Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) globally, representing a major global health burden with limited disease-modifying therapies. Podocyte injury serves as the core pathological hallmark of DN, and conventional treatments targeting metabolic disorders or hemodynamic abnormalities fail to reverse the progressive decline of renal function. Accumulating evidence over the past decade has established that high glucose-induced podocyte pyroptosis—a pro-inflammatory form of programmed cell death—is a key driving force in DN progression. Its core molecular mechanism hinges on the activation of the TXNIP-NLRP3 inflammasome axis. Under sustained hyperglycemic conditions, excessive reactive oxygen species (ROS) are generated via pathways including the polyol pathway, advanced glycation end products (AGEs) accumulation, and mitochondrial dysfunction. Concurrently, methylglyoxal (a glucose metabolite) mediates post-translational modification of thioredoxin-interacting protein (TXNIP). These events collectively trigger the dissociation of TXNIP from thioredoxin (TRX), a redox-regulating protein. The free TXNIP then translocates to the mitochondria, where it binds to The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and promotes inflammasome assembly. This assembly activates cysteine-aspartic acid protease 1 (caspase-1), which cleaves Gasdermin D (GSDMD) to generate its N-terminal fragment (GSDMD-NT). GSDMD-NT oligomerizes to form membrane pores, leading to podocyte swelling, rupture, and the release of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). These cytokines amplify local inflammatory responses, induce mesangial cell proliferation, and accelerate extracellular matrix deposition, ultimately exacerbating glomerulosclerosis. MCC950, a highly selective NLRP3 inhibitor, exerts its therapeutic effects through a multi-layered mechanism: it binds to the NACHT domain (NAIP, CIITA, HET-E and TP1 domain) of NLRP3 with nanomolar affinity, forming hydrogen bonds with key residues (Lys-42 and Asp-166) within the ATP-hydrolysis pocket to block ATP hydrolysis, thereby locking NLRP3 in an inactive conformational state. Additionally, MCC950 interferes with the protein-protein interaction between TXNIP and NLRP3 and regulates mitochondrial homeostasis to reduce ROS production. Preclinical studies have demonstrated that MCC950 dose-dependently reduces proteinuria, restores the expression of podocyte-specific markers (nephrin and Wilms tumor 1 protein, WT1), and alleviates podocyte foot process fusion and glomerulosclerosis in both streptozotocin (STZ)-induced type 1 diabetic models (characterized by absolute insulin deficiency) and db/db type 2 diabetic models (driven by insulin resistance). However, discrepancies in therapeutic outcomes exist across different models—some studies report exacerbated renal inflammation and fibrosis in STZ-induced models—which may stem from differences in disease pathogenesis, intervention timing (early vs. mid-stage disease), and dosing duration. Despite its promising preclinical efficacy, MCC950 faces significant translational challenges, including low oral bioavailability, insufficient podocyte targeting, potential hepatotoxicity, and drug-drug interactions with statins (commonly prescribed to diabetic patients for cardiovascular risk management). Furthermore, off-target effects such as the inhibition of carbonic anhydrase 2 have been identified, raising concerns about its safety profile. Nevertheless, its unique mechanism of action—directly blocking podocyte pyroptosis by targeting the TXNIP-NLRP3 axis—endows it with substantial translational value. In the future, strategies to overcome these barriers are expected to advance its clinical application: targeted delivery via nanocarriers (e.g., PLGA-PEG nanoparticles or nephrin antibody-conjugated systems) to enhance renal accumulation and podocyte specificity; precise patient stratification based on biomarkers such as serum IL-18 and renal TXNIP/NLRP3 expression to identify “inflammatory-phenotype” DN patients most likely to benefit; and combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors—whose metabolic benefits synergize with MCC950’s anti-inflammatory effects. These approaches hold great potential to break through clinical translation bottlenecks, offering a novel, precise anti-inflammatory treatment option for DN and addressing an unmet clinical need for therapies targeting the inflammatory underpinnings of the disease.

Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) globally, representing a major global health burden with limited disease-modifying therapies. Podocyte injury serves as the core pathological hallmark of DN, and conventional treatments targeting metabolic disorders or hemodynamic abnormalities fail to reverse the progressive decline of renal function. Accumulating evidence over the past decade has established that high glucose-induced podocyte pyroptosis—a pro-inflammatory form of programmed cell death—is a key driving force in DN progression. Its core molecular mechanism hinges on the activation of the TXNIP-NLRP3 inflammasome axis. Under sustained hyperglycemic conditions, excessive reactive oxygen species (ROS) are generated via pathways including the polyol pathway, advanced glycation end products (AGEs) accumulation, and mitochondrial dysfunction. Concurrently, methylglyoxal (a glucose metabolite) mediates post-translational modification of thioredoxin-interacting protein (TXNIP). These events collectively trigger the dissociation of TXNIP from thioredoxin (TRX), a redox-regulating protein. The free TXNIP then translocates to the mitochondria, where it binds to The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and promotes inflammasome assembly. This assembly activates cysteine-aspartic acid protease 1 (caspase-1), which cleaves Gasdermin D (GSDMD) to generate its N-terminal fragment (GSDMD-NT). GSDMD-NT oligomerizes to form membrane pores, leading to podocyte swelling, rupture, and the release of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). These cytokines amplify local inflammatory responses, induce mesangial cell proliferation, and accelerate extracellular matrix deposition, ultimately exacerbating glomerulosclerosis. MCC950, a highly selective NLRP3 inhibitor, exerts its therapeutic effects through a multi-layered mechanism: it binds to the NACHT domain (NAIP, CIITA, HET-E and TP1 domain) of NLRP3 with nanomolar affinity, forming hydrogen bonds with key residues (Lys-42 and Asp-166) within the ATP-hydrolysis pocket to block ATP hydrolysis, thereby locking NLRP3 in an inactive conformational state. Additionally, MCC950 interferes with the protein-protein interaction between TXNIP and NLRP3 and regulates mitochondrial homeostasis to reduce ROS production. Preclinical studies have demonstrated that MCC950 dose-dependently reduces proteinuria, restores the expression of podocyte-specific markers (nephrin and Wilms tumor 1 protein, WT1), and alleviates podocyte foot process fusion and glomerulosclerosis in both streptozotocin (STZ)-induced type 1 diabetic models (characterized by absolute insulin deficiency) and db/db type 2 diabetic models (driven by insulin resistance). However, discrepancies in therapeutic outcomes exist across different models—some studies report exacerbated renal inflammation and fibrosis in STZ-induced models—which may stem from differences in disease pathogenesis, intervention timing (early vs. mid-stage disease), and dosing duration. Despite its promising preclinical efficacy, MCC950 faces significant translational challenges, including low oral bioavailability, insufficient podocyte targeting, potential hepatotoxicity, and drug-drug interactions with statins (commonly prescribed to diabetic patients for cardiovascular risk management). Furthermore, off-target effects such as the inhibition of carbonic anhydrase 2 have been identified, raising concerns about its safety profile. Nevertheless, its unique mechanism of action—directly blocking podocyte pyroptosis by targeting the TXNIP-NLRP3 axis—endows it with substantial translational value. In the future, strategies to overcome these barriers are expected to advance its clinical application: targeted delivery via nanocarriers (e.g., PLGA-PEG nanoparticles or nephrin antibody-conjugated systems) to enhance renal accumulation and podocyte specificity; precise patient stratification based on biomarkers such as serum IL-18 and renal TXNIP/NLRP3 expression to identify “inflammatory-phenotype” DN patients most likely to benefit; and combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors—whose metabolic benefits synergize with MCC950’s anti-inflammatory effects. These approaches hold great potential to break through clinical translation bottlenecks, offering a novel, precise anti-inflammatory treatment option for DN and addressing an unmet clinical need for therapies targeting the inflammatory underpinnings of the disease.

Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Objective To systematically evaluate the therapeutic effects of different surgical procedures for ischemic mitral regurgitation (IMR). Methods Computer searches were conducted in CNKI, Wanfang, VIP, CBM, PubMed, Cochrane Library, Embase, and Web of Science, with the search time limit from the inception of the databases to February 2024. Two researchers independently screened the literature, extracted data, used the Cochrane bias risk assessment tool to evaluate the quality of the included studies, and used Stata 17.0 software to analyze the data. Results A total of 19 randomized controlled trials involving 6139 patients were finally included, involving six surgical procedures, and the overall quality of the included studies was relatively high. The results of the network meta-analysis showed that the 30-day all-cause mortality rate of mitral valve repair (MVr) was significantly lower than that of coronary artery bypass grafting (CABG) [OR=0.24, 95%CI (0.07, 0.87), P<0.01], mitral valve replacement (MVR) [OR=0.43, 95%CI (0.23, 0.79), P=0.02], CABG+MVR [OR=0.21, 95%CI (0.04, 0.95), P=0.03] and transcatheter mitral valve edge-to-edge repair (TEER) using MitraClip [OR=0.13, 95%CI (0.02, 0.87), P<0.01]. The 30-day all-cause mortality rate of CABG+MVr was significantly lower than that of CABG [OR=0.56, 95%CI (0.33, 0.93), P=0.02] and CABG+MVR [OR=0.48, 95%CI (0.24, 0.94), P=0.04], and the best probability ranking results showed that MVR might be the most effective in reducing the 30-day all-cause mortality rate. The incidence of renal complications in CABG+MVr was significantly lower than that in CABG+MVR [OR=0.42, 95%CI (0.21, 0.83), P=0.01]; the best probability ranking results showed that CABG+MVr might be the most effective in reducing renal complications. Conclusion The current limited evidence suggests that CABG+MVr and MVr may be the best surgical intervention methods for IMR patients at present. Due to the limitations of the number and quality of included studies, the above conclusions still need to be verified by more high-quality studies.

Objective To systematically evaluate the differences in outcomes between functional mitral regurgitation (FMR) and degenerative mitral regurgitation (DMR) in patients treated with transcatheter edge-to-edge repair (TEER) using the MitraClip device. Methods A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, the CNKI, Wanfang Database, VIP Database, and the CBM from their inception to January 2024. Two researchers independently performed study selection, data extraction, and risk of bias assessment. The quality of cohort studies was evaluated using the Newcastle-Ottawa Scale (NOS). A meta-analysis was performed using Stata 18.0 software. Results A total of 13 cohort studies involving 6 402 patients were included, comprising 4 161 patients in the FMR group and 2 241 in the DMR group. All included studies had NOS scores of ≥6 points. The meta-analysis revealed that compared to the DMR group, the FMR group had a higher 1-year all-cause mortality rate [OR=1.53, 95%CI (1.30, 1.81), P＜0.01] and a higher 1-year rehospitalization rate for heart failure [OR=1.90, 95%CI (1.60, 2.26), P＜0.01]. Conversely, the FMR group had a lower post-procedural mean transmitral gradient [SMD=–0.47, 95%CI (–0.65, –0.30), P＜0.01] and a lower rate of subsequent mitral valve surgery [OR=0.41, 95%CI (0.20, 0.83), P=0.01]. Conclusion Following MitraClip therapy, patients with FMR exhibit favorable short-term outcomes, but their mid- to long-term outcomes are inferior to those of patients with DMR. When determining the treatment strategy with MitraClip, the specific etiology of mitral regurgitation should be considered for a more accurate prediction of therapeutic efficacy and prognosis.

Exercise, as a non-pharmacological intervention, holds a pivotal role in metabolic regulation, neuroplasticity, and immune homeostasis maintenance. However, human exercise studies are constrained by ethical limitations in tissue sampling, especially for key organs such as muscles and the brain. Meanwhile, rodent models like mice exhibit physiological differences in exercise patterns and metabolic rates from human. Despite these challenges, approximately 70% of human and mouse genes are conserved, providing a molecular basis for cross-species comparisons. This paper leverages the GEPREP database, which integrates human and mouse exercise transcriptomic data from multiple platforms, to conduct a comprehensive cross-species analysis of exercise-induced gene expression patterns. We employ a stringent data standardization process, including the conversion of orthologous genes and the filtering of low-expressing genes, to ensure the accuracy and reliability of the analysis. A mixed-effects model is utilized to assess differential gene expression across multiple cohorts, identifying genes that are significantly upregulated or downregulated in response to exercise. The analysis reveals a complex pattern of gene expression, with a significant number of genes showing conserved responses between humans and mice, particularly in acute aerobic exercise, where genes such as ATF3, PPARGC1A, and ANKRD1 are commonly upregulated. These genes are implicated in muscle stress response, metabolic regulation, and muscle adaptation, highlighting the shared molecular pathways activated by exercise across species. However, the study also uncovers substantial species-specific differences in gene expression, especially in chronic aerobic exercise, where the number of divergently regulated genes increases. These differences suggest that while some fundamental biological processes are conserved, the specific regulatory mechanisms and gene expression patterns can vary significantly between humans and mice. Functional enrichment analysis further reveals that conserved genes are involved in muscle development, inflammation regulation, and energy metabolism, while species-specific genes are associated with ion transport, extracellular matrix (ECM) organization, and muscle contraction, indicating the multifaceted impact of exercise on skeletal muscle function. The findings emphasize the importance of considering species-specific differences when interpreting results from animal models and translating them to human health applications. The study highlights the need for a more nuanced understanding of the molecular underpinnings of exercise-induced adaptations and underscores the value of cross-species comparative analyses in uncovering the evolutionary and functional basis of these responses. Future research should focus on integrating multi-omics data and expanding the analysis to include other tissues to provide a more comprehensive view of the systemic effects of exercise. Additionally, the development of species-specific gene editing models and the validation of key genes in exercise physiology will further enhance our understanding of the evolutionary logic behind exercise interventions. This study not only provides valuable insights into the molecular mechanisms of exercise-induced adaptations but also underscores the necessity of validating findings from animal models in human cohorts to ensure the reliability and applicability of translational research in exercise science. By addressing these aspects, the study aims to bridge the gap between basic research and clinical applications, ultimately contributing to the development of personalized exercise prescriptions and interventions that can effectively promote health and prevent diseases.

Objective To systematically evaluate the impact of pulmonary hypertension (PH) on the prognosis of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Methods A computerized search was conducted in CNKI, Wanfang Data, VIP, CBM, PubMed, The Cochrane Library, EMbase, and Web of Science databases from inception to June 2023 for cohort studies on the prognostic impact of PH in severe AS patients undergoing TAVR. Two researchers independently screened the literature, extracted data, and assessed the quality of included studies. Stata 17.0 software was used for meta-analysis. Results A total of 16 cohort studies were included, all with Newcastle-Ottawa Scale scores≥7. Meta-analysis results showed that, compared with AS patients without PH, those with PH had significantly higher 1-year all-cause mortality after TAVR [OR=2.10, 95%CI (1.60, 2.75), P<0.01], 30-day all-cause mortality [OR=2.09, 95%CI (1.54, 2.83), P<0.01], and cardiovascular mortality [OR=1.49, 95%CI (1.18, 1.90), P<0.01]. The differences between the two groups in major bleeding events, stroke, myocardial infarction, pacemaker implantation, and postoperative renal failure were not statistically significant. For outcome indicators with significant heterogeneity, subgroup analyses were performed based on PH measurement methods, diagnostic criteria, and different types of PH. The results showed that most subgroup combined results were consistent with the overall findings and that heterogeneity was significantly reduced. Conclusion PH significantly increases the 30-day all-cause mortality, 1-year all-cause mortality, and cardiovascular mortality in patients with severe AS undergoing TAVR.

Objective: To evaluate the efficacy and safety of plasma exchange (PE) in thymoma-associated myasthenia gravis (MG), thereby to provide theoretical support for its application in the treatment of thymoma-associated MG. Methods: A total of 133 patients with thymoma-associated MG admitted from January 2018 to September 2024 were retrospectively analyzed. Patients were matched using propensity score to reduce selection bias, yielding 22 matched pairs for both PE group (n=22) and non-PE group (n=22). Patient characteristics including gender, age of disease onset, course of disease, history of thymoma resection, clinical absolute scores [clinical absolute scores (CAS) and clinical relative scores (CRS)], and synchronized immunotherapy regimen of the two groups were analyzed. The CAS scores before and after treatment were compared between the two groups, and the CRS was used to assess the treatment efficiency. Safety of the two treatment regimens were also compared. Continuous variables were compared using the t-test or ANOVA, while categorical data were compared by the chi-square test. Results: A total of 133 patients were included and divided into two groups according to whether they underwent plasma exchange treatment: the PE group (n=22) and the non-PE group (n=111). To exclude bias caused by large difference in the number of cases between the two groups, we performed propensity score matching. After matching, the number of cases in both groups was 22. There was no significant difference in baseline clinical characteristics between the two groups (P>0.05), including gender, age of onset, duration of disease course, history of thymectomy and baseline CAS score before treatment. Compared to the non-PE group, patients in the PE group showed more significant improvement in CAS score (5.09±1.95 vs 3.59±1.50, P<0.05) and a higher CRS score (75.00% vs 50.00%, P<0.001). Compared to the non-PE group, PE group had significantly longer ICU stay, longer hospital stay and higher hospitalization cost (P<0.05). There was no statistically significant difference in adverse events between the two groups during treatment (P>0.05). During long-term follow-up, both the PE and non-PE groups showed relatively low 1-, 3-, and 5-year recurrence rate, with no significant difference between the two groups (P>0.05). Conclusion: This study indicates that plasma exchange has clear value in the treatment of patients with thymoma-associated myasthenia gravis. It can not only significantly improve patients' muscle strength to alleviate motor dysfunction and enhance quality of life, but also does not significantly increase the incidence of adverse reactions. Therefore, it can be regarded as one of the preferred treatment options that achieve a "balance between efficacy and safety" for such patients, and provides an important basis for optimizing treatment strategies, improving prognosis, and promoting the application of subsequent treatment regimens.

Esophageal squamous cell carcinoma (ESCC) poses a significant global health challenge, necessitating early detection, timely diagnosis, and prompt treatment to improve patient outcomes. Endoscopic examination plays a pivotal role in this regard. However, despite the availability of various endoscopic techniques, certain limitations can result in missed or misdiagnosed ESCCs. Currently, artificial intelligence (AI)-assisted endoscopic diagnosis has made significant strides in addressing these limitations and improving the diagnosis of ESCC and precancerous lesions. In this review, we provide an overview of the current state of AI applications for endoscopic diagnosis of ESCC and precancerous lesions in aspects including lesion characterization, margin delineation, invasion depth estimation, and microvascular subtype classification. Furthermore, we offer insights into the future direction of this field, highlighting potential advancements that can lead to more accurate diagnoses and ultimately better prognoses for patients.
Humans ; Artificial Intelligence ; Esophageal Squamous Cell Carcinoma/diagnosis* ; Esophageal Neoplasms/diagnosis* ; Precancerous Conditions/diagnosis*