2-deoxyglucose inhibits induction of chemokine expression in 3T3-L1 adipocytes and adipose tissue explants

© 2016 The Obesity Society Objective: To determine the influence of glycolytic inhibition on the adipocyte inflammatory response. Methods: To determine the effect of 2-deoxyglucose (2-DOG) on the inflammatory response, mature 3T3-L1 adipocytes were co-treated with 2-DOG and LPS or TNF. To determine the effect of endoplasmic reticulum stress on TNF-induced induction of chemokines, adipocytes were pretreated with thapsigargin or salubrinal. Chemokine mRNA levels were determined using quantitative real-time PCR, and secretion of CCL2 was determined by Western blot. Results: 2-DOG treatment reduced the ability of LPS and TNF to induce CCL2 mRNA levels and reduced secreted CCL2 protein levels in a dose-dependent manner. A similar pattern of mRNA regulation was observed for other chemokines. The attenuation of TNF-induced CCL2 mRNA levels occurred regardless of whether glucose or pyruvate was present in the media, suggesting that mechanisms other than glycolysis might mediate the observed effects. Treatment with the endoplasmic reticulum stressor thapsigargin and the endoplasmic reticulum signaling activator salubrinal reduced chemokine mRNA levels similarly to 2-DOG. Conclusions: Collectively, our data indicate that 2-DOG suppresses inflammatory chemokine induction in adipocytes. The effects of 2-DOG do not seem to be linked to glycolysis but correlate with endoplasmic reticulum stress activation

Sequential High-Impact Loading and Zoledronic Acid Before Hindlimb Unloading Protects Against Decrements in Bone Microarchitecture and Strength

The purpose of our investigation was to evaluate the efficacy of prophylactic interventions consisting of impact loading (free-fall landing) and/or a bisphosphonate (zoledronic acid), to counter disuse-induced bone loss of adult male rats (6 months old) subjected to 28 days of hindlimb unloading. Furthermore, we aimed to define the effects of these treatments on mechanical strength properties and bone turnover. We hypothesized that monotherapy would mitigate adverse alterations in bone mass, microarchitecture, and strength, while the combined sequential treatment would completely prevent them. Animals were assigned to one of six groups (n=12 each): baseline control (BC, euthanized on study day 0), cage control (CC), hindlimb unloading (HU), zoledronic acid treatment plus hindlimb unloading (ZA+HU), impact loading treatment plus hindlimb unloading (IL+HU), and impact loading and zoledronic acid treatments plus hindlimb unloading (IL+ZA+HU). IL animals were dropped 25 times (five drops from 30 cm followed by 20 drops from 60 cm) three times per week for the first five weeks of the study. ZA (60 μg/kg body weight) was administered on day 36, immediately following IL and just prior to HU. HU began on day 37 and persisted for four weeks. At the distal femur metaphysis (DFM) and femoral neck (FN), HU caused declines in cancellous bone volume fraction (BV/TV, -25%) and total volumetric bone mineral density (vBMD, -14%), respectively, compared to CC. Mechanical strength and bone turnover were also impaired due to unloading. Individually, IL and ZA attenuated HU-induced changes in mass, microarchitecture, and strength, but when given sequentially, IL+ZA fully rescued them. While HU caused an uncoupling of bone remodeling, ZA treatment successfully reduced bone degradation without affecting bone formation. Treatment with IL followed by ZA resulted in enhanced DFM BV/TV (+20%) and trabecular thickness (Tb.Th, +5%). Also, FN ultimate force was highest with combination treatment. While IL and ZA alone attenuated the deleterious effects of disuse on bone quality, when the two were administered in sequence adult male rats were fully protected against HU-induced alterations in bone mass, microarchitecture, strength, and turnover

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection