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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 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 Antioxidant and Anti-Inflammatory Effects of Genus Gynura: A Systematic Review

Tan JN, Mohd Saffian S, Buang F, Jubri Z, Jantan I, Husain K, et al.

Front Pharmacol, 2020;11:504624.
PMID: 33328981 DOI: 10.3389/fphar.2020.504624

Background:Gynura species have been used traditionally to treat various ailments, such as fever, pain, and to control blood glucose level. This systematic review critically discusses studies regarding Gynura species that exhibited antioxidant and anti-inflammatory effects, thus providing perspectives and instructions for future research of the plants as a potential source of new dietary supplements or medicinal agents. Methods: A literature search from internet databases of PubMed, Scopus, Science Direct, e-theses Online Service, and ProQuest was carried out using a combination of keywords such as "Gynura," "antioxidant," "anti-inflammatory," or other related words. Research articles were included in this study if they were experimental (in vitro and in vivo) or clinical studies on the antioxidant or anti-inflammatory effects of Gynura species and if they were articles published in English. Results: Altogether, 27 studies on antioxidant and anti-inflammatory effects of Gynura species were selected. The antioxidant effects of Gynura species were manifested by inhibition of reactive oxygen species production and lipid peroxidation, modulation of glutathione-related parameters, and enzymatic antioxidant production or activities. The anti-inflammatory effects of Gynura species were through the modulation of inflammatory cytokine production, inhibition of prostaglandin E2 and nitric oxide production, cellular inflammatory-related parameters, and inflammation in animal models. The potential anti-inflammatory signaling pathways modulated by Gynura species are glycogen synthase kinase-3, nuclear factor erythroid 2-related factor 2, PPARγ, MAPK, NF-κB, and PI3K/Akt. However, most reports on antioxidant and anti-inflammatory effects of the plants were on crude extracts, and the chemical constituents contributing to bioactivities were not clearly understood. There is a variation in quality of studies in terms of design, conduct, and interpretation, and in-depth studies on the underlying mechanisms involved in antioxidant and anti-inflammatory effects of the plants are in demand. Moreover, there is limited clinical study on antioxidant and anti-inflammatory effects of Gynura species. Conclusion: This review highlighted antioxidant and anti-inflammatory effects of genus Gynura and supported their traditional uses to treat oxidative stress and inflammatory-related diseases. This review is expected to catalyze further studies on genus Gynura. However, extensive preclinical data need to be generated from toxicity and pharmacokinetic studies before clinical studies can be pursued for their development into clinical medicines to treat oxidative stress and inflammatory conditions.
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.
Fulltext Gynura procumbens ethanol extract improves vascular dysfunction by suppressing inflammation in postmenopausal rats fed a high-fat diet

Ahmad Nazri KA, Haji Mohd Saad Q, Mohd Fauzi N, Buang F, Jantan I, Jubri Z

Pharm Biol, 2021 Dec;59(1):1203-1215.
PMID: 34493166 DOI: 10.1080/13880209.2021.1970199

CONTEXT: Gynura procumbens (Lour.) Merr. (Asteraceae) has been reported to have various pharmacological activities including anti-inflammatory effects.
OBJECTIVE: This study sought to determine whether Gynura procumbens (GP) could improve vascular reactivity by suppressing inflammation in postmenopausal rats fed with five-times heated palm oil (5HPO) diet.
MATERIALS AND METHODS: Forty-eight female Sprague-Dawley rats were randomly divided into sham [non-ovariectomized; grouped as control, GP extracts (250 and 500 mg/kg), atorvastatin (ATV, 10 mg/kg)] and postmenopausal (PM) groups [ovariectomized rats fed with 5HPO; grouped as PM, GP extracts (250 and 500 mg/kg) and ATV (10 mg/kg)]. Each group (n = 6) was either supplemented with GP extract or ATV orally once daily for 6 months.
RESULTS: In comparison with the untreated PM group, 250 and 500 mg/kg GP supplementation to PM groups reduced the systolic blood pressure (103 ± 2.7, 86 ± 2.4 vs. 156 ± 7.83 mmHg, p
Validation study of AR Gynae endotrainer - a new mobile laparoscopic simulator

Omar AA, Zon EM, Ismail MP, Mahdi M, Ibrahim A, Engku-Husna EI, et al.

Med J Malaysia, 2023 Nov;78(6):711-716.
PMID: 38031211

INTRODUCTION: In gynaecology, laparoscopy is the choice of treatment for a lot of procedures as it is considered safe and effective. However, laparoscopic surgery requires skills that are different from those required for open surgery. In order to acquire the skills, a surgeon needs specific training. The aim of this study was to validate the AR Gynae endotrainer, a new mobile laparoscopic simulator, as a comparable box trainer for gynaecology laparoscopic training, comparing it with the well-established Karl Storz SZABO-BERCISACKIER laparoscopic trainer.
MATERIALS AND METHODS: A randomised prospective crossover study was designed to compare the AR Gynae endotrainer versus Karl Storz SZABO-BERCI-SACKIER laparoscopic trainer as a tool for training gynaecology laparoscopic skills. Participants were assigned to perform two specially designed tasks used for laparoscopic training using both endotrainers. All subjects evaluated both simulators concerning their performance by the use of a questionnaire comparing: design, ports placement, visibility, ergonomics, triangulation of movement, fulcrum effect, depth perception, ambidexterity, resources for training, and resources for teaching. The overall score was defined as the median value obtained. The ability and time taken for participants to complete the tasks using both endotrainers were also compared. A total of 26 participants were enrolled in this study, including 13 Masters's students from the Department of Obstetrics & Gynaecology and 13 Masters's students from the Department of Surgery, Hospital Universiti Sains Malaysia (HUSM), Kelantan, Malaysia.
RESULTS: A better performance was observed with AR Gynae as compared to Karl Storz endotrainer in five out of ten items evaluated in the questionnaire. Additionally, the overall score of AR Gynae endotrainer (median of 3.98) was comparable to that of Karl Storz endotrainer (median of 3.91) with p=0.519. For the items design and resources for teaching, the evaluation for AR Gynae endotrainer was significantly higher with p-values of 0.003 and 0.032, respectively. All participants were able to complete both tasks using both endotrainers. The time taken to complete both tasks was comparable on both endotrainers. Also, the AR Gynae endotrainer was cheaper.
CONCLUSIONS: The AR Gynae endotrainer was found to be a convenient and cost-effective laparoscopic simulator for gynaecology laparoscopic training and was comparable to the established Karl Storz SZABO-BERCI-SACKIER laparoscopic trainer.
Immunosuppressive Effects of Annona muricata L. Leaf Extract on Cellular and Humoral Immune Responses in Male Wistar Rats

Abdul Wahab SM, Husain K, Jantan I, Arshad L, Haque MA, Mohd Fauzi N, et al.

Curr Pharm Biotechnol, 2023;24(11):1465-1477.
PMID: 36545731 DOI: 10.2174/1389201024666221221113020

BACKGROUND: Annona muricata L. (Annonaceae) (AM)'s remarkable anti-inflammatory and anti-cancer activities make it a targeted plant to be explored for its immunomodulatory properties. Traditional practitioners have employed various components of AM to cure a variety of ailments, including cancer, diabetes, and inflammation.
OBJECTIVE: The present study evaluated the immunosuppressive effects of 80% ethanol extract of of AM leaves in male Wistar rats on different parameters of humoral and cellular immune responses.
METHODS: AM leaf extract (AMLE) was analyzed using UHPLC-MS/MS to profile its secondary metabolites. AMLE was rich in polyphenols which include (epi)catechin-(epi)catechin-(epi) catechin, caffeic acid, coumaroylquinic acid, hyperin, kaempferol, quinic acid and rutin. The rats were administered 100, 200 and 400 mg/kg bw of the extract daily for 14 days. The effects of AMLE on innate immune responses were determined by evaluating phagocytosis, neutrophils migration, reactive oxygen species (ROS) release, CD11b/CD18 integrin expression, and ceruloplasmin, lysozyme and myeloperoxidase (MPO) levels. The adaptive immune parameters were evaluated by immunizing the rats with sheep red blood cells (sRBC) on day 0 and administered orally with AMLE for 14 days.
RESULTS: AMLE established significant immunosuppressive effects on the innate immune parameters by inhibiting the neutrophil migration, ROS production, phagocytic activity and expression of CD11b/CD18 integrin in a dose-dependent pattern. AMLE also suppressed ceruloplasmin, MPO and lysozyme expressions in the rat plasma dose-dependently. AMLE dose-dependently inhibited T and B lymphocytes proliferation, Th1 and Th2 cytokine production, CD4+ and CD8+ co-expression in splenocytes, immunoglobulins (IgM and IgG) expression and the sRBC-induced swelling rate of rat paw in delayed-type hypersensitivity (DTH).
CONCLUSION: The strong inhibitory effects on the different parameters of humoral and cellular responses indicate that AMLE has potential to be an important source of effective immunosuppressive agents.
Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines

Mohd Aluwi MF, Rullah K, Yamin BM, Leong SW, Abdul Bahari MN, Lim SJ, et al.

Bioorg Med Chem Lett, 2016 05 15;26(10):2531-8.
PMID: 27040659 DOI: 10.1016/j.bmcl.2016.03.092

The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.