Pharmacological Prevention of Ectopic Erythrophagocytosis by Cilostazol Mitigates Ferroptosis in NASH.

Hepatic iron overload (HIO) is a hallmark of nonalcoholic fatty liver disease (NAFLD) with a poor prognosis. Recently, the role of hepatic erythrophagocytosis in NAFLD is emerging as a cause of HIO. We undertook various assays using human NAFLD patient pathology samples and an in vivo nonalcoholic steatohepatitis (NASH) mouse model named STAMTM. To make the in vitro conditions comparable to those of the in vivo NASH model, red blood cells (RBCs) and platelets were suspended and subjected to metabolic and inflammatory stresses. An insert-coculture system, in which activated THP-1 cells and RBCs are separated from HepG2 cells by a porous membrane, was also employed. Through various analyses in this study, the effect of cilostazol was examined. The NAFLD activity score, including steatosis, ballooning degeneration, inflammation, and fibrosis, was increased in STAMTM mice. Importantly, hemolysis occurred in the serum of STAMTM mice. Although cilostazol did not improve lipid or glucose profiles, it ameliorated hepatic steatosis and inflammation in STAMTM mice. Platelets (PLTs) played an important role in increasing erythrophagocytosis in the NASH liver. Upregulated erythrophagocytosis drives cells into ferroptosis, resulting in liver cell death. Cilostazol inhibited the augmentation of PLT and RBC accumulation. Cilostazol prevented the PLT-induced increase in ectopic erythrophagocytosis in in vivo and in vitro NASH models. Cilostazol attenuated ferroptosis of hepatocytes and phagocytosis of RBCs by THP-1 cells. Augmentation of hepatic erythrophagocytosis by activated platelets in NASH exacerbates HIO. Cilostazol prevents ectopic erythrophagocytosis, mitigating HIO-mediated ferroptosis in NASH models.

Potential involvement of neutrophils on exercise effects in breast cancer malignancy.

PURPOSE: This review aimed to comprehensively explore and elucidate multifaceted neutrophils in breast cancer, particularly in the context of physical activity. Neutrophils play a critical role in the tumor microenvironment and systemic immune response, despite their short half-life and terminal differentiation. Through a thorough review of research related to changes in immunity in breast cancer during exercise, this review aims to provide comprehensive insights into immunological changes, especially focusing on neutrophils. Recognizing that much of the existing research has predominantly focused on T cells and nature killer (NK) cells, our review seeks to shift the spotlight toward understanding how exercise affects neutrophils, a less-explored but critical immune response component in breast cancer. METHODS: This study involved an extensive review of the literature (from 2000 to 2023) using the PubMed, Science Direct, and Google Scholar databases. The keywords chosen for the searches were "immune cells and exercise," "exercise and breast cancer," "tumor microenvironment and neutrophils," and "neutrophils and exercise and breast cancers." RESULTS: Neutrophils in the tumor microenvironment can exhibit distinct phenotypes and functions. These differences have yielded conflicting results regarding tumor progression. Exercise plays a positive role in breast cancer and alters the immune system. Physical activity can quantitatively and functionally regulate neutrophils under various conditions such as metabolic disruption or senescence. CONCLUSION: This short communication outlines exercise-induced neutrophil diversification and its role in breast cancer progression, both within and systemically within the tumor microenvironment. Exercise may provide benefits through the potential neutrophil involvement in breast cancer.

Hepatic STAMP2 alleviates polychlorinated biphenyl-induced steatosis and hepatic iron overload in NAFLD models.

Polychlorinated biphenyls (PCBs) have been associated with neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. Although the recent studies have demonstrated that PCB exposure leads to nonalcoholic fatty liver disease (NAFLD), the underlying mechanism has remained unsolved. In this study, we examined the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, and PCB 126 in C57BL/6 mice. Male C57Bl/6 mice were fed a standard diet or a 60% high-fat diet and exposed to Aroclor 1260 (10 mg/kg or 20 mg/kg) or PCB 126 (1 mg/kg or 5 mg/kg) by intraperitoneal injection for a total of four injections (2, 3, 4, and 5 weeks) for 6 weeks. In mice, both Aroclor 1260 and PCB 126-induced liver damage, hepatic steatosis and inflammation. We also observed that PCB exposure-induced hepatic iron overload (HIO). We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable therapeutic target for NAFLD patients. Thus, we further examined whether hepatic STAMP2 is involved in PCB-induced NAFLD. We observed that hepatic STAMP2 was significantly decreased in PCB-induced NAFLD models in vivo and in vitro. Furthermore, overexpression of hepatic STAMP2 using an adenoviral delivery system resulted in improvement of PCB-induced steatosis and HIO in vivo and in vitro. Our findings indicate that enhancing hepatic STAMP2 expression represents a potential therapeutic avenue for the treatment of PCB exposure-induced NAFLD.

Effect of Regular Taekwondo Self-Defense Training on Oxidative Stress and Inflammation Markers in Postmenopausal Women.

We aimed to investigate the effect of a 12-week Taekwondo self-defense training course on oxidative stress and inflammation in postmenopausal women. Sixteen middle-aged women participated and were randomized into two groups: a control group (CG, n = 8) and a Taekwondo self-defense training group (TSDG, n = 8). The TSDG was trained for 60 min, four times per week, for 12 weeks. Following the Taekwondo training intervention, side-step was significantly higher in the TSDG than in the CG (p < 0.001). Malondialdehyde levels were significantly lower after the intervention than before in the TSDG (p < 0.01). Superoxide dismutase (SOD) levels were also significantly higher after the intervention than before in the TSDG (p < 0.001). After the Taekwondo training intervention, SOD levels were significantly higher in the TSDG than in the CG (p < 0.01). Tumor necrosis factor α (TNF-α) levels were significantly lower after the intervention than before in the TSDG (p < 0.05). After the Taekwondo training intervention, TNF-α levels were significantly lower in the TSDG than in the CG (p < 0.05). The results of this study suggest that Taekwondo self-defense training is an effective exercise that improves agility, oxidative stress, and inflammatory responses in postmenopausal women.

Exercise without dietary changes alleviates nonalcoholic fatty liver disease without weight loss benefits.

BACKGROUND: This study aimed to analyze the effect of exercise and/or dietary change on improvement of non-alcoholic fatty liver disease (NAFLD) in chronic high-fat diet (HFD)-induced obese mice. METHODS: Forty male C57BL/6 (8 weeks old) mice were divided into normal diet (CO, n = 8) and high-fat diet (HF, n = 32) groups. The HF group was fed with 60% fat chow for 16 weeks to induce obesity. After the obesity induction period, the HF group was subdivided into HFD + sedentary (n = 8), HFD + training (HFT, n = 8), dietary change to normal-diet + sedentary (HFND, n = 8), and dietary change to normal-diet + training (HFNDT, n = 8) groups, and the mice in the training groups underwent treadmill training for 8 weeks, 5 times per week, 40 min per day. RESULTS: A 24-week HFD induced increase of cannabinoid-1 receptor (CB1), fatty acid synthase (FAS), and AMP-activated protein kinase (AMPK) protein expressions (p < 0.05) and decrease of p-AMPK and carnitine palmitoyltransferase1 (CPT1) protein expressions (P < 0.05), resulting in increased liver fat accumulation. Treatment of exercise with dietary change and dietary change alone decreased CB1 and AMPK protein expressions with increased p-AMPK and CPT1 protein expressions (P < 0.05), leading to decreased body weight and liver fat (P < 0.05). The CB1 and FAS protein expressions in the HFT group were still higher than those in the CO group (P < 0.05), but the p-AMPK and CPT1 protein expressions were higher than those in the HF group (P < 0.05). Moreover, improved glucose tolerance and decreased liver fat were confirmed, although treatment of exercise alone had no effect on weight loss compared to pre-exercise. CONCLUSIONS: Even in the case of obesity induced by chronic HFD, exercise and/or dietary interventions have preventive and therapeutic effects on fat accumulation in the liver, resulting from upregulations of lipolytic factors. Therefore, the results of this study suggested that treatment of exercise alone without dietary change also leads to improvement of NAFLD and glucose tolerance without weight loss benefits.

Exercise training improves intramuscular triglyceride lipolysis sensitivity in high-fat diet induced obese mice.

BACKGROUND: The purpose of this study was to determine whether regular exercise training enhances intramuscular triglyceride (IMTG) lipolysis sensitivity during consumption of a continued high-fat diet by exploring changes in biochemical factors activated by IMTG lipolysis. METHODS: Male C57BL/6 mice aged 4 weeks were randomly divided into a high-fat diet group (HF) to induce obesity for 6 weeks and a control (CO) group. Thereafter, the HF group was divided into a high-fat diet group (HF) and high-fat diet + training group (HFT). The HFT group was trained on an animal treadmill 40 min/day, 5 days/week for 8 weeks. PKA, Plin5, p-Plin5, CGI-58, ATGL, and HSL were analyzed to investigate IMTG sensitivity by western blotting. RESULTS: PKA, CGI-58, and HSL protein levels in the HF group were significantly lower than those in the CO group (p < 0.05). However, PKA, CGI-58, and HSL protein levels in the HFT group were significantly higher than those in the HF group, and ATGL and p-Plin5 protein levels as well as the p-Plin5/Plin5 ratio in the HFT group were significantly higher than those in the HF group (p < 0.05). In addition, the HF group showed a significantly higher IMTG volume than the CO and HFT groups (p < 0.05). CONCLUSIONS: These results suggest that in an obese mouse model, 8 weeks of treadmill exercise contributes to decreased IMTG volume by activating lipolysis factors, such as PKA, PLIN5, CGI-58, and lipases. Therefore, regular exercise training may play an important role in obesity treatment by increasing IMTG lipolysis sensitivity.

The effects of detraining and training on adipose tissue lipid droplet in obese mice after chronic high-fat diet.

BACKGROUND: It is well known that exercise promotes lipolysis by stimulating the lipid droplet (LD) signaling pathway. However, few studies have been conducted to examine the effect of detraining with high fat diet (HFD) and training effects after long-term HFD. Here, we investigated the effect of detraining and training on adipose tissue LD pathway in diet-induced obese mice after continuous HFD. METHODS: Seventy male C57BL/6 mice were randomly assigned into a Normal diet + Sedentary group (ND, n = 10) or a High-fat diet + Sedentary group (HF, n = 50); in the HF group, obesity was induced by a 45% fat chow for six weeks. For the subsequent eight weeks, the HF group was randomly subdivided into an HF (n = 30) or an HF + training group (HFT, n = 20), and the HFT group was subjected to treadmill training while on an HFD. Following this eight-week period, the HFT group stopped exercising (HFT-DT group, n = 10), and the mice in the HF group were randomly subdivided into an HF (n = 10) or an HF + training group (HF-T, n = 10). After training and detraining, abdominal visceral fat was obtained and analyzed by histological staining and western blot. RESULTS: Treadmill exercise decreased body weight and fat mass (P <0.05), and increased the levels of PKA, perilipin1, CGI-58, ATGL, and HSL (P <0.05) after eight weeks of training. Following eight weeks of detraining, the levels of PKA and HSL were decreased (P <0.05); however, exercise after chronic HFD increased the levels of PKA, perilipin1, CGI-58, ATGL, and HSL (P <0.05), and decreased body weight and fat mass (P <0.05). CONCLUSIONS: Regardless of dietary restrictions, exercise is an effective treatment for obesity, owing to the regulation of LD signaling proteins. Moreover, the effects of regular exercise after chronic HFD were similar to those of exercise in the absence of HFD. Therefore, although obesity is induced by chronic HFD, exercise without dietary change is sufficiently effective for obesity treatment regardless of the preceding HFD period.