Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.

Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis.

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ­FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

Overexpression of Pref-1 in pancreatic islet ß-cells in mice causes hyperinsulinemia with increased islet mass and insulin secretion.

Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet ß-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet ß-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet ß-cells and insulin production.

Nuclear receptors and metabolism: from feast to famine.

The ability to adapt to cycles of feast and famine is critical for survival. Communication between multiple metabolic organs must be integrated to properly metabolise nutrients. By controlling networks of genes in major metabolic organs, nuclear hormone receptors (NHRs) play central roles in regulating metabolism in a tissue-specific manner. NHRs also establish daily rhythmicity by controlling the expression of core clock genes both centrally and peripherally. Recent findings show that many of the metabolic effects of NHRs are mediated through certain members of the fibroblast growth factor (FGF) family. This review focuses on the roles of NHRs in critical metabolic organs, including adipose tissue, liver and muscle, during the fed and fasted states, as well as their roles in circadian metabolism and downstream regulation of FGFs.

The effect of social network based motivational interviewing on health behaviors among infertile women with polycystic ovary syndrome: A randomized controlled trial.

Polycystic ovary syndrome is one of the commonest and complex endocrine disorders in females of reproductive age. Attention to self-care behaviors such as health-promoting behaviors can improve physiological and psychological conditions in women with PCOS. This study aimed to determine the efficacy of Social Network-Based Motivational Interviewing on health-promoting behaviors and quality of life of infertile women with polycystic ovary syndrome. In this randomized controlled trial, 60 infertile women with polycystic ovary syndrome were randomly selected and assigned to the interventio (n = 30) or a control group (n = 30). Participants in the control group received routine care. Those in the intervention group received five motivational group sessions in WhatsApp, which were conducted in five groups of six participants each. The data related to health-promoting behaviors and quality of life were collected through an online questionnaire. Both groups were followed up immediately and 2 months after the intervention. Data collected in the two stages were analyzed using the paired-samples t-test, Chi-square, and repeated measures analysis. No significant difference was observed between the two groups before the intervention means health-promoting behaviors and quality of life scores (p>0.05). Immediately and two months after the intervention, the mean scores of health-promoting behaviors and their domains increased in the intervention group. This increase is statistically compared to the first test, and the scores obtained by the control group in the second (p< 0.001, ES = 1.5) and the third test (p< 0.001, ES= 1.3) were significant. The score of the quality of life variable increase was not statistically significant compared to the first test and also to the scores obtained by the control group. However According to the Generalized estimating equations (GEE) test, the changes in quality of life score between the two groups in the three stages of measurement are statistically significant. WhatsApp support increases the health-promoting self-care behaviors rate and has favorable effects on follow-up.Trial registration: Iranian Registry for Clinical Trial (the link to trial: https://www.irct.ir/trial/48089 ). Registered August 11 2020.

Association of the corona virus (Covid-19) epidemic with environmental risk factors.

The current outbreak of the novel coronavirus SARS-CoV-2 (coronavirus disease 2019; previously 2019-nCoV), epicenter in Hubei Province (Wuhan), People's Republic of China, has spread too many other countries. The transmission of the corona virus occurs when people are in the incubation stage and do not have any symptoms. Therefore, the role of environmental factors such as temperature and wind speed becomes very important. The study of Acute Respiratory Syndrome (SARS) indicates that there is a significant relationship between temperature and virus transmission and three important factors, namely temperature, humidity and wind speed, cause SARS transmission. Daily data on the incidence and mortality of Covid-19 disease were collected from World Health Organization (WHO) website and World Meter website (WMW) for several major cities in Iran and the world. Data were collected from February 2020 to September 2021. Meteorological data including temperature, air pressure, wind speed, dew point and air quality index (AQI) index are extracted from the website of the World Meteorological Organization (WMO), The National Aeronautics and Space Administration (NASA) and the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor. Statistical analysis carried out for significance relationships. The correlation coefficient between the number of infected people in one day and the environmental variables in the countries was different from each other. The relationship between AQI and number of infected was significant in all cities. In Canberra, Madrid and Paris, a significant inverse relationship was observed between the number of infected people in one day and wind speed. There is a significant positive relationship between the number of infected people in a day and the dew point in the cities of Canberra, Wellington and Washington. The relationship between the number of infected people in one day and Pressure was significantly reversed in Madrid and Washington, but positive in Canberra, Brasilia, Paris and Wuhan. There was significant relationship between Dew point and prevalence. Wind speed showed a significant relationship in USA, Madrid and Paris. AQI was strongly associated with the prevalence of covid19. The purpose of this study is to investigate some environmental factors in the transmission of the corona virus.

Robust antibacterial activity of functionalized carbon nanotube- levofloxacine conjugate based on in vitro and in vivo studies.

A new nano-antibiotic was synthesized from the conjugation of multi-walled carbon nanotubes with levofloxacin (MWCNT-LVX) through covalent grafting of drug with surface-modified carbon nanotubes in order to achieve an effective, safe, fast-acting nano-drug with the minimal side effects. This study is the first report on the evaluation of in vitro cell viability and antibacterial activity of nano-antibiotic along in addition to the in vivo antibacterial activity in a burn wound model. The drug-loading and release profile at different pH levels was determined using an ultraviolet-visible spectrometer. MWCNT-LVX was synthesized by a simple, reproducible and cost-effective method for the first time and characterized using various techniques, such as scanning electron microscope, transmission electron microscopy, and Brunauer-Emmett-Teller analysis, and so forth. The noncytotoxic nano-antibiotic showed more satisfactory in vitro antibacterial activity against Staphylococcus aureus compared to Pseudomona aeruginosa. The novel synthetic nano-drug possessed high loading capacity and pH-sensitive release profile; resultantly, it exhibited very potent bactericidal activity in a mouse S. aureus wound infection model compared to LVX. Based on the results, the antibacterial properties of the drug enhanced after conjugating with surface-modified MWCNTs. The nano-antibiotic has great industrialization potential for the simple route of synthesis, no toxicity, proper drug loading and release, low effective dose, and strong activity against wound infections. In virtue of unique properties, MWCNTs can serve as a controlled release and delivery system for drugs. The easy penetration to biological membranes and barriers can also increase the drug delivery at lower doses compared to the main drug alone, which can lead to the reduction of its side effects. Hence, MWCNTs can be considered a promising nano-carrier of LVX in the treatment of skin infections.

ß3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity.

The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine ß3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). ß3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNF-α treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice and with BMI in 2 independent cohorts of humans. These data implicate a signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with ß3-adrenergic receptor agonists.

Characterization of desnutrin functional domains: critical residues for triacylglycerol hydrolysis in cultured cells.

Murine desnutrin/human ATGL is a triacylglycerol (TAG) hydrolase with a predicted catalytic dyad within an alpha-beta hydrolase fold in the N-terminal region. In humans, mutations resulting in C-terminal truncation cause neutral lipid storage disease with myopathy. To identify critical functional domains, we measured TAG breakdown in cultured cells by mutated or truncated desnutrin. In vitro, C-terminally truncated desnutrin displayed an even higher apparent V(max) than the full-length form without changes in K(m), which may be explained by our finding of an interaction between the C- and N-terminal domains. In live cells, however, C-terminally truncated adenoviral desnutrin had lower TAG hydrolase activity. We investigated a role for the phosphorylation of C-terminal S406 and S430 residues but found that these were not necessary for TAG breakdown or lipid droplet localization in cells. The predicted N-terminal active sites, S47 and D166, were both critical for TAG hydrolysis in live cells and in vitro. We also identified two overlapping N-terminal motifs that predict lipid substrate binding domains, a glycine-rich motif (underlined) and an amphipathic alpha-helix (bold) within amino acid residues 10-24 (ISFAGCGFLGVYHIG). G14, F17, L18, and V20, but not G16 and G19, were important for TAG hydrolysis, suggesting a potential role for the amphipathic alpha-helix in TAG binding. This study identifies for the first time critical sites in the N-terminal region of desnutrin and reveals the requirement of the C-terminal region for TAG hydrolysis in cultured cells.

Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3.

Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of ß-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.

Correlation of Maternal Stress Because of Positive Aneuploidy Screening Serum Analytes and Uterine Arteries' Doppler Ultrasound Index: A Prospective Cohort Study.

BACKGROUND: Antenatal anxiety or maternal stress is a prevalent chronic mental disorder in pregnant women. We have assessed the effect of maternal stress from positive aneuploidy screening results on the changes in uterine artery blood flow. MATERIALS AND METHODS: We performed a prospective cohort (one sample) pilot study at a hospital in Tehran, Iran. A total of 60 pregnant women who were candidates for amniocentesis due to abnormal sequential screening test results entered the study. We conducted 2 standard psychological tests, the Spielberger's State-Trait Anxiety Inventory and the Beck Anxiety Inventory, to determine anxiety levels in the participants before amniocentesis and two weeks after amniocentesis. The uterine artery resistance index was also measured before and two weeks after amniocentesis. The level of maternal stress was compared with the uterine artery resistance index. RESULTS: Patients had a mean State Trait Anxiety Inventory score before amniocentesis of greater than 40, which meant that the mothers experienced high anxiety. There were no correlations between both inventories' anxiety scores and uterine artery blood flow before amniocentesis. However, two weeks after amniocentesis, we observed significant negative correlations between the State Anxiety (P=0.0041) and Trait Anxiety (P=0.010) Inventory scores and the uterine artery resistance indexes. Also, there was an association between the decreased right uterine artery resistance index and State Anxiety scores (P=0.036). There were significant correlations between State and Trait Anxiety scores and second trimester analytes of ß-human chorionic gonadotropin (ß-hCG, P<0.001), α-fetoprotein (P<0.001), and unconjugated estriol (P=0.048). CONCLUSION: Maternal anxiety because of positive aneuploidy screening serum analytes and amniocentesis can affect perinatal outcomes via mood-based alterations in blood flow of the uterine arteries and the screening markers ß-hCG,unconjugated estriol, and α-fetoprotein.

Monoclinic modification of 1,2-bis-(diphenyl-seleno-phosphino-yl)ethane.

The complete mol-ecule of the title compound, C(26)H(24)P(2)Se(2), is generated by crystallographic 2-fold symmetry, with the rotation axis bisecting the central C-C bond. The dihedral angle between the terminal aromatic rings is 74.1 (1)°.

ERRγ Preserves Brown Fat Innate Thermogenic Activity.

Brown adipose tissue (BAT) adaptively transfers energy from glucose and fat into heat by inducing a gene network that uncouples mitochondrial electron transport. However, the innate transcription factors that enable the rapid adaptive response of BAT are unclear. Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor for maintaining BAT identity. ERRγ is selectively expressed in BAT versus WAT, in which, in the absence of PGC1α, it drives a signature transcriptional network of thermogenic and oxidative genes in the basal (i.e., thermoneutral) state. Mice lacking ERRγ in adipose tissue (ERRγKO mice) display marked downregulation of BAT-selective genes that leads to a pronounced whitening of BAT. Consistent with the transcriptional changes, the thermogenic capacity of ERRγKO mice is severely blunted, such that they fail to survive an acute cold challenge. These findings reveal a role for ERRγ as a critical thermoneutral maintenance factor required to prime BAT for thermogenesis.

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.

Psychosocial Predictors of Breast Self-Examination among Female Students in Malaysia: A Study to Assess the Roles of Body Image, Self-efficacy and Perceived Barriers.

BACKGROUND: Early detection is a critical part of reducing the burden of breast cancer and breast selfexamination (BSE) has been found to be an especially important early detection strategy in low and middle income countries such as Malaysia. Although reports indicate that Malaysian women report an increase in BSE activity in recent years, additional research is needed to explore factors that may help to increase this behavior among Southeastern Asian women. OBJECTIVE: This study is the first of its kind to explore how the predicting variables of self-efficacy, perceived barriers, and body image factors correlate with self-reports of past BSE, and intention to conduct future breast self-exams among female students in Malaysia. MATERIALS AND METHODS: Through the analysis of data collected from a prior study of female students from nine Malaysian universities (n=842), this study found that self-efficacy, perceived barriers and specific body image sub-constructs (MBSRQ-Appearance Scales) were correlated with, and at times predicted, both the likelihood of past BSE and the intention to conduct breast self-exams in the future. RESULTS: Self-efficacy (SE) positively predicted the likelihood of past self-exam behavior, and intention to conduct future breast self-exams. Perceived barriers (BR) negatively predicted past behavior and future intention of breast self-exams. The body image sub-constructs of appearance evaluation (AE) and overweight preoccupation (OWP) predicted the likelihood of past behavior but did not predict intention for future behavior. Appearance orientation (AO) had a somewhat opposite effect: AO did not correlate with or predict past behavior but did correlate with intention to conduct breast self-exams in the future. The body image sub-constructs of body area satisfaction (BASS) and self-classified weight (SCW) showed no correlation with the subjects' past breast self-exam behavior nor with their intention to conduct breast self-exams in the future. CONCLUSIONS: Findings from this study indicate that both self-efficacy and perceived barriers to BSE are significant psychosocial factors that influence BSE behavior. These results suggest that health promotion interventions that help enhance self-efficacy and reduce perceived barriers have the potential to increase the intentions of Malaysian women to perform breast self-exams, which can promote early detection of breast cancers. Future research should evaluate targeted communication interventions for addressing self-efficacy and perceived barriers to breast self-exams with at-risk Malaysian women. and further explore the relationship between BSE and body image.

ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive ß Cells.

Pancreatic ß cells undergo postnatal maturation to achieve maximal glucose-responsive insulin secretion, an energy intensive process. We identify estrogen-related receptor γ (ERRγ) expression as a hallmark of adult, but not neonatal ß cells. Postnatal induction of ERRγ drives a transcriptional network activating mitochondrial oxidative phosphorylation, the electron transport chain, and ATP production needed to drive glucose-responsive insulin secretion. Mice deficient in ß cell-specific ERRγ expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge. Notably, forced expression of ERRγ in iPSC-derived ß-like cells enables glucose-responsive secretion of human insulin in vitro, obviating in vivo maturation to achieve functionality. Moreover, these cells rapidly rescue diabetes when transplanted into ß cell-deficient mice. These results identify a key role for ERRγ in ß cell metabolic maturation, and offer a reproducible, quantifiable, and scalable approach for in vitro generation of functional human ß cell therapeutics.

Insufficient Knowledge of Breast Cancer Risk Factors Among Malaysian Female University Students.

BACKGROUND: Despite continuous argument about the efficacy of breast self-examination; it still could be a life-saving technique through inspiring and empowering women to take better control over their body/breast and health. This study investigated Malaysian female university students' knowledge about breast cancer risk factors, signs, and symptoms and assessed breast self-examination frequency among students. METHOD: A cross-sectional survey was conducted in 2013 in nine public and private universities in the Klang Valley and Selangor. 842 female students were respondents for the self-administered survey technique. Simple descriptive and inferential statistics were employed for data analysis. RESULTS: The uptake of breast self-examination (BSE) was less than 50% among the students. Most of students had insufficient knowledge on several breast cancer risk factors. CONCLUSION: Actions and efforts should be done to increase knowledge of breast cancer through the development of ethnically and traditionally sensitive educational training on BSE and breast cancer literacy.

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.

Relationship between body image and breast self-examination intentions and behavior among female university students in Malaysia.

This study aimed to examine the relationship between body image satisfaction and breast self-screening behavior and intentions. The sample for this cross-sectional study consisted of 842 female university students who were recruited from a number of public and private universities. Data were obtained between the months of November and December, 2013, using multistage random cluster sampling. Main research variables were breast cancer screening behavior and intentions, demographic factors, and the total scores on each of the Multidimensional Body-Self Relations Questionnaire (MBSRQ-Appearance Scales) subscales. Results of multivariate analysis showed that having higher satisfaction and more positive evaluation of appearance were related to having performed breast self-examination more frequently in the last year and intending to perform breast self-examination more frequently in the next year. Longitudinal research can potentially provide detailed information about overall body image satisfaction and breast cancer screening behavior among various communities.