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Empagliflozin (EMPA) is an SGLT-2 inhibitor that can control hyperglycemia. Clinical trials have indicated its cardio-protective effects against cardiac remodeling in diabetes or non-diabetes patients. However, the underlying molecular mechanisms of EMPA's cardio-protective effects remain elusive. We evaluated whether the EMPA attenuated the pressure-overload-induced cardiac hypertrophy by inhibiting the Wnt/β-catenin pathway. Furthermore, the effects of the EMPA on a mouse model of transverse aortic constriction (TAC) induced cardiac hypertrophy was also evaluated. Mice were administrated with 0.5% CMC-Na as a vehicle or EMPA (10 mg/kg/day, daily, throughout the study) by intragastric gavage. The echocardiography and histologic morphological analyses revealed that EMPA attenuated TAC-induced cardiac hypertrophy. Moreover, it also ameliorated TAC-induced cardiac fibrosis and decreased the cell size of the cardiomyocytes in isolated adult cardiomyocytes. Molecular mechanism analysis revealed that the EMPA reduced the TAC-induced enhanced expression of the Wnt/β-catenin pathway . For assessments, isolated neonatal rat cardiomyocytes (NRCMs) were treated with Angiotensin II (AngII) and EMPA; the results showed that in the absence of EMPA, the expression of the Wnt/β-catenin pathway was enhanced. In the trans-genetic heterozygous β-catenin deletion mice, EMPA attenuated TAC-induced cardiac remodeling by reducing the Wnt/β-catenin pathway. In addition, molecular docking analysis indicated that EMPA interacts with FZD4 to inhibit the TAC and AngII induced Wnt/β-catenin pathway in cardiomyocytes. Our study illustrated that EMPA might directly interact with FZD4 to inhibit the TAC and AngII-induced activation of the Wnt/β-catenin pathway to attenuate the adverse cardiac remodeling.

Aims. To investigate the distribution of diabetic retinopathy (DR) by sex in patients with type 2 diabetes mellitus (T2DM) in a twelve-province cross-sectional study in China. Methods. Patients with T2DM, whose ages were ≥18 years, were recruited from 76 cities/counties in 12 provinces in mainland China between January 2015 and December 2018. All participants received a standardized interview, eye examinations, and digital fundus photography. The presence and severity of DR were diagnosed and classified by retina specialists according to the DR domestic typing method. Results. A total of 12,766 participants (5963 males and 6803 females) were eligible for this study. The total prevalence of DR was 30.1%. Females exhibited a significantly higher prevalence of DR than males (31.1% vs. 29.0%, P=0.011). A multivariate logistic regression analysis confirmed that female sex was an independent predictor for a higher prevalence of DR after adjusting for age, the duration of diabetes, economic status, and the presence of hypertension (OR: 1.096, 95% CI: 1.013-1.186, P=0.023). Even after stratification by the diabetic duration, age, and economic status, female sex was still independently associated with the presence of DR in patients whose T2DM history was more than 10 years, whose ages were over 60 years, or who were in a relatively intermediate economic area. Conclusion. Females had a higher prevalence of DR than males in T2DM patients with a diabetic history of more than 10 years, ages over 60 years, or a relatively intermediate economic status.

Background To develop a predictive nomogram for breast cancer lympho-vascular invasion (LVI), based on digital breast tomography (DBT) data obtained from intra- and peri-tumoral regions. Methods One hundred ninety-two breast cancer patients were enrolled in this retrospective study from 2 institutions, in which Institution 1 served as the basis for training ( n  = 113) and testing ( n  = 49) sets, while Institution 2 served as the external validation set ( n  = 30). Tumor regions of interest (ROI) were manually-delineated on DBT images, in which peri-tumoral ROI was defined as 1 mm around intra-tumoral ROI. Radiomics features were extracted, and logistic regression was used to construct intra-, peri-, and intra- + peri-tumoral radiomics models. Patient clinical data was analyzed by both uni- and multi-variable logistic regression analyses to identify independent risk factors for the non-radiomics clinical imaging model, and the combination of both the most optimal radiomics and clinical imaging models comprised the comprehensive model. The best-performing model out of the 3 types (radiomics, clinical imaging, comprehensive) was identified using receiver operating characteristic (ROC) curve analysis, and used to construct the predictive nomogram. Results The most optimal radiomics model was the intra- + peri-tumoral model, and 3 independent risk factors for LVI, maximum tumor diameter (odds ratio [OR] = 1.486, 95% confidence interval [CI] = 1.082–2.041, P  = 0.014), suspicious malignant calcification (OR = 2.898, 95% CI = 1.232 ~ 6.815, P  = 0.015), and axillary lymph node (ALN) metastasis (OR = 3.615, 95% CI = 1.642–7.962, P  < 0.001) were identified by the clinical imaging model. Furthermore, the comprehensive model was the most accurate in predicting LVI occurrence, with areas under the curve (AUCs) of 0.889, 0.916, and 0.862, for, respectively, the training, testing and external validation sets, compared to radiomics (0.858, 0.849, 0.844) and clinical imaging (0.743, 0.759, 0.732). The resulting nomogram, incorporating radiomics from the intra- + peri-tumoral model, as well as maximum tumor diameter, suspicious malignant calcification, and ALN metastasis, had great correspondence with actual LVI diagnoses under the calibration curve, and was of high clinical utility under decision curve analysis. Conclusions The predictive nomogram, derived from both radiomics and clinical imaging features, was highly accurate in identifying future LVI occurrence in breast cancer, demonstrating its potential as an assistive tool for clinicians to devise individualized treatment regimes.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes 1 , 2 . Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized 3 – 6 . Here we define a critical role of IL-27–IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK–PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy. Therapeutic administration of IL-27—serum levels of which are decreased in individuals with obesity—improves thermogenesis, protects against diet-induced obesity and ameliorates insulin resistance in mouse models of obesity.

This study is aimed at exploring the value of a high-resolution vessel wall imaging (HR-VWI)-based radiomics approach for identifying symptomatic basilar atherosclerotic plaques. This retrospective study included 154 patients, hospitalized at Shanxi Cardiovascular Hospital for cerebrovascular disease, who had basilar artery stenosis and underwent HR-VWI examinations between July 2020 and December 2023. The patients were randomly divided into training and validation sets in a 7:3 ratio and further classified into symptomatic and asymptomatic groups based on the presence or absence of acute infarction lesions in the basilar artery supply area, respectively. Clinical and traditional imaging features were collected for all patients. Manual plaque segmentation and radiomics feature extraction were performed on the layers of basilar artery plaques identified in the plain-scanning and enhanced HR-VWI images. Feature denoising was performed using minimum redundancy maximum correlation, and the least absolute shrinkage and selection operator (LASSO) algorithm was applied to reduce feature variables. The most suitable features were selected through univariate and multivariate logistic regression analyses. The plain-scanning, enhanced, and plain - scanning + enhanced models were established. Finally, a combined model was constructed by integrating selected clinical and traditional imaging features (intraplaque hemorrhage [IPH], enhanced plaque signal) with the plain - scanning + enhanced HR - VWI radiomics features. The recognition efficiency of each model for symptomatic basilar atherosclerotic plaques was evaluated using the receiver operating characteristic (ROC) curve and the area under the receiver operating characteristic curve (AUC). A statistically significant difference in age was observed between symptomatic and asymptomatic groups (p < 0.05). Conventional imaging features, including IPH, vessel diameter at stenosis, lumen area at stenosis, enhanced plaque signal, stenosis rate, and plaque load, also demonstrated statistically significant differences between the two groups (p < 0.05). Firth-penalized logistic regression analysis identified IPH and enhanced plaque signal as risk factors for symptomatic basilar artery plaques. In the training set, the AUC values for detecting symptomatic plaques were 0.813, 0.853, and 0.898 for plain-scanning, enhanced, and plain - scanning + enhanced models, respectively. In the validation set, the AUC values were 0.786, 0.848, and 0.880, respectively. The efficacy of models was in the order of plain - scanning + enhanced model > enhanced model > plain - scanning model. The combined model, integrating IPH and enhanced plaque signal with the plain - scanning + enhanced HR - VWI radiomics features, achieved an AUC of 0.916 in the training set, with sensitivity, specificity, and accuracy of 0.821, 0.941, and 0.879, respectively, for predicting symptomatic basilar artery plaques. In the validation set, the AUC value was 0.891, with sensitivity, specificity, and accuracy of 0.792, 0.870, and 0.830, respectively. The combined model demonstrated superior performance compared with the plain - scanning + enhanced model. Our HR-VWI-based radiomics models can accurately distinguish symptomatic from asymptomatic basilar atherosclerotic plaques. It is superior to the traditional model in the identification of high-risk plaques.

Flooding stress, including waterlogging and submergence, is one of the major abiotic stresses that seriously affects the growth and development of plants. In the present study, physiological, epigenetic, and transcriptomic analyses were performed in wheat seedling leaves under waterlogging (WL), half submergence (HS), and full submergence (FS) treatments. The results demonstrate that FS increased the leaves’ hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents and reduced their chlorophyll contents (SPAD), photosynthetic efficiency (Fv/Fm), and shoot dry weight more than HS and WL. In addition, FS increased catalase (CAT) and peroxidase (POD) activities more than HS and WL. However, there were no significant differences in the contents of H2O2, MDA, SPAD, and Fv/Fm, and the activities of superoxide dismutase (SOD) and POD between the HS and WL treatments. The changes in DNA methylation were related to stress types, increasing under the WL and HS treatments and decreasing under the FS treatment. Additionally, a total of 9996, 10,619, and 24,949 genes were differentially expressed under the WL, HS, and FS treatments, respectively, among which the ‘photosynthesis’, ‘phenylpropanoid biosynthesis’, and ‘plant hormone signal transduction’ pathways were extensively enriched under the three flooding treatments. The genes involved in these pathways showed flooding-type-specific expression. Moreover, flooding-type-specific responses were observed in the three conditions, including the enrichment of specific TFs and response pathways. These results will contribute to a better understanding of the molecular mechanisms underlying the responses of wheat seedling leaves to flooding stress and provide valuable genetic and epigenetic information for breeding flood-tolerant varieties of wheat.

Gestational diabetes mellitus (GDM), a prevalent prenatal metabolic disorder characterized by hyperglycemia occurring in approximately 9.2% of pregnancies globally, imposes significant cardiovascular risks on offspring, including developmental cardiac hypertrophy and long-term functional impairment. Despite its clinical importance, the molecular mechanisms governing GDM-induced cardiac malformations remain elusive. This study aimed to delineate the regulatory role of the Wnt/β-catenin/Tcf7l2 signaling pathway in mediating pathological cardiac remodeling in GDM-exposed offspring through experimental manipulation using a clinically relevant murine model. We established a clinically relevant GDM mouse model exhibiting key metabolic features including hyperinsulinemia and impaired glucose tolerance, which faithfully recapitulates human GDM pathology. Cardiomyocyte-specific β-catenin knockout and cardiomyocyte-specific overexpression of constitutively active β-catenin were employed for genetic manipulation. Pharmacological intervention was performed using saxagliptin, a clinically approved DPP-4 inhibitor. Cardiac phenotypes were evaluated by histopathological analysis, echocardiography, and molecular assessments of Wnt/β-catenin pathway activity and hypertrophic markers. Histopathological and echocardiographic analyses revealed pronounced cardiac hypertrophy in GDM-exposed offspring, concomitant with activation of the Wnt/β-catenin/Tcf7l2 pathway in myocardial tissues. Functional studies demonstrated that cardiomyocyte-specific β-catenin ablation attenuated GDM-induced hypertrophic remodeling, whereas constitutive β-catenin overexpression exacerbated cardiac dysfunction. Importantly, pharmacological intervention with saxagliptin significantly ameliorated cardiac hypertrophy in GDM-offspring. This therapeutic effect was paralleled by marked suppression of Wnt/β-catenin signaling activity and reduced expression of ANP. Collectively, these findings provide compelling evidence that dysregulation of the Wnt/β-catenin/Tcf7l2 pathway constitutes a critical mediator in GDM-induced cardiac hypertrophy, and highlight saxagliptin as a potential therapeutic strategy to mitigate adverse cardiac outcomes in GDM offspring.

Pioglitazone hydrochloride (PGZ), a nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a universally adopted oral agent for the treatment of type 2 diabetes (T2D). Previous studies reported that PGZ could ameliorate the symptoms of aging-related diseases and Alzheimer’s disease. However, whether PGZ participates in aging regulation and the underlying mechanism remain undetermined. Here, we found that PGZ significantly prolonged the lifespan and healthspan of Caenorhabditis elegans (C. elegans). We found that a variety of age-related pathways and age-related genes are required for PGZ-induced lifespan extension. The transcription factors DAF-16/FOXO, HSF-1, and SKN-1/NRF2, as well as the nuclear receptors DAF-12 and NHR-49, all functioned in the survival advantage conferred by PGZ. Moreover, our results demonstrated that PGZ induced lifespan extension through the inhibition of insulin/insulin-like signaling (IIS) and reproductive signaling pathways, as well as the activation of dietary restriction- (DR-) related pathways. Additionally, our results also indicated that beneficial longevity mediated by PGZ is linked to its antioxidative activity. Our research may provide a basis for further research on PGZ, as an anti-T2D drug, to interfere with aging and reduce the incidence of age-related diseases in diabetic patients.

Introduction Insulin degludec (degludec), an ultra-long-acting basal insulin analogue, provides equivalent glycemic control to other basal insulin analogues, with lower risk of hypoglycemia and flexible dosing. Chinese TREsiba AudiT (CN-TREAT) investigated outcomes with degludec in people with type 2 diabetes (T2D) in routine clinical practice in China. Methods This was a retrospective chart review study in adults with T2D initiating or switching to degludec at 50 sites in China between January 2020 and July 2021. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study (EOS; week 20). Secondary endpoints included change from baseline to EOS in fasting plasma glucose (FPG), self-measured plasma glucose (SMPG), daily insulin dose, and rate of hypoglycemia. Results Data from 936 participants were included (499 insulin-naïve; 437 insulin-experienced). Mean (95% confidence interval [CI]) HbA1c change from baseline to EOS was − 1.48%-points (− 1.57; − 1.38; P  < 0.0001) overall: − 1.95%-points (− 2.08; − 1.81; P  < 0.0001) in insulin-naïve participants and − 0.95%-points (− 1.08; − 0.82; P  < 0.0001) in insulin-experienced participants. Mean (95% CI) changes in FPG and SMPG were − 2.27 mmol/L (− 2.69; − 1.85; P  < 0.0001) and − 2.89 mmol/L (− 3.52; − 2.25; P  < 0.0001), respectively, with similar reductions in insulin-naïve and insulin-experienced subgroups. Rate of hypoglycemia did not change statistically significantly from baseline to EOS overall, or in insulin-experienced participants, except when adjusted for baseline hypoglycemia. Basal insulin dose did not change statistically significantly in insulin-experienced participants. Conclusion In routine clinical practice in China, initiation or switching to degludec was associated with improvements in glycemic control in people with T2D, with no increased risk of hypoglycemia. Trial Registration ClinialTrials.gov, NCT04227431.

Objective: To evaluate the effectiveness and safety of Shenyi Capsule (SC) combined with conventional anticancer therapies through a comprehensive assessment of systematic reviews/meta-analyses (SRs/MAs), identify limitations in current evidence, and provide evidence-based guide for clinical practice and research. Methods: Registered in PROSPERO (CRD42024573610), this study searched 8 Databases from inception to November 10, 2024. Two separate reviewers were responsible for selecting studies, collecting data, assessing quality, and evaluating the potential for bias, with this research incorporating only SRs/MAs based on randomized controlled trials and utilizing 4 tools (AMSTAR-2, PRISMA 2020, ROBIS, GRADE) to evaluate methodological quality and risk of bias. Results: Thirteen SRs/MAs were included, focusing on 4 cancer types. AMSTAR-2 evaluations revealed no high quality studies. Compliance with PRISMA 2020 guidelines was below 50% for most items, with major deficiencies including lack of protocol registration, incomplete abstracts and search strategies, inappropriate or missing risk-of-bias assessments, insufficient descriptions of data transformation methods, absence of heterogeneity and sensitivity analyses, and failure to report funding sources. ROBIS indicated high bias risk in 11 studies. GRADE assessment of 109 outcomes showed evidence quality as moderate (40.37%), low (34.86%), or very low (24.77%). Discussion: SC may enhance efficacy and safety as an adjuvant cancer therapy. However, methodological flaws in existing SRs/MAs limit reliability. Future research should prioritize standardized SR/MA protocols and RCT designs to improve evidence quality, reduce bias, and strengthen clinical applicability.