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Endothelial function and dysfunction: Impact of sodium-glucose cotransporter 2 inhibitors

Ugusman A, Kumar J, Aminuddin A

Pharmacol Ther, 2021 08;224:107832.
PMID: 33662450 DOI: 10.1016/j.pharmthera.2021.107832

Diabetes mellitus is associated with endothelial dysfunction that leads to cardiovascular complications. Sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrated efficacy in glycemic control in type 2 diabetes patients with positive cardiovascular outcome. Recent research revealed a link between SGLT2 inhibition and improved macro- and microvascular endothelial functions. Mechanisms underlying this phenomenon could be due to the role of SLGT2 in the regulation of endothelial physiology. In this review, current knowledge and hypothesis on the link between SGLT2 and endothelial function were critically appraised and the impact of SGLT2 inhibitors on endothelial dysfunction in pre-clinical and clinical studies was discussed.
Fulltext The changes of aortic stiffness during normal menstrual cycle

Aminuddin, A., Luqman Hakim, A.Z., Chan, S.Y., Nur Elyatulnadia, S., Hul Aamizatkma, H., Nur Shahira Afifa, R., et al.

Medicine & Health, 2018;13(1):117-129.
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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
Fulltext The effects of exercise on vascular markers and C-reactive protein among obese children and adolescents: An evidence-based review

Salamt N, Muhajir M, Aminuddin A, Ugusman A

Bosn J Basic Med Sci, 2020 May 01;20(2):149-156.
PMID: 31509733 DOI: 10.17305/bjbms.2019.4345

Numerous studies have evaluated the effects of exercise training on obese children and adolescents. However, the impact of aerobic and/or resistance exercise alone, without any other interventions, on vascular markers and C-reactive protein (CRP) in obese children and adolescents is still not clear. We performed a literature search in Ovid Medline, PubMed, and SCOPUS databases to identify articles on the effects of exercise on vascular markers and CRP among obese children and adolescents, published between January 2009 and May 2019. Only full-text articles in English that reported on the effect of aerobic and/or resistance exercise on the vascular markers pulse wave velocity (PWV), carotid intima-media thickness (CIMT), flow-mediated dilatation (FMD), augmentation index (AIx), or CRP in obese children and adolescents (5-19 years old) were included. The literature search identified 36 relevant articles; 9 articles that fulfilled all the inclusion criteria were selected by two independent reviewers. Aerobic exercise or a combination of aerobic and resistance exercise training significantly improved CIMT and PWV in obese children and adolescents in all studies in which they were measured (2 studies for PWV and 4 studies for CIMT). However, the effects of exercise on FMD and CRP levels were inconclusive, as only half of the studies demonstrated significant improvements (1/2 studies for FMD and 4/8 studies for CRP). The results of our review support the ability of exercise to improve vascular markers such as PWV and CIMT in obese children and adolescents. This finding is important as obesity is a modifiable risk factor of cardiovascular disease (CVD), and exercise may help in reducing the future occurrence of CVD in this population.
Fulltext Piper sarmentosum inhibits ICAM-1 and Nox4 gene expression in oxidative stress-induced human umbilical vein endothelial cells

Ugusman A, Zakaria Z, Hui CK, Nordin NA

BMC Complement Altern Med, 2011;11:31.
PMID: 21496279 DOI: 10.1186/1472-6882-11-31

Aqueous extract of Piper sarmentosum (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).
Piper sarmentosum attenuates TNF-α-induced VCAM-1 and ICAM-1 expression in human umbilical vein endothelial cells

Ismail SM, Sundar UM, Hui CK, Aminuddin A, Ugusman A

J Taibah Univ Med Sci, 2018 Jun;13(3):225-231.
PMID: 31435328 DOI: 10.1016/j.jtumed.2018.01.003

Objectives: Inflammation plays a key role in the pathogenesis of atherosclerosis. Piper sarmentosum is an herb with antioxidant and anti-atherosclerotic activities. The aim of this study was to evaluate the anti-inflammatory properties of an aqueous extract of P. sarmentosum (AEPS) in human umbilical vein endothelial cells (HUVECs).
Methods: HUVECs were divided into six groups: control, treatment with 10 ng/ml TNF-α, and co-treatment of 10 ng/ml TNF-α with four different concentrations of AEPS (100, 150, 250, and 300 μg/ml) for 24 h. Subsequently, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) protein expression, U937 monocyte cells adhesion, and nuclear factor-kappaB (NF-κB) p65 expression in HUVECs were measured.
Results: Treatment of TNF-α-stimulated HUVECs with AEPS at different concentrations resulted in decreased VCAM-1 and ICAM-1 protein expression in a dose-dependent manner. Furthermore, AEPS also inhibited TNF-α-stimulated U937 monocyte cells adhesion to HUVECs. In addition, AEPS reduced TNF-α-induced NF-κB p65 expression in a dose-dependent manner.
Conclusions: The results indicated that AEPS suppressed TNF-α-induced VCAM-1 and ICAM-1 expression NF-κB signaling.
Effects of moderate alcohol consumption on subclinical femoral atherosclerosis in smokers and non-smokers

Ugusman A, Mohamed IN, Mohamed Pakri Mohamed R, Kumar J

Addiction, 2021 02;116(2):428-429.
PMID: 32945557 DOI: 10.1111/add.15267
Modulation of Matrix Metalloproteinases by Plant-derived Products

Anuar NNM, Zulkafali NIN, Ugusman A

Curr Cancer Drug Targets, 2021;21(2):91-106.
PMID: 33222671 DOI: 10.2174/1568009620666201120144838

Matrix metalloproteinases (MMPs) are a group of zinc-dependent metalloendopeptidases that are responsible for the degradation, repair, and remodeling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases, such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic, and food industries. This review summarises the current knowledge of plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signaling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviors, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.
An investigation of the antiplatelet effects of succinobucol (AGI-1067)

Houston SA, Ugusman A, Gnanadesikan S, Kennedy S

Platelets, 2017 May;28(3):295-300.
PMID: 27681689 DOI: 10.1080/09537104.2016.1218456

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 (10-5-10-4M) 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.
Fulltext Piper sarmentosum Promotes Endothelial Nitric Oxide Production by Reducing Asymmetric Dimethylarginine in Tumor Necrosis Factor-α-Induced Human Umbilical Vein Endothelial Cells

Sundar UM, Ugusman A, Chua HK, Latip J, Aminuddin A

Front Pharmacol, 2019;10:1033.
PMID: 31607906 DOI: 10.3389/fphar.2019.01033

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (eNOS). ADMA is degraded by dimethylarginine dimethylaminohydrolase (DDAH). Elevated levels of ADMA lead to reduction in nitric oxide (NO) production, which is linked to endothelial dysfunction and atherosclerosis. Piper sarmentosum is an herb that has shown stimulation on endothelial NO production by increasing both expression and activity of eNOS. Thus, this study determined whether the positive effect of P. sarmentosum on NO production is related to its modulation on the DDAH-ADMA pathway in cultured human umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis factor-α (TNF-α). HUVEC were divided into four groups: control, treatment with 250 µg/ml of aqueous extract of P. sarmentosum leaves (AEPS), treatment with 30 ng/ml of TNF-α, and concomitant treatment with AEPS and TNF-α for 24 h. After treatments, HUVEC were collected to measure DDAH1 messenger RNA (mRNA) expression using quantitative real-time polymerase chain reaction. DDAH1 protein level was measured using enzyme-linked immunosorbent assay (ELISA), and DDAH enzyme activity was measured using colorimetric assay. ADMA concentration was measured using ELISA, and NO level was measured using Griess assay. Compared to control, TNF-α-treated HUVEC showed reduction in DDAH1 mRNA expression (P < 0.05), DDAH1 protein level (P < 0.01), and DDAH activity (P < 0.05). Treatment with AEPS successfully increased DDAH1 mRNA expression (P < 0.05), DDAH1 protein level (P < 0.01), and DDAH activity (P < 0.05) in TNF-α-treated HUVEC. Treatment with TNF-α caused an increase in ADMA level (P < 0.01) and a decrease in endothelial NO production (P < 0.001). Whereas treatment with AEPS was able to reduce ADMA level (P < 0.01) and restore NO (P < 0.001) in TNF-α-treated HUVEC. The results suggested that AEPS promotes endothelial NO production by stimulating DDAH activity and thus reducing ADMA level in TNF-α-treated HUVEC.
Fulltext Kelulut Honey Regulates Sex Steroid Receptors in a Polycystic Ovary Syndrome Rat Model

Kamal DAM, Ibrahim SF, Ugusman A, Mokhtar MH

Int J Mol Sci, 2022 Nov 25;23(23).
PMID: 36499085 DOI: 10.3390/ijms232314757

Reproductive and metabolic anomalies in polycystic ovary syndrome (PCOS) have been associated with the dysregulation of sex steroid receptors. Kelulut honey (KH) has been shown to be beneficial in PCOS-induced rats by regulating folliculogenesis and the oestrus cycle. However, no study has been conducted to evaluate KH's effect on sex steroid receptors in PCOS. Therefore, the current study examined the effects of KH, metformin, or clomiphene alone and in combination on the mRNA expression and protein distribution of androgen receptor (AR), oestrogen receptor α (ERα), oestrogen receptor β (ERβ), and progesterone receptor (PR) in PCOS-induced rats. The study used female Sprague-Dawley rats, which were treated orally with 1 mg/kg/day of letrozole for 21 days to develop PCOS. PCOS-induced rats were then divided and treated orally for 35 days with KH, metformin, clomiphene, KH + metformin, KH+ clomiphene and distilled water. In this study, we observed aberrant AR, ERα, ERβ and PR expression in PCOS-induced rats compared with the normal control rats. The effects of KH treatment were comparable with clomiphene and metformin in normalizing the expression of AR, ERα, and ERβ mRNA. However, KH, clomiphene and metformin did not affect PR mRNA expression and protein distribution. Hence, this study confirms the aberrant expression of sex steroid receptors in PCOS and demonstrates that KH treatment could normalise the sex steroid receptors profile. The findings provide a basis for future clinical trials to utilize KH as a regulator of sex steroid receptors in patients with PCOS.
Fulltext Role of Terpenophenolics in Modulating Inflammation and Apoptosis in Cardiovascular Diseases: A Review

Abdul Ghani MA, Ugusman A, Latip J, Zainalabidin S

Int J Mol Sci, 2023 Mar 10;24(6).
PMID: 36982410 DOI: 10.3390/ijms24065339

One in every three deaths worldwide is caused by cardiovascular diseases (CVDs), estimating a total of 17.9 million deaths annually. By 2030, it is expected that more than 24 million people will die from CVDs related complications. The most common CVDs are coronary heart disease, myocardial infarction, stroke, and hypertension. A plethora of studies has shown inflammation causing both short-term and long-term damage to the tissues in many organ systems, including the cardiovascular system. In parallel to inflammation processes, it has been discovered that apoptosis, a mode of programmed cell death, may also contribute to CVD development due to the loss of cardiomyocytes. Terpenophenolic compounds are comprised of terpenes and natural phenols as secondary metabolites by plants and are commonly found in the genus Humulus and Cannabis. A growing body of evidence has shown that terpenophenolic compounds exhibit protective properties against inflammation and apoptosis within the cardiovascular system. This review highlights the current evidence elucidating the molecular actions of terpenophenolic compounds in protecting the cardiovascular system, i.e., bakuchiol, ferruginol, carnosic acid, carnosol, carvacrol, thymol and hinokitiol. The potential of these compounds is discussed as the new nutraceutical drugs that may help to decrease the burden of cardiovascular disorders.
Fulltext Smoking and Unstable Plaque in Acute Coronary Syndrome: A Systematic Review of The Role of Matrix Metalloproteinases

Aminuddin A, Cheong SS, Roos NAC, Ugusman A

Int J Med Sci, 2023;20(4):482-492.
PMID: 37057211 DOI: 10.7150/ijms.79889

Smoking is a risk factor of acute coronary syndrome (ACS) that could increase matrix metalloproteinases (MMPs) levels, leading to unstable coronary artery plaque. The current review aimed to identify the relationship between smoking and MMPs in patients with ACS. Literature search was conducted from inception until March 2022 in three online databases. Risk of bias was assessed using the Newcastle-Ottawa Scale. A meta-analysis was performed, and the odds ratio (OR) together with its 95% confidence interval (CI) were determined. A total of 7,843 articles were identified, and only seven studies were included. Four studies investigated the MMP-3 and MMP-9 related genes and found that smokers with certain MMPs genotypes had high risk of ACS. Smoking also increased the MMPs level in patients with ACS compared with non-smokers. Additionally, a meta-analysis of two studies resulted in an increased odd of ACS in smokers with MMP-3 5A allele versus non-smokers with MMP-3 6A6A allele (OR: 15.94, 95% CI: 10.63-23.92; I2 =55%). In conclusion, the current review highlights the role of MMPs in relation to smoking and ACS. The determination of these roles may help in identifying new ACS markers among smokers and the development of drug-targeted treatment.
Fulltext Role of Matrix Metalloproteinase-2 in the Development of Atherosclerosis among Patients with Coronary Artery Disease

Samah N, Ugusman A, Hamid AA, Sulaiman N, Aminuddin A

Mediators Inflamm, 2023;2023:9715114.
PMID: 37457745 DOI: 10.1155/2023/9715114

Coronary artery disease (CAD) is a caused by atherosclerotic plaque buildup in the coronary arteries that supply blood and oxygen to the heart. Matrix metalloproteinase (MMP) is a family of zinc-dependent endopeptidase that is involved in various stages of atherosclerosis as demonstrated in in vitro and in vivo studies. MMP-2 is associated with both stable and unstable atherosclerotic plaque formation. The current review aimed to identify the role of MMP-2 in atherosclerosis development among CAD patients. Literature search was conducted through four online databases and only studies that were published from 2018 until February 2023 were included. The risk of bias was assessed by using the Newcastle-Ottawa Scale. A total of 10,622 articles were initially identified, and only eight studies that fulfilled the selection criteria were included in this review. The results showed that MMP-2 levels and activity were higher in patients with unstable CAD than those with stable CAD and healthy subjects. There was a significant association between MMP-2 levels and cardiovascular disease with MMP-14 levels, which is a pro-MMP-2 activator. In addition, two single nucleotide polymorphisms of the MMP-2 gene (rs243865 and rs243866) were significantly associated with the development of atherosclerosis. In conclusion, MMP-2 plays a crucial role in the development of atherosclerosis among patients with CAD and could be a potential target for CAD therapy.
Fulltext Piper sarmentosum increases nitric oxide production in oxidative stress: a study on human umbilical vein endothelial cells

Ugusman A, Zakaria Z, Hui CK, Nordin NA

Clinics (Sao Paulo), 2010 Jul;65(7):709-14.
PMID: 20668629 DOI: 10.1590/S1807-59322010000700010

Nitric oxide produced by endothelial nitric oxide synthase (eNOS) possesses multiple anti-atherosclerotic properties. Hence, enhanced expression of eNOS and increased Nitric oxide levels may protect against the development of atherosclerosis. Piper sarmentosum is a tropical plant with antioxidant and anti-inflammatory activities. This study aimed to investigate the effects of Piper sarmentosum on the eNOS and Nitric oxide pathway in cultured human umbilical vein endothelial cells (HUVECs).
Fulltext Kelulut Honey Ameliorates Oestrus Cycle, Hormonal Profiles, and Oxidative Stress in Letrozole-Induced Polycystic Ovary Syndrome Rats

Kamal DAM, Ibrahim SF, Ugusman A, Mokhtar MH

Antioxidants (Basel), 2022 Sep 22;11(10).
PMID: 36290602 DOI: 10.3390/antiox11101879

Kelulut honey (KH) has been proven to have excellent antioxidative and anti-inflammatory properties with unique physicochemical characteristics. Therefore, we investigated the isolated and combined effects of KH, metformin, or clomiphene in alleviating oxidative stress and reproductive and metabolic abnormalities in polycystic ovary syndrome (PCOS). Female Sprague-Dawley (SD) rats were given 1 mg/kg/day of letrozole for 21 days to induce PCOS. PCOS rats were then divided into six treatment groups: untreated, metformin (500 mg/kg/day), clomiphene (2 mg/kg/day), KH (1 g/kg/day), combined KH (1 g/kg/day) and metformin (500 mg/kg/day), and combined KH (1 g/kg/day) and clomiphene (2 mg/kg/day). All treatments were administered orally for 35 days. The physicochemical characteristics of KH were assessed through hydroxymethylfurfural, free acidity, diastase number, moisture content, sugar profile, metals, and mineral compounds. Additionally, we determined the semivolatile organic compounds present in KH through gas chromatography-mass spectrometry (GC/MS) analysis. KH and its combination with metformin or clomiphene were shown to improve the oestrus cycle, hormonal profile, and oxidative stress in PCOS rats. However, KH did not reduce the fasting blood glucose, insulin, and body weight gain in PCOS rats. These findings may provide a basis for future studies to discover the potential use of KH as a complementary treatment for women with PCOS.
Fulltext Role of rutin on nitric oxide synthesis in human umbilical vein endothelial cells

Ugusman A, Zakaria Z, Chua KH, Nordin NA, Abdullah Mahdy Z

ScientificWorldJournal, 2014;2014:169370.
PMID: 25093198 DOI: 10.1155/2014/169370

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a major antiatherogenic factor in the blood vessel. Oxidative stress plays an important role in the pathogenesis of various cardiovascular diseases, including atherosclerosis. Decreased availability of endothelial NO promotes the progression of endothelial dysfunction and atherosclerosis. Rutin is a flavonoid with multiple cardiovascular protective effects. This study aimed to investigate the effects of rutin on eNOS and NO production in cultured human umbilical vein endothelial cells (HUVEC). HUVEC were divided into four groups: control; oxidative stress induction with 180 μM H₂O₂; treatment with 300 μM rutin; and concomitant induction with rutin and H₂O₂ for 24 hours. HUVEC treated with rutin produced higher amount of NO compared to control (P < 0.01). In the oxidative stress-induced HUVEC, rutin successfully induced cells' NO production (P < 0.01). Rutin promoted NO production in HUVEC by inducing eNOS gene expression (P < 0.05), eNOS protein synthesis (P < 0.01), and eNOS activity (P < 0.05). Treatment with rutin also led to increased gene and protein expression of basic fibroblast growth factor (bFGF) in HUVEC. Therefore, upregulation of eNOS expression by rutin may be mediated by bFGF. The results showed that rutin may improve endothelial function by augmenting NO production in human endothelial cells.
COVID-19 and Hypertension: The What, the Why, and the How

Muhamad SA, Ugusman A, Kumar J, Skiba D, Hamid AA, Aminuddin A

Front Physiol, 2021;12:665064.
PMID: 34012410 DOI: 10.3389/fphys.2021.665064

It has been a year since the coronavirus disease 2019 (COVID-19) was declared pandemic and wreak havoc worldwide. Despite meticulous research has been done in this period, there are still much to be learn from this novel coronavirus. Globally, observational studies have seen that majority of the patients with COVID-19 have preexisting hypertension. This raises the question about the possible relationship between COVID-19 and hypertension. This review summarizes the current understanding of the link between hypertension and COVID-19 and its underlying mechanisms.
Fulltext Piper sarmentosum Roxb. Attenuates Vascular Endothelial Dysfunction in Nicotine-Induced Rats

Md Salleh MFRR, Aminuddin A, Hamid AA, Salamt N, Japar Sidik FZ, Ugusman A

Front Pharmacol, 2021;12:667102.
PMID: 34194328 DOI: 10.3389/fphar.2021.667102

Exposure to cigarette smoke is an important risk factor for cardiovascular diseases. Nicotine is an addictive compound in cigarette smoke that triggers oxidative stress, which leads to vascular dysfunction. Piper sarmentosum Roxb. is a herb with antioxidant and vascular protective effects. This study evaluated the potential protective effect of the aqueous extract of P. sarmentosum leaf (AEPS) on vascular dysfunction in rats induced with prolonged nicotine administration. A total of 22 male Sprague-Dawley rats were divided into control (normal saline, oral gavage [p.o.]), nicotine (0.8 mg/kg/day nicotine, intraperitoneally [i.p.]), and nicotine + AEPS groups (250 mg/kg/day AEPS, p.o. + 0.8 mg/kg/day nicotine, i.p.). Treatment was given for 21 days. Thoracic aortae were harvested from the rats for the measurement of vasorelaxation, vascular nitric oxide (NO) level, and antioxidant level and the assessment of vascular remodeling. Rats treated with AEPS had improved vasorelaxation to endothelium-dependent vasodilator, acetylcholine (ACh), compared with the nicotine-induced rats (p < 0.05). The presence of endothelium increased the maximum relaxation of aortic rings in response to ACh. Compared with the nicotine group, AEPS enhanced vascular NO level (p < 0.001) and increased antioxidant levels as measured by superoxide dismutase activity (p < 0.05), catalase activity (p < 0.01), and reduced glutathione level (p < 0.05). No remarkable changes in aortic histomorphometry were detected. In conclusion, P. sarmentosum attenuates vascular endothelial dysfunction in nicotine-induced rats by improving vasorelaxation and enhancing vascular NO and antioxidant levels.
Flavonoids of Piper sarmentosum and its cytoprotective effects against oxidative stress

Ugusman A, Zakaria Z, Hui CK, Nordin NA, Mahdy ZA

EXCLI J, 2012;11:705-714.
PMID: 27847456

Abnormalities in endothelial cell structure and function may lead to diseases such as thrombosis and atherosclerosis. Oxidative stress plays an important role in the pathogenesis of various cardiovascular diseases including atherosclerosis. Previous studies have shown a relationship between a diet rich in flavonoid and a reduced incidence of cardiovascular diseases. Piper sarmentosum (PS) is a plant with high flavonoid content and it possesses antioxidant and anti-atherosclerotic activities. Therefore this study aimed to investigate the flavonoids present in aqueous extract of PS (AEPS) and its cytoprotective effects in oxidative stress-induced human umbilical vein endothelial cells (HUVEC). AEPS contained high total phenolic content (91.02 ± 0.02 mg QE/g DM) and total flavonoid content (48.57 ± 0.03 mg GAE/g DM). Screening using high performance liquid chromatography (HPLC) technique showed the presence of rutin and vitexin as the main flavonoids in AEPS. HUVEC were exposed to 180 µM H2O2 and treated with various concentrations of rutin or vitexin (10 to 400 µM) for 24 hours. Both rutin and vitexin at the concentration of 150-400 µM significantly increased the viability of H2O2-induced HUVEC as denoted by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Therefore rutin and vitexin as the main flavonoids present in PS may be involved in the protective effects of PS against oxidative stress.
Revisiting miRNA-21 as a Therapeutic Strategy for Myocardial Infarction: A Systematic Review

Sothivelr V, Hasan MY, Mohd Saffian S, Zainalabidin S, Ugusman A, Mahadi MK

J Cardiovasc Pharmacol, 2022 Sep 01;80(3):393-406.
PMID: 35767710 DOI: 10.1097/FJC.0000000000001305

Several types of cardiovascular cells use microRNA-21 ( miR-21 ), which has been linked to cardioprotection. In this study, we systematically reviewed the results of published papers on the therapeutic effect of miR-21 for myocardial infarction. Studies described the cardioprotective effects of miR-21 to reduce infarct size by improving angiogenesis, antiapoptotic, and anti-inflammatory mechanisms. Results suggest that cardioprotective effects of miR-21 may work synergistically to prevent the deterioration of cardiac function during postischemia. However, there are other results that indicate that miR-21 positively regulates tissue fibrosis, potentially worsening a postischemic injury. The dual functionalities of miR-21 occur through the targeting of genes and signaling pathways, such as PTEN , PDCD4 , KBTBD7 , NOS3 , STRN , and Spry-1 . This review provides insights into the future advancement of safe miR-21 -based genetic therapy in the treatment of myocardial infarction.

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