The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)–eukaryotic translation initiation factor 2α (eIF2α)–activating transcription factor-4 (ATF4) pathway-mediated cisplatin resistance of human gastric cancer cells. However, whether or how ISR activation per se could enhance chemoresistance remains unclear. In this study, we used eIF2α phosphatase inhibitor salubrinal to activate the ISR pathway and found that salubrinal reduced susceptibility to cisplatin. Moreover, salubrinal up-regulated ATF4-modulated gene expression, and knockdown of ATF4 attenuated salubrinal-induced drug resistance, suggesting that ATF4-modulated genes contribute to the process. The ATF4-modulated genes, xCT (a cystine/glutamate anti-transporter), tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), and phosphoenolpyruvate carboxykinase 2 (PCK2), were associated with a poorer prognosis for gastric cancer patients. By silencing individual genes, we found that xCT, but not TRB3, HO-1, or PCK2, is responsible for salubrinal-induced cisplatin resistance. In addition, salubrinal increased intracellular glutathione (GSH) and decreased cisplatin-induced lipid peroxidation. Salubrinal-induced cisplatin resistance was attenuated by inhibition of xCT and GSH biosynthesis. In conclusion, our results suggest that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells.

Previous studies have reported inconsistent results regarding the associations between metabolic syndrome (MetS) and obesity-related indices and bone mineral density (BMD). However, no previous studies have reported these associations among hemodialysis (HD) patients. The aims of this study were to investigate associations between MetS and its components and BMD T-score in HD patients and also between obesity-related indices and BMD T-score in HD patients with and without MetS. MetS was defined according to the Adult Treatment Panel III for Asians, and BMD T-score was calculated using dual-energy X-ray absorptiometry. Eight obesity-related indices were evaluated, including lipid accumulation product (LAP), visceral adiposity index (VAI), body adiposity index, conicity index (CI), body roundness index (BRI), abdominal volume index (AVI), waist-to-height ratio (WHtR), waist–hip ratio, and body mass index (BMI). One hundred and sixty-four patients undergoing HD were enrolled, and the prevalence of MetS was 61.6%. MetS was significantly associated with high lumbar spine and total hip T-scores. Regarding the MetS components, abdominal obesity and low HDL-C were significantly associated with high lumbar spine, femoral neck, and total hip T-scores; hypertriglyceridemia was significantly associated with high lumbar spine and total hip T-scores; hyperglycemia was significantly associated with a high lumbar spine T-score, whereas high blood pressure was not associated with T-score at any site. In the patients with MetS, BMI, WHtR, AVI, and BRI were significantly associated with T-score at all sites, and high CI, VAI, and LAP were also related to a high lumbar T-score. However, these indices were not associated with T-score at any site in patients without MetS. This study demonstrated positive associations between MetS and its five components and BMD T-score among HD patients. MetS, abdominal obesity, hypertriglyceridemia, and low HDL-cholesterol were associated with low risk of osteoporosis among the HD patients. Furthermore, we found that some obesity-related indices were associated with BMD T-score among HD patients with MetS but not in those without MetS. Our study highlights the importance of BMI, WHtR, AVI, and BRI in predicting the risk of osteoporosis among HD patients with MetS. In clinical practice, they can be easily calculated through simple anthropometric measurements and routine laboratory examinations and be used to quickly and conveniently assess the risk of osteoporosis among HD patients.

Type 2 diabetes mellitus (DM) is an increasing global health issue. Peripheral artery occlusive disease (PAOD) is a common complication of diabetes, and it is a complex and costly disease. The association between type 2 DM and obesity is well known, however, the relationship between obesity and PAOD in patients with type 2 DM has yet to be elucidated. Therefore, the aim of this study was to examine associations between obesity-related indices and PAOD in patients with type 2 DM. A total of 1872 outpatients with type 2 DM were recruited from two hospitals in southern Taiwan. An ankle–brachial index (ABI) < 0.9 in either leg was considered to indicate the presence of PAOD. The following obesity-related indices were investigated: conicity index (CI), waist–hip ratio (WHR), body roundness index (BRI), waist-to-height ratio (WHtR), abdominal volume index, a body shape index (ABSI), visceral adiposity index (VAI), lipid accumulation product (LAP), body adiposity index, body mass index and triglyceride–glucose index. Overall, 4.1% of the enrolled patients had an ABI < 0.9. High values of the following obesity-related indices were significantly associated with a low ABI: WHtR (p = 0.045), VAI (p = 0.003), CI (p = 0.042), BRI (p = 0.021) and ABSI (p = 0.043). Furthermore, WHR (area under the curve (AUC) = 0.661), CI (AUC = 0.660) and LAP (AUC = 0.642) had the best performance (all p < 0.001) to predict PAOD. In conclusion, high WHtR, BRI, CI, VAI and BAI values were associated with a low ABI in the enrolled patients, and WHR, CI and LAP were the most powerful predictors of PAOD.

Background:The aim of this study was to investigate the associations among obesity-related indices and MetS in diabetic patients, and explore sex differences in these associations. Methods: Patients with type 2 DM were included from two hospitals in southern Taiwan. The Adult Treatment Panel III criteria for an Asian population were used to define MetS. In addition, the following obesity-related indices were evaluated: waist-to-height ratio, waist-hip ratio (WHR), conicity index (CI), body mass index (BMI), body roundness index, body adiposity index, lipid accumulation product (LAP), abdominal volume index, visceral adiposity index (VAI), abdominal volume index and triglyceride-glucose index. Results: A total of 1,872 patients with type 2 DM (mean age 64.0 ± 11.3 years, 808 males and 1,064 females) were enrolled. The prevalence rates of MetS were 59.8% and 76.4% in the males and female (p < 0.001), respectively. All of the obesity-related indices were associated with MetS in both sex (all p < 0.001). LAP and BMI had the greatest areas under the receiver operating characteristic curves in both sex. In addition, the interactions between BMI and sex (p = 0.036), WHR and sex (p = 0.016), and CI and sex (p = 0.026) on MetS were statistically significant. Conclusions:In conclusion, this study demonstrated significant relationships between obesity-related indices and MetS among patients with type 2 DM. LAP and VAI were powerful predictors in both sex. The associations of BMI, WHR and CI on MetS were more significant in the men than in the women.