Meniere Disease (MD) is a chronic inner ear disorder marked by recurrent episodes of vertigo, sensorineural hearing loss, tinnitus, and aural fullness. Approximately 60–70% of MD cases are sporadic, and increasing evidence supports a significant role for immune-mediated mechanisms in their pathogenesis. This review provides a comprehensive analysis of current evidence on the immunological underpinnings of sporadic MD and explores how these processes give rise to distinct immunophenotypes. Furthermore, in this review, we propose an immunological framework to complement existing clinical diagnostic criteria, enabling more precise classification and personalized management of MD based on immune phenotypes. Research support the concept that MD represents a spectrum of disorders rather than a single disease, comprising at least three distinct immune phenotypes: (1) a T helper 2 (Th2) cytokine–mediated subtype with an allergic-like inflammation; (2) an autoinflammatory subtype characterized by elevated levels of interleukin (IL)-1β; and (3) a subtype associated with autoimmune and/or autoinflammatory comorbidities involving other organs beyond the inner ear. Understanding these phenotypes holds promise for improving diagnostic accuracy and guiding targeted therapeutic strategies in MD. A better understanding of the immune phenotypes in sporadic MD can elucidate promising biomarkers for drug discovery and clinical interventions.

Hypercalcemia is a potentially life-threatening metabolic condition that commonly occurs in advanced malignancies, particularly solid tumors such as breast cancer. This condition often presents nonspecific symptoms like nausea, confusion, or polyuria in the emergency department, frequently leading to misdiagnosis and delayed treatment. In breast cancer, hypercalcemia is typically driven by paraneoplastic mechanisms, including parathyroid hormone-related peptide (PTHrP) secretion and osteolytic bone metastases, both of which disrupt calcium homeostasis. Furthermore, immune dysregulation or ectopic vitamin D production may also contribute to disease progression. This manuscript summarizes current evidence on the emergency presentation, diagnosis, and acute management of hypercalcemia in patients with breast cancer. It highlights key risk factors, including tumor subtypes, endocrine therapies, and changes in bone microenvironment, and outlines practical diagnostic approaches to facilitate early identification. Moreover, it compares therapeutic options, including intravenous hydration, calcitonin, bisphosphonates, and denosumab. Additionally, the review examines the prognostic significance of hypercalcemia, which often indicates disease progression and is associated with increased rates of intensive care unit (ICU) admissions and mortality. Overall, these insights aim to guide clinical decision-making and support future research efforts to establish standardized protocols and predictive models for breast cancer–associated hypercalcemia.

Carotid artery atherosclerosis is one of the leading causes of stroke. However, due to its insidious onset, balancing the risks and benefits of surgery for asymptomatic patients is challenging. Once it leads to a stroke, it has an extremely high mortality and disability rate. Therefore, an accurate, individualized assessment of carotid atherosclerotic plaque is necessary, combined with personalized treatment using existing therapeutic modalities. This article discusses new findings and advances in risk assessment and treatment modalities for carotid atherosclerosis.

Background: Chronic myeloid leukemia (CML) is a cancer caused by uncontrolled growth of myeloid cells in the bone marrow. Tyrosine kinase inhibitors (TKIs) like imatinib have revolutionized treatment, but resistance remains a challenge, possibly due to genetic variations. Specifically, the 3435TT genotype has been linked to lower event-free survival in CML and B-cell acute lymphoblastic leukemia (B-ALL) patients, with multivariate analysis identifying it as an independent risk factor for imatinib resistance in CML cases. Therefore, the aim of our study was to evaluate the association of multidrug resistance mutation 1 (MDR1) C3435T (rs1045642) and G2677T (rs2032581) gene variations with the CML susceptibility and resistance to imatinib mesylate.

Methods: In this case-control study, 50 CML patients and 50 healthy controls from the Saudi population were recruited. DNA was extracted from peripheral blood samples, and the MDR1 C3435T (rs1045642) and G2677T (rs2032581) genotyping were analyzed by using PCR-RFLP analysis to assess the correlation among MDR1 genotypes and the risk of CML.

Results: It has been found that MDR1 C3435T (rs1045642) variation was statistically significant (p = 0.035) between CML patients and healthy controls. In addition, strong association was reported for MDR1 G2677T (rs2032581) variation (p = 0.044) between the CML patients and healthy controls. The results of MDR1 (rs1045642) show that individuals with the TT genotype were significantly associated with risk of developing CML as evidenced by the odds ratio (OR) is 6.75 (95% CI: 1.3181 to 34.5662), and p = 0.021. Similarly in dominant model, CT + TT genotypes vs CC genotype was significantly associated with risk of developing CML as evidenced by the odds ratio is 2.25 (95% CI: 1.010 to 5.008), p = 0.047. The allelic comparison highlighted a strong association of the MDR1-T allele with CML risk (OR = 2.26, p = 0.009). Under the codominant model, the MDR1 rs2032581-GT genotype showed a substantial link with CML susceptibility, evidenced by an OR of 2.56, p = 0.041. Additionally, the MDR1-TT genotype indicated increased susceptibility with an OR of 3.16, p = 0.049. The allelic comparison highlighted a strong association of the MDR1-T allele with CML risk OR = 2.04, p = 0.014.

Conclusion: It was concluded that MDR1 rs2032581 G>T MDR1 rs1045642 C>T polymorphisms might be a risk factor for imatinib resistance in Saudi CML patients. Significant associations were reported between MDR1 genotypes and molecular responses to imatinib and advanced stage of the disease. Determination of MDR1 polymorphisms MDR1 rs2032581 G>T MDR1 rs1045642 C>T might be useful in response prediction to therapy with imatinib in patients with CML.

Background: Lung cancer is one of the common malignancies worldwide and is spotlighted due to high mortality. Evidence indicates that RhoGDIβ is a crucial driver of lung cancer metastasis. Therefore, this study aims to elucidate the upstream mechanisms underlying the role of RhoGDIβ in metastatic progression of lung cancer.

Methods: Potential RhoGDIβ-interacting proteins were identified using bioinformatic approaches. Functional assays were performed in lung cancer cell lines to assess migration, invasion, and epithelial-mesenchymal transition (EMT) following C-C chemokine receptor type 1 (CCR1) overexpression, extracellular signal-regulated kinase (ERK) pathway inhibition, or Proto-Oncogene C-Fos (c-FOS) induction. Moreover, signaling activity and RhoGDIβ expression were evaluated by immunoblotting. Additionally, a lung metastasis mouse model was used to validate metastatic nodule formation and pathway activation in vivo.

Results: CCR1 overexpression significantly enhanced the metastatic behaviors of lung cancer cells, including migration, invasion, and EMT, and increased lung nodule formation in mice (p < 0.05). CCR1 overexpression also activated the ERK pathway, elevated levels of phosphorylated ERK (p-ERK) and c-FOS, and suppressed RhoGDIβ expression both in vitro and in vivo (p < 0.05). These trends were abolished by treatment with an ERK pathway inhibitor. Importantly, c-FOS overexpression rescued the effect of ERK blockade on metastasis inhibitory and RhoGDIβ upregulation, confirming that c-FOS was a downstream factor of ERK (p < 0.05). In vivo experiments further substantiated that CCR1 promoted metastasis through ERK/c-FOS-mediated repression of RhoGDIβ (p < 0.05).

Conclusion: Our study unveils a novel CCR1-ERK-c-FOS signaling axis that promotes lung cancer metastasis and is associated with RhoGDIβ. Intervening in this axis represents a promising strategy for the migration of lung cancer metastasis.

Background: Acute exacerbation of bronchiectasis (AEB) is a fatal disease in the respiratory system. Herein, we aimed to compare the detection efficacy of metagenomic next-generation sequencing (mNGS) and standard methods between high-risk and low-risk AEB patients.

Methods: Retrospectively, medical data of AEB patients (n = 52) were collected between March 2022 and January 2023. Based on the number of acute exacerbations in the previous year and hospitalization history, patients were categorized into a high-risk group and a low-risk group. According to the study's inclusion and exclusion criteria, a total of 52 AEB patients were included (28 high-risk and 24 low-risk). Baseline clinical data were analyzed, and mNGS of bronchoalveolar lavage fluid (BALF) samples was performed.

Results: Significant differences were observed between the high-risk and low-risk groups in disease duration, number of clinical visits, number of admissions, white blood cell count, neutrophil percentage, high-sensitivity C-reactive protein (hs-CRP), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) levels (p < 0.05). mNGS demonstrated clear advantages in detecting pathogens in BALF samples from patients with bronchiectasis, offering higher sensitivity and broader pathogen spectrum coverage. mNGS can effectively complement the limitations of conventional culture methods. The mNGS results showed that the infection rates of Pseudomonas aeruginosa and Klebsiella pneumoniae were higher in the high-risk group compared to the low-risk group (p < 0.05).

Conclusion: The mNGS proves to be an effective tool in assessing the respiratory microbiota and has the potential to improve the diagnosis and treatment of AEB patients by enabling rapid and precise pathogen detection.

Background: Primary aldosteronism (PA) is a common cause of secondary hypertension. Despite considerable advances in medical sciences, the underlying molecular mechanisms of PA remain inadequately investigated. Therefore, this study aims to identify potential therapeutic targets for PA by using transcriptome sequencing, providing promising insights for early diagnosis and precise management of this condition.

Methods: Transcriptomic sequencing was performed on blood samples from PA patients and healthy controls. DESeq2 identified differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) of DEGs identified core module genes, which underwent functional enrichment for significant pathways and target detection. Subsequently, aldosterone-producing adenoma (APA) rat models were established. Potential targets (e.g., tuberous sclerosis complex 2 (TSC2)) were modulated via overexpression or shRNA interference, with effects validated physiologically, cellularly, and molecularly.

Results: Our analysis identified 277 DEGs and 8 functional modules. Eigengenes in the pink module exhibited the strongest association with disease clinical phenotypes. The genes within this module were significantly enriched in the mammalian target of rapamycin (mTOR) signaling pathway, with TSC2 identified as a central hub gene, indicating its potential as a promising therapeutic target for PA. In APA rats, TSC2 overexpression significantly inhibited plasma aldosterone (ALD) increase (p < 0.0001) and elevated plasma renin activity (PRA) (p < 0.001). Furthermore, it inhibited adrenal cell proliferation (p < 0.0001), reduced S-phase fraction (p < 0.0001), decreased Ki67 (p < 0.0001), and increased p21 expression (p < 0.01). Western blot analysis revealed that TSC2 overexpression reduced the adrenal p-mTOR/mTOR ratio (p < 0.0001), while increasing p-eukaryotic translation initiation factor 4E-binding protein (p-4EBP)/4EBP (p < 0.001) in APA rats. Conversely, sh-TSC2 knockdown produced opposing patterns.

Conclusions: Transcriptome analysis identified TSC2 as a promising therapeutic target for PA, which was later confirmed in rat models. TSC2 likely alleviates PA by inhibiting mTOR pathway activation, thereby reducing abnormal adrenal cell proliferation and aldosterone secretion.

Background: Maslinic acid (MA), a pentacyclic triterpenoid found in plants, has beneficial effects at low doses, but its impact on liver damage and cholesterol gallstone (CGS) formation at high doses remains unclear. This study explored the effects of high-dose MA on liver damage and CGS formation in C57BL/6J mice.

Methods: This study used animal model experiments, network pharmacology, RNA transcriptome sequencing, molecular docking, and molecular dynamics simulation to explore the molecular mechanism by which high-dose MA promotes CGS formation and cholestatic liver injury (CLI).

Results: High-dose MA significantly promoted CGS formation (p < 0.05) and induced CLI in mice fed a lithogenic diet. Gallstone severity progressed with MA administration, accompanied by significant alterations in biliary lipid composition: increased cholesterol levels alongside decreased phospholipid and bile acid concentrations (p < 0.05), collectively leading to an elevated cholesterol saturation index (CSI, p < 0.05). Serum biochemical analysis confirmed hepatobiliary injury, showing significantly elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bile acids (p < 0.05). Histopathological examination revealed hepatic inflammatory infiltration and structural damage. Mechanistically, MA downregulated key proteins involved in bile acid synthesis and biliary excretion, while modulating regulators of cholesterol and drug metabolism. Transcriptomic profiling revealed that MA significantly disrupted pathways related to bile acid, cholesterol, and drug metabolism, particularly the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and bile secretion. Integrated network pharmacology, molecular docking, and dynamics simulations identified PPARα and PPARγ as core targets, with MA showing stable binding to multiple gallstone-related proteins. Subsequent validation confirmed that MA increased PPARα expression and decreased PPARγ expression (p < 0.05), supporting the conclusion that MA promotes gallstone formation by interfering with the PPAR signaling pathway and bile acid homeostasis.

Conclusion: Our findings indicate that high-dose MA promotes CGS formation via the PPAR signaling pathway, highlighting the potential risks of MA-induced CLI and providing a basis for assessing its safety and developing targeted interventions.

Background: The hypothalamic feeding circuit is highly vulnerable to obesity-inducing diets, as observed in diet-induced obesity (DIO) models. Programmed cell death factor 4 (PDCD4) is widely expressed in various tissues and organs. Depending on the context, it exhibits both pro-inflammatory and anti-inflammatory properties. This study aimed to analyze serum PDCD4 levels and investigate its correlation with hypothalamic inflammation in obesity.

Methods: A total of 195 participants were separated into two groups according to their body mass index (BMI): normal weight group (18.5 kg/m² ≤ BMI < 24 kg/m²) and obesity group (BMI ≥28 kg/m²). Serum levels of the following were measured using enzyme-linked immunosorbent assay (ELISA): PDCD4, neuropeptide Y (NPY), Ionized calcium-binding adapter molecule 1 (Iba1), and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3). Other biochemical indicators were analyzed. Statistical analyses were performed to evaluate the association between serum PDCD4 levels and other biochemical indicators.

Results: A significant increase in serum PDCD4 level was evident in the obesity group compared with the control group. A binary logistic regression analysis revealed a statistically significant relationship between PDCD4 and obesity (p < 0.05). Based on Spearman correlation analysis, a positive correlation was found between the serum PDCD4 level and BMI, and the serum PDCD4 level was positively correlated with NPY, Iba1 and NLRP3 levels (p < 0.05). Furthermore, serum PDCD4 level was found to be independently associated with Iba1 and NLRP3, indicating the role of PDCD4 in regulating hypothalamic inflammation in the obesity context.

Conclusion: In addition to a significant elevation in obese patients, serum PDCD4 level is independently correlated with Iba1 and NLRP3 levels, suggesting a mediating role of PDCD4 in the activation of Iba1 and NLRP3, which is crucial for facilitating peripheral-to-central inflammatory crosstalk and ultimately the occurrence of hypothalamic inflammation.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation, neuroinflammation, and neuronal loss. Interferon gamma-inducible protein 16 (IFI16) regulates inflammatory processes in AD, while ubiquitin-specific peptidase 16 (USP16) has been shown to ameliorate memory deficits in AD models. This study aimed to elucidate the interplay between USP16 and IFI16 in AD pathogenesis.

Methods: Differentially expressed genes associated with AD were identified using dataset GSE129296. Glial cells were exposed to β-amyloid peptide (Aβ)1–42 to establish an in vitro AD model, followed by indirect co-culture with neuronal cells. Neuronal viability and apoptosis were evaluated using the Cell Counting Kit-8 assay and flow cytometry, respectively. Levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in model glial cells were quantified by Enzyme-linked immunosorbent assay (ELISA). A potential deubiquitylating enzyme of IFI16 was predicted using Ubibrowser and confirmed by co-immunoprecipitation, while the ubiquitination levels of IFI16 were assessed. The expression of USP16/IFI16 and toll-like receptor 4 (TLR4)/NLR family pyrin domain containing 3 (NLRP3) was determined by reverse transcription-quantitative PCR (RT-PCR) and western blotting.

Results: IFI16 was markedly upregulated in AD. Silencing of IFI16 attenuated Aβ1–42-induced proinflammatory responses in glial cells, reduced neuronal apoptosis, and enhanced neuronal viability, accompanied by decreased inflammatory cytokine levels and downregulation of TLR4/NLRP3 expression. USP16, identified as the deubiquitylating enzyme of IFI16, was significantly elevated in Aβ1–42-stimulated glial cells, and its silencing reduced IFI16 expression. Furthermore, IFI16 overexpression reversed the effects of USP16 knockdown on cell survival, apoptosis, and inflammation.

Conclusion: USP16 depletion alleviates inflammation and apoptosis in AD cellular models through modulation of IFI16, suggesting that USP16 may serve as a promising therapeutic target for AD.

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common condition, posing significant morbidity and mortality. Combined triglyceride-glucose (TyG) index-body mass index (BMI) may offer enhanced predictive performance for CSA-AKI compared to TyG or BMI alone. Therefore, this study aims to assess whether the preoperative TyG-BMI index outperforms individual TyG or BMI measurements in predicting CSA-AKI.

Methods: This retrospective cohort study included adult patients (n = 652) undergoing cardiac surgery with cardiopulmonary bypass (CPB). The TyG-BMI was calculated as ln[triglyceride (mg/dL) × fasting glucose (mg/dL)/2] × BMI (kg/m²) and CSA-AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The discriminative performance of combined TyG-BMI and individual TyG and BMI was compared using receiver operating characteristic (ROC) analysis. These three indicators were incorporated independently into a baseline predictive model, and model performance was examined. Multivariable logistic regression and restricted cubic splines (RCS) were applied to evaluate the association between TyG-BMI and CSA-AKI. Subgroup analyses were performed to assess effect heterogeneity by age, sex, hypertension, diabetes, and other comorbidities.

Results: Among the study cohort (n = 652), CSA-AKI was reported in 34.4% (224/652) of the cases. TyG-BMI showed superior discriminative performance compared to TyG or BMI alone (AUC: 0.712 vs. 0.666 and 0.681; DeLong test p = 0.021 and <0.001, respectively). Incorporating TyG-BMI, TyG, and BMI into the baseline prediction model (AUC: 0.773) increased the AUC to 0.814 for TyG-BMI, 0.794 for TyG, and 0.805 for BMI. RCS indicated a linear association between TyG-BMI and CSA-AKI (p for nonlinearity = 0.496). For every 15-unit increase in TyG-BMI, the risk of CSA-AKI increased by 41% (adjusted OR: 1.41, 95% CI 1.28–1.55; p < 0.001). Patients in the highest TyG-BMI quartile had significantly higher odds of CSA-AKI (adjusted OR: 5.00; 95% CI 2.68–9.35; p < 0.001) compared to those in the lowest quartile. Subgroup analyses confirmed these findings, except in those with diabetes (p = 0.279).

Conclusions: Preoperative TyG-BMI is independently associated with CSA-AKI in a linear dose-response manner. As a cost-effective composite marker of insulin resistance and adiposity, TyG-BMI improves preoperative risk stratification and enables targeted interventions to mitigate postoperative renal injury. Prospective studies are needed to further validate its clinical applicability.

Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR2500103685).

Background: Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease globally, with podocyte injury recognized as a central contributor to proteinuria and disease progression. Caveolin-1 (Cav-1) has been implicated in the regulation of podocyte function, yet its precise role in DKD-related endocytosis and stress responses remains unclear. This study aimed to investigate the role of Cav-1 in podocyte injury, elucidate its molecular mechanisms in regulating endocytosis and stress signaling, and assess the potential contribution of Dynamin-2 in this process.

Methods: Cav-1 knockout mouse models and high-glucose-treated human podocytes (HPCs) were established. Western blotting, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, albumin endocytosis assays, and analyses of protein expression were performed to evaluate the effects of Cav-1 and Dynamin-2 on podocyte endocytic capacity and apoptosis. Expression of endocytosis-related molecules (clathrin heavy chain (CHC), Ras-related protein Rab 5 (Rab5), Rab7, EH-domain containing protein 2 (EHD2), Caveolae-associated protein 1 (CAVIN1)) and signaling pathway proteins (Src family kinases (SFKs), Ras homolog family member A (RhoA)) was also examined.

Results: Under high-glucose conditions, Cav-1 and endocytosis-related proteins (Dynamin-2, CHC, Rab5, Rab7) were significantly upregulated (p < 0.05), accompanied by enhanced podocyte endocytic activity (p < 0.05) and increased apoptosis (p < 0.05). Cav-1 deletion attenuated proteinuria and glomerular pathology in mice (p < 0.05), reduced the proportion of TUNEL-positive cells (p < 0.05), and suppressed the SFKs-RhoA signaling pathway as well as EHD2/CAVIN1 expression (p < 0.05).

Conclusion: Cav-1 serves as a central regulator of DKD-associated podocyte injury, promoting high-glucose-induced damage through cooperative interaction with Dynamin-2. Targeting Cav-1 and Dynamin-2 may provide a novel therapeutic approach to mitigate DKD progression and provide a theoretical basis for translating mechanistic insights into clinical applications.

Background: Sorafenib exerts its anti-tumor effects partly by inducing ferroptosis. However, the upstream regulatory mechanisms governing this process, particularly the role of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, remain largely unclear in renal cell carcinoma (RCC). Therefore, this study aimed to investigate the role and regulatory mechanism of eIF2α phosphorylation in sorafenib-induced ferroptosis in RCC.

Methods: To determine the optimal concentration, RCC cells were treated with sorafenib at doses of 0, 2.5, 5, 10, and 20 μM. Subsequently, sorafenib (10 μM) was administered to RCC cells either alone or in combination with ferrostatin-1 (Fer-1, 5 μM) or Isrib (200 nM). Lipid peroxidation, cell viability, apoptosis, and intracellular Fe²⁺ levels were assessed. In vivo BALB/c nude mice bearing orthotopic RCC tumors received intraperitoneal injections of sorafenib (20 mg/kg) or Isrib (2.5 mg/kg). Tumor volume and survival were recorded, while ferroptosis-related proteins, p-EIF2α/EIF2α ratios, and tumor lipid peroxidation (4-hydroxynonenal, 4-HNE) were evaluated.

Results: Sorafenib significantly reduced cell viability, increased apoptosis and lipid peroxidation, downregulated glutathione peroxidase 4 (GPX4), and elevated Fe²⁺ levels and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression (p < 0.05). Fer-1 reduced the effects of sorafenib (p < 0.05), whereas Isrib enhanced them (p < 0.05). Fer-1 further promoted sorafenib-induced phosphorylation of eIF2α (p < 0.01), while Isrib inhibited this regulation (p < 0.001). In vitro experiments also confirmed that inhibition of eIF2α phosphorylation enhanced the anti-tumor effect of sorafenib (p < 0.05).

Conclusion: This study reveals eIF2α phosphorylation as a pivotal regulator of sorafenib-induced ferroptosis in RCC. Specifically, inhibition of eIF2α phosphorylation enhances sorafenib-mediated ferroptosis by modulating key ferroptosis-associated proteins and lipid peroxidation, thereby improving sorafenib sensitivity and anti-tumor efficacy in RCC. Targeting eIF2α phosphorylation thus represents a potential strategy to optimize sorafenib-based RCC therapy, based on these new insights into the drug's molecular mechanism of action.

Background: Diabetic Cardiomyopathy (DCM), a common cardiac complication in diabetic patients, is characterized by cardiac structural injury and myocardial metabolic dysfunction, ultimately leading to heart failure. Frizzled Related Protein (FRZB) contributes to the regulation of a variety of diseases, including diabetes and cardiovascular failure. However, the specific mechanism underlying its role in DCM is unclear. Therefore, this study investigated the cardioprotective role of FRZB in diabetic heart injury.

Methods: Male C57BL/6J mice were employed to construct an in vivo DCM mouse model using a high-fat diet combined with a streptozotocin injection. Similarly, an in vitro DCM model was established in H9C2 cells through high glucose (HG) exposure. Histological staining, Cell Counting Kit-8 assay, TdT-mediated dUTP Nick-End Labeling (TUNEL staining), flow cytometry, and biochemical kits were used to examine cardiac tissue morphology, cell activity, apoptosis and oxidative stress. The expression levels of ferroptosis-related indicators were quantified. Furthermore, FRZB was overexpressed or knocked down to assess its effect and determine changes in Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α) signaling pathway-related protein levels after HG exposure.

Results: HG induced cardiomyocyte injury, ferroptosis and oxidative stress, along with downregulation of FRZB expression in vitro and in vivo. Overexpression of FRZB activated the AMPK/PGC-1α signaling pathway and significantly attenuated HG-induced oxidative stress and ferroptosis in cardiomyocytes. In contrast, silencing of FRZB effectively inhibited this pathway, exacerbating oxidative stress and ferroptosis under HG conditions. Additionally, when FRZB was overexpressed while inhibiting the AMPK/PGC-1α signaling pathway, its cardioprotective effects were abolished.

Conclusion: FRZB attenuates diabetes-induced oxidative stress and ferroptosis in cardiomyocytes by regulating the AMPK/PGC-1α signaling pathway, offering novel insights into the cardioprotective mechanisms for diabetic patients.

Background: The association between osteoporosis (OP) and gut microbiota (GM) has been extensively investigated to identify novel probiotics for disease management for effective OP treatment remains imperative. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reduce bone loss caused by ovariectomy (OVX); however, the contribution of GM in this reduction remains unclear. Therefore, this study investigates the impact of UA on OP and demonstrates that it ameliorates disease by remodeling the GM, with metagenomic sequencing identifying potential probiotics that likely mediate these effects.

Methods: OVX mice received daily UA (200 mg/kg) or vehicle for 7 weeks. Bone mass and microarchitecture were assessed via microcomputed tomography (micro-CT) and Alisin Blue Haematoxylin/Orange G (ABH) staining. Bone formation (Runx2, alkaline phosphatase (ALP), osteocalcin (OCN) immunohistochemistry) and resorption (tartrate-resistant acid phosphatase (TRAP) staining) were evaluated in these treated mice. Fecal microbiota transplantation (FMT) from UA-treated donors to antibiotic-pre-treated OVX recipients was performed to test GM causality. The gut microbial composition was analyzed using metagenomic sequencing, with key species identified via Linear Discriminant Analysis Effect Size (LEfSe) and correlated with bone parameters. To further investigate the impact of Parabacteroides goldsteinii (P. goldsteinii) on bone mass, OVX mice were administered either live P. goldsteinii, pasteurized P. goldsteinii or PBS via oral gavage daily for 6 weeks. Micro-CT analysis was used to evaluate the effect of P. goldsteinii on bone mass.

Results: UA treatment significantly increased bone mineral density (BMD, p < 0.01), bone volume fraction (BV/TV, p < 0.05), and trabecular thickness (Tb.Th, p < 0.001), while decreasing trabecular separation (Tb.Sp, p < 0.01) in OVX mice. Critically, FMT from UA-treated donors recapitulated these osteoprotective effects in recipient OVX mice, confirming the mediating role of GM. Metagenomic analysis revealed that UA significantly altered GM structure, enriching Akkermansia muciniphila (A. muciniphila, p < 0.01) and P. goldsteinii (p < 0.01). Abundance of A. muciniphila strongly correlated with improved BV/TV (p < 0.01), and Tb.Th (p < 0.05), and reduced Tb.Sp (p < 0.01). P. goldsteinii abundance also showed a significant positive correlation with BMD (p < 0.05) and a negative correlation with Tb.Sp (p < 0.01). Furthermore, P. goldsteinii significantly increased the BMD of the distal femur (p < 0.05), BV/TV (p < 0.05), and Tb.Th (p < 0.01), while decreasing Tb.Sp (p < 0.001) in OVX mice.

Conclusion: GM contributes to the protective effect of UA against osteoporosis, mediated by the enrichment of specific probiotics such as A. muciniphila and P. goldsteinii. This study provides the first direct evidence that P. goldsteinii supplementation protects against bone loss, making it a promising probiotic candidate for managing OP.

Background: Prostate cancer (PCa) is one of the most common malignancies among men worldwide, and accurate differentiation between benign and malignant nodules remains challenging. Magnetic resonance imaging (MRI) provides valuable soft-tissue contrast but still suffers from interpretive variability. Deep learning–based computer-aided diagnostic (CAD) systems may help improve diagnostic accuracy and consistency. Therefore, this study aimed to evaluate a convolutional neural network (CNN)–based deep learning system for computer-aided classification of benign versus malignant prostate nodules using multiparametric MRI (mpMRI).

Methods: In this retrospective study, 80 patients with histopathologically confirmed prostate nodules (39 malignant, 41 benign) were enrolled between January 2021 and June 2024. Univariate and multivariate analyses were conducted to identify key imaging risk factors associated with malignancy. The diagnostic performance of conventional MRI was compared with that of five CNN-assisted models (CNN-1 to CNN-5) based on sensitivity, specificity, and overall accuracy.

Results: Significant differences (p < 0.001) were observed between malignant and benign groups in imaging features, including signal distribution (χ² = 31.473), lesion margins (χ² = 19.776), lesion volume (t = 19.421), short-axis diameter (t = 10.337), long-axis diameter (t = 9.071), and the product of diameters (t = 6.548). Multivariate logistic regression identified these parameters as independent malignancy predictors, with odds ratios (ORs) ranging from 2.818 to 3.277 across training and validation cohorts. These variables were incorporated into a malignancy risk score model. Among all CNN models, CNN-3, characterized by three max-pooling layers, achieved the highest diagnostic sensitivity and accuracy. Receiver operating characteristic (ROC) analysis further confirmed its superior performance, demonstrating the largest area under the curve (AUC) and outperforming both conventional MRI and other CNN variants.

Conclusion: The CNN-based deep learning diagnostic system significantly enhances the classification accuracy of prostate nodules on mpMRI. The CNN-3 model enables automated lesion detection and feature extraction, improving early diagnosis and risk stratification. It shows strong potential to support clinical decision-making in prostate cancer management.

Background: Intestinal injury represents a key driver of multiple organ dysfunction syndrome (MODS) in patients with severe acute pancreatitis (SAP). Regulatory T cells (Treg cells) are crucial in maintaining normal physiological function of the intestine, and growth differentiation factor 11 (GDF11) exerts anti-inflammatory effects across diverse disease models. Nevertheless, the impact of GDF11 on SAP-associated intestinal injury and its role in modulating Treg cells' function remain incompletely elucidated. Therefore, this study aimed to investigate whether GDF11 mitigates SAP-induced intestinal damage by enhancing Treg cells' function.

Methods: A mouse model of SAP was induced using cerulein combined with lipopolysaccharide (LPS). Serum amylase and lipase levels, and hematoxylin-eosin (HE) staining, were used to assess pancreatic and intestinal tissue injury. The levels of inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were assessed using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Moreover, flow cytometry was used to analyze the proportion of splenic CD4⁺CD25⁺FOXP3⁺ cells to evaluate Treg cells. To evaluate Treg differentiation, naïve CD4⁺ T cells were cultured, Treg-related markers (CD134 and CD357) were measured by flow cytometry, and the proportion of CD25⁺FOXP3⁺ cells was determined.

Results: In vivo, GDF11 treatment substantially reduced serum amylase and lipase levels in SAP mice. Furthermore, the treatment alleviated histological injury in both the pancreatic and intestinal tissues (p < 0.01), decreased intestinal inflammation by reducing IL-6, IL-1β, and TNF-α (p < 0.05) levels, and increased the proportion of CD25⁺FOXP3⁺ regulatory T cells in the spleen of SAP mice (p < 0.05). Moreover, GDF11 induced the differentiation of mouse naïve CD4⁺ T cells into CD25⁺FOXP3⁺ Treg cells (p < 0.01), and GDF11-induced naïve CD4⁺ T cells exhibited the potential to enhance the expression of key suppressive molecules in Treg cells (p < 0.01).

Conclusion: The effect of GDF11 to promote CD25⁺FOXP3⁺ Treg cells' function represents a significant mechanism by which GDF11 safeguards intestinal tissue in the context of SAP.

Background: Acute myocardial infarction (AMI) is a type of myocardial necrosis caused by acute ischemia or blood flow interruption in the coronary arteries, which poses a serious threat to human health. Activation of cardiac fibroblasts (CFs) and macrophage polarization play a crucial role in the pathogenesis of AMI. This study aims to elucidate the regulatory mechanisms between CFs and macrophage polarization during AMI progression.

Methods: RNA-seq data of AMI were downloaded for analysis. Differential expression analyses were performed on genes encoding secreted proteins, differentially expressed genes in single-cell infarct fibroblasts, and infarct tissues using the Human Protein Atlas (HPA) database. Differentially expressed genes Latent transforming growth factor-β binding protein 3 (LTBP3) and podocan (PODN) were analyzed in single-cell data comparing AMI samples with CFs, followed by receiver operating characteristic (ROC) analysis. LTBP3 and PODN protein expression was examined in a hypoxic cell model. LTBP3 recombinant protein was used to transfect macrophages, and the expression of CD16, CD86, iNOS, MHC-II, CD163, CD206, and arginase (Arg), as well as levels of heparin-binding EGF-like growth factor (HBEGF), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were assessed.

Results: A total of 11 cell types were identified through RNA-seq analysis, and 12 genes co-expressed across three datasets. Notably, LTBP3 and PODN exhibited specifically high expression in myocardial infarction (MI) samples. Both LTBP3 and PODN were significantly upregulated in MI, particularly in CFs (p < 0.05). Western blotting validated the upregulation of LTBP3 in CFs from MI samples compared with normal controls (p < 0.05), while PODN expression showed no significant difference in the AMI cell model relative to controls (p > 0.05). Co-immunoprecipitation (Co-IP) assay demonstrated that LTBP3 interacts with HBEGF. Overexpression of LTBP3 in CFs promoted macrophages polarization toward the M1 phenotype, as indicated by increased levels of M1 markers (CD16, CD86, iNOS, and MHC-II), and decreased levels of M2 markers (CD163, CD206, and Arg) (p < 0.05). Additionally, elevated HBEGF expression in macrophages enhanced the secretion of pro-inflammatory factors IL-1β, IL-6, and TNF-α (p < 0.05). HBEGF knockdown reversed the effects of LTBP3-transfected CFs on macrophage differentiation and mitigated the inflammatory response, as evidenced by reduced IL-1β, IL-6, and TNF-α levels (p < 0.05).

Conclusion: LTBP3 in CFs modulates AMI progression by regulating macrophage polarization.

Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease with a high mortality rate. Macrophage infiltration and vascular smooth muscle cell (VSMC) apoptosis are crucial in AAD pathogenesis. However, Annexin A1 (ANXA1) may protect against AAD by mitigating aortic damage and cell apoptosis. Therefore, this study assesses the protective effects of ANXA1 in an Angiotensin II (Ang II)-induced AAD mouse model, focusing on survival rates, aortic structural integrity, and the mechanism underlying apoptosis in human aortic vascular smooth muscle cells (HAVSMCs) through regulation of M1 macrophages.

Methods: C57BL/6J mice (n = 40) were divided into four groups: the control group, ANXA1-treated group, Ang II-induced AAD group, and Ang II+ANXA1-treated group. The survival rate was monitored in AAD mice over a 28-day time point, and the diameters of the ascending aorta and aortic arch were evaluated by histological analysis. Immunohistochemistry (IHC) was used to examine cleaved caspase-3 levels in the thoracic aorta to assess VSMC apoptosis. In vitro, M1 macrophages were co-cultured with HAVSMCs. Immunofluorescence was performed to determine macrophage infiltration and oxidative stress by measuring F4/80 levels, Tetramethyl Rhodamine Ethyl Ester (TMRE) mitochondrial membrane potential, TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells, and reactive oxygen species (ROS) levels in tissues and cells. Additionally, cleaved caspase-3 expression was evaluated both in vivo and in vitro using Western blot analysis to further assess VSMC apoptosis.

Results: ANXA1 exhibited significant protective effects in the Ang II-induced AAD mouse model. The survival rate in the Ang II+ANXA1 group was markedly higher than in the Ang II group (p < 0.001). The Ang II group had significantly dilated ascending aorta (AA) and aortic arch (Arch) compared to the Ang II+ANXA1 group (p < 0.001), whereas ANXA1 treatment did not alter aortic diameter in healthy mice. ANXA1 treatment substantially alleviated aortic dissection, intramural hematoma, and elastic fiber rupture in AAD mice. The Ang II+ANXA1 group has significantly reduced cleaved caspase-3 expression compared to the Ang II group (p < 0.001), indicating decreased VSMCs apoptosis. Furthermore, ANXA1 treatment reduced macrophage infiltration (F4/80 expression) and the number of Neutrophil Cytosolic Factor 1 (NCF1)-positive macrophages (p < 0.001). In vitro co-culture of HAVSMCs with M1 macrophages showed that ANXA1 substantially alleviated NCF1-positive cells, mitochondrial dysfunction, and apoptosis (p < 0.001). However, NCF1 upregulation in M1 macrophages effectively counteracted these effects.

Conclusions: In summary, ANXA1 protects against Ang II-induced AAD by improving survival rates, reducing vascular abnormalities, and preserving aortic structural integrity. It also inhibits vascular smooth muscle cell apoptosis, macrophage infiltration, and NCF1 expression. Mechanistically, ANXA1 reduces mitochondrial-dependent smooth muscle cell apoptosis by suppressing M1 macrophage-derived NCF1. These findings suggest ANXA1 has a potential therapeutic agent for AAD by targeting both inflammation and oxidative stress.

Background: Disruption of epithelial tight junctions (TJs) promotes loss of polarity and increased invasiveness in gastric cancer. Claudin-18.2 (CLDN18.2), a stomach-specific TJ protein, is frequently downregulated or mislocalized in tumors. However, its functional role remains unclear. This study investigated how CLDN18.2 regulates tight junction integrity and interacts with junction-associated proteins in gastric cancer cells.

Methods: CLDN18.2 expression and subcellular localization in gastric cancer cells (MKN45) and normal gastric epithelial cells (GES-1) were examined using Western blotting and immunofluorescence. CLDN18.2 was silenced using siRNA in MKN45 and SNU-16 cells, and epithelial barrier function was evaluated by transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-Dextran permeability assays. The effects of CLDN18.2 knockdown on tight junction and adherens junction proteins were analyzed by Western blotting. Cell migration and invasion were evaluated using Transwell assays and wound-healing assays in MKN45 cells. Co-immunoprecipitation (Co-IP) was performed to validate CLDN18.2–Zonula occludens-1 (ZO-1) interactions, and rescue experiments with ZO-1 overexpression were performed to determine its ability to restore tight junction integrity following CLDN18.2 silencing. An orthotopic gastric cancer xenograft model was established in BALB/c nude mice using stably transfected MKN45 cells.

Results: CLDN18.2 was highly expressed in MKN45 cells and predominantly localized at the plasma membrane, co-localizing with ZO-1 and occludin. CLDN18.2 knockdown significantly reduced ZO-1, occludin, E-cadherin, and β-catenin expression (p < 0.001), decreased TEER, and increased FITC-Dextran permeability (p < 0.001), while markedly enhancing cell migration and invasion (p < 0.01). Pull-down assays confirmed that CLDN18.2 forms a complex with ZO-1 in an expression-dependent manner. ZO-1 overexpression partially restored tight junction protein levels and barrier function impaired by CLDN18.2 knockdown. In vivo, silencing of CLDN18.2 significantly increased the number of metastatic nodules in the orthotopic xenograft model (p < 0.001). In contrast, overexpression of ZO-1 effectively reversed this pro-metastatic effect and restored junctional protein expression.

Conclusion: CLDN18.2 maintains tight junction integrity in gastric cancer cells through interaction with ZO-1. Its downregulation disrupts cell-cell junctions, weakens epithelial barrier function, and promotes cell migration and invasion, whereas compensatory ZO-1 overexpression can partially reverse these effects. These findings reveal a key regulatory role of CLDN18.2 in gastric cancer progression, offering mechanistic support for CLDN18.2-targeted therapeutic strategies.

Background: Dysmenorrhea and menorrhagia are common consequences of adenomyosis. While conservative surgery can effectively preserve fertility in women with adenomyosis, they are still vulnerable to postoperative recurrence, for which a reliable long-term predictive tool is lacking. This study aimed to develop and validate a 5-year recurrence predictive model for adenomyosis patients after conservative surgery based on their clinical and imaging features.

Methods: In this retrospective study, 150 women aged 18–50 years who underwent uterus-preserving surgery for adenomyosis were analyzed. Clinical data, including imaging parameters, surgical characteristics, and postoperative management, were collected. Recurrence was defined as either a ≥3-point increase in Visual Analog Scale score for dysmenorrhea or a ≥50% increase in Pictorial Blood Assessment Chart score within five years. Multivariate Cox regression was used to construct a nomogram, with its predictive performance evaluated using concordance index (C-index), time-dependent receiver operating characteristic curves, calibration, and decision curve analysis (DCA).

Results: Four independent predictors were identified: older age, larger uterine volume, shorter duration of postoperative hormonal therapy, and concomitant endometriosis. The nomogram demonstrated good discriminative ability (C-index 0.766; AUCs 0.68, 0.73, 0.76 at 15, 24, and 48 months, respectively), along with reliable calibration and evident clinical net benefit. Kaplan–Meier analysis revealed that the nomogram effectively distinguished risk groups, with five-year recurrence-free survival rates of 78% in the low-risk group and 17% in the high-risk group.

Conclusion: By integrating clinical and imaging variables, the nomogram developed in this study demonstrates strong clinical applicability, accurately predicting recurrence risk in adenomyosis patients after conservative surgery and guiding personalized postoperative management.

Background: Kanamycin (KM) is a commonly used antibacterial agent in clinical practice, but it can induce ototoxicity, leading to sensorineural hearing loss. Previous studies have reported that deletion of the vacuolar H⁺-ATPase B2 subunit (ATP6V1B2) results in hearing impairment and that the mitogen-activated protein kinase (MAPK) pathway exerts a protective effect on cochlear cells in mice. Therefore, this study aimed to elucidate the role of ATP6V1B2 in KM-induced cochlear hair cell injury in mice and to explore the specific mechanisms involved.

Methods: KM and siRNA/overexpression constructs were used in combination in vivo and in vitro to evaluate the protective effect of ATP6V1B2 on cochlear hair cell injury. Auditory function in individual mice was assessed using auditory brainstem response (ABR) testing. HEI-OC1 cell viability was measured using the Cell Counting Kit-8 (CCK-8). Apoptosis in HEI-OC1 cells was detected with flow cytometry. Intracellular reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescin diacetate (DCFH-DA) through flow cytometry. The expression of vital regulatory factors, apoptotic markers, inflammatory mediators, and MAPK pathway proteins in HEI-OC1 cells was evaluated by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis.

Results: Following KM induction, the ABR threshold increased, the number of viable cells decreased, apoptosis was promoted, ROS accumulation was enhanced, and inflammatory factor expression in HEI-OC1 cells was elevated (p < 0.05). Compared with the KM group, Ad-ATP6V1B2 reversed the effects of KM on the ABR threshold, cell viability, apoptosis, ROS accumulation, and inflammatory factor expression (p < 0.05). In contrast, si-ATP6V1B2 exacerbated the effects of KM on the ABR threshold, viable cell number, apoptosis, ROS accumulation, and expression of inflammatory factors (p < 0.05). Ad-ATP6V1B2 exerted its protective effects on injured HEI-OC1 cells by inhibiting the p38 MAPK pathway and activating the ERK MAPK pathway (p < 0.05).

Conclusion: Ad-ATP6V1B2 protects against KM-induced HEI-OC1 cell injury by inhibiting the p38/MAPK axis and activating the ERK1/2/MAPK pathway. ATP6V1B2 effectively reverses KM-mediated cellular damage by modulating the MAPK signaling pathway. These findings suggest ATP6V1B2 may represent a novel therapeutic target for preventing and treating KM-mediated HEI-OC1 cell injury and hearing impairment.

Background: Temporal lobe epilepsy (TLE) is a common form of epilepsy, characterized by recurrent seizures, hippocampal tissue cell loss, and cognitive impairment. This study aimed to investigate the role of aspartyl-tRNA synthetase 2 (DARS2) in regulating the pathophysiological characteristics and apoptosis of hippocampal tissue in a rat model of TLE.

Methods: TLE was induced in rats using pilocarpine. Gene and protein expression levels in hippocampal tissues were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Spatial memory was evaluated using the Morris water maze test, and histopathological changes were analyzed by hematoxylin and eosin (HE) staining. The levels of inflammatory cytokines and antioxidant-related factors were determined by enzyme-linked immunosorbent assay (ELISA).

Results: DARS2 expression was significantly reduced in hippocampal tissues of TLE rats (p < 0.05). Upregulation of DARS2 improved spatial memory, alleviated histopathological damage, decreased cell apoptosis and inflammation, enhanced antioxidant capacity, increased expression of heme oxygenase-1 (HO-1) and B-cell lymphoma 2 (Bcl-2), and reduced cleaved caspase-3 levels (p < 0.05). Mechanistically, DARS2 promoted nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in rat hippocampal tissues, and silencing Nrf2 reversed the protective effects of DARS2 overexpression (p < 0.05).

Conclusion: DARS2 exerts neuroprotective effects in TLE by mitigating rat hippocampal pathophysiological damage, suppressing apoptosis, and enhancing antioxidant defenses through activation of the Nrf2 signaling pathway. These findings suggest that DARS2 may serve as a promising therapeutic target for the treatment of TLE and related cognitive deficits.

Background: Acute kidney injury (AKI) poses a serious threat to patients' health, creating an urgent need for effective prevention and treatment strategies. Propofol, an anesthetic used in clinical practice, has demonstrated protective effects across several organs. This study aims to explore the effect of propofol on AKI and its underlying mechanism.

Methods: An AKI model was established by using lipopolysaccharide (LPS) injection. At 24 hours post-operation, renal function was evaluated through biochemical analyzers and hematoxylin-eosin staining. The level of oxidative stress was detected using a biochemical kit. Iron death-related proteins in kidney tissues were evaluated by Western blot (WB) analysis, and iron deposition was observed by Perls staining. The levels of inflammatory factors were detected by Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. In vitro experiments were performed using human proximal tubular epithelial cells (HK-2). Cell viability was detected by Cell Counting Kit-8 assay, intracellular reactive oxygen species (ROS) was detected by flow cytometry, and the expression of ferroptosis-related proteins was determined by WB.

Results: In the in vivo experiments, propofol treatment significantly improved renal function (p < 0.05). The indicators related to oxidative stress and ferroptosis were downregulated (p < 0.05). The levels of inflammatory factors were reduced, and the activation of the inflammatory body was suppressed (p < 0.05). The in vitro experiments showed that propofol could significantly increase the cell viability of HK-2 (p < 0.05), reduce ROS production (p < 0.05), downregulate ferroptosis-related proteins levels (p < 0.05), and inflammatory responses (p < 0.05). Upon induction of ferroptosis with Erastin, the protective effect of propofol was attenuated (p < 0.05).

Conclusions: Propofol has a significant protective effect on AKI, mainly through inhibiting ferroptosis and inflammatory responses in renal tubular epithelial cells. This research provides a strong theoretical basis and experimental foundation for the clinical application of propofol in the prevention and treatment of AKI.