TCF12 Activates TGFB2 Expression to Promote the Malignant Progression of Melanoma.

As one of the most common malignant tumors, melanoma is a serious threat to human health. More than half of melanoma patients have a BRAF mutation, and 90% of them have a BRAF(V600E) mutation. There is a targeted therapy for patients using a BRAF(V600E) inhibitor. However, no response to treatment is generally inevitable due to the heterogeneity of melanoma. Coupled with its high metastatic character, melanoma ultimately leads to poor overall survival. This study aimed to explore the possible mechanisms of melanoma metastasis and identify a more effective method for the treatment of melanoma. In this paper, we report that TCF12 expression is higher in melanoma, especially in metastatic tumors, through analyzing data from TCGA. Then, cell proliferation, colony formation, and transwell assays show that the upregulated expression of TCF12 can promote proliferation and metastasis of melanoma cells in vitro. The same result is confirmed in the subcutaneous tumor formation assay. Moreover, TGFB2 is identified as a direct downstream target of TCF12 by RNA-seq, qPCR, immunoblotting, ChIP, and a dual luciferase reporting assay. Interestingly, depletion of TCF12 can sensitize melanoma to BRAF inhibition both in vitro and in vivo. Overall, our results demonstrate that TCF12 promotes melanoma progression and can be a potential tumor therapeutic target.

Saturated fatty acids synergizes cadmium to induce macrophages M1 polarization and hepatic inflammation.

Exposure to the toxic metal cadmium (Cd) is a well-established risk factor for hepatic inflammation, but it remains unclear how metabolic components, such as different fatty acids (FAs), interact with Cd to influence this process. Understanding these interactions is essential for identifying potential preventative and therapeutic targets for this disorder. To address this question, we conducted in vitro and in vivo studies to investigate the combinatorial effect of Cd and saturated FAs on hepatic inflammation. Specifically, we assessed the cytotoxicity of Cd on macrophages and their polarization and inflammatory activation upon co-exposure to Cd and saturated FAs. Our results showed that while saturated FAs had minimal impact on the cytotoxicity of Cd on macrophages, they significantly collaborated with Cd in predisposing macrophages towards a pro-inflammatory M1 polarization, thereby promoting inflammatory activation. This joint effect of Cd and saturated FAs resulted in persistent inflammation and hepatic steatohepatitis in vivo. In summary, our study identified macrophage polarization as a novel mechanism by which co-exposure to Cd and saturated lipids induces hepatic inflammation. Our findings suggest that intervening in macrophage polarization may be a potential approach for mitigating the adverse hepatic effects of Cd.

Chronic exposure to low-dose cadmium facilitated nonalcoholic steatohepatitis in mice by suppressing fatty acid desaturation.

Exposure to cadmium (Cd), a toxic metal, is epidemiologically linked to nonalcoholic steatohepatitis (NASH) in humans. However, the role of Cd in NASH remains to be fully elucidated. This study employed a novel murine NASH model to investigate the effects of chronic low-dose Cd on hepatic pathology and its underlying mechanisms. NASH is characterized by lipid accumulation, extensive cell death, and persistent inflammation in the liver. We found that treatment with Cd in drinking water (10 mg/L) for 6 or 12 weeks significantly boosted hepatic fat deposition, increased hepatocyte destruction, and amplified inflammatory responses in mice, confirming that low-dose Cd can facilitate NASH development in vivo. Mechanistically, chronic Cd exposure reshaped the hepatic transcriptional landscape, with PPAR-mediated fatty acid metabolic pathways being the most significantly altered. In particular, Cd repressed fatty acid desaturation, leading to the accumulation of saturated fatty acids whose lipotoxicity exacerbated cell death and, consequently, inflammatory activation. In summary, we validated the causal effects of chronic low-dose Cd on NASH in vivo and identified the fatty acid desaturation program as a novel target for Cd to instigate hepatopathological alterations.

Carpesium abrotanoides (L.) Root as a Potential Source of Natural Anticancer Compounds: Targeting Glucose Metabolism and PKM2/HIF-1α Axis of Breast Cancer Cells.

Carpesium abrotanoides L. (CA) is widely used as a medicinal plant in Asia. The biological activities of the extract from the roots of Carpesium abrotanoides L. (PCA) and its major components were analyzed in this study. PCA was separated and identified with mass spectrometry. Furthermore, we sought to elucidate the anticancer activity of PCA and its mechanisms. PCA exerted its anti-breast cancer activity through inhibiting the expression of glycolysis-related genes, such as glucose transporter 1, lactate dehydrogenase A, and hexokinase 2. Moreover, PCA downregulated the expression of pyruvate kinase M2 and altered its cellular translocation. We also demonstrated PCA is an inhibitor of the PKM2/hypoxia-inducible factor-1α axis, indicating that PCA is potentially useful as an anti-breast cancer agent. PRACTICAL APPLICATION: In this study, the extract from roots of Carpesium abrotanoides Linn. (PCA) was shown to have a noticeable anticancer effect against breast cancer in vitro, and PCA exerts the anticancer activity by regulating glucose metabolism and PKM2 expression. These findings indicate that PCA is a promising agent with practical applications in the development of functional food containing Carpesium abrotanoides L. root extracts.