Role of interferons (IFNs) in the differentiation of T peripheral helper (Tph) cells.

T follicular helper (Tfh) cells and T peripheral helper (Tph) cells produce interleukin (IL)-21 and are thought to contribute to follicular and extra-follicular B-cell activation, respectively, in autoimmune diseases. It is known that programmed cell death-1 (PD-1)-positive CXCR5+ Tfh-like cells are differentiated from human naive CD4+ T cells by IL-12 plus transforming growth factor (TGF)-ß. However, it remains unclear what cytokines are required for Tph differentiation. In this study, we found that interferon (IFN)-α and IFN-ß reduce the frequency of Tfh-like cells under the IL-12 plus TGF-ß condition, whereas they promote generation of PD-1+CXCR5-CD4+ T cells and secretion of IL-21, IFN-γ and CXCL13. Intracellular cytokine staining and T-cell-B-cell co-culture studies indicated that IFN-α promotes generation of IL-21+IFN-γ +CXCR5-CD4+ T cells thereby enhancing B-cell helper function. By IFN-α treatment, the mRNA levels of IL21, IFNG, CXCL13, CD244, SLAMF7, GZMB and PRDM1 were significantly up-regulated but BCL6 mRNA expression was down-regulated, suggesting a Tph-related gene expression pattern. On the other hand, IL-2-neutralization increased mRNA levels of IL21, CXCL13 and CXCR5, retained BCL6, but showed no clear effect on IFNG or PRDM1. RNA sequencing analyses revealed that PD-1hiCXCR5-CD4+ T cells prepared from in vitro culture show a Tph-related gene expression pattern similar with that of PD-1hiCXCR5- Tph cells obtained from the blood of patients with systemic lupus erythematosus. From our findings, it is highly probable that type I IFNs play a key role in differentiation of Tph cells and trigger Tph cell expansion in autoimmune diseases.

Cytotoxic Tph subset with low B-cell helper functions and its involvement in systemic lupus erythematosus.

T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. However, the role of Tph subsets is not fully elucidated. Here, we investigate the immunological functions of Tph subsets and their involvement in systemic lupus erythematosus (SLE). We have defined four Tph subsets (Tph1: CXCR3+CCR6-, Tph2: CXCR3-CCR6-, Tph17: CXCR3-CCR6+, and Tph1-17: CXCR3+CCR6+) and performed RNA sequencing after cell sorting. Tph1 and Tph17 subsets express substantial levels of IL21, indicating B cell helper functions. However, Tph2 and Tph1-17 subsets express low IL21. Interestingly, we have found Tph2 subset express high levels of CX3CR1, GZMB, PRF1, GLNY, S1PR5, TBX21, EOMES, ZNF863, and RUNX3, indicating a feature of CD4+ cytotoxic T lymphocytes. In SLE patients, the frequency of Tph1 and Tph2 subsets are significantly increased and positively correlated with SLE disease activity indexes. Tph1 cells expansion has been observed in patients with cutaneous and musculoskeletal manifestations. On the other hand, Tph2 cell expansion has been found in patients with lupus nephritis in addition to the above manifestations. Our findings imply that Tph1 and Tph2 subsets exert distinct immunological functions and are contributed to the complexity of clinical manifestations in SLE.

[Data-driven drug discovery for drug repurposing].

To improve the decreased efficiency of drug discovery and development, drug repurposing (also called drug repositioning) has been expected, that it is a strategy for identifying new medical indications for approved, investigational or suspended drugs. Particularly, according to the rapid expansion of medical and life science data and the remarkable technological progress of AI technology in recent years, the approach of computational drug repurposing has been attracted as one of the applications in data-driven drug discovery. Computational drug repurposing is a method of systematical and strategical research for identifying novel indication candidates and prioritizing the indication candidates based on the various profiles of drugs, genes, and diseases. In this review article, the typical data science techniques for data-driven drug repurposing, 1. drug-target interaction prediction, 2. transcriptomics-based approach by using differentially gene expression profiles, 3. natural language processing and word embedding, and their current status were summarized. We have also introduced a use case of data-driven drug repurposing for the PPARγ/α agonist Netoglitazone that we actually analyzed. In addition, as an excellent successful case of data-driven drug repurposing in recent years, we have also discussed a repurposing case reported by BenevolentAI in 2020, that Baricitinib has been identified as a potential intervention for COVID-19, based on immunomodulatory treatment by its mechanism of action as a JAK1 and JAK2 inhibition.

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis.

BACKGROUND: Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc). METHODS: The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-ß (TGF-ß)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed. RESULTS: Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-ß-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117. CONCLUSIONS: MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.

Pathogenic importance of cysteinyl leukotrienes in development of gastric lesions induced by ischemia/reperfusion in mice.

We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT(1)R) antagonist] as well as 1-[[5'-(3''-methoxy-4''-ethoxycarbonyl-oxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT(1)R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT(1)R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT(1)R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT(1)R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.

Effects of mask fitness and worker education on the prevention of occupational dust exposure.

To decrease the incidence of pneumoconiosis, we examined dust protective mask performance and its relation to pulmonary function as well as the effects of worker education on the proper wearing of masks. One hundred and seventy-eight workers from 15 factories subject to dust exposure participated in this study. All participants were interviewed to obtain relevant personal information and underwent both a mask leakage and a pulmonary function test. The mask leakage was expressed as a percentage, with under 10% leakage indicating that the dust protective mask worked efficiently. In addition, 23 workers from 2 factories were educated on how to wear masks properly. The average mask leakage was 24.3%, and 58% of workers wore ineffective masks. Though pulmonary function was almost normal, the percent vital capacity (%VC) tended to be lower depending on the mask leakage. Mask education, which was very easy and took only a short time, dramatically decreased average mask leakage from 32.1% to 10.5% (p0.001). Educating workers to wear masks properly might prevent the worsening of pulmonary function in response to dust exposure. Appropriate mask fitness by education could be useful in preventing the development of pneumoconiosis.

Ruthenium complexes carrying a disialo complex-type oligosaccharide: enzymatic synthesis and its application to a luminescent probe to detect influenza viruses.

Tris-bipyridine ruthenium-complexes carrying a disialo complex-type oligosaccharide were prepared via a one-pot transglycosylation using endo-glycosidase (Endo M); they bind to type-A influenza viruses with excellent affinity (IC50 = 8.4 microM), and their luminescence intensity is strongly depressed by virus-binding.

Social support, self-efficacy and psychological stress responses among outpatients with diabetes in Yogyakarta, Indonesia.

We attempted to study whether social support promotes self-efficacy and reduces stress responses of patients with diabetes in Yogyakarta, Indonesia. Diabetic outpatients at Dr. Sardjito Hospital voluntarily participated in a questionnaire survey. Data from 125 patients were subjected to analysis. The questionnaires included the scales and subscales of social support, self-efficacy, psychological stress response, and demographic measure. Data were analyzed by Spearman's rank correlation test to examine the relationships between parameters, Mann-Whitney U-test and Kruskal-Wallis test to compare the scales by characteristics, and structural equation modeling to explore the best-fit model. This study was performed in September 2003. It was found that augmentation of emotional support to patients significantly increased the 'active coping for the disease' and 'controllability of health', and that 'helplessness' was reduced significantly. Behavioral support affected only 'controllably of health'. Self-efficacy reduced stress response of the patients. It was also found that subjects who received support from their children significantly scored higher in perceived availability of social support than those without support from their children. To know their behavioral support better as well as emotional support may be one area to focus on in improving the health status of people with diabetes in Yogyakarta.

Practicality of Veterans Specific Activity Questionnaire in evaluation of exercise capacity of community-dwelling Japanese elderly.

OBJECTIVE: The aim of this study is to determine whether a questionnaire-based method using the Veterans Specific Activity Questionnaire (VSAQ) is a practical tool for the development of a safe exercise program to prevent a reduction in physical performance. METHODS: One hundred and twenty-one senior residents of Yakage, Okayama, agreed to voluntarily participate in this study. They were asked to complete a questionnaire for information on age, sex, subjective health status, exercise habits and VSAQ. We investigated the relationship between age and exercise capacity predicted by VSAQ (predicted metabolic equivalents (METs)). In addition, for 36 out of the 121 participants, we performed a 6-min walk distance test (6MD) and investigated whether its results correlate with the predicted METs. Furthermore, we prepared a modified VSAQ and examined its practicality in the evaluation of the exercise capacity of Japanese elderly (n=50). RESULTS: We found that the predicted METs correlate well with age. Habitual exercise and subjective health status did not affect the predicted METs. A significant correlation was observed between the predicted METs and the results of 6MD (r=0.56, p<0.001). We also found that certain activities included in the original VSAQ are unfamiliar to Japanese elderly; thus, we made a few modifications to the original VSAQ in order to evaluate the physical fitness of Japanese elderly. The number of inadequate answers was reduced by employing the modified VSAQ. CONCLUSION: These findings imply that the modified VSAQ is useful in evaluating the exercise capacity of Japanese elderly adequately and is a practical scale for safe exercise.