Metformin use correlated with lower risk of cardiometabolic diseases and related mortality among US cancer survivors: evidence from a nationally representative cohort study.

BACKGROUND: In the USA, the prolonged effective survival of cancer population has brought significant attention to the rising risk of cardiometabolic morbidity and mortality in this population. This heightened risk underscores the urgent need for research into effective pharmacological interventions for cancer survivors. Notably, metformin, a well-known metabolic regulator with pleiotropic effects, has shown protective effects against cardiometabolic disorders in diabetic individuals. Despite these promising indications, evidence supporting its efficacy in improving cardiometabolic outcomes in cancer survivors remains scarce. METHODS: A prospective cohort was established using a nationally representative sample of cancer survivors enrolled in the US National Health and Nutrition Examination Survey (NHANES), spanning 2003 to 2018. Outcomes were derived from patient interviews, physical examinations, and public-access linked mortality archives up to 2019. The Oxidative Balance Score was utilized to assess participants' levels of oxidative stress. To evaluate the correlations between metformin use and the risk of cardiometabolic diseases and related mortality, survival analysis of cardiometabolic mortality was performed by Cox proportional hazards model, and cross-sectional analysis of cardiometabolic diseases outcomes was performed using logistic regression models. Interaction analyses were conducted to explore the specific pharmacological mechanism of metformin. RESULTS: Among 3995 cancer survivors (weighted population, 21,671,061, weighted mean [SE] age, 62.62 [0.33] years; 2119 [53.04%] females; 2727 [68.26%] Non-Hispanic White individuals), 448 reported metformin usage. During the follow-up period of up to 17 years (median, 6.42 years), there were 1233 recorded deaths, including 481 deaths from cardiometabolic causes. Multivariable models indicated that metformin use was associated with a lower risk of all-cause (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.81) and cardiometabolic (HR, 0.65; 95% CI, 0.44-0.97) mortality compared with metformin nonusers. Metformin use was also correlated with a lower risk of total cardiovascular disease (odds ratio [OR], 0.41; 95% CI, 0.28-0.59), stroke (OR, 0.44; 95% CI, 0.26-0.74), hypertension (OR, 0.27; 95% CI, 0.14-0.52), and coronary heart disease (OR, 0.41; 95% CI, 0.21-0.78). The observed inverse associations were consistent across subgroup analyses in four specific cancer populations identified as cardiometabolic high-risk groups. Interaction analyses suggested that metformin use as compared to non-use may counter-balance oxidative stress. CONCLUSIONS: In this cohort study involving a nationally representative population of US cancer survivors, metformin use was significantly correlated with a lower risk of cardiometabolic diseases, all-cause mortality, and cardiometabolic mortality.

In vitro differentiation of human amniotic epithelial stem cells into keratinocytes regulated by OPN3.

Human amniotic epithelial stem cells (hAESCs) are regarded as potential alternatives to keratinocytes (KCs) used for skin wound healing. Light is an alternative approach for inducing stem cell differentiation. Opsins (OPNs), a family of light-sensitive, G protein-coupled receptors, play a multitude of light-dependent and light-independent functions in extraocular tissues. However, it remains unclear whether the light sensitivity and function of OPNs are involved in light-induced differentiation of hAESCs to KCs. Herein, we determine the role of OPNs in differentiation of hAESCs into KCs through cell and molecular biology approaches in vitro. It is shown that mRNA expression of OPN3 in the amniotic membrane and hAESCs was higher than the other four primary OPNs by RT-qPCR analysis. Changes in OPN3 gene expression had a significant impact on cell proliferation, stemness and differentiation capability of hAESCs. Furthermore, we found a significant upregulation of OPN3, KRT5 and KRT14 with hAESCs treated at 3 × 33 J/cm2 irradiation from blue-light LED. Taken together, these results suggest that OPN3 acts as a positive regulator of differentiation of hAESCs into KCs. This study provides a novel insight into photosensitive OPNs associated with photobiomodulation(PBM)-induced differentiation in stem cells.

Functionality-Directed Regio- and Enantio-Selective Olefinic C-H Functionalization of Aryl Alkenes.

Aryl alkenes represents one of the most widely occurring structural motif in countless drugs and natural products, and direct C-H functionalization of aryl alkenes provides atom- step efficient access toward valuable analogues. Among them, group-directed selective olefinic α- and ß-C-H functionalization, bearing a directing group on the aromatic ring, has attracted remarkable attentions, including alkynylation, alkenylation, amino-carbonylation, cyanation, domino cyclization and so on. These transformations proceed by endo- and exo-C-H cyclometallation and provide aryl alkene derivatives in excellent site- stereo-selectivity. Enantio-selective α- and ß- olefinic C-H functionalization were also covered to synthesis axially chiral styrenes.

Synthesis of 3-Oxo Quinolines by Cyclization Using Lignin Models and 2-Aminobenzyl Alcohols.

Phenoxy acetophenones were usually employed as ß-O-4' lignin models for chemical conversion. Herein, an iridium-catalyzed dehydrogenative annulation between 2-aminobenzylalcohols and phenoxy acetophenones was demonstrated to prepare valuable 3-oxo quinoline derivatives, which are hard to prepare using previous methods. This operationally simple reaction tolerated a wide scope of substrates and enabled successful gram-scale preparation.

The effects of missense OPN3 mutations in melanocytic lesions on protein structure and light-sensitive function.

Opsin 3 (OPN3), a member of the light-sensitive, retinal-dependent opsin family, is widely expressed in a variety of human tissues and plays a multitude of light-dependent and light-independent roles. We recently identified five missense variants of OPN3, including p. I51T, p. V134A, p. V183I, p. M256I and p. C331Y, in human melanocytic tumours. However, it remains unclear how these OPN3 variants affect OPN3 protein structure and function. Herein, we conducted structural and functional studies of these variant proteins in OPN3 by molecular docking and molecular dynamics simulations. Moreover, we performed in vitro fluorescence calcium imaging to assess the functional properties of five single-nucleotide variant (SNV) proteins using a site-directed mutagenesis method. Notably, the p. I51T variant was not able to effectively dock with 11-cis-retinal. Additionally, in vitro, the p. I51T SNVs failed to induce any detectable changes in intracellular Ca2+ concentration at room temperature. Taken together, these results reveal that five SNVs in the OPN3 gene have deleterious effects on protein structure and function, suggesting that these mutations, especially the p. I51T variant, significantly disrupt the canonical function of the OPN3 protein. Our findings provide new insight into the role of OPN3 variants in the loss of protein function.

Ruthenium-catalyzed C-H amination of aroylsilanes.

Acylsilane represents a valuable synthon in synthetic chemistry. We report on ruthenium(ii)-catalyzed ortho-C-H amination of aroylsilanes to provide facile access to synthetically useful imidobenzoylsilanes and tosyl-amidobenzoylsilanes. The protocols, with broad substrate scope and excellent functional group tolerance, are enabled with the weak chelation-assistance of acylsilane via C-H cyclometallation.

Novel lignin α-O-4 derived hydrogen donors in CQ-based photoinitiating systems for dental resins.

The purpose of this work is to explore the properties of the lignin-derived amine-free photoinitiating systems (PISs) during the curing process. Four novel hydrogen donors (HD1, HD2, HD3, and HD4) derived from lignin α-O-4 structural were designed and synthesized by simple methods, and their low C-H bond dissociation energies on methylene were determined by molecular orbitals theory. Four experimental groups using CQ (camphorquinone)/HD PIs formulated with Bis-GMA/TEGDMA (70 w%/30 w%) were compared to CQ/EDB (ethyl 4-dimethylamino benzoate) system. The photopolymerization profiles and double bond conversion rate was tracked by FTIR experiments; the color bleaching ability of the samples and color aging test assay were performed using color indexes measurements; The cytotoxicity of the samples was also compared to EDB related systems. All of the experimental groups with new HDs were compared to the control group with EDB by statistical analysis. Compared to CQ/EDB system, new lignin-derived hydrogen donors combined with CQ showed comparable or even better performances in polymerization initiation to form resin samples, under a blue dental LED in air. Excellent color bleaching property was observed with the new HDs. Aging tests and cytotoxicity examination of the resin were performed, indicating the new lignin compounds to be efficient hydrogen donors for amine-free CQ-based photo-initiating system. Novel lignin α-O-4 derived hydrogen donors are promising for further usage in light-curing materials.

Lignin-derived new hydrogen donors for photoinitiating systems in dental materials.

OBJECTIVES: The aim of this study is to develop amine free photo-initiating system (PIs) for the photopolymerization of dental methacrylate resins, using seven new hydrogen donors HDA-HDG derived from ß-O-4 lignin model. METHODS: Seven experimental CQ/HD PIs were formulated with Bis-GMA/TEGDMA (70 w%/30 w%). CQ/EDB system was chosen as the comparison group. FTIR-ATR was used to monitor the polymerization kinetics and double bond conversion. Bleaching property and color stability were evaluated using a spectrophotometer. Molecular orbitals calculations were used to demonstrate C-H bond dissociation energies of the novel HDs. Depth of cure of the HD based systems were compared to the EDB based one. Cytotoxicity was also studied by CCK8 assay using tissue of mouse fibroblasts (L929 cells). RESULTS: Compared to CQ/EDB system, the new CQ/HD systems show comparable or better photopolymerization performances (1 mm-thick samples). Comparable or even better bleaching properties were also obtained with the new amine-free systems. Comparing to EDB, all HDs exhibited significantly lower C-H bond dissociation energies by molecular orbitals calculations. Groups with new HD showed higher depth of cure. OD and RGR values were similar to that of the CQ/EDB group, ensuring the feasibility of the new HDs in dental materials. CLINICAL SIGNIFICANCE: The new CQ/HD PI systems could be potentially useful in dental materials, presenting improvements in restorations' esthetic and biocompatibility.