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  1. Kumbargere Nagraj S, Eachempati P, Uma E, Singh VP, Ismail NM, Varghese E
    Cochrane Database Syst Rev, 2019 Dec 11;12(12):CD012213.
    PMID: 31825092 DOI: 10.1002/14651858.CD012213.pub2
    BACKGROUND: Halitosis or bad breath is a symptom in which a noticeably unpleasant breath odour is present due to an underlying oral or systemic disease. 50% to 60% of the world population has experienced this problem which can lead to social stigma and loss of self-confidence. Multiple interventions have been tried to control halitosis ranging from mouthwashes and toothpastes to lasers. This new Cochrane Review incorporates Cochrane Reviews previously published on tongue scraping and mouthrinses for halitosis.

    OBJECTIVES: The objectives of this review were to assess the effects of various interventions used to control halitosis due to oral diseases only. We excluded studies including patients with halitosis secondary to systemic disease and halitosis-masking interventions.

    SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 8 April 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 3) in the Cochrane Library (searched 8 April 2019), MEDLINE Ovid (1946 to 8 April 2019), and Embase Ovid (1980 to 8 April 2019). We also searched LILACS BIREME (1982 to 19 April 2019), the National Database of Indian Medical Journals (1985 to 19 April 2019), OpenGrey (1992 to 19 April 2019), and CINAHL EBSCO (1937 to 19 April 2019). The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (8 April 2019), the World Health Organization International Clinical Trials Registry Platform (8 April 2019), the ISRCTN Registry (19 April 2019), the Clinical Trials Registry - India (19 April 2019), were searched for ongoing trials. We also searched the cross-references of included studies and systematic reviews published on the topic. No restrictions were placed on the language or date of publication when searching the electronic databases.

    SELECTION CRITERIA: We included randomised controlled trials (RCTs) which involved adults over the age of 16, and any intervention for managing halitosis compared to another or placebo, or no intervention. The active interventions or controls were administered over a minimum of one week and with no upper time limit. We excluded quasi-randomised trials, trials comparing the results for less than one week follow-up, and studies including advanced periodontitis.

    DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently selected trials, extracted data, and assessed risk of bias. We estimated mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach.

    MAIN RESULTS: We included 44 trials in the review with 1809 participants comparing an intervention with a placebo or a control. The age of participants ranged from 17 to 77 years. Most of the trials reported on short-term follow-up (ranging from one week to four weeks). Only one trial reported long-term follow-up (three months). Three studies were at low overall risk of bias, 16 at high overall risk of bias, and the remaining 25 at unclear overall risk of bias. We compared different types of interventions which were categorised as mechanical debridement, chewing gums, systemic deodorising agents, topical agents, toothpastes, mouthrinse/mouthwash, tablets, and combination methods. Mechanical debridement: for mechanical tongue cleaning versus no tongue cleaning, the evidence was very uncertain for the outcome dentist-reported organoleptic test (OLT) scores (MD -0.20, 95% CI -0.34 to -0.07; 2 trials, 46 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Chewing gums: for 0.6% eucalyptus chewing gum versus placebo chewing gum, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.10, 95% CI -0.31 to 0.11; 1 trial, 65 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Systemic deodorising agents: for 1000 mg champignon versus placebo, the evidence was very uncertain for the outcome patient-reported visual analogue scale (VAS) scores (MD -1.07, 95% CI -14.51 to 12.37; 1 trial, 40 participants; very low-certainty evidence). No data were reported for dentist-reported OLT score or adverse events. Topical agents: for hinokitiol gel versus placebo gel, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.27, 95% CI -1.26 to 0.72; 1 trial, 18 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Toothpastes: for 0.3% triclosan toothpaste versus control toothpaste, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -3.48, 95% CI -3.77 to -3.19; 1 trial, 81 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Mouthrinse/mouthwash: for mouthwash containing chlorhexidine and zinc acetate versus placebo mouthwash, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.20, 95% CI -0.58 to 0.18; 1 trial, 44 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Tablets: no data were reported on key outcomes for this comparison. Combination methods: for brushing plus cetylpyridium mouthwash versus brushing, the evidence was uncertain for the outcome dentist-reported OLT scores (MD -0.48, 95% CI -0.72 to -0.24; 1 trial, 70 participants; low-certainty evidence). No data were reported for patient-reported OLT score or adverse events.

    AUTHORS' CONCLUSIONS: We found low- to very low-certainty evidence to support the effectiveness of interventions for managing halitosis compared to placebo or control for the OLT and patient-reported outcomes tested. We were unable to draw any conclusions regarding the superiority of any intervention or concentration. Well-planned RCTs need to be conducted by standardising the interventions and concentrations.

  2. Ismail NM, Abdul Ghafar N, Jaarin K, Khine JH, Top GM
    Int J Food Sci Nutr, 2000;51 Suppl:S79-94.
    PMID: 11271860
    The present study aims to examine the effects of a palm-oil-derived vitamin E mixture containing tocotrienol (approximately 70%) and tocopherol (approximately 30%) on plasma lipids and on the formation of atherosclerotic plaques in rabbits given a 2% cholesterol diet. Eighteen New Zealand White rabbits (2.2-2.8 kg) were divided into three groups; group 1 (control) was fed a normal diet, group 2 (AT) was fed a 2% cholesterol diet and group 3 (PV) was fed a 2% cholesterol diet with oral palm vitamin E (60 mg/kg body weight) given daily for 10 weeks. There were no differences in the total cholesterol and triacylglycerol levels between the AT and PV groups. The PV group had a significantly higher concentrations of HDL-c and a lower TC/HDL-c ratio compared to the AT group (P < 0.003). The aortic tissue content of cholesterol and atherosclerotic lesions were comparable in both the AT and PV groups. However, the PV group had a lower content of plasma and aortic tissue malondialdehyde (P < 0.005). Our findings suggest that despite a highly atherogenic diet, palm vitamin E improved some important plasma lipid parameters, reduced lipid peroxidation but did not have an effect on the atherosclerotic plaque formation.
  3. Kung AW, Chao HT, Huang KE, Need AG, Taechakraichana N, Loh FH, et al.
    J Clin Endocrinol Metab, 2003 Jul;88(7):3130-6.
    PMID: 12843154
    In healthy Caucasian postmenopausal women, raloxifene increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and lowers low-density lipoprotein (LDL) cholesterol, without effects on high-density lipoprotein (HDL) cholesterol and triglycerides. This randomized, double-blind study examines the effects of raloxifene 60 mg/d (n = 483) or placebo (n = 485) in healthy postmenopausal Asian women (mean age 57 yr) from Australia, Hong Kong, India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, Taiwan, and Thailand. Serum osteocalcin, serum N-telopeptide, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were assessed at baseline and 6 months. Lumbar spine BMD was measured at baseline and 1 yr in 309 women from 4 countries. Clinical adverse events were recorded at each interim visit. At 6 months, raloxifene 60 mg/d significantly decreased osteocalcin, N-telopeptide, total cholesterol, and LDL cholesterol by medians of 15.9%, 14.6%, 5.3%, and 7.7%, respectively, from placebo. Changes in HDL cholesterol and triglycerides were similar between raloxifene and placebo. Raloxifene 60 mg/d increased mean lumbar spine BMD (1.9%) from placebo at 1 yr (P = 0.0003). The incidences of hot flashes (placebo 3.5%, raloxifene 5.6%, P = 0.12), and leg cramps (placebo 2.7%, raloxifene 4.3%, P = 0.16) were not different between groups. No case of venous thromboembolism was reported. The effects of raloxifene 60 mg/d on bone turnover, BMD, and serum lipids in healthy postmenopausal Asian women were similar to that previously reported in Caucasian women.
  4. Azis NA, Agarwal R, Ismail NM, Ismail NH, Kamal MSA, Radjeni Z, et al.
    Mol Biol Rep, 2019 Jun;46(3):2841-2849.
    PMID: 30977084 DOI: 10.1007/s11033-019-04730-w
    This study investigated the effects of a standardised ethanol and water extract of Ficus deltoidea var. Kunstleri (FDK) on blood pressure, renin-angiotensin-aldosterone system (RAAS), endothelial function and antioxidant system in spontaneously hypertensive rats (SHR). Seven groups of male SHR were administered orally in volumes of 0.5 mL of either FDK at doses of 500, 800, 1000 and 1300 mg kg- 1, or captopril at 50 mg kg- 1 or losartan at 10 mg kg- 1 body weight once daily for 4 weeks or 0.5 mL distilled water. Body weight, systolic blood pressures (SBP) and heart rate (HR) were measured every week. 24-hour urine samples were collected at weeks 0 and 4 for electrolyte analysis. At week 4, sera from rats in the control and 1000 mg kg- 1 of FDK treated groups were analyzed for electrolytes and components of RAAS, endothelial function and anti-oxidant capacity. SBP at week 4 was significantly lower in all treatment groups, including captopril and losartan, when compared to that of the controls. Compared to the controls, ACE activity and concentrations of angiotensin I, angiotensin II and aldosterone were lower whereas concentrations of angiotensinogen and angiotensin converting enzyme 2 were higher in FDK treated rats. Concentration of eNOS and total anti-oxidant capacity were higher in FDK treated rats. Urine calcium excretion was higher in FDK treated rats. In conclusion, it appears that ethanol and water extract of FDK decreases blood pressure in SHR, which might involve mechanisms that include RAAS, anti-oxidant and endothelial system.
  5. Ghashm AA, Othman NH, Khattak MN, Ismail NM, Saini R
    PMID: 20840769 DOI: 10.1186/1472-6882-10-49
    The treatment of oral squamous cell carcinomas (OSCC) and human osteosarcoma (HOS) includes surgery and/or radiotherapy which often lead to reduced quality of life. This study was aimed to study the antiproliferative activity of local honey (Tualang) on OSCC and HOS cell lines.
  6. Arora A, Khattri S, Ismail NM, Kumbargere Nagraj S, Prashanti E
    Cochrane Database Syst Rev, 2017 12 21;12:CD012595.
    PMID: 29267989 DOI: 10.1002/14651858.CD012595.pub2
    BACKGROUND: School dental screening refers to visual inspection of children's oral cavity in a school setting followed by making parents aware of their child's current oral health status and treatment needs. Screening at school intends to identify children at an earlier stage than symptomatic disease presentation, hence prompting preventive and therapeutic oral health care for the children. This review evaluates the effectiveness of school dental screening in improving oral health status.

    OBJECTIVES: To assess the effectiveness of school dental screening programmes on overall oral health status and use of dental services.

    SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 15 March 2017), the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Register of Studies, to 15 March 2017), MEDLINE Ovid (1946 to 15 March 2017), and Embase Ovid (15 September 2016 to 15 March 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Centralised Search Project to identify all clinical trials and add them to CENTRAL.

    SELECTION CRITERIA: We included randomised controlled trials (RCTs) (cluster or parallel) that evaluated school dental screening compared with no intervention or with one type of screening compared with another.

    DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.

    MAIN RESULTS: We included six trials (four were cluster-RCTs) with 19,498 children who were 4 to 15 years of age. Four trials were conducted in the UK and two were based in India. We assessed two trials to be at low risk of bias, one trial to be at high risk of bias and three trials to be at unclear risk of bias.None of the six trials reported the proportion of children with untreated caries or other oral diseases.Four trials evaluated traditional screening versus no screening. We performed a meta-analysis for the outcome 'dental attendance' and found an inconclusive result with high heterogeneity. The heterogeneity was found it to be, in part, due to study design (three cluster-RCTs and one individual-level RCT). Due to the inconsistency, we downgraded the evidence to 'very low certainty' and are unable to draw conclusions about this comparison.Two cluster-RCTs (both four-arm trials) evaluated criteria-based screening versus no screening and showed a pooled effect estimate of RR 1.07 (95% CI 0.99 to 1.16), suggesting a possible benefit for screening (low-certainty evidence). There was no evidence of a difference when criteria-based screening was compared to traditional screening (RR 1.01, 95% CI 0.94 to 1.08) (very low-certainty evidence).In one trial, a specific (personalised) referral letter was compared to a non-specific one. Results favoured the specific referral letter with an effect estimate of RR 1.39 (95% CI 1.09 to 1.77) for attendance at general dentist services and effect estimate of RR 1.90 (95% CI 1.18 to 3.06) for attendance at specialist orthodontist services (low-certainty evidence).One trial compared screening supplemented with motivation to screening alone. Dental attendance was more likely after screening supplemented with motivation, with an effect estimate of RR 3.08 (95% CI 2.57 to 3.71) (low-certainty evidence).None of the trials had long-term follow-up to ascertain the lasting effects of school dental screening.None of the trials reported cost-effectiveness and adverse events.

    AUTHORS' CONCLUSIONS: The trials included in this review evaluated short-term effects of screening, assessing follow-up periods of three to eight months. We found very low certainty evidence that was insufficient to allow us to draw conclusions about whether there is a role for traditional school dental screening in improving dental attendance. For criteria-based screening, we found low-certainty evidence that it may improve dental attendance when compared to no screening. However, when compared to traditional screening there was no evidence of a difference in dental attendance (very low-certainty evidence).We found low-certainty evidence to conclude that personalised or specific referral letters improve dental attendance when compared to non-specific counterparts. We also found low-certainty evidence that screening supplemented with motivation (oral health education and offer of free treatment) improves dental attendance in comparison to screening alone.We did not find any trials addressing cost-effectiveness and adverse effects of school dental screening.

  7. Jamilah J, Ahmad Najib A, Dzulkhairi MR, Ariff HO, Nasri Ismail NM
    MyJurnal
    Muslim doctors are those qualified doctors who practise their professional knowledge and skills in line with Islam and upholds the highest standards of ethical and professional behaviour. The medical curriculum of the Faculty of Medicine and Health Sciences of Universiti Sains Islam Malaysia (USIM) was designed with the integration of Islamic input which aims at producing doctors who are able to practise medicine that is integrated with Islamic, moral and ethical values. Halaqah Studies and Fundamental Islamic Knowledge (FIK) courses such as History of Medicine in Islam, Science and Medicine in Quran and Sunnah, Akhlak and Tasawuf, Islamic Jurisprudence and Medical Ethics and Fiqh Issues are taught to students during the pre-clinical and clinical phases. Memorization of selected Quranic verses throughout the programme aim to get the students to apply the verses of the al-Quran into practice in everyday life and especially in their clinical practice. Islamic values are emphasised during doctor-patient interactions in all clinical postings. Islamic knowledge and values integrated in the curriculum are assessed in written and clinical examinations. The outcome of the integration of the Naqli component in the medical curriculum has been demonstrated positively by the students in the patient management problems and clinical consultations. Studies on the outcome of the integrated Islamic input in the medical curriculum among the clinical students and graduates are being carried out.
  8. Ismail NM, Mustapha MS, Megat R
    Ann Acad Med Singap, 1997 Nov;26(6):754-7.
    PMID: 9522974
    The aim of this study was to investigate if colloidal bismuth subcitrate (CBS) can penetrate the gastric mucus barrier to reach the different sites of the antral mucosa and to estimate the time course for CBS to reach and remain in the mucosa. A single dose of CBS was administered orally to rats that were sacrificed at different time intervals post treatment. The control group received gum acacia without CBS. Colloidal bismuth subcitrate, visualised as electron dense precipitate (EDP), was seen in the gastric mucus layer, intercellular spaces and intracellularly after 30 minutes and disappeared after 6 hours. Scant amounts of EDP were observed in the gastric crypts, confined only to the upper parts of these structures. We concluded that CBS can penetrate the mucus and has a wide but uneven distribution in the gastric mucosa. Colloidal bismuth subcitrate, in the concentration given only penetrated the upper two-thirds of gastric pits and not the lower one-third. We also concluded that CBS has to be given 6 hourly to ensure its continuous presence in the gastric mucosa.
  9. Nawawi HM, Yazid TN, Ismail NM, Mohamad AR, Nirwana SI, Khalid BA
    Malays J Pathol, 2001 Dec;23(2):79-88.
    PMID: 12166596
    The objectives of this study were to: (i) evaluate the diagnostic sensitivity and specificity of the biochemical bone markers: serum total alkaline phosphatase (TALP), bone specific alkaline phosphatase (BSALP) and urinary deoxypyridinoline (Dpyr) in postmenopausal osteoporosis, (ii) compare the bone turnover of postmenopausal osteoporotic patients without and with hormone replacement therapy (HRT) against controls and (iii) identify the correlation between these bone markers and bone mineral density (BMD). We examined 42 postmenopausal women with BMD proven osteoporosis and 35 control subjects. Serum TALP, BSALP and urinary Dpyr were measured. All three biochemical bone markers showed comparable moderate diagnostic sensitivity but Dpyr had the highest diagnostic specificity. There were significantly higher serum TALP, BSALP and urinary Dpyr levels in non-HRT treated patients compared to controls (p<0.005, <0.0001 and <0.005 respectively). There were no significant differences in the levels of all three bone markers between HRT treated patients and control subjects. There was no significant correlation between TALP, BSALP or Dpyr and BMD in both controls and patients. In conclusion, the biochemical bone markers are not useful in diagnosis of postmenopausal osteoporosis but may have a role in monitoring progress and response to treatment. HRT treatment reduces bone turnover of postmenopausal osteoporosis.
  10. Ismail NM, Ibrahim IA, Hashim NB, Jaarin K
    Arch Med Sci, 2013 Dec 30;9(6):1132-7.
    PMID: 24482662 DOI: 10.5114/aoms.2012.31252
    INTRODUCTION: Captopril is an angiotensin-converting enzyme inhibitor, which is used as an antihypertensive agent and has shown antioxidant properties. This study aims at determining the effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions.
    MATERIAL AND METHODS: Eighteen male Sprague-Dawley (200-250 g) rats that were given aspirin (40 mg/100 g body weight) were divided into three groups: the control, captopril (1 mg/100 g body weight daily) and ranitidine (2.5 mg/100 g body weight twice daily) groups. Ranitidine and captopril were given orally for 28 days. Rats in all groups were sacrificed and the parameters measured.
    RESULTS: Captopril reduced gastric acidity, and increased gastric glutathione (GSH) and prostaglandin E2 (PGE2) significantly in comparison to the control group. Captopril also reduced malondialdehyde (MDA) and gastric lesions insignificantly compared to the control group. Ranitidine healed the lesions significantly compared to the control group. There was no difference between ranitidine and captopril on the severity of lesions, gastric acidity, MDA and GSH. Captopril increased PGE2 compared to ranitidine (p < 0.05).
    CONCLUSIONS: Captopril has desirable effects on the factors affecting gastric mucosal integrity (acidity, PGE2 and GSH) and is comparable to ranitidine in ulcer healing.
    KEYWORDS: aspirin; captopril; gastric lesions; ranitidine
  11. Razali N, Agarwal R, Agarwal P, Kapitonova MY, Kannan Kutty M, Smirnov A, et al.
    Eur J Pharmacol, 2015 Feb 15;749:73-80.
    PMID: 25481859 DOI: 10.1016/j.ejphar.2014.11.029
    Steroid-induced ocular hypertension (SIOH) is associated with topical and systemic use of steroids. However, SIOH-associated anterior and posterior segment morphological changes in rats have not been described widely. Here we describe the pattern of intraocular pressure (IOP) changes, quantitative assessment of trabecular meshwork (TM) and retinal morphological changes and changes in retinal redox status in response to chronic dexamethasone treatment in rats. We also evaluated the responsiveness of steroid-pretreated rat eyes to 5 different classes of antiglaucoma drugs that act by different mechanisms. Up to 80% of dexamethasone treated animals achieved significant and sustained IOP elevation. TM thickness was significantly increased and number of TM cells was significantly reduced in SIOH rats compared to the vehicle-treated rats. Quantitative assessment of retinal morphology showed significantly reduced thickness of ganglion cell layer (GCL) and inner retina (IR) in SIOH rats compared to vehicle-treated rats. Estimation of retinal antioxidants including catalase, superoxide dismutase and glutathione showed significantly increased retinal oxidative stress in SIOH animals. Furthermore, steroid-treated eyes showed significant IOP lowering in response to treatment with 5 different drug classes. This indicated the ability of SIOH eyes to respond to drugs acting by different mechanisms. In conclusion, SIOH was associated with significant morphological changes in TM and retina and retinal redox status. Additionally, SIOH eyes also showed IOP lowering in response to drugs that act by different mechanisms of action. Hence, SIOH rats appear to be an inexpensive and noninvasive model for studying the experimental antiglaucoma drugs for IOP lowering and neuroprotective effects.
  12. Agarwal R, Iezhitsa I, Agarwal P, Abdul Nasir NA, Razali N, Alyautdin R, et al.
    Drug Deliv, 2016 May;23(4):1075-91.
    PMID: 25116511 DOI: 10.3109/10717544.2014.943336
    Topical route of administration is the most commonly used method for the treatment of ophthalmic diseases. However, presence of several layers of permeation barriers starting from the tear film till the inner layers of cornea make it difficult to achieve the therapeutic concentrations in the target tissue within the eye. In order to circumvent these barriers and to provide sustained and targeted drug delivery, tremendous advances have been made in developing efficient and safe drug delivery systems. Liposomes due to their unique structure prove to be extremely beneficial drug carriers as they can entrap both the hydrophilic and hydrophobic drugs. The conventional liposomes had several drawbacks particularly their tendency to aggregate, the instability and leakage of entrapped drug and susceptibility to phagocytosis. Due to this reason, for a long time, liposomes as drug delivery systems did not attract much attention of researchers and clinicians. However, over recent years development of new generation liposomes has opened up new approaches for targeted and sustained drug delivery using liposomes and has rejuvenated the interest of researchers in this field. In this review we present a summary of current literature to understand the anatomical and physiological limitation in achieving adequate ocular bioavailability of topically applied drugs and utility of liposomes in overcoming these limitations. The recent developments related to new generation liposomes are discussed.
  13. Mani SA, Aziz AA, John J, Ismail NM
    J Indian Soc Pedod Prev Dent, 2010 Apr-Jun;28(2):78-83.
    PMID: 20660972 DOI: 10.4103/0970-4388.66741
    The role of caretakers at day-care centers has become more imperative in promoting oral health care in children since many new mothers opt to work outside their homes, leaving their children at day-care centers. The aim of this study is to assess the knowledge, attitude and practice of oral health promoting factors among secondary caretakers of children attending day-care centers.
  14. Gopinath VK, Ling KT, Haziani KN, Ismail NM
    J Clin Pediatr Dent, 2008;33(1):39-42.
    PMID: 19093650
    This study reports on the predisposing factors and prevalence of fractured anterior teeth among 12 and 16 years-old school children in Kubang Kerian, Kelantan, West Malaysia.
  15. Razali N, Agarwal R, Agarwal P, Tripathy M, Kapitonova MY, Kutty MK, et al.
    Exp Eye Res, 2016 Feb;143:9-16.
    PMID: 26424219 DOI: 10.1016/j.exer.2015.09.014
    Steroid-induced hypertension and glaucoma is associated with increased extracellular meshwork (ECM) deposition in trabecular meshwork (TM). Previous studies have shown that single drop application of trans-resveratrol lowers IOP in steroid-induced ocular hypertensive (SIOH) rats. This IOP lowering is attributed to activation of adenosine A1 receptors, which may lead to increased matrix metalloproteinase (MMP)-2 activity. This study evaluated the effect of repeated topical application of trans-resveratrol for 21 days in SIOH animals on IOP, changes in MMP-2 level in aqueous humor, trabecular meshwork and retinal morphology and retinal redox status. We observed that treatment with trans-resveratrol results in significant and sustained IOP reduction in SIOH rats. This IOP reduction is associated with significantly higher aqueous humor total MMP-2 level; significantly reduced TM thickness and increased number of TM cells. Treatment with trans-resveratrol also significantly increased ganglion cell layer (GCL) thickness, the linear cell density in the GCL and inner retina thickness; and significantly reduced retinal oxidative stress compared to the SIOH vehicle-treated group. In conclusion, repeated dose topical application of trans-resveratrol produces sustained IOP lowering effect, which is associated with increased level of aqueous humor MMP-2, normalization of TM and retinal morphology and restoration of retinal redox status.
  16. Jafri AJA, Agarwal R, Iezhitsa I, Agarwal P, Ismail NM
    Amino Acids, 2019 Apr;51(4):641-646.
    PMID: 30656415 DOI: 10.1007/s00726-019-02696-4
    This study aimed to evaluate effect of TAU on NMDA-induced changes in retinal redox status, retinal cell apoptosis and retinal morphology in Sprague-Dawley rats. Taurine was injected intravitreally as pre-, co- or post-treatment with NMDA and 7 days post-treatment retinae were processed for estimation of oxidative stress, retinal morphology using H&E staining and retinal cell apoptosis using TUNEL staining. Treatment with TAU, particularly pre-treatment, significantly increased retinal glutathione, superoxide dismutase and catalase levels compared to NMDA-treated rats; whereas, the levels of malondialdehyde reduced significantly. Reduction in retinal oxidative stress in TAU pre-treated group was associated with significantly greater fractional thickness of ganglion cell layer within inner retina and retinal cell density in inner retina. TUNEL staining showed significantly reduced apoptotic cell count in TAU pre-treated group compared to NMDA group. It could be concluded that TAU protects against NMDA-induced retinal injury in rats by reducing retinal oxidative stress.
  17. Sadikan MZ, Nasir NAA, Agarwal R, Ismail NM
    Biomolecules, 2020 04 05;10(4).
    PMID: 32260544 DOI: 10.3390/biom10040556
    : Oxidative stress plays an important role in retinal neurodegeneration and angiogenesis associated with diabetes. In this study, we investigated the effect of the tocotrienol-rich fraction (TRF), a potent antioxidant, against diabetes-induced changes in retinal layer thickness (RLT), retinal cell count (RCC), retinal cell apoptosis, and retinal expression of vascular endothelial growth factor (VEGF) in rats. Additionally, the efficacy of TRF after administration by two different routes was compared. The diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin. Subsequently, diabetic rats received either oral or topical treatment with vehicle or TRF. Additionally, a group of non-diabetic rats was included with either oral or topical treatment with a vehicle. After 12 weeks of the treatment period, rats were euthanized, and retinas were collected for measurement of RLT, RCC, retinal cell apoptosis, and VEGF expression. RLT and RCC in the ganglion cell layer were reduced in all diabetic groups compared to control groups (p < 0.01). However, at the end of the experimental period, oral TRF-treated rats showed a significantly greater RLT compared to topical TRF-treated rats. A similar observation was made for retinal cell apoptosis and VEGF expression. In conclusion, oral TRF supplementation protects against retinal degenerative changes and an increase in VEGF expression in rats with streptozotocin-induced diabetic retinopathy. Similar effects were not observed after topical administration of TRF.
  18. Kamarudin SN, Iezhitsa I, Tripathy M, Alyautdin R, Ismail NM
    Acta Neurobiol Exp (Wars), 2020;80(1):1-18.
    PMID: 32214270
    Poly (lactide‑co‑glycolide) (PLGA) nanoparticles (NPs) are biodegradable carriers that participate in the transport of neuroprotective drugs across the blood brain barrier (BBB). Targeted brain‑derived neurotrophic factor (BDNF) delivery across the BBB could provide neuroprotection in brain injury. We tested the neuroprotective effect of PLGA nanoparticle‑bound BDNF in a permanent middle cerebral artery occlusion (pMCAO) model of ischemia in rats. Sprague‑Dawley rats were subjected to pMCAO. Four hours after pMCAO, two groups were intravenously treated with BDNF and NP‑BDNF, respectively. Functional outcome was assessed at 2 and 24 h after pMCAO, using the modified neurologic severity score (mNSS) and rotarod performance tests. Following functional assessments, rats were euthanized blood was taken to assess levels of the neurobiomarkers neuron‑specific enolase and S100 calcium‑binding protein β (S100β), and the brain was evaluated to measure the infarct volume. The NP‑BDNF‑treated group showed significant improvement in mNSS compared with pMCAO and BDNF‑treated groups and showed improved rotarod performance. The infarct volume in rats treated with NP‑BDNFs was also significantly smaller. These results were further corroborated by correlating differences in estimated NSE and S100β. NP‑BDNFs exhibit a significant neuroprotective effect in the pMCAO model of ischemia in rats.
  19. Razali N, Agarwal R, Agarwal P, Kumar S, Tripathy M, Vasudevan S, et al.
    Clin Exp Ophthalmol, 2015 Jan-Feb;43(1):54-66.
    PMID: 24995479 DOI: 10.1111/ceo.12375
    BACKGROUND: Steroid-induced ocular hypertension is currently treated in the same way as primary open-angle glaucoma. However, the treatment is often suboptimal and is associated with adverse effects. We evaluated the oculohypotensive effects of topical trans-resveratrol in rats with steroid-induced ocular hypertension and involvement of adenosine receptors (AR) in intraocular pressure (IOP) lowering effect of trans-resveratrol.
    METHODS: The oculohypotensive effect of unilateral single-drop application of various concentrations of trans-resveratrol was first studied in oculonormotensive rats. Concentration with maximum effect was similarly studied in rats with steroid-induced ocular hypertension. Involvement of AR was studied by observing the alterations of IOP in response to trans-resveratrol after pretreating animals with AR subtype-specific antagonists. Additionally, we used computational methods, including 3D modelling, 3D structure generation and protein-ligand interaction, to determine the AR-trans-resveratrol interaction.
    RESULTS: All concentrations of trans-resveratrol produced significant IOP reduction in normotensive rat eyes. Maximum mean IOP reduction of 15.1% was achieved with trans-resveratrol 0.2%. In oculohypertensive rats, trans-resveratrol 0.2% produced peak IOP reduction of 25.2%. Pretreatment with A₁ antagonist abolished the oculohypotensive effect of trans-resveratrol. Pretreatment with A₃ and A₂A AR antagonists produced significant IOP reduction in both treated and control eyes, which was further augmented by trans-resveratrol application in treated eyes. Computational studies showed that trans-resveratrol has highest affinity for A₂B and A₁, followed by A2A and A₃ AR.
    CONCLUSION: Topically applied trans-resveratrol reduces IOP in rats with steroid-induced ocular hypertension. Trans-resveratrol-induced oculohypotension involves its agonistic activity at the A₁ AR.
    KEYWORDS: adenosine receptors; docking simulation; intraocular pressure; resveratrol; topical
  20. Razali N, Agarwal R, Agarwal P, Froemming GRA, Tripathy M, Ismail NM
    Eur J Pharmacol, 2018 Nov 05;838:1-10.
    PMID: 30171854 DOI: 10.1016/j.ejphar.2018.08.035
    Trans-resveratrol was earlier shown to lower intraocular pressure (IOP) in rats; however, its mechanisms of action remain unclear. It has been shown to modulate adenosine receptor (AR) and TGF-β2 signaling, both of which play a role in regulating IOP. Hence, we investigated effects of trans-resveratrol on AR and TGF-β2 signaling. Steroid-induced ocular hypertensive (SIOH) rats were pretreated with A1AR, phospholipase C (PLC) and ERK1/2 inhibitors and were subsequently treated with single drop of trans-resveratrol. Metalloproteinases (MMP)-2 and -9 were measured in aqueous humor (AH). In another set of experiments, effect of trans-resveratrol on AH level of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) was determined after single and multiple drop administration in SIOH rats. Effect of trans-resveratrol on ARs expression, PLC and pERK1/2 activation and MMPs, tPA and uPA secretion was determined using human trabecular meshwork cells (HTMC). Further, effect of trans-resveratrol on TGF-β2 receptors, SMAD signaling molecules and uPA and tPA expression by HTMC was determined in the presence and absence of TGF-β2. Pretreatment with A1AR, PLC and ERK1/2 inhibitors antagonized the IOP lowering effect of trans-resveratrol and caused significant reduction in the AH level of MMP-2 in SIOH rats. Trans-resveratrol increased A1AR and A2AAR expression, cellular PLC, pERK1/2 levels and MMP-2, tPA and uPA secretion by HTMC. Additionally, it produced TGFβRI downregulation and SMAD 7 upregulation. In conclusion, IOP lowering effect of trans-resveratrol involves upregulation of A1AR expression, PLC and ERK1/2 activation and increased MMP-2 secretion. It downregulates TGFβRI and upregulates SMAD7 hence, inhibits TGF-β2 signaling.
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