Ferroptosis exhibits a potent antitumor effect and dihydroorotate dehydrogenase (DHODH) has recently been identified as a novel ferroptosis defender. However, the role of DHODH inhibition in cervical cancer cells is unclear, particularly in synergy with cisplatin via ferroptosis. Herein, shRNA and brequinar were used to knock down DHODH and directly inhibit DHODH, respectively. Immunohistochemistry and Western blotting assays were performed to measure the expression of proteins. CCK-8 and colony formation assays were employed to assess the cell viability and proliferation. Ferroptosis was monitored through flow cytometry, the malondialdehyde assay kit and JC-1 staining analyses. The nude mouse xenograft model was generated to examine the effect of combination of DHODH inhibition and cisplatin on tumor growth in vivo. The expression of DHODH was increased in cervical cancer tissues. DHODH inhibition inhibited the proliferation and promoted the ferroptosis in cervical cancer cells. A combination of DHODH inhibition and cisplatin synergistically induced both in vitro and in vivo ferroptosis and downregulated the ferroptosis defender mTOR pathway. Therefore, the combination of DHODH inhibition and cisplatin exhibits synergistic effects on ferroptosis induction via inhibiting the mTOR pathway could provide a promising way for cervical cancer therapy.
Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) have been increasing at an alarming rate worldwide. Many clinical studies have underlined the link between NAFLD and atherosclerosis. Our previous experiments have discovered that Lactobacillus (L.) plantarum ATCC14917 supplementation could decrease the progression of atherosclerotic lesion formation. In this study, we aimed to investigate the role of supplementation of L. plantarum ATCC14917 mitigates liver injury in rats fed with a high-fat diet (HFD, 45% kcal from fat). A total of 32 rats were randomly divided into four groups, including two intervention groups, who fed with HFD and administering either 1 × 107 or 1 × 109 colony forming units (CFU) of L. plantarum ATCC14917, the normal control group, and the HFD control group. The results showed that supplementation with low-dose and high-dose of L. plantarum ATCC14917 for 8 weeks could alleviate the body weight gain (p < 0.05), hepatic steatosis, and serum lipid metabolism (p < 0.05) in HFD-fed rats. Moreover, supplementation of L. plantarum ATCC 14917 decreased total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels (p < 0.05) in serum, and improved HFD-associated inflammation (p < 0.05). Furthermore, cecal contents were analyzed by high-throughput 16S ribosomal RNA sequencing. The results indicated that supplementation of L. plantarum ATCC 14917 could ameliorate HFD-induced gut dysbiosis. In summary, our findings suggest that supplementation of L. plantarum ATCC 14917 could mitigate NAFLD in rats, suggesting it may be considered as a probiotic agent for preventing HFD-induced obesity.
Background: Uterine leiomyomas (ULs) is the most common gynecological benign tumor in women. Our previous study showed that the phenomenon of vitamin D deficiency existed in patients with ULs. However, the association of vitamin D anabolism-related gene polymorphisms and susceptibility to ULs was unclear.Methods: Vitamin D anabolism-related gene polymorphisms in 110 patients with ULs and 110 healthy controls were detected by sequencing and the differences of the 92 SNPs were analyzed in the two groups via chi-square test. To verify the association between the significantly different SNPs and the risk of ULs, the SNPs were genotyped in another 340 patients and 340 healthy controls. Additionally, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) of ULs occurrence and the 95% confidence interval (CI), adjusting for age and BMI.Findings: In sequencing samples, there were differences in DHCR7 rs1044482 C > T (p = 0.008) and NADSYN1 rs2276360 G > C (p = 0.025) between patients with ULs and healthy controls. DHCR7 rs1044482 was related to the susceptibility to ULs in validation samples (heterogeneous: adjusted OR = 1.967, p = 0.002; homogenous: adjusted OR = 2.494, p = 0.002; additive: adjusted OR = 1.485, p < 0.041; and dominant: adjusted OR = 2.084, p < 0.001). Stratified analysis further showed that the DHCR7 rs1044482 polymorphisms were associated with ULs risks in women over 40 and with 18.5–25.0 BMI. In contrast to the wild-type CG haplotype vectors, individuals with TC haplotypes had a higher risk of developing ULs.Interpretation: The vitamin D anabolism-related gene DHCR7 rs1044482 C > T polymorphism was a risk factor of ULs, especially in patients over 40 with 18.5–25.0 BMI, while the relationship between NADSYN1 rs2276360 and ULs risk was not clear.
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