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Despite advances in our understanding of endotoxic shock, novel therapeutic interventions that can reduce the burden of sepsis remain elusive. Current treatment options are limited, and it is only through refinements in the ways that we deliver supportive care that mortality has fallen over the years. In this study, the role of kynurenine 3-monooxygenase (KMO) in immune regulation was examined in LPS-induced endotoxemia using KMO−/− and KMO+/+ mice treated with the KMO inhibitor Ro61-8048. We showed that LPS-induced or cecal ligation and puncture–induced mortality and hepatic IL-6 production increased in the absence of KMO, possibly involving increased activating transcription factor 4 (ATF4) signaling in hepatic macrophages. Moreover, treatment of septic mice with 3-hydroxykynurenine reduced mortality rates and inflammatory responses regardless of the presence or absence of KMO. According to our results, the administration of 3-hydroxykynurenine as part of the treatment approach for sepsis or as an adjuvant therapy might reduce the overproduction of IL-6, which is responsible for severe endotoxemia, and ultimately improve the survival rates of patients with sepsis.

Introduction: Tuberculosis (TB) is a communicable disease of global public health threat. Poor and vulnerable populations are mainly affected with it. In association with Diabetes Mellitus (DM), TB may get worsen as increased relapse rates, delayed sputum culture conversion, increase in the case fatality rates etc. Conversely, TB may increase the incidence of DM, and worsen glycaemic control in diabetes patients. Aim: To study the effectiveness of bidirectional screening for TB and DM in rural hospital. Materials and Methods: A cross-sectional cohort study conducted at Medicine and Pulmonology department of MediCiti Institute of Medical Sciences (MIMS) for a period of nine months in June 2019-February 2020. All TB patients were screened for DM and vice versa. All TB patients were followed-up for treatment outcome of TB and all DM patients were followed-up for glycaemic control. Relative risk was calculated using incidence of outcome or control of disease in TB with DM patients to TB patients and DM with TB patients to DM patients. Results: Of 256 TB patients, 38 (14.8%) were TB with DM cases. All 256 patients were followed-up for TB treatment outcome, 100% TB patients without DM had recovery, whereas 97.3% TB patients with DM had recovery after two months of therapy. Relative risk of DM on TB outcome was 0.97. Of 256 DM patients screened, 9 (3.5%) had been newly diagnosed with TB. All 256 people were followed-up for impact on glycaemic control. Relative risk of TB on glycemic control was 1.87. Conclusion: Bidirectional screening would potentially improve care and prevention of TB and DM.

Aim: We developed the Training Program on Child Abuse Prevention for Citizens (TCAP-C) and tested its effects and acceptability among citizen leaders (CLs). Methods: Community-based participatory research using a pretest–posttest follow-up design was conducted in Tokyo, Japan from September 2021 to March 2022. Participants completed questionnaires before, upon completion, and one month and three months after TCAP-C. Recognition, knowledge, and behaviors regarding child abuse and community consciousness were collected and compared before and one and three months after TCAP-C, and the degree of satisfaction, understanding, and meaningfulness were collected upon completion. We analyzed data using repeated-measures ANCOVA. Results: A total of 111, 98, 101, and 94 participants completed the questionnaires before, upon completion, and one and three months after TCAP-C, respectively. Overall, the recognition, knowledge, and community consciousness scores significantly improved from before to one month and three months after TCAP-C. Regarding the behaviors, only the behaviors of learning and watching over were significantly improved from before to one month after TCAP-C; however, those behaviors were not different between before and three months after TCAP-C. Furthermore, 95% participants reported being entirely satisfied with TCAP-C, and 85% and 91% reported good understanding and meaningfulness of the program. Conclusions: TCAP-C is acceptable and can improve CL recognition, knowledge, and community consciousness.

Background Inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation leading to intestinal mucosal damage. Inflammatory bowel disease causes dysregulation of mucosal T cell responses, especially the responses of CD4+ T cells. Previously, we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis. Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan (Trp) and immunomodulatory Trp metabolites, the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear. Aim To investigate role of kynurenine 3-monooxygenase (KMO) in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis. Methods Colitis was induced in eight-week-old male KMO+/+ or KMO-/- mice of C57BL/6N background using TNBS. Three days later, the colon was used for hematoxylin-eosin staining for histological grading, immunohistochemical or immunofluorescence staining for KMO, cytokines, and immune cells. Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR, and kynurenine (Kyn) pathway metabolites were measured by high-performance liquid chromatography. The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry. Results KMO expression levels in the colonic mononuclear phagocytes, including dendritic cells and macrophages increased upon TNBS induction. Notably, KMO deficiency reduced TNBS-induced colitis, resulting in an increased frequency of Foxp3+ regulatory T cells and increased mRNA and protein levels of anti-inflammatory cytokines, including transforming growth factor-β and interleukin-10. Conclusion Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+ regulatory T cells by producing Kyn. Thus, Kyn may play a therapeutic role in colon protection during colitis.

Liquorice is usually used as crude drug in traditional Japanese Kampo medicine and traditional Chinese medicine. Liquorice-containing glycyrrhizin (GL) can cause pseudohyperaldosteronism as a side effect. Previously, we identified 18β-glycyrrhetyl-3-O-sulfate (3) as a GL metabolite in Eisai hyperbilirubinuria rats (EHBRs) with the dysfunction of multidrug resistance-related protein (Mrp2). We speculated that 3 was associated with the onset of liquorice-induced pseudohyperaldosteronism, because it was mainly detected in serum of patients with suspected to have this condition. However, it is predicted that other metabolites might exist in the urine of EHBRs orally treated with glycyrrhetinic acid (GA). We explored other metabolites in the urine of EHBRs, and investigated the pharmacokinetic profiles of the new metabolite in EHBRs and normal Sprague-Dawley rats. We further analyzed the serum concentrations of the new metabolite in the patients of pseudohyperaldosteronism. Finally, we developed the analyzing method of these metabolites as a preventive biomarker for the onset of pseudohyperaldosteronism using an enzyme-linked immunosorbent assay (ELISA). We isolated a new GL metabolite, 18β-glycyrrhetyl-3-O-sulfate-30-O-glucuronide (4). Compound 4 significantly inhibited rat type-2 11β-hydroxysteroid dehydrogenase (11β-HSD2) and was a substrate of both organic anion transporter (OAT) 1 and OAT3. Compound 4 was also detected in the serum of patients with suspected pseudohyperaldosteronism at an approximately 10-fold lower concentrations than 3, and these concentrations were positively correlated. Compound 4 showed a lower serum concentration and weaker inhibitory titer on 11β-HSD2 than 3. We developed an enzyme-linked immunosorbent assay system using an anti-18β-glycyrrhetyl-3-O-glucuronide (3MGA) monoclonal antibody to measure the serum concentration of 3 to facilitate the measurement of biomarkers to predict the onset of pseudohyperaldosteronism. Although we found 4 as the secondary candidate causative agent, 3 could be the main potent preventive biomarker of liquorice-induced pseudohyperaldosteronism. Compound 3 was detected in serum at a higher concentration than GA and 4, implying that 3 may be a pharmacologically active ingredient mediating not only the development of pseudohyperaldosteronism but anti-inflammatory effects in humans administered GL or other liquorice-containing preparations.

The sense of smell is related to the quality of life and not only can protect oneself from dangers such as food poisoning, gas leakage, and fire. But also various pleasures such as enjoying a delicious meal and the scent of flowers. This time, we report that we conducted an olfactory cognitive test using open essence on healthy 45 female university students. The Open Essence (made by FUJIFILM) has the smell as same as the odor Stick Identification Test (OSIT-J). The aromas used in the open essence includes curry, perfume, Japanese cypress, India ink, menthol, rose, wood, stinky socks/sweat, roasted garlic, condensed milk, gas for cooking, and Japanese mandarin aromas. This 12 different odorants perception is not necessarily culture-free; the Japanese version employed. Depending on the type of odor, some of them were difficult to understand, and some that were easy to understand. The most will-recognized odor was the smell of stinky socks/sweat, and the most hard to understand odor was mandarin orange. In the future, it is necessary to individually examine not only the number recognized in the olfactory recognition test but also the odor that was understand.

Kynurenine (Kyn) plays an important role as an immune check-point molecule and regulates various immune responses through its aryl hydrocarbon receptor (Ahr). Kyn is synthesized by indoleamine 2,3-dioxygenase (Ido) and tryptophan 2,3-dioxygenase (Tdo). Ido contributes approximately 90% of tryptophan catabolism. Although Kyn is increased in various liver disorders, the roles of Kyn in liver injury are complicated because Ido1, Ido2, and Tdo are activated in different cell types. In this study, the roles of Ido2 in carbon tetrachloride (CCl4; 1 ml/kg, i.p.)-induced acute liver injury were examined using Ido2 knockout mice and Ido2 inhibitor. After CCl4 treatment, the ratio of Kyn to tryptophan and levels of Kyn in the liver were increased, accompanied by activation of Ahr-mediated signaling, as revealed by increased nuclear Ahr and Cyp1a1 mRNA. Knockout of Ido2 (Ido2-/-) and treatment with Ido2 inhibitor 1-methyl-D-tryptophan (D-1MT; 100 mg/kg, i.p.) attenuated CCl4-induced liver injury, with decreased induction of Ahr-mediated signaling. Administration of D-Kyn (100 mg/kg, i.p.) to Ido2-/- mice canceled the effect of Ido2 deficiency and exacerbated acute liver damage by CCl4 treatment. In addition, liver fibrosis induced by repeated CCl4 administration was suppressed in Ido2-/- mice. In conclusion, the action of Ido2 and Kyn in the liver may prevent severe hepatocellular damage and liver fibrosis.

The plant hormone jasmonate and its conjugates (JAs) have important roles in growth control, leaf senescence and defense responses against insects and microbial attacks. JA biosynthesis is induced by several stresses, including mechanical wounding, pathogen attacks, drought and salinity stresses. However, the roles of JAs under abiotic stress conditions are unclear. Here we report that increased expression of the Cyt P450 family gene CYP94C2b enhanced viability of rice plants under saline conditions. This gene encodes an enzyme closely related to CYP94C1 that catalyzes conversion of bioactive jasmonate-isoleucine (JA-Ile) into 12OH-JA-Ile and 12COOH-JA-Ile. Inactivation of JA was facilitated in a rice line with enhanced CYP94C2b expression, and responses to exogenous JA and wounding were alleviated. Moreover, salt stress-induced leaf senescence but not natural senescence was delayed in the transgenic rice. These results suggest that bioactive JAs have a negative effect on viability under salt stress conditions and demonstrate that manipulating JA metabolism confers enhanced salt tolerance in rice.

Rheumatoid arthritis (RA) damages joints, and the destructed and/or deformed joint causes the pain and reduces the joint function. The prognosis can be improved by early treatment, but it requires accurate evaluation of the degree of RA progression to apply appropriate treatment. The modified total sharp (mTS) score in hand or foot X-ray image has been used to quantitatively evaluate the RA progression evaluation. However, the mTS score measurement takes huge labor and it is very time consuming method because a physician should evaluate progression grade for all hand joints, and the evaluation is subjective. This paper proposes an automated finger joint detection and mTS score estimation method using support vector machine. The experiment in 45 RA patients shows that the proposed method succeeded in detecting the finger joint and estimating the mTS score. As the number of learning data increases, the proposed method can estimate the mTS score with higher accuracy.