Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice.

Abnormal productions of amyloid beta (Aß) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer's disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aß peptides have been unsuccessful in treating Alzheimer's disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aß pathological progression of Alzheimer's disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aß plaque in the brain of 5xFAD mice. This reduction in Aß pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer's disease.

8-Methoxybutin inhibits α-MSH induced melanogenesis and proliferation of skin melanoma by suppression of the transactivation activity of microphthalmia-associated transcription factor.

Microphthalmia-associated transcription factor (MITF) is highly expressed in melanocytes and is the main regulator of melanogenesis and melanocyte cell fate. Although MITF is important for the differentiation and development of melanocytes, it is also considered an oncogene of skin melanoma. Based on these findings, MITF could be an attractive therapeutic target for skin cancer intervention. This study identified 8-methoxybutin as an inhibitor of MITF and investigated the underlying mechanism. 8-Methoxybutin inhibited α-MSH-induced melanogenesis in murine melanoma cells (B16F10) and skin melanoma proliferation by reducing melanogenic gene expression via blockade of the transactivation activity of MITF. In silico docking analysis and pull-down analysis suggested that 8-methoxybutin binds to the DNA-binding domain of MITF and further inhibits its binding to the E-box in the promoter of target genes, including tyrosinase. In addition, 8-methoxybutin suppressed growth of skin melanoma in a xenograft mouse model. These results indicate that 8-methoxybutin has potential as a therapeutic agent for hyperpigmentation disorder and skin cancer. SIGNIFICANCE STATEMENT: 8-Methoxybutin inhibits MITF transactivation activity resulting suppression of melanogenesis and skin melanoma growth.

Deficiencies of Circulating Mucosal-associated Invariant T Cells and Natural Killer T Cells in Patients with Multiple Trauma.

Mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells are known to play important roles in autoimmunity, infectious diseases and cancers. However, little is known about the roles of these invariant T cells in multiple trauma. The purposes of this study were to examine MAIT and NKT cell levels in patients with multiple trauma and to investigate potential relationships between these cell levels and clinical parameters. The study cohort was composed of 14 patients with multiple trauma and 22 non-injured healthy controls (HCs). Circulating MAIT and NKT cell levels in the peripheral blood were measured by flow cytometry. The severity of injury was categorised according to the scoring systems, such as Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, and Injury Severity Score (ISS). Circulating MAIT and NKT cell numbers were significantly lower in multiple trauma patients than in HCs. Linear regression analysis showed that circulating MAIT cell numbers were significantly correlated with age, APACHE II, SAPS II, ISS category, hemoglobin, and platelet count. NKT cell numbers in the peripheral blood were found to be significantly correlated with APACHE II, SAPS II, and ISS category. This study shows numerical deficiencies of circulating MAIT cells and NKT cells in multiple trauma. In addition, these invariant T cell deficiencies were found to be associated with disease severity. These findings provide important information for predicting the prognosis of multiple trauma.

Mucosal-Associated Invariant T Cell Deficiency in Chronic Obstructive Pulmonary Disease.

Mucosal-associated invariant T (MAIT) cells have been reported to play an important role in mucosal immunity. However, little is known about the roles of MAIT cells in chronic obstructive pulmonary disease (COPD). The aims of this study were to examine the levels of circulating MAIT cells and their subsets in COPD patients and to investigate the potential relationship between clinical parameters and MAIT cell levels. Forty-five COPD patients and 57 healthy control subjects were enrolled in the study. Circulating MAIT cells and their subset levels in the peripheral blood were measured by flow cytometry. Disease grades were classified according to the GOLD criteria for the assessment of severity of COPD. Circulating MAIT cell levels were found to be significantly reduced in COPD patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets. Interestingly, elevated serum C-reactive protein level and reduced FEV1/FVC ratio were associated with MAIT cell deficiency in COPD patients. Furthermore, the circulating MAIT levels were found to be significantly lower in patients with moderate to severe COPD than in patients with mild COPD. Our data shows that MAIT cells are numerically deficient in the peripheral blood of patients with COPD. In addition, this MAIT cell deficiency was found to reflect inflammatory activity and disease severity. These findings provide important information for monitoring the changes in MAIT cell levels and for predicting the prognosis during the disease course.

Dysregulated osteoclastogenesis is related to natural killer T cell dysfunction in rheumatoid arthritis.

OBJECTIVE: To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction. METHODS: Patients with rheumatoid arthritis (RA) (n = 25) and healthy controls (n = 12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of macrophage colony-stimulating factor and RANKL. PBMCs were cultured in vitro with α-galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer-stimulated NKT cells on inflammation and bone destruction were determined in mice with collagen-induced arthritis. RESULTS: In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer-stimulated NKT cells inhibited osteoclastogenesis mainly via interferon-γ production in a cytokine-dependent manner (not by cell-cell contact) and down-regulated osteoclast-associated genes. Mice treated with αGalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment. CONCLUSION: This study primarily demonstrates that αGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect against inflammatory bone destruction. However, it also shows that these effects of αGalCer are diminished in RA patients and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA.

Mucosal-associated invariant T cells are numerically and functionally deficient in patients with mycobacterial infection and reflect disease activity.

Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections. The aims of this study were to examine the levels of MAIT cells in pulmonary tuberculosis (TB) and nontuberculous mycobacteria (NTM) lung disease patients, to evaluate the clinical relevance of MAIT cell levels, and to investigate the functions of MAIT cells. Patients with pulmonary TB (n = 35), NTM (n = 29), and healthy controls (n = 75) were enrolled in the study. MAIT cell levels and functions were measured by flow cytometry. Circluating MAIT cell levels were found to be reduced in TB and NTM patients. MAIT cell deficiency reflects a variety of clinical conditions. In particular, MAIT cell numbers were significantly correlated with sputum AFB positivity, extent of disease, hemoglobin levels, lymphocyte counts, CRP and ESR levels. MAIT cells in TB patients failed to produce interferon-γ irrespective of the mode of stimulation, whereas NTM patients displayed a defect in MR1-dependent signaling pathway. Notably, an elevated expression of programmed death-1 was also associated with MAIT cell deficiency in TB. This study shows that MAIT cells are numerically and functionally deficient in TB and NTM patients and these deficiencies could contribute to immune system dysreguation in mycobacterial infection.

Analysis of predictors influencing indeterminate whole-blood interferon-gamma release assay results in patients with rheumatic diseases.

Triggers of indeterminate results from interferon-gamma release assays (IGRA) in patients with rheumatic diseases are still elusive. The aim of the present study was to describe predictors of indeterminate results from IGRA in the field of rheumatology. This cross-sectional study was retrospectively performed by using a database of patients with a request for QuantiFERON-TB Gold-In Tube test (QFT-GIT) for screening of latent tuberculosis infection. The study cohort included 631 patients with rheumatic diseases. All variables influencing indeterminate QFT-GIT results were investigated by logistic regression analysis. The overall frequency of indeterminate IGRA results was 6.8 % (43/631). Those with indeterminate results were more likely to be aged ≥70 years, female, visitors in winter, suffering from systemic lupus erythematosus (SLE), and using sulfasalazine or a tumor necrosis factor (TNF)-α inhibitor. In addition, a longer incubation time of >6 h increased the odds ratio of indeterminate IGRA results. In contrast, the automated ELISA processor, ankylosing spondylitis, and the use of a non-steroidal anti-inflammatory drug decreased the likelihood of indeterminate IGRA results. Lymphopenia, thrombocytopenia, anemia, and hypoalbuminemia were significantly associated with indeterminate IGRA results. Multivariate analysis revealed that SLE, use of sulfasalazine or a TNF-α inhibitor, and a manual ELISA system were significantly independent predictors of indeterminate IGRA results. The proportion of indeterminate results in patients with rheumatic diseases is not infrequent. Careful attention to the pre-analytical conditions should minimize the indeterminate results. Automation of the ELISA process seems to be a promising solution to decrease the rate of indeterminate response.