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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.
Fulltext Paternal Fenitrothion Exposures in Rats Causes Sperm DNA Fragmentation in F0 and Histomorphometric Changes in Selected Organs of F1 Generation

Yusoff NA, Taib IS, Budin SB, Mohamed M

Toxics, 2021 Jul 05;9(7).
PMID: 34357902 DOI: 10.3390/toxics9070159

The adverse effects of maternal pesticides exposure on the progeny is very well established. However, the impact of paternal exposure to pesticides such as Fenitrothion (FNT) on the histomorphometry of progeny's organs in unexposed mothers are much less well studied. Therefore, this study aims to evaluate the effects of paternal FNT exposure on the sperm quality of the parent rat and its effects on the histomorphometry of the progeny's organs. Randomly, male Sprague Dawley rats (n = 24) categorized as F0 were distributed equally into three groups namely Control, FNT-10, and FNT-20. Control received 1 mL/kg corn oil while FNT-10 and FNT-20 received 10 mg/kg and 20 mg/kg of FNT, respectively, via oral force feeding for 28 consecutive days. At the end of the study, male rats were mated with unexposed female rats and the male rats were sacrificed to obtain sperm for sperm characterization and DNA damage evaluation. Meanwhile, the rats' progeny (F1) namely pControl, pFNT-10, and pFNT-20 were left to grow until postnatal day 70 before being sacrificed to obtain the matured organs for histology and morphometric analysis. Our results showed that both doses of FNT reduced sperm quality and caused DNA fragmentation in F0 rats compared with the control group (p < 0.05). The number of Leydig cells as well as the diameter of the seminiferous tubules and glomerulus of the pFNT-20 group had significantly decreased (p < 0.05) compared with the pControl group. The Bowman's space of the pFNT-20 group had significantly increased (p < 0.05) compared with the pFNT-10 and pControl groups. Therefore, paternal exposure to FNT reduced the sperm quality and increased sperm DNA fragmentation in F0 male Sprague Dawley rats and altered the histology and morphometry of the selected organs in the F1 progeny.
Chromosomal Analysis in Lineage-Specific Mouse Hematopoietic Stem Cells and Progenitors

Yusoff NA, Abd Hamid Z, Chow PW, Shuib S, Taib IS, Budin SB

Methods Mol Biol, 2024;2736:65-76.
PMID: 36749486 DOI: 10.1007/7651_2022_477

Hematopoiesis is maintained throughout life from the hematopoietic stem cell niche in which hematopoietic stem cells and lineage-specific hematopoietic progenitors (HSPCs) reside and regulate hematopoiesis. Meanwhile, HSPCs behavior is modulated by both cell intrinsic (e.g., transcriptional factors) and cell extrinsic (e.g., cytokines) factors. Dysregulation of these factors can alter HSPCs function, leading to disrupted hematopoiesis, cellular changes, and subsequent hematological diseases and malignancies. Moreover, it has been reported that chromosomal aberration (CA) in HSPCs following exposure to carcinogenic or genotoxic agents can initiate leukemia stem cells (LSCs) formation which lays a fundamental mechanism in leukemogenesis. Despite reported studies concerning the chromosomal integrity in HSPCs, CA analysis in lineage-specific HSPCs remains scarce. This indicates a need for a laboratory technique that allows the study of CA in specific HSPCs subpopulations comprising differential hematopoietic lineages. Thus, this chapter focuses on the structural (clastogenicity) and numerical (aneugenicity) form of CA analysis in lineage-specific HSPCs comprised of myeloid, erythroid and lymphoid lineages.In this protocol, we describe how to perform CA analysis in lineage-specific HSPCs derived from freshly isolated mouse bone marrow cells (MBMCs) using the combined techniques of colony-forming unit (CFU) and karyotyping. Prior to CA analysis, lineage-specific HSPCs for myeloid, erythroid, and lymphoid were enriched through colony-forming unit (CFU) assay. CFU assay assesses the proliferative ability and differentiation potential of an individual HSPC within a sample. About 6 to 14 days of cultures are required depending on the type of HSPCs lineage. The optimal duration is crucial to achieve sufficient colony growth that is needed for accurate CFU analysis via morphological identification and colony counting. Then, the CA focusing on clastogenicity and aneugenicity anomalies in respective HSPCs lineage for myeloid, erythroid and Pre-B lymphoid were investigated. The resulted karyotypes were classified according to the types of CA known as Robertsonian (Rb) translocation, hyperploidy or complex. We believe our protocol offers a significant contribution to be utilized as a reference method for chromosomal analysis in lineage-specific HSPCs subpopulations.
Linking Benzene, in Utero Carcinogenicity and Fetal Hematopoietic Stem Cell Niches: A Mechanistic Review

Yusoff NA, Abd Hamid Z, Budin SB, Taib IS

Int J Mol Sci, 2023 Mar 28;24(7).
PMID: 37047305 DOI: 10.3390/ijms24076335

Previous research reported that prolonged benzene exposure during in utero fetal development causes greater fetal abnormalities than in adult-stage exposure. This phenomenon increases the risk for disease development at the fetal stage, particularly carcinogenesis, which is mainly associated with hematological malignancies. Benzene has been reported to potentially act via multiple modes of action that target the hematopoietic stem cell (HSCs) niche, a complex microenvironment in which HSCs and multilineage hematopoietic stem and progenitor cells (HSPCs) reside. Oxidative stress, chromosomal aberration and epigenetic modification are among the known mechanisms mediating benzene-induced genetic and epigenetic modification in fetal stem cells leading to in utero carcinogenesis. Hence, it is crucial to monitor exposure to carcinogenic benzene via environmental, occupational or lifestyle factors among pregnant women. Benzene is a well-known cause of adult leukemia. However, proof of benzene involvement with childhood leukemia remains scarce despite previously reported research linking incidences of hematological disorders and maternal benzene exposure. Furthermore, accumulating evidence has shown that maternal benzene exposure is able to alter the developmental and functional properties of HSPCs, leading to hematological disorders in fetus and children. Since HSPCs are parental blood cells that regulate hematopoiesis during the fetal and adult stages, benzene exposure that targets HSPCs may induce damage to the population and trigger the development of hematological diseases. Therefore, the mechanism of in utero carcinogenicity by benzene in targeting fetal HSPCs is the primary focus of this review.
Fulltext Foot sensation status of Malay women with type 2 diabetes mellitus

Yong SP, Kamaralzaman S, Budin SB

Jurnal Sains Kesihatan Malaysia, 2012;10(2):43-47.
MyJurnal

This study aimed to identify the foot sensory status of Malay women with type 2 diabetes mellitus and to determine its relation with: demographic factors, glycated haemoglobin level in plasma, and body mass index. A cross-sectional study was conducted on 71 Malay women with type 2 diabetes mellitus who attend three health clinics in Hulu Langat District, Selangor. Foot sensation was assessed using the Semmes-Weinstein Monofilament 5.07 in nine locations on the plantar and dorsal of the feet. Loss of protective sensation was defined as inability to sense the monofilament in one or more sites of either foot. This study found that 56.3% of women had loss of protective sensation, with common sites being the heel, fifth metatarsal head, lateral mid-foot and little toe. Duration of diabetes mellitus were significantly related to foot sensation. The age, HbA1C level and body mass index did not show any significant correlation. Loss of protective sensation may lead to serious foot complication and therefore early screening involving multidisciplinary team is essential for prevention.
Fulltext Toxic effects of Litsea elliptica Blume essential oil on red blood cells of Sprague-Dawley rats

Taib IS, Budin SB, Siti Nor Ain SM, Mohamed J, Louis SR, Das S, et al.

J Zhejiang Univ Sci B, 2009 Nov;10(11):813-9.
PMID: 19882755 DOI: 10.1631/jzus.B0920199

Litsea elliptica Blume leaves have been traditionally used as medicinal herbs because of its antimutagenicity, chemopreventative and insecticidal properties. In this study, the toxic effects of L. elliptica essential oil against Sprague-Dawley rat's red blood cells (RBCs) were evaluated. L. elliptica essential oil was given by oral gavage 5 times per week for 3 treated groups in the doses of 125, 250, and 500 mg/(kg body weight), respectively, and the control group received distilled water. Full blood count, RBC osmotic fragility, RBC morphological changes, and RBC membrane lipid were analyzed 28 d after the treatment. Although L. elliptica essential oil administration had significantly different effects on hemoglobin (Hb), mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), and mean cell hemoglobin (MCH) in the experimental groups as compared to the control group (P<0.05), the values were still within the normal range. L. elliptica induced morphological changes of RBC into the form of echinocyte. The percentage of echinocyte increased significantly among the treated groups in a dose-response manner (P<0.001). The concentrations of RBC membrane phospholipids and cholesterol of all treated groups were significantly lower than those of control group (P<0.001). However, the RBC membrane osmotic fragility and total proteins of RBC membrane findings did not differ significantly between control and treated groups (P>0.05). It is concluded that structural changes in the RBC membrane due to L. elliptica essential oil administration did not cause severe membrane damage.
Fenitrothion alters sperm characteristics in rats: ameliorating effects of palm oil tocotrienol-rich fraction

Taib IS, Budin SB, Ghazali AR, Jayusman PA, Mohamed J

Exp Anim, 2014;63(4):383-93.
PMID: 25030881

Exposure to organophosphate insecticides such as fenitrothion (FNT) in agriculture and public health has been reported to affect sperm quality. Antioxidants may have a potential to reduce spermatotoxic effects induced by organophosphate. The present study was carried out to evaluate the effects of palm oil tocotrienol-rich fraction (TRF) in reducing the detrimental effects occurring in spermatozoa of FNT-treated rats. Adult male Sprague-Dawley rats were divided into four equal groups: a control group and groups of rats treated orally with palm oil TRF (200 mg/kg), FNT (20 mg/kg) and palm oil TRF (200 mg/kg) combined with FNT (20 mg/kg). The sperm characteristics, DNA damage, superoxide dismutase (SOD) activity, and levels of reduced glutathione (GSH), malondialdehyde (MDA), and protein carbonyl (PC) were evaluated. Supplementation with TRF attenuated the detrimental effects of FNT by significantly increasing the sperm counts, motility, and viability and decreased the abnormal sperm morphology. The SOD activity and GSH level were significantly increased, whereas the MDA and PC levels were significantly decreased in the TRF+FNT group compared with the rats receiving FNT alone. TRF significantly decreased the DNA damage in the sperm of FNT-treated rats. A significant correlation between abnormal sperm morphology and DNA damage was found in all groups. TRF showed the potential to reduce the detrimental effects occurring in spermatozoa of FNT-treated rats.
Fenitrothion induced oxidative stress and morphological alterations of sperm and testes in male Sprague-Dawley rats

Taib IS, Budin SB, Ghazali AR, Jayusman PA, Louis SR, Mohamed J

Clinics (Sao Paulo), 2013 Jan;68(1):93-100.
PMID: 23420164

OBJECTIVE: Fenitrothion residue is found primarily in soil, water and food products and can lead to a variety of toxic effects on the immune, hepatobiliary and hematological systems. However, the effects of fenitrothion on the male reproductive system remain unclear. This study aimed to evaluate the effects of fenitrothion on the sperm and testes of male Sprague-Dawley rats.
METHODS: A 20 mg/kg dose of fenitrothion was administered orally by gavages for 28 consecutive days. Blood sample was obtained by cardiac puncture and dissection of the testes and cauda epididymis was performed to obtain sperm. The effects of fenitrothion on the body and organ weight, biochemical and oxidative stress, sperm characteristics, histology and ultrastructural changes in the testes were evaluated.
RESULTS: Fenitrothion significantly decreased the body weight gain and weight of the epididymis compared with the control group. Fenitrothion also decreased plasma cholinesterase activity compared with the control group. Fenitrothion altered the sperm characteristics, such as sperm concentration, sperm viability and normal sperm morphology, compared with the control group. Oxidative stress markers, such as malondialdehyde, protein carbonyl, total glutathione and glutathione S-transferase, were significantly increased and superoxide dismutase activity was significantly decreased in the fenitrothion-treated group compared with the control group. The histopathological and ultrastructural examination of the testes of the fenitrothion-treated group revealed alterations corresponding with the biochemical changes compared with the control group.
CONCLUSION: A 20 mg/kg dose of fenitrothion caused deleterious effects on the sperm and testes of Sprague-Dawley rats.
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.
Roselle is cardioprotective in diet-induced obesity rat model with myocardial infarction

Si LY, Ali SAM, Latip J, Fauzi NM, Budin SB, Zainalabidin S

Life Sci, 2017 Dec 15;191:157-165.
PMID: 29066253 DOI: 10.1016/j.lfs.2017.10.030

AIMS: Obesity increase the risks of hypertension and myocardial infarction (MI) mediated by oxidative stress. This study was undertaken to investigate the actions of roselle aqueous extract (R) on cardiotoxicity in obese (OB) rats and thereon OB rats subjected to MI.
MAIN METHODS: Male Sprague-Dawley rats were fed with either normal diet or high-fat diet for 8weeks. Firstly, OB rats were divided into (1) OB and (2) OB+R (100mg/kg, p.o, 28days). Then, OB rats were subjected to MI (ISO, 85mg/kg, s.c, 2days) and divided into three groups: (1) OB+MI, (2) OB+MI+R and (3) OB+MI+enalapril for another 4weeks.
KEY FINDINGS: Roselle ameliorated OB and OB+MI's cardiac systolic dysfunction and reduced cardiac hypertrophy and fibrosis. The increased oxidative markers and decreased antioxidant enzymes in OB and OB+MI groups were all attenuated by roselle.
SIGNIFICANCE: These observations indicate the protective effect of roselle on cardiac dysfunction in OB and OB+MI rats, which suggest its potential to be developed as a nutraceutical product for obese and obese patients with MI in the future.
Fulltext Roselle attenuates cardiac hypertrophy after myocardial infarction in vivo and in vitro

Si LY, Ramalingam A, Ali SS, Aminuddin A, Ng PY, Latip J, et al.

EXCLI J, 2019;18:876-892.
PMID: 31645847 DOI: 10.17179/excli2019-1792

Roselle (Hibiscus sabdariffa Linn) has been traditionally used as folk medicine for hypertension and maintaining cardiovascular health, with therapeutic potential in protecting against numerous cardiovascular diseases. However, it remains unclear whether roselle can be used for management of cardiac hypertrophy seen after myocardial infarction (MI). This study therefore investigated the effects of aqueous roselle extract on cardiac hypertrophy arising from myocardial infarction both in vivo and in vitro. For in vivo study, male Sprague-Dawley rats were divided into control or MI groups (receiving 85 mg/kg isoproterenol s.c. for 2 days) and were given roselle extract (100 mg/kg, p.o daily) for 28 days. Cardiac structure and functional changes were evaluated at study end-point using histology, Langendorff analysis and gene expression analysis. In vitro effects of roselle were also assessed on ANG II-induced cardiomyocytes hypertrophy using H9c2 cells, simulating cardiac hypertrophy evident after MI. Roselle significantly ameliorated MI-induced cardiac systolic and diastolic dysfunction, as seen across improvement in left ventricular developed pressure (LVDP) and its derivative (LVdP/dtmax) and isovolumic relaxation (Tau). Oxidative stress evident across elevated pro-oxidant markers (NOX2 subunit of NADPH oxidase and 8-isoprostane) as well as reduced antioxidant markers (superoxide dismutase and glutathione) were also significantly attenuated by roselle. Furthermore, roselle treatment markedly reduced markers of cardiac remodeling (cardiac hypertrophy and fibrosis) compared to the untreated MI rats. On in vitro analysis, roselle significantly attenuated ANG II-induced cardiomyoycte hypertrophy in dose-dependent manner. This study demonstrated that roselle attenuates cardiac hypertrophy and dysfunction seen after MI both in vivo and in vitro, and these effects are likely mediated by phenolic compounds found in roselle extract.
The Role of Promyelocytic Leukemia Zinc Finger (PLZF) and Glial-Derived Neurotrophic Factor Family Receptor Alpha 1 (GFRα1) in the Cryopreservation of Spermatogonia Stem Cells

Shamhari A', Jefferi NES, Abd Hamid Z, Budin SB, Idris MHM, Taib IS

Int J Mol Sci, 2023 Jan 18;24(3).
PMID: 36768269 DOI: 10.3390/ijms24031945

The cryopreservation of spermatogonia stem cells (SSCs) has been widely used as an alternative treatment for infertility. However, cryopreservation itself induces cryoinjury due to oxidative and osmotic stress, leading to reduction in the survival rate and functionality of SSCs. Glial-derived neurotrophic factor family receptor alpha 1 (GFRα1) and promyelocytic leukemia zinc finger (PLZF) are expressed during the self-renewal and differentiation of SSCs, making them key tools for identifying the functionality of SSCs. To the best of our knowledge, the involvement of GFRα1 and PLZF in determining the functionality of SSCs after cryopreservation with therapeutic intervention is limited. Therefore, the purpose of this review is to determine the role of GFRα1 and PLZF as biomarkers for evaluating the functionality of SSCs in cryopreservation with therapeutic intervention. Therapeutic intervention, such as the use of antioxidants, and enhancement in cryopreservation protocols, such as cell encapsulation, cryoprotectant agents (CPA), and equilibrium of time and temperature increase the expression of GFRα1 and PLZF, resulting in maintaining the functionality of SSCs. In conclusion, GFRα1 and PLZF have the potential as biomarkers in cryopreservation with therapeutic intervention of SSCs to ensure the functionality of the stem cells.
Fulltext Bisphenol A and Its Analogues Deteriorate the Hormones Physiological Function of the Male Reproductive System: A Mini-Review

Shamhari A', Abd Hamid Z, Budin SB, Shamsudin NJ, Taib IS

Biomedicines, 2021 Nov 22;9(11).
PMID: 34829973 DOI: 10.3390/biomedicines9111744

BPA is identified as an endocrine-disrupting chemical that deteriorates the physiological function of the hormones of the male reproductive system. Bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF) are actively explored as substitutes for BPA and are known as BPA analogues in most manufacturing industries. These analogues may demonstrate the same adverse effects as BPA on the male reproductive system; however, toxicological data explaining the male reproductive hormones' physiological functions are still limited. Hence, this mini-review discusses the effects of BPA and its analogues on the physiological functions of hormones in the male reproductive system, focusing on the hypothalamus-pituitary-gonad (HPG) axis, steroidogenesis, and spermatogenesis outcomes. The BPA analogues mainly show a similar negative effect on the hormones' physiological functions, proven by alterations in the HPG axis and steroidogenesis via activation of the aromatase activity and reduction of spermatogenesis outcomes when compared to BPA in in vitro and in vivo studies. Human biomonitoring studies also provide significant adverse effects on the physiological functions of hormones in the male reproductive system. In conclusion, BPA and its analogues deteriorate the physiological functions of hormones in the male reproductive system as per in vitro, in vivo, and human biomonitoring studies.
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.
Fulltext The Role of Anthocyanin in Modulating Diabetic Cardiovascular Disease and Its Potential to Be Developed as a Nutraceutical

Sapian S, Taib IS, Katas H, Latip J, Zainalabidin S, Hamid ZA, et al.

Pharmaceuticals (Basel), 2022 Oct 30;15(11).
PMID: 36355516 DOI: 10.3390/ph15111344

Cardiovascular disease (CVD) is directly linked to diabetes mellitus (DM), and its morbidity and mortality are rising at an alarming rate. Individuals with DM experience significantly worse clinical outcomes due to heart failure as a CVD consequence than non-diabetic patients. Hyperglycemia is the main culprit that triggers the activation of oxidative damage, inflammation, fibrosis, and apoptosis pathways that aggravate diabetic CVD progression. In recent years, the development of phytochemical-based nutraceutical products for diabetic treatment has risen due to their therapeutic properties. Anthocyanin, which can be found in various types of plants, has been proposed for preventing and treating various diseases, and has elicited excellent antioxidative, anti-inflammation, anti-fibrosis, and anti-apoptosis effects. In preclinical and clinical studies, plants rich in anthocyanin have been reported to attenuate diabetic CVD. Therefore, the development of anthocyanin as a nutraceutical in managing diabetic CVD is in demand. In this review, we unveil the role of anthocyanin in modulating diabetic CVD, and its potential to be developed as a nutraceutical for a therapeutic strategy in managing CVD associated with DM.
Fulltext Therapeutic Approach of Flavonoid in Ameliorating Diabetic Cardiomyopathy by Targeting Mitochondrial-Induced Oxidative Stress

Sapian S, Taib IS, Latip J, Katas H, Chin KY, Mohd Nor NA, et al.

Int J Mol Sci, 2021 Oct 27;22(21).
PMID: 34769045 DOI: 10.3390/ijms222111616

Diabetes cardiomyopathy is one of the key factors of mortality among diabetic patients around the globe. One of the prior contributors to the progression of diabetic cardiomyopathy is cardiac mitochondrial dysfunction. The cardiac mitochondrial dysfunction can induce oxidative stress in cardiomyocytes and was found to be the cause of majority of the heart morphological and dynamical changes in diabetic cardiomyopathy. To slow down the occurrence of diabetic cardiomyopathy, it is crucial to discover therapeutic agents that target mitochondrial-induced oxidative stress. Flavonoid is a plentiful phytochemical in plants that shows a wide range of biological actions against human diseases. Flavonoids have been extensively documented for their ability to protect the heart from diabetic cardiomyopathy. Flavonoids' ability to alleviate diabetic cardiomyopathy is primarily attributed to their antioxidant properties. In this review, we present the mechanisms involved in flavonoid therapies in ameliorating mitochondrial-induced oxidative stress in diabetic cardiomyopathy.
Fulltext Effects of Canarium odontophyllum leaves on plasma glucose and T lymphocyte population in streptozotocin-induced diabetic rats

Saari SM, Basri DF, Budin SB, Warif NM

Saudi J Biol Sci, 2017 Feb;24(2):320-323.
PMID: 28149168 DOI: 10.1016/j.sjbs.2015.09.032

Type 1 diabetes mellitus is a chronic disease characterized by lack of insulin production. Immune mechanisms are implicated in the pathogenesis of Type 1 diabetes. Canarium odontophyllum (CO) fruits and leaves have been shown to possess high antioxidant activity. This study was conducted to evaluate the effects of CO leaves aqueous extract on the blood glucose and T lymphocyte population in the spleen of streptozotocin (STZ)-induced diabetic rats. Nineteen male Sprague-Dawley rats were randomly divided into three groups: normal, diabetic control and CO treated diabetic groups. Diabetes was induced by a single intraperitoneal injection of 65 mg STZ/kg body weight. The extract of CO leaves was administered orally by force feeding daily at the dose of 300 mg/kg for 28 days. The rats were sacrificed at the end of the study and the spleen was harvested for flow cytometry analysis. The results showed a significant decrease in body weight of diabetic and CO treated diabetic groups compared with the normal group (p
Protective Role of Natural Products in Cisplatin-Induced Nephrotoxicity

Ridzuan NRA, Rashid NA, Othman F, Budin SB, Hussan F, Teoh SL

Mini Rev Med Chem, 2019;19(14):1134-1143.
PMID: 30894108 DOI: 10.2174/1389557519666190320124438

Cisplatin is a widely used antineoplastic agent for the treatment of metastatic tumors, advanced bladder cancer and many other solid tumors. However, at higher doses, toxicities such as nephrotoxicity may appear. Cisplatin leads to DNA damage and subsequently renal cell death. Besides that, oxidative stress is also implicated as one of the main causes of nephrotoxicity. Several studies showed that numerous natural products: ginseng, curcumin, licorice, honey and pomegranate were able to reduce the oxidative stress by restoring the levels of antioxidant enzymes and also at the same time act as an anti-inflammatory agent. Furthermore, pre-treatment with vitamin supplementation, such as vitamin C, E and riboflavin markedly decreased serum urea and increased the levels of antioxidant enzymes in the kidney even after cisplatin induction in cancer patients. These natural products possess potent antioxidant and anti-inflammatory medicinal properties, and they can be safely used as a supplementary regime or combination therapy against cisplatin-induced nephrotoxicity. The present review focused on the protective role of a few natural products which is widely used in folk medicines in cisplatin-induced nephrotoxicity.
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.

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