ABSTRACT
Obesity, a condition characterized by excessive accumulation of body fat, is a metabolic disorder related to an increased risk of chronic inflammation. Obesity is mediated by signal transducer and activator of transcription (STAT) 3, which is regulated by genes associated with retinoid-interferon-induced mortality (GRIM) 19, a protein ubiquitously expressed in various human tissues. In this study, we investigated the role of GRIM19 in diet-induced obese C57BL/6 mice via intravenous or intramuscular administration of a plasmid encoding GRIM19. Splenocytes from wild-type and GRIM19-overexpressing mice were compared using enzyme-linked immunoassay, real-time polymerase chain reaction, Western blotting, flow cytometry, and histological analyses. GRIM19 attenuated the progression of obesity by regulating STAT3 activity and enhancing brown adipose tissue (BAT) differentiation. GRIM19 regulated the differentiation of mouse-derived 3T3-L1 preadipocytes into adipocytes, while modulating gene expression in white adipose tissue (WAT) and BAT. GRIM19 overexpression reduced diet-induced obesity and enhanced glucose and lipid metabolism in the liver. Moreover, GRIM19 overexpression reduced WAT differentiation and induced BAT differentiation in obese mice. GRIM19-transgenic mice exhibited reduced mitochondrial superoxide levels and a reciprocal balance between Th17 and Treg cells. These results suggest that GRIM19 attenuates the progression of obesity by controlling adipocyte differentiation.
Subject(s)
Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , NADH, NADPH Oxidoreductases/metabolism , T-Lymphocytes, Regulatory/cytology , Th17 Cells/cytology , 3T3-L1 Cells , Adipocytes/cytology , Animals , Cell Differentiation , Cell Line , Diet, High-Fat/adverse effects , Female , Gene Expression Regulation , Inflammation , Lipid Metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , Obesity/metabolism , STAT3 Transcription Factor/metabolism , Spleen/cytologyABSTRACT
Cucurbitacin E (CuE) is a biochemical compound found in plants that are members of the family CuE has been studied for its roles in anti-inflammation and the inhibition of angiogenesis as well as for its properties as an antioxidant. CuE is a new agent that was identified as a selective inhibitor of the signal transducer and activator of transcription 3 (STAT3)-related pathway. STAT3, a pivotal transcription factor for Th17 differentiation, is critical for T cell alloactivation in acute graft-versus-host disease (aGvHD). We investigated whether CuE attenuates the development of aGvHD through the suppression of Th17 cells. The alloreactive proliferation of mouse and human T cells was reduced by CuE treatment. CuE also decreased pro-inflammatory cytokines, such as IL-17 and IFN-γ, in alloreactive T cells. STAT3-responsive and IL-17A-promoter activities were also suppressed by CuE treatment, confirming that activated STAT3 was decreased by CuE treatment. To construct an aGvHD-induced mouse line, splenocytes and bone marrow cells from C57BL/6 mice were transplanted into BALB/c mice with complete mis-matched major histocompatibility complex molecules. CuE was administered to aGvHD animals 3 days per week via intraperitoneal injection. CuE attenuated the severity of aGvHD disease-related scores compared to the vehicle group. CuE inhibited skin inflammation and fibrosis, as evidenced by the expression of α-Sma and Col-I in aGvHD mice compared to the vehicle group. Additionally, aGvHD mice treated with CuE showed improved histopathological features in the small and large intestines, whereas the vehicle group showed collapsed villi in the small intestine and cryptic structures in the large intestine. We also observed a marked reduction of pro-inflammatory cytokines in the intestinal tissue. Collectively, our data suggest that CuE could serve as a therapeutic agent for patients with aGvHD.
Subject(s)
Graft vs Host Disease , STAT3 Transcription Factor/immunology , Th17 Cells , Triterpenes/pharmacology , Acute Disease , Animals , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Graft vs Host Disease/prevention & control , Humans , Mice , Mice, Inbred BALB C , Th17 Cells/immunology , Th17 Cells/pathologyABSTRACT
Notoginseng Radix and Rehmanniae Radix Preparata have been widely used traditionally for treating inflammatory diseases. This research studies the therapeutic effects of YH23537, the extracts of Notoginseng Radix and Rehmanniae Radix Preparata, on pain and cartilage degeneration in an experimental osteoarthritis (OA) model. Male Wistar rats were inoculated intra-articularly with 3 mg of monosodium iodoacetate (MIA) in the right intra-articular. Four days later, the animals were administrated orally with YH23537 daily for 24 days. Tactile allodynia and weight bearing were measured. Macroscopic and microscopic observations for articular cartilage were performed at the end of the experiment. Protein expression in the joint was determined by immunohistochemistry. The effects of YH23537 on mRNA levels in chondrocytes stimulated with interleukin (IL)-1ß were analyzed using random polymerase chain reaction. OA induction was confirmed by significant decrease of paw withdrawal latency, paw withdrawal threshold, and weight bearing compared with the normal group at 3 days after MIA injection. The YH23537-treated groups displayed significant increases in pain thresholds and weight bearing throughout the observation period. The damage to articular cartilage was significantly lessened visually and histopathologically by YH23537 treatment. YH23537 suppressed the expression of metalloproteinase-3, nitrotyrosine, IL-1ß and IL-6 increased in OA joints. YH23537 upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 in IL-1ß-stimulated human OA chondrocytes. The protein levels of the NF-κBp65 and HIF-2α in the joint tissues were reduced by YH23537. YH23537 exerted antinociceptive effects and cartilage protective effects in experimental OA rats by suppressing oxidative injury, inflammatory mediators, and inducing anabolic factors. We suggest that YH23537 may have efficacy for treating OA in humans.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cartilage Diseases/drug therapy , Osteoarthritis/drug therapy , Pain/drug therapy , Panax , Plant Extracts/pharmacology , Rehmannia , Administration, Oral , Animals , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/therapeutic use , Cartilage Diseases/chemically induced , Cartilage, Articular/drug effects , Disease Models, Animal , Iodoacetates , Male , Osteoarthritis/chemically induced , Pain Measurement , Phytotherapy , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , Rats , Rats, WistarABSTRACT
Metal and metal oxide nanoparticles (NPs) supported on high surface area carbon (NP/Cs) were prepared by the physical vapor deposition of bulk materials on an α-D-glucose (Glu) substrate, followed by the deposition of the NPs on carbon supports. Using Glu as a carrier for the transport of NPs from the bulk materials to the carbon support surfaces, ultrafine NPs were obtained, exhibiting a stabilizing effect through OH moieties on the Glu surfaces. This stabilizing effect was strong enough to stabilize the NPs, but weak enough to not significantly block the metal surfaces. As only the target materials and Glu are required in our procedure, it can be considered environmentally friendly, with the NPs being devoid of hazardous chemicals. Furthermore, the resulting NP/Cs exhibited an improvement in activity for various electrochemical reactions, mainly attributed to their high surface area.
