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S-allylcysteine improves ischemia/reperfusion alteration on cardiac function, antioxidant, and mitochondrial permeability

Aziz NF, Ramalingam A, Latip J, Zainalabidin S

Life Sci, 2021 Mar 15;269:119080.
PMID: 33465387 DOI: 10.1016/j.lfs.2021.119080

S-Allylcysteine (SAC) is an extensively studied natural product which has been proven to confer cardioprotection. This potentiates SAC into many clinical relevance possibilities, hence, the use of it ought to be optimally elucidated. To further confirm this, an ischemia/reperfusion model has been used to determine SAC at 10 mM and 50 mM on cardiac function, cardiac marker, and mitochondrial permeability. Using Langendorff setup, 24 adult male Wistar rats' hearts were isolated to be perfused with Kreb-Henseleit buffer throughout the ischemia/reperfusion method. After 20 min of stabilization, global ischemia was induced by turning off the perfusion for 35 min followed by 60 min of reperfusion with either Kreb-Henseleit buffer or SAC with the dose of 10 mM or 50 mM. The cardiac function was assessed and coronary effluent was collected at different timepoints throughout the experiment for lactate dehydrogenase (LDH) measurement. The harvested hearts were then used to measure glutathione while isolated mitochondria for mPTP analysis. SAC-reperfused hearts were shown to prevent the aggravation of cardiac function after I/R induction. It also dose-dependently upregulated glutathione reductase and glutathione level and these were also accompanied by significant reduction of LDH leakage and preserved mitochondrial permeability. Altogether, SAC dose-dependently was able to recover the post-ischemic cardiac function deterioration alongside with improvement of glutathione metabolism and mitochondrial preservation. These findings highly suggest that SAC when sufficiently supplied to the heart would be able to prevent the deleterious complications after the ischemic insult.
Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart

Lim YC, Budin SB, Othman F, Latip J, Zainalabidin S

Cardiovasc Toxicol, 2017 Jul;17(3):251-259.
PMID: 27402292 DOI: 10.1007/s12012-016-9379-6

Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500 μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dtmax, suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca2+channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.
Fulltext Mitochondrial Dysfunction in Diabetic Cardiomyopathy: The Possible Therapeutic Roles of Phenolic Acids

Jubaidi FF, Zainalabidin S, Mariappan V, Budin SB

Int J Mol Sci, 2020 Aug 22;21(17).
PMID: 32842567 DOI: 10.3390/ijms21176043

As the powerhouse of the cells, mitochondria play a very important role in ensuring that cells continue to function. Mitochondrial dysfunction is one of the main factors contributing to the development of cardiomyopathy in diabetes mellitus. In early development of diabetic cardiomyopathy (DCM), patients present with myocardial fibrosis, dysfunctional remodeling and diastolic dysfunction, which later develop into systolic dysfunction and eventually heart failure. Cardiac mitochondrial dysfunction has been implicated in the development and progression of DCM. Thus, it is important to develop novel therapeutics in order to prevent the progression of DCM, especially by targeting mitochondrial dysfunction. To date, a number of studies have reported the potential of phenolic acids in exerting the cardioprotective effect by combating mitochondrial dysfunction, implicating its potential to be adopted in DCM therapies. Therefore, the aim of this review is to provide a concise overview of mitochondrial dysfunction in the development of DCM and the potential role of phenolic acids in combating cardiac mitochondrial dysfunction. Such information can be used for future development of phenolic acids as means of treating DCM by alleviating the cardiac mitochondrial dysfunction.
Fulltext Resveratrol Supplementation Protects Against Nicotine-Induced Kidney Injury

Ramalingam A, Santhanathas T, Shaukat Ali S, Zainalabidin S

Int J Environ Res Public Health, 2019 11 12;16(22).
PMID: 31726798 DOI: 10.3390/ijerph16224445

Prolonged exposure to nicotine accelerates onset and progression of renal diseases in habitual cigarette smokers. Exposure to nicotine, either via active or passive smoking is strongly shown to enhance renal oxidative stress and augment kidney failure in various animal models. In this study, we investigated the effects of resveratrol supplementation on nicotine-induced kidney injury and oxidative stress in a rat model. Male Sprague-Dawley rats were given nicotine (0.6 mg/kg, i.p.) alone or in combination with either resveratrol (8 mg/kg, i.p.), or angiotensin II type I receptor blocker, irbesartan (10 mg/kg, p.o.) for 28 days. Upon completion of treatment, kidneys were investigated for changes in structure, kidney injury markers and oxidative stress. Administration of nicotine alone for 28 days resulted in significant renal impairment as shown by marked increase in plasma creatinine, blood urea nitrogen (BUN) and oxidative stress. Co-administration with resveratrol however successfully attenuated these changes, with a concomitant increase in renal antioxidants such as glutathione similar to the conventionally used angiotensin II receptor blocker, irbesartan. These data altogether suggest that targeting renal oxidative stress with resveratrol could alleviate nicotine-induced renal injury. Antioxidants may be clinically important for management of renal function in habitual smokers.
Hibiscus sabdariffa (roselle) polyphenol-rich extract averts cardiac functional and structural abnormalities in type 1 diabetic rats

Mohammed Yusof NL, Zainalabidin S, Mohd Fauzi N, Budin SB

Appl Physiol Nutr Metab, 2018 Dec;43(12):1224-1232.
PMID: 29726706 DOI: 10.1139/apnm-2018-0084

Diabetes mellitus is often associated with cardiac functional and structural alteration, an initial event leading to cardiovascular complications. Roselle (Hibiscus sabdariffa) has been widely proven as an antioxidant and recently has incited research interest for its potential in treating cardiovascular disease. Therefore, this study aimed to determine the cardioprotective effects of H. sabdariffa (roselle) polyphenol-rich extract (HPE) in type-1-induced diabetic rats. Twenty-four male Sprague-Dawley rats were randomized into 4 groups (n = 6/group): nondiabetic, diabetic alone (DM), diabetic supplemented with HPE (DM+HPE), and diabetic supplemented with metformin. Type-1 diabetes was induced with streptozotocin (55 mg/kg intraperitoneally). Rats were forced-fed with HPE (100 mg/kg) and metformin (150 mg/kg) daily for 8 weeks. Results showed that HPE supplementation improved hyperglycemia and dyslipidemia significantly (p < 0.05) in the DM+HPE compared with the DM group. HPE supplementation attenuated cardiac oxidative damage in the DM group, indicated by low malondialdehyde and advanced oxidation protein product. As for the antioxidant status, HPE significantly (p < 0.05) increased glutathione level, as well as catalase and superoxide dismutase 1 and 2 activities. These findings correlate with cardiac function, whereby left ventricle developed pressure in DM+HPE (79.13 ± 3.08 mm Hg) was higher significantly compared with DM (45.84 ± 1.65 mm Hg). Coronary flow of DM+HPE (17.43 ± 0.62 mL/min) was also greater compared with DM (13.02 ± 0.6 mL/min), showing that HPE supplementation improved cardiac contractility and relaxation rate significantly (p < 0.05). Histological analysis showed a marked decrease in cardiomyocyte hypertrophy and fibrosis in DM+HPE compared with the DM group. Ultrastructural changes and impairment of mitochondria induced by diabetes were minimized by HPE supplementation. Collectively, these findings suggest that HPE is a potential cardioprotective agent in a diabetic setting through its hypoglycemic, anti-hyperlipidemia, and antioxidant properties.
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 Cardioprotective Properties of Kaempferol: A Review

Kamisah Y, Jalil J, Yunos NM, Zainalabidin S

Plants (Basel), 2023 May 24;12(11).
PMID: 37299076 DOI: 10.3390/plants12112096

Cardiac diseases, such as myocardial infarction and heart failure, have become a major clinical problem globally. The accumulating data demonstrate that bioactive compounds with antioxidant and anti-inflammatory properties have favorable effects on clinical problems. Kaempferol is a flavonoid found in various plants; it has demonstrated cardioprotective properties in numerous cardiac injury models. This review aims to collate updated information regarding the effects of kaempferol on cardiac injury. Kaempferol improves cardiac function by alleviating myocardial apoptosis, fibrosis, oxidative stress, and inflammation while preserving mitochondrial function and calcium homeostasis. However, the mechanisms of action of its cardioprotective properties remain unclear; therefore, elucidating its action could provide insight into directions for future studies.
Fulltext Impact of prolonged nicotine administration on myocardial function and susceptibility to ischaemia-reperfusion injury in rats

Ramalingam A, Mohd Fauzi N, Budin SB, Zainalabidin S

Basic Clin Pharmacol Toxicol, 2021 Feb;128(2):322-333.
PMID: 32991780 DOI: 10.1111/bcpt.13500

This study investigated the impact of prolonged nicotine administration on myocardial susceptibility to ischaemia-reperfusion (I/R) injury in a rat model and determined whether nicotine affects mitochondrial reactive oxygen species (ROS) production and permeability transition in rat hearts. Sprague-Dawley rats were administered 0.6 or 1.2 mg/kg nicotine for 28 days, and their hearts were isolated at end-point for assessment of myocardial susceptibility to I/R injury ex vivo. Rat heart mitochondria were also isolated from a subset of rats for analysis of mitochondrial ROS production and permeability transition. Compared to the vehicle controls, rat hearts isolated from nicotine-administered rats exhibited poorer left ventricular function that worsened over the course of I/R. Coronary flow rate was also severely impaired in the nicotine groups at baseline and this worsened after I/R. Nicotine administration significantly increased mitochondrial ROS production and permeability transition relative to the vehicle controls. Interestingly, pre-incubation of isolated mitochondria with ROS scavengers (superoxide dismutase and mitoTEMPO) significantly abolished nicotine-induced increase in mitochondria permeability transition in isolated rat heart mitochondria. Overall, our data showed that prolonged nicotine administration enhances myocardial susceptibility to I/R injury in rats and this is associated with mitochondrial ROS-driven increase in mitochondrial permeability transition.
Fulltext Aortic remodelling in chronic nicotine-administered rat

Zainalabidin S, Budin SB, Ramalingam A, Lim YC

Korean J Physiol Pharmacol, 2014 Oct;18(5):411-8.
PMID: 25352761 DOI: 10.4196/kjpp.2014.18.5.411

Vascular remodelling is an adaptive mechanism, which counteracts pressure changes in blood circulation. Nicotine content in cigarette increases the risk of hypertension. The exact relationship between nicotine and vascular remodelling still remain unknown. Current study was aimed to determine the effect of clinically relevant dosage of nicotine (equivalent to light smoker) on aortic reactivity, oxidative stress markers and histomorphological changes. Twelve age-matched male Sprague-Dawley rats were randomly divided into two groups, i.e.: normal saline as control or 0.6 mg/kg nicotine for 28 days (i.p., n=6 per group). On day-29, the rats were sacrificed and the thoracic aorta was dissected immediately for further studies. Mean arterial pressure (MAP) and pulse pressure (PP) of nicotine-treated vs. control were significantly increased (p<0.05). Nicotine-treated group showed significant (p<0.05) increase tunica media thickness, and decrease in lumen diameter, suggesting vascular remodelling which lead to prior hypertension state. The phenylephrine (PE)-induced contractile response in nicotine group was significantly higher than control group (ED50=1.44×10(5) M vs. 4.9×10(6) M) (p<0.05~0.001). However, nicotine-treated rat showed significantly lower endothelium-dependent relaxation response to acetylcholine (ACh) than in control group (ED50=6.17×10(7) M vs. 2.82×10(7) M) (p<0.05), indicating loss of primary vascular function. Malondialdehyde (MDA), a lipid peroxidation marker was significantly higher in nicotine group. Superoxide dismutase (SOD) enzymatic activity and glutathione (GSH) were all reduced in nicotine group (p<0.05) vs. control, suggesting nicotine induces oxidative imbalance. In short, chronic nicotine administration impaired aortic reactivity, probably via redox imbalance and vascular remodelling mechanism.
Lactobacillus casei strain C1 attenuates vascular changes in spontaneously hypertensive rats

Yap WB, Ahmad FM, Lim YC, Zainalabidin S

Korean J Physiol Pharmacol, 2016 Nov;20(6):621-628.
PMID: 27847439

Hypertension can be caused by various factors while the predominant causes include increase in body fluid volume and resistance in the circulatory system that elevate the blood pressure. Consumption of probiotics has been proven to attenuate hypertension; however, the effect is much strain-dependent. In this study, a newly isolated Lactobacillus casei (Lb. casei) strain C1 was investigated for its antihypertensive properties in spontaneously hypertensive rats (SHR). Lactic acid bacteria (LAB) suspension of 11 log colony-forming unit (CFU) was given to SHR (SHR+LAB, n=8), and phosphate buffer saline (PBS) was given as a control in SHR (SHR, n=8) and in Wistar rats as sham (WIS, n=8). The treatment was given via oral gavage for 8 weeks. The results showed that the weekly systolic blood pressure (SBP), mean arterial pressure (MAP), diastolic blood pressure (DBP) and aortic reactivity function were remarkably improved after 8 weeks of bacterial administration in SHR+LAB. These effects were mostly attributed by restoration of wall tension and tensile stress following the bacterial treatment. Although not statistically significant, the level of malondialdehye (MDA) in SHR+LAB serum was found declining. Increased levels of glutathione (GSH) and nitric oxide (NO) in SHR+LAB serum suggested that the bacterium exerted vascular protection through antioxidative functions and relatively high NO level that induced vasodilation. Collectively, Lb. casei strain C1 is a promising alternative for hypertension improvement.
Fulltext Implication of dietary phenolic acids on inflammation in cardiovascular disease

Ali SS, Ahmad WANW, Budin SB, Zainalabidin S

Rev Cardiovasc Med, 2020 Jun 30;21(2):225-240.
PMID: 32706211 DOI: 10.31083/j.rcm.2020.02.49

In spite of medical advances, cardiovascular disease remains a significant concern, imposing a great burden upon the economy and public health of nations by causing the highest morbidity and mortality cases globally. Moreover, it is well established that inflammation is closely linked to the pathogenesis of cardiovascular diseases. Hence, targeting inflammation seems to be a promising strategy in reducing cardiovascular risks. Currently, the importance of natural products in modern medicine is well recognised and continues to be of interest to the pharmaceutical industry. Phenolic acids are a class of phytochemical compounds that are well-known for their health benefits. They consists of various phytochemical constituents and have been widely studied in various disease models. Research involving both animals and humans has proven that phenolic acids possess cardioprotective properties such as anti-hypertensive, anti-hyperlipidemia, anti-fibrotic and anti-hypertrophy activity. Furthermore, numerous studies have proven that phenolic acids in phytochemical constituents such as gallic acid, caffeic acid and chlorogenic acid are promising anti-inflammatory agents. Hence, in this review, we outline and review recent evidence on the role of phenolic acids and their anti-inflammatory significance in studies published during the last 5 years. We also discuss their possible mechanisms of action in modulating inflammation related to cardiovascular disease.
Fulltext Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury

Chung CH, Bretherton B, Zainalabidin S, Deuchars SA, Deuchars J, Mahadi MK

Front Neurosci, 2020;14:906.
PMID: 33013299 DOI: 10.3389/fnins.2020.00906

Background: Myocardial infarction (MI) reperfusion therapy causes paradoxical cardiac complications. Following restoration of blood flow to infarcted regions, a multitude of inflammatory cells are recruited to the site of injury for tissue repair. Continual progression of cardiac inflammatory responses does, however, lead to adverse cardiac remodeling, inevitably causing heart failure.
Main Body: Increasing evidence of the cardioprotective effects of both invasive and non-invasive vagal nerve stimulation (VNS) suggests that these may be feasible methods to treat myocardial ischemia/reperfusion injury via anti-inflammatory regulation. The mechanisms through which auricular VNS controls inflammation are yet to be explored. In this review, we discuss the potential of autonomic nervous system modulation, particularly via the parasympathetic branch, in ameliorating MI. Novel insights are provided about the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages. Acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages polarizes the pro-inflammatory into anti-inflammatory subtypes. Activation of the α7nAChR stimulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This inhibits the secretion of pro-inflammatory cytokines, limiting ischemic injury in the myocardium and initiating efficient reparative mechanisms. We highlight recent developments in the controversial auricular vagal neuro-circuitry and how they may relate to activation of the cholinergic anti-inflammatory pathway.
Conclusion: Emerging published data suggest that auricular VNS is an inexpensive healthcare modality, mediating the dynamic balance between pro- and anti-inflammatory responses in cardiac macrophages and ameliorating cardiac ischemia/reperfusion injury.
Anti-fibrotic Actions of Roselle Extract in Rat Model of Myocardial Infarction

Ali SS, Mohamed SFA, Rozalei NH, Boon YW, Zainalabidin S

Cardiovasc Toxicol, 2019 02;19(1):72-81.
PMID: 30128816 DOI: 10.1007/s12012-018-9478-7

Heart failure-associated morbidity and mortality is largely attributable to extensive and unregulated cardiac remodelling. Roselle (Hibiscus sabdariffa) calyces are enriched with natural polyphenols known for antioxidant and anti-hypertensive effects, yet its effects on early cardiac remodelling in post myocardial infarction (MI) setting are still unclear. Thus, the aim of this study was to investigate the actions of roselle extract on cardiac remodelling in rat model of MI. Male Wistar rats (200-300 g) were randomly allotted into three groups: Control, MI, and MI + Roselle. MI was induced with isoprenaline (ISO) (85 mg/kg, s.c) for two consecutive days followed by roselle treatment (100 mg/kg, orally) for 7 days. Isoprenaline administration showed changes in heart weight to body weight (HW/BW) ratio. MI was especially evident by the elevated cardiac injury marker, troponin-T, and histological observation. Upregulation of plasma levels and cardiac gene expression levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 was seen in MI rats. A relatively high percentage of fibrosis was observed in rat heart tissues with over-expression of collagen (Col)-1 and Col-3 genes following isoprenaline-induced MI. On top of that, cardiomyocyte areas were larger in heart tissues of MI rats with upregulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression, indicating cardiac hypertrophy. Interestingly, roselle supplementation attenuated elevation of plasma troponin-T, IL-6, IL10, and gene expression level of IL-10. Furthermore, reduction of cardiac fibrosis and hypertrophy were observed. In conclusion, roselle treatment was able to limit early cardiac remodelling in MI rat model by alleviating inflammation, fibrosis, and hypertrophy; hence, the potential application of roselle in early adjunctive treatment to prevent heart failure.
Fulltext The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

Jubaidi FF, Zainalabidin S, Taib IS, Hamid ZA, Budin SB

Int J Mol Sci, 2021 May 12;22(10).
PMID: 34065781 DOI: 10.3390/ijms22105094

Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.
Fulltext Genus Parkia: Phytochemical, Medicinal Uses, and Pharmacological Properties

Saleh MSM, Jalil J, Zainalabidin S, Asmadi AY, Mustafa NH, Kamisah Y

Int J Mol Sci, 2021 Jan 09;22(2).
PMID: 33435507 DOI: 10.3390/ijms22020618

The genus Parkia (Fabaceae, Subfamily, Mimosoideae) comprises about 34 species of mostly evergreen trees widely distributed across neotropics, Asia, and Africa. This review aims to provide an overview of the current status of the species from the genus Parkia in terms of its relationship between its phytochemistry and medical uses. Comprehensive information on Parkia species was retrieved from electronic databases, which were Web of Science, ScienceDirect, PubMed, and Google Scholar. This review identified nine species from genus Parkia with properties of medicinal use. They are used traditionally to treat several ailments, such as diabetes, diarrhea, wounds, hypertension, cough, chronic piles, conjunctivitis, and measles. The most common species studied are P. biglobosa, P. speciosa, P. javanica, P. bicolor, P. biglandulosa, P. filicoidea, and P. clappertoniana. A considerable number of secondary metabolites, such as terpenoids, phenolic acids, flavonoids (aglycone and glycosides), and numerous volatile compounds have been identified in this genus, which are responsible for their diverse pharmacological activities. Their extracts, pure compounds and seed lectins have been reported for their anticancer, antimicrobial, antihypertensive, antiulcer, antidiabetic, anti-inflammatory, antioxidant, antimalarial, hepatoprotective, and antidiarrheal activities. The information gathered in this review might be of help for future studies in terms of the current knowledge on the link between the phytochemical components and medicinal uses. This could facilitate more discoveries on its potentials particularly in the pharmacological characteristics and potential to be developed into modern medicines.
Roselle supplementation prevents nicotine-induced vascular endothelial dysfunction and remodelling in rats

Si LY, Kamisah Y, Ramalingam A, Lim YC, Budin SB, Zainalabidin S

Appl Physiol Nutr Metab, 2017 Jul;42(7):765-772.
PMID: 28249121 DOI: 10.1139/apnm-2016-0506

Vascular endothelial dysfunction (VED) plays an important role in the initiation of cardiovascular diseases. Roselle, enriched with antioxidants, demonstrates high potential in alleviating hypertension. This study was undertaken to investigate the effects of roselle supplementation of VED and remodelling in a rodent model with prolonged nicotine administration. Male Sprague-Dawley rats (n = 6 per group) were administered with 0.6 mg/kg nicotine for 28 days to induce VED. The rats were given either aqueous roselle (100 mg/kg) or normal saline orally 30 min prior to nicotine injection daily. One additional group of rats served as control. Thoracic aorta was isolated from rats to measure vascular reactivity, vascular remodelling and oxidative stress. Roselle significantly lowered aortic sensitivity to phenylephrine-induced vasoconstriction (Endo-(+) Cmax = 234.5 ± 3.9%, Endo-(-) Cmax = 247.6 ± 5.2%) compared with untreated nicotine group (Endo-(+) Cmax = 264.5 ± 6.9%, Endo-(-) Cmax = 276.5 ± 6.8%). Roselle also improved aortic response to endothelium-dependent vasodilator, acetylcholine (Endo-(+) Rmax = 73.2 ± 2.1%, Endo-(-) Rmax = 26.2 ± 0.8%) compared to nicotine group (Endo-(+) Rmax = 57.8 ± 1.7%, Endo-(-) Rmax = 20.9 ± 0.8%). In addition, roselle prevented an increase in intimal media thickness and elastic lamellae proliferation to preserve vascular architecture. Moreover, we also observed a significantly lowered degree of oxidative stress in parallel with increased antioxidant enzymes in aortic tissues of the roselle-treated group. This study demonstrated that roselle prevents VED and remodelling, and as such it has high nutraceutical value as supplement to prevent cardiovascular diseases.
Fulltext Angiotensin II Type I Receptor Antagonism Attenuates Nicotine-Induced Cardiac Remodeling, Dysfunction, and Aggravation of Myocardial Ischemia-Reperfusion Injury in Rats

Ramalingam A, Budin SB, Mohd Fauzi N, Ritchie RH, Zainalabidin S

Front Pharmacol, 2019;10:1493.
PMID: 31920673 DOI: 10.3389/fphar.2019.01493

Increased exposure to nicotine contributes to the development of cardiac dysfunction by promoting oxidative stress, fibrosis, and inflammation. These deleterious events altogether render cardiac myocytes more susceptible to acute cardiac insults such as ischemia-reperfusion (I/R) injury. This study sought to elucidate the role of angiotensin II type I (AT1) receptors in cardiac injury resulting from prolonged nicotine administration in a rat model. Male Sprague-Dawley rats were given nicotine (0.6 mg/kg ip) for 28 days to induce cardiac dysfunction, alone or in combination with the AT1 receptor antagonist, irbesartan (10 mg/kg, po). Vehicle-treated rats were used as controls. Rat hearts isolated from each experimental group at study endpoint were examined for changes in function, histology, gene expression, and susceptibility against acute I/R injury determined ex vivo. Rats administered nicotine alone exhibited significantly increased cardiac expression of angiotensin II and angiotensin-converting enzyme (ACE) in addition to elevated systolic blood pressure (SBP) and heart rate. Furthermore, nicotine administration markedly reduced left ventricular (LV) performance with concomitant increases in myocardial oxidative stress, fibrosis, and inflammation. Concomitant treatment with irbesartan attenuated these effects, lowering blood pressure, heart rate, oxidative stress, and expression of fibrotic and inflammatory genes. Importantly, the irbesartan-treated group also manifested reduced susceptibility to I/R injury ex vivo. These findings suggest that AT1 receptors play an important role in nicotine-induced cardiac dysfunction, and pharmacological approaches targeting cardiac AT1 receptors may thus benefit patients with sustained exposure to nicotine.
Fulltext Targeting mitochondrial reactive oxygen species-mediated oxidative stress attenuates nicotine-induced cardiac remodeling and dysfunction

Ramalingam A, Budin SB, Mohd Fauzi N, Ritchie RH, Zainalabidin S

Sci Rep, 2021 07 05;11(1):13845.
PMID: 34226619 DOI: 10.1038/s41598-021-93234-4

Long-term nicotine intake is associated with an increased risk of myocardial damage and dysfunction. However, it remains unclear whether targeting mitochondrial reactive oxygen species (ROS) prevents nicotine-induced cardiac remodeling and dysfunction. This study investigated the effects of mitoTEMPO (a mitochondria-targeted antioxidant), and resveratrol (a sirtuin activator) , on nicotine-induced cardiac remodeling and dysfunction. Sprague-Dawley rats were administered 0.6 mg/kg nicotine daily with 0.7 mg/kg mitoTEMPO, 8 mg/kg resveratrol, or vehicle alone for 28 days. At the end of the study, rat hearts were collected to analyze the cardiac structure, mitochondrial ROS level, oxidative stress, and inflammation markers. A subset of rat hearts was perfused ex vivo to determine the cardiac function and myocardial susceptibility to ischemia-reperfusion injury. Nicotine administration significantly augmented mitochondrial ROS level, cardiomyocyte hypertrophy, fibrosis, and inflammation in rat hearts. Nicotine administration also induced left ventricular dysfunction, which was worsened by ischemia-reperfusion in isolated rat hearts. MitoTEMPO and resveratrol both significantly attenuated the adverse cardiac remodeling induced by nicotine, as well as the aggravation of postischemic ventricular dysfunction. Findings from this study show that targeting mitochondrial ROS with mitoTEMPO or resveratrol partially attenuates nicotine-induced cardiac remodeling and dysfunction.
Role of Polyphenol in Regulating Oxidative Stress, Inflammation, Fibrosis, and Apoptosis in Diabetic Nephropathy

Sapian S, Budin SB, Taib IS, Mariappan V, Zainalabidin S, Chin KY

Endocr Metab Immune Disord Drug Targets, 2021 Nov 19.
PMID: 34802412 DOI: 10.2174/1871530321666211119144309

Diabetic nephropathy (DN) is known as one of the driving sources of end-stage renal disease (ESRD). DN prevalence continues to increase in every corner of the world andthat has been a major concern to healthcare professionals as DN is the key driver of diabetes mellitus (DM) morbidity and mortality. Hyperglycaemia is closely connected with the production of reactive oxygen species (ROS) that cause oxidative stress response as well as numerous cellular and molecular modifications. Oxidative stress is a significant causative factor to renal damage, as it can activate other immunological pathways, such as inflammatory, fibrosis, and apoptosis pathways. These pathways can lead to cellular impairment and death as well as cellular senescence. Natural substances containing bioactive compounds, such as polyphenols, have been reported to exert valuable effects on various pathological conditions, including DM. The role of polyphenols in alleviating DN conditions has been documented in many studies. In this review, the potential of polyphenols in ameliorating the progression of DN via modulation of oxidative stress, inflammation, fibrosis, and apoptosis, as well as cellular senescence, has been addressed. This information may be used as the strategies for the management of DN and development as nutraceutical products to overcome DN development.
Current Updates on Potential Role of Flavonoids in Hypoxia/Reoxygenation Cardiac Injury Model

Ali SS, Noordin L, Bakar RA, Zainalabidin S, Jubri Z, Wan Ahmad WAN

Cardiovasc Toxicol, 2021 08;21(8):605-618.
PMID: 34114196 DOI: 10.1007/s12012-021-09666-x

Clinically, timely reperfusion strategies to re-establish oxygenated blood flow in ischemic heart diseases seem to salvage viable myocardium effectively. Despite the remarkable improvement in cardiac function, reperfusion therapy could paradoxically trigger hypoxic cellular injury and dysfunction. Experimental laboratory models have been developed over the years to explain better the pathophysiology of cardiac ischemia-reperfusion injury, including the in vitro hypoxia-reoxygenation cardiac injury model. Furthermore, the use of nutritional myocardial conditioning techniques have been successful. The cardioprotective potential of flavonoids have been greatly linked to its anti-oxidant, anti-apoptotic and anti-inflammatory properties. While several studies have reviewed the cardioprotective properties of flavonoids, there is a scarce evidence of their function in the hypoxia-reoxygenation injury cell culture model. Hence, the aim of this review was to lay out and summarize our current understanding of flavonoids' function in mitigating hypoxia-reoxygenation cardiac injury based on evidence from the last five years. We also discussed the possible mechanisms of flavonoids in modulating the cardioprotective effects as such information would provide invaluable insight on future therapeutic application of flavonoids.

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