An investigation of the antiplatelet effects of succinobucol (AGI-1067)

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet–platelet and platelet–vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10−5–10−4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress

Effect of early clinical skills teaching on 3rd year medical students' learning: The student perspective

AbstractObjectivesThe main purpose of the early introduction of Clinical Skills Learning (CSL) to pre-clinical years is to allow medical students to gain experience in clinical examination skills, basic medical procedures, history-taking and clinical communication. The objective of this study was to determine the effectiveness of the early teaching of clinical skills in preparing medical students for their clinical years.MethodsA validated questionnaire assessing the value of CSL on students in their first clinical year was distributed to 3rd year medical students. The questionnaire consisted of 8 items with a five-point Likert scale and one open-ended question.ResultsThe response rate to the questionnaire was approximately 62%. Nearly 97 (70.8%) students suggested that CSL was a favourable teaching strategy. A high percentage of students (90.5%) agreed that CSL was a useful pre-clinical module to prepare them for their clinical years. The students gave positive feedback on the teaching of history-taking and physical examination, exposure to the hospital environment and acquisition of communication skills with supervisors and patients. No student perceived the CSL module as poor.ConclusionsEarly CSL was well-perceived by students in preparing them for their clinical years. CSL is a vital part of the pre-clinical curriculum and should be further enriched with frequent hospital visits to enhance students' confidence level and performance when interacting with patients during their clinical years

Piper sarmentosum inhibits ICAM-1 and Nox4 gene expression in oxidative stress-induced human umbilical vein endothelial cells

<p>Abstract</p> <p>Background</p> <p>Aqueous extract of <it>Piper sarmentosum </it>(AEPS) is known to possess antioxidant and anti-atherosclerotic activities but the mechanism responsible for it remains unclear. In early part of atherosclerosis, nuclear factor-kappa B (NF-κB) induces the expression of cellular adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin. NADPH oxidase 4 (Nox4) is the predominant source of superoxide in the endothelial cells whereas superoxide dismutase 1 (SOD1), catalase (CAT) and glutathione peroxidase (GPx) are the antioxidant enzymes responsible for inactivating reactive oxygen species. The present study aimed to investigate the effects of AEPS on the gene expression of NF-κB, VCAM-1, ICAM-1, E-selectin, Nox4, SOD1, CAT and GPx in cultured human umbilical vein endothelial cells (HUVECs).</p> <p>Methods</p> <p>HUVECs were divided into four groups:- control; treatment with 180 μM hydrogen peroxide (H₂O₂); treatment with 150 μg/mL AEPS and concomitant treatment with AEPS and H₂O₂for 24 hours. Total RNA was extracted from all the groups of HUVEC using TRI reagent. Subsequently, qPCR was carried out to determine the mRNA expression of NF-κB, VCAM-1, ICAM-1, E-selectin, Nox4, SOD1, CAT and GPx. The specificity of the reactions was verified using melting curve analysis and agarose gel electrophoresis.</p> <p>Results</p> <p>When stimulated with H₂O₂, HUVECs expressed higher level of ICAM-1 (1.3-fold) and Nox4 (1.2-fold) mRNA expression. However, AEPS treatment led to a reduction in the mRNA expression of ICAM-1 (p < 0.01) and Nox4 (p < 0.05) in the H₂O₂-induced HUVECs. AEPS also upregulated the mRNA expression of SOD1 (p < 0.05), CAT (p < 0.01) and GPx (p < 0.05) in oxidative stress-induced HUVECs. There was no significant change in the mRNA expression of VCAM-1 and E-selectin.</p> <p>Conclusion</p> <p>The expressional suppression of ICAM-1 and Nox4 and induction of antioxidant enzymes might be an important component of the vascular protective effect of AEPS.</p

Hyperandrogenism and Its Possible Effects on Endometrial Receptivity: A Review

Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to hyperandrogenism or androgen excess, this condition can lead to pregnancy loss or infertility. Hyperandrogenism encompasses a wide range of clinical manifestations, including polycystic ovary syndrome (PCOS), idiopathic hirsutism, hirsutism and hyperandrogaenemia, non-classical congenital adrenal hyperplasia, hyperandrogenism, insulin resistance, acanthosis nigricans (HAIR-AN), ovarian or adrenal androgensecreting neoplasms, Cushing’s syndrome, and hyperprolactinaemia. Recurrent miscarriages have been shown to be closely related to elevated testosterone levels, which alter the endometrial milieu so that it is less favourable for embryo implantation. There are mechanisms for endometrial receptivity that are affected by excess androgen. The HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11 were the genes and proteins affect endometrial receptivity in the presence of a hyperandrogenic state. In this review, we would like to explore the other manifestations of androgen excess focusing on causes other than PCOS and learn possible mechanisms of endometrial receptivity behind androgen excess leading to pregnancy loss or infertilit

The changes of aortic stiffness during normal menstrual cycle

Pulse wave velocity (PWV), augmentation index (AI) and finger photoplethysmography fitness index (PPGF) are non-invasive markers of vascular function and may predict future cardiovascular disease (CVD) risk. In women, the changes from both oestrogen and progesterone levels during menstrual cycle may give significant impact on vascular function. Thus, this study was designed to investigate the variation of vascular function during follicular and luteal phase in healthy young women. Twenty-two healthy young women with regular menstrual cycle were recruited. Blood pressure (BP), body mass index (BMI), PWV, AI, PPGF, estradiol (Es) and progesterone (Prog) level were measured during follicular (F) and mid-luteal (L) phase. Data was analyzed via SPSS version 20 and P value < 0.05 was considered to be significant. The mean age of the subjects was 22.73 ± 0.60 years. There was significant variations of estradiol and progesterone levels during menstrual cycle whereby the level of estradiol (EsF = 107.6 ± 52.56 pmol/L vs. EsL = 555.16 ± 152.79 pmol/L, P<0.05) and progesterone (ProgF = 0.62 ± 0.26 nmol/L vs. ProgL = 46.74 ± 14.59 nmol/L, P<0.05) were higher in mid-luteal compared to follicular phase. PWV value was higher during follicular phase when compared to mid-luteal phase (PWVF = 6.67 ± 0.66 m/s vs. PWVL = 6.31 ± 0.52 m/s, P=0.01). The levels of BP, BMI, PPGF (PPGFF = 55.43 ± 7.50% vs. PPGFL = 56.59 ± 7.23 %, P=0.41) and AI (AIF = 12.87 ± 5.13% vs. AIL = 10.80 ± 4.52%, P=0.11) were unchanged between the two phases. In conclusion, PWV differs between follicular and mid-luteal phases of menstrual cycle in healthy young women. Thus, history of menstrual cycle must be taken into account when assessing PWV among women

Anti-angiogenic effect of polygonum species: a comprehensive review of literature

Angiogenesis is a physiological, tightly regulated process which is characterized by the development of new blood vessels. Compounds with the potential to control angiogenesis would be highly valuable as therapeutics, as an imbalance in angiogenesis may lead to several pathological disorders, including cancer, retinopathy, and arthritis. In this study, the anti-angiogenic effect of Polygonum sp. has been comprehensively reviewed and this plant also has been known to possess other medicinal benefits such as antioxidative, anti-inflammatory, anti-proliferative, and anti-tumor agents. Hence, this study systematically identified the evidence reporting the anti-angiogenic effects of Polygonum sp. Four electronic databases, namely PubMed, Ovid MEDLINE, Scopus and Web of Science were searched for relevant articles. Based on the pre-set eligibility criteria, 50 relevant articles were identified, and ten qualified articles were selected and reviewed. It was demonstrated that four namely P. cuspidatum, P. barbatum, P. hydropiper, and P. perfoliatum showed anti-angiogenic activities mainly through inhibition of the vascular endothelial growth factor-signaling pathways. Therefore, these species Polygonum have the potential to be developed as natural anti-angiogenic agents for prevention and treatment of various diseases related to pathological angiogenesis

Quantified Piper sarmentosum Roxb. leaves aqueous leaf extract and its antihypertensive effect in dexamethasone-induced hypertensive rats

The quality control of raw herbal materials is important to ensure the safety, efficacy, and reproducibility of herbal products. Herbal products with consistent efficacy should be standardized and quantified based on their bioactive phytochemical compounds. Piper sarmentosum Roxb. has been reported for its antihypertensive activity. However, its antihypertensive effect on dexamethasone-induced hypertension still lacks information. In this study, the quality of two batches of raw P. sarmentosum leaf materials was assessed for heavy metal and microbial contents, and their aqueous extracts were assayed for antioxidant activity. The aqueous extract of the second batch of P. sarmentosum leaves was the only extract that passed the heavy metal and microbial limits and had the highest antioxidant activity (50.00 ± 2.88%); therefore, this extract was used for subsequent studies. The extract was quantified for two phytochemical markers, rutin (0.09 ± 0.002%) and vitexin (0.23 ± 0.007%), using a validated ultrahigh performance liquid chromatography method. The quantified extract (500 mg/kg/day orally) was able to lower the systolic blood pressure, diastolic blood pressure, and mean arterial pressure of dexamethasone-induced hypertensive rats comparable to the positive control drug, captopril. In summary, the quantified aqueous extract of P. sarmentosum based on rutin and vitexin lowers the blood pressure of dexamethasone-induced hypertensive rats, but its underlying mechanism warrants further investigation

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

Background and aim: Perivascular adipose tissue (PVAT) positively regulates vascular function through production of factors such as adiponectin but this effect is attenuated in obesity. The enzyme AMP-activated protein kinase (AMPK) is present in PVAT and is implicated in mediating the vascular effects of adiponectin. In this study, we investigated the effect of an obesogenic high fat diet (HFD) on aortic PVAT and whether any changes involved AMPK.Methods: Wild type Sv129 (WT) and AMPKα1 knockout (KO) mice aged 8 weeks were fed normal diet (ND) or HFD (42% kcal fat) for 12 weeks. Adiponectin production by PVAT was assessed by ELISA and AMPK expression studied using immunoblotting. Macrophages in PVAT were identified using immunohistochemistry and markers of M1 and M2 macrophage subtypes evaluated using real time-qPCR. Vascular responses were measured in endothelium-denuded aortic rings with or without attached PVAT. Carotid wire injury was performed and PVAT inflammation studied 7 days later.Key results: Aortic PVAT from KO and WT mice was morphologically indistinct but KO PVAT had more infiltrating macrophages. HFD caused an increased infiltration of macrophages in WT mice with increased expression of the M1 macrophage markers Nos2 and Il1b and the M2 marker Chil3. In WT mice, HFD reduced the anticontractile effect of PVAT as well as reducing adiponectin secretion and AMPK phosphorylation. PVAT from KO mice on ND had significantly reduced adiponectin secretion and no anticontractile effect and feeding HFD did not alter this. Wire injury induced macrophage infiltration of PVAT but did not cause further infiltration in KO mice.Conclusions: High-fat diet causes an inflammatory infiltrate, reduced AMPK phosphorylation and attenuates the anticontractile effect of murine aortic PVAT. Mice lacking AMPKα1 phenocopy many of the changes in wild-type aortic PVAT after HFD, suggesting that AMPK may protect the vessel against deleterious changes in response to HFD

Profiling of Differentially Expressed MicroRNAs in Human Umbilical Vein Endothelial Cells Exposed to Hyperglycemia via RNA Sequencing

Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, apoptosis, and diabetic vascular endothelial dysfunction. An increasing number of microRNAs (miRNAs) have been found to be involved in the pathogenesis of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemia. Therefore, this study aims to analyze the miRNA profile of human umbilical-vein endothelial cells (HUVECs) exposed to hyperglycemia. HUVECs were divided into two groups: the control (treated with 5.5 mM glucose) and hyperglycemia (treated with 33.3 mM glucose) groups. RNA sequencing identified 17 differentially expressed miRNAs between the groups (p < 0.05). Of these, 4 miRNAs were upregulated, and 13 miRNAs were downregulated. Two of the most differentially expressed miRNAs (novel miR-1133 and miR-1225) were successfully validated with stem-loop qPCR. Collectively, the findings show that there is a differential expression pattern of miRNAs in HUVEC following exposure to hyperglycemia. These 17 differentially expressed miRNAs are involved in regulating cellular functions and pathways related to oxidative stress and apoptosis that may contribute to diabetic vascular endothelial dysfunction. The findings provide new clues on the role of miRNAs in the development of diabetic vascular endothelial dysfunction, which could be useful in future targeted therapy