T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress.

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.

Effect of "T2-rim sign" related parameters on high-intensity focused ultrasound ablation of uterine fibroids.

PURPOSE: To investigate the effect of "high-signal-intensity peripheral rim on T2-weighted MR images (T2-rim sign)" related parameters on non-perfused volume ratio (NPVR) after high-intensity focused ultrasound (HIFU) ablation of uterine fibroids. METHODS: Data from 616 patients with uterine fibroids treated with HIFU were retrospectively analyzed. Univariate and multivariate logistic regression was used to analyze the factors influencing the ablation effect. The effect of T2-rim sign on ablation parameters and results was also analyzed. Spearman correlation analysis was used to compare the correlation between coverage ratio, average thickness of T2-rim sign and NPVR in 207 cases of fibroids with T2-rim sign. RESULTS: The presence of T2-rim sign was an independent risk factor affecting the ablation effect. The coverage ratio of T2-rim sign was negatively correlated with treatment efficiency (r = -0.174, p = 0.012) and NPVR (r = -0.186, p = 0.007), and positively correlated with energy efficiency factor (EEF) (r = 0.156, p = 0.024). The average thickness of T2-rim sign was positively correlated with treatment intensity (r = 0.203, p = 0.003) and negatively correlated with NPVR (r = -0.363, p < 0.001). There was a negative correlation between the average thickness of the T2-rim sign and NPVR in isointense fibroids (r = -0.484, p < 0.001). CONCLUSION: The presence of T2-rim sign increases the difficulty of ablation and reduces the ablation effect. In clinical practice, the presence and related parameters of T2-rim sign should be fully considered when screening for HIFU indications and formulating treatment plans.

Application of Ti4+ embedded functional composite materials in simultaneous enrichment of glycopeptides and phosphopeptides.

Glycosylation and phosphorylation of proteins represent crucial forms of post-translational modifications (PTMs), playing pivotal roles in various biological processes. Research indicates a strong correlation between the development of type 2 diabetes (T2D) and abnormal protein translation in the body. Therefore, studying glycosylation and phosphorylation at the molecular level can be used for monitoring disease progression and refining research methodologies. In this study, the material is modified and functionally engineered by utilizing graphene oxide (GO) as the substrate, and incorporating titanium ions (Ti4+) into chondroitin sulfate. The composite was successfully applied to the selective enrichment of glycopeptides and phosphopeptides by utilizing the bifunctionality of hydrophilic interaction chromatography and metal ion chelation chromatography. This approach allowed for the capture of 57 glycopeptides and 2 phosphopeptides from normal human serum, and 141 glycopeptides and 10 phosphopeptides from T2D serum, respectively. This approach effectively tackles the challenges of detecting low-abundance glycopeptides and phosphopeptides in complex environments, enabling the successful capture from serum samples. The design and application of this material provide new insights into the development of PTMs and their connection to the study of T2D diabetes.

17ß-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation.

Benign prostatic hyperplasia (BPH) is one of the major chronic complications of type 2 diabetes mellitus (T2DM), and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH. The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients, including simple BPH patients, newly diagnosed T2DM patients, T2DM complicated with BPH patients and matched healthy individuals. The G protein-coupled estrogen receptor (GPER) inhibitor G15, GPER knockdown lentivirus, the YAP1 inhibitor verteporfin, YAP1 knockdown/overexpression lentivirus, targeted metabolomics analysis, and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH. The homeostasis of sex steroid hormone is disrupted in the serum of patients, accompanying with the proliferated prostatic epithelial cells (PECs). The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals. Elevated 17ß-estradiol (E2) is the key contributor to the disrupted sex steroid hormone homeostasis, and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH. Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose (HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer. Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells. The anti-proliferative effects of verteporfin, an inhibitor of YAP1, are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells. Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

Clustered ultra-small iron oxide nanoparticles as potential T1/T2dual-modal magnetic resonance imaging contrast agents and application to tumor model.

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many -COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r1= 3.9 s‒1mM‒1and high r2/r1ratio of 14.6. Their ability to function as a dual-modal T1/T2MRI-CA in T1-weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T1-weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor. .

Key biomarkers in type 2 diabetes patients: A systematic review.

Type 2 diabetes mellitus (T2DM) is not just a local health issue but a significant global health burden, affecting patient outcomes and clinical management worldwide. Despite the wealth of studies reporting T2DM biomarkers, there is an urgent need for a comparative review. This review aims to provide a comprehensive analysis based on the reported T2DM biomarkers and how these are linked with other conditions, such as inflammation and wound healing. A comparative review was conducted on 24 001 study participants, including 10 024 T2DM patients and 13 977 controls (CTL; age 30-90 years). Four main profiles were extracted and analysed from the clinical reports over the past 11 years: haematological (1084 cases vs. 1458 CTL), protein (6753 cases vs. 9613 CTL), cytokine (975 cases vs. 1350 CTL) and lipid (1212 cases vs. 1556 CTL). This review provides a detailed analysis of the haematological profile in T2DM patients, highlighting fundamental changes such as increased white blood cells and platelet counts, accompanied by decreases in red blood cell counts and iron absorption. In the serum protein profile, a reduction in albumin and anti-inflammatory cytokines was noted along with an increase in globulin levels and pro-inflammatory cytokines. Furthermore, changes in lipid profiles were discussed, specifically the decreases in high-density lipoprotein (HDL) and the increases in low-density lipoprotein (LDL) and triglycerides. Understanding the changes in these four biomarker profiles is essential for developing innovative strategies to create diagnostic and prognostic tools for diabetes management.

Enhancement of Subcutaneous Islet Transplant Performance by Collagen 1 Gel.

Human islets can be transplanted into the portal vein for T1 diabetes, and a similar procedure is being used in a clinical trial for stem cell-derived beta-like cells. Efforts have been underway to find an alternative transplant site that will foster better islet cell survival and function. Although conceptually attractive, the subcutaneous (SC) site has yielded disappointing results, in spite of some improvements resulting from more attention paid to vascularization and differentiation factors, including collagen. We developed a method to transplant rat islets in a disk of type 1 collagen gel and found improved efficacy of these transplants. Survival of islets following transplantation (tx) was determined by comparing insulin content of the graft to that of the pre-transplant islets from the same isolation. At 14 days after transplantation, grafts of the disks had more than double the recovered insulin than islets transplanted in ungelled collagen. SC grafts of disks had similar insulin content to grafts in a kidney site and in epididymal fat pads. In vivo disks underwent contraction to 10% of initial volume within 24 h but the islets remained healthy and well distributed. Whole mount imaging showed that residual donor vascular cells within the islets expanded and connected to ingrowing host blood vessels. Islets (400 rat islet equivalents (IEQ)) in the collagen disks transplanted into an SC site of NOD scid IL2R gammanull (NSG) mice reversed streptozotocin (STZ)-induced diabetes within 10 days as effectively as transplants in the kidney site. Thus, a simple change of placing islets into a gel of collagen 1 prior to transplantation allowed a prompt reversal of STZ-induced diabetes using SC site.

Enhancing Variant Calling in Whole-Exome Sequencing Data Using Population-Matched Reference Genomes.

Whole-exome sequencing (WES) data are frequently used for cancer diagnosis and genome-wide association studies (GWAS), based on high-coverage read mapping, informative variant calling, and high-quality reference genomes. The center position of the currently used genome assembly, GRCh38, is now challenged by two newly published telomere-to-telomere (T2T) genomes, T2T-CHM13 and T2T-YAO, and it becomes urgent to have a comparative study to test population specificity using the three reference genomes based on real case WES data. Here we report our analysis along this line for 19 tumor samples collected from Chinese patients. The primary comparison of the exon regions among the three references reveals that the sequences in up to ∼ 1% target regions in T2T-YAO are widely diversified from GRCh38 and may lead to off-target in sequence capture. However, T2T-YAO still outperforms GRCh38 genomes by obtaining 7.41% more mapped reads. Due to more reliable read-mapping and closer phylogenetic relationship with the samples than GRCh38, T2T-YAO reduces half of variant calls of clinical significance which are mostly benign, while maintaining sensitivity in identifying pathogenic variants. T2T-YAO also outperforms T2T-CHM13 in reducing calls of Chinese-specific variants. Our findings highlight the critical need for employing population-specific reference genomes in genomic analysis to ensure accurate variant analysis and the significant benefits of tailoring these approaches to the unique genetic backgrounds of each ethnic group.

Diffusion MRI is superior to quantitative T2-FLAIR mismatch in predicting molecular subtypes of human non-enhancing gliomas.

PURPOSE: This study compared the classification performance of normalized apparent diffusion coefficient (nADC) with percentage T2-FLAIR mismatch-volume (%T2FM-volume) for differentiating between IDH-mutant astrocytoma (IDHm-A) and other glioma molecular subtypes. METHODS: A total of 105 non-enhancing gliomas were studied. T2-FLAIR digital subtraction maps were used to identify T2FM and T2-FLAIR non-mismatch (T2FNM) subregions within tumor volumes of interest (VOIs). Median nADC from the whole tumor, T2FM, and T2NFM subregions and %T2FM-volume were obtained. IDHm-A classification analyses using receiver-operating characteristic curves and multiple logistic regression were performed in addition to exploratory survival analyses. RESULTS: T2FM subregions had significantly higher nADC than T2FNM subregions within IDHm-A with ≥ 25% T2FM-volume (P < 0.0001). IDHm-A with ≥ 25% T2FM-volume demonstrated significantly higher whole tumor nADC compared to IDHm-A with < 25% T2FM-volume (P < 0.0001), and both IDHm-A subgroups demonstrated significantly higher nADC compared to IDH-mutant oligodendroglioma and IDH-wild-type gliomas (P < 0.05). For classification of IDHm-A vs. other gliomas, the area under curve (AUC) of nADC was significantly greater compared to the AUC of %T2FM-volume (P = 0.01, nADC AUC = 0.848, %T2FM-volume AUC = 0.714) along with greater sensitivity. In exploratory survival analyses within IDHm-A, %T2FM-volume was not associated with overall survival (P = 0.2), but there were non-significant trends for nADC (P = 0.07) and tumor volume (P = 0.051). CONCLUSION: T2-FLAIR subtraction maps are useful for characterizing IDHm-A imaging characteristics. nADC outperforms %T2FM-volume for classifying IDHm-A amongst non-enhancing gliomas with preserved high specificity and increased sensitivity, which may be related to inherent diffusivity differences regardless of T2FM. In line with previous findings on visual T2FM-sign, quantitative %T2FM-volume may not be prognostic.

Computational Drug Design Approaches for the Identification of Novel Antidiabetic Compounds from Natural Resources through Molecular Docking, ADMET, and Toxicological Studies.

Type 2 diabetes mellitus (T2DM) is usually depicted by relative insulin deficiency, raised blood glucose levels, and the predominant risk factor, insulin resistance. Hence, the development of insulin sensitizer drugs targeting PPAR-γ receptors has expanded enormous interest as an attractive choice for T2DM treatment. Thiazolidinediones (TZD) enhance insulin sensitivity either by directly functioning on gene transcription of the PPARγ receptor related to glucose homeostasis or by systemic sensitization of insulin and, therefore, improved hyperglycemia in a wide range of patients. However, severe complications and adverse effects of TZDs necessitate the development of an efficacious and reliable insulin sensitizer from alternative resources. On the contrary, Nature is a rich source of anticipated effective and safer medicine; more than fifty percent of drugs on the market are developed from natural products. Hence, searching for a new PPAR-γ agonist from bioactive secondary compounds of medicinal plants along with greater efficacy and safety is a recognized and consistent tactic for developing novel antidiabetic agents. Pulicaria jaubertii is a fragrant perennial aromatic plant with anti-inflammatory, antidiabetic, antimicrobial, antimalarial, and insecticidal properties. The current study was designed to use a computer-aided drug design to explore the best antidiabetic compounds from P. jaubertii. Herein, the molecular docking study of 80 investigated ligands against the PPAR-γ receptor identifies the highest docking score for five ligands ranging from -8.9 kcal/mol to 8.0 kcal/mol, which is also more significant than the standard drug pioglitazone (-7.7 kcal/mol) determined by the PyRx 8.0 virtual screening software. GLN286, CYS285, SER289, TYR473, MET364, ARG288, ILE341, and LEU333 residues are found to be significant contributors to the non-bonded interaction between ligands and receptors. Molecular electrostatic potential (MEP), DFT, molecular orbital (MO), ADMET, and toxicological analyses were performed on the selected five high-scored ligands of P. jaubertii. Results documented that all investigated ligands, especially L4, show considerably excellent profiles in molecular docking, MEP, DFT, MO, ADMET, and toxicological predictions, suggesting our drug-designing approaches may contribute to the development of a novel antidiabetic drug for the treatment of T2DM from natural resources.

The joint effect of cumulative metabolic parameters on the risk of type 2 diabetes: a population-based cohort study.

BACKGROUND AND AIMS: This study aimed to examine the cumulative effects of body mass index (BMI), body roundness index (BRI), pulse pressure (PP), triglycerides (TG), high-density lipoprotein cholesterol (HDL) and fasting plasma glucose (FPG) on Type 2 diabetes (T2D) morbidity. METHODS: A total of 78,456 participants aged older than 45 years were extracted from basic public health services in China. During the 2-year follow-up, 6,942 individuals had developed T2D. The binary logistic regression models and multinomial logistic regression models were conducted to investigate the effects of cumulative metabolic parameters on incident T2D, prediabetes regression and progression. RESULTS: We found statistically deleterious impacts of exposure to high cumulative BMI, BRI, PP, TG and low cumulative HDL on T2D morbidity and prediabetes progression. Compared to the group with low cumulative of all five parameters, the adjusted ORs for new-onset T2D for participants presenting with 1-2, 3, and 4-5 elevated metabolic parameters were 1.41(1.31,1.52), 1.93(1.74,2.13) and 2.21(1.94,2.51), respectively. There was additive interaction between FPG level and cumulative metabolic parameters with T2D. Compared with participants with the lowest quartile of FPG and low cumulative of all 5 parameters, those with the highest quartile of FPG and high cumulative of 4-5 parameters had a 14.63 [95% CI (12.27, 17.42)] higher risk of incident T2D. CONCLUSIONS: Participants with more numbers of high-cumulative metabolic parameters were associated with a higher risk of incident T2D and prediabetes progression. A high level of normal FPG could enhance these risks.

The burden of type 2 diabetes attributable to dietary risks in China: Insights from the global burden of disease study 2021.

OBJECTIVES: This study aims to comprehensively assess how dietary risk factors have influenced the prevalence of Type 2 Diabetes Mellitus (T2DM) in China from 1990 to 2021. The study seeks to provide robust data and scientific evidence essential for formulating effective preventive and control strategies to combat T2DM in China. STUDY DESIGN: This cross-sectional study conducted secondary analyses using data from the Global Burden of Disease 2021 (GBD 2021) to assess the burden of T2DM in China attributable to dietary risks. METHODS: The study analyzed age-adjusted metrics related to T2DM, including death counts, Disability-Adjusted Life Years (DALYs), and Age-Standardized Rates (ASRs), using GBD 2021 data, stratified by age and sex. Additionally, Estimated Annual Percentage Changes (EAPCs) were employed to track trends over time. RESULTS: In 2021, the results show that 21.43 % of T2DM-related deaths and 23.51 % of DALYs were attributable to dietary risk factors, notably a diet low in whole grains and high in red and processed meats. Over the period from 1990 to 2021, there has been an increasing trend in the EAPCs of death rates and DALYs associated with dietary risks in China, suggesting a substantial impact of dietary factors on the burden of T2DM in the country. CONCLUSION: This study highlights the urgent need for targeted public health interventions to promote dietary changes and reduce the burden of T2DM in China.

Assessing the accuracy of CMRtools software for diagnosing liver iron overload in thalassemia patients: influencing factors and optimisation strategies.

Background: CMRtools is a software package that can be used to measure T2* values to diagnose liver iron overload, however, its accuracy in terms is affected by multiple factors, including goodness-of-fit (R2 value), the number of echo time (TE) images, and the liver iron concentration (LIC). To investigate the effects of the R2 value, the number of TE images, and the LIC on the accuracy of CMRtools software for measuring T2* values to diagnose liver iron overload (LIO). Materials and methods: CMRtools software was used to measure liver T2* values among 108 thalassemia patients via the truncation method, and the R2 values, the number of TE images, and T2* values were recorded. These values were subsequently converted into liver iron concentration (LICT) values. The LICF (derived from MRI-R2/FerriScan) was used as a reference, and the diagnostic accordance rate (DAR) was compared between R2 value subgroups, between TE image number subgroups, and between LIC subgroups. Results: The greater the R2 value was, the greater the standardized DAR (SDAR) was (p < 0.05). The SDAR are not identical between each TE image number subgroup (p > 0.05). However, the relationship between TE image number subgroups and SDAR was analysed using Spearman's correlation, and it was found to be positively correlated (rs = 0.729, p = 0.017). The SDAR are not identical between each LIC subgroup (p > 0.05), furthermore, the relationship between LIC subgroup and SDAR was found irrelevant (p = 0.747). Conclusion: The accuracy of CMRtools software for diagnosing LIO in patients with thalassemia can be improved by artificially controlling the number of TE images to be fitted and selecting higher R2 values.

Exploring the design of clinical research studies on the efficacy mechanisms in type 2 diabetes mellitus.

This review examines the complexities of Type 2 Diabetes Mellitus (T2DM), focusing on the critical role of integrating omics technologies with traditional experimental methods. It underscores the advancements in understanding the genetic diversity of T2DM and emphasizes the evolution towards personalized treatment modalities. The paper analyzes a variety of omics approaches, including genomics, methylation, transcriptomics, proteomics, metabolomics, and intestinal microbiomics, delineating their substantial contributions to deciphering the multifaceted mechanisms underlying T2DM. Furthermore, the review highlights the indispensable role of non-omics experimental techniques in comprehending and managing T2DM, advocating for their integration in the development of tailored medicine and precision treatment strategies. By identifying existing research gaps and suggesting future research trajectories, the review underscores the necessity for a comprehensive, multidisciplinary approach. This approach synergistically combines clinical insights with cutting-edge biotechnologies, aiming to refine the management and therapeutic interventions of T2DM, and ultimately enhancing patient outcomes. This synthesis of knowledge and methodologies paves the way for innovative advancements in T2DM research, fostering a deeper understanding and more effective treatment of this complex condition.

Evaluating Blood Pressure Variability in Type 2 Diabetic Patients: An Insight into Non-Dipping Patterns and Their Clinical Implications.

Background: Hypertension (HTN) is prevalent in individuals with type 2 Diabetes Mellitus (T2DM), doubling the risk of developing chronic complications. Despite normal routine checks, many patients with diabetes exhibit abnormal blood pressure (BP) profiles identified by 24-hour ambulatory Blood Pressure monitoring (ABPM). This study aimed to analyse blood pressure variability in patients with diabetes to enhance current knowledge and improve clinical practice. Methods: This cross-sectional study obtained ethical approval from Jazan University and involved 58 patients with type 2 Diabetes Mellitus (T2DM) who adhered to the strict inclusion and exclusion criteria. Comprehensive clinical and laboratory data, including demographic, clinical, and essential laboratory parameters, were collected using a standardized form. Blood Pressure (BP) was meticulously monitored using the Sun Tech Oscar 2 ABPMR device, with measurements commencing between 8 am and 10 am, extending over 24 hours. The study calculated averages and evaluated systolic and diastolic percentage dipping during 24-hour, daytime, and night-time intervals. Participants classified as "dippers" experienced a BP reductions of at least 10%. Results: Fifty-eight normotensive T2DM patients, with a mean age of 45.51 ± 6.7 years, were monitored over 24 months. Among the 58 individuals assessed using ABPM, a non-dipping pattern was observed in 45 participants (77.58%), whereas 13 (22.41%) exhibited a dipping pattern. Postprandial and fasting blood sugar levels were distinct; the dipper group demonstrated better post-meal glucose control (p=0.02), whereas the non-dipper group had superior fasting glucose control (p=0.04). The dipper group showed a higher 24-hour average systolic BP (p=0.00) and increased dipping percentages for systolic and diastolic BP during sleep. Conclusion: Over 77% of ABPM-evaluated individuals showed non-dipping patterns, with a higher BMI being strongly associated. Laboratory findings revealed distinct variations in the postprandial and fasting blood sugar levels, suggesting a potential genetic predisposition.

Androgens have therapeutic potential in T2 asthma by mediating METTL3 in bronchial epithelial cells.

Studies have shown that androgens can alleviate the symptoms of T2 asthma and are inversely correlated with the severity of allergic asthma. METTL3, a crucial component of m6A modification, mitigates the development of T2 asthma by inhibiting Th2 cell differentiation. However, the impact of androgens, such as dihydrotestosterone (DHT), on the progression of T2 asthma through METTL3 has yet to be investigated. At the clinical level, patients with T2 asthma exhibited reduced levels of DHT and METTL3 mRNA, along with increased levels of 17ß-estradiol (E2). DHT and METTL3 were found to be negatively associated with the severity of T2 asthma, while E2 was positively associated with it. Administration of DHT and E2 in induced T2 asthma mouse models showed that DHT improved lung function, reduced airway inflammation, and inhibited Th2 cell differentiation. Interestingly, DHT reversed the damage to METTL3, whereas E2 had the opposite effect. In vitro studies of mouse bronchial epithelial cells (BECs) confirmed that METTL3-dependent m6A modification inhibited the T2 inflammatory response, and DHT inhibited Th2 cell differentiation in T2 asthma by promoting METTL3 expression in BECs. In conclusion, our study suggests that DHT has therapeutic potential for T2 asthma by regulating METTL3 in BECs.

The built environment and its association with type 2 diabetes mellitus incidence: A systematic review and meta-analysis of longitudinal studies.

This study aimed to systematically review longitudinal studies examining associations between the incidence of type 2 diabetes mellitus (T2DM) and built environmental factors. This review adhered to the 2020 PRISMA guidelines. Longitudinal studies examining associations between T2DM incidence and built environmental features were eligible. Built environment constructs corresponded to the following themes: 1) Walkability - factors such as sidewalks/footpaths, crosswalks, parks, and density of businesses and services; (2) Green/open space - size, greenness, and type of available public outdoor spaces; (3) Food environment - ratio of healthful food outlets (e.g., greengrocers, butchers, supermarkets, and health food shops) to unhealthful food outlets (e.g., fast-food outlets, sweet food retailers, and convenience stores). Five databases (e.g., Medline) were searched from inception until July 2023. Qualitative and quantitative synthesis were used to summarise key findings, including a meta-analysis of adjusted Hazard Ratios (aHR). Of 3,343 articles, 16 longitudinal studies from seven countries, published between 2015 and 2023, involving 13,403,902 baseline participants (median of 83,898), were included. In four of the five studies, unhealthful food environment was significantly associated with higher incident T2DM. Five of seven greenspace studies and two of four walkability studies showed that greater greenery and greater walkability were statistically significantly associated with lesser incident T2DM. In pooled analyses, greater T2DM incidence was associated with unhealthful relative to healthful food environments (pooled HR: 1.21; 95% CI: 1.04, 1.42), and T2DM incidence was inversely associated with green/open space environments (pooled HR: 0.82; 95% CI: 0.74, 0.92). Greater walkability was associated with a slight 2% lesser incidence of T2DM (pooled HR: 0.98; 95% CI: 0.98, 0.99). This review underscores consistency in the nature of associations between built environment features related to T2DM. We observed statistically significant inverse or "protective" associations between T2DM and walkability and healthful food environments. These results support calls for policies and guidelines that promote healthful food environments and walkability.

Potential involvement of connective tissue growth factor in chondrocytes apoptosis of Kashin-Beck disease.

BACKGROUND: Kashin-Beck disease (KBD) is an endemic osteoarthropathy characterized by excessive chondrocytes apoptosis. T-2 toxin exposure has been proved to be its etiology. Connective tissue growth factor (CTGF) exerts a profound influence on cartilage growth and metabolism. We investigated the potential role of CTGF in KBD development and examined CTGF alterations under T-2 toxin stimulation. METHODS: The levels of CTGF and chondrocyte apoptosis-related markers in cartilage and primary chondrocytes from KBD and control groups were measured using qRT-PCR, Western blotting, immunohistochemistry, and immunofluorescence. We analyzed expression changes of these genes in response to T-2 toxin. Apoptosis rates of chondrocytes induced by T-2 toxin were measured by flow cytometry and TUNEL assay. The active pharmaceutical ingredient targeting CTGF was screened through Comparative Toxicogenomics Database, and molecular docking was performed using AutoDock Tools. RESULTS: The CTGF levels in KBD cartilage and chondrocytes were significantly elevated and positively associated with the levels of apoptosis-related genes. T-2 toxin exposure increased CTGF and apoptosis-related gene levels in chondrocytes, with apoptosis rates rising alongside T-2 toxin concentration. Curcumin was identified as targeting CTGF and exhibited effective binding. It could down-regulate CTGF, apoptosis-related genes, such as Cleaved caspase 3 and BAX, and also significantly reduce apoptosis rate in chondrocytes treated with T-2 toxin. CONCLUSION: CTGF plays a crucial role in the development of KBD. Curcumin has shown potential in inhibiting CTGF levels and reducing chondrocyte apoptosis, highlighting its promise as a therapeutic agent for preventing cartilage damage in KBD. Our findings provided valuable insights into the pathogenesis of KBD and could promote the development of novel therapeutic strategies for this debilitating disease.

In vivo and In silico Insights into the Anti-Diabetic Efficacy of EVOO and Hydroxytyrosol in a Rat Model.

Extra virgin olive oil (EVOO) has a putative antidiabetic activity mostly attributed to its polyphenol hydroxytyrosol. In this study, we explored the antidiabetic effects of EVOO and hydroxytyrosol on an in vivo T2D-simulated rat model as well as in in silico study. Wistar rats were divided into four groups. The first group served as a normal control (NC), while type 2 diabetes (T2D) was induced in the remaining groups using a high-fat diet (HFD) for 12 weeks followed by a single dose of streptozotocin (STZ, 30 mg/kg). One diabetic group remained untreated (DC), while the other two groups received an eight-week treatment with either EVOO (90 g/kg of the diet) (DO) or hydroxytyrosol (17.3 mg/kg of the diet) (DH). The DC group exhibited hallmark features of established T2D, including elevated fasting blood glucose levels, impaired glucose tolerance, increased HOMA-IR, widespread downregulation of insulin receptor expression, heightened oxidative stress, and impaired ß-cell function. In contrast, treatments with EVOO and hydroxytyrosol elicited an antidiabetic response, characterized by improved glucose tolerance, as indicated by accelerated blood glucose clearance. Systematic analysis revealed the underlying antidiabetic mechanisms: both treatments enhanced insulin receptor expression in the liver and skeletal muscles, increased adiponectin levels, and mitigated oxidative stress. Moreover, while EVOO reduced intramyocellular lipids, hydroxytyrosol restored adipose tissue insulin sensitivity and enhanced ß-cell survival. Molecular docking and dynamics confirm hydroxytyrosol's high affinity binding to PGC-1α, IRE-1α, and PPAR-γ, particularly IRE-1α, highlighting its potential to modulate diabetic signaling pathways. Collectively, these mechanisms highlight the putative antidiabetic role of EVOO and hydroxytyrosol. Moreover, the favorable docking scores of hydroxytyrosol with PGC-1α, IRE-1α, and PPAR-γ support the antidiabetic potential and offer promising avenues for further research and the development of novel antidiabetic therapies.