Identification of genes with high heterogeneity of expression as a predictor of different prognosis and therapeutic responses in colorectal cancer: a challenge and a strategy.

BACKGROUND: Molecular heterogeneity is one of the most important concerns in colorectal cancer (CRC), which results in a wide range of therapy responses and patient prognosis. We aimed to identify the genes with high heterogeneity of expression (HHE) and their relation with prognosis and drug resistance. METHODS: Two cohort studies, the cancer genome atlas (TCGA) and the GSE39582, were used to discover oncogenes genes with HHE. The relationship between identified genes with clinical and genomic characteristics was evaluated based on TCGA data. Also, the GDSC and CCLE data were used for drug resistance and sensitivity. Sixty CRC samples were used to validate the obtained data by RT-qPCR. RESULTS: Findings revealed that 132 genes with HHE were found to be up-regulated in both cohorts and were enriched in pathways such as hypoxia, angiogenesis, and metastasis. Forty-nine of selected genes related to clinical and genomic variables, including stage, common mutations, the tumor site, and microsatellite state that were ignored. The expression level of CXCL1, SFTA2, SELE, and SACS as genes with HHE were predicted survival patients, and RT-qPCR results demonstrated that levels of SELE and SACS had HHE in CRC samples. The expression of many identified genes like BGN, MMP7, COL11A1, FAP, KLK10, and TNFRSE11B was associated with resistance to chemotherapy drugs. CONCLUSIONS: Some genes expression, including SELE, SACS, BGN, KLK10, COL11A1, and TNFRSE11B have an oncogenic function with HHE, and their expression can be used as indicators for differing treatment responses and survival rates in CRC.

The combination of endurance exercise and SGTC (Salvia-Ginseng-Trigonella-Cinnamon) ameliorate mitochondrial markers' overexpression with sufficient ATP production in the skeletal muscle of mice fed AGEs-rich high-fat diet.

BACKGROUND: Skeletal muscle mitochondria is one of the most important affected sites of T2DM and its molecular mechanism is yet to be elucidated. Some recent theories believed that mitochondrial markers are upregulated in response to high fat induced T2DM; however, the reasons and the affected factors are still uncertain. In this regard, we aimed to investigate the effect of high fat induced T2DM on mitochondrial markers of skeletal muscle, and an herbal component along with endurance exercise, as probable treatments, in AGE-rich high-fat diet (AGEs-HFD) induced T2DM mice. METHODS: T2DM was induced by 16 weeks of AGEs-HFD consumption in male C57BL/6 mice, followed by 8 weeks of drugs ingestion and endurance exercise treatments (n = 6 in each group and total number of 42 mice). The herbal component was an aquatic extract of Salvia officinalis, Trigonella foenum-graecum, Panax ginseng, and Cinnamomum zeylanicum, termed "SGTC". We then examined the relative expression of several mitochondrial markers, including Ppargc1α, Tfam, and electron transport chain genes and ATP levels, in skeletal muscle samples. RESULTS: T2DM was successfully induced according to morphological, biochemical, and molecular observations. All mitochondrial markers, including Ppargc1a, Tfam, Cpt2, and electron transport chain genes, were upregulated in T2DM group compared to controls with no significant changes in the ATP levels. Most mitochondrial markers were downregulated by drug treatment compared to T2DM, but the ATP level was not significantly altered. All mitochondrial markers were upregulated in exercised group compared to T2DM with mild increase in the ATP level. The Ex + SGTC group had moderate level of mitochondrial markers compared to T2DM, but the highest ATP production. CONCLUSION: The highly significant overexpression of mitochondrial markers may be in response to free fatty acid overload. However, the lack of significant change in the ATP level may be a result of ROS generation due to electron leakage in the AGEsRAGE axis and electron transport chain. Almost all treatments ameliorate mitochondrial markers' overexpression. The SGTC appears to regulate this with its antioxidant properties. Instead, exercise upregulated mitochondrial markers efficiently; however, the most efficient results, i.e. the most ATP production among the treatments, were observed in the Ex + SGTC group.

Anti-inflammatory and -apoptotic effects of a long-term herbal extract treatment on DSS-induced colitis in mice fed with high AGEs-fat diet.

BACKGROUND: Obesity is associated with many comorbidities including inflammatory bowel disease (IBD). We investigated prophylactic effects of an herbal extract (HE) on the DSS-induced colitis mice challenged with high AGEs-fat diet 60% (HFD). METHODS: Six-week-old C57BL/6 male mice were fed with either HFD (8 groups, 6 mice in each group), or normal diet (ND) (8 groups, 6 mice in each group). After 6 weeks, animals received HE (combination of turmeric, ginger, boswellia and cat's claw extract) for 7 weeks in three doses (high dose (0.6 mg/g); low dose (0.15 mg/g) and mid dose (0.3 mg/g)). Next, mice were subjected to 2.5% DSS in drinking water. Control mice received ND and instead of HE and DSS they received distilled water. Obesity index markers were determined, H&E staining and TUNEL assay evaluated apoptosis. Colonic expressions of IL-6, RAGE, AGER1, Sirt1, Bax, Bcl2, ZO-1 and P53 were determined. RESULTS: HE ameliorated colitis in HFD mice by reducing colonic myeloperoxidase activity (by 2.3-fold), macrophage accumulation (by 2.6-fold) and mRNA expression of IL-6 (by 2.3-fold) in HFD mice. Moreover, HE restored ZO-1 (by 2.7-fold), prevented apoptosis and maintained immune homeostasis. HE reduced activation of NF-κB protein (by 1.3-fold) through decreasing RAGE (by 1.93-fold) and up-regulation of Sirt1 (by 7.71-fold) and prevented down-regulation of DDOST (by 6.6-fold) in HFD mice. CONCLUSIONS: HE ameliorated colitis in prophylactic in HFD mice and it was, at least partly, due to the restoration of the gut integrity, suppression of inflammation and apoptosis via modulation of colonic Sirt1, RAGE and DDOST signaling.