Endothelial Dysfunction Research Articles

Elucidating novel mechanism of action of spiperone for drug repurposing to prevent and treat murine colitis and sepsis

AimsWhile Ca2+ signaling plays a vital role in maintaining normal endothelial function and vascular activity, aberrant Ca2+ signaling in endothelial dysfunction is involved in the pathogenesis of inflammation. As a safe anti-psychotic drug to mobilize Ca2+ signaling, we repurposed spiperone as a potential drug for two intestinal epithelial injury related diseases, colitis and sepsis. Materials and methodsSpiperone-induced vasorelaxation of human submucosal arterioles and mesenteric arterioles from wide-type and TRPV4 KO mice was determined by Mulvany-style wire myograph. The action of spiperone in HUVEC was tested by Ca2+ imaging and patch clamp, and its action on murine mesenteric arterioles was measured in vivo. LPS- and CLP-induced septic mice and DSS-induced colitic mice were used to examine the anti-inflammatory effects of spiperone. Key findingsSpiperone induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of healthy arterioles with EC50 of ∼50 nM predominately via PLC/IP3/IP3R pathway to induce endoplasmic reticulum (ER) Ca2+ release and further to promote Ca2+ entry via TRPV4-constituted SOCE. In both LPS- and CLP-induced septic mice, spiperone effectively prevented and treated sepsis by reducing serum proinflammatory factors, alleviating multiple organ dysfunction, rescuing the impaired EDH-mediated vasorelaxation and improving murine survival rate. Similarly, spiperone could also protect against murine colitis. SignificanceWe reveal new action mode and mechanism of spiperone to induce EDH-mediated vasorelaxation of both human and murine arterioles to protect against colitis and sepsis by innovatively inducing PLC/IP3R/Ca2+ signaling rather than canonically antagonizing GPCR. Spiperone could be repurposed as a potential new drug for the prevention/treatment of colitis and sepsis.

Reduced neurovascular coupling is associated with increased cardiovascular risk without established cerebrovascular disease: A cross-sectional analysis in UK biobank.

Mid-life vascular risk factors predict late-life cerebrovascular diseases and poor global brain health. Although endothelial dysfunction is hypothesized to contribute to this process, evidence of impaired neurovascular function in early stages remains limited. In this cross-sectional study of 31,934 middle-aged individuals from UK Biobank without established cerebrovascular disease, the overall 10-year risk of cardiovascular events was associated with reduced neurovascular coupling (p < 2 × 10-16) during a visual task with functional MRI, including in participants with no clinically apparent brain injury on MRI. Diabetes, smoking, waist-hip ratio, and hypertension were each strongly associated with decreased neurovascular coupling with the strongest relationships for diabetes and smoking, whilst in older adults there was an inverted U-shaped relationship with DBP, peaking at 70-80 mmHg DBP. These findings indicate that mid-life vascular risk factors are associated with impaired cerebral endothelial-dependent neurovascular function in the absence of overt brain injury. Neurovascular dysfunction, measured by neurovascular coupling, may play a role in the development of late-life cerebrovascular disease, underscoring the need for further longitudinal studies to explore its potential as a mediator of long-term cerebrovascular risk.

Regulation of the HMGA2-SNAI2/CXCR4 axis in atherosclerosis and retinal neovascularization: new therapeutic insights.

Atherosclerosis (AS) is a vascular disease associated with endothelial damage, plaque formation, and retinal neovascularization (RNV), leading to visual impairment. Research indicates that vascular endothelial dysfunction, lipid deposition, and inflammatory responses contribute to the formation of plaques and atherosclerotic lesions. Among the common complications, studies have shown that RNV and the molecular mechanisms of AS hold significant clinical importance. In this study, we identified the overexpression of the gene heat shock protein 90 (HSP90) through transcriptome sequencing. Subsequent protein expression analysis and inhibition experiments in corresponding animal models confirmed the crucial role of HSP90 in the modulation of this disease. Research findings revealed an increase in the expression of HSP90, HMGA2, Snail family transcriptional repressor 2 gene (SNAI2), CXC chemokine receptor 4 (CXCR4), and vascular endothelial growth factor (VEGF) in atherosclerotic mouse tissues. Inhibition of HSP90 expression reduced vascular neovascularization and downregulated the expression of HMGA2 and VEGF. Given that HSP90 can promote HMGA2 expression, which, in turn, facilitates angiogenesis, we conducted lentiviral infection experiments on primary retinal endothelial cells obtained from atherosclerotic mice, confirming the regulatory role of HSP90 in modulating HMGA2 expression through the SNAI2/CXCR4 signaling pathway and its involvement in retinal endothelial neovascularization. In conclusion, our study highlights the significant regulatory role of HSP90 in AS-induced RNV, providing a new target for disease treatment. Furthermore, this research extensively explores the mechanism of HSP90 in regulating RNV and associated signaling pathways, offering novel insights and laying a solid foundation for future studies in this disease domain.

A Review of Cardiovascular Effects of Marijuana Use.

Cannabinoids exert their effects on body tissues via cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. Receptors are present in brain, myocardium, vascular endothelium, platelets, and adipose tissues. Under normal physiologic conditions, endocannabinoid effects are minimal. The use of exogenous cannabis leads to endothelial dysfunction and increases vascular thrombosis via CB1 receptor stimulation. On the other hand, CB2 receptors may have a beneficial anti-inflammatory response. We reviewed reports of the effects of cannabis on the cardiovascular system utilizing PUBMED from the last 20years with emphasis on the most recent reports. Despite a plethora of reviews and some retrospective studies, there is a need for more definitive data regarding the effect of cannabis use on cardiovascular events (CVE). Marijuana does not appear to accelerate atherosclerosis. There is a suggestion that it may induce myocardial infarction in a small percentage of users, especially in male users, particularly during recent use. It has a possibility of increasing cerebrovascular events when combined with other risk factors such as tobacco use. There is an association between cannabis use and increased evidence of peripheral vascular disease. To have a definitive answer to the question of whether cannabis contributes to CVE, there is an urgent need for prospective controlled studies with patients presenting to academically oriented medical facilities with CVE following cannabis use for either medicinal or recreational use.

Time-Dependent Relationship Between Endothelial Dysfunction and High Blood Pressure in Fructose Drinking Rats.

This study aims to investigate the duration required for endothelium dysfunction to develop in the fructose drinking-induced hypertension and examine the relative contributions of endothelium-dependent relaxing factors to changes in mesenteric arterial reactivity in male Wistar Albino rats. Metabolic parameters (water intake and food consumption) and hemodynamic parameters systolic blood pressure (SBP) and diastolic blood pressure (DBP)-were monitored in vivo. Vascular reactivity was examined in the isolated organ bath. Endothelium-dependent relaxation (EDR) to acetylcholine was observed in the absence and presence of pharmacological inhibitors of endothelial nitric oxide (NO) synthase, cyclooxygenase, and KCa2.3 channels. Contractile responses to phenylephrine and relaxation of sodium nitroprusside (SNP) were also determined. A significant increase in daily water intake and decrease in food consumption were typically observed in rats treated with 10% fructose for 4 weeks (p < 0.05). SBP and DBP increased significantly as early as 2 weeks of induction and continued to rise gradually throughout the induction period (p < 0.05). Fructose consumption significantly impaired EDR at week 3 and worsened at week 4 (p < 0.05). Impairment of the KCa3.1 channel-mediated component of endothelium-dependent hyperpolarisation (EDH)-type relaxation contributed to worsening EDR, whereas the contribution of NO-mediated relaxation was not apparent compared with the controls. The reduction in EDH-type relaxation in fructose-fed rats appears to be partially compensated by increased NO sensitivity in the smooth muscle region, as fructose induction increased SNP relaxation compared with the control. These data provide evidence of early endothelial dysfunction developing concurrently with increased blood pressure in 10% fructose-fed rats. Decreased KCa3.1-mediated part of EDH-type relaxation appears to contribute to the impairment of endothelium-dependent vasorelaxation over time in this model.

Acer tegmentosum Maxim and Bacillus subtilis-fermented products inhibit TNF-α-induced endothelial inflammation and vascular dysfunction of the retina: the role of tyrosol moiety in active compounds targeting Glu230 in SIRT1.

Acer tegmentosum Maxim (AT) is a medicinal plant used to treat hepatic, neurological diseases, and cancer. However, the beneficial effects of AT on endothelial dysfunction have not been reported yet. In this study, we evaluated the effects of AT and the main compounds against TNF-α-mediated inflammatory responses and their possible mechanism of action. The anti-inflammatory effect and its molecular mechanism were analyzed by adhesion assay, immunoblotting, promoter-luciferase assay, ELISA, RT-PCR, immunocytochemistry, immunoprecipitation, siRNA gene knockdown, docking, and molecular dynamics simulation. AT and its compounds salidroside and tyrosol reduced TNF-α-induced adhesion between monocytes and endothelial cells. Fermentation of AT with Bacillus subtilis converted salidroside to tyrosol, which is salidroside's aglycone. The fermented AT product (ATF) potently inhibited TNF-α-mediated monocyte adhesion with higher potency than AT. AT or ATF abrogated TNF-α-induced expression of adhesion molecules (VCAM-1 and ICAM-1) and production of MCP-1 with the inhibition of phosphorylated MAP kinases. TNF-α-mediated NF-κB transactivation and RelA/p65 acetylation were suppressed by AT and ATF through the interaction of NF-κB with sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase. Sirt1 gene knockdown diminished the protective effects of AT and ATF against TNF-α-mediated signaling and inflammatory response. Interestingly, SIRT1 protein expression was significantly increased by ATF and tyrosol rather than by AT and salidroside, respectively. Molecular docking showed that the tyrosol moiety is critical for the interaction with Glu230 of SIRT1 (PDB ID: 4ZZH and 4ZZJ) for the deacetylase activity. Molecular dynamics revealed that tyrosol can induce the movement of the N-terminal domain toward the catalytic domain of SIRT1. This study demonstrates the potential of AT and ATF to prevent endothelial inflammation and vascular dysfunction of the retina by the MAPK/NF-κB/SIRT1 signaling pathways and targeting of the tyrosol moiety to Glu230 in SIRT1.

Assessment of Endothelial Function in Patients with COVID-19 Using Peripheral Arterial Tonometry.

There is increasing evidence that COVID-19 induces endothelial dysfunction that may precede thrombotic and cardiovascular complications. The aim of this study is to evaluate endothelial function using peripheral arterial tonometry (EndoPAT). The primary endpoint is the hyperemic vascular response index (LnRHI) at two months post-discharge. Secondary endpoints include the LnRHI during hospitalization and at six-month follow-up, the proportion of patients with endothelial dysfunction (LnRHI ≤ 0.51), and the incidence of thrombotic events, cardiovascular complications, and mortality during the follow-up period. The study included 23 COVID-19 patients and 22 COVID-19-negative, matched controls. The patients exhibited a significant reduction in the LnRHI at two months post-discharge compared to the controls (median = 0.55 [IQR: 0.49-0.68] vs. median = 0.70 [IQR: 0.62-0.83]; p = 0.012). The difference in the LnRHI between patients and controls was evident from hospitalization and persisted at two and six months without significant temporal changes. The proportion of COVID-19 patients with endothelial dysfunction (LnRHI ≤ 0.51) was 61% during hospitalization and 55% at six months. There was no significant difference in thrombotic or cardiovascular events, nor in mortality. This study demonstrates that COVID-19 adversely affects endothelial function, as evidenced by a reduction in the hyperemic vascular response index, and endothelial dysfunction may also persist.

Effects of green coffee supplementation on paraoxonase-1 activity and malondialdehyde levels in Iranian women with polycystic ovary syndrome: a randomized clinical trial.

Polycystic ovary syndrome (PCOS) is a common, heterogeneous clinical syndrome affecting women. Investigating oxidative stress in women is crucial, as it is linked to insulin resistance and endothelial dysfunction. Chlorogenic acid, a bioactive component found in green coffee, has numerous documented health benefits. This study aimed to assess the beneficial effects of green coffee consumption on paraoxonase-1 (PON-1) activity and malondialdehyde (MDA) levels in women with PCOS. This study was a double-blind randomized clinical trial that included 44 patients with PCOS. Participants were randomly assigned to either the intervention or control group. For 6 weeks, the intervention group (n=22) received 400 mg of green coffee supplements, while the control group (n=22) received 400 mg of a starch-based placebo. Anthropometric indices, dietary assessments, and physical activity levels were evaluated before and after the 6-week intervention period. Additionally, blood samples were collected for laboratory analysis. Supplementation with green coffee increased PON-1 levels by 3.5 units, a significant finding (p=0.038). Additionally, the intake of green coffee supplements significantly reduced blood cholesterol levels by 18.8 units (p=0.013) and triglyceride levels by 6.1 units (p=0.053). However, no significant differences were observed in the levels of MDA, high-density lipoprotein, low-density lipoprotein, fasting blood sugar, insulin, or homeostatic model assessment of insulin resistance as a result of the intervention. Supplementation with green coffee alters PON-1 activity and cholesterol levels in women with PCOS. However, it has no significant impact on MDA levels or glycemic status.

Endothelial Dysfunction in Pulmonary Hypertension: Does ADP-ribosylation Factor 6-mediated HIF-2α Stabilization Matter?

Endothelial Dysfunction in Pulmonary Hypertension: Does ADP-ribosylation Factor 6-mediated HIF-2α Stabilization Matter?

Amyloid beta-induced mitochondrial dysfunction and endothelial permeability in cerebral microvascular endothelial cells: The protective role of dexmedetomidine

Postoperative cognitive dysfunction (POCD) is a common complication in patients who undergo anesthesia in different types of surgeries. Emerging evidence implicates elevated beta-amyloid (Aβ) in the pathogenesis of POCD. Meanwhile, Dexmedetomidine (DEX) has recently shown promise in reducing POCD incidence. This study aimed to elucidate the role of Aβ in inducing endothelial permeability in cerebral microvascular endothelial cells and the underlying mechanisms and testing the effects of DEX. We demonstrated that Aβ1–42, the prevalent Aβ form related to POCD, is cytotoxic to HBMECs, increasing transendothelial permeability and inducing mitochondrial dysfunction, as evidenced by elevated mitochondrial reactive oxygen species (ROS) and decreased ATP production and mitochondrial membrane potential. Furthermore, Aβ1–42 was shown to inhibit Sirt3, exacerbating mitochondrial dysfunction. Conversely, DEX was found to prevent Aβ1–42-induced mitochondrial dysfunction and permeability increases and preserved tight junction proteins in HBMECs.These findings suggest that DEX, as a Sirt3 activator, may offer a pharmacological strategy to mitigate Aβ1–42-related cerebral microvascular endothelial cell dysfunction and preserve cognitive function post-surgery.

Low-magnitude high-frequency vibration ameliorates high glucose-induced endothelial injury by restoring mitochondrial function via AMPK/mTOR pathway

ABSTRACT High glucose-induced dysfunction of endothelial cells is a critical and initiating factor in the genesis of diabetic vascular complications. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical intervention. It has been reported that it exhibits protective effects on high glucose-induced osteoblast dysfunction, but little was known on diabetic vascular complications. In this work, we aim to clarify the role of LMHFV on high glucose-induced endothelial dysfunction and hypothesized that the protective effects functioned through adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. We cultured primary murine aortic endothelial cells (MAECs) in normal or HG medium, respectively, before exposing to LMHFV. The tube formation, paracellular permeability assay, and aortic ring sprouting assay showed that the high glucose injured-function of MAECs was improved after LMHFV treatment. The intracellular ROS generation analysis, mitochondrial complex I activities measurement, ATP measurement and mitochondrial membrane potential (MMP), and mitochondrial ROS generation analysis of MAECs indicated that mitochondrial function was restored by LMHFV loading in a high glucose environment. Mechanically, western blot assays showed that AMPK phosphorylation was promoted and mTOR was inhibited in LMHFV-induced endothelial function restoration. After the administration of the AMPK inhibitor, Compound C, these protective effects resulting from LMHFV are reversed. These findings suggest that LMHFV plays a significant role in protecting endothelial cells’ function and mitochondrial function in high glucose-induced injured MAECs via AMPK/mTOR signalling.

Non-bacterial thrombotic endocarditis: a clinical and pathophysiological reappraisal.

Non-bacterial thrombotic endocarditis (NBTE), formerly recognized as marantic endocarditis, represents a rare cardiovascular pathology intricately linked with hypercoagulable states, notably malignancy and autoimmune disorders. Characterized by the development of sterile vegetations comprised of fibrin and platelets on cardiac valves, NBTE poses a diagnostic challenge due to its resemblance to infective endocarditis. Therapeutic endeavours primarily revolve around addressing the underlying aetiology and instituting anticoagulant regimens to forestall embolic events, with surgical intervention seldom warranted. Non-bacterial thrombotic endocarditis frequently coexists with malignancies and autoimmune conditions, such as lupus and antiphospholipid antibody syndrome, and, more recently, has been associated with COVID-19. Its pathogenesis is underpinned by a complex interplay of endothelial dysfunction, hypercoagulability, hypoxia, and immune complex deposition. Clinical manifestations typically manifest as embolic phenomena, particularly cerebrovascular accidents, bearing substantial mortality rates. Diagnosis necessitates a high index of suspicion and meticulous exclusion of infective endocarditis, often facilitated by advanced cardiac imaging modalities. Anticoagulation, typically employing low molecular weight heparin or warfarin, constitutes the cornerstone of pharmacological intervention. Surgical recourse may be warranted in instances of refractory heart failure or recurrent embolic events. Given its multifaceted nature, the management of NBTE mandates a multidisciplinary approach, with prognosis contingent upon individual clinical intricacies. Future endeavours should prioritize further research to refine therapeutic strategies and enhance patient outcomes.

Impaired endothelial function contributes to cardiac dysfunction - role of mitochondrial dynamics.

The endothelial microvasculature is essential for the regulation of vasodilation and vasoconstriction, and improved functioning of the endothelium is linked to improved outcomes for individuals with coronary artery disease (CAD). People with endothelial dysfunction exhibit a loss of NO-mediated vasodilation, achieving vasodilation instead through mitochondria-derived H2O2. Mitochondrial dynamics is an important autoregulatory mechanism that contributes to mitochondrial and endothelial homeostasis and plays a role in formation of reactive oxygen species (ROS), including H2O2. Dysregulation of mitochondrial dynamics leads to increased ROS production, decreased ATP production, impaired metabolism, activation of pathological signal transduction, impaired calcium sensing, and inflammation. We hypothesize that dysregulation of endothelial mitochondrial dynamics plays a crucial role in the endothelial microvascular dysfunction seen in individuals with CAD. Therefore, proper regulation of endothelial mitochondrial dynamics may be a suitable treatment for individuals with endothelial microvascular dysfunction and we furthermore postulate that improving this microvascular dysfunction will directly improve outcomes for those with CAD.

The therapeutic role of exercise training during menopause for reducing vascular disease.

Menopause marks a major milestone in female reproductive ageing. It is characterized by the cessation of ovarian function and a concomitant decline in hormones such as oestradiol. Subsequently, females undergoing menopausal transition experience a progressive increase in cardiovascular and cerebrovascular disease risk. During menopause, reductions in nitric oxide (NO) bioavailability, endothelial dysfunction, increases in systemic inflammation, oxidative stress, and impaired vascular remodelling may contribute towards an accelerated decline in the function of cerebral and peripheral vascular systems. Historically, hormone therapy (HT) has been used as a means of managing vascular disease risk and reducing menopause-associated vasomotor symptoms such as hot flushes, though some studies suggest regular exercise has the potential to be a promising alternative. Regular aerobic exercise during early postmenopause may slow vascular decline by improving NO and oestradiol bioavailability, promoting positive vascular remodelling and lowering systemic inflammation. However, exercise-mediated improvements in markers of vascular function are not consistently observed in oestradiol-deficient postmenopausal women. Emerging evidence suggests that due to the greater oestradiol bioavailability during early postmenopause, vascular adaptations to exercise may be enhanced during this stage, as opposed to late postmenopause. Subsequently it may be important to begin regular exercise in the years preceding and immediately following the final menstrual period to slow the progression of vascular disease risk during perimenopause and beyond. The present review will provide a summary of our current understanding of how vascular function is affected during menopause and the role of regular aerobic and resistance exercise training in managing vascular disease risk.

The Role of Platelets in Atherosclerosis: A Historical Review.

Atherosclerosis is a chronic, multifactorial inflammatory disorder of large and medium-size arteries, which is the leading cause of cardiovascular mortality and morbidity worldwide. Although platelets in cardiovascular disease have mainly been studied for their crucial role in the thrombotic event triggered by atherosclerotic plaque rupture, over the last two decades it has become clear that platelets participate also in the development of atherosclerosis, owing to their ability to interact with the damaged arterial wall and with leukocytes. Platelets participate in all phases of atherogenesis, from the initial functional damage to endothelial cells to plaque unstabilization. Platelets deposit at atherosclerosis predilection sites before the appearance of manifest lesions to the endothelium and contribute to induce endothelial dysfunction, thus supporting leukocyte adhesion to the vessel wall. In particular, platelets release matrix metalloproteinases, which interact with protease-activated receptor 1 on endothelial cells triggering adhesion molecule expression. Moreover, P-selectin and glycoprotein Ibα expressed on the surface of vessel wall-adhering platelets bind PSGL-1 and β2 integrins on leukocytes, favoring their arrest and transendothelial migration. Platelet-leukocyte interactions promote the formation of radical oxygen species which are strongly involved in the lipid peroxidation associated with atherosclerosis. Platelets themselves actively migrate through the endothelium toward the plaque core where they release chemokines that modify the microenvironment by modulating the function of other inflammatory cells, such as macrophages. While current antiplatelet agents seem unable to prevent the contribution of platelets to atherogenesis, the inhibition of platelet secretion, of the release of MMPs, and of some specific pathways of platelet adhesion to the vessel wall may represent promising future strategies for the prevention of atheroprogression.

A Combined Extract Derived from Black Sticky Rice and Dill Improves Clinical Symptoms and Ischemic Stroke Biomarkers in Transient Ischemic Attack and Ischemic Stroke Patients.

Currently, the adjuvant therapy to optimize the restorative process after stroke is required due to the unsatisfied therapeutic efficacy. A combined extract of black sticky rice and dill showed potential in the preclinical state, so we hypothesized that it could provide clinical benefits. A three-arm, randomized, placebo-controlled study was set up to elucidate this issue. Both males and females (18-80 years old) who had experienced transient ischemic attacks or ischemic strokes within the last 5-10 days with an NIHSS score ≤ 7 and received standard treatment were randomly assigned to receive either a placebo or capsule containing a combined extract of black sticky rice and dill at a dose of 600 or 1200 mg per day. The safety parameters, movement control, and degree of disability were assessed 1, 2, and 6 weeks after the intervention, and serum stroke biomarkers were assessed at the mentioned time points, except at 2 weeks. After week 1, the high-dose (1200 mg/day) treatment group had improved NIHSSS, VCAM1, and MMP-9. Both S100β and VCAM1 also improved at week 6, while the low-dose treatment group (600 mg/day) only exhibited improved VCAM1. Therefore, a high dose of the developed adjuvant supplement improves stroke recovery by improving motor impairment by reducing endothelial dysfunction and inflammation.

Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO's aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe-TMAO pathway.

Untargeted Urinary Volatilomics Reveals Hexadecanal as a Potential Biomarker for Preeclampsia.

Preeclampsia (PE) is a severe hypertensive pregnancy disorder characterized by endothelial dysfunction, placental ischemia and oxidative stress; however, reliable non-invasive biomarkers for early detection are limited. In this study, untargeted solid-phase microextraction with gas chromatography-mass spectrometry (SPME-GC-MS) was used to analyze volatile organic compounds in the urine of 45 women with PE and 46 healthy controls. Among the 29 metabolites identified, hexadecanal-a product of lipid peroxidation and sphingolipid metabolism-was found to be the most significant, with an area under the receiver operating characteristic (ROC) curve of 0.618, highlighting its diagnostic potential. This result emphasizes the role of hexadecanal in oxidative stress and placental dysfunction, which are central to the pathophysiology of PE. The results support hexadecanal as a potential non-invasive biomarker while demonstrating the efficacy of SPME-GC-MS in identifying metabolic disorders associated with PE, paving the way for further research to confirm its clinical utility for early diagnosis and risk assessment.

Relative protective activities of avenanthramide A, B, and C against H2O2-induced endothelial dysfunction in EA.hy926 cells.

This study compared the antihypertensive effects of avenanthramides A, B, and C, with a focus on their antioxidant and anti-inflammatory properties. Treatment with avenanthramides A, B, and C (50μM) significantly enhanced cell viability and nitric oxide production in H2O2-induced endothelial dysfunction in EA.hy926 cells. Avenanthramides notably increased the levels of antioxidant enzymes and glutathione while reducing malondialdehyde and reactive oxygen species. Moreover, avenanthramides promoted the Nrf2 translocation to nucleus, enhancing the expression of antioxidant enzymes. Furthermore, avenanthramides inhibited the protein levels of iNOS and COX-2, as well as the phosphorylation of IkBα and translocation of p65, thereby mitigating endothelial inflammation. Molecular docking analysis revealed that avenanthramide A exhibited the strongest binding affinity for HO-1 and iNOS, which was correlated with its superior biological activity. Overall, by upregulating Nrf2/HO-1 pathways and downregulating NF-kB pathways, avenanthramides show potential as therapeutic agents for the treatment of endothelial dysfunction.

The Effects of SGLT2 Inhibitors on Blood Pressure and Other Cardiometabolic Risk Factors.

Beyond their established hypoglycemic, cardioprotective, and nephroprotective properties, sodium-glucose cotransporters 2 (SGLT2) inhibitors exert other pleiotropic actions on blood pressure levels, body weight, and lipid metabolism. Blood pressure (BP) reduction varies based on the background history, including an effect on systolic, diastolic BP, and 24 h BP measurements. The reduction in body weight between 1 and 2 kg for the first months is caused by a reduction in visceral and subcutaneous fat due to glycosuria and loss of calories. Regarding lipid metabolism, a reduction in triglycerides and an increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, although these alterations are small and could provide additional cardiovascular protection. Various pathophysiologic mechanisms have been proposed to explain the above-mentioned pleiotropic actions of SGLT2 inhibitors. Natriuresis, osmotic diuresis, body weight reduction, amelioration of endothelial dysfunction and arterial stiffness, sympathetic tone decrease, and uric acid reduction are among those that have been suggested for BP reduction. Apart from glycosuria and calorie loss, other mechanisms seem to contribute to body weight reduction, such as the beiging of white adipose tissue, while the mechanisms involved in lipid metabolism alterations have not been clearly determined.