In recent years, chronic overnutrition, such as consumption of a high-fat diet (HFD), has been increasingly viewed as a significant modifiable risk factor for diseases such as diabetes and certain types of cancer. However, the mechanisms by which HFDs exert adverse effects on human health remains poorly understood. Here, this paper will review the recent scientific literature about HFD-induced inflammation and subsequent development of diseases and cancer, with an emphasis on mechanisms involved. Given the expanding global epidemic of excessive HFD intake, understanding the impacts of a HFD on these medical conditions, gaining great insights into possible underlying mechanisms, and developing effective therapeutic strategies are of great importance.

Obesity-associated chronic inflammation is characterized by an accumulation of adipose tissue macrophages (ATMs). It is generally believed that those macrophages are derived from peripheral blood monocytes. However, recent studies suggest that local proliferation of macrophages is responsible for ATM accumulation. In the present study, we revealed that both migration and proliferation contribute to ATM accumulation during obesity development. We show that there is a significant increase in ATMs at the early stage of obesity, which is largely due to an enhanced in situ macrophage proliferation. This result was obtained by employing fat-shielded irradiation and bone marrow reconstitution. Additionally, the production of CCL2, a pivotal chemoattractant of monocytes, was not found to be increased at this stage, corroborating with a critical role of proliferation. Nonetheless, as obesity proceeds, the role of monocyte migration into adipose tissue becomes more significant and those new immigrants further proliferate locally. These proliferating ATMs mainly reside in crown-like structures formed by macrophages surrounding dead adipocytes. We further showed that IL-4/STAT6 is a driving force for ATM proliferation. Therefore, we demonstrated that local proliferation of resident macrophages contributes to ATM accumulation during obesity development and has a key role in obesity-associated inflammation.

Erlotinib can induce both apoptosis and autophagy in sensitive NSCLC cell lines with activating EGFR mutation (exon 19 del). Inhibition of autophagy can further enhance sensitivity to erlotinib in EGFR-mutated NSCLC, suggesting that autophagy may serve as a protective mechanism.

Under nutrient and energy-limiting conditions, plants up-regulate sophisticated catabolic pathways such as autophagy to remobilize nutrients and restore energy homeostasis. Autophagic flux is tightly regulated under these circumstances through the AuTophaGy-related1 (ATG1) kinase complex, which relays upstream nutrient and energy signals to the downstream components that drive autophagy. Here, we investigated the role(s) of the Arabidopsis (Arabidopsis thaliana) ATG1 kinase during autophagy through an analysis of a quadruple mutant deficient in all four ATG1 isoforms. These isoforms appear to act redundantly, including the plant-specific, truncated ATG1t variant, and like other well-characterized atg mutants, homozygous atg1abct quadruple mutants display early leaf senescence and hypersensitivity to nitrogen and fixed-carbon starvations. Although ATG1 kinase is essential for up-regulating autophagy under nitrogen deprivation and short-term carbon starvation, it did not stimulate autophagy under prolonged carbon starvation. Instead, an ATG1-independent response arose requiring phosphatidylinositol-3-phosphate kinase (PI3K) and SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE1 (SnRK1), possibly through phosphorylation of the ATG6 subunit within the PI3K complex by the catalytic KIN10 subunit of SnRK1. Together, our data connect ATG1 kinase to autophagy and reveal that plants engage multiple pathways to activate autophagy during nutrient stress, which include the ATG1 route as well as an alternative route requiring SnRK1 and ATG6 signaling.

Obesity increases the risk of developing insulin resistance and diabetes and is a major public health concern. Our previous study shows that dietary β‐hydroxy‐β‐methylbutyrate (HMB) improves lipid metabolism in a pig model. However, it remains unclear whether HMB blocks obesity through gut microbiota. In this study, we found that HMB reduced body weight, alleviated the whitening of brown adipose tissue, and improved insulin resistance in mice fed a high‐fat diet (HFD). High‐throughput pyrosequencing of the 16S rRNA demonstrated that HMB administration significantly reversed the gut microbiota dysbiosis in HFD‐fed mice, including the diversity of gut microbiota and relative abundances of Bacteroidetes and Firmicutes. Moreover, microbiota transplantation from HMB‐treated mice attenuated HFD‐induced lipid metabolic disorders. Furthermore, HFD‐fed mice showed lower short‐chain fatty acids, whereas administration of HMB increased the propionic acid production. Correlation analysis identified a significant correlation between propionic acid production and the relative Bacteroidetes abundance. Sodium propionate treatment also attenuated HFD‐induced lipid metabolic disorders. Collectively, our results indicated that HMB might be used as a probiotic agent to reverse HFD‐induced obesity, and the potential mechanism was associated with reprogramming gut microbiota and metabolism, especially Bacteroidetes‐mediated propionic acid production. In future studies, more efforts should be made to confirm and expand the beneficial effects of HMB to human models.—Duan, Y., Zhong, Y., Xiao, H., Zheng, C., Song, B., Wang, W., Guo, Q., Li, Y., Han, H., Gao, J., Xu, K., Li, T., Yin, Y., Li, F., Yin, J., Kong, X. Gut microbiota mediates the protective effects of dietary β‐hydroxy‐β‐methylbutyrate (HMB) against obesity induced by high‐fat diets. FASEB J. 33, 10019–10033 (2019). http://www.fasebj.org

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BACKGROUND: The oriental fruit fly Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) causes serious damage that affects fruit production. Chemical insecticides have been widely used for the prevention and control of this destructive pest. However, the resistance of B. dorsalis to these compounds has become a serious problem. This study tested six sweeteners for their toxicity to B. dorsalis. RESULTS:B. dorsalis fed on erythritol, aspartame and saccharin exhibited significantly higher mortality than those fed on sucrose. Flies fed on erythritol died faster than did the control flies (water). However, no dose-dependent effects were observed at the concentrations tested. These three sweeteners decreased the climbing ability of B. dorsalis. Notably, adults fed on saccharin exhibited significantly decreased climbing ability after 12 h compared with those fed on sucrose. Additionally, these three sweeteners had a negative effect on the frequency and duration of the flies' behaviour patterns (flying, walking, grooming and inactivity). Saccharin not only induced a marked reduction in the frequency of flights and walks but also induced decreases in the time spent flying and walking and increases in inactivity compared with sucrose. Erythritol induced a reduction in movement and increased the time spent inactive compared with the control and other treatments. CONCLUSION: Three sweeteners had significant negative effects on the survival of B. dorsalis. Erythritol was toxic to B. dorsalis. Aspartame and saccharin also decreased the survival and behaviour of adult flies and may be toxic to (or contribute to poor nutrition in) B. dorsalis. These sweeteners could therefore be developed as additive ingredients in baits.

Abstract. Arsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC 50 values below 10 µM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation. IntroductionSCLC, accounting for 15-20% of newly diagnosed lung cancer, is an extremely aggressive malignancy with early metastasis and poor prognosis. Despite a prompt response to chemotherapy, relapses occur in the majority of patients with SCLC. Therefore the development of an alternative therapy against SCLC becomes imperative (1).ATO has been proven to be an effective therapeutic agent in acute promyelocytic leukemia (APL) with high complete remission rate and prolonged survival (2,3). ATO can induce apoptosis through PML-RARα-independent pathways in APL or other cancer cells via p53 activation (4,5), Bcl-2 downregulation (6,7), mitochondrial membrane depolarization and cytochrome c release (8-10), depletion of intracellular reduced glutathione (GSH) content and elevation of reactive oxygen species (11,12). More recently, the application of ATO in lung cancer treatment has been explored in preclinical models, mainly in non-small cell lung cancer (NSCLC). ATO induces growth inhibition and apoptosis in NSCLC cells through G2/M cell cycle arrest (13,14), Bcl-2 downregulation and GSH depletion (15). Recently, downregulation of thymidylate synthase and E2F1 were obser...