Hypoxic-ischemic encephalopathy (HIE) is a severe perinatal brain injury that often leads to neurological impairments in survivors. Currently, effective therapeutic strategies for HIE remain limited and require further exploration. Emerging evidence indicates that microglia-mediated neuroinflammation plays a pivotal role in the pathophysiology of HIE. Nevertheless, clinically effective anti-inflammatory agents specifically targeting HIE are still lacking. Glycerol-3-phosphate (G3P) is a biologically significant metabolite involved in various cellular metabolic pathways. In this study, we investigated the neuroprotective effects of G3P against hypoxic-ischemic (HI)-induced brain injury by modulating microglial activation. In LPS-treated microglia, G3P suppressed the release of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential (MMP), and promoted a shift toward an anti-inflammatory microglial phenotype. In addition, G3P treatment in zebrafish showed no toxicity and significantly mitigated HI-induced oxidative stress, while suppressing both the recruitment and pro-inflammatory activation of mpeg1⁺ macrophages and lyzc⁺ neutrophils. Moreover, administration of G3P dramatically reduced infarct volume and alleviated neuronal loss in rats with hypoxic-ischemic brain damage (HIBD). Y-maze and Morris water maze tests demonstrated that G3P treatment significantly enhanced spatial learning and memory in HIBD rats. Furthermore, G3P markedly reduced the hyperactivation of microglia and astrocytes in both cortical and hippocampal regions. Mechanistically, Immunofluorescence and Western blot analyses revealed that G3P exerted anti-inflammatory effects by inhibiting cyclic GMP-AMP synthase -stimulator of interferon genes (cGAS-STING) signalling pathway and its downstream TBK1/the nuclear factor kappa B (NF-κB) signaling pathway. These findings highlight G3P as a promising therapeutic candidate for HIE.

Fracture healing is a complex biological process influenced by systemic conditions and medications. Given the high prevalence of cardiovascular disease in fracture surgery patients and the use of beta-blockers, evidence linking beta-adrenergic signaling to bone metabolism has raised interest in their effects on postoperative healing. This narrative review synthesizes experimental, translational, and clinical evidence regarding the impact of beta-blocker therapy on fracture healing. A structured literature-based approach was used to evaluate studies addressing β-adrenergic signaling in cardiovascular regulation, bone cell function, angiogenesis, and postoperative fracture outcomes. Both preclinical models and observational human studies were critically analyzed to identify mechanistic pathways and clinical associations. Experimental studies indicate that β-adrenergic signaling inhibits osteoblast activity and callus formation, enhances osteoclast activity, and impairs angiogenesis during bone repair. Beta-blockade, particularly with non-selective and lipophilic agents, may counteract these effects, thereby promoting bone formation and microvascular function in animal models. However, clinical evidence remains heterogeneous. Some observational studies report potential benefits, including reduced postoperative mortality or lower fracture risk, whereas other studies show no significant association with healing outcomes or suggest a possible increase in non-union risk. Confounding factors such as comorbid cardiovascular disease, polypharmacy, and differences in drug selectivity limit causal interpretation. Beta-blocker therapy may influence fracture healing through neurovascular and cellular pathways, but current clinical evidence is insufficient to confirm a definitive beneficial or harmful effect. Further prospective, mechanistic, and stratified clinical studies are required to clarify their role in optimizing both cardiovascular and skeletal outcomes in patients undergoing fracture surgery.

We performed a post hoc exploratory secondary analysis to investigate whether baseline circadian blood pressure (BP) pattern was associated with changes in serum uric acid (SUA) during 8-week antihypertensive therapy. Of the 494 hypertensive patients who received amlodipine (5-10 mg) or nifedipine GITS (30-60 mg) for 8 weeks, 369 patients with available laboratory data and valid follow-up ambulatory BP monitoring data were included in the present analysis, including 221 dippers (nocturnal systolic BP decline ≥ 10%) and 148 non-dippers (nocturnal systolic BP decline < 10%). Analysis of covariance was used to estimate least square mean changes in SUA according to baseline dipping pattern. After 8-week antihypertensive treatment, SUA decreased significantly in dippers (-12.4 ± 3.4 µmol/L, p = 0.0004) but not in non-dippers (-3.3 ± 4.2 µmol/L, p = 0.44). In the repeated-measures analysis, SUA levels decreased significantly over time (p = 0.002), whereas no significant time-by-dipping interaction was observed (p = 0.23). Baseline BP dipping pattern may be modestly associated with short-term SUA changes during antihypertensive therapy. However, the absence of a significant time-by-dipping interaction suggests that these findings should be interpreted cautiously and require further confirmation.

Oral anticoagulation (OAC) and left atrial appendage closure (LAAC) are stroke prevention strategies for patients with atrial fibrillation.

To compare stroke and bleeding outcomes from a meta-analysis of randomized controlled trials comparing LAAC to OAC.

The primary outcome was stroke or systemic embolism (stroke/SE). Secondary outcomes included ischemic stroke, hemorrhagic stroke, major bleeding (MB), clinically significant bleeding (MB + clinically relevant nonmajor bleeding), non-procedure related clinically-significant bleeding, and cardiovascular or all-cause mortality.

Seven randomized controlled trials met inclusion criteria (n = 7,353 patients; CHA₂DS₂-VASc score: 3.9; mean follow-up: 37.6 months), including 294 stroke/SE events. LAAC was similar to OAC for preventing stroke/SE (risk ratio [RR]: 1.10, 95% CI: 0.82-1.48). Clinically significant bleeding (RR: 0.60, 95% CI: 0.36-0.98) and non-procedure-related clinically significant bleeding (RR: 0.50, 95% CI: 0.39-0.64) were less frequent after LAAC. No statistically significant differences were observed for ischemic stroke, hemorrhagic stroke, MB, cardiovascular mortality, or all-cause mortality. The annualized incidence rate difference of stroke with LAAC did not increase with higher CHA₂DS₂-VASc scores and did not exceed 0.37%/year in any nonwarfarin-OAC comparative trial. In postablation patients, LAAC showed similar stroke/SE rates (RR: 0.92, 95% CI: 0.53-1.60; P-interaction = 0.76) and less nonprocedural clinically significant bleeding (RR: 0.51, 95% CI: 0.42-0.62; P-interaction = 0.56).

LAAC prevents stroke/SE at rates not significantly different from OAC while reducing clinically significant bleeding, with possibly a more favorable benefit in postablation patients. In the full cohort, the numerically higher ischemic stroke rate was not statistically significant, and small in absolute terms. These findings support LAAC based on individualized, patient-centered decision-making, balancing stroke and bleeding risks.

Cuffless blood pressure (BP) monitoring remains challenging for clinical hypertension management. Although photoplethysmography offers promising solutions for cuffless BP measurement, its clinical validation is limited. This study evaluated the accuracy and clinical utility of photoplethysmography-based finger cuffless BP monitoring following European Society of Hypertension recommendations.

The 2-phase study enrolled 1173 participants. In phase 1 (n=768), a novel photoplethysmography-based finger cuffless BP monitor was validated against invasive BP, office BP, and 24-hour ambulatory BP monitoring across 7 European Society of Hypertension-recommended scenarios. In phase 2 (n=405 hypertensive patients), the clinical utility of photoplethysmography- versus ambulatory BP monitoring-derived mean systolic BP (SBP), SBP time-in-target range, and variability was assessed by examining their associations with hypertension-mediated organ damage and cardiovascular complications, including arterial stiffness, endothelial dysfunction, coronary heart disease, and stroke.

The photoplethysmography-based finger cuffless BP monitor fulfilled all validation criteria, with mean differences ≤5 mm Hg and standard deviations ≤8 mm Hg of both systolic and diastolic BP across 7 scenarios, including invasive, static, awake/asleep, device position, treatment, exercise, and recalibration test. Both ambulatory BP monitoring-derived time-in-target range and photoplethysmography-derived mean SBP and time-in-target range were significantly associated with endothelial injury and arterial stiffness. Notably, photoplethysmography-derived mean SBP and time-in-target range, but not ambulatory BP monitoring-derived metrics, showed a significant association with coronary artery disease. Furthermore, photoplethysmography-derived SBP variability was significantly and positively associated with endothelial injury.

Our data demonstrated that the novel photoplethysmography-based finger cuffless BP monitor reached the criteria of clinical application following European Society of Hypertension recommendations and provided additional clinical implications for the evaluation of hypertension-mediated organ damage and cardiovascular complications.

Psoriasis is an immune-mediated chronic inflammatory skin disease characterized by scaly plaques, erythema, and thick skin. Psoriasis management is complicated and multifaceted as this disease is linked to serious systemic consequences like infections, psoriatic arthritis, cardiovascular diseases, and psychological complications. In the current study, a mice model of psoriasis was established by topical application of 5% imiquimod (IMQ) cream on the shaved dorsal skin and left ear pinna of mice for 7 days. The animals in treatment groups were treated topically with different concentrations of clove oil (CO) (5, 10 and 20%), alone and in combination with flurbiprofen (FBR 5 and 10%), and betamethasone and salicylic acid combination (betasalic® ointment, a standard drug) for the next 7 days. Disease induction and treatment responses were assessed based on modified psoriasis area and severity index (modified PASI) score. On day 15, animals were euthanised, and blood and skin samples were collected for biochemical and histopathological analyses, along with a quantitative assessment of psoriasis-associated inflammatory gene expression using RT-qPCR techniques. Phytochemical tests were performed to detect total tannin, flavonoid, phenolic, and saponin contents of CO. CO 20% and FBR 5% combination and betasalic ointment treatments resulted in a significant (p < 0.05) reduction in erythema, scaling, and skin thickness with an overall modified PASI score of 4.5 ± 0.29 and 4.33 ± 0.33 when compared with the DC group (PASI score = 12 ± 00). Complete blood count analysis revealed a significant reduction (p < 0.05) in total leukocytes, neutrophils, and lymphocytes counts in the CO 20% and FBR 5% combination and betasalic ointment treated groups as compared with DC group. Moreover, a significant decrease in the spleen-to-body weight index (SBWI) was observed in the CO 20% and FBR 5% combination and betasalic ointment treated groups as compared with SBWI of DC group, highlighting the potential immune regulatory properties of CO and FBR. Histopathological analysis of skin tissues revealed a significant improvement in epidermal architecture and a reduction in inflammatory cells infiltration in the treated groups. RT-qPCR analysis revealed down-regulation in the mRNA expression of pro-inflammatory and oxidative stress-inducing genes. Phytochemical analyses confirmed the presence of flavonoids, tannins, phenolic compounds, and saponins in the CO. Overall, these findings suggest that the clove oil-flurbiprofen combination has the potential to reduce skin inflammatory conditions possibly via modulation of oxidative and inflammatory pathways.

Environmental exposure to endocrine-disrupting chemicals has been increasingly implicated in cardiovascular disease, yet the causal molecular mechanisms linking such exposures to atherosclerosis remain incompletely defined. Benzyl butyl phthalate (BBP), a widely used plasticizer, has been associated with vascular dysfunction, but its mechanistic contribution to atherogenesis is unclear. Here, we employed an integrative systems biology framework combining network toxicology, transcriptomic profiling, protein-protein interaction network analysis, molecular docking, molecular dynamics simulations, and summary-data-based Mendelian randomization to systematically elucidate BBP-associated atherosclerotic mechanisms. A total of 114 overlapping targets were identified between BBP-related and atherosclerosis-associated datasets, with MMP9 emerging as a central hub across network topology, transcriptomic validation, and structural analyses. Molecular docking and molecular dynamics simulations demonstrated stable and high-affinity binding between BBP and MMP9, supporting the concept that BBP may act as an exogenous modulator of protease function. Functional enrichment and gene set enrichment analyses consistently revealed immune activation and leukocyte recruitment as dominant biological processes across independent datasets. Furthermore, Mendelian randomization analysis provided genetic evidence supporting causal involvement of immune-related genes, particularly CXCR2, a key regulator of leukocyte trafficking. Integrative multi-level evidence and functional in vitro assays point toward an MMP9-associated, CXCR2-related inflammatory recruitment mechanism, in which BBP-induced modulation of MMP9 may alter chemokine processing, which subsequently enhances neutrophil chemotaxis and potentially contributes to vascular inflammation and atherosclerosis. Collectively, these findings suggest that BBP exposure is associated with alterations in vascular inflammatory processes involving MMP9 and CXCR2. By integrating computational analyses with experimental validation, our study provides evidence supporting an inflammatory recruitment mechanism involving MMP9 and CXCR2 in BBP-associated vascular responses and offers a framework for future investigation into the contribution of environmental pollutants to atherosclerosis.

The maintenance of stable vascular tone is functionally important for buffering flow and redistributing blood oxygen and glucose to match the metabolic demands of organs and tissues. As the tone of other hollow organs, build by smooth muscle cells, vascular tone is governed by the reversible phosphorylation of the 20-kDa regulatory light chains of myosin (MLC₂₀) controlled by two opposing enzymes: the calcium/calmodulin (Ca²⁺-CaM)-activated myosin light chain kinase (MLCK), which phosphorylates MLC₂₀, and myosin light chain phosphatase (MLCP), which dephosphorylates it. In this review, we summarize the key aspects of tone regulation across different brain regions and peripheral vascular beds, with particular emphasis on the central role of the enzyme myosin light chain phosphatase (MLCP) in both physiological and pathological contexts. We propose that MLCP functions as a central molecular integrator of Ca²⁺-dependent, RhoA/ROCK-mediated, cyclic nucleotide-dependent, redox- and hypoxia-sensitive, and splice variant-controlled signalling pathways that collectively determine vascular tone. Finally, we discuss clinically relevant perspectives for research aimed at improving the management of diseases associated with impaired MLCP function.

Cardiovascular disease (CVD) encompasses a group of severe cardiac and vascular disorders with high global prevalence and mortality rates. CVD is characterized by abnormal cell death and inflammation of cardiomyocytes and vascular endothelial cells, involving mutually interconnected pathogenic mechanisms. N6-methyladenosine (m6A) RNA modification has emerged as a key mechanism promoting the progression of CVDs through regulation of gene expression. Among the key mediators, Methyltransferase-like 14 (METTL14)-mediated m6A modification modulates the stability of mRNAs and the processing of pre-miRNAs. We critically discuss recent advances elucidating the function of METTL14 in regulating cardiomyocyte death, which leads to myocardial ischemia/reperfusion injury, heart failure and cardiac fibrosis. In addition, METTL14 promotes endothelial inflammation and atherosclerosis. The long noncoding RNA NEAT1 serves as a central effector integrating the functions of most METTL14 substrates in the pathogenesis of CVD. These analyses on METTL14-mediated signaling pathways highlight METTL14, PHLPP2, TLR4 and NEAT1 as potential therapeutic targets. We thoroughly discuss the structure-based design, binding mechanisms, potency, pharmacokinetic properties and safety of small peptides directly targeting METTL14, and stapled peptides disrupting the interface between METTL3 and METT14 in the catalytic complex. The advantages and limitations of these peptides are compared with METTL3-targeting proteolysis-targeting chimeras (PROTACs), which induce the degradation of both METTL3 and METTL14. Our molecular docking analyses, combined with previous structural biology and medicinal chemistry studies, propose potential binding modes of inhibitors to METTL14, PHLPP1/2, and TLR4. These interdisciplinary discussion reveals various novel concepts in designing the therapeutics to combat METTL14-mediated pathologies.