Obacunone, a limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-fibrosis ones. However, the anti-fibrotic effect of obacunone and the detailed underlying mechanism in liver fibrosis remain unclear. Liver fibrosis is a debilitating disease threatening human health. Transforming growth factor (TGF)-β/P-Smad is a major pathway of fibrosis featured with epithelia mesenchymal transformations (EMT) and collagen depositions, accompanying with excessive oxygen-free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the glutathione peroxidase family that directly inhibits phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of obacunone in mouse liver fibrosis model induced by carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-β. Obacunone demonstrated potent ameliorative effects on liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and vimentin. Obacunone also remarkably suppressed the TGF-β/P-Smad signals and EMT process. Meanwhile, obacunone exerted a potent anti-oxidation effect by reducing the levels of reactive oxygen species (ROS) in both models. The antioxidant effect of obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the therapeutic effect of obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that obacunone is able to attenuate liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-β/P-Smad pathway and EMT process.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis and high mortality. Although a large number of studies have explored its potential prognostic markers using traditional RNA sequencing (RNA-Seq) data, they have not achieved good prediction effect. In order to explore the possible prognostic signaling pathways leading to the difference in prognosis, we identified differentially expressed genes from one scRNA-seq cohort and four GEO cohorts, respectively. Then Cox and Lasso regression analysis showed that 12 genes were independent prognostic factors for PDAC. AUC and calibration curve analysis showed that the prognostic model had good discrimination and calibration. Compared with the low-risk group, the high-risk group had a higher proportion of gene mutations than the low-risk group. Immune infiltration analysis revealed differences in macrophages and monocytes between the two groups. Prognosis related genes were mainly distributed in fibroblasts, macrophages and type 2 ducts. The results of cell communication analysis showed that there was a strong communication between cancer-associated fibroblasts (CAF) and type 2 ductal cells, and collagen formation was the main interaction pathway.

Purpose: Transrectal ultrasound-guided prostate biopsy (TRUS-GB) is associated with the underdiagnosis of prostate cancer, and prostate-specific membrane antigen (PSMA)-PET–targeted prostate biopsy (PSMA-TB) may reduce the misclassification of prostate cancer. The primary outcome of the study was the accuracy of the two methods in identifying clinically significant prostate cancer (csPCa). The secondary outcomes included accuracy in identifying clinically insignificant prostate cancer (GG1) and GG3 or greater tumors, cancer detection stratified by the previous biopsy status, and the detection rate of csPCa using the combination of PSMA-TB and TRUS-GB. Patients and Methods: In this multicenter, two-arm, randomized study, biopsy-naïve patients suspected of having prostate cancer and advised to undergo prostate biopsy were randomly assigned to the PSMA-TB + TRUS-GB (combined) and TRUS-GB (control) groups. Results: A total of 815 men were assessed for eligibility, and 727 men were randomly assigned to the PSMA-TB + TRUS-GB group or the TRUS-GB group. The detection rate of csPCa in the group subjected to the combination of PSMA-TB and TRUS-GB was significantly greater than that in the conventional TRUS-GB group (67.0% vs. 60.1%; P = 0.042). In the PSMA-TB + TRUS-GB group, the rate of csPCa detection by PSMA-TB was significantly greater than that by TRUS-GB (63.5% vs. 57.7%; P < 0.001), whereas the combined strategies achieved the highest detection rate (67.0% vs. 63.5%, P < 0.001; 67.0% vs. 57.7%, P < 0.001). Conclusions: The diagnostic efficacy of TRUS-GB with PSMA-TB was significantly greater than that of TRUS-GB alone. If available, PSMA-TB should be performed alongside TRUS-GB in a combined manner rather than each method alone for the most accurate pathologic results.

Blood metabolomes have been linked to osteoporosis, yet the precise causal relationship with osteopenia, its preventable early stage, remains unclear. This study aimed to uncover the genetic causality between blood metabolomes and osteopenia, pinpointing potential targets for mechanomedicine. Utilizing genome-wide association study summary statistics, we analyzed 1091 metabolites and 309 metabolite ratios from 8299 individuals, correlating them with total body bone mineral density (BMD) from 56,284 individuals in the IEU GWAS database and osteopenia data from 408,961 European populations. Through two-sample Mendelian randomization, we investigated the association between blood metabolomes and skeletal characteristics. We then conducted summary-data-based Mendelian randomization (MR) analysis and colocalization analyses to identify causal genes related to skeletal phenotypes, predicting therapeutic targets for osteopenia. Expression of potential targets in osteocytes under fluid shear stress (FSS) stimulation was tested using qRT-PCR to explore mechanical sensitivity and bone health mechanisms. Our findings revealed five metabolites affecting total body BMD and osteopenia, with biliverdin emerging as a potential protective factor against osteopenia (OR ​= ​0.93, 95 ​%CI ​= ​0.88–0.98, P ​= ​0.009). Additionally, three genes—LRRC14, SLC22A16, and TNFRSF1A—were identified as potential therapeutic targets for osteopenia. Notably, LRRC14 and TNFRSF1A are also associated with other musculoskeletal diseases. In vitro experiments showed that FSS significantly increased LRRC14 expression in osteocytes, suggesting its potential as a mechanosensitive factor. This study identifies candidate blood metabolites and mechanomedicine targets for osteopenia, offering a scientific basis for new diagnostic and treatment strategies and deepening our understanding of bone mechanics response characteristics.

Table S5 The diagnostic performance of PSMA PET in combined and control group