Endothelial Protective Effects Research Articles

Sodium-glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19. Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442. Three eligible trials randomly assigned 6096 participants (3025 to the SGLT2 inhibitor group and 3071 to the usual care or placebo group). 2381 (39%) patients were women and 1547 (25%) had type 2 diabetes at randomisation. By 28 days, there were 351 deaths in the SGLT2 inhibitor group and 382 deaths in the usual care or placebo group (summary OR 0·93 [95% CI 0·79-1·08]; p=0·33, I2 for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group. Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19. None.

Liraglutide ameliorates high glucose-induced vascular endothelial injury through TRIB3/NF-κB signaling pathway.

As one of the most commonly used antidiabetic medications clinically, liraglutide is involved in the protection of vascular endothelium, and whether it can relieve high glucose-induced vascular endothelial damage was unknown. This study aims to address the response of liraglutide (LIRA) on human umbilical vein endothelial cells, as well as to elucidate its possible underlying mechanism. We established a vascular endothelial cell injury model by exposing human umbilical vein endothelial cells (HUVECs) to high glucose, and used LIRA pretreatment before HG treatment to address the endothelial protective effect of LIRA. Our results suggest that LIRA prevented HG-induced HUVEC apoptosis, oxidative stress, inflammasome activation, and pyroptosis. Furthermore, silencing of tribbles homolog 3 (TRIB3) could markedly reduce HG-induced HUVEC apoptosis, ROS level, the expressions of TXNIP, cleaved caspase3, NLRP3, and caspase1, indicating TRIB3 inhibition protected HUVECs against HG-induced vascular endothelial injury. In addition, LIRA restrained NF-κB/IκB-α signaling pathway activation in HUVECs. Thus, LIRA appears to mitigate HG-induced apoptosis, oxidative stress, inflammasome activation, and pyroptosis in HUVECs via regulating the TRIB3/NF-κB/IκB-α signaling pathway. Our study provides new insight into the mechanisms underlying the protective activity of LIRA against the vascular endothelial injury in diabetic vascular complication.

X-Paste improves wound healing in diabetes via NF-E2-related factor/HO-1 signaling pathway

BACKGROUND Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP’s main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP’s treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2 ) knockdown elucidated Andro’s molecular mechanisms. RESULTS XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2 /HO-1 pathway activation, with Nrf2 knockdown reducing Andro’s proliferative and endothelial protective effects. CONCLUSION XP significantly promotes wound healing in STZ-induced diabetic models. As XP’s key component, Andro activates the Nrf2 /HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.

Unlocking Vitality: A Comprehensive Review of Vitamin D's Impact on Clinical Outcomes in Critically Ill Children.

This comprehensive review explores the multifaceted role of vitamin D (VD) in critically ill children, examining its implications for clinical outcomes. Although this substance has long been known for its function in maintaining bone health, it is now becoming more widely known for its extensive physiological effects, which include immune system and inflammation regulation. Observational research consistently associates VD levels with outcomes like duration of hospitalization, mortality, and illness severity in critically ill pediatric patients. Mechanistically, it exerts anti-inflammatory and endothelial protective effects while modulating the renin-angiotensin system. Increasing VD levels through supplementation presents promise as a therapeutic strategy; however, further research is necessary to elucidate optimal dosage regimens and safety profiles. This review emphasizes the significance of comprehending the intricate relationship between VD and critical illnesses among pediatric populations.

The role of FPR2-mediated ferroptosis in formyl peptide-induced acute lung injury against endothelial barrier damage and protective effect of the mitochondria-derived peptide MOTS-c

BackgroundAcute lung injury (ALI) has garnered significant attention in the field of respiratory and critical care due to its high mortality and morbidity, and limited treatment options. The role of the endothelial barrier in the development of ALI is crucial. Several bacterial pathogenic factors, including the bacteria-derived formyl peptide (fMLP), have been implicated in damaging the endothelial barrier and initiating ALI. However, the mechanism by which fMLP causes ALI remains unclear. In this study, we aim to explore the mechanisms of ALI caused by fMLP and evaluate the protective effects of MOTS-c, a mitochondrial-derived peptide. MethodsWe established a rat model of ALI and a human pulmonary microvascular endothelial cell (HPMVEC) model of ALI by treatment with fMLP. In vivo experiments involved lung histopathology assays, assessments of inflammatory and oxidative stress factors, and measurements of ferroptosis-related proteins and barrier proteins to evaluate the severity of fMLP-induced ALI and the type of tissue damage in rats. In vitro experiments included evaluations of fMLP-induced damage on HPMVEC using cell activity assays, assessments of inflammatory and oxidative stress factors, measurements of ferroptosis-related proteins, endothelial barrier function assays, and examination of the key role of FPR2 in fMLP-induced ALI. We also assessed the protective effect of MOTS-c and investigated its mechanism on the fMLP-induced ALI in vivo and in vitro. ResultsResults from both in vitro and in vivo experiments demonstrate that fMLP promotes the expression of inflammatory and oxidative stress factors, activates ferroptosis and disrupts the vascular endothelial barrier, ultimately contributing to the development and progression of ALI. Mechanistically, ferroptosis mediated by FPR2 plays a key role in fMLP-induced injury, and the Nrf2 and MAPK pathways are involved in this process. Knockdown of FPR2 and inhibition of ferroptosis can attenuate ALI induced by fMLP. Moreover, MOTS-c could protect the vascular endothelial barrier function by inhibiting ferroptosis and suppressing the expression of inflammatory and oxidative stress factors through Nrf2 and MAPK pathways, thereby alleviating fMLP-induced ALI. ConclusionOverall, fMLP disrupts the vascular endothelial barrier through FPR2-mediated ferroptosis, leading to the development and progression of ALI. MOTS-c demonstrates potential as a protective treatment against ALI by alleviating the damage induced by fMLP.

Correction of endothelial dysfunction in patients with type 2 diabetes mellitus, diabetic kidney disease and non-alcoholic steatohepatitis

Background. Non-alcoholic fatty liver disease and chronic kidney disease are public health concerns worldwide due to their increasing prevalence, adverse prognosis, and health care burden. The purpose of the study was to determine the probable effect of a combination of metformin, rosuvastatin, essential phospholipids and quercetin on the blood lipids, endothelial function, fibrinolysis system and platelet hemostasis, which are factors for the progression of nonalcoholic steatohepatitis. Materials and methods. Studies were performed on the dynamics of treatment in 60 patients with non-alcoholic fatty liver disease, type 2 diabetes mellitus and diabetic kidney disease (stage I–III). Depending on the prescribed treatment at random, the examined patients were divided into 2 groups. Twenty-eight persons of the first group received a low-calorie diet with dietary restrictions, essential phospholipids, metformin hydrochloride, rosuvastatin. Thirty-two patients from the second group received quercetin in addition to similar dietary recommendations, essential phospholipids, hypoglycemic and hypolipidemic therapy. The mean age of patients was 53.80 ± 3.52 years. The comparison group consisted of 30 healthy individuals of the corresponding age. Results. To evaluate the degree of endothelial-protective effect of quercetin on the background of the recommended protocol therapy, markers of endothelial dysfunction, fibrinolysis and platelet hemostasis were studied. NO content significantly reduced (1.7 times) in patients of group 2 before treatment, increased by 1.5 times (p < 0.05). This can be explained by the effect of quercetin, as well as the use of metformin, which reduces the degree of insulin resistance and the level of hyperlipidemia. Conclusions. The effectiveness of a combination therapy for non-alcoholic steatohepatitis and type 2 diabetes mellitus with diabetic kidney disease using essential phospholi­pids, statins and metformin with the addition of quercetin is higher than that of traditional therapy, as it significantly restores the functional state of the endothelium, eliminates the phenomena of hypercoagulation syndrome without the additional prescription of antiplatelet agents.

Dapagliflozin alleviates high glucose-induced injury of endothelial cells via inducing autophagy.

Hyperglycaemia is a key factor in the progression of diabetes complications. Dapagliflozin (DAPA), a new type of hypoglycaemicagent, has been shown to play an important role in anti-apoptotic, anti-inflammatory and antioxidant activities. Previous studies have demonstrated an endothelial protective effect of DAPA, but the underlying mechanism was still unclear. Autophagy is a homeostatic cellular mechanism that circulates unfolded proteins and damaged organelles through lysosomal dependent degradation. In this study, we aimed to investigate whether DAPA plays a protective role against high glucose (HG)-induced endothelial injury through regulating autophagy. The results showed that DAPA treatment resulted in increased cell viability. Additionally, DAPA treatment decreased interleukin (IL)-1β, IL-6, and tumour necrosis factor-α levels in endothelial cells subjected to HG conditions. We observed that HG inhibited autophagy, and DAPA increased the autophagy level by inhibiting the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway. Chloroquine reversed all of these beneficial effects as an autophagy inhibitor. In summary, the endothelial protective effect of DAPA in HG can be attributed in part to its role in activating of autophagy via the AKT/mTOR signalling pathway. Therefore, suggesting that the activation of autophagy by DAPA may be a novel target for the treatment of HG-induced endothelial cell injury.

Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study

BackgroundAlbumin has potential endothelial protective effects through antioxidant and anti-inflammatory properties. However, the effect of albumin on peripheral tissue perfusion in human sepsis remains poorly known.MethodsBi-centric prospective study included patients with sepsis with or without shock and prolonged CRT > 3 s despite initial resuscitation. Clinicians in charge of the patients were free to infuse either saline 500 mL or human serum albumin 20% 100 mL over 15 min. Global hemodynamic parameters as well as peripheral tissue perfusion were analyzed after 1 (H1) and 4 h (H4). The primary endpoint was CRT normalization (< 3 s) at H1.Results62 patients were screened, and 50 patients (13 sepsis and 37 septic shock) were included, 21 in the saline group and 29 in the albumin group. SOFA score was 8 [5–11], and SAPS II was 53 [45–70]. Median age was 68 [60–76] years with a higher proportion of men (74%). The primary sources of infection were respiratory (54%) and abdominal (24%). At baseline, comorbidities, clinical and biological characteristics were similar between groups. At H1, CRT normalization (< 3 s) was more frequent in patients receiving albumin as compared to patients treated by saline (63 vs 29%, P = 0.02). The decrease in fingertip CRT was more important in the albumin group when compared to saline group (− 1.0 [− 0.3; − 1.5] vs − 0.2 [− 0.1; − 1.1] seconds, P = 0.04) as well as decrease in mottling score. At H4, beneficial effects of albumin on peripheral tissue perfusion were maintained and urinary output trended to be higher in the albumin group (1.1 [0.5–1.8] vs 0.7 [0.5–0.9] ml/kg/h, P = 0.08). Finally, arterial lactate level did not significantly change between H0 and H4 in the saline group but significantly decreased in the albumin group (P = 0.03).ConclusionIn patients with resuscitated sepsis, albumin infusion might lead to greater improvement of tissue hypoperfusion compared to saline. ClinicalTrials.gov Identifier: NCT05094856.

Studying the possibilities of pharmacological correction of hypoxia-induced pulmonary hypertension using a phenolic compound with a laboratory cypher KUD975

The aim of our work was to study a pharmacological activity of a selective arginase-2 and thrombin inhibitor from a phenolic compounds group with a laboratory cypher KUD975 on a model of arterial pulmonary hypertension induced by hypoxia.Materials and methods. To simulate pulmonary hypertension (РН), animals were placed in a normobaric hypoxic chamber and subjected to 5 weeks of hypoxia with an oxygen content of 10% in the air. After 3 weeks of hypoxia, the animals were administered with the test compound KUD975 (intragastrically, at a dose of 2 mg/kg once a day for 2 weeks). L-norvaline (intragastrically, 20 mg/kg) was used as a reference drug. To assess the development and correction of РН, measurements of cardiohemodynamics, analysis of blood gas composition, study of the number of circulating endothelial precursor cells (EPCs), quantitative PCR assessing the expression of mRNA VEGF-R2, SGF-1 (stromal growth factor-1) and MCP-1 (monocyte chemoattractant protein-1). Next, a histological examination of the lungs and heart was performed, the degree of pulmonary edema and the concentration of cardiotrophin-1 and atrial natriuretic peptide were assessed.Results. The administration of the studied phenolic compound with laboratory cypher KUD975, as well as the reference drug L-norvaline, led to a decrease in the right ventricular systolic pressure against the background of modeling РН. The present study shows a more than twice-fold decrease in the number of circulating (EPCs) in the animals group with modeling a hypoxia-induced circulatory РН (171.3±12.1) in comparison with the group of intact animals (296.1±31.7; p=0.0018). The recovery of EPCs was noted in the animals group administered with KUD-975 and L-norvaline, up to 247.5±34.2 (p=0.0009 compared with a pulmonary arterial hypertension (PAH) and 235.6±36.4 (p=0.008 compared to PAH), respectively. The studied compounds had a protective effect by statistically significantly increasing the expression of VEGF-R2 mRNA and decreasing the expression of SGF-1 mRNA, reducing the lung moisture coefficient and the concentrations of cardiotrophin-1 and atrial natriuretic peptide and preventing vascular remodeling caused by hypoxia.Conclusion. When studying the pharmacological activity, it was shown that the phenolic compound with the laboratory cypher KUD975 normalizes hemodynamic parameters, reduces the signs of remodeling of the heart and pulmonary vessels and has a pronounced endothelial protective effect on the model of hypoxia-induced РН, and is superior to the activity of the reference drug L-norvaline.

Alleviation of endothelial dysfunction of Pheretima guillemi (Michaelsen)-derived protein DPf3 in ponatinib-induced thrombotic zebrafish and mechanisms explored through ox-LDL-induced HUVECs and TMT-based proteomics

Ethnopharmacological relevanceThrombus generation is one of the leading causes of death in human, and vascular endothelial dysfunction is a major contributor to thrombosis. Pheretima guillemi (Michaelsen), a traditional medicinal animal known as “Dilong”, has been utilized to cure thrombotic disorders for many years. DPf3, a group of functional proteins extracted from P. guillemi, has been characterized and identified to possess antithrombotic bioactivity via in vitro and ex vivo experiments. Aim of the studyThis study is aimed to investigate the vascular-protection activity and related mechanism of antithrombotic protein DPf3 purified from Pheretima guillelmi systematically. Materials and methodsThe antithrombotic activity and vascular endothelium protection effect of DPf3 was explored in vivo using ponatinib-induced vascular endothelial injury zebrafish thrombus model. Then, (hi) ox-LDL-induced HUVECs was applied to investigate the protection mechanism of DPf3 against the injury of vascular endothelium. In addition, TMT-based proteomics analysis was used to study the biomarkers, biological processes and signal pathways involved in the antithrombotic and vascular protective effects of DPf3 holistically. ResultsDPf3 exerted robust in vivo antithrombosis and vascular endothelial protection ability. DPf3 was identified to prevent HUVECs from damage by reducing ROS production, and to reduce monocyte adhesion by decreasing the protein content of adhesion factor VCAM 1. DPf3 was also observed to weaken the migration ability of injured cells and inhibit abnormal angiogenesis. The mechanism of DPf3's antithrombotic and vascular protective activity was mainly related to the regulation of lipid metabolism, energy metabolism, complement and coagulation system, ECM receptor interaction, MAPK signal pathway, etc. ConclusionsThis study demonstrates that DPf3 has strong antithrombotic and endothelial protective effects. The endothelial protective ability and related mechanisms of DPf3 provide a scientific reference for the traditional use of earthworms in the treatment of thrombosis.

Peculiarities of paravulvar microcirculation in skin and muscle in blast wound in variants of early local injection of reparative active agent

Introduction. A promising method of correcting microcirculatory disorders in the area of soft tissue injury is the use of agents with antihypoxant action, which include deproteinized calf-blood hemoderivate.The aim of the work was to reveal the peculiarities of subcutaneous and intramuscular local injection of deproteinized calfblood hemoderivate on the changes of microcirculation in the skin and muscles in the experimental blast wound area.Materials and methods. The experiments were performed on 90 male Wistar rats weighing (320±20) g in compliance with international rules of work with laboratory animals. Modeling of an explosive wound of the soft tissues of the femur with mild degree of blood loss was carried out according to the original author’s method (Patent RU No. 2741238 dated 22.01.2021). After primary surgical treatment was performed paravulnarly, deproteinized calf-blood hemoderivate was injected intramuscularly, intramuscularly and subcutaneously (Actovegin drug) once in six points with an insulin syringe. Microcirculation in the skin and muscles of the injured area was assessed by laser Doppler flowmetry using the device LAKK-M (Russia). To determine the normal values of microcirculation, data obtained from healthy animals were used.Results. Local intramuscular injection into the paravular area resulted in an increase of the constant perfusion component (M) by 24.1−35.9 % (p &lt; 0.05) and by 18.0−56.4 % (p &lt; 0.05) in the skin and muscles during all periods of observation, an increase of the variable perfusion component (σ) in the skin by 31.4−38.0 % (p &lt; 0.05) during 28 days and in muscles by 8.8−58.7 % (p &lt; 0.05) during the first 14 days only, increase of Kv ratio in skin by 12.4 % (p = 0.01) early after injury (7 days) and decrease in muscles by 18.3−20.8% (p &lt; 0.05) at 14−28 days. Local combined administration (intramuscularly and subcutaneously) of the drug around the wound promoted the increase of the constant perfusion component (M) in the skin by 23.8 % (p = 0.005) and 6.9 % (p = 0.01) at the 7th and 28th days of observation, increase of σ index in skin by 14.2−45.1 % (p &lt; 0.007) on the 7−14 days and its decrease in muscles by 15.7 % (p = 0.009) by the end of the 7th day of observation in comparison with animals after only intramuscular injection only. Also, the coefficient of variation (Kv) with the combined route of injection was increased in the skin by 8.8−23.8 % (p &lt; 0.009) in the first 14 days and decreased in the muscles by 15.7 % (p = 0.008) in the early period after injury (7 days) relative to its values in animals with intramuscular injection.Discussion. The results of the study allow noting the stimulating effect of deproteinized calf-blood hemoderivate on neovasculogenesis in the damaged tissues, which can be judged by the increase in the constant perfusion component (M). In addition, we can conclude that the direct endothelium-protective effect of the drug consists in the modulation of microcirculatory flow, which confirms the significant increase in the variable perfusion component (σ) throughout the experiment.Conclusion. Local paravular administration of deproteinized calf-blood hemoderivate in experimental blast wound promotes microcirculation increase in the soft tissues of the injury area. Combined (intramuscular and subcutaneous) local paravular injection of the drug allows more effective stimulation of microcirculation in the skin and muscles of the injury area.

Role of Defibrotide in the Prevention of Murine Model Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vascular endothelial cells are entirely exposed and damaged during the pathogenesis of acute GVHD. Defibrotide is a mixture of single-stranded oligonucleotides that has several pharmacological effects that contribute to its endothelial protective properties. B10.BR mice were conditioned followed by the infusion of donor C57BL/6J T-cell depleted (TCD) bone marrow cells with or without splenocytes. Animals were either treated with defibrotide or appropriate controls daily for the first week and then three times per week thereafter. Allogeneic defibrotide-treated recipients demonstrated significantly better survival with reduced clinical GVHD. Significantly reduced organ pathology in the gut was associated with significantly decreased T-cell infiltration in the ileum and colon on day +28. Serum cytokine analysis revealed significantly reduced level of TNF and IL-6 at day +7 and TNF at day +28 in allogeneic defibrotide treated recipients. Significantly reduced levels of ICAM-1, Angiopoietin-2 in serum and reduced VCAM-1 and HCAM in the ileum and colon of allogeneic defibrotide-treated recipients were observed. Improved survival was seen in the GVL model (C3H.SW into C57BL/6J mice with C1498-luc). Defibrotide treatment through its anti-inflammatory and endothelial-protective effects reduces the severity of acute GVHD, while not impairing GVL activity.

Nutraceutical support in the prevention and treatment of cardiovascular diseases

Cardiovascular disease is the most common cause of death worldwide. In this regard, there is a need to find and implement effective methods for the prevention and treatment of such diseases. Lifestyle modification is an important component of a complex of preventive and therapeutic measures, including nutrition optimization, increased physical activity, and breaking bad habits. Currently, an actively developing area is the use of biologically active additives to food, in order to replenish the missing nutrients in the diet and maintain health. In the course of the present review, an analysis was made of randomized clinical trials performed over the past 5 years. The studies investigated both the short-term effects of taking omega-3 polyunsaturated fatty acids (effect on the blood lipid spectrum, blood pressure levels) and longterm results (development of myocardial infarction, stroke, cardiovascular mortality). This supplement has demonstrated a positive effect on immediate outcomes, namely the reduction of total cholesterol, low-density lipoprotein, triglycerides (lipid-lowering effect). However, there was no significant effect on long-term results. It also provides information on studies that have examined the cardioprotective effects of supplements such as resveratrol, red yeast rice, L-arginine, and curcumin. An analysis of publications has shown that these supplements have the potential to reduce the risk of development and progression of cardiovascular diseases due to possible hypolipidemic, endothelial protective, and antihypertensive effects. Nutraceutical support can be an effective addition to the basic treatment and help reduce morbidity and mortality due to cardiovascular disease.

Agext and Its Active Compounds as Potential Therapeutic Prevention against Atherosclerosis and Cardiovascular Disease

Advanced Glycation End-Products (AGEs) have been implicated in the chronic complications of Diabetes Mellitus (DM) and play an important role in the pathogenesis of atherosclerosis in human arteries. The main active compounds found in Aged Garlic Extract (AGExt) are S-Allyl Cysteine (SAC), N-Acetylcysteine (NAC) and S-allyl Mercaptocysteine (SAMC) and have powerful protective effects against oxidative stress and inhibit cellular damage by AGEs. Aims: To explore the effect of AGExt on the development of atherosclerosis also investigated the endothelial protective effects of AGExt, using Human Coronary Artery-Derived Endothelial Cells (HCAEC). The use of an optimised mixture of the above compounds required to obtain and provide maximal beneficial effects against oxidative stress, cell apoptosis and protein glycation. Results: AGExt has protective effects against the cellular damage of HCAEC. In addition, the in vivo study accessed the activity of SAC and NAC to reduce the severity of atherosclerosis formation in Apolipoprotein (ApoE-/-) DM model mouse. The compounds of AGExt in vitro had strong protective actions against the AGEs induced damage to ECs even at low concentrations (100 ng/ml). Such low concentrations may have therapeutic usefulness in patients with diabetes.

Reduction of the risk of failure to achieve blood pressure control in patients with arterial hypertension and coronary heart disease: the role of quercetin

Aim. Determine the effect of quercetin on predictors of not reaching target blood pressure (BP) levels in patients with arterial hypertension (AH) and coronary heart disease (CHD). Materials and methods. 120 patients with stable coronary heart disease and hypertension of the II stage 2–3 degrees (66 women and 54 men) were examined. The patients were divided into 2 groups: Group I – 58 patients who, in addition to basic therapy (ramipril/amlodipine), received quercetin (Corvitin®), Group II – 62 patients who received only basic antihypertensive therapy. The parameters of daily blood pressure monitoring, blood lipid spectrum, C-reactive protein, the concentration of adhesion molecules (s-VCAM, s-ICAM-1), levels of endothelin-1 (ET-1), IL-1, IL-6, TNF-α were determined. Statistical processing of materials was carried out using the following programs: Minitab 21.0, StatPlus Pro 7.6.5, Wizard Pro, Jamovi, MedCalc. Results. We have established that the risk of not reaching the target level of daily SBP in the group of basic treatment of hypertension (group II) significantly increases with exceeding the level of LDL &gt;4.0 mmol/l (by 3.6 times), an increase in the level of IL-6 &gt;7 ng/ml (by 10 times), an increase in the level of TNF-α &gt;9 pg/ml (by 7 times), an increase in the level of VCAM &gt;1100 ng/ml (by 2.4 times). In the group of people who additionally took quercetin (group I), with an increase in the level of ET-1 &gt;1.1 pg/ml, the risk of failure to reach the target SBP increases by 2.6 times, in the II group – by 3.5 times toward to daily SBP and 8.6 times – toward to daily DBP. We found out that an increase in the concentration of IL-6 &gt; 7 ng/mg significantly increases the risk of arrhythmias by 6 times in group II. Conclusions. When quercetin is used, it is possible to achieve the target values of SBP (daily, daytime, nighttime) and DBP (daily, daytime, nighttime) in a significantly higher proportion of patients compared with those who are prescribed only standard antihypertensive therapy. Quercetin has an endothelial protective effect, as evidenced by a significant decrease in the levels of vascular endothelial adhesion molecules (s-VCAM), type I intercellular adhesion molecules (s-ICAM-1), ET-1, IL-1, IL-6, TNF-α. The additional use of quercetin against the background of standard antihypertensive therapy significantly reduces the risk of failure to achieve the target levels of SBP, DBP and the risk of heart rhythm disturbances even against the background of increased levels of proinflammatory cytokines and markers of endothelial dysfunction.

Statin Therapy After Myocardial Infarction in Patients With Renal Failure: The Longer, the Merrier!

Among the ongoing clinical challenges for cardiologists in the 21 th century, there is the necessity of being able to cope with multimorbidity and polypharmacy. Irrespectively, beneficial drugs should be continued long-term, to ensure mortality and morbidity benefits continue to be accrued. This is evidently the case for the use of statins to improve long-term outcomes in chronic kidney disease (CKD) patients with acute coronary syndromes (ACS), as the combination of CKD and ACS represents a veritable crucible of adverse risk factors. Furthermore, statins have pleiotropic effects, including anti-inflammatory, antioxidant and endothelial-protective effects. Even though these effects are debated in CKD patients, it is biologically plausible that statins may reduce the inflammatory burden and improve glomerular hemodynamics. Awaiting for further clinical studies, for instance focused on the identification of possible biomarkers of statins action on renal function, it is pivotal to maintain our CKD patients with history of ACS on lifesaving medications such as statins.

Allii Macrostemonis Bulbus: A Comprehensive Review of Ethnopharmacology, Phytochemistry and Pharmacology.

The dried bulbs of Allii Macrostemonis Bulbus (AMB) are called "" in China and are mainly distributed in Asia. The plant species included in the 2020 Edition of the Chinese Pharmacopoeia (ChP) are Allium macrostemon Bunge (called xiaogensuan in Chinese, A. macrostemon) and Allium chinense G. Don (called xie in Chinese, A. chinense), respectively. In the traditional Chinese medicine (TCM) theoretical system, AMB is warm in nature, acrid-bitter taste, and attributive to the heart, lung, stomach, large intestine meridian. AMB has the function of activating Yang and removing stasis, regulating Qi and eliminating stagnation. Modern pharmacological studies have shown that AMB has anti-platelet aggregation, hypolipidemic, anti-atherosclerotic, cardiomyocyte, vascular endothelial cell protection, anti-cancer, anti-bacterial, anti-asthmatic, and anti-oxidant effects. In some Asian countries, AMB is often used to treat coronary heart disease (CHD), angina pectoris (AP), asthma, and diarrhea. This review collates the botanical background, ethnopharmacology, phytochemistry, pharmacological activities, quality control, and toxicological studies of AMB, and provides an outlook on the current research deficiencies and future research priorities of AMB, intending to provide ideas for future research directions and commercial development.

The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (β = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

Quince extract resists atherosclerosis in rats by down-regulating the EGFR/PI3K/Akt/GSK-3β pathway

We identified the effective components and the underlying mechanisms of Quince (Cydonia oblonga Mill, COM) extract against atherosclerosis. The effective components of COM extract were identified with UHPLC-Q-TOF-MS/MS. Network pharmacology was performed. A rat model of atherosclerosis induced by high-fat emulsion combined with vitamin D3 was established. The anti-atherosclerosis effect of COM extract was evaluated from various aspects such as blood lipid regulation, anti-oxidative stress, anti-inflammatory response, and vascular protection function. We identified 14 serum components of COM extract using UHPLC-Q-TOF-MS/MS. Through prediction, 573 targets were obtained, among which 224 targets were atherosclerosis specific targets. The key targets included GSK3β, ESR1, EGFR, and HSP90AA1. The key signaling pathway was PI3K-Akt signaling pathway. Pharmacodynamics analysis showed that COM extract reduced the levels of TC, TG, and LDL-C as well as ALT and AST, while increased the level of HDL-C. Mechanistically, COM extract significantly increased serum SOD and GSH-Px activities, but decreased MDA content in atherosclerosis rats, showing antioxidant effects. Meanwhile, COM extract significantly down-regulated the levels of pro-inflammatory factors IL-1β, IL-6, TNF-α and CRP, but up-regulated anti-inflammatory factor IL-10. Additionally, COM extract increased the levels of NO, eNOS, and 6-keto-PGF1α; whereas, decreased the levels of ET-1 and TXB2. Furthermore, COM extract significantly inhibited the mRNA and protein levels of EGFR, p-PI3K, p-AKT, GSK-3β, Bax, and Caspase-3 as well as the Bax/Bcl-2 ratio. Conclusively, COM extract exerts hypolipidemic, anti-oxidative, anti-inflammatory, anti-thrombotic and vascular endothelium protective effects on atherosclerosis rat model, which may be related to the inhibition of EGFR/PI3K/AKT/GSK-3β signaling pathway.

Comparative Study of Different H2S Donors as Vasodilators and Attenuators of Superoxide-Induced Endothelial Damage.

In the last years, research proofs have confirmed that hydrogen sulfide (H2S) plays an important role in various physio-pathological processes, such as oxidation, inflammation, neurophysiology, and cardiovascular protection; in particular, the protective effects of H2S in cardiovascular diseases were demonstrated. The interest in H2S-donating molecules as tools for biological and pharmacological studies has grown, together with the understanding of H2S importance. Here we performed a comparative study of a series of H2S donor molecules with different chemical scaffolds and H2S release mechanisms. The compounds were tested in human serum for their stability and ability to generate H2S. Their vasorelaxant properties were studied on rat aorta strips, and the capacity of the selected compounds to protect NO-dependent endothelium reactivity in an acute oxidative stress model was tested. H2S donors showed different H2S-releasing kinetic and produced amounts and vasodilating profiles; in particular, compound 6 was able to attenuate the dysfunction of relaxation induced by pyrogallol exposure, showing endothelial protective effects. These results may represent a useful basis for the rational development of promising H2S-releasing agents also conjugated with other pharmacophores.