Tanshinone IIA protects mouse testes from heat stress injury by inhibiting apoptosis and TGFß1/Smad2/Smad3 signaling pathway.

Heat stress can cause testicular damage and affect male fertility. Tanshinone IIA (TSA) is a monomer substance derived from plants, with antioxidant and anti-apoptotic effects. Whether it can repair testicular damage caused by heat stress is unclear. This study aims to construct a mouse testicular heat stress injury model and intervene with TSA. Various methods such as histopathology, high-throughput sequencing, bioinformatics analysis, and molecular biology were used to investigate whether TSA can alleviate heat stress-induced testicular injury and its mechanism. Results showed that heat stress significantly reduced the diameter of the mouse seminiferous tubules, increased cell apoptosis in the testicular tissue, and significantly decreased testosterone levels. After TSA intervention, testicular morphology and cell apoptosis improved significantly, and testosterone secretion function was restored. High-throughput transcriptome sequencing found that key differentially expressed genes between the HS group and the control and TSA groups clustered in the apoptosis and TGFß signaling pathways. Using western blot technology, we found that the HS group upregulated TGFß1/Smad2/Smad3 pathway protein expression, causing cell apoptosis, testicular tissue organic lesions, and affecting testicular secretion function. Through TSA intervention, we found that it can inhibit TGFß1/Smad2/Smad3 pathway protein expression, thereby restoring testicular damage caused by heat stress. This study confirms that TSA can effectively restore testicular damage caused by heat stress in mice, possibly by inhibiting the TGFß1/Smad2/Smad3 pathway to suppress apoptosis.

The Prognostic Significance of RIMKLB and Related Immune Infiltrates in Colorectal Cancers.

RimK-like family member B (RIMKLB) is an enzyme that post-translationally modulates ribosomal protein S6, which can affect the development of immune cells. Some studies have suggested its role in tumor progression. However, the relationships among RIMKLB expression, survival outcomes, and tumor-infiltrating immune cells (TIICs) in colorectal cancer (CRC) are still unknown. Therefore, we analyzed RIMKLB expression levels in CRC and normal tissues and investigated the correlations between RIMKLB and TIICs as well as the impact of RIMKLB expression on clinical prognosis in CRC using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), PrognoScan, and UALCAN databases. Enrichment analysis was conducted with the cluster Profiler package in R software to explore the RIMKLB-related biological processes involved in CRC. The RIMKLB expression was significantly decreased in CRC compared to normal tissues, and correlated with histology, stage, lymphatic metastasis, and tumor status (p < 0.05). Patients with CRC with high expression of RIMKLB showed poorer overall survival (OS) (HR = 2.5,p = 0.00,042), and inferior disease-free survival (DFS) (HR = 1.9,p = 0.19) than those with low expression of RIMKLB. TIMER analysis indicated that RIMKLB transcription was closely related with several TIICs, including CD4+ and CD8+ T cells, B cells, tumor-associated macrophages (TAMs), monocytes, neutrophils, natural killer cells, dendritic cells, and subsets of T cells. Moreover, the expression of RIMKLB showed significant positive correlations with infiltrating levels of PD1 (r = 0.223, p = 1.31e-06; r = 0.249, p = 1.25e-03), PDL1 (r = 0.223, p = 6.03e-07; r = 0.41, p = 5.45e-08), and CTLA4 (r = 0.325, p = 9.68e-13; r = 0.41, p = 5.45e-08) in colon and rectum cancer, respectively. Enrichment analysis showed that the RIMKLB expression was positively related to extracellular matrix and immune inflammation-related pathways. In conclusion, RIMKLB expression is associated with survival outcomes and TIICs levels in patients with CRC, and therefore, might be a potential novel prognostic biomarker that reflects the immune infiltration status.

Development and Validation of a Predictive Scoring System for Colorectal Cancer Patients With Liver Metastasis: A Population-Based Study.

Liver metastasis in colorectal cancer (CRC) is common and has an unfavorable prognosis. This study aimed to establish a functional nomogram model to predict overall survival (OS) and cancer-specific survival (CSS) in patients with colorectal cancer liver metastasis (CRCLM). A total of 9,736 patients with CRCLM from 2010 to 2016 were randomly assigned to training, internal validation, and external validation cohorts. Univariate and multivariate Cox analyses were performed to identify independent clinicopathologic predictive factors, and a nomogram was constructed to predict CSS and OS. Multivariate analysis demonstrated age, tumor location, differentiation, gender, TNM stage, chemotherapy, number of sampled lymph nodes, number of positive lymph nodes, tumor size, and metastatic surgery as independent predictors for CRCLM. A nomogram incorporating the 10 predictors was constructed. The nomogram showed favorable sensitivity at predicting 1-, 3-, and 5-year OS, with area under the receiver operating characteristic curve (AUROC) values of 0.816, 0.782, and 0.787 in the training cohort; 0.827, 0.769, and 0.774 in the internal validation cohort; and 0.819, 0.745, and 0.767 in the external validation cohort, respectively. For CSS, the values were 0.825, 0.771, and 0.772 in the training cohort; 0.828, 0.753, and 0.758 in the internal validation cohort; and 0.828, 0.737, and 0.772 in the external validation cohort, respectively. Calibration curves and ROC curves revealed that using our models to predict the OS and CSS would add more benefit than other single methods. In summary, the novel nomogram based on significant clinicopathological characteristics can be conveniently used to facilitate the postoperative individualized prediction of OS and CSS in CRCLM patients.

An Oxidative Stress Index-Based Score for Prognostic Prediction in Colorectal Cancer Patients Undergoing Surgery.

Oxidative stress plays an important role in the development of colorectal cancer (CRC). This study is aimed at developing and validating a novel scoring system, based on oxidative stress indexes, for prognostic prediction in CRC patients. A retrospective analysis of 1422 CRC patients who underwent surgical resection between January 2013 and December 2017 was performed. These patients were randomly assigned to the training set (n = 1022) or the validation set (n = 400). Cox regression model was used to analyze the laboratory parameters. The CRC-Integrated Oxidative Stress Score (CIOSS) was developed from albumin (ALB), direct bilirubin (DBIL), and blood urea nitrogen (BUN), which were significantly associated with survival in CRC patients. Furthermore, a survival nomogram was generated by combining the CIOSS with other beneficial clinical characteristics. The CIOSS generated was as follows: 0.074 × albumin (g/L), -0.094 × bilirubin (µmol/L), and -0.099 × blood urea nitrogen (mmol/L), based on the multivariable Cox regression analysis. Using 50% (0.1025) and 85% (0.481) of CIOSS as cutoff values, three prognostically distinct groups were formed. Patients with high CIOSS experienced worse overall survival (OS) (hazard ratio [HR] = 4.33; 95% confidence interval [CI], 2.80-6.68; P < 0.001) and worse disease-free survival (DFS) (HR = 3.02; 95% CI, 1.96-4.64; P < 0.001) compared to those with low CIOSS. This predictive nomogram had good calibration and discrimination. ROC analyses showed that the CIOSS possessed excellent performance (AUC = 0.818) in predicting DFS. The AUC of the OS nomogram based on CIOSS, TNM stage, T stage, and chemotherapy was 0.812, while that of the DFS nomogram based on CIOSS, T stage, and TNM stage was 0.855. Decision curve analysis showed that these two prediction models were clinically useful. CIOSS is a CRC-specific prognostic index based on the combination of available oxidative stress indexes. High CIOSS is a powerful indicator of poor prognosis. The CIOSS also showed better predictive performance compared to TNM stage in CRC patients.