Mitigation of myocardial ischemia/reperfusion-induced chronic heart failure via Shexiang Baoxin Pill-mediated regulation of the S1PR1 signaling pathway.

BACKGROUND: Well-defined and effective pharmacological interventions for clinical management of myocardial ischemia/reperfusion (MI/R) injury are currently unavailable. Shexiang Baoxin Pill (SBP), a traditional Chinese medicine Previous research on SBP has been confined to single-target treatments for MI/R injury, lacking a comprehensive examination of various aspects of MI/R injury and a thorough exploration of its underlying mechanisms. PURPOSE: This study aimed to investigate the therapeutic potential of SBP for MI/R injury and its preventive effects on consequent chronic heart failure (CHF). Furthermore, we elucidated the specific mechanisms involved, contributing valuable insights into the potential pharmacological interventions for the clinical treatment of MI/R injury. METHODS: We conducted a comprehensive identification of SBP components using high-performance liquid chromatography. Subsequently, we performed a network pharmacology analysis based on the identification results, elucidating the key genes influenced by SBP. Thereafter, through bioinformatics analysis of the key genes and validation through mRNA and protein assays, we ultimately determined the centralized upstream targets. Lastly, we conducted in vitro experiments using myocardial and endothelial cells to elucidate and validate potential underlying mechanisms. RESULTS: SBP can effectively mitigate cell apoptosis, oxidative stress, and inflammation, as well as promote vascular regeneration following MI/R, resulting in improved cardiac function and reduced CHF risk. Mechanistically, SBP treatment upregulates sphingosine-1-phosphate receptor 1 (S1PR1) expression and activates the S1PR1 signaling pathway, thereby regulating the expression of key molecules, including phosphorylated Protein Kinase B (AKT), phosphorylated signal transducer and activator of transcription 3, epidermal growth factor receptor, vascular endothelial growth factor A, tumor necrosis factor-α, and p53. CONCLUSION: This study elucidated the protective role of SBP in MI/R injury and its potential to reduce the risk of CHF. Furthermore, by integrating downstream effector proteins affected by SBP, this research identified the upstream effector protein S1PR1, enhancing our understanding of the pharmacological characteristics and mechanisms of action of SBP. The significance of this study lies in providing compelling evidence for the use of SBP as a traditional Chinese medicine for MI/R injury and consequent CHF prevention.

Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment.

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

Small molecule oral targeted therapies in ulcerative colitis.

The incidence and prevalence of ulcerative colitis are increasing globally. Although the exact cause and pathogenesis of this disease is unclear, research has led to a better understanding of the condition and to identification of new targets for therapy, which in turn has encouraged the development of new therapies. As well as biologic therapies, which have changed the way inflammatory bowel disease is managed, small molecules have been developed for the treatment of ulcerative colitis. These small molecule treatments are orally administered and are likely to bring a substantial shift in the way this chronic disease is treated. Oral therapies offer many advantages over infusion therapies, such as ease of use, increased acceptability by patients, and reduction of cost. This Review focuses not only on oral therapies that have been approved for use in ulcerative colitis, but also on those that are in development, providing a comprehensive overview for clinicians of available oral therapies and drugs that are likely to become available. We have also reviewed drugs that have shown promise in preclinical studies and could be effective future therapies.