Adipose tissue-derived extracellular vesicles from obese mice suppressed splenocyte-mediated pancreatic cancer cell death.

Background: Obesity is a risk factor for pancreatic cancer and negatively contributes to the immune system. However, the mechanisms by which obesity mediates these actions are still poorly understood. Recent studies have demonstrated that extracellular vesicles (EVs) are key mediators of communication between cells and may influence various aspects of cancer progression. Objectives: We aim to explore the influence of EVs derived from adipose tissue of obese mice on cytokine production within the interactions between cancer cells and immune cells. Design: We isolated EVs from the adipose tissue of both C57BL6/J mice and Ob/Ob mice. Subsequently, we treated EVs with Panc02 cells, the murine ductal pancreatic cancer cell line, which were co-cultured with splenocytes. Viability and SMAD4 gene expression were examined in Panc02 cells, and cytokine concentrations of IL-6, IL-4, IL-12, and IL-12p70 were measured in the cultured medium. Results: Interestingly, we observed a significant reduction in splenocyte-mediated Panc02 cell death when treated with EVs derived from the adipose tissue of Ob/Ob mice, compared to those from C57BL6/J mice. Additionally, EVs from Ob/Ob mice-derived adipose tissue significantly increased the levels of IL-4, IL-2, and IL-12p70 in the culture media of Panc02 cells co-cultured with splenocytes, compared to EVs from C57BL6/J mice-derived adipose tissue. Conclusion: Adipose tissue-derived EVs from obese mice suppressed splenocyte-mediated Panc02 cell death and upregulated IL-4, IL-2, and IL-12p70 in cultured medium.

Black Ginger Extract Suppresses Fat Accumulation by Regulating Lipid Metabolism in High-Fat Diet-Fed Mice.

This study investigated the antiobesity effects of black ginger extract (BGE) in high-fat diet (HFD)-induced obese mice. Mice were divided into six groups: normal diet control (NC, AIN-93G normal diet), 60% HFD control (HFD), HFD containing metformin at 250 mg/kg b.w. (Met, positive control), and HFD containing BGE at 5, 10, or 20 mg/kg b.w. for 15 weeks. BGE administration significantly prevented HFD-induced increases in weight gain, organ weight, and adipose tissue mass. Furthermore, it resulted in decreased adipogenesis and lipogenesis-related factors, including phosphorylated mitogen-activated protein kinase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins, sterol regulatory element-binding protein 1, phosphorylated cAMP response element-binding protein, glucose-6-phosphate dehydrogenase, fatty acid synthase, dephosphorylated ATP-citrate lyase, dephosphorylated acetyl-CoA carboxylase, and lipoprotein lipase, in white adipose tissues. Moreover, BGE administration enhanced lipolysis in white adipose tissue, as evidenced by elevated levels of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and protein kinase A, along with reduced levels of perilipin and phosphodiesterase 3B. BGE induced thermogenesis in brown adipose tissues, as reflected by the increased expression of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1 and decreased levels of fatty acid-binding protein 4. In conclusion, this study provides comprehensive evidence supporting the antiobesity effects of BGE, elucidating the underlying molecular mechanisms involved in preventing weight gain, suppressing adipogenesis, promoting lipolysis, and stimulating thermogenesis. These findings suggest the potential therapeutic utility of BGE in combating obesity and associated metabolic disorders (KHGASP-2023-034).

Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term.

Introduction: Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. Methods: We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Results: Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Discussion: Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

Liver-Derived Exosomes Induce Inflammation and Lipogenesis in Mice Fed High-Energy Diets.

The liver is an endocrine organ and is the first organ exposed to nutrients when they are absorbed into the body before being metabolized by the distal organs. Although the liver plays an essential role in the interactions between the metabolic organs, their regulatory mechanisms have not been elucidated. Exosomes mediate communication between cells and primarily enable the transport of lipids, mRNAs, miRNAs, and proteins between cells. In this study, we investigated the effects of lipid metabolism on the liver and adipose tissue between mice fed high-fat (HF) and high-fat/sucrose (HFS) diets and determined the effects of liver tissue-derived exosomes on adipocytes to understand the underlying mechanisms associated with obesity-related metabolic diseases. Normal, HF, and HFS diets were fed to the mice for 12 weeks to compare differences based on dietary patterns. We showed different lipid metabolism effects on the liver and adipose tissue between HF- and HFS-fed mice. In the liver, fibrosis, inflammation, and lipogenesis were activated at higher levels in the HFS than in the HF group, and lipolysis was activated at higher levels in the HF than in the HFS group. In adipose tissue, adipogenesis, fatty acid transport, and lipolysis were activated at higher levels in the HF than in the HFS group, and inflammation and lipogenesis were activated at higher levels in the HFS than in the HF group. This result followed a similar trend reported in 3T3-L1 cells treated with liver-derived exosomes. In addition, the TG content of the liver-derived exosomes was significantly higher, and lipid accumulation was accelerated in the HFS than in the HF group. Based on these results, continuous exposure to HF and HFS diets induces lipid accumulation mediated by liver-derived exosomes; however, there is a difference in lipid metabolism. These results contribute to the elucidation of the mechanisms of exosome function in relation to obesity-related metabolic diseases and the metabolic relationship between tissues.

Overcoming the Intrinsic Gefitinib-resistance via Downregulation of AXL in Non-small Cell Lung Cancer.

BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is a limited factor in the treatment of non-small-cell lung cancer (NSCLC) patients. Therefore, ongoing studies are trying to identify EGFR-TKIs-resistant mechanisms and to discover novel therapeutic strategies and targets for NSCLC treatment. METHODS: In the present study, the possibility of overcoming intrinsic gefitinib-resistance was examined by regulating the expression of AXL. A natural product-derived antitumor agent, yuanhuadine (YD) was employed to modulate the expression of AXL in the cells. RESULTS: Treatment with YD effectively downregulated AXL expression in AXL-overexpressed gefitinib-resistant H1299 cells. The combination of gefitinib and YD exhibited a synergistic grwoth-inhibitory activity in H1299 cells by downregulation of AXL expression. CONCLUSIONS: Based on these findings, AXL was found to be a promising therapeutic target to overcome the intrinsic resistance to gefitinib in NSCLC. Furthermore, YD is able to effectively regulate the expression of AXL and thus it may be applicable as a potential lead compound for the treatment of gefitinib-resistant NSCLC.