Ischemic stroke is a leading cerebrovascular disorder frequently complicated by cerebral ischemia-reperfusion injury (CIRI), which aggravates neurological damage and worsens clinical outcomes. Yangyin Formula (YYF), a traditional Chinese medicine composed of Rehmannia glutinosa, Dendrobium officinale, and Pueraria lobata, has shown potential in mitigating CIRI. To elucidate its therapeutic mechanisms, we integrated network pharmacology, molecular docking, and molecular dynamics simulations, followed by in vivo validation in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). A total of 61 bioactive compounds and 768 targets were identified, enriched in 136 signaling pathways. Computational analyses revealed strong binding affinities between key YYF components and CIRI-related targets. In vivo, YYF administration significantly improved neurological function, reduced infarct volume, and alleviated histopathological damage. Furthermore, YYF suppressed IL-17A, TNF-α, IL-1β, Caspase-3, p38 MAPK, and NF-κB p65 expression in brain and serum, with effects comparable to IL-17A inhibition. These findings suggest that YYF exerts neuroprotective effects against CIRI by modulating the IL-17A/p38 MAPK/NF-κB p65 signaling pathway, highlighting its potential as a therapeutic strategy for ischemic stroke.

Ischemia-reperfusion injury (IRI) is a complex and clinically significant pathophysiological process that occurs when blood flow is restored to an organ following ischemia. While reperfusion is essential for tissue survival, it paradoxically exacerbates damage through mechanisms such as oxidative stress, inflammation, mitochondrial dysfunction, and endothelial injury. This phenomenon contributes significantly to morbidity and mortality in various clinical settings, including organ transplantation, myocardial infarction, stroke, and liver and kidney injuries. Despite increasing knowledge of the molecular pathways involved, effective treatment options remain limited. Recent scientific advances have highlighted the potential of natural bioactive compounds to reduce oxidative and inflammatory responses during IRI. Hass avocado (Persea americana Mill.) has garnered considerable attention as a rich source of phytochemicals with strong antioxidant and anti-inflammatory properties, including carotenoids, tocopherols, polyphenols, and monounsaturated fatty acids (MUFAs). These compounds may act synergistically to neutralize reactive oxygen species, inhibit proinflammatory mediators, and modulate key cellular pathways involved in IRI. This comprehensive review explores the current evidence regarding the protective effects of Hass avocado bioactive compounds against IRI. We examined their molecular mechanisms of action and discussed the therapeutic implications of incorporating these natural agents into clinical practice. To our knowledge, this is the first review specifically addressing the role of Hass avocado phytochemicals in reducing oxidative damage and inflammation in IRI, offering a novel perspective for future research and clinical application.

Systemic sclerosis is a rare autoimmune connective tissue disease characterized by progressive fibrosis of the skin and internal organs, vasculopathy, and the presence of specific autoantibodies. Despite its low prevalence, systemic sclerosis is associated with high morbidity. Early features often include Raynaud phenomenon, hand edema, and fatigue. Diagnosis requires a comprehensive approach, including clinical assessment, laboratory evaluation, imaging, and pulmonary function testing. The American College of Rheumatology and European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism) provide classification criteria and updated treatment recommendations. Management focuses on addressing eight disease domains: Raynaud phenomenon, digital ulcers, pulmonary artery hypertension, interstitial lung disease, renal crisis, gastrointestinal involvement, skin fibrosis, and musculoskeletal involvement. Vasodilator therapy is first-line treatment for Raynaud phenomenon, whereas phosphodiesterase-5 inhibitors and intravenous iloprost are used to treat digital ulcers. Combination therapy with phosphodiesterase-5 inhibitors and endothelin receptor antagonists is first-line treatment for pulmonary artery hypertension. Mycophenolate mofetil is the preferred treatment for interstitial lung disease.

This Swedish nationwide cohort study used large-scale data to investigate the associations between bipolar disorder and somatic disorders and whether these risks differ by subtype, sex, or exposure to compulsory care.

61,071 individuals diagnosed with bipolar disorder in inpatient (from 1973) or outpatient care (from 2001) care were compared with the general population without bipolar disorder. The cohort included individuals born in 1932 or later, with follow-up from 1973 to 2020. Cox regression models estimated associations with a range of somatic conditions, including cardiovascular, endocrine, neurological, and infectious diseases. Subtype-specific analyses were conducted in individuals with type 1 (n = 8,352) or type 2 (n = 9,674), and in those with a history of compulsory care (n = 6,748).

Bipolar disorder was associated with significantly increased risks for most examined somatic conditions. The highest hazard ratios (HRs) were observed for sleep disorders (HR 3.79; 95% CI, 3.71-3.87) and dementias (HR 4.32; 95% CI, 3.82-4.79). Type 2 diabetes risk was elevated, while no association was found for type 1 diabetes. Most risks were comparable across bipolar subtypes, though certain conditions-such as migraine and fibromyalgia-were more strongly associated with type 2. Individuals with a history of compulsory psychiatric care showed elevated risks for several conditions.

Regardless of sex or subtype, bipolar disorder is associated with substantially higher lifetime risks of a broad range of somatic conditions. Integrated psychiatric and somatic health care may help reduce morbidity and improve outcomes.

To determine whether ivermectin improves outcomes for critically and noncritically ill hospitalized patients with COVID-19.

An ongoing international, multifactorial, adaptive platform, randomized, controlled trial.

Hospitals in Pakistan, India, and Ireland between June 11, 2021, and September 9, 2022.

Critically and noncritically ill patients.

Randomized to ivermectin or no ivermectin (control).

The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors. Analyses used a Bayesian cumulative logistic model. Enrollment was closed for operational futility, following external evidence suggesting no benefit with ivermectin in nonhospitalized patients with COVID-19. Among 61 critically ill patients, the median number of organ support-free days was -1, indicating death was the most common vital outcome (interquartile range [IQR], -1 to 17), for the ivermectin group and -1 (IQR, -1 to 17.25) for the control group (adjusted proportional odds ratio [OR], 0.94; 95% credible interval [CrI], 0.40-2.07) and the posterior probability of superiority to control was 44.2%. Among 89 noncritically ill patients, the median number of organ support-free days was 22 (IQR, 18.5-22) for ivermectin and 22 (IQR, 16-22) for control (adjusted proportional OR, 1.04; 95% CrI, 0.48-2.34) and the posterior probability of superiority was 53.7%. Among critically ill patients, hospital survival was 35.1% (13/37) for ivermectin and 37.5% (9/24) for control (adjusted OR, 1.00; 95% CrI, 0.39-2.32), posterior probability of superiority was 50.0%. Among noncritically ill patients, hospital survival was 84.1% (37/44) for ivermectin and 77.8% (35/45) for control (adjusted OR, 1.16; 95% CrI, 0.5-3.07), posterior probability of superiority was 63.3%.

For critically and noncritically ill hospitalized patients with COVID-19, ivermectin was unlikely to improve the primary composite outcome of organ support-free days and hospital survival.

Mitiperstat is a novel myeloperoxidase inhibitor being investigated for the treatment of heart failure, metabolic dysfunction-associated steatohepatitis, and chronic obstructive pulmonary disease. Pharmacokinetic data from five clinical trials were used to develop a mitiperstat population pharmacokinetics (popPK) model. In total, 2856 plasma samples from 128 mitiperstat-treated participants were collected during the first-in-human single-ascending dose (SAD) study; multiple-ascending dose studies (MAD) in healthy volunteers, including healthy Japanese and Chinese volunteers (JCMAD); the phase 2a SATELLITE study in patients with heart failure with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF); and from a study in patients with severe renal impairment. The mitiperstat concentration-time data were pooled and analyzed with the software NONMEM. The covariates considered in this analysis were baseline estimated glomerular filtration rate (eGFR), baseline body weight, baseline body mass index, sex, race (Asian or non-Asian), age, disease status (healthy volunteers or patients with HFpEF/HFmrEF), and formulation (oral suspension or tablet). The final popPK model is a two-compartment model with first-order absorption and linear elimination. Baseline body weight, disease status, Asian race, and eGFR were identified as significant covariates for apparent clearance, and age was identified as a significant covariate for apparent central volume of distribution. The final model predicts that severe renal impairment and lower body weight have the largest impact on exposure. Exposure to mitiperstat increased as eGFR declined. This popPK model constitutes an important step toward optimizing doses for efficacy and safety in the different mitiperstat development programs. Trial Registration: ClinicalTrials.gov: NCT02712372.

Aging is accompanied by a chronic low-grade inflammatory process, known as inflammaging, as well as immunosenescence, an age-related decline and dysregulation of immune function, and cellular senescence, a process in which cells enter a state of irreversible growth arrest while actively releasing pro-inflammatory factors. These processes alter the host immune regulation and tissue homeostasis. Aging-associated mechanisms are being explored for their role in periodontal and peri-implant diseases because of their promotion of dysregulated inflammation, impaired healing, and heightened susceptibility to tissue destruction. Rather than viewing periodontitis as a condition driven solely by microbial burden, it should be understood as a multifactorial disease shaped by complex host-microbe interactions, in which host-driven processes, particularly senescence and inflammaging, play a central role in amplifying bidirectional oral-systemic interactions.

This scoping review aims to (i) highlight the current understanding of the role of aging and its alterations in host inflammatory responses on immune function, tissue homeostasis, and cellular stress responses; (ii) explore the potential impact of "inflammaging" on the periodontium and interactions with systemic health; and (iii) explore possible therapeutic targets for senotherapy.

A literature search of the PubMed database was conducted using Boolean search strategies to identify publications related to the potential connections between aging and inflammation in the context of the oral cavity.

Of the total 283 articles that were screened, 87 met the eligibility criteria and were included in this scoping review. An additional 51 articles were obtained via manual search. The evidence demonstrates a link between inflammaging, age-related cellular senescence, and periodontal vulnerability to periodontal pathogens and periodontal destruction. Both experimental and clinical studies have shown increased senescence markers, dysregulated immune responses, and enhanced osteoclastic activity that lead to greater tissue destruction and alveolar bone loss. Systemic conditions such as Alzheimer's disease, diabetes, and cardiovascular disease can also amplify the inflammatory burden through shared pathways. Overall, our findings support the idea that older adults undergo immune dysregulation when challenged with microbes that ultimately cause a chronic periodontal inflammatory state.

Cardiovascular and metabolic diseases account for an increasing share of morbidity and mortality globally. Folic acid supplementation has been linked to a lowered risk of stroke and some metabolic indicators due to its involvement in homocysteine and one-carbon metabolism and its role in the production of nitric oxide; however, the evidence on these associations is inconclusive.

We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (dietary intake, supplementation, or blood concentrations) with any cardiometabolic outcome. We performed screening, data abstraction, and risk of bias assessment in duplicate, and assessed the credibility of the evidence using predefined criteria.

We identified 113 unique associations from 49 reviews. The included syntheses mostly had low risk of bias of and provided pooled risk estimates from intervention trials or prospective cohorts. A larger volume of evidence was available for composite cardiovascular outcomes, coronary heart disease, and stroke compared to other outcomes. No association reached a convincing or highly suggestive level of credibility. Six directional associations and five null associations met the criteria for a suggestive level of credibility. Three dose-response relationships, all at suggestive levels of credibility, supported an association between higher dietary folate intake and a reduced risk of coronary heart disease and stroke.

The available evidence on the association between folate status and cardiometabolic outcomes primarily focuses on secondary prevention of cardiometabolic diseases and substantially underrepresents low- and middle-income countries. More large-scale studies are warranted to validate a relationship between folate status and cardiometabolic events or indicators. Overall, the evidence landscape around folate and cardiometabolic diseases appears to be limited both in volume and scope.

PROSPERO: CRD42021265041.

Cinnamaldehyde, a bioactive constituent derived from Cinnamomum cassia Presl, exhibits diverse pharmacological effects, including vasodilatory and antihypertensive properties. However, its pharmacological impact and underlying mechanism concerning ischemic heart failure (IHF) remain poorly understood. This study aimed to investigate the cardioprotective effects of cinnamaldehyde on IHF and thereby elucidate its potential mechanism both in vivo and in vitro. To do so, a hypoxic injury model was established using AC16 cells, and male C57BL/6J mice underwent left anterior descending (LAD) artery ligation for eight weeks before receiving varying doses of cinnamaldehyde from the fourth week onward. Cardiac function and morphology were assessed via M-mode echocardiography, H&E staining, and Masson staining. Western blotting, co-immunoprecipitation (IP) assays, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) analysis, and siRNA transfection were employed to evaluate the mechanism. Cinnamaldehyde significantly improved cardiac function, ameliorated cardiac fibrosis, and reduced myocardial inflammation in LAD-induced IHF mice. Concurrently, it protected cardiomyocytes and inhibited the inflammatory response in oxygen-glucose-deprived (OGD)-treated AC16 cells. Mechanistically, cinnamaldehyde was directly bound to USP18 and thus upregulated its expression. Further investigation revealed that cinnamaldehyde inhibited [Formula: see text]-adrenergic receptor ([Formula: see text]-AR) ubiquitination, thereby increasing its protein level. It also suppressed the TAK1/NF-κB pathway. Crucially, silencing USP18 eliminated both the cardioprotective and anti-inflammatory effects of cinnamaldehyde while also halting the inhibition of both [Formula: see text]-AR ubiquitination and the TAK1/NF-κB pathway. Cinnamaldehyde thus collectively enhances cardiac function against IHF by upregulating USP18 to thereby subsequently suppress both [Formula: see text]-AR ubiquitination and the activation of the TAK1/NF-κB pathway.

Reliable molecular biomarkers for poststroke cognitive impairment (PSCI) remain limited. Using publicly available bulk transcriptomic and single-cell RNA-seq datasets from GEO, we investigated lactate metabolism- and pyroptosis-related signatures and developed a diagnostic model. Differential expression analysis, KEGG pathway enrichment, and weighted gene coexpression network analysis (WGCNA) were performed, followed by multialgorithm feature selection (LASSO, SVM-RFE, and random forest). A logistic regression classifier was trained in the discovery cohort and externally validated in an independent cohort. Glycolysis/lactate metabolism, HIF-1 signaling, and NOD-like receptor-related pathways were enriched in PSCI-associated samples, and key coexpression modules were strongly correlated with ischemic injury traits. Cross-model consensus identified LDHA, GSDMD, and CASP1 as hub genes, yielding an AUC of 0.912 (95% bootstrap CI: 0.841-0.983) in the training cohort and 0.885 (95% bootstrap CI: 0.798-0.972) in the validation cohort. Immune deconvolution and scRNA-seq validation suggested increased proinflammatory microglia-associated signals, with relatively higher LDHA expression in microglia than in neurons; cell-cell communication analysis highlighted inflammatory interactions including IL1B-IL1R1. Connectivity map (CMap) analysis nominated candidate compounds, and molecular docking predicted favorable binding between oxamate and LDHA (binding energy = -9.5 kcal/mol). Collectively, these findings propose a compact LDHA/GSDMD/CASP1 biomarker panel for PSCI diagnosis and provide hypothesis-generating therapeutic leads that warrant further experimental validation.