Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines

BACKGROUND: MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation. METHODS: Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed. RESULTS: Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells. CONCLUSION: Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses

Effects of the Proprioceptive Neuromuscular Facilitation Technique on Scapula Function in Office Workers with Scapula Dyskinesis

Background and Objectives; Proprioceptive neuromuscular facilitation (PNF) are effective in improving and maintaining Range of motion(ROM), increasing muscular strength and power, and increasing athletic performance, especially after exercise. The scapula patterns defined in PNF are activated within the upper extremity patterns and scapula motions together. Proper function of the upper extremities requires both motion and stability of the scapula. The purpose of this study was to compare the effects of scapula stabilization exercise training involving muscle strengthening, muscle balance, and movement control exercises on office workers with scapula dysfunction. Materials and Methods: A total of 42 office workers with scapula dyskinesis were recruited and randomly divided into three groups: muscle strengthening exercise group (n = 14), muscle balance exercise group (n = 14), and movement control exercise group (n = 14). The participants underwent 18 sessions (25 min/session, 3 days a week for 6 weeks) of training involving the three types of exercises. Results: The measurement outcomes included the scapula index, measured using a digital Vernier caliper; scapula function, evaluated using the Disability of the Arm, Shoulder, and Hand (DASH) outcome questionnaire (pain and performing, work ability, and sports and art activities); and scapulohumeral movements (scapula upward rotation at humeral abduction angles of 0°, 45°, 90°, 135°, and 180°), evaluated using inclinometers. After the exercise intervention, the scapula index (p = 0.002), DASH pain and performing score (p = 0.000), DASH work ability score (p = 0.000), DASH sports and art activity score (p = 0.027), and scapulohumeral movements (scapula upward rotation at 0° (p = 0.013) and 45° (p = 0.043) humeral abduction) showed significantly greater improvements in the movement control group than in the muscle strengthening and muscle balance groups. Conclusions: Thus, proprioceptive neuromuscular facilitation can be used as a rehabilitation intervention for scapula position and movement, pain reduction, and functional improvement in office workers with scapula dyskinesis

Effects of Curved-Path Gait Training on Gait Ability in Middle-Aged Patients with Stroke: Protocol for a Randomized Controlled Trial

(1) Introduction: This study aimed to investigate the effects of curved-path stride gait training on the gait ability of patients with stroke. (2) Materials and Methods: Thirty patients with stroke were randomly assigned to curved-path stride gait training (n = 15) and general gait training groups (n = 15). Both groups underwent training for 30 min five times a week for 8 weeks. The gait ability of each was assessed using the Dynamic Gait Index (DGI), Timed-Up-and-Go (TUG) test, 10-meter walk test, and Figure-of-8 walk test (F8WT). (3) Results: The curved-path gait training group showed significant differences in the DGI, TUG test, 10-m walk test, and F8WT pre- versus post- intervention (p p > 0.05). Additionally, there was a statistically significant intergroup difference in gait ability (p < 0.05). (4) Conclusions: Curved-path gait training resulted in greater improvement in gait ability than general gait training. Therefore, curved-path gait training can be a meaningful intervention for improving the gait ability of patients with stroke

Brief Report: Heterogeneity of Acquired Resistance Mechanisms to Osimertinib and Savolitinib

Introduction: MET amplification is a frequently observed mechanism of resistance to osimertinib, and coinhibition strategy of MET and EGFR revealed promising results in recent clinical trials. Nevertheless, acquired resistance mechanisms to combined EGFR and MET inhibition are poorly understood. In this study, we investigated the mechanisms of acquired resistance to osimertinib and savolitinib by using pretreatment and post-treatment tissue analysis. Methods: Whole-exome sequencing was performed in EGFR-mutant, MET-amplified patients who received osimertinib and savolitinib using tissues obtained both before and after therapy. All patients achieved partial response or durable stable disease to osimertinib and savolitinib before developing acquired resistance. Results: After progression on osimertinib and savolitinib, whole-exome analysis revealed MET-dependent mechanisms of resistance, such as acquired MET p.D1246H mutation, MET p.Y1230C mutation, and MET copy number gain. As for MET-independent mechanisms, development of ERBB2 mutation and amplification and copy number gains in amplifications in CCNE, CCND1, CDK6, and EGFR were observed. Patient 2 harbored an acquired PIK3CA p.H1047R mutation in which resistance could be overcome with combination of PI3K inhibitor and osimertinib in the patient-derived xenograft model. Conclusions: Our study reveals that acquired resistance to savolitinib plus osimertinib can occur from both MET-dependent and MET-independent mechanisms

Ion-Exchangeable Functional Binders and Separator for High Temperature Performance of Li1.1Mn1.86Mg0.04O4 Spinel Electrodes in Lithium Ion Batteries

Since LiMn2O4 spinel materials are inexpensive, environmentally-friendly, and safe, they are considered a promising cathode candidate for lithium ion batteries in EVs to replace commercialized materials such as LiCoO2, LiNi1/3Mn1/3Co1/3O2 and LiNi0.5Co0.2Mn0.3O2. However, LiMn2O4 spinel electrodes severely degrade at high temperature due to Mn dissolution. Also, the dissolved Mn2+ ions causes self-discharge where reduction of Mn2+ ions into Mn metals occurs on a graphite anode surface accompanied by oxidation of lithiated graphite at a charged state, and this results in severe capacity fading at high temperature. In this study, ion-exchangeable binders and a separator having functional groups of sodium carboxylate or sulfonate are, for the first time, examined to solve the Mn dissolution problem of LiMn2O4 spinel materials at high temperature. Ion exchange between Na+ ions of the functional groups of the binders and the separator and dissolved Mn2+ ions of the LiMn2O4 electrodes inhibits self-discharge, resulting in improved cycle performance. This result is supported by the IR spectra of the binders, an ICP analysis of the electrolytes, and ex situ XRD patterns of lithiated graphite electrodes.close0