Icariin alleviates the injury of Sertoli cell junction function by upregulating PKR pathway via ERα/c-fos signaling in aged mice.

ETHNOPHARMACOLOGICAL RELEVENACE: Sertoli cells are vital to maintain spermatogenesis and their function decline during aging. Epimedium has the effects of tonifying kidney-yang, strengthening bones and muscles, and expelling wind and dampness, and is commonly used in the treatment of kidney-yang deficiency, impotence and spermatorrhea. Icariin is the main active ingredients from Epimedium exhibiting delaying aging effects and improving male reproductive dysfunction. Whereas, it remains poorly understood how icariin alleviates age-associated decline in testicular function by protecting against the damage of junction function of Sertoli cells. AIM OF THE STUDY: This study aimed to evaluate the improvement effect of icariin on Sertoli cell junction function damage and explore the underlying mechanisms. MATERIALS AND METHODS: Male C57BL/6 mice and mouse Sertoli cell line TM4 cells were utilized to assess the improvement effect of icariin on aging-associated Sertoli cell junction function injury. H&E staining, transmission electron microscopy, qPCR, Western blot, molecular docking, siRNA transfection, and immunofluorescence were performed in this study. RESULTS: Dietary administration of icariin remarkly attenuated age-associated deterioration in spermatogenic function as evidenced by elevated testicular weight and index, sperm concentration and sperm viability. In addition, icariin protected Sertoli cell junction function from age-associated damage as proven by increased Sertoli cell numbers, improved tight junction ultrastructure, and upregulated junction-related proteins (ZO-1, Occludin and ß-Catenin). Moreover, icariin significantly upregulated ERα/c-fos signaling and PKR pathway in testicular Sertoli cells. Similarly, in vitro studies revealed that deletion of ERα, c-fos or PKR abolished the improvement effects of icariin on Sertoli cell junction function damage. CONCLUSIONS: Icariin effectively mitigates age-associated decline in testicular function by diminished Sertoli cell junction function damage through upregulating PKR pathway via ERα/c-fos signaling. Therefore, attenuating Sertoli cell junction function injury by the upregulation of PKR pathway via ERα/c-fos signaling probably indicates an effective target for the prevention and treatment of testicular spermatogenic function with aging.

Clinical T1/2 renal cell carcinoma: multiparametric dynamic contrast-enhanced MRI features-based model for the prediction of individual adverse pathology.

BACKGROUND: The detection of renal cell carcinoma (RCC) has been rising due to the enhanced utilization of cross-sectional imaging and incidentally discovered lesions with adverse pathology demonstrate potential for metastasis. The purpose of our study was to determine the clinical and multiparametric dynamic contrast-enhanced magnetic resonance imaging (CEMRI) associated independent predictors of adverse pathology for cT1/2 RCC and develop the predictive model. METHODS: We recruited 105 cT1/2 RCC patients between 2018 and 2022, all of whom underwent preoperative CEMRI and had complete clinicopathological data. Adverse pathology was defined as RCC patients with nuclear grade III-IV; pT3a upstage; type II papillary RCC, collecting duct or renal medullary carcinoma, unclassified RCC; sarcomatoid/rhabdoid features. The qualitative and quantitative CEMRI parameters were independently reviewed by two radiologists. Univariate and multivariate binary logistic regression analyses were utilized to determine the independent predictors of adverse pathology for cT1/2 RCC and construct the predictive model. The receiver operating characteristic (ROC) curve, confusion matrix, calibration plot, and decision curve analysis (DCA) were conducted to compare the diagnostic performance of different predictive models. The individual risk scores and linear predicted probabilities were calculated for risk stratification, and the Kaplan-Meier curve and log-rank tests were used for survival analysis. RESULTS: Overall, 45 patients were pathologically confirmed as RCC with adverse pathology. Clinical characteristics, including gender, and CEMRI parameters, including RENAL score, tumor margin irregularity, necrosis, and tumor apparent diffusion coefficient (ADC) value were identified as independent predictors of adverse pathology for cT1/2 RCC. The clinical-CEMRI predictive model yielded an area under the curve (AUC) of the ROC curve of 0.907, which outperformed the clinical model or CEMRI signature model alone. Good calibration, better clinical usefulness, excellent risk stratification ability of adverse pathology and prognosis were also achieved for the clinical-CEMRI predictive model. CONCLUSIONS: The proposed clinical-CEMRI predictive model offers the potential for preoperative prediction of adverse pathology for cT1/2 RCC. With the ability to forecast adverse pathology, the predictive model could significantly benefit patients and clinicians alike by providing enhanced guidance for treatment planning and decision-making.

Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma.

Renal cell carcinoma (RCC) is a frequent urological malignancy characterized by a high rate of metastasis and lethality. The treatment strategy for advanced RCC has moved through multiple iterations over the past three decades. Initially, cytokine treatment was the only systemic treatment option for patients with RCC. With the development of medicine, antiangiogenic agents targeting vascular endothelial growth factor and mammalian target of rapamycin and immunotherapy, immune checkpoint inhibitors (ICIs) have emerged and received several achievements in the therapeutics of advanced RCC. However, ICIs have still not brought completely satisfactory results due to drug resistance and undesirable side effects. For the past years, the interests form researchers have been attracted by the combination of ICIs and targeted therapy for advanced RCC and the angiogenesis and immunogenic tumor microenvironmental variations in RCC. Therefore, we emphasize the potential principle and the clinical progress of ICIs combined with targeted treatment of advanced RCC, and summarize the future direction.

Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells.

Cholesterol from peripheral tissue, carried by HDL, is metabolized in the liver after uptake by the HDL receptor, SR-B1. Hepatocytes have long been considered the only liver cells expressing SR-B1; however, in this study we describe two disparate immunofluorescence (IF) experiments that suggest otherwise. Using high-resolution confocal microscopy employing ultrathin (120 nm) sections of mouse liver, improving z-axis resolution, we identified the liver sinusoidal endothelial cells (LSEC), marked by FcγRIIb, as the cell within the liver expressing abundant SR-B1. In contrast, the hepatocyte, identified with ß-catenin, expressed considerably weaker levels, although optical resolution of SR-B1 was inadequate. Thus, we moved to a different IF strategy, first separating dissociated liver cells by gradient centrifugation into two portions, hepatocytes (parenchymal cells) and LSEC (non-parenchymal cells). Characterizing both portions for the cellular expression of SR-B1 by flow cytometry, we found that LSEC expressed considerable amounts of SR-B1 while in hepatocytes SR-B1 expression was barely perceptible. Assessing mRNA of SR-B1 by real time PCR we found messenger expression in LSEC to be about 5 times higher than in hepatocytes.