues for about 5 days before the embryo implants in the uterus, or womb. At this stage, stem cells begin to differentiate.
Embryonic stem cells can differentiate into more cell types than adult stem cells.
MSCs come from the connective tissue or stroma that surrounds the bodys organs and other tissues.
Scientists have used MSCs to create new body tissues, such as bone, cartilage, and fat cells. They may one day play a role in solving a wide range of health problems.
Scientists create these in a lab, using skin cells and other tissue-specific cells. These cells behave in a similar way to embryonic stem cells, so they could be useful for developing a range of therapies.
However, more research and development is necessary.
To grow stem cells, scientists first extract samples from adult tissue or an embryo. They then place these cells in a controlled culture where they will divide and reproduce but not specialize further.
Stem cells that are dividing and reproducing in a controlled culture are called a stem-cell line.
Researchers manage and share stem-cell lines for different purposes. They can stimulate the stem cells to specialize in a particular way. This process is known as directed differentiation.
Until now, it has been easier to grow large numbers of embryonic stem cells than adult stem cells. However, scientists are making progress with both cell types.
Researchers categorize stem cells, according to their potential to differentiate into other types of cells.
Embryonic stem cells are the most potent, as their job is to become every type of cell in the body.
The full classification includes:
Totipotent: These stem cells can differentiate into all possible cell types. The first few cells that appear as the zygote starts to divide are totipotent.
Pluripotent: These cells can turn into almost any cell. Cells from the early embryo are pluripotent.
Multipotent: These cells can differentiate into a closely related family of cells. Adult hematopoietic stem cells, for example, can become red and white blood cells or platelets.
Oligopotent: These can differentiate into a few different cell types. Adult lymphoid or myeloid stem cells can do this.
Unipotent: These can only produce cells of one kind, which is their own type. However, they are still stem cells because they can renew themselves. Examples include adult muscle stem cells.
Embryonic stem cells are considered pluripotent instead of totipotent because they cannot become part of the extra-embryonic membranes or the placenta.
Stem cells themselves do not serve any single purpose but are important for several reasons.
First, with the right stimulation, many stem cells can take on the role of any type of cell, and they can regenerate damaged tissue, under the right conditions.
This potential could save lives or repair wounds and tissue damage in people after an illness or injury. Scientists see many possible uses for stem cells.
Tissue regeneration is probably the most important use of stem cells.
Until now, a person who needed a new kidney, for example, had to wait for a donor and then undergo a transplant.
There is a shortage of donor organs but, by instructing stem cells to differentiate in a certain way, scientists could use them to grow a specific tissue type or organ.
As an example, doctors have already used stem cells from just beneath the skins surface to make new skin tissue. They can then repair a severe burn or another injury by grafting this tissue onto the damaged skin, and new skin will grow back.
In 2013, a team of researchers from Massachusetts General Hospital reported in PNAS Early Edition that they had created blood vessels in laboratory mice, using human stem cells.
Within 2 weeks of implanting the stem cells, networks of blood-perfused vessels had formed. The quality of these new blood vessels was as good as the nearby natural ones.
The authors hoped that this type of technique could eventually help to treat people with cardiovascular and vascular diseases.
Doctors may one day be able to use replacement cells and tissues to treat brain diseases, such as Parkinsons and Alzheimers.
In Parkinsons, for example, damage to brain cells leads to uncontrolled muscle movements. Scientists could use stem cells to replenish the damaged brain tissue. This could bring back the specialized brain cells that stop the uncontrolled muscle movements.
Researchers have already tried differentiating embryonic stem cells into these types of cells, so treatments are promising.
Scientists hope one day to be able to develop healthy heart cells in a laboratory that they can transplant into people with heart disease.
These new cells could repair heart damage by repopulating the heart with healthy tissue.
Similarly, people with type I diabetes could receive pancreatic cells to replace the insulin-producing cells that their own immune systems have lost or destroyed.
The only current therapy is a pancreatic transplant, and very few pancreases are available for transplant.
Doctors now routinely use adult hematopoietic stem cells to treat diseases, such as leukemia, sickle cell anemia, and other immunodeficiency problems.
Hematopoietic stem cells occur in blood and bone marrow and can produce all blood cell types, including red blood cells that carry oxygen and white blood cells that fight disease.
People can donate stem cells to help a loved one, or possibly for their own use in the future.
Donations can come from the following sources:
Bone marrow: These cells are taken under a general anesthetic, usually from the hip or pelvic bone. Technicians then isolate the stem cells from the bone marrow for storage or donation.
Peripheral stem cells: A person receives several injections that cause their bone marrow to release stem cells into the blood. Next, blood is removed from the body, a machine separates out the stem cells, and doctors return the blood to the body.
Umbilical cord blood: Stem cells can be harvested from the umbilical cord after delivery, with no harm to the baby. Some people donate the cord blood, and others store it.
This harvesting of stem cells can be expensive, but the advantages for future needs include:
Stem cells are useful not only as potential therapies but also for research purposes.
For example, scientists have found that switching a particular gene on or off can cause it to differentiate. Knowing this is helping them to investigate which genes and mutations cause which effects.
Armed with this knowledge, they may be able to discover what causes a wide range of illnesses and conditions, some of which do not yet have a cure.
Abnormal cell division and differentiation are responsible for conditions that include cancer and congenital disabilities that stem from birth. Knowing what causes the cells to divide in the wrong way could lead to a cure.
Stem cells can also help in the development of new drugs. Instead of testing drugs on human volunteers, scientists can assess how a drug affects normal, healthy tissue by testing it on tissue grown from stem cells.
Watch the video to find out more about stem cells.
There has been some controversy about stem cell research. This mainly relates to work on embryonic stem cells.
The argument against using embryonic stem cells is that it destroys a human blastocyst, and the fertilized egg cannot develop into a person.
Nowadays, researchers are looking for ways to create or use stem cells that do not involve embryos.
Stem cell research often involves inserting human cells into animals, such as mice or rats. Some people argue that this could create an organism that is part human.
In some countries, it is illegal to produce embryonic stem cell lines. In the United States, scientists can create or work with embryonic stem cell lines, but it is illegal to use federal funds to research stem cell lines that were created after August 2001.
Some people are already offering stem-cells therapies for a range of purposes, such as anti-aging treatments.
However, most of these uses do not have approval from the U.S. Food and Drug Administration (FDA). Some of them may be illegal, and some can be dangerous.
Anyone who is considering stem-cell treatment should check with the provider or with the FDA that the product has approval, and that it was made in a way that meets with FDA standards for safety and effectiveness.
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Stem cells: Sources, types, and uses - Medical News Today
Degenerative Disc Disease (DDD), Herniated Discs & Sciatica Causing Lumbar Back Pain
What is degenerative disc disease and what are the symptoms?
Spinal disc degeneration and disc herniations are two of the most common causes of back pain, affecting in particular the lumbar spine (low back). Spinal discs are soft, compressible structures that separate the vertebrae of the spine. The discs act as shock absorbers, allowing the spine to flex, bend, and twist.
Sciatica is the name for the horrible leg pain that is caused when a bulging lumbar disc irritates a lumbar nerve root. The discomfort can be a combination of burning pain and numbness that responds poorly to pain medication.
There is a normal amount of expected wear and tear of our spinal discs as we age. On the other hand, arthritis, injury, and extreme wear and tear of sports can accelerate the degeneration. On a cellular level, there is continual loss of healthy cells inside the disc that is responsible for the discs structure. Over time, normal cells are damaged and hydration is lost, leading to tears in the internal structure of the discs.
When discs degenerate, mobility is affected and function is limited, resulting in symptoms that include stiffness, weakness, and ultimately, unrelenting pain.
What is spinal facet disease and what are the symptoms?
Spinal facet disease is one of the most common causes of neck and back pain and can cause pain at any level of the spine. The spinal facets joints are located on both sides of the back of each spinal segment. They connect each spinal level and are responsible for stabilizing the vertebral bodies and counterbalancing the intervertebral discs. The facets can be injured during acute trauma often seen in flexion extension injuries such as a whiplash event or sports accident. The surfaces of the facet joints are covered by articular cartilage and are also prone to chronic degenerative arthritis much like the larger joints such as knees and hips.
Pain that is caused by facet dysfunction is typically isolated to the back of the lumbar spine, thoracic region and neck. The discomfort can be isolated to one side or may affect both sides of the spine at once. The pain may radiate into the muscles but does not extend into the extremities like sciatic pain that is caused from a disc herniation. Typically the pain is worsened with extension and or rotation of the neck or back. Diagnosis of facet pain begins with a physical exam and imaging studies, but often requires diagnostic injection with local anesthetic and or steroid to confirm the diagnosis.
When the facet joints are injured mobility is affected and function is limited, resulting in symptoms that can mimic disc disease such as stiffness, weakness, and ultimately, unrelenting pain.
Read more here:
Stem Cells For Back Pain | Stem Cells For Herniated Discs
Fat cells are the basic building blocks of fat tissue. Fat (or adipose) tissue is found throughout the human body and is concentrated beneath the skin, between the muscles, and around the internal organs.
The primary functions of fat cells are to store lipids for energy, to produce and secret hormones, and to release heat energy from lipids.
Fat cells (AKA adipocytes or adipose cells) are the cells that make up the adipose tissue. Their main functions are to store energy in the form of lipids and to create an insulating layer beneath the skin for the conservation of body heat. Adipose tissue also insulates, cushions, and protects the internal organs.
Fat cells are primarily located beneath the skin, between the muscles, and around the internal organs. Adipose tissue under the skin is known as subcutaneous fat, and it mainly functions as an insulating layer and energy store. Fat tissue found between the muscles and internal organs is called visceral fat. Visceral fat also helps to insulate the body and prevent heat loss, whilst acting as a shock absorber to cushion and protect the organs.
There are three main types of adipocytes in vertebrates; there are white fat cells, brown fat cells, and beige fat cells. Different types of fat cells are found in different regions of the body and have different functions to one another.
Most fat in the human body is white fat tissue. White fat cells are highly specialized for fat storage and contain large lipid droplets. For this reason, they function as the bodys main energy reserve.
White adipose tissue also makes up the bulk of the insulating layer that lies beneath the skin and surrounds the internal organs. This layer is important for the conservation of body heat and, therefore, regulation of body temperature.
Brown adipose tissue also stores energy but, unlike white fat cells, brown fat cells are specialized to release energy in the form of heat. This process (known as thermogenesis) is switched on in response to low external temperatures, and helps to maintain body temperature in cold conditions.
Brown fat cells are typically smaller than white fat cells and may contain multiple, small lipid droplets (rather than the single large droplet found in white adipocytes). They are also equipped with abundant mitochondria, which is how these cells get their brown color. During thermogenesis, the mitochondria in brown fat cells convert the chemical energy stored in lipids into heat energy. The heat is released from the fat cell and dissipates through the tissues of the body to maintain or raise its overall temperature.
Brown fat tissue is found in specific regions of the body, including between the neck muscles and shoulder blades, along the spinal cord, above the collarbone, and, sometimes, surrounding the internal organs.
Beige adipocytes are halfway between white and brown fat cells and have characteristics of both. They are found in similar areas to white fat cells and behave like white adipocytes until they are activated by low temperatures. When this happens, they go through a process called browning and begin to behave like brown adipocytes (i.e., they start to burn lipids for energy).
Adipocytes are specialized to store fat and mainly function as a fuel reserve for the body. However, fat cells also have two other key functions, and these are the release of hormones and the production of heat.
White fat cells function as a long-term energy store and are specialized to store lipids in the form of triglycerides. They are the bodys safety net against starvation and, in times of fasting, will release fatty acids and glycerol as fuel for the rest of the body.
When we consume excess calories, our bodies store more fats, and the size of the lipid droplets inside the fat cells increases. This gradually causes an increase in the mass of adipose tissue and can contribute to obesity.
The storage and release of fatty acids by white blood cells is controlled by hormones, such as insulin. The release of pancreatic insulin stimulates fat cells to take up and store triglycerides, while a drop in insulin levels causes fat cells to release their fatty acids.
Adipose tissue is more than just an energy-storing mass. It also functions as an endocrine organ, meaning it synthesizes and releases hormones. These hormones influence a wide range of biological processes in the body, including the regulation of food intake and control of sensitivity to insulin.
Like white adipocytes, brown fat cells store lipids for energy. However, they also have their own unique function, and this is thermogenesis: the use of lipids to produce heat.
Brown adipose tissue protects vertebrates from the cold and is switched on by exposure to low temperatures. When this happens, the abundant mitochondria in brown fat cells are triggered to increase their oxidation of fatty acids, a process that wastes chemical energy as heat. The heat produced by thermogenesis dissipates through the tissues surrounding the brown fat cells, helping to maintain the body temperature of the organism.
Whether brown or white, all adipose cells consist of a large lipid droplet surrounded by a thin layer of cytoplasm and a plasma membrane. Each cell also contains organelles including a nucleus, Golgi apparatus, endoplasmic reticulum, ribosomes, and mitochondria. Brown fat cells contain lots more mitochondria than white fat cells do, which is what gives their lipid droplets their darker color.
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Fat Cells - The Definitive Guide | Biology Dictionary
-- First Site Will Enroll First Patient in the Clinical Study--
MELVILLE, NY., June 13, 2022 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (the Company” or BioRestorative”) (NASDAQ: BRTX), a clinical stage company focused on stem cell-based therapies, today announced site initiation for its Phase 2 clinical trial targeting chronic lumbar disc disease (cLDD). The Denver Spine and Pain Institute is the first clinical site to be initiated. Additional selected sites are expected to be initiated in 2022.
BioRestorative’s Phase 2 trial is a double-blind controlled, randomized study to evaluate the safety and preliminary efficacy of a single dose intradiscal injection of the Company’s autologous investigational stem cell-based therapeutic, BRTX-100. A total of up to 99 eligible patients will be randomized at up to 15 centers in the United States to receive either the investigational drug (BRTX-100) or control in a 2:1 fashion.
Currently there are no approved, cell-based therapies for cLDD. While there is encouraging data that suggests that patients with cLDD could benefit from autologous stem cell transplants, the low oxygen micro-environment of the disc makes cell-based therapies challenging. BRTX-100 is manufactured under low oxygen conditions and engineered to survive this environment,” said Scott Bainbridge, M.D., Principal Investigator for the BRTX-100 trial at The Denver Spine and Pain Institute. Positive proof-of-concept data in this trial could be disruptive and support the potential applicability of BRTX-100 to other spine and musculoskeletal disorders where low oxygen micro-environments are found.”
We are pleased to initiate the first of several sites across the United States that will be enrolling for the trial,” said Lance Alstodt, Chief Executive Officer of BioRestorative Therapies. Our sites have been carefully reviewed and selected and have clinical expertise in treating patients who could potentially benefit from BRTX-100. We look forward to working with the principal investigators and their clinical trial teams.”
About BioRestorative Therapies, Inc.
BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:
Forward-Looking Statements
This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission and other public filings. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.
CONTACT: Email: ir@biorestorative.com
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2022-06-13 | OTCPK:BRTXD | Press Release | BioRestorative Therapies - Stockhouse
Introduction to DPP-4 Enzyme
In 1966, Hopsu-Havu and Glenner found dipeptidyl peptidase-4 (DPP-4) in rat liver during the processing of the cells and commercially enzymatic preparations as an activity that liberates naphthylamine from GlyPro-2-naphthylamide, and it was originally called glycylproline naphthylamidase.1 Meanwhile, the protein characteristics and distribution were intensively investigated, and it was rediscovered numerous times as a binding protein and a cellular marker.2 DPP-4 is the enzyme for the immune response which is known as antigen CD26 co-stimulator of T- cell, having a multiuse protein that serves as a binding protein and a ligand for a range of extracellular molecules in addition to its catalytic activity.3 It is a membrane protein that is expressed on cells all over the body, but it is also detached from the membrane and comes into circulation in the plasma as a soluble protein.4,5 Lymphocytes, fibroblasts, endothelial cells, and apical portions of acinar and epithelial cells express DPP-4, which is also found in plasma as in soluble circulating form.6,7
All membrane-bound molecules like proline or alanine-specific exopeptidases have been proposed to have a biological function in the degradation of bioactive peptides,8 but the DPP-4 role has been explored and reported most. In comparison to other peptidase enzymes, like aminopeptidase and carboxypeptidase, which have a limited distribution, DPP-4 is found in almost all vertebrate tissues, but its activity varies greatly.9
The enzyme is found largely in the cortical region and in the brush-border and microvillus portions of the kidney and hepatocytes at the cytoplasmic membrane surrounding bile canaliculi and on epithelial of the bile duct in the liver. It can also be detected on pancreatic duct epithelial cells.10 DPP-4 is thus present in body compartments/fluids engaged in nutrition and excretion (bile, pancreatic fluid, intestinal lumen, urine). As a result, DPP-4 plays a digestive role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues.11 In both rats and humans, DPP-4 is a ubiquitous enzyme, including the exocrine pancreas, biliary tract, spleen, small intestine, and brain.12,13 DPP-4 possesses differentially expressed biological functions, as evidenced by its extensive organ distribution. The liver is among the organs with the highest levels of DPP-4 expression.14 DPP-4 marking is high in hepatic acinar zones 2 and 3, but never in zone 1, in a normal healthy liver.15 DPP-4 may be implicated in the control of hepatic metabolism, based on the uneven lobular distribution.16
DPP-4, on the other hand, is in direct touch with hormones flowing in the blood, as it is present on blood vessels endothelial cells17 and as a mobile enzyme in plasma. DPP-4 is expressed on excited T-helper lymphocytes18 as well as fractions of macrophages19 among immune system cells.20 DPP-4 is highly expressed in the endocrine organs, but occasionally in parenchymal cells, such as thyroid follicular epithelial cells and luteal cells.21 DPP-4 is expressed in specialized fibroblasts in a variety of tissues, including the skin, mammary gland, and synovia.22 The concentration and activity of DPP-4 in different organs/tissues/cells are shown in Figure 1.
Figure 1 Graphical representation of the concentration and activity of DPP-4 in different organs/tissues/cells.
DPP-4 includes membrane-bound peptidases like fibroblast activation protein (FAP)/seprase, resident cytoplasmic enzymes, and nonenzymatic members, which are found in neuronal membranes, as well as prolyl endopeptidase. Despite other major changes in sequence, the position and identity of the residues are crucial for catalytic activity within the C-terminal region of these related enzymes and are highly conserved in prokaryotes and eukaryotes.23 DPP-4 interacts with other membrane proteins and sends signals across cell membranes. The molecular structure of DPP-4 is shown in Figure 2.
Figure 2 Molecular structure of DPP-4.
Notably, the majority of the protein is extracellular, including the catalytic domain at the C-terminus, a cysteine-rich region, and a large glycosylated region connected to the transmembrane portion by a flexible stalk. Only six amino acids at the N-terminus are expected to reach into the cytoplasm. DPP-4 can form tetramers between two soluble proteins or two membrane-bound proteins, which could alter the efficiency of substrate entrance and cleavage by the catalytic active site or facilitate cellcell communication, as reported in a study of the protein crystal structure.23
The intracellular signalling of membrane-bound DPP-4 is initiated by the interactions with T-cell antigen CD-45, Adenosine deaminase (ADA), caveolin-1, and the caspase recruitment domain-containing protein 11.24,25 DPP-4 binds to the extracellular matrix proteins, collagen, and fibronectin, as well as ADA, binding to these proteins and ADA, is mediated by amino acid residues that are not part of the substrate-binding site26,27 (Figure 2). DPP-4 which is catalytically active is released from the plasma membrane, resulting in DPP-4 (727 aa), a soluble circulating form that lacks the intracellular tail and transmembrane portions (cytoplasmic domain, flexible stalk)28,29 and accounts for a significant amount of DPP-4 activity in human blood.30 Moreover, both membrane-bound and circulating soluble DPP-4 share some domains such as ADA binding domain, glycosylated region, cytosine-rich domain, catalytic domain, fibronectin domain, and the disulfide bonds.25 Here are some examples of target peptides of DPP-4 as shown in Table 1.
Table 1 Various Target Peptide of DPP-4
DPP-4 is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretin, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. GLP-1, peptide YY, GLP-2, chemokine ligand 12/stromal-derived factor-1 (CXCL12/SDF-1), and substance P are examples of potential targets. Consequently, DPP-4 peptidase activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. Figure 3 shows that DPP-4 has different modes of action on chemokine production and metabolism through its peptidase activity. DPP-4 is also implicated in immunological stimulation, anti-cancer drug resistance, and ECM (Extracellular Matrix) binding and breakdown. DPP-4 also has an impact on lipid build-up.
Figure 3 Physiological properties of DPP-4 in various regions.
The functions and abundance of DPP-4 in the body have already been discussed in the above section. But the major focus is on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting consequences.
Incretins are hormones with an important role in the homeostasis of glucose, type 2 diabetes pathophysiology, and other metabolic disorders.54 These incretin hormones help in lowering the blood glucose level by stimulating the release of insulin and insulin opens the GLUT4 channel so that glucose can enter the cell and is utilized by the cells for energy production.55 There is an interesting fact that oral administration of glucose stimulates more insulin release than the intravenous administration of glucose while the concentration of glucose reaches circulation remains the same.56 This situation is known as the incretin effect and it is credited to specialized cells enteroendocrine present in the gut and coupled with glucose absorption. When glucose is administered orally, it reaches the enteroendocrine cells during absorption, and incretin hormones like glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) are released from enteroendocrine cells, which stimulate pancreatic -cells to release insulin.57 On the other hand, in the intravenous administration of glucose, the enteroendocrine cells are bypassed and thus less availability of incretins leads to less stimulation of pancreatic -cells as compared to oral administration of glucose at the same concentration.56,58 When blood glucose concentrations rise beyond a threshold of roughly 66 mg dL1, gut hormones including incretins generated in response to dietary absorption of glucose which provides the endocrine signal to the pancreatic -cells, boosting insulin production and modifying glucagon secretion.59 Incretin hormones stimulate insulin secretion physiologically, whereas physiological degrees of hyperglycemia constitute to provide a stimulus accordingly for the release of insulin.56,60,61 An isoglycemic intravenous glucose administration induces an identical increase in arterial blood glucose level just as an oral glucose load leads to a rise in insulin secretion that is around one-third of the stimulation responses induced by oral glucose, which is the combined action of hyperglycemia and incretin hormones.62 The contribution of incretin hormones in the secretion of insulin responses following oral glucose administration is estimated to be in the range of 25% and 75%, depending on the dosage of glucose used. Undoubtedly, this measurable contribution supports incretin hormones physiological role in the maintenance of normal glucose homeostasis.56 The endocrine pancreas receives three signals from the gut, which is possible due to three substrates viz. incretin hormones, glucose, and neural signals by the autonomic nervous system.62,63
After the utilization of glucose by the cells throughout the body, insulin release is reduced accordingly and extra available incretins are degraded by the enzyme DPP-4 as a part of homeostasis. However, excess availability of enzyme DPP-4 leads to a condition by unnecessarily inhibiting the activity of incretins, which leads to a reduction in the secretion of insulin, and reduced insulin is not able to open the sufficient amount of glucose channels GLUT4 leads to cause glucose intolerance or hyperglycemia. As the intestinal hormone, glucagon-like peptide-1 (GLP-1) was discovered to be a DPP-4 substrate, the relationship between DPP-4 and glucose homeostasis was discovered.64,65 GLP-1 role in managing glycemia was discovered in 198666 when this unknown peptide was discovered to have dramatic effects on the endocrine pancreas. Denmark and the United States researchers described potent insulinotropic67 and glucagonostatic effects.68 Whenever the level of glucose increases then incretins stimulate the release of insulin which lowers the blood glucose, but when the DPP-4 level increases due to any cause, it metabolizes the GLP-1 and reduces the availability of the incretin hormones. The level of glucose continuously increases but incretin hormones are unable to stimulate insulin release which can result in hyperglycemia or glucose intolerance due to the high availability of DPP-432 (Figure 4). It is observed that the level of DPP-4 is increased in various liver conditions. The pathological role of DPP-4 in liver diseases and associated glucose intolerance with their therapeutic management are discussed below in detail.
Figure 4 Role of Incretins and DPP-4 in glucose regulation.
As per research, as the DPP-4 level increases in individuals with liver conditions6971 and up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance.72,73 The effects of DPP-4 on each liver disease with pathology are described below.
HCV is a serious public health concern around the world. Consequently, HCV has a high proclivity for causing severe infection, and chronic hepatitis C affects 58 million people worldwide, with about 1.5 million new infections occurring per year as per reports by WHO. This can progress to severe hepatic fibrosis, cirrhosis, and hepatic cancer in the long run. As a result, in developed countries, HCV is a very common reason for liver transplantation.74 Interferon has always been the cornerstone of HCV treatment for almost two decades. In 1998, ribavirin was added to the medication, and subsequently, in 20012002, the interferon (INF) molecule was linked to polyethylene glycol (PEG) to enhance treatment responses.75,76 IP-10 (interferon-inducible protein of 10 kDa), commonly known as chemokine ligand 10 (CXCL10), is a CXC chemokine that binds to chemokine receptor 3 (CXCR3) and plays a vital role in selecting candidates for T lymphocytes and natural killer cells. IP-10 and other chemokines are secreted by hepatocytes infected with the hepatitis C virus to boost the adaptive and innate immune response.20 Surprisingly, elevated blood levels of IP-10, a powerful chemoattractant, have been linked to PEG-IFN and ribavirin therapy failure. IP-10 is usually changed by DPP-4, which produces the antagonist version of IP-10 by cleaving two amino acids from the amino terminal portion of IP-10. Antagonist version of IP-10 has the ability to bind to the IP-10 receptor but does not cause signalling. CD8+ T-cells, which express DPP-4, have also been seen in the portal and periportal areas of patients with HCV infection. In hepatocytes, DPP-4 expression is enhanced in patients with HCV infection.69,77 In patients with HCV infection, a high baseline blood soluble DPP-4 concentration is linked to poor treatment results. The IP-10 and DPP-4 proteins expression and binding capabilities are affected by genetic differences in the IP-10 and DPP-4 genes.78,79
According to lymphocyte subset analysis, HCV attacks CD8+ T-cells; hence, HCV-infected T-cells could be blamed for the elevated blood DPP-4 activation in HCV patients. DPP-4 alters the immune response by cleaving two amino acids from the amino-terminal portion of IP-10 which suppress the immune responses toward the HCV which may lead to more severe hepatic infection.80,81 Furthermore, Hepatitis-C is related to hyperglycemia and insulin sensitivity, which is linked to the progression of the disease and prognosis because of elevation in DPP-4 level.8289 HCV is engaged in the development of insulin resistance by the disruption of signaling pathway substrate,90 in addition to hepatic inflammation and steatosis. Furthermore, Hepatitis-C has been linked to higher DPP-4 expression in the intestinal lumen, hepatic portion, and blood.77,91 Transfection of hepatocyte cell lines with cDNA expressing a portion of the Hepatitis viral non-structural genomic region 4B/5A increases DPP-4 expression.92 HCV infection may directly upregulate DPP-4 activity, resulting in glucose metabolism impairment.16,77 Inhibition of DPP-4 is significant in HCV infection as well as in glucose intolerance as successfully shown in Figure 5.
Figure 5 Schematic representation of HCV infected hepatocytes releases IP-10 responsible for an immune response towards HCV infection but DPP-4 level elevated due to CD8+ cells attacked by HCV. Increased DPP-4 converted the IP-10 into an inactive form which suppresses the immune response and on the other hand DPP-4 results in glucose intolerance by degrading incretins. Interferon and DPP-4 inhibitors are found to be significant in both HCV resulting conditions.
Hence, interferon therapy for HCV eradication lowers serum DPP-4 levels and helps in treating the HCV,90,9396 and Sitagliptin treatment dramatically improves HCV-related glucose intolerance.97,98
NAFLD is the most prevalent cause of chronic liver disease.99102 It is a hepatic expression of metabolic syndrome. Whereas many factors contribute to the formation of NAFLD, elevated blood glucose has been observed, stimulated by DPP-4 expression in hepatoma cells (HepG2), and the amount of liver DPP-4 mRNA activity in the liver is much higher in NAFLD patients than in healthy subjects.103 Cui et al 2016 conducted a randomized controlled trial for NAFLD by DPP-4 inhibitor (sitagliptin) versus placebo. Researchers randomized, double-blind, placebo-controlled clinical study to compare the effectiveness of sitagliptin (100 mg/day orally) versus an identical placebo for 24 weeks to improve hepatic steatosis as measured by MRI-PDFF (Magnetic Resonance Imaging Proton Density Fat Fraction), which is a proven, precise, and quantifiable biomarker for hepatic steatosis. Fifty patients of NAFLD were randomised to receive sitagliptin and placebo from January 2014 to March 2015. The research included 84 patients in total. The primary outcomes of their study towards the liver fat which is measured by MRI-PDFF, when compared to the placebo group, was not substantially lowered in the sitagliptin group. Sitagliptin was not really substantially superior than placebo for lowering liver fat as evaluated by MRI-PDFF in this randomised, double-blind, placebo-controlled clinical study. Sitagliptin did not outperform placebo in terms of improving supplementary targets such as LDL, AST, ALT, and HOMA IR. Sitagliptin did not markedly reduce fibrosis as determined by MRE, despite the fact that participants in the placebo group had more fibrosis. In the conclusion, it is reported that sitagliptin was shown to be safe but ineffective in lowering liver fat in persons with NAFLD who were pre-diabetic or diabetic, and this trial was observed for 24 weeks only.104 On the other hand, Alam et al105 conducted a randomized controlled trial for the impact of sitagliptin on nonalcoholic steatohepatitis patients hepatic histological activity and fibrosis which was observed for 12 months in a randomized control study. That randomized controlled research found that using sitagliptin (100 mg daily) for one year, a DPP-4 inhibitor reduces steatosis and swelling in NASH patients. The NAS (score for NASH) in coupled biopsy samples was considerably reduced as a result of these two adjustments. This intervention did not affect fibrosis. The control groups NAS was likewise reduced by steatosis reduction, although hepatocyte ballooning remained the same. The sitagliptin group was shown to have a much larger reduction in steatosis and NAS than the control group. Regardless of diabetes condition, sitagliptin (100 mg once daily) for a year reduces NAS through alleviating steatosis and hepatocyte enlargement. Sitagliptin has a more powerful effect than weight loss. Sitagliptin has identical safety profile to the control. To validate and solidify these findings, future major, double-blind, randomised control clinical studies are recommended. In a study of fructose-fed rats with metabolic syndrome, sitagliptin shown to be reduced liver steatosis, -cell apoptosis, and insulin sensitivity.106 Another animal research in Japan found that sitagliptin helps to reduce hepatic steatosis in mice fed a high-fructose diet and prevents the growth of NAFLD by suppressing inflammatory cytokines and the expression levels of genes involved in lipid production in the liver.107 The studys most important conclusion was that sitagliptin reduced the severity of hepatocyte ballooning hepatic histopathology. Ballooning degradation, which was identified as a characteristic of steatohepatitis, is connected to cytoskeletal damage in NASH and is associated with cell swelling.108,109 As a result, it is tempting to say that DPP-4 inhibitors may improve histology activity by lowering steatosis and swelling. Another uncontrolled experimental trial from Turkey found a similar histologically verified advantage.110
Apart from DPP-4 inhibitors, Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a kind of glucose-lowering medication that has been authorized to treat Type 2 diabetes.111 Large randomized controlled trials on GLP-1 RAs have also consistently shown that these medicines reduce the risk of adverse cardiovascular events, all-cause morbidity, and nephropathy worsening in T2DM patients112,113 GLP-1 RAs reduce body weight and insulin sensitivity while improving glycemic management.111 A number of RCTs have recently investigated the putative positive hepatic effects of liraglutide and other long-acting injectable GLP-1 RAs among individuals with NAFLD, regardless of diabetes status. GLP-1 RAs were studied for their effectiveness and safety in treating NAFLD or NASH in people either with or without pre-existing T2DM. Mantovani et al114 compared and conducted the largest and most up-to-date systematic review and meta-analysis of RCTs that used different GLP-1 RAs (including two new long-acting injectable GLP-1 RAs, such as dulaglutide and semaglutide) for the treatment of NAFLD or NASH, regardless of T2DM status. Treatment given with GLP-1RAs was observed to be related to a substantial improvement in the absolute percentage of liver fat content, as measured by magnetic resonance-based methods, as well as blood liver enzymes (particularly serum ALT and GGT levels), as compared to control or standard therapy. The current meta analysis does not include a detailed examination of the hypothesized molecular pathways via which GLP-1 RAs may help people with NAFLD. However, it is plausible to infer that liraglutides and other GLP-1 RAs good effects on individual NASH histologic scores are multidimensional and a result of their combined effects on hyperglycemia or insulin resistance, weight loss, and a direct positive impact on the liver (beyond the reduction in body weight and hyperglycemia). In reality, GLP-1 RAs are effective in the treatment of T2DM and can also help people lose weight (on mean 45 kg).115 GLP-1 RAs are also able to alleviate hepatic steatosis through lowering de novo lipogenesis, boosting fatty acid oxidation, and improving several aspects of the insulin signaling pathways, according to experimental findings based on both human hepatocytes and animal models.116120 Furthermore, preclinical NASH investigations have revealed that GLP-1 RAs may lower hepatic inflammation via independent pathways, at least in part, of body weight loss.121 Obesity could be a reason for NAFLD and for that cause GLP-1 RAs could be a choice, as recent clinical studies have been shown to successfully promote weight loss in diabetic individuals. The existing evidence suggests that weight loss caused by GLP-1R agonism in humans is mostly due to reduced food consumption. GLP-1 (glucagon-like peptide-1) is known as an endogenous peptide produced in the gastrointestinal tract by enteroendocrine specifically by L cells. GLP-1RAs can help with glucoregulation by promoting satiety, delaying stomach emptying, and lowering calorie intake. The only GLP-1RA licensed for the treatment of obesity is liraglutide. Semaglutides first Phase III clinical trial has finished, and the results indicated a considerable weight loss benefit. GLP-1RAs have been shown in clinical studies to be effective and safe, and they are regarded as potential anti-obesity medications.122 On the other side, according to Velija-Asimi et al 2013, it is found that DP-4 inhibitors DPP-4 inhibitors in combination with metformin were related to improved glycaemic control and a decrease in body weight in obese adults with type 2 diabetes.123
The increase of intrahepatic triglycerides (TGs) is the major symptom of NAFLD, which affects 7590% of people with type 2 diabetes.124,125 NAFLD can proceed to NASH, which is marked by extensive histologic transformation, such as hepatocellular ballooning, lobular inflammation, fibrosis, and an increased risk of hepatocellular carcinoma. Various pharmacotherapies are being explored since insulin resistance, oxidative stress, lipotoxicity, immunology, mitochondrial damage, the cytokine system, and apoptosis are all implicated in the pathophysiology of NASH. Although no medicine is available for the evidence-based therapy of NASH, antidiabetic therapies may be beneficial in individuals who also have diabetes mellitus. Several investigations have found a relationship between DPP-4 and hepatic insulin sensitivity. Upregulation of DPP-4 in hepatocytes is linked to hepatic insulin resistance and liver steatosis as observed in rats,73 whereas knocking down DPP-4 optimizes insulin sensitivity and lowers lipid buildup in cultured hepatocytes.126 DPP-4 has also been linked to the occurrence of insulin sensitivity and glucose intolerance in the liver and adipose tissue, according to other research. Obesity and accompanying visceral adipose tissue inflammation cause insulin sensitivity in mice, a process that appears to be driven by increased hepatic DPP-4 production and release, since abolishing hepatocyte DPP-4 expression reduces inflammation and improves insulin sensitivity. DPP-4 is thought to be a new adipokine that affects insulin sensitivity in both autocrine and paracrine ways. DPP-4 release is closely correlated with adipocyte size, suggesting that adipocytes may be a major source of DPP-4.127 The more fat in the liver, the higher the activation of hepatokine DPP-4, which might lead to NAFLD and subsequently, NASH in a paracrine and autocrine manner. Thus, omarigliptin may inhibit the activity of DPP-4, which is abundantly released from the liver in NAFLD/NASH, preventing the stimulation of adipose inflammation and insulin resistance in the liver.128 According to Wang et al 2021, study findings show that the major cause of hepatic inflammation like NFB pathway activation, oxidative stress, and cell apoptosis inhibition reduces hepatic inflammation. In the study, sitagliptin was found to be restricting the DPP-4 activity in hepatocytes reducing NFB pathway activation and oxidative stress, as well as cell apoptosis, in diabetic conditions, and sitagliptins ROS cleaning function promotes NFB pathway deactivation; additionally, sitagliptin can reduce Streptozotocin chronic hepatotoxicity and oxidative stress. Under diabetes circumstances, sitagliptin inhibits DPP4 activity in hepatocytes, resulting in reduced NFB pathway activation, oxidative stress, and cell death.122 The inactivation of the NFB pathway is promoted by sitagliptins ROS cleansing action and DPP-4 inhibitors are also known for the reduction in body weight in obese adults with type 2 diabetes.122 But there is vildagliptin, which is also a strong and selective DPP-4 inhibitor that is weight neutral in type 2 diabetic patients in several solotherapy and combined studies. Because of its glucose-dependent mode of action, vildagliptin has a reduced risk of hypoglycemia, which eliminates the defensive eating that can emerge with insulin injections or independent glucose-insulin secretagogues. More data show that vildagliptin may affect postprandial lipid and lipoprotein metabolism by decreasing the absorption of triglyceride from the gut and boosting sympathetically triggered lipid mobilization and catabolism in the postabsorptive phase. Additional research into these pathways might offer a molecular foundation for understanding the weight-loss benefits of vildagliptin medication.129 Vildagliptin is an important DPP-4 inhibitor that may be used for lowering the risk or decreasing hepatic inflammation without body weight reduction.
In reality, hepatic DPP-4 expression and serum DPP-4 activity are linked to hepatic steatosis and fatty liver grading.130,131 Furthermore, as compared to wild-type rats, DPP-4 deficient animals have lower levels of liver pro-inflammatory and pro-fibrotic cytokines, as well as less hepatic steatosis. These beneficial alterations in lipid metabolism are not caused by changes in glucose metabolism.132 In individuals with NAFLD, DPP-4 activity in serum and liver specimens correlates with indicators of hepatic injury like blood gamma-glutamyl transferase (GGT) and alanine aminotransferase amounts, but not with fasting blood glucose levels or glycosylated hemoglobin (HbA1c) values, similar to the findings in animal studies. As a result, hepatic DPP-4 expression in NAFLD could be linked to hepatic lipogenesis and liver damage.133,134 In humans and rodents, a DPP-4 inhibitor has been shown to ameliorate hepatic steatosis.135 The activity of DPP-4 inhibitors is successfully shown in Figure 6.
Figure 6 Non-alcoholic fatty liver disease results in an increased level of DPP-4 expression leads to hepatic insulin sensitivity and liver steatosis but sitagliptin and omarigliptin improve the conditions.
A case of refractory fatty liver that was successfully treated with sitagliptin, a DPP-4 inhibitor.136 In addition, omarigliptin and sitagliptin have been shown to reduce liver enzymes and hepatocyte ballooning in patients with NASH.110,128 These data suggest that DPP-4 inhibitors may help patients with NAFLD with hepatic damage and glucose intolerance.
The cirrhotic liver has been shown to have increased hepatic DPP-4 expression.128,137 Although the consequence of increased DPP-4 expression is unknown, recently showed that human liver stem cells express DPP-4 but not CD34 or CD45, which are markers of hematopoietic stem and endothelial progenitor cells.138 If we understand the concept of Cell-released chemokines, cytokines, and other growth-modulating substances that elicit their effects through particular receptor-mediated intracellular signaling modulate hematopoietic progenitor cell (HPC) and hematopoietic stem cell (HSC) functions in a paracrine manner.139 Other progenitor and stem cell types are regulated by these proteins, and also impact the more mature cells function. On HPCs expressing CD26, inhibiting DPP4 enzymatic activity with short peptides such diprotin A (ILE-PRO-ILE) or VAL-PYR improves chemotaxis to the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12)140 as well as homing and engraftment of HSCs.141143 CXCL12 with a DPP4 truncation lacked chemotactic efficacy but prevented chemotaxis triggered by full-length SDF-1.140 A pilot clinical trial evaluated the effects of sitagliptin (inhibitor of DPP4 used to treat type 2 diabetes)144 administration to patients with high-risk hematologic malignancies receiving single-unit cord blood transplants. With the findings that DPP4 has a detrimental effect on CSFs6, which nourish immature cell types in the bone marrow, attempts are being made to change the dosing schedule of sitagliptin to improve the time to engraftment of cord blood.145 Chemokines are important for degranulation, angiogenesis, and leukocyte trafficking in the immune system,146 and DPP4 may have a major impact on the activity of chemokine. DPP4 induces negative feedback by lowering CCL22/MDC activity, similar to its actions on CXCL.140,147,148 CCL22 purportedly possesses antiHIV-1 action and attracts activated lymphocytes, dendritic cells, natural killer cells, and monocytes. In CCR4-transfected cells, DPP4-truncated CCL22 fails to desensitize calcium mobilization by full-length CCL22 or thymus and activation-regulated chemokine.149 HUT-78 T-cell chemotactic activity is reduced by truncated CCL22, which is 100 times less effective than full-length CCL22. As a result, DPP4s N-terminal truncation of CCL22 has various effects on its multiple immunologic roles. Eosinophils are drawn to allergic inflammation and parasite infections by the CCL11 (eotaxin) and, CC chemokine. When DPP4 truncates it, its chemotactic potency for signaling capability and blood eosinophils through CCR3 are lowered 30-fold.44 These examples show the importance of DPP4 in infectious processes and inflammatory, as well as in steady-state hematopoiesis. It has been documented that the DPP4-truncated versions of the chemokines studied (CCL2, CCL3, CXCL8/IL-8, and CXCL9) lost their suppressive effect and blocked myelosuppression in vitro and in vivo when compared to their full-length counterparts. The shortened molecule functions as a dominant-negative or competitive inhibitor form of the full-length molecule in both circumstances. This could lead to feedback regulation of their full-length molecules actions. Its also possible that DPP4 truncation enhances a molecules stimulatory or inhibitory activity beyond that of the full-length version.145 Its critical to double-check protein sequences in databases containing potential DPP4 truncation domains on a regular basis to make sure they have not been altered. TGF-, for example, once had a DPP4 truncation site; however, the sequence has since been changed and no longer possesses a DPP4 site. Finally, biochemical and biological (in vitro and in vivo) studies are needed to confirm whether the putative DPP4 truncation sites are true truncation sites for each protein, especially when different alanine, proline, serine, or other potential DPP4 truncation sites are present at the N-terminus of every molecule. If that is the case, it is crucial to figure out whether the abbreviated forms activity differs from that of its full-length counterpart, and if so, how. Overall understanding of the in vitro and in vivo control of various stem, progenitor, and more mature hematopoietic and other kinds of cells might result from such studies. This data might have therapeutic implications.145
Through activation of insulin resistance (IR), obesity-related inflammation raises the risk of type 2 diabetes mellitus (T2DM), obstructive sleep apnea syndrome (OSAS), and polycystic ovary syndrome (PCOS).150 In obesity-related NAFLD, IR is nearly universally found, leading to the development of the metabolic syndrome and hepatocarcinoma.151 Stem cell growth factor-beta (SCGF-) has been shown to have activity on macrophage/granulocyte progenitor cells.152,153 C-reactive protein (CRP) levels were found to be elevated only in one-third of obese patients in the investigation, indicating a link with SCGF. The study characterizes itself by the prediction of homeostatic metabolic assessment (HOMA) values by SCGF levels, possibly mediated by indicators of inflammation, offering some insight on processes inducing/worsening IR in male patients with obesity-related NAFLD. M-CSF, TNF-, IL-12p40, and IL-6, among other pro-inflammatory cytokines, were not linked with HOMA values, with the exception of IL-6, which predicted a reduced chronic inflammation state. The small rise in CRP levels supports this notion. According to the study of Tarantino et al 2020, suggest that barely raised CRP levels might make IL-10 more accessible in an attempt to partially decrease inflammation, the major cause of IR, in line with data that CRP affects the anti-inflammatory or pro-inflammatory balance, exacerbating inflammation. In this regard, we would like to call attention to our results, which include the presence of IR in almost half of the obese individuals, increased levels of IL-10, and IL-12p40s defensive response. SCGF- serum concentrations might also be due to hematopoietic stem or progenitor cells limited autocrine/paracrine activity. It is thought that by switching M1 to M2, inflammation could be reversed and IR reduced. Even though our median HOMA values overlapped according to gender, individuals with a more prominent HOMA had a greater frequency of moderate-to-severe steatosis than those with a HOMA below the median. The finding that SCGF levels solely predicted the severity of hepatic steatosis in men might indicate that these patients obesity influences their inflammatory state and/or immune system. As a result, only males CRP and IL-6 levels predicted SCGF-concentrations. These findings support the observation that SCGF levels solely predict IR, as measured by HOMA, in males. CRPs mediating involvement is conceivable when we consider its functional role in inflammation. In summary, this study is characterized by the estimation of HOMA values by SCGF levels, which is likely mediated by inflammation, providing insights on processes worsening IR in male patients having obesity-related NAFLD.154 As a result, DPP-4 is a particular marker of adult hepatic stem and progenitor cells, suggesting that it may play a role in liver regeneration in chronically inflamed patients. CXCL12/SDF-1 is a chemokine that promotes the homing of hematopoietic stem cells (HSCs) and is critical for hepatic regeneration.155,156 CXCL12/SDF-1 is a DPP-4 target peptide, and inhibiting cell-surface DPP-4 activity promotes CXCL12/SDF-1 directed chemotaxis, homing, and engraftment in HSC/hematopoietic progenitor cell populations. As a result, inhibiting DPP-4 might be a good way to improve the efficacy and success of HSC/hematopoietic progenitor cell transplantation.157 DPP-4 suppression also increases the number of progenitor cells, and DPP-4 inhibition can stabilize endogenous CXCL12/SDF-1, which could be a promising technique for increasing the sequestration of regenerative stem cells.158
Breast cancer,159,160 malignant mesothelioma,161 lung cancer,162 and squamous cell laryngeal carcinoma163 are all known to have increased DPP-4 expression. Increased DPP-4 expression is also found in liver tissues and serum from rats164 and humans with hepatocellular carcinoma (HCC).165
Higurashi et al (2016) conducted a multicentre double-blind, placebo-controlled, randomized Phase 3 trial for the chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes and it is observed that non-diabetic patients were given a small dose of metformin for a year with no side effects. After polypectomy, a small dose of metformin decreased the prevalence and quantity of metachronous adenomas or polyps. Metformin shows the potential to prevent colorectal cancer through chemoprevention. However, further large-scale, long-term studies are required to draw definitive results.166
Kawakita et al (2021) observed the potential influence of DPP-4 inhibitors and DPP-4 on cancer with diabetes and states that there is currently no obvious link between DPP-4 inhibitors and cancer incidence or prognosis in diabetic individuals, according to available clinical evidence. However, the safety profile of a DPP-4 inhibitor (which is the same as different anti-diabetic medications) on cancer development or recurrence has yet to be shown. The results suggested for further mechanistic studies into the relationship between DPP-4 inhibitors and cancer biology, particularly in diabetic situations, are an important study subject in both diabetes and oncology.167 Zhao et al 2017 worked on a meta-analysis of randomized clinical trials on DPP-4 inhibitors and cancer risk in patients with type 2 diabetes and there were 72 studies in all, with 35,768 and 33,319 patients recruited in the DPP-4 inhibitors and comparator medicine trials, respectively. In comparison to the usage of other active medicines or placebo, no significant connections between DPP-4 inhibitor use and cancer development were found. The findings were similar in pre-defined subgroups stratified by DPP-4 inhibitor type, cancer kind, comparative medication, trial duration, or baseline characteristics. The findings of this meta-analysis reveal that people with type 2 diabetes who take DPP-4 inhibitors have no increased risk of cancer than people who take a placebo or other medicines. Wilson et al 2021 provide clear evidence data that the currently authorized medication sitagliptin (DPP-4 inhibitors) can boost antitumor immunity in a syngeneic ovarian cancer mouse model, lowering metastatic burden and lengthening longevity. Our findings suggest a method for improving immune responses in ovarian cancer patients, as well as a justification for using DPP4 inhibitors as a fast translatable 2nd line therapy for this illness.168
According to Hsu et al 2021, DPP-4 inhibitors can lower the incidence of hepatocellular carcinoma in individuals with chronic hepatitis C infection with type 2 diabetes. In this study, individuals with type 2 diabetes and persistent HCV infection who used DPP-4 inhibitors had a decreased risk of HCC. DPP-4 inhibitors were associated with a greater incidence of HCC-free patients. This suggests that DPP-4 inhibitors may help people with type 2 diabetes and persistent HCV infection avoid developing HCC. DPP-4 inhibitors may be used as a second-line treatment after metformin for individuals with type 2 diabetes with persistent HCV infection.69
DPP-4 inhibition suppresses tyrosine kinase in human hepatoma cells, resulting in anti-apoptotic effects.165 Recently, a case has been discussed in which a patient with HCV-related chronic hepatitis experienced remarkable HCC reduction following four weeks of treatment with a DPP-4 inhibitor (Figure 7). Although it is unclear whether the DPP-4 inhibitor is directly involved in the regression of HCC, a significant invasion of CD8+ T-cells around the HCC tissue was observed, suggesting that the DPP-4 inhibitor may have improved the immune response, which has been compromised by chronic HCV infection.169 Whereas treatment with exogenous insulin or sulfonylureas raises the risk of HCC,85 treatment with a DPP-4 inhibitor had no tumor-promoting effects in mice.170 As a result, a DPP-4 inhibitor may have a safe effect on HCV-related HCC through modulating immunity.
Figure 7 Liver diseases cause an increase in DPP-4, which causes glucose intolerance and DPP-4 inhibitors lead to relief in glucose intolerance as well as in liver conditions.
This review discussed the various liver conditions and glucose intolerance management with DPP-4 inhibitors. The summarizing table with the mechanism of action and treatment of liver conditions associated with DPP-4 is given in Table 2.
Table 2 Various Mechanisms of Action and Management of Some DPP-4-Associated Liver Diseases
DPP-4 elevation could be considered a biomarker for diabetes and is a very interesting molecule in understanding the relationship between diabetes and liver or other organs, and inhibition of DPP-4 could help to reduce the risk of its associated diseases but, on the other hand, DPP-4 inhibitors have some negative aspects. DPP-4 inhibitors have been linked to an increase in gastrointestinal side effects in 24-week research, 1091 T2DM patients were randomly assigned to different combinations of sitagliptin and metformin.173 There have been a number of instances of allergic responses occurring spontaneously in people using sitagliptin and angioedema has also been documented with DPP-4 inhibitors, usually commonly within the first three months of therapy, with some responses occurring even before the first dosage.174176 As per the study design of saxagliptin (2.5mg/day v/s 5mg/day v/s 10mg/day) with placebo on metformin for 24 weeks revealed that skin disorders, nasopharyngitis, headache, sinusitis, urinary tract infection, and arthralgia are the adverse effects produced by saxagliptin which are in high proportion than the placebo.176 Alogliptin versus placebo (Population 5380 and duration is 18 months) study showed the adverse effects of alogliptin at more proportion than placebo such as acute and chronic pancreatitis, angioedema, malignancy, renal dialysis, and hypoglycemia but without a comparison of proportions of alogliptin and placebo showed non-fatal myocardial infarction or non-fatal stroke.177 Similarly, other DPP-4 inhibitors also showed some side effects such as musculoskeletal disorders, infections (immune-related disorders such as irritable bowel syndrome, arthritis, and multiple sclerosis because of their potential influence on immunological function), nervous system (Headache and dizziness), Fertility (A 39-year-old physician started on sitagliptin, he had issues with spermatogenesis, according to a case study), and Blood effects (increase in white blood cell count).178
In glucose regulation, the role of incretins (GIP & GLP-1) is very important. They are released from the GIT lumen in response to the increased level of glucose during absorption and then stimulate pancreatic beta-cells to release insulin which lowers the blood glucose level by enhancing the entry of glucose in the cell through the GLUT4 channel and the cell utilizes the glucose to form energy. But there is an enzyme that inhibits this process by degrading the incretins and creating low availability of incretins which leads to reduced signaling towards pancreatic -cells to release insulin resulting in an increased level of blood glucose as glucose remains in the blood, unable to enter in the cell through GLUT4. Apart from that, it is commonly observed that in various liver disorders such as hepatitis C, Non-alcoholic fatty liver, hepatocellular carcinoma, hepatic regeneration, and stem cell the serum level of DPP-4 is increased and leads to glucose intolerance. It is observed and reported that DPP-4 inhibitors are commonly used as a reliever in glucose intolerance and diabetes and have potential activities to improve liver conditions also. Hence, DPP-4 inhibitors like Sitagliptin could be a choice of drug in DPP-4-associated glucose intolerance because of various liver conditions and also in the therapy of liver conditions.
GIP, Glucose-dependent insulinotropic peptide; GLP, Glucagon-like peptide; VIP, Vasoactive intestinal peptide; PACAP-38, Pituitary adenylate cyclase-activating polypeptide-38; GRP, Gastrin-releasing peptide; NPY, Neuropeptide Y; RANTES, Regulated upon activation; CCL, Chemokine (C-C motif) ligand; CXCL, Chemokine (C-X-C motif) ligand; SDF-1, Stromal-derived factor-1; MDC, Macrophage-derived chemokine; MIg, Monokine induced by gamma interferon; IP-10, Protein 10 from interferon ()-induced cell line; GHRH, Growth hormone-releasing hormone; I-TAC, Interferon-inducible T-cell chemoattractant; LH, Leutinizing hormone chain; IGF-1, Insulin-like growth factor-1; CGRP, Calcitonin-related peptide; hCG, Human chorionic gonadotropin subunit.
The authors declare no conflicts of interest in relation to this work.
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Hepatic Diseases and Associated Glucose Intolerance | DMSO - Dove Medical Press
In the mid-2010s, when gonzo biohacking was first picking up steam, a team of California scientists put a form of chlorophyll into a mans eyes. The idea was to give him night vision, and their experiment sort of worked. For a brief period of time, the man could reportedly see people moving 160 feet away in a pitch-black wood.
In recent years, there has been a steady stream of biohacking tests and tips, some of them somehow even crazier than applying eyedrops of a photosensitivity solution (like implanting radio transponders in necks), but most of it is mainstream and buzzy the sort of hacks often touted on podcasts and featured in Instagram ads. You know the classics: nootropics, elimination diets, infrared therapy, intermittent fasting and thermoregulation.
A lot of that stuff works, in moderation, but biohackers as is too often the case in the fitness world have a soft spot for pseudoscience and absolutism. The DIY nature of a process intended to [change] our chemistry and our physiology through science and self-experimentation (a Tony Robbins quote, not mine) is fertile ground for credulous experimenters to agonize over every perceived disadvantage in the body.
One of the most famous biohackers out there, Ben Greenfield, employs over 30 different habits in his daily quest to take over his body. (Thats according to Biohack Stack, a site dedicated to tracking the proclivities of biohackers.) On top of the usual (fish oil supplements) and the unique (a system that filters air as if youre walking outside), Greenfield also apparently injects stem cells from his own fat throughout his whole body, and regularly uses something called a penis pump.
Its sensible to harbor a healthy skepticism for trends like biohacking, and any other wellness venture that comes along and sounds like it. But a recent movement that definitely fits that criteria, under the name bulletproofing, is actually worthy of your attention. While offbeat, the practice isnt all that sexy. It advocates for slow-cooked, foundational fitness, of the sort thats obsessed with preventing injuries.
Preemptive training might be a tough sell for Americans who can hardly be convinced to go outside for a run, let alone stretch before that run. But the regimen is far more dynamic than it sounds; while its premise (keep everything intact) sounds boring, bulletproofing is about challenging the body to do things it rarely does anymore, through movement progressions that most of us have never heard of or committed ourselves to.
In essence, the goal of bulletproofing is to gain the joint stability and mobility necessary to feel and perform explosively again. Most men past the age of 40 cant run a 40-yard dash without fear of tearing a hamstring. They wouldnt dream of trying to dunk a basketball or take on a high-speed batting cage again, either. But in training yourself not to get injured while attempting those feats, its possible to find yourself as adept as you were at them decades before. Think of it as getting fit by accident. A little humility shown towards Father Time could end up zipping you back to the glory days. Its not a bad deal.
Bulletproofing is not mutually exclusive from biohacking. There are many, many fitness influencers who practice and pedal elements of both. This can make filtering through YouTube videos confusing. But the key is in identifying (and implementing in your own life, if youre so inclined) a few choice commandments from the practice. Start slow and build up. The endgame isnt to take control over your body, but to take control back from it, and give yourself the opportunity, as some bulletproofers like to say, to lift forever.
Most strength or cardio regimens are preoccupied with immediate concerns: getting fit for summer, getting in shape for the upcoming season, or getting ready for a race (even marathon training, which can last months, has a hard cut once the 26.2 is finished). These patterns generally recruit a form of progressive training where the body beats itself up more and more until it attains a short-term goal. It can be an enormously gratifying process, but is a little less than ideal from a longevity perspective.
Theres a reason so many aging trainees suffer from repetitive use injuries, low back pain and seemingly inexplicable plateaus. Theyre relying too heavily on the same moves and workouts they picked up years ago, when they should be prioritizing full-body, joint-friendly drills. A crucial rule of thumb? Respect the muscles you cant see. (And the ligaments and the tendons, too.) This often means subbing traditional exercises for targeted mobility work. Think: reverse grip bench press, towel push-ups, overhead kettlebell presses. The key is to avoid the locked in grip that fixed plane movements so often engender which put your joints at risk and instead train the wrists, elbows and shoulders back to full rotational mobility.
Despite the hard-nosed moniker, bulletproofing doesnt necessarily involve throwing heavy weights around. In fact, it can thrive on you using minimal weight (at first, anyway) and learning to make use of resistance bands and bodyweight. Some of us entertained a crash course in both during the pandemic, once gyms shuttered, but its likely that you stuck to endless repetitions of the usual suspects (bicep curls, push-ups, air squats), while neglecting some of the most unconventional and effective movements preferred by bulletproofing experts.
There are a ton of options out there on the resistance bands front, and a number of them are explicitly designed to fortify your core, which is at the nexus of any bulletproofing routine. A strong, stabilized core prevents improper swaying of hips while running which puts undue pressure on cartilage in the kneecaps and also makes sure you wont feel a strain in the back every time you bend down to pick up a kettlebellor a pile of snow while shoveling. Tie a resistance band to the wall, a door or a bar at your gym, and practice Russian twists, thePallof press and wood chops. Reverse crunches are also fantastic.
Meanwhile, for a comprehensive look at how just a few bodyweight movements can eliminate pain and build strength, check out this clip from Graham Tuttle (commonly known as @thebarefootsprinter), a renowned bulletproofer who dislocated his shoulder nine years ago, tried to continue playing sports and exercising, but proceeded to see it pop out another 10 times in four years. He credits his bodyweight routine (snow angels, arm swings, thoracic extensions, etc.) with restoring his mobility, and getting him back to cartwheels and jiujitsu. Unlike conventional physical therapy, Tuttles M.O. relies on engaging fascia and connective tissue.
Another favorite of bulletproofers alongside farmers carries, plank variations, single-leg anything is retro movement, a practice that looks and feels goofy, but is actually a dynamite workout for your lower half and core. Backwards running doesnt compound pain from patellofemoral joint compression forces (a relationship between ground force and the vector of the knee) in the same way that forward running does. And instead of causing the area duress a pretty common side-effect of constant running backwards running actually strengthens the area. It does so by engaging little-known muscles and tendons such as the tibialis anterior (located along the shins) and the vastus medialis muscles (just inside of each knee).
The key appears to bemixingbackwards running into your forward running regimen. Obviously, you shouldnt give up forward running forever.Not only is that wildly impractical, but you also wouldnt get to see all the positives that retro running can bring to your conventional routine. How do you start? Find a treadmill and try deadmills, a concept popularized by Ben Patrick (more commonly known as@kneesovertoesguyon Instagram) and Derek Williams (more commonly known as @mr1nf1n1ty). The duo are pioneers in the resisted backward training space. Both have a history of torn ligaments. Both are currently able to dunk.
Before graduating to their sleds, slant boards and straps (all used to increase range of motion at their knee joints and create more bounce in their legs), situate yourself atop a treadmill and hold the bars on each side. Donotturn it on (hence the deadmill nickname). Then just walk backwards, using your power and momentum to move the belt. You can hang out there as long as you like (go for three minutes if you can), or turn around, now facing the screen, and push back against it. This will feel extremely difficult and unnatural, but its the godsend your legs never knew they needed. See a demohere.
Theres a reason so few of us want to stretch were never in stretching shape. If youre accustomed to spending the day A) crammed into a tiny workspace, then B) going 0 to 60 in a workout class or on a Peloton, your body is just cycling through endless variations of tightness. Its little wonder that once-in-a-while stretching feels somewhere between tedious and hopeless. A pleasant side effect of joint-friendly bulletproofing, though, is that youre constantly performing exercises that catalyze range of motion and open up the body, which turns stretching into a more turn-key operation.
An added bonus: While bulletproofing workouts involve more dynamic and unfamiliar progressions, feel free to largely stick to the stretches you know well here (the hard part, of course, is actually sticking to them). To open up the back, perform trunk rotations, cat-camel stretches, hamstring stretches, hip flexor stretches and childs poses. If youre looking for a newer, bulletproof-approved stretch to play with, try out the 90-90. Its on the more aggressive side of the stretching spectrum, but its very much worth shooting for. The endgame is to get your front leg at 90 degrees, relative to the knee and the hip, and the same with the rear leg, all while keeping an upright trunk position. Its not as mind-blowing as night-vision, perhaps, but who needs that anyway?
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Why Fitness Experts Are Obsessed With "Bulletproofing" the Body - InsideHook
When blood vessels that feed the heart become blocked, damage to the heart muscle can occur and this can affect cardiac function. By stimulating the formation of new blood vessels, a new stem-cell-carrying gel helps mice overcome this condition called myocardial Infarction. The stem cell delivery system was developed by scientists from Kansai University, Japan. It is published in Science and Technology of Advanced Materials.
The hydrogel acts like a scaffold to hold the stem cells in place at injection site and keep them alive longer. The stem cells release cytokines, which stimulate the formation blood vessels and help the heart to recover. The gel is biodegradable so that it eventually dissolves and can be discarded by the body. Image credit: Kansai University
In their application, the team used stem cells from fat tissue. These stem cells, also known as adipose derived stem cells, have been used in the treatment of damaged cardiac tissue due to reduced blood flow. This is called myocardial Ischemia. Once injected into damaged tissue, the stem cells are supposed to release stimulants that can help regenerate blood vessels. However, they are not able to be retained in the tissue or survive long enough. Scientists have also found that injecting biodegradable hydrogels, which are cell-free, into damaged heart tissue can help partial recovery.
They first created hydrogels that could hold stem cells in place longer at the site where there is tissue damage. They are best used at room temperature. This allows you to easily mix the stem cells. The solution reacts with the body to heat and transforms into a gel when it is injected into the organ.
One hydrogel was particularly good at keeping its gel state. It was made from a mixture of molecules called tri-PCG with acrolyl group attached. The tri-PCG-acryl mixture was then combined with a polythiol derivative.
The team also added stem cells from adipose tissue to the hydrogel. They then observed how long they lived in petri dishes as well as the production of different genes and substances.
The stem cells were able to survive in our injectable hydrogel and released molecules that stimulate blood vessel formation, improving heart function and making it effective for treatment of ischemic heart.
Yuichi Ohya, Bioengineer, Kansai University
After confirming safety, the team plans to next test the therapy on larger animals and then conduct clinical trials in humans. They plan to use their injectable hydrogel for immune cells to treat cancer and in vaccines against viral infections.
Source:
Journal reference:
Yoshizaki, Y.,et al.(2021) Cellular therapy for myocardial ischemia using a temperature-responsive biodegradable injectable polymer system with adipose-derived stem cells.Science and Technology of Advanced Materials.doi.org/10.1080/14686996.2021.1938212.
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New Stem cell conveying hydrogel could assist the heart with recuperating myocardial ischemia - Microbioz India
Aclinical trial testing a novel gene therapy for a rare neurological disease has been put on hold after one of the participants in a Phase 3 trial developed a bone marrow disorder that can lead to cancer. The pause, announced Monday by the trials sponsor, bluebird bio, and mandated by the US Food and Drug Administration (FDA), was taken out of an abundance of caution, the companys president of rare genetic diseases, Andrew Obenshain, said in a recent quarterly call.
The therapy targets cerebral adrenoleukodystrophy, which is caused by a mutation in the gene for an enzyme called adrenoleukodystrophy protein (ALDP) that breaks down fats. The mutation causes fat to build up in the brain, where it breaks down the insulating myelin that allows neurons to communicate with one another. Because the gene is on the X chromosome, women typically have a least one good copy, so the disease primarily strikes men. Left untreated, it causes damage to hearing, vision, cognition, and coordination. It is often fatal.
Bluebirds gene therapy uses an engineered lentivirus to correct the mutation associated with the disease. Lentiviruses belong to the same family as HIVretrovirusesand have been widely used in gene therapies and other medical applications for many years. While other virus-based platforms using retroviruses had previously been linked to cancer among patients, it is only recently that a lentivirus has been implicated in such an outcome: in February of this year, bluebird bio paused another trial, one for a blood disorder, after two patients developed leukemia-like cancer, Sciencereports, although it was later determined that the virus was likely not the cause, and the trial resumed.
Most in the field were hoping that we would not see such an event with lentiviral vectors, Harry Malech, a gene therapy researcher at the National Institutes of Health, tells Science, adding, I dont think anybodys been . . . saying this couldnt happen.
The cerebral adrenoleukodystrophy therapy involves taking samples of a patients bone marrow and treating the stem cells therein with the modified virus that contains a corrected copy of the gene that encodes ALDP. After a round of chemotherapy to reduce the persons bone marrow cells, the treated cells are infused back into the patient. Thereafter, the patients stem cells produce healthy blood cells with a functional copy of the gene for ALDP. The therapy entered the market in Europe last month following a previous safety and efficacy trial that included 32 patients. A second trial, the one that has now been paused, was set to finish in 2024.
Speaking on the call, bluebird bios Chief Scientific Officer Philip Gregory said that one patient in the second trial developed myelodysplastic syndrome (MDS), a blood disorder that sometimes leads to leukemia, and another two had abnormal bone marrow cells that could progress to MDS. When scientists examined their cells, they found lentiviral DNA inserted at a site in the genome that has previously been linked to MDS in retrovirus-based therapies, suggesting that the virus may have caused the changes.
Specifically, Gregory said the issue is likely caused by the virus promoter, the DNA sequence that turns on the therapeutic copy of the gene. To ensure the gene produces enough ALDP in the brain to be an effective treatment, the researchers needed a strong promoter, but as a consequence, the promoter had off-target effects, turning on other genes in the area around the mutation, including cancer genes, Gregory speculated.
Donald Kohn, a gene therapy researcher at the University of California, Los Angeles, who helped design the viral vector, tells Sciencethat in the time since bluebird bio first began developing the therapy, researchers have identified other promoters that might be able to do the job with a lower risk of causing cancer. He adds that this particular incident shouldnt preclude scientists from pursuing other lentivirus treatments, as the issue seems to come down to design, and Kohn doesnt know of any other lentivirus therapies that use the same type of promoter.
Panam Malik, a hematologist at Cincinnati Childrens Hospital who was not involved in the work, similarly tells Science that virus-based platforms should be highlighted for the good they have done. This is a severe adverse event, she says, but adds, we should never lose sight of the fact that so many patients . . . have been helped. Despite this rare incident, the findings could help scientists and researchers design safer and better vectors for the future.
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Participants Diagnosis Halts Gene Therapy Clinical Trial - The Scientist