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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominantly inherited cerebral small-vessel disease (SVD). CADASIL has diverse clinical features such as migraine with aura, dementia, and recurrent strokes, and is caused by a pathogenic mutation in the NOTCH3 gene which encodes a transmembrane receptor found in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3 , leading to the abnormal accumulation of granular osmiophilic material in the vessels of affected individuals. In addition, potential signaling pathways, such as transforming growth factor beta (TGF-β), may be involved in pathogenesis of the disease. This review aims to elucidate these mechanisms, particularly NOTCH3, in the context of CADASIL pathogenesis, providing insight into the role of NOTCH3 signaling and discussing the significance of these pathways for potential future therapeutic interventions in CADASIL patients. Key points • CADASIL is a rare hereditary cerebral small-vessel disease caused by mutations in NOTCH3 and its associated factors. • Understanding the role of the NOTCH3 signaling pathway may help in understanding that pathomechanisms of CADASIL and its manifestations. • Recognizing the potential involvement of other signaling pathways, including TGF-β, that may contribute to the development or progression of CADASIL is important. • Exploring the roles of these key signaling pathways associated with CADASIL provides a foundation for advancing management and treatment strategies.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disorder characterized by fatty liver disease alongside overweight or obesity and/or type 2 diabetes mellitus (T2DM). Timely intervention is crucial for a potential cure. This study aimed to investigate the effects of bilirubin, an endogenous antioxidant, on lipid metabolism and inflammation in MAFLD. Specifically, it examined bilirubin’s impact on SIRT1, PPAR-α, and NF-κB in the livers of rats with MAFLD induced by a high-fat diet (HFD) and streptozotocin (STZ) administration. Forty eight-week adult male Sprague Dawley rats were divided into five groups (n = 8): Control, HFD-STZ, HFD-S-BR6, HFD-S-BR14, and C-BR14. In the last three groups, bilirubin administration was performed intraperitoneally for 6 and 14 weeks (10 mg/kg/day). We selected the key genes associated with MAFLD and subsequently performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses to explore the enriched biological processes and signaling pathways. Hence, the gene expression of SIRT1, PGC-1α, PPAR-α, and inflammatory genes (NF-κB, TNF-α, IL-6, and IL-1β) was measured using Real-time quantitative PCR. Stereological and histopathological alterations of liver structure as well as lipid profile, biochemical indices, and liver indices, were also assessed among different groups. The enrichment analysis identified that several signaling pathways and biological processes might be related to MAFLD. Bilirubin-treated rats contained higher PPAR-α, PGC-1α, and SIRT1 expression levels by approximately 5.7-, 2.1-, and 2.2-fold, respectively, compared to the HFD-receiving rats (p < 0.0001, p < 0.05, and p < 0.05). Whereas, the genes involved in the inflammatory cascades, including NF-κB, TNF-α, and IL-6, were downregulated by 0.6-fold (p < 0.05) following 14-week treatment of bilirubin, while only significantly decreased expression of NF-κB and IL-6 (approximately 0.6-fold, p < 0.05) were observed after 6-week treatment of bilirubin. Remarkably, bilirubin administration favorably reversed the effects of HFD on the liver’s volume and cell numbers and ameliorated the related structural changes. It also improved lipid profile, biochemical parameters, and liver indices of HFD-STZ rats. This study indicated that bilirubin acts as a protective/ameliorative compound against MAFLD, particularly through regulating the key genes involved in lipid metabolism and inflammation in HFD-STZ rats.

Background Atherosclerosis is a chronic inflammatory condition affecting the large arteries and is a major cause of cardiovascular diseases (CVDs) globally. Increased levels of adhesion molecules in cardiac tissue serve as prognostic markers for coronary artery occlusion risk. Given the antioxidant properties of bilirubin and its inverse correlation with atherosclerosis, this study aimed to assess the beneficial effects of bilirubin on atherosclerotic indices and heart structure in high-fat diet-fed diabetic rats with atherosclerosis. Methods Atherosclerosis was induced in three out of five groups of adult male Sprague Dawley rats through a 14-week period of high-fat diet (HFD) consumption and a single low dose of streptozotocin (STZ) (35 mg/kg). The atherosclerotic rats were then treated with intraperitoneal administration of 10 mg/kg/day bilirubin for either 6 or 14 weeks (treated and protected groups, respectively), or the vehicle. Two additional groups served as the control and bilirubin-treated rats. Subsequently, the mRNA expression levels of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), lectin-like LDL receptor 1 (LOX-1), and the inducible nitric oxide synthase (iNOS) were analyzed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Histopathological and stereological analyses were performed to assess changes in the heart structure. Results Bilirubin significantly decreased the expression of VCAM-1, ICAM-1, LOX-1, and iNOS genes in the treated group. Moreover, bilirubin mitigated pathological damage in the left ventricle of the heart. Stereological analysis revealed a decrease in the left ventricle and myocardium volume, accompanied by an increase in vessel volume in rats treated with bilirubin. Conclusion These findings demonstrate that mild hyperbilirubinemia can protect against the progression of atherosclerosis and heart failure by improving lipid profile, modulating adhesion molecules, LOX-1, and iNOS gene expression levels.

Background and purpose The tumor microenvironment (TME) is widely acknowledged as a pivotal regulator of cancer progression. However, the dualistic role of tertiary lymphoid structures (TLSs), which serve as critical immune hubs within the TME, remains incompletely characterized, particularly with respect to their context-dependent capacity to either inhibit or facilitate tumor development. This review aims to synthesize current understanding of the complex interactions between stromal cells and TLSs, addressing existing gaps in mechanistic insight and exploring therapeutic avenues to exploit TLS plasticity. Key reviewed topics The current study critically reviews the mechanisms by which stromal components, including cancer-associated fibroblasts and endothelial cells, contribute to TLS neogenesis through chemokine-mediated recruitment of lymphocytes. Furthermore, it highlights the dual functional roles of TLSs as sites of both anti-tumor immune activation and immunosuppression, notably via the enrichment of regulatory T cells. The clinical implications of mature TLS presence, particularly their association with improved patient prognosis and enhanced therapeutic responsiveness, are also analyzed. Main conclusions TLSs demonstrate a bifunctional nature, wherein their spatial organization and dynamic interactions with stromal elements dictate the balance between immune activation and tolerance within the TME. While mature TLSs are generally correlated with favorable clinical outcomes, their potential to foster immunosuppressive microenvironments necessitates the development of precision-targeted interventions. The interplay between stromal cells and TLSs represents a promising therapeutic axis for modulating the tumor immune milieu. Future perspectives Future research should prioritize strategies aimed at promoting TLS maturation, disrupting immunosuppressive niches, and integrating TLS-modulating agents with existing immunotherapeutic regimens to enhance clinical efficacy. Additionally, the identification of robust biomarkers reflective of TLS functional states and the rigorous validation of stromal-targeted therapies within combinatorial treatment frameworks are imperative for advancing translational applications. Graphical abstract