This study investigated the protective effects of aldehyde dehydrogenase 2 (ALDH2) activation (via Alda-1), ALDH2 inhibition (via Daidzin), and the modulation of sirtuin 1 (SIRT1) and endoplasmic reticulum stress (ERS) on methyl-nitrosourea (MNU)-induced retinal damage in C57BL/6 mice. Seventy-two mice were randomly assigned to eight groups, including a control group, a MNU-alone group, and various treatment combination groups. Mice were administered with intraperitoneal injections of agonists and inhibitors targeting the ALDH2-SIRT1-ERS axis, respectively. Body weight, retinal layer thickness, and aldehyde metabolism biomarkers were assessed on the second and fourth day post-treatment. MNU administration induced retinal degeneration, resulting in significant body weight loss in all groups except the control. Treatment with Alda-1 attenuated retinal damage, while Daidzin exacerbated it. Pharmacological inhibition of SIRT1 (via EX-527) diminished the protective effects of Alda-1, and ERS induction (via TUN) nearly abolished its benefits. Conversely, SIRT1 activation (via SRT1720) mitigated the adverse effects of Daidzin, while ERS inhibition (via 4-PBA) partially alleviated Daidzin's impact. Furthermore, MNU increased levels of aldehyde metabolism markers (malondialdehyde [MDA] and 4-hydroxy-2-nonenal [4-HNE]), with Alda-1 reducing and Daidzin elevating these levels. Besides, pharmacological modulation of the SIRT1/ERS pathways intervened in the regulatory effects of Alda-1 and Daidzin on the aldehyde metabolism. Overall, ALDH2 activation protected retinal structure and regulated aldehyde metabolism, highlighting the critical role of the ALDH2-SIRT1/ERS signaling axis in mitigating retinal degeneration.

Objective: Myocardial fibrosis (MF) is a pathological process often triggered by chronic inflammation and pressure overload. This study aimed to investigate the therapeutic potential of ranitidine, a histamine H2 receptor antagonist, on MF and explore its underlying mechanisms, focusing on the FAK/Src pathway and inflammatory responses. Methods: A mouse model of MF was established by transverse aortic constriction (TAC). Cardiac function was assessed by echocardiography. Histopathological changes, collagen deposition, mast cell infiltration, and the expression of histamine and its H2 receptor were examined. In vitro , NIH/3T3 fibroblasts were stimulated with TGF-β1 to induce fibrotic activation. The effects of ranitidine on collagen synthesis, the expression of fibrotic markers (α-SMA, Collagen I/III), and the phosphorylation of FAK/Src were evaluated. Key Findings: Ranitidine treatment significantly improved TAC-induced cardiac dysfunction and attenuated myocardial fibrosis, as evidenced by reduced collagen deposition. It also markedly decreased mast cell infiltration and the expression of histamine and H2 receptor in cardiac tissues. In TGF-β1-stimulated fibroblasts, ranitidine dose-dependently reduced collagen synthesis, downregulated α-SMA, Collagen I, and Collagen III expression, and suppressed the activation of the FAK/Src pathway. Conclusion: Our findings demonstrate that ranitidine ameliorates pressure overload-induced myocardial fibrosis, likely in association with attenuation of histamine/H2 receptor-related inflammatory responses and reduced FAK/Src activation. This study suggests the repurposing potential of ranitidine for treating MF.

Introduction: High-altitude (HA) illness threatens health after acute high-altitude exposure, but its molecular mechanisms and effective interventions remain unclear. Drug–food homologous (DFH) substances have potential for HA illness intervention, yet their active components and targets are unknown. Methods: Datasets related to HA illness, as well as 106 DFH substances and their corresponding chemical components, were obtained in this study. Differentially expressed genes were identified, and active components were screened according to the criteria of drug-likeness ≥0.18 and oral bioavailability ≥30%. The GraphBAN tool was used to predict high-confidence compound–protein interaction pairs, so as to obtain the corresponding candidate active components and candidate genes. Meanwhile, the ADMETlab3 platform was employed to evaluate the druggability and toxicity of these active components, thereby determining the core active components and core genes. Candidate genes were screened were screened out by machine learning, and relevant interaction networks were constructed. Finally, further studies such as pathway enrichment, immune infiltration, molecular docking, and molecular dynamics simulation were carried out. Results: Of the 95 candidate active components subjected to toxicological screening, only 8 passed the safety evaluation, and 6 of these met both physicochemical and toxicological criteria; five candidate genes (DNAJC19, MRFAP1L1, TBPL1, RPS21, and NABP1) and two key active components (polyacetylene PQ-2, PQ-2) were identified, and these candidate genes corresponded to the DFH substance “ Panacis Quinquefolii Radix ”. The abovementioned candidate genes were enriched in pathways such as ribosome and oxidative phosphorylation, and they were correlated with most differential immune cells. Except for RPS21 and MRFAP1L1, the binding abilities of the other candidate genes with the key active components were good (binding energies <−5.0 kcal/mol). Molecular dynamics simulation confirmed that the interaction of their binding was stable. Discussion: Panacis Quinquefolii Radix might intervene in HA illness via active components (PQ-2) that target five candidate genes, regulating immunity and metabolism. This provided a preliminary computational basis for DFH-based HA illness prevention/treatment.