Acute myeloid leukemia (AML) is a highly heterogeneous disease, and molecular events such as DNMT3A gene mutations are associated with poor prognosis in AML patients. Consequently, there is an urgent need for a novel therapeutic approach for AML.

DNMT3A mRNA and protein expression were confirmed in DNMT3A-mutant AML cells via RT-qPCR and Western blotting. Cell proliferation and apoptosis were assessed via CCK-8 and Annexin V/PI staining, respectively. Flow cytometry was used to analyze surface antigens and CD44v6 CAR-T-cell transfection efficiency. CD44v6-directed CAR plasmids were constructed, and lentiviruses were packaged. Methylation-specific PCR was used to evaluate differences in promoter methylation, whereas ELISA was used to measure cytokine secretion.

In this study, we found that the DNMT3A-mutant group presented significantly increased expression of CD44v6 on the cell surface. Methylation of the CD44 promoter region was lower in the mutant group than in the control group. CD44v6 CAR-T cells exhibited specific cytotoxicity against DNMT3A-mutant AML cells. Furthermore, pretreatment with low concentrations of decitabine significantly enhanced the killing effect of CD44v6 CAR-T cells on DNMT3A-mutant AML cells (P < 0.05). Additionally, decitabine treatment upregulated the expression of CD44v6 on the surface of DNMT3A-mutant AML cells (P < 0.05).

CD44v6 is a promising CAR-T-cell therapy target in AML patients with DNMT3A mutations. Notably, treatment with decitabine resulted in increased CD44v6 expression on the cell surface of DNMT3A-mutant AML cells. This increase in CD44v6 expression facilitates improved recognition and targeting by CD44v6 CAR-T cells.

To develop a novel prognostic scoring system for severe cytokine release syndrome (CRS) in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 chimeric antigen receptor (CAR)-T-cell therapy, aiming to optimize risk mitigation strategies and improve clinical management.

This single-center retrospective cohort study included 125 B-ALL patients who received anti-CD19 CAR-T-cell therapy from January 2017 to October 2023. These cases were selected from a cohort of over 500 treated patients on the basis of the availability of comprehensive baseline data, documented CRS grading, and at least 3 months of follow-up. Data on patient demographics, treatment history, laboratory parameters, CAR-T-cell characteristics, safety, and efficacy endpoints were collected. CRS severity was graded according to the 2019 ASTCT consensus criteria. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with CRS severity, and a prognostic model was constructed.

The overall incidence of CRS was 67.2%, with 13.6% having grade ≥ 3 (severe) CRS. Higher baseline and post-lymphodepletion minimal residual disease (MRD) levels and neutropenia on day 7 post-infusion were significantly associated with severe CRS. Inflammatory markers (CRP, ferritin, and IL-6) and coagulation dysfunction (APTT) on day 7 post-infusion were also predictive of CRS severity. The prognostic model incorporating these factors demonstrated robust discriminatory ability, with an area under the ROC curve of 0.875.

This study developed a novel prognostic scoring system for severe CRS in Chinese B-ALL patients receiving anti-CD19 CAR-T-cell therapy. The model integrates clinical and laboratory parameters to facilitate early identification and management of severe CRS. Further validation in larger, prospective cohorts is warranted.

This study investigates the role of miR-144-5p in doxorubicin (DOX)-induced heart failure and explores its potential mechanisms by targeting ACSM1 and inhibiting lipid peroxidation.

Bioinformatics analysis was performed using the gene expression omnibus dataset GSE136547 to identify differentially expressed miRNAs in heart failure. DOX-induced in vitro and in vivo heart failure models were used to study the effects of miR-144-5p on cardiomyocyte viability, apoptosis, and lipid peroxidation. The targeting relationship between miR-144-5p and ACSM1 was verified using dual-luciferase reporter assays. Cardiac function was assessed by echocardiography, and biochemical markers of heart failure were measured using ELISA. The GO and KEGG enrichment analyses of ACSM1 were performed via the bioinformatic tools GeneMANIA and STRING.

miR-144-5p was significantly upregulated in DOX-treated cardiomyocytes and mouse hearts. Inhibition of miR-144-5p attenuated DOX-induced cardiomyocyte apoptosis, lipid peroxidation, and cardiac dysfunction. ACSM1 was identified as a direct target of miR-144-5p, and its expression was downregulated by DOX. Silencing ACSM1 abolished the protective effects of the miR-144-5p inhibitor on the viability, apoptosis, and lipid peroxidation of cardiomyocytes. Furthermore, miR-144-5p inhibition improved cardiac function in DOX-treated mice, as evidenced by reduced left ventricular dysfunction and decreased levels of heart failure markers (BNP, LDH, Ang II, and ALD).

Our findings demonstrate that inhibiting miR-144-5p alleviates DOX-induced heart failure by targeting ACSM1 and suppressing lipid peroxidation. The miR-144-5p/ACSM1 axis may represent a novel therapeutic target for heart failure. Future studies should focus on further elucidating the mechanisms underlying this axis and exploring its potential clinical applications.

Pulmonary arterial hypertension (PAH) poses a growing global health challenge, yet comprehensive epidemiological data remain limited. This study aims to assess the burden of PAH from 1990 to 2021 and project trends to 2040, addressing critical gaps in incidence, mortality, and disability-adjusted life years (DALYs) across diverse socio-demographic contexts.

Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed PAH burden across 204 countries and territories, stratified by age, sex, region, and socio-demographic index (SDI). Age-standardized rates (per 100,000 populations) for incidence (ASIR), mortality (ASMR), and DALYs (ASDR) were calculated. Future trends were projected via a Bayesian age-period-cohort (BAPC) model.

In 2021, there were 43,251 (95% uncertainty interval [UI]: 34,705, 52,441) global incident PAH cases (age standardized incidence rate [ASIR]: 0.52). From 1990 to 2021, PAH incidence rose by 85.62%, with the steepest increase in high-middle SDI regions (average annual percentage change [AAPC]: + 0.19%). Despite a 48.36% rise in deaths, the age-standardized mortality rate (ASMR) declined annually by 0.84%, reflecting improved management. Central Europe had the highest ASMR (1.06 per 100,000), while low SDI regions showed reduced ASIR (−0.31% AAPC), likely due to underdiagnosis. PAH caused 642,104 DALYs globally in 2021, with infants (< 1 year) bearing the highest DALY rate. Projections indicate 75,000 annual cases by 2040, emphasizing an escalating burden.

PAH burden is increasing disproportionately in aging populations and high-middle SDI regions, while low SDI areas face underdiagnosis and healthcare disparities. Targeted interventions, equitable resource allocation, and enhanced diagnostic capacity are urgently needed to mitigate future PAH-related morbidity and mortality.

To investigate the curative effect of the Qifangfeixian granule on interstitial lung disease (ILD).

This study combined animal experiments and clinical trials. Pathological changes in bleomycin (BLM)-induced pulmonary fibrosis in mice were assessed using hematoxylin and eosin (H&E), Masson, and Sirius Red staining. In the clinical study, 40 ILD patients were enrolled, with 20 in the control group and 20 in the treatment group. The treatment group received Qifangfeixian granules in addition to standard therapy for 12 weeks. Pulmonary function parameters, including forced vital capacity (FVC, L), FVC_pred%, diffusing capacity for carbon monoxide (DLCO, mmol/min/kPa), and DLCO_pred%, were measured before and after treatment.

Compared with those of the control group, the inflammatory infiltration and collagen fibres in the BLM group were significantly increased, and the inflammatory infiltration and collagen fibres in the BLM group were significantly reduced after Qifangfeixian granule treatment. Compared with those in the control group, the lung function parameters in the treatment group were significantly improved. Specifically, the FVC increased by +0.10 ± 0.18 L in the treatment group, whereas the control group showed a decrease of –0.05 ± 0.21 L (P = 0.008). Additionally, FVC_pred% was improved significantly in the treatment group (+2.6% ± 5.3%) compared with the control group (–2.0% ± 6.7%, P = 0.009).

Qifangfeixian granules can improve not only the pulmonary fibrosis of BLM-induced model mice but also the pulmonary function of patients with ILD in practice, and their clinical efficacy is accurate.

Our earlier research revealed a connection between microRNA-29b (miR-29b) and bromodomain-containing protein 4 (BRD4) and airway inflammation in chronic obstructive pulmonary disease (COPD). We examined their correlation with airway inflammation and dysbiosis in COPD individuals who had ceased smoking.

Bacterial community composition and diversity were evaluated in bronchoalveolar lavage fluid (BALF) from COPD patients who had ceased smoking, and the expression of miR-29b/BRD4, interleukin (IL)-6 and IL-8 in bronchial brushings was measured. BEAS-2B cells were exposed to COPD BALF filtrate to establish an in vitro model. The expression levels of miR-29b, BRD4, IL-6, and IL-8 were subsequently assessed in these treated cells.

The bacterial community composition in the lungs of individuals with COPD was different from that in the lungs of non-COPD subjects. In COPD patients, lung microbial diversity was significantly reduced, and this decline was correlated with both pulmonary function and airway inflammation. Additionally, the expression of miR-29b was lowered, whereas BRD4 expression was elevated in the lower airways of individuals with COPD. Both miR-29b and BRD4 were linked with pulmonary function, airway inflammation, and diversity indices. miR-29b regulated the production of inflammatory cytokines induced by BALF filtrate through its targeting of BRD4 in bronchial epithelial cells.

Our findings indicate that airway inflammation is associated with airway dysbiosis in COPD patients after smoking cessation and that miR-29b/BRD4 are involved in dysbiosis-associated airway inflammation.

Optimizing sedation to minimize respiratory depression during fiberoptic bronchoscopy (FOB) presents an ongoing challenge. This trial compared the safety and efficacy of remimazolam-remifentanil versus propofol-remifentanil for maintaining spontaneous ventilation in patients undergoing FOB.

This pre-registered randomized controlled trial enrolled 103 consecutive candidates for FOB (April 2023 to April 2024). After excluding 10 ineligible participants, 93 were enrolled in a two-phase study. In the initial dose-determination phase, 21 participants underwent dose escalation to establish the induction dose of remimazolam (0.35 mg/kg) using the modified Dixon’s method. Subsequently, 72 participants were randomly assigned in a 1:1 ratio to remimazolam-remifentanil group (Group R-R) or propofol-remifentanil group (Group P-R) (n = 36 each). Remifentanil was administered by target-controlled infusion (3.0 ng/mL plasma concentration) in both groups. Group R-R received remimazolam 0.35 mg/kg, while Group P-R received propofol 2.0 mg/kg after remifentanil loading. Standardized supplemental doses were administered for inadequate sedation (Modified Observer’s Assessment of Alertness/Sedation score >1 or Bispectral index >75). The primary endpoint was the incidence of respiratory depression, defined as SpO₂ <95% or a respiratory rate <8 breaths/min. Secondary outcomes included procedure completion, movement or cough-related interruptions, hemodynamic stability, adverse events, procedural time, and satisfaction ratings from both bronchoscopists and participants.

Group R-R demonstrated a significantly lower incidence of respiratory depression (11.1% vs. 33.3%; P = 0.045) and of hypotension requiring vasopressors (16.7% vs. 41.7%; P = 0.020). However, transient involuntary movements (25.0% vs. 8.3%; P = 0.111) and cough (38.9% vs. 22.2%; P = 0.125) were numerically more frequent in Group R-R, though not statistically significant. All procedures were completed successfully without discontinuation. Hypertension, arrhythmias, procedural times, and satisfaction scores were comparable between groups (all P > 0.05).

Compared to propofol-remifentanil, remimazolam-remifentanil provides effective moderate sedation for FOB with superior respiratory safety and reduced hypotension requiring vasopressors, despite a numerically higher incidence of transient movement and cough. It thus represents a promising alternative for maintaining spontaneous ventilation during FOB.

This study aimed to develop an effective predictive tool that combines radiomics and clinical information to predict the survival outcomes of patients with advanced non-small cell lung cancer (NSCLC) undergoing chemoimmunotherapy.

Data were collected from 201 patients with advanced NSCLC who received first-line chemoimmunotherapy across three institutions: those from Centers I & II (n = 164) were randomly split in a 7:3 ratio into training (n = 115) and validation (n = 49) cohorts, and those form Center III (n = 37) were designated as the external test cohort. The analysis was conducted using CT images and clinical data obtained before and after induction chemoimmunotherapy. We developed multiple intratumoral and peritumoral radiomics-based models, along with clinical prediction model that integrated patients’ baseline clinicopathological characteristics with plasma biomarker profiles, to predict progression-free survival (PFS). Based on expectations derived from prior established models, a stepwise backward elimination approach was utilized to select candidate submodels for the combined model construction. This combined model was internally validated using time-dependent ROC curves in training and validation sets and externally validated in the external test set.

The combined model was constructed by integrating four candidate sub-models (DeltaSub, Clinical, P4mm, and Habitat) selected through the stepwise regression analysis. The combined model demonstrated superior performance compared to conventional models that utilized only clinical features, as well as Classical-Pre, Classical-Post, delta intratumor feature-based, and peritumor feature-based models. The combined model demonstrated satisfactory predictive performance across all three datasets, achieving a C-index of 0.849 (95% CI: 0.812–0.885) in the training set, 0.744 (95% CI: 0.664–0.842) in the validation set, and 0.731 (95% CI: 0.639–0.824) in the external test set for PFS.

We developed a novel radiomic-clinical model to predict PFS for advanced NSCLC patients treated with first-line chemoimmunotherapy. This model enhanced survival assessment through comprehensive feature integration.

This study aimed to evaluate the potential of a collagen-coated, 3D-printed tracheal scaffold (3D-TechTra) integrated with human umbilical cord mesenchymal stem cells (hUC-MSCs) for tracheal tissue regeneration.

The thermoplastic polyurethane/polylactic acid (TPU/PLA) scaffold was engineered to optimize mechanical properties and biocompatibility, with the goal of mimicking the structural and tensile characteristics of native tracheal tissue. Subsequently, preclinical experiments were conducted using rabbit models: the performance of the collagen-coated TPU/PLA scaffold with hUC-MSCs was compared with that of uncoated scaffolds and collagen-only scaffolds. In vitro tests were also performed to assess the adhesion, proliferation, and differentiation of hUC-MSCs on the scaffold. For in vivo evaluation, multiple analytical methods were employed, including immunohistological analysis (to detect glycosaminoglycan deposition and extracellular matrix remodeling), radiographic and endoscopic evaluations (to assess tracheal contour and airway obstruction), and survival analysis (to monitor animal outcomes and systemic toxicity).

In vitro, hUC-MSCs successfully adhered to and proliferated on the TPU/PLA scaffold, and differentiated into adipogenic, osteogenic, and chondrogenic lineages, which supported the potential for tissue-specific regeneration; in vivo, compared with uncoated or collagen-only scaffolds, the collagen-coated TPU/PLA scaffold integrated with hUC-MSCs exhibited enhanced integration with host tissues, superior biocompatibility, and reduced tracheal stenosis, while also preserving airway patency, alleviating inflammation, and facilitating epithelial regeneration, smooth muscle formation, and vascularization. Immunohistological analysis further revealed significant glycosaminoglycan deposition and extracellular matrix remodeling in the hUC-MSC-treated group, and radiographic and endoscopic evaluations confirmed preserved tracheal contour and reduced airway obstruction; additionally, survival analysis showed significantly improved outcomes in animals treated with the collagen-coated TPU/PLA scaffold containing hUC-MSCs, with no systemic toxicity observed.

This study demonstrated the synergistic potential of TPU/PLA scaffolds, collagen coatings, and hUC-MSCs, providing valuable evidence for advancing the application of these components in tracheal tissue engineering.

Chronic hepatitis B (CHB), characterized by a significant global disease burden and substantial healthcare costs, remains a critical public health challenge. Although tenofovir amibufenamide (TMF) and tenofovir alafenamide (TAF), including formulations from centralized volume-based procurement (CVBP-TAF) and imported sources (I-TAF), are all recommended treatment regimens, comparative studies on the efficacy, safety, and cost-effectiveness of these three regimens remain relatively limited. This retrospective cohort study aims to systematically compare the application effects of these three regimens in the treatment of CHB.

We conducted a single-center retrospective cohort study at Tianjin University Central Hospital from September 2019 to September 2024. CHB patients who had received TMF, CVBP-TAF, or I-TAF for 48 weeks were enrolled. Efficacy endpoints included HBV-DNA negative conversion, HBeAg seroclearance, and alanine aminotransferase (ALT) normalization. Safety outcomes encompassed nephrotoxicity, hepatotoxicity, and lipid profile changes. Cost-effectiveness analysis was used to calculate the cost-effectiveness ratio (CER) per unit efficacy gain and incremental CER using a healthcare payer perspective.

A total of 173 patients were included, with 58 in the TMF group, 58 in the I-TAF group, and 57 in the CVBP-TAF group. TMF demonstrated superior efficacy to I-TAF and CVBP-TAF, as evidenced by significantly higher HBV-DNA negative conversion rate and ALT normalization rate. No significant differences in safety outcomes were observed among the three groups. Cost-effectiveness analysis showed that CVBP-TAF had the lowest CER (4.62 CNY/%), followed by TMF with an intermediate CER (60.45 CNY/%), while I-TAF had the highest CER (66.49 CNY/%).

TMF demonstrates stronger antiviral efficacy than both TAF formulations, with comparable safety profiles. Despite the cost advantages of CVBP-TAF resulting from procurement policies, the clinical benefits of TMF support its use. Future strategies should improve the affordability of TMF to expand its accessibility.

Iron overload resulting from chronic alcohol consumption may aggravate liver damage, and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.

Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin (100 mg/kg.bw) or iron-rich/limited treatment for 12 weeks, and liver damage, as well as the underlying mechanisms of lysosome-dependent ferritinophagy, was explored, following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.

Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio, hepatic lipid accumulation and triglyceride (TG) content of the mice and induced the release of alanine aminotransferase (ALT), aspartate transaminase (AST), and serum TG levels, which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation. Similar findings were observed in vitro. Moreover, quercetin intervention alleviated iron deposition, inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain 3 (LC3)-II, and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1 (FOXO1) induced by ethanol. These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation, NCOA4 transfection, or AS1842856, a FOXO1 inhibitor.

Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.

Konjac oligosaccharide (KOS), which is produced through the degradation of konjac glucomannan via enzymatic, chemical, or physical treatments, has been found to have laxative effects. The current study aimed to elucidate the mechanisms underlying the laxative effect of KOS.

KOS was administered by gavage to wild-type and 5-hydroxytryptamine 4 receptor (5-HT4R)-knockout C57BL/6 mice subjected to loperamide-induced constipation for four weeks. Following treatment, feces, blood, small intestine, colonic tissue, and intestinal contents were collected. Constipation-related parameters, gastrointestinal hormones, and Ca²⁺ concentrations were evaluated. Histopathological changes were examined via hematoxylin and eosin staining. Immunofluorescence staining, Western blotting, and immunohistochemical staining were performed to detect the 5-HT4R/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. Isolated smooth muscle cells (SMCs) were treated with KOS and GR113808 (a 5-HT4R antagonist), morphologically observed under an inverted microscope, and identified by α-SMA immunofluorescence staining. Cell viability was assessed via CCK-8 assays. 5-HT4R/cAMP/PKA/p-CREB pathway activity in SMCs was detected via Western blotting.

KOS alleviated loperamide-induced constipation in mice. KOS activated the 5-HT4R/cAMP/PKA/p-CREB pathway in loperamide-induced constipated mice. The protective effect of KOS was significantly diminished in 5-HT4R^−/− mice. KOS promoted the proliferation of SMCs by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.

KOS improves loperamide-induced constipation by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.

IgA nephropathy (IgAN) is the most prevalent form of primary glomerular disease. However, its diagnosis is contingent on kidney biopsy. Therefore, noninvasive biomarkers are urgently needed for diagnosis. This study aims to identify novel urinary biomarkers that differentiate IgAN from other common primary glomerular diseases, specifically membranous nephropathy (MN) and minimal change disease (MCD).

The peripheral blood mononuclear cell (PBMC) transcriptome dataset GSE73953 was obtained from the GEO database. Differential gene expression, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene Ontology (GO) enrichment, and immune infiltration analyses were performed. Protein–protein interaction (PPI) analysis and lysosome-related genes were used to identify hub genes. The expression of the hub gene ATP6V1D in urine and kidney tissues from individuals with IgAN, healthy controls, MCD and MN patients was assessed using enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunostaining techniques. Spearman’s correlation analysis was employed to investigate the relationships between the concentration of ATP6V1D in urine, the concentration of galactose-deficient IgA1 (GD-IgA1), and the clinical data of patients. The receiver operating characteristic (ROC) curve was used to assess the role of urine ATP6V1D levels in distinguishing IgAN from MN and MCD.

ATPase was identified as the principal intracellular structure associated with differentially expressed genes (DEGs) between IgAN patients and healthy controls in PBMCs. ATP6V1D was identified as a hub gene at the intersection of lysosome-related and differential genes. ATP6V1D levels were lower in PBMCs, urine, and kidney samples from IgAN patients than in those from healthy individuals, MCD and MN patients. The decreased urinary ATP6V1D levels and increased GD-IgA1 levels in IgAN patients were further validated. These changes were positively correlated with 24-h urine protein levels. Notably, a negative correlation was observed between ATP6V1D and GD-IgA1 levels. ROC curve analysis demonstrated that urinary ATP6V1D (AUC = 0.972) and GD-IgA1 (AUC = 0.952) had significant discriminative power in distinguishing IgAN patients from MCD and MN patients, with no significant difference in predictive performance between the two biomarkers (P > 0.05).

The findings underscore the potential utility of the urine ATP6V1D concentration as a biomarker to distinguish IgAN from MN and MCD.

Traditional Chinese medicine exhibits positive therapeutic effects as a primary or adjunctive treatment for diabetic nephropathy (DN). This study aimed to evaluate the impact and mechanism of action of Xiaoke decoction (XKD), a traditional Chinese medicine, on renal function in DN rats.

A rat model of DN was established, and the rats were divided into five groups (n = 7 per group): normal control group (NC), DN model group (DN), low-dose XKD treatment group (DN + XKD-L, 1.5 g/kg/d), high-dose XKD treatment group (DN + XKD-H, 6 g/kg/d), and cyclooxygenase-2 (COX-2) inhibitor (NS398) treatment group (DN + NS398, 8 mg/kg/d). Medications were administered via gavage for 12 consecutive weeks, while equal volumes of normal saline were given to the NC and DN groups. A glucometer was used to detect changes in blood glucose (BG). Enzyme-linked immunosorbent assay (ELISA) and an automatic biochemical analyzer were employed to measure levels of insulin, serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 24-h urine protein quantity (UP/24 h) in rats. Renal tissue sections from different treatment groups were prepared, with tissue lesions examined via periodic acid-Schiff (PAS) and hematoxylin–eosin (HE) staining. Tissue inflammation and lipid deposition were evaluated using ELISA and Oil Red O staining. Immunohistochemistry and Western blotting were used to detect changes in the expression levels of COX-2 and low-density lipoprotein receptor (LDLr) in tissues, and to clarify the regulatory mechanism of XKD on renal function in DN rats.

XKD, particularly at the high dose (XKD-H, 6 g/kg/d), significantly reduced BG, insulin levels, renal weight ratio, Scr, BUN, and UP/24 h in DN rats. DN rats showed significant renal lesions, and XKD gavage (especially XKD-H) markedly improved these pathological changes. In DN rats, XKD significantly decreased the protein expression levels of COX-2 and LDLr, downregulated the levels of inflammatory factors and lipid factors, reduced lipid deposition in renal tissues, and ameliorated structural abnormalities in glomeruli, basement membranes, and renal tubules.

XKD alleviates renal tissue damage by regulating the COX-2-mediated LDLr pathway, thereby reducing the release of inflammatory factors and lipid accumulation in DN rats and protecting renal function.

XKD improves renal function in streptozotocin (STZ)-induced DN rats by regulating the COX-2-mediated LDLr pathway, reducing inflammatory factors and lipid deposition, and alleviating renal tissue damage.

Endothelial dysfunction is a central contributor to the vascular complications observed in individuals with diabetes. cAMP response element-binding protein (CREB) plays a crucial role in mediating hyperglycemia-induced endothelial dysfunction. Phosphatase and tensin homolog (PTEN) has been implicated in the regulation of endothelial inflammation, yet the precise mechanism by which CREB modulates PTEN to protect endothelial cells under high glucose conditions remains unknown. This study aims to elucidate this potential mechanism.

Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (30 mM) or normal glucose (5.5 mM) for 6 days. Cell viability and apoptosis were assessed via the Cell Counting Kit-8 and flow cytometry. To evaluate oxidative stress, the levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA) were measured via commercial assay kits. The interaction between CREB and endothelial specific molecule 1 (ESE-1) was assessed via coimmunoprecipitation. Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the transcriptional regulation of PTEN by ESE-1 and CREB. Western blotting was performed to analyze the expression of intercellular adhesion molecule-1 and E-selectin. The adhesion of HUVECs was evaluated via monocyte‒endothelial cell adhesion assays.

Our findings revealed a direct interaction between CREB and ESE-1, which together regulate PTEN expression to activate the phosphoinositide 3-kinase/protein kinase B pathway. Under high-glucose conditions, we observed significant increases in oxidative stress, inflammatory responses, and adhesion in HUVECs. ESE-1 knockdown reversed these effects, restoring endothelial cell function. Moreover, the overexpression of PTEN in high glucose–treated HUVECs rescued the endothelial injury induced by ESE-1 knockdown, suggesting that PTEN plays a pivotal role in mediating the protective effects.

ESE-1, through the regulation of CREB-mediated PTEN expression, activates the PI3K/AKT pathway and modulates key processes such as oxidative stress, inflammation, and adhesion in endothelial cells under high-glucose stress.

To investigate the differential expression of microRNA-144-3p in endometrial cells exposed to copper ions in vitro. The specific mechanism by which microRNA-144-3p is involved in Cu²⁺-induced damage to the human endometrial epithelial cells (HEECs) was explored.

HEECs were cultured in copper-containing culture medium to simulate changes in the endometrium after copper intrauterine device (Cu-IUD) implantation. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the differential expression of miR-144-3p in HEECs after Cu²⁺ treatment. MiRNAs, siRNAs and related inhibitors were used to treat HEECs. The expression levels of related downstream genes were then analyzed by RT-qPCR, Western blotting and immunofluorescence to explore the specific mechanism involved.

MiR-144-3p was significantly upregulated in the Cu²⁺-treated HEECs. The expression of P-NF-κB, MMP9, TGF-β3 and P-SMAD3 was significantly decreased in HEECs treated with 10 μg/mL Cu²⁺. MiR-144-3p regulated the expression of metallothionein 1A (MT1A) and thrombospondin-1 (THBS-1) in Cu²⁺-treated HEECs. The expression of P-NF-κB can be regulated by MT1A, and an inhibitor of P-NF-κB can significantly reduce the expression of MMP9 in Cu²⁺-treated HEECs. The expression of TGF-β3 can be regulated by THBS-1, and a TGF-β3 inhibitor can significantly reduce the expression of SMAD3 in Cu²⁺-treated HEECs. The proliferative capacity of HEECs treated with MMP9 or SMAD3 inhibitors was significantly reduced.

The increased Cu²⁺ concentration led to the upregulation of miR-144-3p, further reducing the expression levels of its target genes (MT1A and THBS-1), which in turn downregulated the expression of NF-κB, MMP9, TGF-β3 and SMAD3, ultimately leading to increased endometrial cell damage and decreased cell proliferation.

Although immune dysregulation is implicated in the pathogenesis of endometriosis (EMs), the specific role of prostate transmembrane protein androgen induced 1 (PMEPA1) in modulating the function of regulatory T cells (Tregs) remains inadequately understood. This study aimed to elucidate the regulatory mechanisms by which PMEPA1 influences the activity of Tregs, thereby facilitating the invasion of endometrial stromal cells (ESCs).

Single-cell RNA sequencing (scRNA-seq) was performed on matched ectopic ovarian lesions and eutopic endometria from 3 patients. Clinical specimens from patients with EMs and control subjects were examined for PMEPA1 expression. Primary human Tregs isolated from peripheral blood mononuclear cells were subjected to PMEPA1 overexpression (via plasmid) or knockdown (via siRNA). Modulation of the PI3K pathway was conducted via the activator 740Y-P or the inhibitor LY294002. The secretion of IL-10 and TGF-β by Tregs was quantified using an enzyme-linked immunosorbent assay. Ectopic ESCs cocultured with modified Tregs were assessed for their proliferation, migration, and invasion capabilities.

scRNA-seq data revealed significant upregulation of PMEPA1 in Tregs from ectopic ovarian lesions compared with paired eutopic endometria. PMEPA1 expression was increased in the ectopic lesions and peritoneal fluid mononuclear cells of patients with EMs. Tregs overexpressing PMEPA1 demonstrated reduced secretion of IL-10 and TGF-β but exhibited hyperactivation of the PI3K/AKT signaling pathway. Treatment with LY294002 ameliorated the impairment in cytokine secretion. Coculture experiments with Tregs expressing high levels of PMEPA1 resulted in increased invasion, migration, and proliferation of ESCs.

PMEPA1 impairs Treg-mediated immunosuppression by hyperactivating the PI3K/AKT pathway, thereby facilitating the invasiveness of ESCs in EMs.

Placental dysfunction induced by fetal cardiopulmonary bypass (CPB) imposes limitations on the clinical application of this procedure. The potential impact of microRNA-mediated autophagy in placental endothelial cells on overall placental function remains elusive, necessitating a comprehensive exploration of the underlying mechanisms involved.

We established fetal sheep CPB models and employed immunohistochemistry to assess the placental expression of ATG7. Bioinformatic analysis, coupled with dual-luciferase reporter assays, was used to elucidate the intricate relationship between miR-320a and ATG7. Changes in ATG7 expression were further investigated through Western blotting and quantitative polymerase chain reaction (qPCR). Human umbilical vein endothelial cells (HUVECs) were cultured, and in vitro experiments were conducted to evaluate their regulatory effects on endothelial function. Immunoblotting was used to measure the expression levels of ATG7, endothelin-1 (ET-1), SIRT1, and FOXO1, whereas enzyme-linked immunosorbent assay (ELISA) was used to quantify nitric oxide (NO) production.

Sixty minutes after CPB, a substantial decrease in ATG7 expression in placental tissue was observed. The downregulation of ATG7 expression led to increased ET-1 production in HUVECs, concomitant with decreased NO production. miR-320a was identified as a specific regulator of ATG7 expression, with subsequent experiments demonstrating a significant reduction in placental ATG7 levels upon injection of the miR-320a agomir compared with the miR-320a antagomir during fetal sheep CPB. In HUVECs, miR-320a downregulated ATG7, resulting in increased ET-1 production and diminished NO production. Treatment with the miR-320a mimic/miR-320a inhibitor revealed that miR-320a inhibited the SIRT1/FOXO1 pathway in HUVECs by downregulating ATG7 expression, culminating in increased ET-1 production and reduced NO levels.

The observed downregulation of placental ATG7 expression subsequent to fetal CPB is intricately associated with endothelial dysfunction. Furthermore, our findings underscore the specific regulatory role of miR-320a in modulating ATG7 expression within the placenta. At the cellular level, increasing the level of miR-320a has emerged as a potential strategy for modulating endothelial function through the inhibition of ATG7 and the SIRT1/FOXO1 pathway.

The aim of this study was to explore the influence of working length (determined by the screw position) on the stiffness and interfragmentary strain (IFS) of femoral locking compression plate (LCP) external fixators for lower tibial fractures under full weight-bearing conditions, with the goal of providing a reference basis for clinical applications.

Finite element analysis software was used to construct a model of a lower tibial fracture with external femoral LCP fixation. The models were divided into four groups according to the different working lengths (external femoral locking plate fixation 1 [EF1], EF2, EF3, and EF4). Stress distribution clouds, fracture end displacements, stiffness and IFS were tested for each model group at different loads.

Compared with those in the EF1 group, the stiffnesses in the EF2, EF3, and EF4 groups decreased by 28%, 31%, and 37%, respectively, under axial compression loading. Compared with those in the EF1 group, the stiffnesses in the EF2, EF3, and EF4 groups decreased by 19%, 33%, and 35%, respectively, under axial torsion loading. Compared with those in the EF1 group, the stiffnesses in the EF2, EF3, and EF4 groups decreased by 32%, 33%, and 35%, respectively, under a three-point bending load. The IFS of the four finite element models increased with the working length of the plate, with EF1 (76%) < EF2 (107%) < EF3 (110%) < EF4 (122%). Finite element analysis revealed that under full weight-bearing conditions, the structural stiffness of the femoral LCP external fixator decreased with increasing working length, leading to an increase in the IFS, which resulted in an IFS that exceeded the ideal range required for secondary healing.

For unstable lower tibial fractures, screws in the femoral LCP external fixator should be placed as close to the fracture end as possible to increase stability and promote fracture healing.

Conjunctival vascularization and fibroblasts are important factors leading to filtering bleb scarring after glaucoma filtering surgery. Previous studies have shown that nintedanib can inhibit the transformation of conjunctival fibroblasts into myofibroblasts, alleviating scar formation. This study aimed to investigate the effect of nintedanib on vascular endothelial growth factor (VEGF)-induced neovascularization of human conjunctival vascular endothelial cells and to reveal the molecular mechanisms involved.

Primary human conjunctival vascular endothelial cells were cultured with VEGF alone or in combination with nintedanib, and cell proliferation and migration were measured via cell counting kit-8 and scratch assays, respectively. The effect of nintedanib on human conjunctival vascular endothelial cell tube formation was also assayed. The phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) were measured via Western blotting.

VEGF (120 ng/mL) significantly promoted the proliferation of human conjunctival vascular endothelial cells. Nintedanib inhibited the VEGF-induced proliferation of these cells while also suppressing cell migration (P < 0.0001) and vascularization (P < 0.01). Furthermore, nintedanib reduced ERK1/2 (P < 0.01) and JNK phosphorylation (P < 0.001).

Our study provides new evidence that nintedanib inhibits the proliferation, migration, and neovascularization of human conjunctival vascular endothelial cells and downregulates the expression of p-ERK and p-JNK in the MAPK pathway.