Suppression of Adaptive Immune Cell Activation Does Not Alter Innate Immune Adipose Inflammation or Insulin Resistance in Obesity

Obesity-induced inflammation in visceral adipose tissue (VAT) is a major contributor to insulin resistance and type 2 diabetes. Whereas innate immune cells, notably macrophages, contribute to visceral adipose tissue (VAT) inflammation and insulin resistance, the role of adaptive immunity is less well defined. To address this critical gap, we used a model in which endogenous activation of T cells was suppressed in obese mice by blocking MyD88-mediated maturation of CD11c⁺ antigen-presenting cells. VAT CD11c⁺ cells from Cd11cCre⁺Myd88^(fl/fl) vs. control Myd88^(fl/fl) mice were defective in activating T cells in vitro, and VAT T and B cell activation was markedly reduced in Cd11cCre⁺Myd88^(fl/fl) obese mice. However, neither macrophage-mediated VAT inflammation nor systemic inflammation were altered in Cd11cCre⁺Myd88^(fl/fl) mice, thereby enabling a focused analysis on adaptive immunity. Unexpectedly, fasting blood glucose, plasma insulin, and the glucose response to glucose and insulin were completely unaltered in Cd11cCre⁺Myd88^(fl/fl) vs. control obese mice. Thus, CD11c⁺ cells activate VAT T and B cells in obese mice, but suppression of this process does not have a discernible effect on macrophage-mediated VAT inflammation or systemic glucose homeostasis

Three-dimensional volumetric analysis of the maxillary sinus: a cone-beam computed tomography study

Background: This study aimed to determine the volumetric size of the maxillary sinus and investigate the effect of gender and age on maxillary sinus volume (MSV) using cone-beam computed tomography (CBCT) images in a Turkish subpopulation. Materials and methods: This retrospective volumetric CBCT study was carried out on 133 individuals (84 females, 49 males) between 8 and 51 years old. MSV was measured using the MIMICS 21.0 software (Materialise HQ Technologielaan, Leuven, Belgium). All statistical analyses were performed using the SPSS 21.0 (SPSS, Chicago, IL, USA) software. Mean and standard deviation of both maxillary sinuses measurements were calculated and compared to gender and age. P values < 0.05 were considered to indicate statistical significance. Results: Mean volume of the right maxillary sinus was 13.173 cm3, while for the left was 13.194 cm3. There was no significant difference between right and left maxillary sinus volumes (p > 0.05). There was no significant correlation between MSV and age (p > 0.05). It was found that MSV did not change according to gender (p > 0.05). Conclusions: Right and left maxillary sinus volumes were not different from each other. Gender and age were not found to be related to maxillary sinus volume

NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

ER stress signaling involving calcium and CaMKII induces NADPH oxidase and oxidative stress, which amplify CHOP-mediated apoptosis via PKR activation

Geranylgeranyl isoprenoids and hepatic Rap1a regulate basal and statin-induced expression of PCSK9

LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin-induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin-mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small-molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin-mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post-transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9

Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Obesity Mediates Suppression of Hepatic Insulin Signaling

SummaryA hallmark of obesity is selective suppression of hepatic insulin signaling (“insulin resistance”), but critical gaps remain in our understanding of the molecular mechanisms. We now report a major role for hepatic CaMKII, a calcium-responsive kinase that is activated in obesity. Genetic targeting of hepatic CaMKII, its downstream mediator p38, or the p38 substrate and stabilizer MK2 enhances insulin-induced p-Akt in palmitate-treated hepatocytes and obese mouse liver, leading to metabolic improvement. The mechanism of improvement begins with induction of ATF6 and the ATF6 target p58IPK, a chaperone that suppresses the PERK—p-eIF2α—ATF4 branch of the UPR. The result is a decrease in the ATF4 target TRB3, an inhibitor of insulin-induced p-Akt, leading to enhanced activation of Akt and its downstream metabolic mediators. These findings increase our understanding of the molecular mechanisms linking obesity to selective insulin resistance and suggest new therapeutic targets for type 2 diabetes and metabolic syndrome