Aims: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose-stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice. Results: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1a pathway. Innovation: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H 2 O 2 ) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen-initiated H 2 O 2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1a as the main mediator for that link. Conclusion: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. Redox Signal. 20,[191][192][193][194][195][196][197][198][199][200][201][202][203]

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two‐sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long‐term cancer risk. Single‐nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large‐scale genome‐wide association studies were used as genetic instruments. Summary‐level data for 24 site‐specific cancers were obtained from UK Biobank. We found that a 1‐SD increase in childhood BMI (kg/m2) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12‐2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09‐1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27‐0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64‐0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.

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The artificial ceroid/lipofuscin pigments originated from different organ tissues, including liver, brain, heart, and kidney of rats, and biomaterials were studied with improved fluorometric techniques. With all tissue materials exposed under ultraviolet (UV) light, a series of similar fluorescent colors were observed under microfluorometer. Analogous fluorescence spectra were also demonstrated with a three-dimensional (3-D) front-surface fluorometric technique despite of the tissue differences. Measured with 3-D fluorometry, relatively simple lipofuscin-like fluorophores were observed from the reactions of malondialdehyde (MDA) with critical biological macromolecules, such as bovine serum albumin (BSA) and DNA. Our results demonstrated that the biomaterials from different tissues have a similar fate under accelerated oxidative/carbonyl stresses but may be differentiated by a fluorescence intensity ratio.