Project description:Aristolochic acid (AA) is an active component of herbal drugs derived from the Aristolochia species that have been used for medicinal purposes since antiquity. However, AA is genotoxic and induces tumors in animals and humans. AA induces mutations and tumors in the kidney but solely mutations in the liver. To evaluate whether miRNAs could indicate AA’s tissue-specific carcinogenicity and mutagenicity, we first conducted microarray analysis of miRNA expression in kidneys and livers of rats treated with a carcinogenic dose of AA. Then, miR-21, a biomarker for carcinogenicity, and miR-34a, a biomarker for mutagenicity, the two miRNAs whose expressions were most altered, were evaluated for their expression in the kidney (the AA’s mutagenic and carcinogenic target tissue), liver (the AA’s mutagenic target tissue), and testis, the non-target tissue where neither tumors nor mutation induction was found in previous studies and in this study. Genomic analysis of miRNA expression for kidney and liver samples showed that miRNA expression was globally changed by the treatment. Nineteen miRNAs were significantly dysregulated by the treatment in the kidney. Most of these miRNAs are related to carcinogenesis. Only one miRNA, miR-34a, was differentially expressed in the liver. Expression of miR-21 was induced in the kidney by AA treatment in a dose-dependent manner while no changes occurred in the liver or testis, indicating that the kidney is the carcinogenic target. miR-34a was dose-dependently up-regulated in the kidneys and livers of rats treated with AA, but not in the testis, suggesting that the kidney and liver are mutagenic target tissues, but the testis is not. Our results demonstrate that miRNA profiles can reflect the AA’s carcinogenicity in a tissue-specific manner while specific miRNAs can signify the target tissues for carcinogenicity or mutagenicity of AA.
Project description:Knee osteoarthritis (KOA), as a degenerative multifactorial disease, affects the quality of life and mental health of patients, and also brings a huge socioeconomic burden. Treating synovitis have shown promise as anti-inflammatory therapeutics in mitigating OA symptoms and disease progression. Here, by analysing synovial single-cell sequencing (scRNA-seq) data from KOA, we found that synovial fibroblasts (FLS) in OA synovium showed a distinct pro-inflammatory phenotype. We collected synovial tissue from patients with clinical OA as well as from healthy donors, and histological examination was consistent with findings in scRNA-seq. Inspired by recent cross-tissue fibroblast lineage studies, we identified by sequencing that healthy FLS in synovial tissues share transcriptome-level similarities with dermal fibroblasts (DFb). Subsequently, we revealed the local as well as systemic distribution of intra-articular injected DFbs by constructing/extracting two types of rat fibroblasts (luciferase DFbs as well as GFP DFbs). The results demonstrate that DFbs can be locally retained in the synovium for up to three weeks following targeted engrafting on it. And intra-articular injection does not result in DFbs migration to vital organs or the occurrence of histological changes in these organs. A rat model of KOA was constructed by anterior cruciate ligament transection (ACLT) in order to study the therapeutic effect of DFbs on KOA. After injection, the rats showed improvement in painful gait. In addition, histological as well as imaging results showed reduced synovitis and improvement in articular cartilage. Finally we verified the protective effect of DFbs on cytokine-stimulated chondrocytes in a co-culture system.
Project description:Male Sprague-Dawley rats were used to establish exhausted-exercise model by motorized rodent treadmill. Yu-Ping-Feng-San at doses of 2.18 g/kg was administrated by gavage before exercise training for 10 consecutive days. Quantitative proteomics was performed for assessing the related mechanism of Yu-Ping-Feng-San.
Project description:Effect of furan on transcriptomic and gene-specific DNA methylation changes in the livers of Fischer 344 rats in a two-year carcinogenicity study
Project description:Aristolochic acid nephropathy (AAN) is characterised by rapidly progressive tubulointerstitial nephritis culminating in end stage renal failure and urothelial malignancy. microRNAs (miRs) are small endogenous post-transcriptional regulators of gene expression implicated in numerous physiological and pathological processes. We aimed to characterise the mechanism of AA induced cell cycle arrest and its regulation by miRs. The microarray experiment was performed to identify differentially regulated microRNAs in human proximal tubulal epithelial cells treated with aristolochic acid (AA). Analysis or differential miR expression in human proximal tubular epithelial cell line (HK-2) treated with 5ug/ml aristolochic acid, control (n=3) vs aristolochic acid (n=3)