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Aims Doxorubicin (DOX), a widely used powerful chemotherapeutic component for cancer treatment, can give rise to severe cardiotoxicity that limits its clinical use. Pyroptosis is characterized by proinflammation and has been defined as a new type of programmed cell death in recent years. However, whether the DOX-induced cardiotoxicity is related to pyroptosis, and if so, which genes are involved in this process is largely unknown. In this study, we sought to identify the effect of DOX on cardiomyocyte pyroptosis and further reveal the underlying regulatory mechanism. Methods and results In vitro and in vivo experiments showed that DOX treatment induced cardiomyocyte pyroptosis as evidenced by increased cell death and upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-3, IL-1β, IL-18 and GMDSD-N. Inhibition of NLRP3 rescued the DOX-induced pyroptosis. qRT-PCR showed that TINCR lncRNA was upregulated by DOX treatment and knockdown of TINCR reversed the DOX-induced pyroptosis both in vitro and in vivo. Mechanistic investigations revealed that TINCR increased NLRP3 level via recruiting IGF2BP1 to enhance NLRP3 mRNA. And the effect of TINCR on cardiomyocyte pyroptosis was attenuated by the inhibition of NLRP3 or IGF2BP1. Finally, TINCR was not involved in DOX-induced pyroptosis in cancer cells. Conclusion TINCR mediates the DOX-induced cardiotoxicity and pyroptosis in an IGF2BP1-dependent manner. Therefore, TINCR may serve as a promising therapeutic target to overcome the cardiotoxicity of chemotherapy for cancer therapy.

The aim of this cross-sectional study was to investigate the association of serum 25-hydroxyvitamin D (25[OH]D) levels and vitamin D receptor (VDR) genotypes with skeletal muscle mass and function in elderly subjects in northern China.A total of 275 men and 510 women, ages 63.1 to 72.5 y, in two randomly selected communities in Beijing were investigated. The investigation included a questionnaire, physical measurements, muscle mass and function measurements, serum 25(OH)D levels, and VDR gene polymorphisms analysis.In the group with 25(OH)D levels10.0 ng/mL, the proportion with low handgrip strength was 3.04 times higher than that in the group with 25(OH)D levels20.0 ng/mL for men (odds ratio: 3.04; 95% confidence interval, 1.13-8.20) but not for women. The general linear model showed that higher 25(OH)D levels and having T allele of Fok1 and the bb genotype of Bsm1 were significantly associated with more handgrip strength. The regression coefficients (β) were 1.80 (P0.01), 1.26 (P0.01), and 2.90 (P0.01), respectively. There was a significant interaction between 25(OH)D and VDR gene polymorphisms for handgrip strength for both Fok1 (β = 2.86; P0.01) and Bsm1 (β = 3.14; P = 0.02) after adjustment for potential confounders (sex, age, body mass index, fat mass, physical activity, sun exposure, energy, and protein intake).25(OH)D levels are associated with handgrip strength for men and this relationship could be modified with the interaction between 25(OH)D and VDR gene polymorphisms (Fok1 and Bsm1).

Background Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. We aimed to investigate whether Homocysteine-responsive endoplasmic reticulum protein (Herp) was involved in VSMC phenotypic switching and affected atheroprogression. Methods To assess the role of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp −/− and LDLR −/− double knockout mice were generated and fed with a high methionine diet (HMD) to induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of VSMCs were assessed in vivo . We used siRNAs to knockdown Herp in cultured VSMCs to further validate our findings in vitro . Results HMD significantly activated the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR −/− mice, and induced the phenotypic switch of VSMCs, with the loss of contractile proteins (SMA and calponin) and an increase of OPN protein. Herp −/− /LDLR −/− mice developed reduced atherosclerotic lesions in the aortic sinus and the whole aorta when compared with LDLR −/− mice. However, Herp deficiency had no effect on diet-induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, decreased proliferation and collagen accumulation were observed in Herp −/− /LDLR −/− mice when compared with LDLR −/− mice. In vitro experiments demonstrated that Hcy caused VSMC phenotypic switching, promoted cell proliferation and migration; this was reversed by Herp depletion. We achieved similar results via inhibition of ER stress using 4-phenylbutyric-acid (4-PBA) in Hcy-treated VSMCs. Conclusion Herp deficiency inhibits the phenotypic switch of VSMCs and the development of atherosclerosis, thus providing novel insights into the role of Herp in atherogenesis.

Background Angiotensin II (Ang II)-induced damage to endothelial cells (ECs) plays a crucial role in the pathogenesis of atherosclerosis. This study aimed to investigate the role of microRNA-384 (miR-384) in endothelial cell apoptosis. Methods The expression of five various miRNAs in Ang II-treated human umbilical vein endothelial cells (HUVECs) were detected by qPCR. The Ang II-induced apoptosis of HUVECs was determined by flow cytometry, TUNEL staining and western blot. Endoplasmic reticulum (ER) stress markers were detected by western blot analysis. The target gene of miR-384 was determined by bioinformatics analyses. qPCR, western blotting and immunofluorescence were performed to determine the expression level of homocysteine inducible ER protein with ubiquitin like domain 1 (Herpud1). Results miR-384 expression level was significantly decreased in Ang II-treated HUVECs. Ang II-induced HUVEC apoptosis was accompanied by the occurrence of ER stress. A decreased rate of HUVEC apoptosis and a decreased rate of ER stress were observed following restoration of miR-384 expression. Herpud1 expression level was increased in HUVECs treated with Ang II, and miR-384 mimics effectively inhibited Herpud1 expression. Mechanistically, miR-384 directly targets the 3′-untranslated region of Herpud1. Furthermore, effects of miR-384 on HUVECs apoptosis and ER stress were at least partly reversed by knockdown of Herpud1 expression. Conclusion The results of the present study collectively indicated that miR-384 expression level was downregulated in Ang II-treated HUVECs and miR-384 overexpression protected HUVECs against Ang II-induced apoptosis by negatively regulating Herpud1. These findings point towards new strategies by which apoptosis of ECs can be suppressed.

OBJECTIVES: The present study aimed to investigate the prevalence of sarcopenia among 18–75y community dwelling residents in eight cities of China, and also the interrelationship between overall dietary quality and sarcopenia. METHODS: This study used data from the Chinese Urban Adults Diet and Health Study (CUADHS), a cross-sectional survey conducted in eight cities from March to July, 2016. Muscle mass was measured by a direct segmental multifrequency bioelectrical impedance analysis (BIA) (In-Body S10; Biospace Co., Ltd, Seoul, Korea). Sarcopenia was defined per the recommended algorithm of the Asian Working Group for Sarcopenia (AWGS) for participants ≥65y, while for subjects aged 18–64y, sarcopenia was defines as a Sarcopenia index (SI, calculated as ASM/BMI) of

OBJECTIVES: The main aim of the present study was to investigate the nutrition knowledge and diary knowledge of elderly and middle-aged urban community-dwelling population, and their effects on diet quality and dairy consumption. METHODS: Data shown in present study was extracted from a cross-sectional survey, the Chinese Urban Adults Diet and Health Study, conducted in eight cities from March to July, 2016. Data were collected from subjects by trained interviewers using an interviewer-administered questionnaire in two parts related to social-demographic factors and knowledge, attitude, and practice (KAP). For knowledge, seven questions and six questions were used to measure subjects’ knowledge towards nutrition and the health benefits of dairy products, respectively. One-time 24-h dietary recall and the semi-quantitative Food Frequency Questionnaire (semi-FFQ) for one recent month were used to investigate the food consumption with the help of a standard reference picture book, bowls, plates, and spoons. China Healthy Diet Index (CHDI) and Dietary Diversity Scores (DDS) were used to measure dietary quality. Covariates were determined by questionnaires and interviews. RESULTS: A total of 1090 individuals aged 62.12 ± 8.62 (range 45–81 years) were included, 60.8% were female. Males, subjects with lower household monthly income and lower education level had significantly lower knowledge scores. Participants with better nutrition knowledge had significantly higher CHDI score (63 vs 54, P

There is limited information regarding the intake and status of polyunsaturated fatty acids (PUFA) in Chinese pregnant women with different dietary patterns. We hypothesize that there will be significant differences in long chain n-3 and n-6 PUFA status in pregnant women from 3 regions of China (river/lake, coastal and inland). Dietary fatty acid intakes and fatty acid profiles in maternal and umbilical erythrocyte phosphatidylcholine (PC) were analyzed. The median daily intakes (mg) of eicosapentanoic acid and docosahexaenoic acid (DHA) in the coastal group (64.6 and 93.9, n = 42) were significantly higher than those in the river/lake group (27.9 and 41.8, n = 41) and the inland group (12.1 and 41.1, n = 40). Daily intake of arachidonic acid (AA) was highest (170.2 mg) in the inland group. The median DHA level (%) of maternal erythrocyte PC was comparable between river/lake and inland groups (5.7 vs. 5.6) while both were significantly lower than in coastal group (8.4). The median AA level (%) of maternal erythrocyte PC tended to be lower in the coastal group than in the inland group but the difference was not significant. The AA and DHA levels in umbilical erythrocyte PC were comparable among the 3 groups. In conclusion, differences in long chain n-3 PUFA intake between geographic regions, in particular in DHA, were reflected in differences in maternal erythrocyte PC DHA status but did not result in differences in umbilical erythrocyte PC.

Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.

Although the beneficial effects of n-3 fatty acids on several physiologic functions have been widely reported, information about the effects of oily fish in the Asian diet on cardiovascular disease (CVD) risk is diminutive. We hypothesize that daily inclusion of oily fish for 8 weeks in the Chinese diet will elevate serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels and reduce CVD risk markers in dyslipidemic adult men, comparable with the effects generally observed by inclusion of oily fish in the Western diet. In this 8-week randomized, parallel-arm, food-based intervention study, lunches were prepared with 500 g pork/chicken/beef, typically consumed fish (hairtail and freshwater carp), or oily fish (salmon). Male subjects aged between 35 and 70 years with hyperlipidemia were randomly assigned to eat lunches with pork/chicken/beef (n = 30 subjects at 8 weeks), freshwater fish (n = 30), or oily fish (n = 32). Circulating markers were measured at baseline and at 8 weeks. In the oily fish diet, dietary EPA and DHA levels were significantly increased as compared with other diets; and the n-6:n-3 polyunsaturated fatty acid ratio was decreased (P < .05). Thus, the oily fish diet significantly elevated serum EPA and DHA concentrations (P < .01) and lowered serum n-6:n-3 ratio at 8 weeks (P < .05). Furthermore, oily fish intake significantly reduced serum levels of triglycerides (P < .05) and interleukin-6 (P < .01) and increased levels of high-density lipoprotein cholesterol (P < .01). In conclusion, daily inclusion of oily fish as part of the Chinese diet for 8 weeks is sufficient to significantly increase the serum content of long-chain n-3 polyunsaturated fatty acids and reduce levels of CVD risk markers in dyslipidemic adult men.

A simple, fast and sensitive liquid chromatography-electrospray tandem mass spectrometry method was established for trace levels of nine haloacetic acids (HAAs) in drinking water. Water samples were removed of residual chlorine by adding L-ascorbic acid, and directly injected after filtered by 0.22 microm membrane. Nine HAAs were separated by liquid chromatography in 7.5 min, and the limits of detection were generally between 0.16 and 0.99 microg/L except for chlorodibromoacetic acid (1.44 microg/L) and tribromoacetic acid (8.87 microg/L). The mean recoveries of nine target compounds in spiked drinking water samples were 80.1-108%, and no apparent signal suppression was observed. Finally, this method was applied to determine HAAs in the tap water samples collected from five waterworks in Shandong, China. Nine HAAs except for monochloroacetic acid, monobromoacetic acid, dibromochloroacetic acid and tribromoacetic acid were detected, and the total concentrations were 7.79-36.5 microg/L. The determination results well met the first stage of the Disinfectants/Disinfection By-Products (D/DBP) Rules established by U.S.EPA and Guidelines for Drinking-water Quality of WHO.