SignificanceNonapoptotic cell death-induced tissue damage has been implicated in a variety of diseases, including neurodegenerative disorder, inflammation, and stroke. In this study, we demonstrate that ferroptosis, a newly defined iron-dependent cell death, mediates both chemotherapy- and ischemia/reperfusion-induced cardiomyopathy. RNA-sequencing analysis revealed up-regulation of heme oxygenase 1 by doxorubicin as a major mechanism of ferroptotic cardiomyopathy. As a result, heme oxygenase 1 degrades heme and releases free iron in cardiomyocytes, which in turn leads to generation of oxidized lipids in the mitochondria membrane. Most importantly, both iron chelation therapy and pharmacologically blocking ferroptosis could significantly alleviate cardiomyopathy in mice. These findings suggest targeting ferroptosis as a strategy for treating deadly heart disease.
BackgroundAlthough studies have examined the association between dietary magnesium intake and health outcome, the results are inconclusive. Here, we conducted a dose–response meta-analysis of prospective cohort studies in order to investigate the correlation between magnesium intake and the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and all-cause mortality.MethodsPubMed, EMBASE, and Web of Science were searched for articles that contained risk estimates for the outcomes of interest and were published through May 31, 2016. The pooled results were analyzed using a random-effects model.ResultsForty prospective cohort studies totaling more than 1 million participants were included in the analysis. During the follow-up periods (ranging from 4 to 30 years), 7678 cases of CVD, 6845 cases of coronary heart disease (CHD), 701 cases of heart failure, 14,755 cases of stroke, 26,299 cases of T2D, and 10,983 deaths were reported. No significant association was observed between increasing dietary magnesium intake (per 100 mg/day increment) and the risk of total CVD (RR: 0.99; 95% CI, 0.88–1.10) or CHD (RR: 0.92; 95% CI, 0.85–1.01). However, the same incremental increase in magnesium intake was associated with a 22% reduction in the risk of heart failure (RR: 0.78; 95% CI, 0.69–0.89) and a 7% reduction in the risk of stroke (RR: 0.93; 95% CI, 0.89–0.97). Moreover, the summary relative risks of T2D and mortality per 100 mg/day increment in magnesium intake were 0.81 (95% CI, 0.77–0.86) and 0.90 (95% CI, 0.81–0.99), respectively.ConclusionsIncreasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD. These findings support the notion that increasing dietary magnesium might provide health benefits.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0742-z) contains supplementary material, which is available to authorized users.
Numerous studies have suggested that excess body weight is associated with increased cancer risk. To examine this putative association, we performed a systematic review and quantitative meta-analysis of cohort studies reporting body mass index (BMI) and the risk of 23 cancer types. PubMed, Embase, and Web of Science were searched for cohort studies, yielding 325 articles with 1,525,052 cases. Strong positive associations were observed between BMI and endometrial cancer (RR: 1.48), esophageal adenocarcinoma (RR: 1.45), and kidney cancer (RR: 1.20); weaker associations (RR< 1.20) were also found for several other cancer types. Interestingly, we found significant inverse associations between BMI and oral cavity (RR: 0.93), lung (RR: 0.91), premenopausal breast (RR: 0.95), and localized prostate (RR: 0.97) cancers. A male-specific association was found for colorectal cancer (p = 0.023), and a female-specific association was found for cancer in brain (p = 0.025) or kidney (p = 0.035). With respect to geography, the strongest positive association was found for total cancer in North America (p = 0.038). This comprehensive meta-analysis provides epidemiological evidence supporting the association between BMI and cancer risk. These findings can be used to drive public policies and to help guide personalized medicine in order to better manage body weight, thereby reducing the risk of developing obesity-related cancer.
Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.