Membranous nephropathy is an autoimmune disease associated with antibodies against podocyte proteins, and it is the main cause of nephrotic syndrome in adults. Rituximab has now become the first-line treatment for membranous nephropathy, with 80% of patients achieving remission. However, some patients develop drug resistance or experience relapse to rituximab. Potential resistance mechanisms include changes in bioavailability and pharmacokinetics, rituximab internalization by B cells, memory B cells escape from rituximab, generation of anti-rituximab antibodies, impact of phospholipase A2 receptor antibodies and epitope spreading, and chronic and irreversible kidney injury. Understanding these specific resistant mechanisms has driven the development of multiple therapies. Emerging treatments, including next-generation anti-CD20 monoclonal antibodies, B lymphocyte stimulator inhibitors, proteasome inhibitors, complement inhibitors, and plasma cell-targeted drugs, offer new hope for these patients. This review summarizes the potential mechanisms of rituximab resistance in membranous nephropathy and recent therapeutic advances, aiming to provide guidance for clinical management of membranous nephropathy.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, hepatocellular injury and fibrosis, with the capacity to progress to cirrhosis and hepatocellular carcinoma. Recent evidence highlights cellular senescence, particularly in hepatic stellate cells (HSCs) as a key regulator of MASH pathogenesis. Senescent HSCs exhibit a context-dependent duality whereby, while transient senescence limits fibrosis through cell-cycle arrest, matrix degradation and enhanced immune clearance, persistent senescence under chronic metabolic and inflammatory stress drives disease progression. Through an expanded senescence-associated secretory phenotype (SASP), senescent HSCs exacerbate inflammation, promote extracellular matrix deposition, alter immune responses and facilitate malignant transformation. The present review summarizes the molecular mechanisms inducing HSC senescence, including lipotoxicity, oxidative stress, DNA damage, mitochondrial dysfunction and impaired autophagy. The mechanisms by which SASP factors mediate crosstalk between senescent HSCs and other cell types are discussed, including hepatocytes, macrophages, T cells and natural killer cells, collectively altering the inflammatory and fibrotic microenvironment of MASH. Finally, emerging therapeutic strategies targeting cellular senescence are highlighted, such as senolytics, senomorphics and biomarker-guided interventions, which may offer promising avenues for modifying the course of MASH and preventing disease progression.

Rituximab is an established therapy for primary membranous nephropathy, but anti-rituximab antibodies (ARA) have been associated with rituximab treatment failure. We report a 66-year-old woman with PLA2R-positive membranous nephropathy who developed ARA positivity and clinical features consistent with rituximab treatment failure, including B-cell reconstitution, undetectable serum rituximab levels, and worsening proteinuria despite declining anti-PLA2R antibody titers. Kidney biopsy confirmed stage III membranous nephropathy. She was subsequently treated with the humanized type II anti-CD20 antibody obinutuzumab, which induced complete depletion of circulating B cells, achieved therapeutic serum concentration, follow by both immunological and clinical remission within 8.5 months, despite persistent ARA positivity. This case suggests that obinutuzumab may be an effective rescue option after rituximab failure associated with ARA and underscores the importance of integrating therapeutic drug monitoring, ARA detection, and B-cell kinetics assessment in the management of refractory membranous nephropathy.

BACKGROUND:Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) but its underlying mechanisms remain incompletely understood. Our previous study demonstrated that insulin-like growth factor-binding protein 5 (IGFBP-5) promotes glycolytic reprogramming in vascular endothelial cells (ECs) and exacerbates renal inflammation in diabetic kidney disease. METHODS:Human renal proximal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVECs) were used. A co-culture system was employed to investigate endothelial cell-tubular epithelial cell (EC-TEC) crosstalk. Unilateral ureteral obstruction (UUO) and aristolochic acid nephropathy (ANN) models were established in wild-type (WT), global IGFBP-5-/- and endothelial-specific Tie-2 Cre;IGFBP-5-/- mice. Expression levels of IGFBP-5, TGF-β1 and fibrosis markers were assessed to investigate the role of IGFBP-5 in renal fibrogenesis. RESULTS:Serum IGFBP-5 levels were significantly elevated in patients with CKD. Genetic ablation of IGFBP-5 attenuated renal fibrosis in murine models, demonstrating its critical role in fibrogenesis. IGFBP-5 was predominantly expressed in ECs and endothelial-specific deletion delayed renal fibrosis progression via suppression of the TGF-β1/Smad3 pathway. In vitro, endothelial-derived IGFBP-5 promoted a profibrotic phenotypic transformation in TECs through AKT-mediated phosphorylation of the TGF-β1/Smad3 axis. Conversely, TGF-β1 stimulated IGFBP-5 biosynthesis and secretion in ECs via the ERK signalling pathway, establishing a self-amplifying feedback loop. This reciprocal IGFBP-5/TGF-β1 crosstalk between ECs and TECs was confirmed in co-culture experiments. CONCLUSION:Our findings reveal a novel EC-TEC crosstalk axis mediated by reciprocal IGFBP-5/TGF-β1 signalling, which is a critical driver of renal fibrosis. IGFBP-5 emerges as a promising therapeutic target for inhibiting renal fibrogenesis in CKD.

BACKGROUND AND HYPOTHESIS:Rituximab (RTX) is a first-line therapy targeting B cells; however, 30%-40% of patients exhibit treatment resistance or relapse. Studies have shown that anti-rituximab antibodies (ARA) may lead to RTX resistance through mechanisms such as drug neutralization. The objective of this study is to explore the relationship between the emergence of ARA and the clinical efficacy of initial RTX treatment in adult MN. METHODS:Patients with MN who received RTX therapy were included in this study. Clinical data and laboratory results of the patients were collected, and ARA levels in serum samples were measured using a commercial ELISA kit. The impact of ARA on the clinical outcomes of MN patients treated with RTX was analyzed. RESULTS:Among 58 patients with membranous nephropathy who received initial RTX treatment, 11 patients (19.0%) tested positive for ARA. ARA were identified after a median of 9.3 months (IQR 8.2-11.1) following the last RTX injection. Among the patients who received initial RTX treatment and were monitored for over 6 months, ARA-positive patients (n = 11) exhibited a higher relapse rate (80.0% vs. 24.1%, P = 0.029) than ARA-negative patients (n = 41), which was also confirmed by Kaplan-Meier analysis (log-rank test, P = 0.027). At 6 months post-initial RTX, ARA-positive patients demonstrated higher B cell levels (p = 0.021). Four RTX-resistant and ARA-positive patients achieved clinical remission with obinutuzumab, with a median remission time of 4.8 months (IQR 3.0-6.8). CONCLUSION:This study confirms that adult patients with MN who are ARA positive have a higher relapse rate after initial RTX treatment. Patients who are RTX-resistant and ARA positive can achieve rapid clinical remission after receiving obinutuzumab treatment.

Interstitial cystitis/bladder pain syndrome (IC/BPS) and metabolic syndrome (MetS) are complex disorders with overlapping clinical features, and emerging evidence suggests oxidative stress and ferroptosis may underlie their pathogenesis. Here, using an integrative approach combining bioinformatics, immunohistochemistry, and functional studies in cellular and animal models, we identified NFE2 as a key regulator significantly upregulated in IC/BPS patients, particularly those with MetS comorbidity, where it promotes ferroptosis through competitive inhibition of Nrf2-mediated antioxidant responses, leading to reactive oxygen species accumulation and lipid peroxidation. We further demonstrated that the natural flavonoid naringenin (NAG) specifically binds to NFE2, downregulates its expression, and activates the Nrf2/NQO-1 pathway, resulting in improved bladder function, reduced inflammation, and attenuated fibrosis in animal models. These findings establish NFE2-mediated ferroptosis as a novel pathogenic link between IC/BPS and MetS and identify NAG as a promising therapeutic agent capable of simultaneously targeting metabolic and inflammatory components in refractory IC/BPS patients with metabolic dysfunction.

Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a common challenge in various clinical practices, yet effective therapies remain elusive. Endothelial injury plays a crucial role in the pathogenesis of renal IRI. Endothelial progenitor cells (EPCs) derived extracellular vesicles (EVs) hold promise as cell-free therapies for treating renal IRI; however, their efficacy is limited by low delivery efficiency. In this study, we developed neutrophils (NEs) membrane-modified EVs (N-EVs) by exploiting the natural properties of NEs to target damaged endothelium. N-EVs inherited the characteristic membrane proteins of NEs along with the biological functions of EPCs-EVs. Results from in vitro and in vivo experiments demonstrated that N-EVs significantly enhanced the targeting efficiency of EVs towards IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). Moreover, N-EVs effectively promoted the proliferation, migration, and tube-formation abilities of injured endothelial cells (ECs) and contributed to overall renal function improvement in IRI kidneys through targeted delivery of miR-21-5p. Additionally, N-EVs could restore damaged endothelial integrity, reduce cytokine release, and inhibit leukocyte infiltration, hence alleviating renal inflammation. In conclusion, our accessible engineering approach represents a promising strategy for treating renal IRI. Furthermore, this membrane hybrid modification can be tailored and optimized for broader applications in treating other diseases.

BackgroundGastric cancer (GC) is a malignant tumor with poor prognosis. The diverse patterns of programmed cell death (PCD) are significantly associated with the pathogenesis and progression of GC, and it has the potential to serve as prognostic and drug sensitivity indicators for GC.MethodThe sequencing data and clinical characteristics of GC patients were downloaded from The Cancer Genome Atlas and GEO databases. LASSO cox regression method was used to screen feature genes and develop the PCD score (PCDS). Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore immunotherapy response. By integrating PCDS with clinical characteristics, we constructed and validated a nomogram that demonstrated robust predictive performance.ResultsWe screened nine PCD-related genes (SERPINE1, PLPPR4, CDO1, MID2, NOX4, DYNC1I1, PDK4, MYB, TUBB2A) to create the PCDS. We found that GC patients with high PCDS experienced significantly poorer prognoses, and PCDS was identified as an independent prognostic factor. Furthermore, there was a significant difference in immune profile between high PCDS and low PCDS groups. Additionally, drug sensitivity analysis indicated that patients with a high PCDS may exhibit resistance to immunotherapy and standard adjuvant chemotherapy regimens; however, they may benefit from the FDA-approved drug Dasatinib.ConclusionOverall, we confirmed that the PCDS is a prognostic risk factor and a valuable predictor of immunotherapy response in GC patients, which provides new evidence for the potential application of GC.

The use of tourniquets (TQ) during the total knee arthroplasty (TKA) induced ischemia–reperfusion (I/R) injury in the limb, resulting in the release of inflammatory cytokines and reactive oxygen species (ROS), therefore leading to myocardial damage. This study aimed to investigate the effects and molecular mechanism of Esketamine on myocardial injury (MI) caused by TQ-induced I/R injury. A randomized numerical table method was used to divide 23 patients into the C group (11 cases, ACB + conventional anesthesia) and M group (12 cases, ACB + conventional anesthesia + 0.5 mg/kg Esketamine). The levels of lactate dehydrogenase (LDH), Malondialdehyde (MDA), Fe2+, Glutathione Peroxidase (GSH-Px), glutathione (GSH), IL-6, TNF-α, Creatine Kinase (CK) and CreatineKinase-MB (CKMB) were determined by reagent kits. The expression of CGAMP interaction factor (STING), Glutathione Peroxidase 4 (GPX4), and Ferritin Heavy Chain 1 (FTH1) was examined by Western blot. The ROS level was tested by flow cytometry. The expression of STING was validated by immunofluorescence. Compared with the C group, the levels of GSH-Px and GSH were increased while the levels of IL-6, TNF-α, MDA, Fe2+, CK, CKMB, and LDH were decreased in the M group. Furthermore, esketamine relieved the OGD/R-induced increase of MDA, Fe2+, and ROS and the decrease of GSH-Px, GSH, GPX4, and FTH1, which were reversed by STING overexpression. Esketamine alleviated cardiomyocyte ferroptosis via STING, which might be the molecular mechanism of Esketamine to ameliorate the MI caused by TQ-induced I/R injury.

BackgroundPatients with primary hypertension are always comorbid with hyperuricemia. Serum uric acid exhibits a dual role in cognitive function. Evidence regarding the relationship between uric acid (SUA) and cognitive dysfunction in specific hypertensive patients remains inconsistent.ObjectiveTo develop a predictive model to evaluate the association between serum uric acid level and mild cognitive impairment (MCI) in hypertensive populations.MethodsThis cross-sectional study involved 420 middle-aged and elderly hypertensive patients. Cognitive function was evaluated using MMSE and MoCA. Univariate and multivariate logistic regression, restricted cubic splines (RCS), and SHAP analysis were employed.ResultsIn MCI group, diabetes prevalence, hyperuricemia prevalence, arteriosclerosis prevalence, education level, MMSE score, MoCA score, AD8 score and HbA1c were higher, while weight, BMI, SUA, TC, LDL, Alb, TT3, TSH, and FT3 were lower. After adjusting for confounding factors, it was found that the SUA level (OR = 0.754, 95%CI: 0.578–0.985, 0.038) could still be used as an independent protective factor for MCI. Subgroup analyses indicated effects varied significantly with diabetes history and regular exercise. Shap values showed that SUA is the fifth most related factor, with more significant ones including age, education level, albumin and thyroxin. A nonlinear association was found between SUA and MCI risk, with an inflection point at approximately 450 μmol/L.ConclusionSUA has a certain correlation with MCI in the middle-aged and elderly hypertensive populations. Although SUA is considered as a neuroprotective agent, its neuroprotective function gradually diminishes and may even become detrimental when SUA higher than a threshold. These results suggest maintaining SUA within an optimal range may help mitigate MCI risk in hypertensive populations.

Abstract Background and Aims Renal fibrosis is a common pathophysiological characteristic of chronic kidney disease (CKD) for which there is no effective treatment. The mechanism of renal fibrosis is complicated and remains unclear. Our previous study revealed that Insulin-like growth factor binding protein 5 (IGFBP-5) induces glycolytic activation in ECs and ultimately aggravates renal inflammation in diabetic kidney disease (DKD). This study aims to discover the relationship between IGFBP-5 and renal fibrosis. Method HK-2 and HUVEC cells were included in this study. UUO and ANN model were obstructed by Wild-type, IGFBP-5−/− and IGFBP-5flox/flox, cre mice. IGFBP-5, TGF-β and fibrosis makers were detected to explore the mechanism of IGFBP-5 in fibrosis. Results We found that the serum IGFBP-5 levels were significantly increased in CKD, that IGFBP-5 was dominantly localized in vascular endothelial cells (ECs) of kidney tissue, and that IGFBP-5 deficiency relieved renal fibrosis in CKD model mice. In vitro experiments indicated that IGFBP-5 exacerbated the fibrosis phenotypic alteration of tubular epithelial cells (TECs) by the TGF-β1/p-Smad3 signaling pathway. In turn, TGF-β1 could facilitate the synthesis of IGFBP-5 in ECs. The crosstalk between TECs and ECs mediated by IGFBP-5 and TGF-β1 was confirmed in a coculture system and endothelial-specific IGFBP-5-deficient mice. Conclusion Renal fibrosis is exacerbated by TEC-EC cellular crosstalk through the feedback loop consisting of IGFBP-5 and TGF-β1. These findings suggest that IGFBP-5 may be a new pathogenic factor in renal fibrosis and a potential new therapeutic target in CKD.

Cancer, being one of the most lethal illnesses, presents an escalating clinical dilemma on a global scale. Despite significant efforts and advancements in cancer treatment over recent decades, the persistent challenge of resistance to traditional chemotherapeutic agents and/or emerging targeted drugs remains a prominent issue in the field of cancer therapies. Among the frequently inactivated tumor suppressor genes in cancer, phosphatase and Tensin Homolog (PTEN) stands out, and its decreased expression may contribute to the emergence of therapeutic resistance. MicroRNAs (miRNAs), characterized by their short length of 22 nucleotides, exert regulatory control over target mRNA expression by binding to complementary sequences. Recent findings indicate that microRNAs play varied regulatory roles, encompassing promotion, suppression, and dual functions on PTEN, and their aberration is implicated in heightened resistance to anticancer therapies. Significantly, recent research has revealed that competitive endogenous RNAs (ceRNAs) play a pivotal role in influencing PTEN expression, and the regulatory network involving circRNA/lncRNA-miRNA-PTEN is intricately linked to resistance in various cancer types to anticancer therapies. Finally, our findings showcase that diverse approaches, such as herbal medicine, small molecule inhibitors, low-intensity ultrasound, and engineered exosomes, can effectively overcome drug resistance in cancer by modulating the miRNA-PTEN axis.

Efferocytosis of massive non-viable germ cells by Sertoli cells (SCs), the specialized phagocytes, is essential for maintaining testis homeostasis. What elusive is the contribution of mitochondrial metabolism to this energy-consuming process, as SC has a preference of aerobic glycolysis. All-trans retinoic acid (ATRA, hereafter referred to as RA) is a well-known morphogen that primarily acts through the nuclear RA receptor (RAR). It sustains SC blood-testisbarrier integrity, and it’s SC-derived RA sets the timing of meiotic commitment. In this study, we revisited RA in SC biology, from the perspective of SC-mediated efferocytosis. We provide evidence that RA induces transcriptional programming of multiple regulators involved in efferocytosis, which thereby represses SC-mediated efferocytosis, via a RAR-independent mechanism, as blocking pan-RAR activity fails to rescue RA-induced defective efferocytosis. RA-treated SCs exhibit alternations in mitochondrial dynamics and metabolism, and the hindered efferocytosis can be rescued by stimulating mitochondrial OXPHOS via pharmacological targeting of AMPK and PDK. We thus prefer to propose a signaling axis of RA-mitochondrial metabolism-efferocytosis. Our study uncovers a hitherto unappreciated role of RA in SC biology and tiers mitochondria metabolism to SC-mediated efferocytosis, contributing a deeper understanding of SC in male reproduction.

The safety of proximal gastrectomy (PG) for the treatment of advanced Siewert II adenocarcinoma of the esophagogastric junction (AEG) remains debatable. In this study, we aim to evaluate the oncological safety of PG and the metastasis rate of key distal lymph node dissection, which is typically excluded in PG. This study retrospective collected advanced Siewert II AEG patients who underwent gastrectomy at the First Medical Center of the General Hospital of the People’s Liberation Army (PLA) from January 2014 to December 2019. A total of 421 patients were enrolled, including 237 PG and 184 total gastrectomy (TG). Propensity score matching (PSM) in a 1:1 ratio was performed to reduce the influence of confounding variables. After PSM, 153 cases were matched in each group. The TG group had longer operation time, more lymph node detection and longer postoperative hospitalization time than the PG group (Both P < 0.05). The postoperative complications of the two groups were not statistically significant (P > 0.05). For long-term complications, the incidence of reflux esophagitis and anastomotic stenosis were significantly higher in the PG group than in the TG group (Both P < 0.05), but dumpling syndrome and anemia were significantly lower in the PG group compared to the TG group (Both P < 0.05). The 3-year overall survival (OS) and disease-free survival (DFS) between the two groups were no statistically significant difference (OS: 77.4

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.

Abstract Background and Aims Renal ischemia‒reperfusion injury (IRI) is one of the most important causes of acute kidney injury (AKI). Interleukin (IL)-37 is a novel anti-inflammatory factor, but its application is still limited by its low stability and delivery efficiency. In recent years, engineered extracellular vesicles (EVs) have attracted substantial attention as an emerging drug delivery system. The aim of this study was to investigate the reparative effect of neutrophil membranes-derived nanovesicle (N-MV)-delivered IL-37 on renal IRI and its mechanism of action. Method The density gradient centrifugation method was used to extract peripheral blood neutrophils from rats, and the differential centrifugation method was used to extract neutrophil membranes. Cell membranes and IL-37 were then extruded with polycarbonate porous membranes with different pore sizes using a mini extruder to prepare IL-37 that was coated with neutrophil membrane (N-MV@IL-37). Subsequently, the physical and chemical properties and in vitro biological functions were identified. The in vivo distribution of N-MV@IL-37 as well as the renal function and inflammatory response in rats were further evaluated in a rat renal IRI model, and the targeting and anti-inflammatory mechanisms of N-MV@IL-37 were further explored. Results N-MV@IL-37 not only enhanced the stability of IL-37 but also targeted endothelial cells via P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophil membrane surfaces. In vitro experiments showed that N-MV@IL-37 inhibited endothelial cell apoptosis and inflammatory factor production and promoted endothelial cell viability and angiogenesis. In the rat renal IRI model, N-MV@IL-37 inhibited renal cell apoptosis and alleviated inflammatory responses, thereby improving renal function in IRI rats. Conclusion N-MVs provide an effective method of delivering IL-37, thereby alleviating the inflammatory response due to renal IRI and repairing renal endothelial cells; these vesicles could be a potential system for the treatment of renal IRI. Meanwhile, N-MVs also provided a drug delivery platform to provide a new strategy for the treatment of other IRI-like diseases.