Decreased microbial co-occurrence network stability and SCFA receptor level correlates with obesity in African-origin women.

We compared the gut microbial populations in 100 women, from rural Ghana and urban US [50% lean (BMI < 25 kg/m2) and 50% obese (BMI ≥ 30 kg/m2)] to examine the ecological co-occurrence network topology of the gut microbiota as well as the relationship of short chain fatty acids (SCFAs) with obesity. Ghanaians consumed significantly more dietary fiber, had greater microbial alpha-diversity, different beta-diversity, and had a greater concentration of total fecal SCFAs (p-value < 0.002). Lean Ghanaians had significantly greater network density, connectivity and stability than either obese Ghanaians, or lean and obese US participants (false discovery rate (FDR) corrected p-value ≤ 0.01). Bacteroides uniformis was significantly more abundant in lean women, irrespective of country (FDR corrected p < 0.001), while lean Ghanaians had a significantly greater proportion of Ruminococcus callidus, Prevotella copri, and Escherichia coli, and smaller proportions of Lachnospiraceae, Bacteroides and Parabacteroides. Lean Ghanaians had a significantly greater abundance of predicted microbial genes that catalyzed the production of butyric acid via the fermentation of pyruvate or branched amino-acids, while obese Ghanaians and US women (irrespective of BMI) had a significantly greater abundance of predicted microbial genes that encoded for enzymes associated with the fermentation of amino-acids such as alanine, aspartate, lysine and glutamate. Similar to lean Ghanaian women, mice humanized with stool from the lean Ghanaian participant had a significantly lower abundance of family Lachnospiraceae and genus Bacteroides and Parabacteroides, and were resistant to obesity following 6-weeks of high fat feeding (p-value < 0.01). Obesity-resistant mice also showed increased intestinal transcriptional expression of the free fatty acid (Ffa) receptor Ffa2, in spite of similar fecal SCFAs concentrations. We demonstrate that the association between obesity resistance and increased predicted ecological connectivity and stability of the lean Ghanaian microbiota, as well as increased local SCFA receptor level, provides evidence of the importance of robust gut ecologic network in obesity

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a β cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate. Recent studies of FFA2 suggest that it may act as a regulator of β cell function. Here, we set out to explore what role FFA2 may play in regulation of β cell mass. Interestingly, Ffar2(-/-) mice exhibit diminished β cell mass at birth and throughout adulthood, and increased β cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of β cell mass. Additionally, activation of FFA2 with Gαq/11-biased agonists substantially increased β cell proliferation in in vitro and ex vivo proliferation assays. Collectively, these data suggest that FFA2 may be a novel therapeutic target to stimulate β cell growth and proliferation

Methotrexate binding causes structural and functional changes in lung cystatin

Regulation of cysteine proteinases and their inhibitors is of utmost importance in diseases like lung cancer, chronic inflammatory conditions such as asthma, emphysema, and idiopathic pulmonary fibrosis. Protease-antiprotease imbalance accelerates disease progression. In the present study, the effect of antineoplastic and antirheumatic drug methotrexate (MTX) on lung cystatin (a cysteine protease inhibitor) was studied to explore drug induced changes in functional and structural integrity of the protein. The basic binding interaction was studied by UV-absorption, FT-IR and fluorescence spectroscopy. The quenching of protein fluorescence confirmed the binding of MTX with goat lung cystatin (GLC-I). Stern-Volmer analysis of MTX-GLC-I system at different temperatures indicates the presence of static component in the quenching mechanism. The thermodynamic parameters ΔH0 and ΔS0 were -3.8 kJ/mol and 94.97 J•mol-1•K-1, respectively, indicating that both hydrogen bonds and hydrophobic interactions played a major role in the binding of MTX to GLC-I. Methotrexate (7 µM) caused complete inactivation of lung cystatin after 6 hours. The results of FT-IR spectroscopy reflect perturbation of the goat lung cystatin on interaction with MTX. Methotrexate induced loss of function change in the inhibitor could provide a rationale for the off target tissue injury caused by the drug and for the design of agents against such an injury

Predictors of Obesity among Gut Microbiota Biomarkers in African American Men with and without Diabetes

Gut microbiota and their biomarkers may be associated with obesity. This study evaluated associations of body mass index (BMI) with circulating microbiota biomarkers in African American men (AAM) (n = 75). The main outcomes included fecal microbial community structure (16S rRNA), gut permeability biomarkers (ELISA), and short-chain fatty acids (SCFAs, metabolome analysis). These outcomes were compared between obese and non-obese men, after adjusting for age. The results showed that lipopolysaccharide-binding protein (LBP), the ratio of LBP to CD14 (LBP/CD14), and SCFAs (propionic, butyric, isovaleric) were higher in obese (n = 41, age 58 years, BMI 36 kg/m2) versus non-obese (n = 34, age 55 years, BMI 26 kg/m2) men. BMI correlated positively with LBP, LBP/CD14 (p < 0.05 for both) and SCFAs (propionic, butyric, isovaleric, p < 0.01 for all). In the regression analysis, LBP, LBP/CD14, propionic and butyric acids were independent determinants of BMI. The study showed for the first time that selected microbiota biomarkers (LBP, LBP/CD14, propionic and butyric acids) together with several other relevant risks explained 39%–47% of BMI variability, emphasizing that factors other than microbiota-related biomarkers could be important. Further research is needed to provide clinical and mechanistic insight into microbiota biomarkers and their utility for diagnostic and therapeutic purposes

COVID-19: Understanding the Pandemic Emergence, Impact and Infection Prevalence Worldwide

Coronavirus disease (COVID-19) has showed high transmission across the continents due to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) with total infected cases of around ~ 44 million people. This communicable virus that initiated from the Wuhan city of China in the month of December 2020 has now spread to 189 different countries with 1.1 million fatalities worldwide (till 28 Oct, 2020). The World Health Organization (WHO) declared this outbreak as Public Health Emergency of International Concern in January, 2020. The infection spreads mainly due to contact with infected droplets or fomites, highlighting flu like symptoms initially, which may further progress into severe pneumonia and respiratory failure, often observed in elderly patients with prehistory of other diseases. The diagnosis is based on detection of viral antigen, human antibody and viral gene (RT-PCR). Further, various other diagnostic tools including X-ray, CT-scan are used for imaging purpose, recently artificial intelligence based imaging (contactless scanning) gained popularity. Generally testing of existing drugs (repurposing) and development of new molecules are the main strategies adopted by researchers. However, as per initial findings, various drugs, monoclonal antibody and plasma therapy were found to show effectiveness against COVID-19. Further, many vaccine candidates have entered or will soon enter phase III clinical testing. This disease has further challenged the global economy. Thus, this review uniquely compares the strategies adopted by developed and developing countries worldwide including protective measures like lockdown, continuous testing, utilizing latest tools (artificial intelligence) in curbing this infection spread

Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity

Summary: Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1F121A) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy. Autophagy hyperactivation enhances insulin signaling, via suppressing ER stress in insulin-responsive cells, but decreases insulin secretion by selectively sequestrating and degrading insulin granule vesicles in β cells, a process we term “vesicophagy.” The reduction in insulin storage, insulin secretion, and glucose tolerance is reversed by transient treatment of autophagy inhibitors. Thus, β cells and insulin-responsive tissues require different autophagy levels for optimal function. To improve insulin sensitivity without hampering secretion, acute or intermittent, rather than chronic, activation of autophagy should be considered in diabetic therapy development. : Yamamoto et al. report that, in response to a high-fat-diet challenge, Becn1-mediated autophagy hyperactivation increases insulin sensitivity by reducing ER stress but decreases insulin secretion and storage via autophagic degradation of insulin granules. The results reveal differing roles of autophagy on metabolic regulation in insulin-responsive cells versus insulin-secreting β cells. Keywords: autophagosome, autophagy, β cell, Becn1, glucose tolerance, insulin granule, insulin-responsive tissue, insulin sensitivity, type 2 diabetes, vesicophag

The future treatment for type 1 diabetes: Pig islet- or stem cell-derived β cells?

Replacement of β cells is only a curative approach for type 1 diabetes (T1D) patients to avoid the threat of iatrogenic hypoglycemia. In this pursuit, islet allotransplantation under Edmonton's protocol emerged as a medical miracle to attain hypoglycemia-free insulin independence in T1D. Shortage of allo-islet donors and post-transplantation (post-tx) islet loss are still unmet hurdles for the widespread application of this therapeutic regimen. The long-term survival and effective insulin independence in preclinical studies have strongly suggested pig islets to cure overt hyperglycemia. Importantly, CRISPR-Cas9 technology is pursuing to develop "humanized" pig islets that could overcome the lifelong immunosuppression drug regimen. Lately, induced pluripotent stem cell (iPSC)-derived β cell approaches are also gaining momentum and may hold promise to yield a significant supply of insulin-producing cells. Theoretically, personalized β cells derived from a patient's iPSCs is one exciting approach, but β cell-specific immunity in T1D recipients would still be a challenge. In this context, encapsulation studies on both pig islet as well as iPSC-β cells were found promising and rendered long-term survival in mice. Oxygen tension and blood vessel growth within the capsules are a few of the hurdles that need to be addressed. In conclusion, challenges associated with both procedures, xenotransplantation (of pig-derived islets) and stem cell transplantation, are required to be cautiously resolved before their clinical application

Predictors of HbA1c among Adipocytokine Biomarkers in African-American Men with Varied Glucose Tolerance

This study explored adipocytokine associations with acute and chronic hyperglycemia in African-American men (AAM). Fourteen adipocytokines were measured from men with normal glucose tolerance (NGT) or type 2 diabetes (T2D, drug-naïve MF(−) or using metformin MF(+)). Acute and chronic hyperglycemia were evaluated by 120 min oral glucose tolerance test (OGTT) and glycohemoglobin A1c (HbA1c). AAM with T2D (n = 21) compared to NGT (n = 20) were older, had higher BMI and slightly higher glucose and insulin. In the fasted state, TNF-α, IL-6, PAI-1, IL-13, adiponectin, adipsin, and lipocalin were lower in T2D vs. NGT. At 120 min post-glucose load, TNF-α, IL-6, IL-13, IL-8, PAI-1, adiponectin, adipsin, lipocalin, and resistin were lower in T2D vs. NGT. There were no statistical differences for GM-CSF, IL-7, IL-10, IP-10, and MCP-1. Regression analysis showed that fasting IL-8, TNF-α, adiponectin, lipocalin, resistin, adipsin, and PAI-1 were associated with HbA1c. After adjusting for age, BMI, glucose tolerance, and metformin use, only adipsin remained significantly associated with HbA1c (p = 0.021). The model including adipsin, TNF-α, age, BMI, and group designation (i.e., NGT, MF(−), MF(+)) explained 86% of HbA1c variability. The data suggested that adipsin could be associated with HbA1c in AAM with varied glucose tolerance