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Background and Purpose: Bardoxolone methyl (2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oic acid methyl ester, CDDO‐Me) is a potent activator of nuclear factor erythroid 2‐related factor 2 (Nrf2), which induces the expression of antioxidative‐associated genes. CDDO‐Me exerts protective effects against chronic inflammatory diseases in the kidneys and lungs. However, its pharmacological effects on metabolic dysfunction‐associated steatohepatitis (MASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO‐Me in a diet‐induced MASH mouse model and elucidated its pharmacological mechanisms using RNA‐seq analysis. Experimental Approach: CDDO‐Me was orally administered to mice fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD), and histological, biochemical, and transcriptomic analyses were performed on livers of mice that developed MASH. Key results: CDDO‐Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly prevented the symptoms of MASH. Whole‐transcriptome analysis revealed that CDDO‐Me inhibited the inflammatory pathway that led to phagocyte recruitment, in addition to activating the Nrf2‐dependent pathway. Among inflammatory pathways, CC chemokine ligands (CCL)3 and CCL4, which are downstream of NF‐κB and are associated with the recruitment of macrophages expressing CC chemokine receptors (CCR)1 and CCR5, were released into the blood in MASH mice. However, CDDO‐Me directly inhibited the expression of CCL3‐CCR1 and CCL4‐CCR5 in macrophages. Conclusions and Implications: Overall, we revealed the potent hepatoprotective effect of CDDO‐Me in a MASH mouse model and demonstrated that its pharmacological effects were closely associated with a reduction of macrophage infiltration, through CCL3‐CCR1 and CCL4‐CCR5 inhibition, in addition to Nrf2‐mediated hepatoprotective effects. [ABSTRACT FROM AUTHOR]

In recent years, the development of functional foods targeting gastrointestinal disorders has been in progress. Partially hydrolyzed guar gum (PHGG), which is a water‐soluble dietary fiber, is known to have a constipation‐improving effect. However, many aspects of the mechanism remain unclear. In this study, we investigated the role of aquaporin‐3 (AQP3), which regulates the water content of feces in ameliorative effect of PHGG on constipation. Rats were allowed to freely consume a normal diet or a diet containing 5% PHGG for 14 days, and defecation parameters were measured. We also analyzed the expression levels of genes involved in water transport in the colon. The defecation frequency and volume of rats treated with PHGG were not different from those from the control group, but the fecal water content was significantly increased, and soft stools were observed. The expressions of claudin‐1, tight junction protein‐1, and cadherin‐1, which are involved in tight junctions or adherens junctions, were almost the same in the PHGG‐treated group and the control group. The expression level of AQP3 in the colon was significantly decreased in the PHGG‐treated group. In this study, PHGG decreased the colonic AQP3 expression, thereby suppressing water transport from the luminal side to the vascular side and improving constipation. [ABSTRACT FROM AUTHOR]

This prospective observational study aimed to evaluate the ocular biometry of Japanese people through a multicenter approach. The uncorrected and corrected distance visual acuity (UDVA and CDVA, respectively) in the log minimum angle of resolution (logMAR), subjective and objective spherical equivalent values (SE) of ocular refraction, anterior and posterior corneal curvature (ACC and PCC, respectively), anterior and posterior corneal asphericity (ACA and PCA, respectively), central corneal thickness (CCT), anterior chamber depth (ACD), and ocular axial length (AL) were measured in the eyes of 250 participants (mean age = 46.5 ± 18.0 years, range: 20–90 years) across five institutions in Japan. The mean UDVA, CDVA, subjective SE, objective SE, ACC, PCC, ACA, PCA, CCT, ACD, and AL were 0.68, −0.08, −2.42 D, −2.66 D, 7.77 mm, 6.33 mm, −0.31, −0.39, 0.55 mm, 2.92 mm, and 24.78 mm, respectively. Age-related changes and sex-based differences were noted in the visual acuity, refraction, corneal shape, ACD, and AL. Our results serve as basis for future studies aiming to develop refractive correction methods and various vision-related fields. [ABSTRACT FROM AUTHOR]

In recent years, the development of functional foods targeting gastrointestinal disorders has been in progress. Partially hydrolyzed guar gum (PHGG), which is a water-soluble dietary fiber, is known to have a constipation-improving effect. However, many aspects of the mechanism remain unclear. In this study, we investigated the role of aquaporin-3 (AQP3), which regulates the water content of feces in ameliorative effect of PHGG on constipation. Rats were allowed to freely consume a normal diet or a diet containing 5% PHGG for 14 days, and defecation parameters were measured. We also analyzed the expression levels of genes involved in water transport in the colon. The defecation frequency and volume of rats treated with PHGG were not different from those from the control group, but the fecal water content was significantly increased, and soft stools were observed. The expressions of claudin-1, tight junction protein-1, and cadherin-1, which are involved in tight junctions or adherens junctions, were almost the same in the PHGG-treated group and the control group. The expression level of AQP3 in the colon was significantly decreased in the PHGG-treated group. In this study, PHGG decreased the colonic AQP3 expression, thereby suppressing water transport from the luminal side to the vascular side and improving constipation., Competing Interests: M.O. and Z.Y. are employees of Taiyo Kagaku Co., Ltd. Neither the external organization nor the funding agency participated in research design or no competing interests. The other authors (R.K., N.I., K.O., H.S., and J.K.) declared that the study was conducted in the absence of financial relationships that could be constructed as potential conflicts of interest., (© 2022 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Background: Bardoxolone methyl activates nuclear factor erythroid 2-related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored., Methods: We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model ( Col4a5 -G5X)., Results: Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change., Conclusions: UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD., Competing Interests: H. Kai received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. S. Kaseda received research funding from the Japan Society for the Promotion of Science. T. Shuto reports received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVβ3 and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of αVβ3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that αVβ3, CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin αVβ3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced αVβ3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated αVβ3 and CD47 signaling in OA pathogenesis and suggest that activation of αVβ3 and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting αVβ3, CD47, and their signaling pathways as a disease-modifying therapy.