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Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.

Renal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy (DN), and renal tubular injury might associate with abnormal mitophagy. In this study, we investigated the effects and molecular mechanisms of AMPK agonist metformin on mitophagy and cellular injury in renal tubular cell under diabetic condition. The high fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice model and HK-2 cells were used in this study. Metformin was administered in the drinking water (200 mg/kg/d) for 24 weeks. Renal tubulointerstitial lesions, oxidative stress and some indicators of mitophagy (e.g., LC3II, Pink1, and Parkin) were examined both in renal tissue and HK-2 cells. Additionally, compound C (an AMPK inhibitor) and Pink1 siRNA were applied to explore the molecular regulation mechanism of metformin on mitophagy. We found that the expression of p-AMPK, Pink1, Parkin, LC3II, and Atg5 in renal tissue of diabetic mice was decreased obviously. Metformin reduced the levels of serum creatinine, urine protein, and attenuated renal oxidative injury and fibrosis in HFD/STZ induced diabetic mice. In addition, Metformin reversed mitophagy dysfunction and the over-expression of NLRP3. In vitro pretreatment of HK-2 cells with AMPK inhibitor compound C or Pink1 siRNA negated the beneficial effects of metformin. Furthermore, we noted that metformin activated p-AMPK and promoted the translocation of Pink1 from the cytoplasm to mitochondria, then promoted the occurrence of mitophagy in HK-2 cells under HG/HFA ambience. Our results suggested for the first time that AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in HFD/STZ-induced diabetic mice via activating mitophagy through a p-AMPK-Pink1-Parkin pathway.

Background The efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive. Methods Cell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA. Results Anlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect. Conclusion Anlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.

Background Emerging evidence indicates the pivotal involvement of circular RNAs (circRNAs) in cancer initiation and progression. Understanding the functions and underlying mechanisms of circRNAs in tumor development holds promise for uncovering novel diagnostic indicators and therapeutic targets. In this study, our focus was to elucidate the function and regulatory mechanism of hsa-circ-0003764 in hepatocellular carcinoma (HCC). Methods A newly discovered hsa-circ-0003764 (circPTPN12) was identified from the circbase database. QRT-PCR analysis was utilized to assess the expression levels of hsa-circ-0003764 in both HCC tissues and cells. We conducted in vitro and in vivo experiments to examine the impact of circPTPN12 on the proliferation and apoptosis of HCC cells. Additionally, RNA-sequencing, RNA immunoprecipitation, biotin-coupled probe pull-down assays, and FISH were employed to confirm and establish the relationship between hsa-circ-0003764, PDLIM2, OTUD6B, P65, and ESRP1. Results In HCC, the downregulation of circPTPN12 was associated with an unfavorable prognosis. CircPTPN12 exhibited suppressive effects on the proliferation of HCC cells both in vitro and in vivo. Mechanistically, RNA sequencing assays unveiled the NF-κB signaling pathway as a targeted pathway of circPTPN12. Functionally, circPTPN12 was found to interact with the PDZ domain of PDLIM2, facilitating the ubiquitination of P65. Furthermore, circPTPN12 bolstered the assembly of the PDLIM2/OTUD6B complex by promoting the deubiquitination of PDLIM2. ESRP1 was identified to bind to pre-PTPN12, thereby fostering the generation of circPTPN12. Conclusions Collectively, our findings indicate the involvement of circPTPN12 in modulating PDLIM2 function, influencing HCC progression. The identified ESRP1/circPTPN12/PDLIM2/NF-κB axis shows promise as a novel therapeutic target in the context of HCC. Graphical Abstract

Autophagy is a process of intracellular self-recycling and degradation that plays an important role in maintaining cell homeostasis. However, the molecular mechanism of autophagy remains to be further studied. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the region of the ER that mediate communication between the ER and mitochondria. MAMs have been demonstrated to be involved in autophagy, Ca2+ transport and lipid metabolism. Here, we discuss the composition and function of MAMs, more specifically, to emphasize the role of MAMs in regulating autophagy. Finally, some key information that may be useful for future research is summarized.

Background/Aims: Vitamin D (VD) is widely recognized as renal protective. However, whether VD supplementation provides benefit to patients with diabetic nephropathy (DN) remains controversial. Here, we performed a meta-analysis to systematically evaluate the impact of VD supplementation on indexes of renal function, inflammation and glycemic control in DN patients, and to explore the potential renal protective mechanism of VD. Methods: We searched Pubmed, Embase, Cochrane Library, and three major Chinese biomedical databases (CNKI, WANGFANG and VIP) for randomized controlled trials (RCTs) examining the effects of VD or its analogs in DN patients, published between September 2007 and July 2018. Quality assessment and data extraction were performed independently by two authors, according to the Cochrane systematic review methods. Meta-analysis based on the extracted results were performed via Revman 5.2 software. Results: We included 20 RCTs representing 1,464 patients with DN in this meta-analysis. VD supplementation significantly reduced 24-hour urine protein [MD = -0.26; 95% CI (-0.34, -0.17); P < 0.00001; I 2 = 95%], UAER [MD = -67.36; 95% CI (-91.96, -42.76); P < 0.00001; I 2 = 97%], hs-CRP [MD = -0.69; 95% CI (-0.86,-0.53); P < 0.00001; I 2 = 0%], TNF-α [MD = -56.79; 95% CI (-77.05, -36.52); P < 0.00001; I 2 = 89%] and IL-6 [MD = -0.73; 95% CI(-1.03, -0.44); P < 0.00001; I 2 = 0%]. However, VD supplementation failed to decrease SCr [MD = -0.83; 95% CI (-3.67,2.02); P = 0.57; I 2 = 0%] or increase eGFR [MD = 2.13; 95% CI (-2.06, 6.32); P = 0.32; I 2 = 0%]. In addition, VD supplementation showed no impact on indexes of glycemic control, such as HbA1c [MD = 0.01; 95% CI (-0.09, 0.11); P = 0.84; I 2 = 0%] and FBG [MD = -0.05; 95% CI (-0.29, 0.20); P = 0.70; I 2 = 0%]. Analysis of 24-hour urine protein, SCr, eGFR, hs-CRP or HbA1c revealed no difference between subgroups based on the type of VD supplementation, including calcitriol, alfacalcidol and vitamin D3, and the dose or duration of calcitriol usage. Conclusion: In patients with DN, VD supplementation provides beneficial effects on 24-hour urine protein and inflammation indexes, but not on SCr, eGFR or glycemic control indexes. More RCTs that comprehensively evaluate the impact of VD supplementation on indexes of renal function, inflammation and glycemic control in DN atients are required in order to reach conclusive results.

Objective and significance To systematically evaluate and model the risk factors for new - onset conduction block after transcatheter aortic valve replacement, aiming to establish a scientific risk - prediction nomogram model. This model is intended to guide clinical screening of high - risk patients, develop more targeted prevention and treatment strategies, and ultimately improve the overall prognosis and quality of life of patients by effectively reducing the incidence of postoperative conduction block. Methods Data of 163 patients who underwent transcatheter aortic valve replacement in our hospital from January 2022 to November 2024 were collected, including patients’ anatomical characteristics, surgical operation parameters, and other self - factors. First, the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis method was used to optimize variable selection. By introducing the predictive factors selected in the LASSO regression analysis, univariate and multivariate logistic regression analyses were then carried out to establish a prediction model. According to the selected variables, a visual nomogram was established. Subsequently, the model was verified by the receiver operating characteristic curve, calibration curve, and decision curve analysis. Results Through LASSO regression analysis, three predictive factors, namely age, basal valve diameter(mm), and annulus size, were screened out from the 29 variables studied. The model constructed using these three predictive factors had good predictive ability, with an area under the ROC curve of 0.988 in the training set and 0.989 in the validation set. The DCA curve showed that the nomogram could be applied clinically when the risk threshold was between 0.1 and 0.7. Conclusion Incorporating age, basal valve diameter(mm), and annulus size into the risk - prediction model significantly improves the accuracy of predicting the risk of new - onset conduction block in patients after transcatheter aortic valve replacement. This strategy provides a more reliable basis for preoperative risk stratification and helps optimize clinical decision - making and patient management.

Objectives This study aimed to evaluate the diagnostic utility of GATA3 and CD138 as basal compartment markers in differentiating benign prostatic hyperplasia (BPH) from prostate cancer (PCa). Methods Immunohistochemical analysis of GATA3, CD138, CK34βE12, and P63 was performed on 131 prostate tissue samples (77BPH,54PCa). Expression profiles, sensitivity, specificity, and Cohen’s Kappa agreement were compared between markers. Results In BPH samples, nuclear expression of GATA3 and p63 showed identical positive rates (92.21%, 95%CI: 89.3–94.8%), while CD138 (antibody concentration 1:200) and CK34βE12 (antibody concentration 1:100) demonstrated cytoplasmic/membranous positivity in 96.10% (93.4–98.1%) and 93.51% (90.2–95.9%) of cases respectively. All markers exhibited complete negativity (H-score < 5) in PCa basal cells.GATA3 achieved 100% diagnostic concordance (95%CI: 97.8–100%) with p63 in both BPH and PCa (perfect agreement, κ  = 1, p  < 0.001 by McNemar-Bowker test). Compared to CK34βE12:In BPH: Sensitivity = 98.61% (97.2–99.4%), Specificity = 100% (NPV 96.3%);In PCa: Diagnostic accuracy = 100% (AUC 1.0);(Inter-rater reliability κ  = 0.902-1.0, weighted least squares method).CD138 achieved 100% analytic sensitivity but suboptimal specificity (57.1%, 95%CI: 44.8–68.7%) in BPH when referenced against p63/CK34βE12, while achieving perfect discrimination ( κ  = 0.926, p  = 7.6 × 10 − 12 ) in PCa cohorts. Conclusions GATA3 and CD138 demonstrate basal compartment enrichment patterns that complement conventional markers for PCa diagnosis (accuracy 96–100%). Their nuclear (GATA3) and cytoplasmic (CD138) localization enhances reliability, particularly in cases with fixation artifacts or ambiguous morphology.

Mounting research indicates that circRNAs are pivotal elements in tumorigenesis and progression. Understanding the mechanisms by which circRNAs function in tumors is crucial for identifying undiscovered diagnostic and treatment targets. This research centers on unraveling the mechanisms by which the novel circRNA, circFADS1, influences hepatocellular carcinoma (HCC) progression. CircFADS1 shows elevated expression in HCC and is linked to unfavorable prognosis. Functionally, circFADS1 overexpression accelerates HCC progression through inducing HCC proliferation and inhibited apoptosis. Mechanistically, RNA‐seq analysis demonstrates its connection to the Wnt/β‐catenin pathway. Moreover, circFADS1 interacts with GSK3β and promotes its ubiquitination and degradation by recruiting the ubiquitin ligase RNF114 while EIF4A3 facilitates the biogenesis of circFADS1. Additionally, circFADS1 is closely linked to lenvatinib resistance. Overall, this study reveals that circFADS1 regulates GSK3β function, influencing the progression of hepatocellular carcinoma. The EIF4A3/circFADS1/GSK3β/β‐catenin axis is discovered to hold promise as a novel therapeutic target for hepatocellular carcinoma, while circFADS1 is also a significant factor in lenvatinib resistance. In this study, a novel circRNA, circFADS1 is identified, which is expressed at higher levels in HCC. circFADS1 is associated with poor prognosis in HCC patients and promotes HCC cell proliferation while inhibiting apoptosis. Mechanistically, circFADS1 exerts its biological function through the EIF4A3/GSK3β/β‐catenin axis and is closely associated with resistance to lenvatinib.