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The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review)

Siti HN, Kamisah Y, Kamsiah J

Vascul. Pharmacol., 2015 Aug;71:40-56.
PMID: 25869516 DOI: 10.1016/j.vph.2015.03.005

The concept of mild chronic vascular inflammation as part of the pathophysiology of cardiovascular disease, most importantly hypertension and atherosclerosis, has been well accepted. Indeed there are links between vascular inflammation, endothelial dysfunction and oxidative stress. However, there are still gaps in our understanding regarding this matter that might be the cause behind disappointing results of antioxidant therapy for cardiovascular risk factors in large-scale long-term randomised controlled trials. Apart from the limitations of our knowledge, limitations in methodology and assessment of the body's endogenous and exogenous oxidant-antioxidant status are a serious handicap. The pleiotropic effects of antioxidant and anti-inflammation that are shown by some well-established antihypertensive agents and statins partly support the idea of using antioxidants in vascular diseases as still relevant. This review aims to provide an overview of the links between oxidative stress, vascular inflammation, endothelial dysfunction and cardiovascular risk factors, importantly focusing on blood pressure regulation and atherosclerosis. In view of the potential benefits of antioxidants, this review will also examine the proposed role of vitamin C, vitamin E and polyphenols in cardiovascular diseases as well as the success or failure of antioxidant therapy for cardiovascular diseases in clinical trials.
Fulltext De novo transcriptome dataset of Stevia rebaudiana accession MS007

Samsulrizal NH, Khadzran KS, Shaarani SH, Noh AL, Sundram TC, Naim MA, et al.

Data Brief, 2020 Feb;28:104811.
PMID: 31871974 DOI: 10.1016/j.dib.2019.104811

Stevia rebaudiana (S. rebaudiana) is a herbaceous and perennial plant belonging to Asteraceae family. The genus stevia is well known as a natural producer of sweetener comprising non-caloric and non-carcinogenic steviol glycosides. In recent years, the capability in producing natural sweetner has increased the demand for S. rebaudiana as substitute of processed sugars. Flowering phase of S. rebaudiana has shown to affect the content of steviol glycosides in the leaves. Steviol glycosides level is the highest at the time of flower bud formation and lowest at time preceding and following flower bud formation. Therefore, sequencing and analysing the genes that are involved in flowering phase will provide platform for gene manipulation in increasing steviol glycosides content. The Stevia transcriptome data that include two stages of growth (before flowering and after flowering), were obtained using Illumina RNA-seq technology and can be accessed at NCBI Sequence Read Archive under Accession No. SRX6362785 and SRX6362784.
Erratum: Effects of citrus leaf extract on aortic vascular reactivity in hypertensive rats fed repeatedly heated vegetable oil

Siti HN, Kamisah Y, Mohamed S, Jaarin K

Appl Physiol Nutr Metab, 2019 07;44(7):804.
PMID: 31237792 DOI: 10.1139/apnm-2019-0390
Fulltext Rutin Modulates MAPK Pathway Differently from Quercetin in Angiotensin II-Induced H9c2 Cardiomyocyte Hypertrophy

Siti HN, Jalil J, Asmadi AY, Kamisah Y

Int J Mol Sci, 2021 May 11;22(10).
PMID: 34064664 DOI: 10.3390/ijms22105063

Rutin is a flavonoid with antioxidant property. It has been shown to exert cardioprotection against cardiomyocyte hypertrophy. However, studies regarding its antihypertrophic property are still lacking, whether it demonstrates similar antihypertrophic effect to its metabolite, quercetin. Hence, this study aimed to investigate the effects of both flavonoids on oxidative stress and mitogen-activated protein kinase (MAPK) pathway in H9c2 cardiomyocytes that were exposed to angiotensin II (Ang II) to induce hypertrophy. Cardiomyocytes were exposed to Ang II (600 nM) with or without quercetin (331 μM) or rutin (50 μM) for 24 h. A group given vehicle served as the control. The concentration of the flavonoids was chosen based on the reported effective concentration to reduce cell hypertrophy or cardiac injury in H9c2 cells. Exposure to Ang II increased cell surface area, intracellular superoxide anion level, NADPH oxidase and inducible nitric oxide synthase activities, and reduced cellular superoxide dismutase activity and nitrite level, which were similarly reversed by both rutin and quercetin. Rutin had no significant effects on phosphorylated proteins of extracellular signal-related kinases (ERK1/2) and p38 but downregulated phosphorylated c-Jun N-terminal kinases (JNK1/2), which were induced by Ang II. Quercetin, on the other hand, had significantly downregulated the phosphorylated proteins of ERK1/2, p38, and JNK1/2. The quercetin inhibitory effect on JNK1/2 was stronger than the rutin. In conclusion, both flavonoids afford similar protective effects against Ang II-induced cardiomyocyte hypertrophy, but they differently modulate MAPK pathway.
Effects of citrus leaf extract on aortic vascular reactivity in hypertensive rats fed repeatedly heated vegetable oil

Siti HN, Kamisah Y, Mohamed S, Jaarin K

Appl Physiol Nutr Metab, 2019 04;44(4):373-380.
PMID: 30216735 DOI: 10.1139/apnm-2018-0175

The prolonged intake of diet containing repeatedly heated vegetable oil can cause hypertension in the long run.
In this study, the effects of citrus leaf extract (CLE) supplementation on vascular reactivity, plasma nitrite, and aortic structure in hypertensive rats were investigated by the consumption of repeatedly heated vegetable oil [corrected]. Male Sprague Dawley rats (n = 56) were divided into 7 groups corresponding to the respective diets. For 16 weeks, 1 group was given standard rat chow (control) while other groups were given diets containing 15% w/w of palm oil, fresh palm oil (FPO), palm oil heated 5 times (5HPO), and palm oil heated 10 times (10HPO), with or without the incorporation of 0.15% w/w CLE (FPO+CLE, 5HPO+CLE, or 10HPO+CLE). Plasma nitrite levels were measured before and at 16 weeks of treatment. After 16 weeks, the rats were sacrificed and aortae were harvested for measuring vascular reactivity and for microscopic study. CLE supplementation had significantly reduced the loss of plasma nitrite and attenuated the vasoconstriction response to phenylephrine in the 5HPO group but not in the 10HPO group. However, CLE had no significant effect on the vasorelaxation response to acetylcholine and sodium nitroprusside. The elastic lamellae of tunica media in 5HPO, 10HPO, and 10HPO+CLE groups appeared disorganised and disrupted. Obtained findings suggested that CLE was able to enhance nitric oxide bioavailability that might dampen the vasoconstriction effect of phenylephrine.
Fulltext Parkia speciosa Hassk. Empty Pod Extract Alleviates Angiotensin II-Induced Cardiomyocyte Hypertrophy in H9c2 Cells by Modulating the Ang II/ROS/NO Axis and MAPK Pathway

Siti HN, Jalil J, Asmadi AY, Kamisah Y

Front Pharmacol, 2021;12:741623.
PMID: 34721028 DOI: 10.3389/fphar.2021.741623

Cardiac hypertrophy is characteristic of heart failure in patients who have experienced cardiac remodeling. Many medicinal plants, including Parkia speciosa Hassk., have documented cardioprotective effects against such pathologies. This study investigated the activity of P. speciosa empty pod extract against cardiomyocyte hypertrophy in H9c2 cardiomyocytes exposed to angiotensin II (Ang II). In particular, its role in modulating the Ang II/reactive oxygen species/nitric oxide (Ang II/ROS/NO) axis and mitogen-activated protein kinase (MAPK) pathway was examined. Treatment with the extract (12.5, 25, and 50 μg/ml) prevented Ang II-induced increases in cell size, NADPH oxidase activity, B-type natriuretic peptide levels, and reactive oxygen species and reductions in superoxide dismutase activity. These were comparable to the effects of the valsartan positive control. However, the extract did not significantly ameliorate the effects of Ang II on inducible nitric oxide synthase activity and nitric oxide levels, while valsartan did confer such protection. Although the extract decreased the levels of phosphorylated extracellular signal-related kinase, p38, and c-Jun N-terminal kinase, valsartan only decreased phosphorylated c-Jun N-terminal kinase expression. Phytochemical screening identified the flavonoids rutin (1) and quercetin (2) in the extract. These findings suggest that P. speciosa empty pod extract protects against Ang II-induced cardiomyocyte hypertrophy, possibly by modulating the Ang II/ROS/NO axis and MAPK signaling pathway via a mechanism distinct from valsartan.
Effects of Quercetin on Cardiac Function in Pressure Overload and Postischemic Cardiac Injury in Rodents: a Systematic Review and Meta-Analysis

Siti HN, Jalil J, Asmadi AY, Kamisah Y

Cardiovasc Drugs Ther, 2022 02;36(1):15-29.
PMID: 33064235 DOI: 10.1007/s10557-020-07100-y

PURPOSE: Cardiac dysfunction can occur as a sequela of a state of prolonged pressure overload and postischemic injury. Flavonoids such as quercetin may be protective against cardiovascular disease. This study aimed to systematically assess the effects of quercetin on cardiac function in pressure overload and postischemia-reperfusion injury in rodents.
METHODS: A systematic search of the literature up to May 2020 was conducted in PubMed, Ovid Medline, EBSCOhost, Scopus, and the Cochrane Library to identify relevant published studies on quercetin and cardiac function using standardized criteria. Meta-analyses were performed on animal studies of pressure overload and ischemia-reperfusion (I/R) injury.
RESULTS: The effects of quercetin on cardiac function in both models were qualitatively reported in 14 studies. The effects of quercetin in four pressure-overload model studies involving 73 rodents and eight I/R-injury model studies involving 120 rodents were quantitatively assessed by meta-analysis. Quercetin improved the overall cardiac function in both pressure overload (n = 4 studies, n = 73 rodents; SMD = - 1.50; 95% CI: - 2.66 to - 0.33; P
Citrus leaf extract reduces blood pressure and vascular damage in repeatedly heated palm oil diet-Induced hypertensive rats

Siti HN, Kamisah Y, Nur Iliyani MI, Mohamed S, Jaarin K

Biomed Pharmacother, 2017 Mar;87:451-460.
PMID: 28068636 DOI: 10.1016/j.biopha.2016.12.075

Prolonged consumption of repeatedly heated vegetable oil increases blood pressure. This study aimed to determine the effects of Citrus leaf extract, (CLE) on blood pressure, blood pressure-regulating enzymes and mediators, as well as aortic histomorphometry in heated palm oil induced-hypertension. Male Sprague Dawley rats (n=56) were divided into seven groups; control group was given normal diet and the other groups were fed with palm oil-enriched diet (15% w/w) either fresh (FPO), five-time-heated (5HPO) or ten-time-heated (10HPO) with or without CLE (0.15%, w/w) supplementation. CLE supplementation reduced the heated oil-raising effect of blood pressure, plasma TBARS, thromboxane and angiotensin-1 converting enzyme in 5HPO but not in 10HPO group. CLE increased serum heme oxygenase-1 in both 5HPO and 10HPO groups. CLE supplementation reduced the increase in aortic intima-media thickness, intima-media area and circumferential wall tension in 5HPO group but not in 10HPO group. These findings suggested that CLE supplementation reduces the blood pressure-raising effects of 5HPO and vascular damage, possibly through its antioxidant effect by modulating vasoactive mediators and blood pressure-regulating enzymes.