Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid (LCA) alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDR^ΔIEC) abolished the therapeutic effect of LCA on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, an FDA-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer. Cuproptosis is suggested to be a novel therapy target for cancer treatment. However, the function of cuproptosis and its key regulator FDX1 in ccRCC remains unclear. In this study, we adequately explored the prognostic factors, clinicopathological characteristics, and function of FDX1 in ccRCC. We found that the expression of FDX1 was significantly downregulated in ccRCC samples. Patients with a higher FDX1 expression had a significantly better prognosis, including overall survival (OS) (Hazard ratio (HR): 2.54, 95% confidence interval (CI): 1.82–3.53, p < 0.001), disease-specific survival (DSS) (HR: 3.04, 95% CI: 2.04–4.54, p < 0.001), and progression-free survival (PFS) (HR: 2.54, 95% CI: 1.82–3.53, p < 0.001). FDX1 was a clinical predictor to stratify patients into the high or low risk of poor survival, independent of conventional clinical features, with the area under the ROC curve (AUC) of 0.658, 0.677, and 0.656 for predicting the 5-year OS, DSS, and PFS. The nomogram model based on FDX1 had greater predictive power than other individual prognostic parameters. FDX1 mainly participated in the oxidative-related process and mitochondrial respiration-related processes but was not associated with immune infiltration levels. In conclusion, the cuproptosis key regulator FDX1 could serve as a potential novel prognostic biomarker for ccRCC patients.

Background: This study aimed to explore the relationship between diabetes risk reduction diet (DRRD) and bladder cancer risk in Prostate, Lung, Colorectal, Ovarian (PLCO) cohort. Methods: Data from 99,001 participants in the PLCO Cancer Screening Trial were analyzed using Cox proportional hazards regression models to estimate HRs and 95% confidence intervals (CI) for the association between DRRD score and bladder cancer incidence. Subgroup analyses were conducted to assess whether variables such as age, sex, body mass index, cigarette smoking status, and history of diabetes influenced the observed association. The DRRD score was formulated on the basis of nine nutrient intake indicators derived from the Dietary History Questionnaire. Results: During the median follow-up of 11.7 years, 761 new bladder cancer cases were identified. Participants with highest DRRD scores exhibited a reduced risk of bladder cancer compared with those in the lowest quartile (unadjusted analysis, HR, 0.65; 95% CI, 0.53–0.82); multivariable adjusted analysis, HR, 0.79; 95% CI, 0.64–0.98; Ptrend = 0.007). A similar risk reduction was seen solely in transitional cell carcinoma (HR, 0.79; 95% CI, 0.64–0.99; P = 0.007). In addition, the significant negative association between DRRD scores and bladder cancer risk persisted even after excluding participants with unique characteristics. Conclusions: This large prospective population-based study suggests that adherence to a DRRD may contribute to the prevention of bladder cancer. Impact: The DRRD could potentially mitigate bladder cancer risk, which warrants further validation in diverse populations.

Background: Chronic allograft damage (CAD) is the leading cause of long-term graft dysfunction. A noninvasive method that can diagnose CAD early and monitor its development is needed. Methods: Kidneys from Fisher rats were transplanted into Lewis rats to establish a CAD model (n = 20). The control group underwent syngeneic kidney transplantation (n = 20). The serum creatinine of the rats was monitored. At 4, 12, and 20 weeks after modeling, a magnetic resonance imaging (MRI) examination was performed. The apparent diffusion coefficient (ADC), pseudo diffusion coefficient (D*), true diffusion coefficient (D) and perfusion fraction (f) of the two groups were analyzed. Chronic allograft damage index (CADI) scoring was used to evaluate the transplanted kidney specimens. Immunohistochemistry was used to detect the expression of fibrosis markers in the transplanted kidney tissues and to analyze their correlations with all MRI parameters. Results: The transplanted kidneys in the experimental group developed CAD changes before the appearance of elevated creatinine. The MRI parameters in the experimental group [ADC (1.460 ± 0.109 VS 2.095 ± 0.319, P < 0.001), D (1.435 ± 0.102 VS 1.969 ± 0.305, P < 0.001), and f (26.532 ± 2.136 VS 32.255 ± 4.013, P < 0.001)] decreased, and D* (20.950 ± 2.273 VS 21.415 ± 1.598, P = 0.131) was not significantly different from those in the control group. ADC, D and f were negatively correlated with the CADI and the α-SMA and vimentin expression levels. Conclusion: Intravoxel incoherent motion (IVIM) imaging could detect CAD earlier than creatinine and reflect the degree of fibrosis in grafts quantitatively.

Background: Lone noncoding RNA (lncRNA) is generally identified as competing endogenous RNA (ceRNA) that plays a vital role in the pathogenesis of kidney renal clear cell carcinoma (KIRC), the most common subtype of renal cell carcinoma with poor prognosis and unclear pathogenesis. This study established a novel ceRNA network and thus identified a three-lncRNA prognostic model in KIRC patients. Methods: Differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) database. The lncATLAS was applied to determine the differentially expressed lncRNAs (DElncRNAs) located in the cytoplasm. The miRcode, miRDB, miRTarBase, and TargetScan databases were utilized to predict the interactions of DElncRNAs, DEmiRNAs, and DEmRNAs. Cytoscape was used to construct the ceRNA network. Then, a lncRNA prognostic model (LPM) was constructed based on ceRNA-related lncRNA that was significantly related to overall survival (OS), and its predictive ability was evaluated. Moreover, an LPM-based nomogram model was constructed. The significantly different expression of genes in the LPM was validated in an independent clinical cohort (N=21) by quantitative RT-PCR. Results: A novel ceRNA regulatory network, including 73 lncRNAs, 8 miRNAs, and 21 mRNAs was constructed. Functional enrichment analysis indicated that integral components of membrane and PI3K-Akt signaling pathway represented the most significant GO terms and pathway, respectively. The LPM established based on three lncRNAs (MIAT, LINC00460, and LINC00443) of great prognostic value from the ceRNA network was proven to be independent of conventional clinical parameters to differentiate patients with low or high risk of poor survival, with the AUC of 1-, 5- and 10-year OS were 0.723, 0.714 and 0.826 respectively. Furthermore, the nomogram showed a better predictive value in KIRC patients than individual prognostic parameters. The expression of MIAT and LINC00460 was significantly upregulated in the KIRC samples, while the expression of LINC00443 was significantly downregulated compared with the adjacent normal samples in the clinical cohort, TCGA, and GTEx. Conclusion: This LPM based on three-lncRNA could serve as an independent prognostic factor with a tremendous predictive ability for KIRC patients, and the identified novel ceRNA network may provide insight into the prognostic biomarkers and therapeutic targets of KIRC.

Background:This study aimed to explore the relationship between diabetes risk reduction diet (DRRD) and bladder cancer risk in Prostate, Lung, Colorectal, Ovarian (PLCO) cohort.Methods:Data from 99,001 participants in the PLCO Cancer Screening Trial were analyzed using Cox proportional hazards regression models to estimate HRs and 95% confidence intervals (CI) for the association between DRRD score and bladder cancer incidence. Subgroup analyses were conducted to assess whether variables such as age, sex, body mass index, cigarette smoking status, and history of diabetes influenced the observed association. The DRRD score was formulated on the basis of nine nutrient intake indicators derived from the Dietary History Questionnaire.Results:During the median follow-up of 11.7 years, 761 new bladder cancer cases were identified. Participants with highest DRRD scores exhibited a reduced risk of bladder cancer compared with those in the lowest quartile (unadjusted analysis, HR, 0.65; 95% CI, 0.53–0.82); multivariable adjusted analysis, HR, 0.79; 95% CI, 0.64–0.98; Ptrend = 0.007). A similar risk reduction was seen solely in transitional cell carcinoma (HR, 0.79; 95% CI, 0.64–0.99; P = 0.007). In addition, the significant negative association between DRRD scores and bladder cancer risk persisted even after excluding participants with unique characteristics.Conclusions:This large prospective population-based study suggests that adherence to a DRRD may contribute to the prevention of bladder cancer.Impact:The DRRD could potentially mitigate bladder cancer risk, which warrants further validation in diverse populations.