Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.

Visual Acuity Outcomes in Diseases Associated with Reduced Visual Acuity: An Analysis of the National Health Insurance Service Database in Korea.

Visual acuity declines with age, and disease-related visual acuity changes vary. We evaluated factors affecting visual acuity and age-related visual acuity in diseases associated with reduced visual acuity such as hypertension, diabetes mellitus (DM), glaucoma, and diabetic retinopathy (DR). The Korean National Health Insurance Service 2015-2016 data were analyzed for age-related visual acuity changes and prevalence of diseases associated with reduced visual acuity. Among 993,062 participants, the prevalence rates of hypertension, DM, glaucoma, and DR were 27.0%, 15.1%, 13.8%, and 2.7%, respectively. Despite having the lowest prevalence, DR alone or DR with hypertension and glaucoma resulted in low visual acuity. Correlation analysis between disease frequency and mean age-related visual acuity revealed higher positive correlations in DR and hypertension than in DM and glaucoma, indicating lower visual acuity. Odds ratios for low visual acuity in cases including one disease such as hypertension, DM, glaucoma, and DR were 1.73, 1.23, 1.04, and 1.52, respectively. The prevalence and number of diseases associated with reduced visual acuity increased with age, and visual acuity decreased. The leading causes of vision loss were DR as a single disease and hypertension as a concomitant disease. Therefore, age-related vision management, through periodic eye examination and correction with age, should be performed along with management of diabetes and hypertension.

Whole-Body Physiologically Based Pharmacokinetic Modeling of Trastuzumab and Prediction of Human Pharmacokinetics.

In the present study, we evaluated the pharmacokinetics (PK) of trastuzumab and sought to predict human PK based on animal studies, through the use of optical imaging and a whole-body physiologically based pharmacokinetic (WB-PBPK) modeling approach. The PK study was conducted in 24 mice, where serial blood samples were withdrawn and major organs were isolated after the last blood withdrawal. The drug concentrations in blood and major organs were measured via optical imaging. The WB-PBPK model was constructed using known physiological values including the volumes of major organs and blood/lymphatic flow. The NONMEM software (version 7.3) was used to determine tissue partition coefficients. Using the WB-PBPK model, a clinical trial simulation was performed with reference to human physiological values acquired from the literature. The simulated human PK was then compared with the actual PK observed in the previous study in which healthy male subjects received 6 mg/kg trastuzumab (Herceptin®) via intravenous route. The ratio of the simulated versus observed area under the concentration-time curve was 1.02 and that of maximal concentration was 0.72. The current study describes the potential synergistic applications of WB-PBPK and optical imaging in human PK prediction based on preclinical data obtained in early-stage drug development.

Schisandrin B suppresses TGFß1-induced stress fiber formation by inhibiting myosin light chain phosphorylation.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis fruit extract (SCE) has been used as a traditional oriental medicine for treating vascular diseases. However, the pharmacologic effects and mechanisms of SCE on vascular fibrosis are still largely unknown. Transforming growth factor ß1 (TGFß1)-mediated cellular changes are closely associated with the pathogenesis of vascular fibrotic diseases. Particularly, TGFß1 induces actin stress fiber formation that is a crucial mechanism underlying vascular smooth muscle cell (VSMC) migration in response to vascular injury. In this study, we investigated the effect of SCE and its active ingredients on TGFß1-induced stress fiber assembly in A7r5 VSMCs. MATERIALS AND METHODS: To investigate pharmacological actions of SCE and its ingredients on TGFß1-treated VSMCs, we have employed molecular and cell biological technologies, such as confocal microscopy, fluorescence resonance energy transfer, western blotting, and radiometric enzyme analyses. RESULTS: We found that SCE inhibited TGFß1-induced stress fiber formation and cell migration. Schisandrin B (SchB) showed the most prominent effect among the active ingredients of SCE tested. SchB reduced TGFß1-mediated phosphorylation of myosin light chain, and this effect was independent of RhoA/Rho-associated kinase pathway. Fluorescence resonance energy transfer and radiometric enzyme assays confirmed that SchB inhibited myosin light chain kinase activity. We also showed that SchB decreased TGFß1-mediated induction of α-smooth muscle actin by inhibiting Smad signaling. CONCLUSIONS: The present study demonstrates that SCE and its active ingredient SchB suppressed TGFß1-induced stress fiber formation at the molecular level. Therefore, our findings may help future investigations to develop multi-targeted therapeutic strategies that attenuate VSMC migration and vascular fibrosis.