Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer\u27s disease

A promising new therapeutic target for the treatment of Alzheimer\u27s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A

Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury

Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions

Methylsulfonylmethane Suppresses Breast Cancer Growth by Down-Regulating STAT3 and STAT5b Pathways

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers

A Study on the Application of Laser Cleaning on the Weld of the Gas Fuel Supply Pipe for DF Engine

While producing gas fuel supply pipes for duel fuel (DF) engines, a welding process is essential. Accordingly, specimen management before and after welding is crucial to obtain highly reliable weldments. In this study, we developed an environmentally friendly laser cleaning technology to address a toxic work environment and environmental pollution problems caused by chemical cleaning technology utilized in post-welding treatment of gas fuel supply for DF engines. An experiment was conducted by implementing surface laser cleaning of the butt and fillet weldment specimens according to process parameters. Conditions of process parameters were identified for facilitating laser cleaning and used in prototype production. The prototypes were processed through laser and chemical cleaning, and the quality of the end products was compared. The results indicated that the proposed method satisfactorily cleans the prototype surface without generating a toxic work environment and environmental pollution problems. Moreover, the roughness of approximately 5 μm was achieved on the laser cleaned surface. This is considered to be able to increase the adhesion of the paint compared to the smooth chemical cleaned surface during the painting for anticorrosion of the product

A Study on the Laser Removal of Epoxy Coatings on SS400 Surface by Beam Scanning Patterns

Shipyards are very interested in improving their working environment and resolving environmental pollution issues by replacing mechanical cleaning technologies used before and after painting processes with laser cleaning technology. Because epoxy paint is thickly coated, with a thickness of 200 μm or greater, it is difficult to remove using both laser cleaning and mechanical cleaning technologies. Therefore, this study tried to obtain effective cleaning results by controlling the process parameters when removing the thick epoxy coating using a Q-switching fiber laser cleaning system with an average power of 100 W developed by our research team. The pulse duration time of the laser is 150 ns. Additionally, in order to determine whether the cleaning was sufficient, the difference in laser-induced plume/plasma was compared. By controlling the beam scanning patterns, line overlap rate, and pulse overlap rate, it was possible to obtain effective cleaning results without introducing removal deviation. In addition, the NOP increased when the laser beam overlap rate increased. This increased the amount of heat input to the material and reduced the number of scans required to remove the epoxy paint. As a result of the plume/plasma analysis, less plume/plasma was generated as the paint was removed if the epoxy paint remained on the surface. On the other hand, when all of the paint was removed, a higher brightness of plume/plasma generated by evaporation of the bare metal was observed