Yasuhiko Yamamoto

Purpose: Whether biological sex modifies the association between diet and liver disease remains unclear. We applied a reverse-translational strategy linking sex-stratified population data with mechanistic studies in a murine model. Methods: We analyzed associations between dietary nutrients and hepatic steatosis in a community-based Japanese cohort (the Shika study). Based on the human findings, mice were fed a Western diet with fructose–sucrose–supplemented water to investigate sex-dependent mechanisms. Results: In the Shika study, steatosis in women—but not in men—was associated with higher dietary cholesterol/fat density and with a higher sucrose-to-total carbohydrate ratio. Modeling this risk in mice revealed a dissociation between systemic metabolism and liver pathology: despite exhibiting milder systemic obesity than males, females developed more pronounced fibrosis and oxidative injury. Transcriptomic analysis identified distinct sex-biased pathways. Males preferentially upregulated genes involved in glutathione metabolism (e.g., Gst, Gpx). In contrast, females exhibited higher expression of genes associated with microsomal ω-oxidation and acyl-CoA hydrolysis (e.g., Cyp4a, Acot), accompanied by marked oxidative stress and a Kupffer cell–skewed inflammatory signature. Conclusions: By integrating sex-stratified epidemiological evidence in humans with the intrinsic oxidative vulnerability identified in mice, our findings highlight biological sex as a critical modifier of nutrition-driven liver injury. These findings suggest that rigorous nutritional management is particularly important for preventing disease progression in women with metabolic dysfunction-associated steatotic liver disease (MASLD).

Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting at least 2% of the global population. Papaverine, an alkaloid with known anti-inflammatory, anti-cancer, and RAGE-antagonistic properties, has not been previously evaluated for anti-psoriatic activity. This study investigated the protective effects and mechanisms of papaverine in an imiquimod (IMQ)–induced psoriasis-like model in BALB/c mice. Papaverine treatment significantly ameliorated clinical symptoms, as evidenced by reductions in psoriatic lesions, skin thickness, severity index scores, T- and B-cell infiltration, and cutaneous angiogenesis. It also downregulated IMQ-induced mRNA expression of keratinocyte differentiation markers Krt10 and Ivl. Flow cytometric analysis revealed a marked reduction in B220⁺CD138⁺ plasmablasts and B220⁻CD138⁺ plasma cells in both circulation and spleen. These effects were associated with modulation of key transcription factors involved in plasma cell differentiation, including Prdm1, Xbp1, and Bcl6. Notably, the population of CD3⁺CD4⁻CD8⁻ double-negative T cells was also decreased following papaverine administration. Inflammatory cytokine and chemokine mRNA levels in IMQ-exposed skin—namely Il1b, Il6, Ifng, Mcp1, Il22, S100a7, and Ager—were significantly suppressed. These findings suggest that papaverine ameliorates psoriasis-like symptoms through inhibition of proinflammatory cytokines and suppression of aberrant plasma cell differentiation. In conclusion, papaverine demonstrates therapeutic potential as a candidate for the treatment of psoriasis.

Diabetes is characterized by chronic hyperglycemia and dyslipidemia, which impose sustained metabolic stress and drive the development of diabetic complications. In this review, we position the axis between advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) as a central hub that couples metabolic stress to persistent cellular stress and inflammatory responses. Ligand engagement of full-length membrane-bound RAGE (mRAGE) enhances reactive oxygen species (ROS) generation and activates nuclear factor kappa B (NF-κB), establishing a self-amplifying feed-forward loop that promotes RAGE expression, inflammation and further AGE accumulation. RAGE exhibits marked structural heterogeneity: in addition to signaling-competent mRAGE, soluble decoy receptors—including soluble RAGE (sRAGE) produced by ectodomain shedding and endogenous secretory RAGE (esRAGE) generated by alternative splicing—sequester ligands and attenuate downstream signaling. Moreover, RAGE recognizes a broad ligand repertoire beyond AGEs, such as S100 proteins and high-mobility group box 1 (HMGB1), reinforcing its role as an integrator of metabolic and sterile inflammatory cues. Notably, RAGE also mediates physiological transport of oxytocin across the blood–brain barrier (BBB), a process implicated in oxytocin-dependent social behaviors, without activating canonical, pro-inflammatory RAGE signaling. Accordingly, therapeutic strategies should selectively suppress pathogenic, ligand-driven RAGE signaling and/or augment decoy RAGE activity while preserving RAGE-dependent oxytocin transport.

Receptor for advanced glycation end-products (RAGE) is implicated in immune and inflammatory diseases as well as the malignant phenotypes of cancer. Blocking RAGE signaling is thought to reduce its impact on disease states. In this study, we investigated the effect of RAGE signaling inhibitors (inhRAGE) on the malignant phenotypes of pancreatic ductal adenocarcinoma (PDAC). Four PDAC cell lines were used. quantitative PCR (qPCR) was performed to evaluate RAGE expression. Assays for cell proliferation, migration, and invasion were performed with or without inhRAGE and the addition of several ligands. The effects of inhRAGE were examined by creating ectopic and orthotopic xenograft tumor models, and the resected specimens were subjected to immunohistochemical analysis. RAGE expression was confirmed in all the cell lines. inhRAGE significantly reduced the migration and invasion abilities of the cells exposed to high-mobility group B1 (HMGB1) or S100B, which are tumor- and inflammation-associated RAGE ligands, without inhibiting cellular proliferation. In both the ectopic and orthotopic models, inhRAGE treatment significantly inhibited tumor growth. Immunostaining confirmed the suppression of angiogenesis and inflammation. inhRAGE inhibits the malignant phenotypes of PDAC, suggesting that inhRAGE may be a novel therapeutic agent for the condition.

Background: Oxytocin (OT) is a nonapeptide hormone produced in the hypothalamus, released into the brain and peripheral circulation, and plays a key role in social behavior. Recent studies indicate that complement component C4a is an OT-binding protein, which modulates plasma OT concentrations in mice. However, the role of C4a is unclear as to whether it contributes to consolation behavior. Methods: Social behavior, especially allogrooming, which is a form of empathy that depends on detecting the emotional states of others, was measured in wild-type or C4a/Slp knockout (Slp^−/−) male mice. Results: Observer mice of both genotypes exhibited comforting (allogrooming) behavior toward a cage-mate demonstrator during reunion after brief isolation of the demonstrator mice. When demonstrator mice experienced body restraint stress during isolation, the allogrooming behavior was significantly increased in both genotypes, with a markedly greater increase in Slp^−/− than in Slp^+/+ mice. Allogrooming behavior in observer Slp^−/− mice was significantly suppressed by an OT receptor antagonist. Furthermore, immunohistochemical analysis revealed that activation was significantly elevated in OT-positive hypothalamic neurons in observer Slp^−/− mice that interacted with stressed demonstrator mice. OT release from the isolated hypothalamus, stimulated via CD38 and TRPM2 channel activation, was greater in Slp^−/− mice than in Slp^+/+ mice. Conclusions: Our results highlight that the data are consistent with a potential role for C4a in modulating neural circuits, possibly via its peripheral action on OT bioavailability. Direct evidence for C4a’s action within the brain remains a hypothesis for future investigation, for example, via site-specific manipulations.

Aim: Fibrosis is a common mechanism underlying the progression of kidney and other organ failures. Complement protein C1q and chemokine receptor 8 (CCR8), whose ligand is CCL1, are implicated in fibrosis. This study aimed to evaluate the clinical significance of CD45+ mononuclear cells coexpressing C1q and CCR8 (CD45 + C1q + CCR8+ cells) in kidney disease. Methods: This prospective observational study included 44 patients with kidney disease. The percentage of CD45 + C1q + CCR8+ cells among CD45+ mononuclear cells in the peripheral blood was measured using flow cytometry at baseline. Correlations between these percentages and clinical parameters, including serum creatinine (Cr) and urinary protein levels, were examined using linear regression models. The association between baseline percentages of CD45 + C1q + CCR8+ cells and kidney outcomes—defined as end‐stage kidney disease or a 30% decrease in the estimated glomerular filtration rate—was examined using Cox proportional hazards models in patients with serum Cr data during follow‐up. Results: The median age of the cohort was 57 years, and 61.4% were male. The median serum Cr and urinary protein levels were 1.73 mg/dL and 1.99 g/g Cr, respectively. Baseline percentages of CD45 + C1q + CCR8+ cells positively correlated with serum Cr ( p = 0.028) and urinary protein ( p = 0.015). Among 21 patients with follow‐up data, 10 (48%) reached kidney outcomes. Patients with moderately elevated percentages had a higher risk of kidney outcomes than those with low levels (HR: 27.31, 95% CI: 1.08–692.3; p = 0.04). Conclusion: CD45 + C1q + CCR8+ cell percentages in peripheral blood may reflect kidney function and are associated with disease progression, indicating their potential as biomarkers.

Sinusoidal obstruction syndrome (SOS) is a fatal liver condition resulting from sinusoidal endothelial cell injury and hepatocyte death, following liver or hematopoietic stem cell transplantation as well as chemotherapy. We showed evidence of platelet displacement and aggregation within the space of Disse in SOS. However, the relationship between platelets and hepatocyte death remains unclear. Using a mouse SOS model by intraperitoneal monocrotaline (270 mg/kg; a pyrrolizidine alkaloide plant toxin) administration, we observed positive stains for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase-3, which are markers for apoptosis, in the liver by immunohistochemistry. At 48 h of the SOS liver, aggregated platelets and hepatocytes around zone 3 were found to express Fas ligand (FasL) and Fas, respectively. Human peripheral blood platelets, when aggregated, could induce expression of FASL on themselves and then lead to apoptosis in co-cultured HepG2 cells. Treatment of recombinant soluble thrombomodulin (rTM), an anticoagulant and vascular endothelium-protective drug, prevented the hepatocyte death in the SOS mice. These findings suggest that the prevention of platelet aggregation is a potential therapeutic intervention against hepatocyte death and severe liver damage in SOS.