A novel Senescence-Based prognostic model unveils tumor interactions and drug resistance in colorectal cancer.

BACKGROUND: In China, CRC incidence is escalating. The main hurdles are heterogeneity and drug resistance. This research delves into cellular senescence in CRC, aiming to devise a prognostic model and pinpoint mechanisms impacting drug resistance. METHODS: Mendelian randomization (MR) analysis confirmed the association between CRC and cellular aging. The Cancer Genome Atlas (TCGA)-CRC data served as the training set, with GSE38832 and GSE39582 as validation sets. Various bioinformatics methods were employed to construct and validate a risk model. CRC cells with NADPH Oxidase 4 (NOX4) knockout were generated using CRISPR-Cas9 technology. Protein blotting and colony formation assays elucidated the role of NOX4 in CRC cell aging and drug resistance. RESULTS: A prognostic model, derived from dataset analysis, uncovered a link between high-risk groups and cancer progression. Notable differences in the tumor microenvironment were observed between risk groups. Finally, NOX4 was found to be linked with aging and drug resistance in CRC. CONCLUSION: This research presents a novel senescence-based CRC prognosis model. It identifies NOX4's role in CRC drug resistance, suggesting it is a potential treatment target.

Deciphering alternative splicing events and their therapeutic implications in colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors with complex molecular regulatory mechanisms. Alternative splicing (AS), a fundamental regulatory process of gene expression, plays an important role in the occurrence and development of CRC. This study analyzed AS Percent Spliced In (PSI) values from 49 pairs of CRC and normal samples in the TCGA SpliceSeq database. Using Lasso and SVM, AS features that can differentiate colorectal cancer from normal were screened. Univariate COX regression analysis identified prognosis-related AS events. A risk model was constructed and validated using machine learning, Kaplan-Meier analysis, and Decision Curve Analysis. The regulatory effect of protein arginine methyltransferase 5 (PRMT5) on poly(RC) binding protein 1 (PCBP1) was verified by immunoprecipitation experiments, and the effect of PCBP1 on the AS of Obscurin (OBSCN) was verified by PCR. Five AS events, including HNF4A.59461.AP and HNF4A.59462.AP, were identified, which can distinguish CRC from normal tissue. A machine learning model using 21 key AS events accurately predicted CRC prognosis. High-risk patients had significantly shorter survival times. PRMT5 was found to regulate PCBP1 function and then influence OBSCN AS, which may drive CRC progression. The study concluded that some AS events is significantly different in CRC and normal tissues, and some of these AS events are related to the prognosis of CRC. In addition, PRMT family-driven arginine modifications play an important role in CRC-specific AS events.

TianJiu therapy for α-naphthyl isothiocyanate-induced intrahepatic cholestasis in rats treated with fresh Ranunculus sceleratus L.

ETHNOPHARMACOLOGICAL RELEVANCE: TianJiu (TJ) therapy, one type of cold moxibustion, applies to specific acupuncture points with herbal patches of hot nature, providing a constant irritant to the skin until the presence of hyperemia and blistering. Traditional and clinical reports suggest that TJ is an effective therapy for the treatment of jaundice with fresh Ranunculus sceleratus L. (RS), in which protoanemonin is one of the main irritant constituents. However, the therapeutic effect of TJ treatment with fresh RS against intrahepatic cholestasis has not been studied in animal experiments. AIM OF THE STUDY: Present study was undertaken to investigate the effect of TJ treatment with fresh RS against intrahepatic cholestasis in rats and provide an experimental basis for the underlying mechanism of TJ therapy. MATERIALS AND METHODS: Male intrahepatic cholestatic Sprague-Dawley rats induced by 2% α-naphthylisothiocyanate (ANIT, 80 mg/kg B.W.) were treated by TJ therapy with fresh RS. The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DBIL), total bilirubin (TBIL), total bile acid (TBA), hepatic malondialdehyde (MDA) and nitric monoxide (NO), as well as hepatic body ratio, bile flow and hepatic histopathological assay were measured and evaluated to investigate the therapeutic effect of TJ treatment with fresh RS. Phytochemical analysis of fresh and dried RS was performed by gas chromatography-mass spectrometer (GC-MS). RESULTS: After TJ treatment with fresh RS, the abnormally elevated levels of serum AST, ALT, ALP, DBIL, TBIL and TBA, as well as hepatic MDA and NO at 108 h were reduced significantly (versus model group, P < 0.01). The hepatic body ratio, bile flow and hepatic pathological change of cholestatic rats at 108 h in TJ group were restored when compared with those of model group. Thirty-one compounds including lactones, flavonoids and phenolic acids were identified and determined by GC-MS analysis. The content of protoanemonin in fresh RS (9.49%) was about 25-fold higher than that in dried RS (0.38%). CONCLUSIONS: TJ treatment with fresh RS exhibited good therapeutic effect on ANIT-induced intrahepatic cholestasis in rats, which may be due to the attenuated oxidative stress in the liver tissue. It is rational for the ancients to choose fresh RS as TJ herbal patches because of its abundant protoanemonin with the character of irritant. The qualitative and quantitative results of GC-MS analysis provided the chemical basis of TJ therapy with fresh RS, which can be regarded as a simple and efficient method for the treatment of cholestasis hepatitis.