Normal Regulation Research Articles

Effect of 3-year changes in adiposity measures on the pre-diabetes regression and progression: a community-based cohort study.

We assessed the impact of a 3-year change-percent in adiposity measures on regression and pre-diabetes (Pre-DM) progression among Iranian adults. Three-year change-percent in body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and visceral adiposity index (VAI) were calculated for 1458 Pre-DM subjects (mean age of 53.0 ± 13.7, 46.8% men), participated in the third examination of the Tehran Lipid and Glucose Study (2006-2008). Multinomial logistic regression models were used to estimate relative risk ratios (RRRs) of the outcomes [i.e., regression to normal glucose regulation (NGR), persistence in Pre-DM, and progression to newly diagnosed type 2 diabetes (T2D)] across 3-year change categories of adiposity measures (i.e., ≥ 5% decrease, 0-5% decrease, increase). Over nine years of follow-up, 37.7 and 39.0% returned to NGR and progressed to T2D, respectively. Decreased BW (0-5 and ≥ 5%) was associated with regression to NGR (RRRs = 1.44, 95% CIs = 1.05-1.98, and 2.64, 1.63-4.28, respectively). Decreased BMI and WC ≥ 5% were also associated with regression to NGR (RRRs = 1.63, 95% CI = 1.01-2.64; 1.69, 1.20-2.37, respectively). Changes in WHR and VAI were not associated with Pre-DM regression or progression. Pre-DM subjects with ≥ 5% BW loss had a constant FSG level overtime and a lower overall mean of FSG (116 vs. 111 and 112mg/dL, P = 0.023 and 0.009, respectively) and 2h-SG (154 vs. 165 and 168mg/dL) compared to those had 0-5% BW loss or BW gain. Short-term management of adiposity measures increases the regression probability to NGR. Targeting BW loss seems a more potent predictor of Pre-DM reversion among the adiposity measures.

Energy metabolism dysregulation, cerebrovascular aging, and time-restricted eating: Current evidence and proof-of-concept findings

Abstract Dysregulated energy metabolism is a hallmark of aging, including brain aging; thus, strategies to restore normal metabolic regulation are at the forefront of aging research. Intermittent fasting, particularly time-restricted eating (TRE), is one of these strategies. Despite its well-established effectiveness in improving metabolic outcomes in older adults, the effect of TRE on preserving or improving cerebrovascular health during aging remains underexplored. We explored how aging itself affects energy metabolism and contextualized these age-related changes to cerebrovascular health. We also conducted a literature search on PubMed and Scopus to identify and summarize current studies on TRE in older adults. Finally, we provided preliminary data from our proof-of-concept pilot trial on the effect of 6-month TRE on cerebrovascular health in older adults. Current evidence shows the potential of TRE to improve energy metabolism and physiological outcomes in older adults. TRE may improve cerebrovascular function indirectly due to its effect on glucose homeostasis. However, to date, direct evidence of the effect of TRE on cerebrovascular parameters is lacking. TRE is a well-tolerated and promising dietary intervention for promoting and maintaining cerebrovascular health in older adults. Further studies on TRE in older adults must be better controlled for energy balance to elucidate its independent effects from those of caloric restriction.

Association between triglyceride-glucose index and in-hospital all-cause mortality under different glucose metabolism status among patients with coronary artery disease

BackgroundThis current study aimed to investigate the relationship between the triglyceride-glucose (TyG) index and in-hospital all-cause mortality of coronary artery disease (CAD) in patients with different glucose metabolic statuses.MethodsParticipants were divided into three groups according to tertiles of the TyG index. Glucose metabolic status was classified as normal glucose regulation, pre-diabetes mellitus, and diabetes mellitus (DM). The primary outcome was in hospital all-cause mortality.ResultsWe observed a significant relationship between the TyG index and in-hospital deaths of patients with CAD in this study. After adjusting for multiple factors in the logistic regression model, the TyG index was still an independent risk factor, and the T3 group (OR, 2.311; 95% CI = 1.237–4.317; P = 0.009) was correlated with a 2.311-fold risk compared with the T1 group. In the subgroup analysis of different glucose metabolic status, the T3 group (OR, 1.541; 95% CI: 1.013–2.344; P = 0.043) were associated with a significantly higher risk of in-hospital deaths in CAD patients with DM.ConclusionsAn increased TyG index was correlated with a higher risk of in-hospital all-cause mortality. Our study indicated that TyG index could be a valuable predictor of in-hospital death of CAD patients, especially for individuals with DM.

Impact of glucose metabolism status on the relationship between remnant cholesterol and ischemic risk after percutaneous coronary intervention: a large-scale long-term cohort study from real-world

Abstract Background Elevated remnant cholesterol (RC) is considered a risk factor for ischemic events in patients with coronary artery disease (CAD). Recently evidence demonstrates a close connection between RC and cardiometabolic disorders, particularly diabetes mellitus (DM). However, it remains unclear whether different glucose metabolism statuses modify the association between RC and ischemic risk after percutaneous coronary intervention (PCI). Purpose This study aims to explore whether glucose metabolism statuses alter the relationship between RC and ischemic risk in CAD patients undergoing PCI. Methods This prospective study enrolled consecutive 10,724 CAD patients undergoing PCI throughout 2013. Patients were categorized into three groups: DM, pre-DM, and normal glucose regulation (NGR) group. Fasting RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, and was analyzed based on tertile levels (low, middle, and high). The clinical endpoint was major adverse cardiovascular and cerebrovascular events (MACCE, including cardiac mortality, revascularization and stroke). Results A total of 9,406 PCI patients were ultimately included, among whom the average age was 58.44 ± 10.26 years and 2,142 (22.80%) were female. During 5-year follow-up, 1,876 (19.9%) patients experienced MACCE. In the overall cohort, the highest RC tertile was associated with a higher risk of MACCE (hazard ratio [HR]: 1.129, 95% confidence interval [CI]: 1.006-1.267) compared to those in the lowest tertile (Figure 1). Importantly, a significant interaction was observed between RC levels and glucose metabolism statuses (P for interaction = 0.032). In the DM group, multivariate Cox regression analysis revealed that the highest tertile of RC significantly increased a 1.172-fold risk of MACCE (HR:1.172, 95% CI:1.004-1.369). However, neither the pre-DM nor NGR groups showed any significant association between RC and MACCE (both P > 0.05). Further subgroup analysis found that the correlation between the highest tertile of RC and an increased MACCE risk was only in the DM group, which was prominent among females (Figure 2). Conclusions In a large-scale 5-year follow-up study, we are the first to demonstrate that RC-related ischemic risk may be exacerbated by diabetes in CAD patients undergoing PCI, highlighting the potential benefits of intensifying RC-lowering treatments for PCI patients combined with DM.

Microscopic Varicocelectomy under Local Anesthesia as the Treatment of Varicocele.

Varicocele, characterized by the dilation of veins within the spermatic cord, is a prevalent disease in males, accounting for 35%-40% of infertility cases among men of reproductive age. This condition may disrupt normal neuroregulation, blood supply, and temperature regulation in the testicles, thereby impacting sperm count, quality (morphology, fragmentation rate), and functionality (motility). It may even induce symptoms such as pain and testicular atrophy. The international standard treatment method is microscopic varicocelectomy, typically performed under general anesthesia. This requires patients to fast before surgery and necessitates recovery and fasting care postoperatively. The arterial blood pressure drop caused by anesthesia may obscure the fluctuation of the spermatic artery, making the precise intraoperative isolation and protection of the spermatic artery more challenging. Therefore, this study proposes and implements microscopic varicocelectomy under local anesthesia. This method facilitates rapid and precise identification of the fluctuating spermatic artery, reducing the risk of spermatic artery damage. It also provides more humane care for patients, reduces economic burden, and offers a new perspective on the treatment of varicocele.

The Impact of Lifestyle Changes on the Prevalence of Prediabetes and Diabetes in Urban and Rural Indonesia: Results from the 2013 and 2018 Indonesian Basic Health Research (RISKESDAS) Survey

(1) Background: Prediabetes represents reversible glycemic abnormalities between normal glucose regulation and diabetes. Indonesia has a high burden of non-communicable diseases, such as diabetes. This study aims to evaluate the impact of lifestyle changes on prediabetes and diabetes in rural and urban populations. (2) Methods: This is a repeated cross-sectional study, and data were obtained from Basic Health Research (RISKESDAS) in 2013 and 2018. (3) Results: The study found that urban populations who ate >3 days/week of vegetables had a lower proportion of prediabetes and diabetes. Rural populations with 2 days/week of vegetable consumption had a higher risk of prediabetes in 2018. From 2013 to 2018, urban and rural populations consumed excessive amounts of sweet food/drink, salty food, fatty/cholesterol/fried food, and meat/chicken/fish-based food with preservatives. In 2018, urban and rural populations who consumed sweet food/drink more than once daily had a higher risk of prediabetes and diabetes. The prevalence of active physical activity declined in normoglycemic individuals, while it increased in prediabetes and diabetes in urban and rural areas. In 2013, physical activity was a protective factor for prediabetes. (4) Conclusions: Lifestyle changes impacted prediabetes and diabetes prevalence. Further research is needed to promote healthy diets and lifestyle modifications.

The association of ideal cardiovascular health and its change with subclinical atherosclerosis according to glucose status: A prospective cohort study.

An updated definition was developed to better evaluate cardiovascular health (CVH). We aimed to investigate whether optimal or improvement of six CVH metrics defined by new Life's Essential 8 (LE8) may counteract the risk of subclinical atherosclerosis among patients with hyperglycemia. We conducted a prospective analysis of 5225 participants without prior cardiovascular diseases, of whom 4768 had complete data on CVH change. Subjects with CVH scores of 0-49, 50-79, and 80-100 points were categorized as having low, moderate, or high CVH, respectively. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity, pulse pressure and albuminuria, both separately and in combination. Of the 5225 participants, 1937 (37.1%) had normal glucose regulation, while 3288 (62.9%) had hyperglycemia. The multivariable-adjusted odds ratio (OR) for composite subclinical atherosclerosis was 2.34 (95% confidence interval [CI], 1.88-2.91), 1.43 (95% CI, 1.21-1.70), and 0.74 (95% CI, 0.46-1.18), for participants with hyperglycemia who had low, moderate, or high overall CVH scores, respectively, compared with participants with normal glucose regulation. In addition, compared with those with stable CVH and normal glucose regulation, participants who exhibited greater improvements in overall CVH from 2010 to 2014 had a reduced risk of composite subclinical atherosclerosis with an OR of 0.72 (95% CI, 0.53-0.98) for those with normal glucose regulation, and 1.13 (95% CI, 0.87-1.48) for those with hyperglycemia. The novel defined CVH using six metrics was inversely associated with subsequent risk of subclinical atherosclerosis. Both the status of CVH and its changes modified the relationship between hyperglycemia and subclinical atherosclerosis.

Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study.

Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes. As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively. In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes. Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions.

Enhancing the fruit yield and quality of pomegranate in a new niche area: Insights into site specific agronomic practices

The sustained higher profitability of a pomegranate orchard relies heavily on the production of a greater proportion of high-quality fruits, a goal achievable through the implementation of effective management practices. The objective of this study is to provide site-specific supplementary knowledge regarding the response of pomegranate plants to various management practices under arid conditions. With the aim of enhancing both marketable fruit yield and quality of pomegranate in arid regions, four separate and simultaneous experiments were conducted in the same orchard to evaluate (i) the response of planting materials derived from tissue culture, air layering, and cutting; (ii) the impact of crop (fruit) load; (iii) the response of crop regulation; and (iv) the application response of organo-mineral fertilizers containing potassium (OMF-K) and phosphorus (OMF-P). The results obtained for plant growth, fruit yield, and fruit quality did not exhibit significant differences among pomegranate plants raised through the three different methods of vegetative propagation. Striking results in terms of producing superior-grade fruits, higher marketable yield, and overall fruit quality were achieved with crop loads of 80 fruits per plant. Staggering the crop regulation from June to September effectively extended the harvesting season to four months, from the last week of November to March, with eventual benefit of reduced fruit cracking compared to the standard two-month harvesting period obtained from normal regulation. Soil application of the indigenously developed OMF-K in two equal splits, along with the recommended N and P through inorganic sources, significantly reduced fruit cracking (only 6.23%) compared to the recommended NPK through inorganic sources (26.9%), while maintaining similar physicochemical quality attributes.

Discovery of GJC1 as a prognostic biomarker in glioma cells: insights into its cell-cycle relationship and differential expression in non-neuronal cells.

Gliomas, originating from the most common non-neuronal cells in the brain (glial cells), are the most common brain tumors and are associated with high mortality and poor prognosis. Glioma cells exhibit a tendency to disrupt normal cell-cycle regulation, leading to abnormal proliferation and malignant growth. This study investigated the predictive potential of GJC1 in gliomas and explored its relationship with the cell cycle. Retrospective analysis of RNA-seq and single-cell sequencing data was conducted using the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. The differential expression of GJC1 in gliomas with various pathological features and in different non-neuronal cell groups was analyzed. Functional data were examined using gene set variation analysis (GSVA). Furthermore, CellMiner was used to evaluate the relationship between GJC1 expression and predicted treatment response across these databases. GJC1 expression was enriched in high-grade gliomas and 1p/19q non-codeletion gliomas. GJC1 enrichment was observed in classical and mesenchymal subtypes within the TCGA glioma subtype group. In single-cell subgroup analysis, GJC1 expression was higher in glioma tissues compared to other non-neuronal cells. Additionally, the TCGA classical subtype of glioma cells exhibited more GJC1 expression than the other subgroups. GJC1 emerged as an independent prognostic factor for overall survival in glioma. GSVA unveiled potential mechanisms by which GJC1 may impact cell-cycle regulation in glioma. Finally, a significant correlation was observed between GJC1 expression and the sensitivity of multiple anti-cancer drugs. These findings confirmed GJC1 as a novel biomarker and provided insights into the differential gene expression in non-neuronal cells and the impact of the cell cycle on gliomas. Consequently, GJC1 may be used to predict glioma prognosis and has potential therapeutic value.

UID-Dual Transcriptome Sequencing Analysis of the Molecular Interactions between Streptococcus agalactiae ATCC 27956 and Mammary Epithelial Cells.

Streptococcus agalactiae ATCC 27956 is a highly contagious Gram-positive bacterium that causes mastitis, has a high infectivity for mammary epithelial cells, and becomes challenging to treat. However, the molecular interactions between it and mammary epithelial cells remain poorly understood. This study analyzed differential gene expression in mammary epithelial cells with varying levels of S. agalactiae infection using UID-Dual transcriptome sequencing and bioinformatics tools. This study identified 211 differentially expressed mRNAs (DEmRNAs) and 452 differentially expressed lncRNAs (DElncRNAs) in host cells, primarily enriched in anti-inflammatory responses, immune responses, and cancer-related processes. Additionally, 854 pathogen differentially expressed mRNAs (pDEmRNAs) were identified, mainly enriched in protein metabolism, gene expression, and biosynthesis processes. Mammary epithelial cells activate pathways, such as the ERK1/2 pathway, to produce reactive oxygen species (ROS) to eliminate bacteria. The bacteria disrupt the host's innate immune mechanisms by interfering with the alternative splicing processes of mammary epithelial cells. Specifically, the bacterial genes of tsf, prfB, and infC can interfere with lncRNAs targeting RUNX1 and BCL2L11 in mammary epithelial cells, affecting the alternative splicing of target genes and altering normal molecular regulation.

Abstract 58: The 5-HT7 receptor contributes to increased hindquarter blood flow caused by skeletal muscle contraction

Exogenous serotonin (5-hydroxytryptamine, 5-HT) causes a reproducible decrease in blood pressure in normotensive and hypertensive rats. This is associated with dilation of arterioles in skeletal muscle. The 5-HT7 receptor KO rat strain allowed us to test the role of this receptor in both responses as well as the effects of endogenous 5-HT -- acting at 5-HT7 receptors -- on normal circulatory regulation. First, we hypothesized that the 5-HT7 receptor KO rat would have a higher hindquarter (HQ) vascular resistance (HQVR) than wildtype (WT) because of loss of this receptor. In rats anesthetized with isoflurane, instrumented with arterial catheters and flow probes on the terminal aorta, male KO rats had significantly higher resting HQVR [mm Hg/ml/min; KO (16.0±2.0) vs WT (10.8±0.6.0), p = 0.04] and lower HQ blood flow than normal Sprague-Dawley (SD) rats. No differences in resting HQVR or HQ flow were observed in female rats. Intravenous infusion of 5-HT (50 ug/kg/min) reduced systemic blood pressure and HQVR; these parameters were significantly attenuated (~56%) in male KO rats versus WT and SD animals. In females, falls in systemic blood pressure and HQVR were absent in both KO and WT rats. Second, as 5-HT has been implicated in the pathophysiology of heart failure (HF), a left anterior descending artery ligation model of HF was used to investigate the potential role of 5-HT7 regulation of HQ flow in HF-associated exercise intolerance. The ability of hindlimb muscle stimulation to increase blood flow using transdermal neuromuscular electrical stimulation was tested (NMES). M and F KO rats showed a reduced ability to increase HQ flow during muscle contraction vs WT (% over basal: M WT = 118±18 vs KO =14.6±7.1; F WT= 101±12 vs KO = 7.6±6) rats. This was observed in both intact and HF rats (in which flow changes were already impaired). Acute administration of the 5-HT7 receptor antagonist SB269970 abolished the ability of NMES to increase HQ flow in normal SD rats. Importantly, the microcirculatory capacity, visualized by Lectin-594, was not significantly different in the gastrocnemius muscle of WT (arbitrary fluorescence units/area: 946±40) vs KO (914±69). These data support that the 5-HT7 receptor, likely activated by endogenous 5-HT, is an important regulator of skeletal muscle vascular resistance. Thus, 5-HT may have a larger role in normal and pathophysiological regulation of the circulation than has previously been appreciated.

Decoding Endothelial MPL and JAK2V617F Mutation: Insight Into Cardiovascular Dysfunction in Myeloproliferative Neoplasms.

Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN. We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL (myeloproliferative leukemia virus oncogene) suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function. JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients.

Endogenous complement 1q binding protein (C1qbp) regulates mitochondrial permeability transition and post-myocardial infarction remodeling and dysfunction

The mitochondrial permeability transition (MPT) pore regulates necrotic cell death following diverse cardiac insults. While the componentry of the pore itself remains controversial, Cyclophilin D (CypD) has been well-established as a positive regulator of pore opening. We have previously identified Complement 1q-binding protein (C1qbp) as a novel CypD-interacting molecule and a negative regulator of MPT-dependent cell death in vitro. However, its effects on the MPT pore and sensitivity to cell death in the heart remain untested. We therefore hypothesized that C1qbp would inhibit MPT in cardiac mitochondria and protect cardiac myocytes against cell death in vivo. To investigate the effects of C1qbp in the myocardium we generated gain- and loss-of-function mice. Transgenic C1qbp overexpression resulted in decreased complex protein expression and reduced mitochondrial respiration and ATP production but MPT was unaffected. In contrast, while C1qbp+/− mice did not exhibit any changes in mitochondrial protein expression, respiration, or ATP, the MPT pore was markedly sensitized to Ca2+ in these animals. Neither overexpression nor depletion of C1qbp significantly affected baseline heart morphology or function at 3 months of age. When subjected to myocardial infarction, C1qbp transgenic mice exhibited similar infarct sizes and cardiac remodeling to non-transgenic mice, consistent with the lack of an effect on MPT. In contrast, cardiac scar formation and dysfunction were significantly increased in the C1qbp+/− mice compared to C1qbp+/+ controls. Our results suggest that C1qbp is required for normal regulation of the MPT pore and mitochondrial function, and influences cardiac remodeling following MI, the latter more likely being independent of C1qbp effects on the MPT pore.

Direct and indirect connections of androgen status with ejaculate parameters in men from infertile couples

In men from infertile couples the serum level of total testosterone (tT) has been shown to vary widely. Is it possible to expect that there is an association of tT content with spermogram disorders in men from infertile couples? Aim of the study was to investigate the patterns of changes in the spermiological status of men from infertile couples depending on tT level in blood serum. Material and methods. Design – observational, retrospective, one-stage study. The analysis of medical histories of 358 men with infertility in marriage was carried out. The sample was divided into comparison groups according to tT level: group 1 – less than 12.1, group 2 – from 12.1 to 20.9, group 3 – 21.0 nmol/l or more. Results. From group 1 to group 3, tT content increases more than twice, as well as concentration of indicators related to the level of T – sex hormone binding globulin (SHBG) and free testosterone (fT). There are no significant differences in luteinizing hormone (LH) and follicle stimulating hormone (FSH) level, although there is a tendency to its increase from group 1 to group 3. From group 1 of men with androgen deficiency to group 3, not only body weight and body mass index (BMI), but also waist circumference (WC) and hip circumference (HC), as well as the WC/HC index, characterizing the degree of abdominal obesity, decrease. The groups examined did not differ in the values of all studied ejaculate parameters. In group 1, a pronounced correlation between the content of tT and fT was found, in groups 2 and 3 – statistically significant inverse relationships between the level of Tob and the values of anthropometric indicators (body weight, BMI, WC and HC), as well as direct ones - with the concentration of SHBG, tT, LH and estradiol, in group 3 – with FSH levels. There were no correlations between tT content and spermogram indicators in any group of examined men. Conclusions. The results obtained suggest that only at high-normal level of testosterone in the blood it can have a stimulating effect on spermatogenesis. As a result of the accumulation of cases of androgenic deficiency in the population, the direct positive effect of serum testosterone on spermatogenesis is becomes insufficient for normal regulation, and the negative effect of testosterone deficiency on spermatogenesis, mediated through the accumulation of overweight and obesity comes to the fore.

The association of body weight change and regression to normoglycemia in different phenotypes of pre-diabetes: Findings of a longitudinal cohort study

AimWe investigated the association of 3-year change in body weight (BW) and regression to normal glucose regulation (NGR) among different phenotypes of pre-diabetes (Pre-DM), i.e., isolated impaired glucose tolerance (iIFG), isolated impaired fasting glucose (iIGT) and combined IFG-IGT. Research Design and Methods1458 Pre-DM subjects (iIFG=618, iIGT=462, and IFG-IGT=378) were assessed for 3-year change-percent in BW (2006-2008 to 2009-2011) and then followed up to 2015-2017, within the national cohort of Tehran Lipid and Glucose Study (TLGS). Binary logistic regression models were used to estimate the probability (odds ratio, ORs) of regression to NGR across categories of 3-year BW change (i.e., ≥5% BW loss, 0-5% BW loss, BW gain) in different phenotypes of Pre-DM. ResultsThe mean age of the participants was 53.0±13.7, and 46.8% were men. Over a median of 6 years of follow-up, the rate of regression to normoglycemia was 50.6, 43.2, and 12.7% in iIGT, iIFG, and combined IFG-IGT, respectively. The baseline-adjusted mean of 3-year BW change was not significantly different across Pre-DM phenotypes (0.68±0.19, 0.32±0.22 and 0.23±0.24 kg, in iIFG, IGT, and IFG-IGT). Three-year BW loss ≥5% was associated with a greater NGR probability in iIGT than other phenotypes (OR=4.29 vs. 3.90 and 2.84 in IFG-IGT and iIFG, respectively). A modest reduction (0-5% of initial BW) resulted in an increased chance of Pre-DM regression among subjects with IGT (OR=1.61, 95% CI=1.03-2.52) but not iIFG or IFG-IGT phenotypes. ConclusionShort-term intensive BW loss (≥5% of initial BW) increased NGR probability in all Pre-DM phenotypes, with an order of iIGT>combined IFG-IGT>iIFG. Only iIGT take advantage of moderate BW loss (0-5% of initial BW) for increasing chance of Pre-DM regression.

Rapid and reversible dissolution of biomolecular condensates using light-controlled recruitment of a solubility tag

Biomolecular condensates are broadly implicated in both normal cellular regulation and disease. Consequently, several chemical biology and optogenetic approaches have been developed to induce phase separation of a protein of interest. However, few tools are available to perform the converse function – dissolving a condensate of interest on demand. Such a tool would aid in testing whether the condensate plays specific functional roles. Here we show that light-gated recruitment of a solubilizing domain, maltose-binding protein (MBP), results in rapid and controlled dissolution of condensates formed from proteins of interest. Our optogenetic MBP-based dissolution strategy (OptoMBP) is rapid, reversible, and can be spatially controlled with subcellular precision. We also provide a proof-of-principle application of OptoMBP by disrupting condensation of the oncogenic fusion protein FUS-CHOP and reverting FUS-CHOP driven transcriptional changes. We envision that the OptoMBP system could be broadly useful for disrupting constitutive protein condensates to probe their biological functions.

Smooth Muscle Cells-Expressed Bmal1 Regulates Vascular Calcification Independent of the Canonical Circadian Pathway.

Vascular calcification is a major cardiovascular issue that increases morbidity and mortality in diabetes patients. While dysregulation of the circadian master regulator Basic Helix-Loop-Helix ARNT-Like Protein 1 (Bmal1) in vascular smooth muscle cells (VSMC) under diabetic conditions has been suggested, its role in vascular calcification is unclear. In VSMC, Bmal1 was upregulated under high glucose treatment and in aortic tissues from a diabetic mouse model. RNA sequencing from isolated VSMC between Bmal1 deletion and wildtype mice indicated Bmal1's pro-calcification role. Indeed, reduced levels of the osteogenic master regulator, Runt-Related Transcription Factor 2 (Runx2), were found in Bmal1 deletion VSMC under diabetic conditions. Alizarin red staining showed reduced calcification in Bmal1 deletion VSMC in vitro and vascular rings ex vivo . Furthermore, in a diabetic mouse model, SMC-Bmal1 deletion showed reduced calcium deposition in aortas. Collectively, diabetes-upregulated circadian regulator Bmal1 in VSMC contributes to vascular calcification. Maintaining normal circadian regulation may improve vascular health in diabetes.

Comprehensive analysis of the association between triglyceride-glucose index and coronary artery disease severity across different glucose metabolism states: a large-scale cross-sectional study from an Asian cohort

BackgroundThe triglyceride-glucose (TyG) index is associated with the development and prognosis of coronary artery disease (CAD). However, the impact of the TyG index on CAD severity across different glucose metabolism states exhibits significant disparities in previous research.MethodsThis cross-sectional study comprised 10,433 participants from a prospective cohort. Participants were categorized into four groups based on glucose metabolism state: normal glucose regulation (NGR), prediabetes (pre-DM), diabetes mellitus (DM) without insulin prescribed (Rx), and DM with insulin Rx. The TyG index was determined by the following formula: Ln [TG (mg/dL) × FPG (mg/dL) / 2], where TG is triglycerides and FPG is fasting plasm glucose. Statistical methods such as binary logistic regression, interaction analysis, restricted cubic spline (RCS), and receiver operating characteristic (ROC) were employed to analyze the relationship between the TyG index and CAD severity across the entire population and glucose metabolism subgroups. Mediation analysis was conducted to examine the mediating effects of glycated hemoglobin (HbA1c) on these relationships. Sensitivity analysis was performed to ensure the robustness of the findings.ResultsMultivariable logistic regression analysis revealed a significant positive association between the TyG index and multi-vessel CAD in the entire population (OR: 1.34; 95% CI: 1.22–1.47 per 1-unit increment). Subgroup analysis demonstrated consistent positive associations in the NGR, pre-DM, and DM non-insulin Rx groups, with the highest OR observed in the NGR group (OR: 1.67; 95% CI: 1.3–2.14 per 1-unit increment). No correlation was found in the DM with insulin Rx subgroup. RCS analyses indicated the distinct dose-response relationships across different glucose metabolism subgroups. Including the TyG index in the established model slightly improved the predictive accuracy, particularly in the NGR group. Mediation analyses showed varying mediating effects of HbA1c among different glucose metabolism subgroups. Sensitivity analysis confirmed the robustness of the aforementioned relationships in the new-onset CAD population and in individuals not using antilipidemic medications.ConclusionsThe TyG index positively associated with CAD severity across all glucose metabolism states, except for individuals receiving insulin treatment. Moreover, it might serve as a supplementary noninvasive predictor of CAD severity in addition to established factors, especially in NGR patients.Graphical abstract

Gestational bisphenol A exposure alters energy homeostasis and adult hypothalamic neurogenesis in female mice

Regulation of physiological homeostasis, including energy balance, is thought to be modified by low levels of adult neurogenesis in the hypothalamus. Hormones such as oestradiol can influence both embryonic and adult hypothalamic neurogenic programs, demonstrating a sensitivity of hypothalamic neural progenitor cells to endogenous hormones. Previously we showed that gestational exposure to environmental levels of the xenoestrogen bisphenol A (BPA) changed neural progenitor cell behaviors in the embryo; however, we did not examine if these changes were permanent to affect adult neurogenesis. Here we investigated whether adult neuro- and/or gliogenesis were altered in mice prenatally exposed to BPA and placed on a high-fat diet challenge. Gestationally exposed adult female mice on a standard diet gained less weight than non-BPA controls, whereas gestationally exposed BPA females on a high-fat diet gained more weight than controls. Males exposed to gestational BPA showed no differences in weight gain relative to control males. Concomitantly, adult neurogenesis was increased in the VMH, DMH, and PVN of adult female mice exposed to BPA on standard diet, suggesting that disrupted adult neurogenesis might perturb normal energy balance regulation in females. These results add to growing evidence that low-dose BPA exposure in utero causes changes to adult hypothalamic function.