Impact of social integration on metabolic functions: evidence from a nationally representative longitudinal study of US older adults

Abstract Background Metabolic functions may operate as important biophysiological mechanisms through which social relationships affect health. It is unclear how social embeddedness or the lack thereof is related to risk of metabolic dysregulation. To fill this gap we tested the effects of social integration on metabolic functions over time in a nationally representative sample of older adults in the United States and examined population heterogeneity in the effects. Methods Using longitudinal data from 4,323 adults aged over 50 years in the Health and Retirement Study and latent growth curve models, we estimated the trajectories of social integration spanning five waves, 1998–2006, in relation to biomarkers of energy metabolism in 2006. We assessed social integration using a summary index of the number of social ties across five domains. We examined six biomarkers, including total cholesterol, high-density lipoprotein cholesterol, glycosylated hemoglobin, waist circumference, and systolic and diastolic blood pressure, and the summary index of the overall burden of metabolic dysregulation. Results High social integration predicted significantly lower risks of both individual and overall metabolic dysregulation. Specifically, adjusting for age, sex, race, and body mass index, having four to five social ties reduced the risks of abdominal obesity by 61% (odds ratio [OR] [95% confidence interval {CI}] = 0.39 [0.23, 0.67], p = .007), hypertension by 41% (OR [95% CI] = 0.59 [0.42, 0.84], p = .021), and the overall metabolic dysregulation by 46% (OR [95% CI] = 0.54 [0.40, 0.72], p < .001). The OR for the overall burden remained significant when adjusting for social, behavioral, and illness factors. In addition, stably high social integration had more potent metabolic impacts over time than changes therein. Such effects were consistent across subpopulations and more salient for the younger old (those under age 65), males, whites, and the socioeconomically disadvantaged. Conclusions This study addressed important challenges in previous research linking social integration to metabolic health by clarifying the nature and direction of the relationship as it applies to different objectively measured markers and population subgroups. It suggests additional psychosocial and biological pathways to consider in future research on the contributions of social deficits to disease etiology and old-age mortality

Impact of social integration on metabolic functions: evidence from a nationally representative longitudinal study of US older adults

BACKGROUND: Metabolic functions may operate as important biophysiological mechanisms through which social relationships affect health. It is unclear how social embeddedness or the lack thereof is related to risk of metabolic dysregulation. To fill this gap we tested the effects of social integration on metabolic functions over time in a nationally representative sample of older adults in the United States and examined population heterogeneity in the effects. METHODS: Using longitudinal data from 4,323 adults aged over 50 years in the Health and Retirement Study and latent growth curve models, we estimated the trajectories of social integration spanning five waves, 1998–2006, in relation to biomarkers of energy metabolism in 2006. We assessed social integration using a summary index of the number of social ties across five domains. We examined six biomarkers, including total cholesterol, high-density lipoprotein cholesterol, glycosylated hemoglobin, waist circumference, and systolic and diastolic blood pressure, and the summary index of the overall burden of metabolic dysregulation. RESULTS: High social integration predicted significantly lower risks of both individual and overall metabolic dysregulation. Specifically, adjusting for age, sex, race, and body mass index, having four to five social ties reduced the risks of abdominal obesity by 61% (odds ratio [OR] [95% confidence interval {CI}] = 0.39 [0.23, 0.67], p = .007), hypertension by 41% (OR [95% CI] = 0.59 [0.42, 0.84], p = .021), and the overall metabolic dysregulation by 46% (OR [95% CI] = 0.54 [0.40, 0.72], p < .001). The OR for the overall burden remained significant when adjusting for social, behavioral, and illness factors. In addition, stably high social integration had more potent metabolic impacts over time than changes therein. Such effects were consistent across subpopulations and more salient for the younger old (those under age 65), males, whites, and the socioeconomically disadvantaged. CONCLUSIONS: This study addressed important challenges in previous research linking social integration to metabolic health by clarifying the nature and direction of the relationship as it applies to different objectively measured markers and population subgroups. It suggests additional psychosocial and biological pathways to consider in future research on the contributions of social deficits to disease etiology and old-age mortality

Corrosion Resistance of Li-Al LDHs Film Modified by Methionine for 6063 Al Alloy in 3.5 wt.% NaCl Solution

Methionine (Met) was introduced to modify the Li-Al layered double hydroxides (LDHs) film prepared on 6063 aluminum alloy by in situ method for the first time. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, Scanning electron microscopy, and X-ray diffraction confirmed the successful insertion of Met into LDHs film and revealed that the introduction of Met could make the LDHs film much denser. Electrochemical tests illustrated that the corrosion rate of the Met modified LDHs film was reduced by more than an order of magnitude compared with the bare Al alloy. Moreover, the corrosion rate of the modified LDHs film after immersion in 3.5 wt.% NaCl solution for 21 days was almost the same as that without immersion, which indicates that the modified film has good corrosion durability. The corrosion resistance of the scratched modified film could recover to the level without a scratch on the 14th day based on the scratch test results, meaning the modified film has a good self-healing property. Finally, the anti-corrosion mechanism of the Met was proved by molecular dynamic simulations and found that the enhanced corrosion resistance may be attributed to the addition of Met that slowed the diffusion of the corrosive medium Cl&minus; and water molecules

Discovery of Novel c-Met Inhibitors Bearing a 3-Carboxyl Piperidin-2-one Scaffold

A series of compounds containing a novel 3-carboxypiperidin-2-one scaffold based on the lead structure BMS-777607 were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against MKN45 cancer cell lines. The results indicated that five compounds exhibited significant inhibitory effect on c-Met with IC50 values of 8.6−81 nM and four compounds showed potent inhibitory activity against MKN45 cell proliferation, with IC50s ranging from 0.57−16 μM

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.</p

Discovery of Anilinopyrimidines as Dual Inhibitors of c‑Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure–activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds <b>3a</b>, <b>3b</b>, <b>3g</b>, <b>3h</b>, and <b>18a</b> exhibited potent antiproliferative effect against c-Met addictive cell lines with IC₅₀ values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with <b>3h</b> has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development

Design, Synthesis, and Biological Evaluation of the First c‑Met/HDAC Inhibitors Based on Pyridazinone Derivatives

Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, <b>2m</b>, inhibited c-Met kinase and HDAC1, with IC₅₀ values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound <b>2m</b> inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule