Publications by authors named "N Aini M Razali"

43 Publications

The effect of frying on browning, acrylamide and 5-hydroxymethylfurfural formation on Malaysian curry puff skin treated with l-asparaginase.

Food Sci Biotechnol 2021 Jan 6;30(1):149-158. Epub 2021 Jan 6.

Food Engineering Technology Section, Universiti Kuala Lumpur (UniKL) MICET, Lot 1988, Kawasan Perindustrian Bandar Vendor, Taboh Naning, 78000 Alor Gajah, Melaka Malaysia.

Acrylamide and 5-hydroxymethylfurfural (HMF) is the product of the Maillard reaction and its accumulation may lead to adverse health effects. Hence, this paper aims to study the effect of l-asparaginase treatment (E100 U/kg and E500 U/kg), frying temperatures (180 °C, 190 °C, 200 °C) and times (2 min, 3 min, 5 min, 7 min) on acrylamide and HMF content after the frying process of curry puff skin. Colour development, moisture content, water activity analysis and sensory evaluation were also carried out. Frying condition at 190 °C for 5 min produced desirable attributes through sensory evaluation. Furthermore, the enzyme reduced the acrylamide and HMF level to 2500 μg/kg and 230 μg/kg respectively. Frying temperature plays a crucial role in acrylamide decomposition leading to the reduction of acrylamide content. Therefore, the use of this enzyme is plausible for the reduction of acrylamide and HMF in puff skin without altering the original quality.
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http://dx.doi.org/10.1007/s10068-020-00849-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847420PMC
January 2021

Vasorelaxant effect of water fraction of and its mechanisms in spontaneously hypertensive rats aortic ring preparation.

Int J Cardiol Hypertens 2020 Mar 11;4:100024. Epub 2020 Jan 11.

Department of Physiology and Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia.

Introduction: has been reported to possess activities including antioxidant, anti-aging and anti-cancer but there is no report on its vasorelaxant effects.

Objective: This study aims to fractionate water extract of , identify the compound(s) involved and elucidate the possible mechanism(s) of its vasorelaxant effects.

Methods: Water extract of was subjected to liquid-liquid extraction to obtain ethyl acetate, n-butanol and water fractions. In SHR aortic ring preparations, water fraction (WF-LPWE) was established as the most potent fraction for vasorelaxation. The pharmacological mechanisms of the vasorelaxant effect of WF-LPWE were investigated with and without the presence of various inhibitors. The cumulative dose-response curves of potassium chloride (KCl)-induced contractions were conducted to study the possible mechanisms of WF-LPWE in reducing vasoconstriction.

Results: WF-LPWE produced dose-dependent vasorelaxant effect in endothelium-denuded aortic ring and showed non-competitive inhibition of dose-response curves of PE-induced contraction, and at its higher concentrations reduced KCl-induced contraction. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) significantly inhibited vasorelaxant effect of WF-LPWE. WF-LPWE significantly reduced the release of intracellular calcium ion (Ca) from the intracellular stores and suppressed the calcium chloride (CaCal)-induced contraction. N-nitro-L-arginine methyl ester (L-NAME), methylene blue, indomethacin and atropine did not influence the vasorelaxant effects of WF-LPWE.

Conclusion: WF-LPWE exerts its vasorelaxant effect independently of endothelium and possibly by inhibiting the release of calcium from intracellular calcium stores, receptor-operated calcium channels and formation of inositol 1,4,5- triphosphate. WF-LPWE vasorelaxant effect may also mediated via nitric oxide-independent direct involvement of soluble guanylate cyclase (sGC)/ cyclic guanosine monophosphate (cGMP) pathways.
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http://dx.doi.org/10.1016/j.ijchy.2020.100024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803023PMC
March 2020

Personalised management of Chronic Obstructive Pulmonary Disease (COPD): Malaysian consensus algorithm for appropriate use of inhaled corticosteroid (ICS) in COPD patients.

Med J Malaysia 2020 11;75(6):717-721

Novartis Corporation (Malaysia) Sdn Bhd, Medical Affairs Department, Petaling Jaya, Selangor, Malaysia.

Background: Regarding the long-term safety issues with the use of inhaled corticosteroids (ICS) and the clinical predominance of dual bronchodilators in enhancing treatment outcomes in chronic obstructive pulmonary disease (COPD), ICS is no longer a "preferred therapy" according to the Global Initiative for Chronic Obstructive Lung Disease except on top of a dual bronchodilator. This has necessitated a change in the current therapy for many COPD patients.

Objective: To determine a standardised algorithm to reassess and personalise the treatment COPD patients based on the available evidence.

Methods: A consensus statement was agreed upon by a panel of pulmonologists in from 11 institutes in Malaysia whose members formed this consensus group.

Results: According to the consensus, which was unanimously adopted, all COPD patients who are currently receiving an ICS-based treatment should be reassessed based on the presence of co-existence of asthma or high eosinophil counts and frequency of moderate or severe exacerbations in the previous 12 months. When that the patients meet any of the aforementioned criteria, then the patient can continue taking ICS-based therapy. However, if the patients do not meet the criteria, then the treatment of patients need to be personalised based on whether the patient is currently receiving long-acting beta-agonists (LABA)/ICS or triple therapy.

Conclusion: A flowchart of the consensus providing a guidance to Malaysian clinicians was elucidated based on evidences and international guidelines that identifies the right patients who should receive inhaled corticosteroids and enable to switch non ICS based therapies in patients less likely to benefit from such treatments.
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November 2020

Poor sleep is associated with higher blood pressure and uterine artery pulsatility index in pregnancy: a prospective cohort study.

BJOG 2020 Nov 3. Epub 2020 Nov 3.

Department of Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore City, Singapore.

Objective: To elucidate the association between sleep disturbances and blood pressure as well as uterine artery Doppler during pregnancy in women with no pre-existing hypertension.

Design: Prospective cohort study.

Setting: Outpatient specialist clinics at KK Women's and Children's Hospital, Singapore.

Population: Women with viable singleton pregnancies confirmed by ultrasonography at less than 14 weeks of amenorrhoea at first visit.

Methods: In all, 926 subjects were recruited for this study in the outpatient specialist clinics at KK Women's and Children's Hospital, Singapore, between 1 September 2010 and 31 August 2014. They were followed up throughout pregnancy with sleep quality, blood pressure and uterine artery Doppler assessed at each visit.

Main Outcome Measures: Sleep quality, blood pressure and uterine artery Doppler.

Results: Sleep progressively worsened as pregnancy advanced. Shorter sleep duration and poorer sleep efficiency were associated with higher blood pressure, especially in the first trimester. Mixed model analysis demonstrated an overall positive association between sleep quality represented by Pittsburgh Sleep Quality Index (PSQI) score and diastolic blood pressure (DBP) (P < 0.001) and mean arterial pressure (MAP) (P = 0.005) during pregnancy after considering all trimesters. Sleep duration was found to be negatively associated with both systolic blood pressure (SBP) (P = 0.029) and DBP (P = 0.002), whereas sleep efficiency was negatively correlated with DBP (P = 0.002) only. Overall poor sleep during pregnancy was also found to be associated with a higher uterine artery pulsatility index.

Conclusion: Our prospective study demonstrated that poor sleep quality is significantly associated with higher blood pressure and uterine artery pulsatility index during pregnancy.

Tweetable Abstract: Poor sleep quality is significantly associated with higher blood pressure and higher uterine artery pulsatility index during pregnancy.
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http://dx.doi.org/10.1111/1471-0528.16591DOI Listing
November 2020

Risk of eczema, wheezing and respiratory tract infections in the first year of life: A systematic review of vitamin D concentrations during pregnancy and at birth.

PLoS One 2020 15;15(6):e0233890. Epub 2020 Jun 15.

Department of Social Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Background: Allergic conditions and respiratory tract infections (RTIs) are common causes of morbidity and mortality in childhood. The relationship between vitamin D status in pregnancy (mothers), early life (infants) and health outcomes such as allergies and RTIs in infancy is unclear. To date, studies have shown conflicting results.

Objective: This systematic review aims to gather and appraise existing evidence on the associations between serum vitamin D concentrations during pregnancy and at birth and the development of eczema, wheezing, and RTIs in infants.

Data Sources: PubMed, MEDLINE, ProQuest, Scopus, CINAHL, Cochrane Library and Academic Search Premier databases were searched systematically using specified search terms and keywords.

Study Selection: Articles on the associations between serum vitamin D concentrations during pregnancy and at birth and eczema, wheezing, and RTIs among infants (1-year-old and younger) published up to 31 March 2019 were identified, screened and retrieved.

Results: From the initial 2678 articles screened, ten met the inclusion criteria and were included in the final analysis. There were mixed and conflicting results with regards to the relationship between maternal and cord blood vitamin D concentrations and the three health outcomes-eczema, wheezing and RTIs-in infants.

Conclusion: Current findings revealed no robust and consistent associations between vitamin D status in early life and the risk of developing eczema, wheezing and RTIs in infants. PROSPERO registration no. CRD42018093039.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233890PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295196PMC
August 2020

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice.

Biol Pharm Bull 2020 ;43(4):649-662

Laboratory of Hygienic Sciences, Kobe Pharmaceutical University.

Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naïve T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D and thromboxane B, a metabolite of thromboxane A, in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1- and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naïve T cells in the thymus.
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http://dx.doi.org/10.1248/bpb.b19-00838DOI Listing
November 2020

Mechanisms underlying the vascular relaxation activities of Zingiber officinale var. rubrum in thoracic aorta of spontaneously hypertensive rats.

J Integr Med 2020 Jan 14;18(1):46-58. Epub 2019 Dec 14.

Department of Physiology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.

Objective: To evaluate vasorelaxant and vasoconstriction effects of Zingiber officinale var. rubrum (ZOVR) on live rats and isolated aortic rings of spontaneously hypertensive rats (SHRs).

Methods: Extracts of ZOVR were subjected to in-vivo antihypertensive screening using noninvasive blood pressures in SHRs. The most potent extract, ZOVR petroleum ether extract (ZOP) was then fractionated using n-hexane, chloroform and water. Isolated thoracic aortic rings were harvested and subjected to vascular relaxation studies of n-hexane fraction of ZOP (HFZOP) with incubation of different antagonists such as N-nitro-l-arginine methyl ester (L-NAME, 10 µmol/L), indomethacin (10 µmol/L), methylene blue (10 µmol/L), atropine (1 µmol/L), glibenclamide (10 µmol/L), prazosin (0.01 µmol/L), and propranolol (1 µmol/L).

Results: During the screening of various ZOVR extracts, ZOP produced the most reduction in blood pressures of SHRs and so did HFZOP. HFZOP significantly decreased phenylephrine-induced contraction and enhanced acetylcholine-induced relaxation. L-NAME, indomethacin, methylene blue, atropine, and glibenclamide significantly potentiated the vasorelaxant effects of HFZOP. Propranolol and prazosin did not alter the vasorelaxant effects of HFZOP. HFZOP significantly suppressed the Ca-dependent contraction and influenced the ratio of the responses to phenylephrine in Ca-free medium.

Conclusion: This study demonstrates that ZOP may exert an antihypertensive effect in the SHR model. Its possible vascular relaxation mechanisms involve nitric oxide and prostacyclin release, activation of cGMP-K channels, stimulation of muscarinic receptors, and transmembrane calcium channel or Ca release from intracellular stores. Possible active compounds that contribute to the vasorelaxant effects are 6-gingerol, 8-gingerol and 6-shogaol.
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http://dx.doi.org/10.1016/j.joim.2019.12.003DOI Listing
January 2020

Cardiovascular Protective Effects of Centella asiatica and Its Triterpenes: A Review.

Planta Med 2019 Nov 20;85(16):1203-1215. Epub 2019 Sep 20.

Department of Pre-clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Selangor, Malaysia.

, a triterpene-rich medicinal herb, is traditionally used to treat various types of diseases including neurological, dermatological, and metabolic diseases. A few articles have previously reviewed a broad range of pharmacological activities of , but none of these reviews focuses on the use of in cardiovascular diseases. This review aims to summarize recent findings on protective effects of and its active constituents (asiatic acid, asiaticoside, madecassic acid, and madecassoside) in cardiovascular diseases. In addition, their beneficial effects on conditions associated with cardiovascular diseases were also reviewed. Articles were retrieved from electronic databases such as PubMed and Google Scholar using keywords "," "asiatic acid," "asiaticoside," "madecassic acid," and "madecassoside." The articles published between 2004 and 2018 that are related to the aforementioned topics were selected. A few clinical studies published beyond this period were also included. The results showed that and its active compounds possess potential therapeutic effects in cardiovascular diseases and cardiovascular disease-related conditions, as evidenced by numerous , and clinical studies. and its triterpenes have been reported to exhibit cardioprotective, anti-atherosclerotic, antihypertensive, antihyperlipidemic, antidiabetic, antioxidant, and anti-inflammatory activities. In conclusion, more clinical and pharmacokinetic studies are needed to support the use of and its triterpenes as therapeutic agents for cardiovascular diseases. Besides, elucidation of the molecular pathways modulated by and its active constituents will help to understand the mechanisms underlying the cardioprotective action of .
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http://dx.doi.org/10.1055/a-1008-6138DOI Listing
November 2019

Are women in Singapore gaining weight appropriately during pregnancy: a prospective cohort study.

BMC Pregnancy Childbirth 2019 Aug 13;19(1):290. Epub 2019 Aug 13.

Department of Maternal Fetal Medicine, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore, 229899,, Singapore.

Background: We aimed to study gestational weight gain (GWG) in a Singaporean population and compare it with Institute of Medicine (IOM) 2009 GWG guidelines.

Methods: Nine hundred twenty-six women with low-risk singleton pregnancy were enrolled in a prospective cohort study from 2010 to 2014 in a Singapore tertiary maternity hospital. Seven hundred twenty-four patients had maternal weight information till term pregnancy and were included in analysis. Participants were categorized according to their first antenatal visit body mass index (BMI) as underweight, normal weight, overweight and obese. Total GWG for each BMI group was calculated. Multivariate logistic regression was performed to determine the predictors of total GWG above and below IOM guidelines.

Results: Obese women had a mean total GWG (9.1 kg) that exceeded the upper limit IOM guidelines (9 kg). In multivariate analysis of predictors of total GWG above IOM guidelines, being overweight (adjusted OR: 3.91 [95% CI, 2.60-5.88]; p < .0001) and obese (adjusted OR: 4.78 [95% CI, 2.80, 8.15]; p < .0001) significantly increased the risks of gaining weight above IOM guidelines during pregnancy, compared to being normal weight.

Conclusions: Overweight and obesity are independent significant risk factors for gaining excessive gestational weight. Appropriate weight management for overweight and obese Singaporean women prior to and during pregnancy is important.
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http://dx.doi.org/10.1186/s12884-019-2443-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693141PMC
August 2019

Development of Copper-Aluminum Layered Double Hydroxide in Thin Film Nanocomposite Nanofiltration Membrane for Water Purification Process.

Front Chem 2019 8;7. Epub 2019 Feb 8.

Faculty of Engineering Technology, Universiti Tun Hussein Onn Malaysia, Parit Raja, Malaysia.

This study aims to fabricate a thin film composite (TFC) membrane, modified with copper-aluminium layered double hydroxide (LDH) nanofillers via interfacial polymerization technique for nanofiltration (NF) processes. It was found that Cu-Al LDH nanofillers possessed layered structured materials with typical hexagonal plate-like shape and positive surface charge. The study revealed that TFN membrane exhibits a relatively smooth surface and a less nodular structure compared to pristine TFC membrane. The contact angle of TFN progressively decreased from 54.1° to 37.25°, indicating enhancement in surface hydrophilicity. Moreover, the incorporation of LDH nanofillers resulted in a less negative membrane as compared to the pristine TFC membrane. The best NF performance was achieved by TFN2 membrane with 0.1° of Cu-Al LDH loading and a water flux of 7.01 Lm-2h-1.bar. The addition of Cu-Al LDH resulted in excellent single salt rejections of NaSO (96.8%), MgCl (95.6%), MgSO (95.4%), and NaCl (60.8%). The improvement in anti-fouling properties of resultant TFN membranes can be observed from the increments of pure water flux recovery and normalized water flux by 14% and 25% respectively. The findings indicated that Cu-Al LDH is a promising material in tailoring membrane surface properties and fouling resistance. The modification of the LDH-filled TFN membrane shows another alternative to fabricating a high-performance composite membrane, especially for water softening and partial desalination process.
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http://dx.doi.org/10.3389/fchem.2019.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375824PMC
February 2019

One-step wet chemical synthesis of gold nanoplates on solid substrate using poly-l-lysine as a reducing agent.

MethodsX 2018 4;5:1618-1625. Epub 2018 Dec 4.

Institute of Microengineering and Nanoelectronics (IMEN), Universiti Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia.

A one-step wet chemical approach or seedless growth process has several advantages compared to the traditional seed-mediated growth method (SMGM), such as being simpler and not requiring a multistep growth of seeds. This study had introduced a one-step wet chemical method to synthesis gold nanoplates on a solid substrate. The synthesis was carried out by simply immersing clean ITO substrate into a solution, which was made from mixing of gold chloride (precursor), cetyltrimethylammonium bromide or CTAB (stabilizing agent), and poly-l-lysine or PLL (reducing agent). Consequently, the size of the nanoplates in the range of (0.40 - 0.89) μm and a surface density within the range (21.89-57.19) % can be easily controlled by changing the concentration of PLL from 0.050 to 0.100 w/v % in HO. At low PLL concentrations, the reduction of the gold precursor by PLL is limited, leading to the formation of gold nanoplates with a smaller size and surface density. The study on the sample by using energy-dispersive x-ray spectroscopy (EDS) confirmed that gold peaks occurred. The optical properties of the samples were examined by a UV-vis Spectrophotometer and showed that there was no strong surface plasmon resonance band observed at UV-vis and infrared regions, which agreed to micron-sized gold nanoplates. •Gold nanoplates synthesized on the substrate using a simple one-step wet chemical synthesis approach with poly-l-lysine (PLL) as a reducing agent and CTAB as a stabilizing agent.•The nanoplate's size and surface density was strongly dependent on the concentration of PLL.•Gold nanoplates synthesized using PLL with a concentration 0.050% showed perfect triangular shape, less by-products and more homogenous in size.
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http://dx.doi.org/10.1016/j.mex.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290129PMC
December 2018

IOP lowering effect of topical trans-resveratrol involves adenosine receptors and TGF-β2 signaling pathways.

Eur J Pharmacol 2018 Nov 29;838:1-10. Epub 2018 Aug 29.

School of Medicine, International Medical University, IMU Clinical School, Bukit Jalil, Malaysia.

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 AAR, 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 AAR, 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 AAR and AAR 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 AAR 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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http://dx.doi.org/10.1016/j.ejphar.2018.08.035DOI Listing
November 2018

Conformational Design and Characterisation of a Truncated Diamine Oxidase from .

High Throughput 2018 Aug 25;7(3). Epub 2018 Aug 25.

Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia.

A functional mini protein can be developed by miniaturising its size. The minimisation technique provides an excellent model system for studying native enzymes, especially in creating an alternative novel biocatalyst. Miniaturised proteins may have enhanced stability, a crucial characteristic for large-scale production and industrial applications. In this study, a huge enzyme molecule, known as diamine oxidase (DAO, comprising 700 amino acids), was selected to undergo the process. By retaining the arrangement of the original functional sites of DAO in the fourth domain, a mini DAO can be designed via homology modelling. After several downsizing processes, a final configuration of 220 amino acids displayed high binding affinity towards histamine, a short-chain substrate that was catalysed by the parental DAO. The configuration also showed enhanced affinity towards a long-chain substrate known as spermidine. The gene for the designed protein was cloned and expressed in pET102/TOPO vector and overexpressed in BL21 (DE3). The new mini DAO had similar temperature tolerance and versatile substrates specificity characteristics as its parental protein. An active mini-protein with these characteristics is potentially useful for several applications such as detecting biogenic amines in the biological fluids and the environment that may give rise to health issues.
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http://dx.doi.org/10.3390/ht7030021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163217PMC
August 2018

Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT).

BMC Complement Altern Med 2018 Jul 16;18(1):217. Epub 2018 Jul 16.

Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.

Background: Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells.

Methods: Interleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways.

Results: Histamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC) value of 4.91 ± 2.50 μM and median lethal concentration (LC) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades.

Conclusion: Taken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.
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http://dx.doi.org/10.1186/s12906-018-2223-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048808PMC
July 2018

Establishing the cut off values of androgen markers in the assessment of polycystic ovarian syndrome.

Malays J Pathol 2018 Apr;40(1):33-39

University of Malaya, Faculty of Medicine, Department of Pathology, 50603, Kuala Lumpur, Malaysia.

Introduction: Hyperandrogenism remains as one of the key features in Polycystic Ovarian Syndrome (PCOS) and can be assessed clinically or determined by biochemical assays. Hirsutism is the most common clinical manifestation of hyperandrogenism. The clinical assessment is subjected to wide variability due to poor interobserver agreement and multiple population factors such as ethnic variation, cosmetic procedures and genetic trait. The difficulty in resolving the androgen excess biochemically is due to a lack of consensus as to which serum androgen should be measured for the diagnosis of PCOS. The aim of the study was to compare and establish the diagnostic cut off value for different androgen biomarker for the diagnosis of PCOS.

Materials And Methods: A total of 312 patients classified to PCOS (n = 164) and non PCOS (n = 148) cohorts were selected from the Laboratory Information System (LIS) based on serum total testosterone (TT) and sex hormone binding globulin (SHBG) from the period of 1st April 2015 to 31st March 2016. PCOS was diagnosed based on Rotterdam criteria. Clinical hyperandrogenism and ultrasound polycystic ovarian morphology were obtained from the clinical records. The other relevant biochemical results such as serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and albumin were also obtained from LIS. Free androgen index (FAI), calculated free testosterone (cFT) and calculated bioavailable testosterone (cBT) were calculated for these patients. Receiver Operating Characteristic (ROC) curve analysis were performed for serum TT, SHBG, FAI, cFT, cBT and LH: FSH ratio to determine the best marker to diagnose PCOS.

Results: All the androgen parameters (except SHBG) were significantly higher in PCOS patients than in control (p<0.0001). The highest area under curve (AUC) curve was found for cBT followed by cFT and FAI. TT and LH: FSH ratio recorded a lower AUC and the lowest AUC was seen for SHBG. cBT at a cut off value of 0.86 nmol/L had the highest specificity, 83% and positive likelihood ratio (LR) at 3.79. This is followed by FAI at a cut off value of 7.1% with specificity at 82% and cFT at a cut off value of 0.8 pmol/L with specificity at 80%. All three calculated androgen indices (FAI, cFT and cBT) showed good correlation with each other. Furthermore, cFT, FAI and calculated BT were shown to be more specific with higher positive likelihood ratio than measured androgen markers.

Conclusions: Based on our study, the calculated testosterone indices such as FAI, cBT and cFT are useful markers to distinguish PCOS from non-PCOS. Owing to ease of calculation, FAI can be incorporated in LIS and can be reported with TT and SHBG. This will be helpful for clinician to diagnose hyperandrogenism in PCOS.
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April 2018

Analyses of antioxidant status and nucleotide alterations in genes encoding antioxidant enzymes in patients with benign and malignant thyroid disorders.

PeerJ 2017 1;5:e3365. Epub 2017 Jun 1.

Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Background: Synthesis of thyroid hormones and regulation of their metabolism involve free radicals that may affect redox balance in the body. Thyroid disorders causing variations in the levels of thyroid hormones may alter cellular oxidative stress. The aim of this study was to measure the antioxidant activities and biomarkers of oxidative stress in serum and red blood cells (RBC) of patients with benign and malignant thyroid disorders and to investigate if changes in the antioxidant activities in these patients were linked to alterations in genes encoding the antioxidant enzymes.

Methods: Forty-one patients with thyroid disorders from University of Malaya Medical Centre were recruited. They were categorised into four groups: multinodular goitre (MNG) ( = 18), follicular thyroid adenoma (FTA) ( = 7), papillary thyroid cancer (PTC) ( = 10), and follicular thyroid cancer (FTC) ( = 6). Serum and RBC of patients were analysed for antioxidant activities, antioxidant enzymes, and biomarkers of oxidative stress. Alterations in genes encoding the antioxidant enzymes were analysed using whole exome sequencing and PCR-DNA sequencing.

Results: Patients with thyroid disorders had significantly higher serum superoxide dismutase (SOD) and catalase (CAT) activities compared to control, but had lower activities in RBC. There were no significant changes in serum glutathione peroxidase (GPx) activity. Meanwhile, GPx activity in RBC was reduced in PTC and FTC, compared to control and the respective benign groups. Antioxidant activities in serum were decreased in the thyroid disorder groups when compared to the control group. The levels of malondialdehyde (MDA) were elevated in the serum of FTA group when compared to controls, while in the RBC, only the MNG and PTC groups showed higher MDA equivalents than control. Serum reactive oxygen species (ROS) levels in PTC group of both serum and RBC were significantly higher than control group. Whole exome sequencing has resulted in identification of 49 single nucleotide polymorphisms (SNPs) in MNG and PTC patients and their genotypic and allelic frequencies were calculated. Analyses of the relationship between serum enzyme activities and the total SNPs identified in both groups revealed no correlation.

Discussion: Different forms of thyroid disorders influence the levels of antioxidant status in the serum and RBC of these patients, implying varying capability of preventing oxidative stress. A more comprehensive study with a larger target population should be done in order to further evaluate the relationships between antioxidant enzymes gene polymorphisms and thyroid disorders, as well as strengthening the minor evidences provided in literatures.
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http://dx.doi.org/10.7717/peerj.3365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457668PMC
June 2017

Comparative characteristics of spermatozoa harvested and cryopreserved in culture and cryoprotectant media with or without donor serum proteins.

Reprod Biol 2017 Jun 13;17(2):172-179. Epub 2017 May 13.

Department of Obstetrics and Gynecology, c/-University Malaya Medical Centre, Faculty of Medicine, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Malaysia. Electronic address:

The objectives of this study is to evaluate the efficacy of protein-free media in the preparation, holding and crypreservation of spermatazoa for use in ART. Normozoospermic semen samples (N=71) were used to compare the effects of media on the survival and quality of spermatozoa when washed and cultured with different media with and without added proteins at 4°C, 15°C, 22°C and 37°C for 0, 4-7 and 24h. Survival and quality of spermatozoa were assessed after freeze-thaw with synthetic cryoprotectant with and without proteins. Ethics/IRB approval was obtained (Ref. 1073.52). Spermatozoa parameters were similar in all media after washing and culture for 24h. Post-thaw survival and quality of spermatozoa was not significantly different 24h after thawing of samples frozen in all cryoprotectant medium. In conclusion synthetic protein-free culture and cryoprotectant media are equal in efficacy to protein-containing media in culture and cryopreservation of spermatozoa . Use of these synthetic media are anticipated to significantly reduce the risk, potentially associated with conventional protein-containing media, of transmission of disease and possibly harmful undeclared proteins to the patient, baby and the healtcare worker. Synthetic media also ensure consistency of quality between batches of media.
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http://dx.doi.org/10.1016/j.repbio.2017.04.004DOI Listing
June 2017

Date fruit consumption at term: Effect on length of gestation, labour and delivery.

J Obstet Gynaecol 2017 Jul 13;37(5):595-600. Epub 2017 Mar 13.

b Department of Obstetrics and Gynaecology, Faculty of Medicine , University Malaya , Kuala Lumpur , Malaysia.

Labour induction and augmentation with Prostaglandin and Oxytocin are well established as standard practice worldwide. They are safe when used judiciously, but may be associated with maternal and neonatal morbidities. Other safer alternatives have been studied including dates consumption during late pregnancy with various outcomes. The aim of this randomised controlled trial was to investigate the effect of date fruit consumption during late pregnancy on the onset of labour and need for induction or augmentation of labour. A total of 154 nulliparous women with an uncomplicated singleton pregnancy were randomly allocated to either dates-consumer (77) or control group (77). The women in the dates-consumer group had significantly less need for augmentation of labour and longer intervention to delivery interval. There was no significant difference in the onset of spontaneous labour. Dates consumption reduces the need for labour augmentation but does not expedite the onset of labour. Impact statement • Dates fruit consumption during late pregnancy has been shown to positively affect the outcome of labour and delivery. In this study, date consumption reduced the need for labour augmentation with oxytocin but did not expedite the onset of labour. Therefore, dates consumption in late pregnancy is a safe supplement to be considered as it reduced the need for labour intervention without any adverse effect on the mother and child. This further supports the finding of earlier studies.
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http://dx.doi.org/10.1080/01443615.2017.1283304DOI Listing
July 2017

Protective effect of magnesium acetyltaurate against NMDA-induced retinal damage involves restoration of minerals and trace elements homeostasis.

J Trace Elem Med Biol 2017 Jan 17;39:147-154. Epub 2016 Sep 17.

Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.

Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.
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http://dx.doi.org/10.1016/j.jtemb.2016.09.005DOI Listing
January 2017

Antioxidant-rich leaf extract of Barringtonia racemosa significantly alters the in vitro expression of genes encoding enzymes that are involved in methylglyoxal degradation III.

PeerJ 2016 25;4:e2379. Epub 2016 Aug 25.

Department of Molecular Medicine, Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.

Background: Barringtonia racemosa is a medicinal plant belonging to the Lecythidaceae family. The water extract of B. racemosa leaf (BLE) has been shown to be rich in polyphenols. Despite the diverse medicinal properties of B. racemosa, information on its major biological effects and the underlying molecular mechanisms are still lacking.

Methods: In this study, the effect of the antioxidant-rich BLE on gene expression in HepG2 cells was investigated using microarray analysis in order to shed more light on the molecular mechanism associated with the medicinal properties of the plant.

Results: Microarray analysis showed that a total of 138 genes were significantly altered in response to BLE treatment (p < 0.05) with a fold change difference of at least 1.5. SERPINE1 was the most significantly up-regulated gene at 2.8-fold while HAMP was the most significantly down-regulated gene at 6.5-fold. Ingenuity Pathways Analysis (IPA) revealed that "Cancer, cell death and survival, cellular movement" was the top network affected by the BLE with a score of 44. The top five canonical pathways associated with BLE were Methylglyoxal Degradation III followed by VDR/RXR activation, TR/RXR activation, PXR/RXR activation and gluconeogenesis. The expression of genes that encode for enzymes involved in methylglyoxal degradation (ADH4, AKR1B10 and AKR1C2) and glycolytic process (ENO3, ALDOC and SLC2A1) was significantly regulated. Owing to the Warburg effect, aerobic glycolysis in cancer cells may increase the level of methylglyoxal, a cytotoxic compound.

Conclusions: BLE has the potential to be developed into a novel chemopreventive agent provided that the cytotoxic effects related to methylglyoxal accumulation are minimized in normal cells that rely on aerobic glycolysis for energy supply.
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http://dx.doi.org/10.7717/peerj.2379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012310PMC
September 2016

Inhibition of G9a/GLP Complex Promotes Long-Term Potentiation and Synaptic Tagging/Capture in Hippocampal CA1 Pyramidal Neurons.

Cereb Cortex 2017 06;27(6):3161-3171

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 597, Singapore.

Epigenetic regulations play an important role in regulating the learning and memory processes. G9a/G9a-like protein (GLP) lysine dimethyltransferase complex controls a prominent histone H3 lysine9 dimethylation (H3K9me2) that results in transcriptional silencing of the chromatin. Here, we report that the inhibition of G9a/GLP complex by either of the substrate competitive inhibitors UNC 0638 or BIX 01294 reinforces protein synthesis-independent long-term potentiation (early-LTP) to protein synthesis-dependent long-term potentiation (late-LTP). The reinforcement effect was observed if the inhibitors were present during the induction of early-LTP and in addition when G9a/GLP complex inhibition was carried out by priming of synapses within an interval of 30 min before or after the induction of early-LTP. Surprisingly, the reinforced LTP by G9a/GLP complex inhibition was able to associate with a weak plasticity event from nearby independent synaptic populations, resulting in synaptic tagging/capture (STC). We have identified brain-derived neurotrophic factor (BDNF) as a critical plasticity protein that maintains G9a/GLP complex inhibition-mediated LTP facilitation and its STC. Our study reveals an epigenetic mechanism for promoting plasticity and associativity by G9a/GLP complex inhibition, and it may engender a promising epigenetic target for enhancing memory in neural networks.
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http://dx.doi.org/10.1093/cercor/bhw170DOI Listing
June 2017

Natural history of asymptomatic gallstones: differential behaviour in male and female subjects.

Med J Malaysia 2015 Dec;70(6):341-5

Universiti Teknologi MARA, Faculty of Medicine, Malaysia.

Objective: The natural history of asymptomatic (silent) gallstones has been inadequately studied. Existing information derives from studies based on oral cholecystography or relatively small sample sizes. We planned a retrospective cohort study in subjects with gallstones to determine conversion rates from asymptomatic to symptomatic.

Methods: We extracted data from computerised databases of one government hospital and two private clinics in Malaysia. Files were scrutinised to ensure that criteria for asymptomatic gallstones were fulfilled. Patients were called on telephone, further questioned to confirm that the gallstones at detection were truly asymptomatic, and asked about symptoms that were consistent with previously defined criteria for biliary colic. Appropriate ethical clearances were taken.

Results: 213 (112 males) patients fulfilled the criteria for asymptomatic gallstones and could be contacted. 23 (10.8%) developed pain after an average follow up interval of 4.02 years (range 0.1-11 years). Conversion rates from asymptomatic to symptomatic gallstones were high in the first two years of follow up, averaging 4.03±0.965 per year. Over time the conversion rates slowed, and by year 10 the annual conversion rate averaged only 1.38±0.29. Conversion rates were much higher for females compared to males (F:M hazard ratio 3.23, SE 1.54, p>z 0.014). The lifetime risks for conversion approached 6.15% for males, and 22.1% for females.

Conclusion: In conclusion, asymptomatic gallstones are much more likely to convert to symptomatic in females than in males. Males in whom asymptomatic stones are discovered should be advised conservative treatment. Surgery may be preferable to conservative management if the subject is a young female.
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December 2015

Carbetocin compared to oxytocin in emergency cesarean section: a randomized trial.

Eur J Obstet Gynecol Reprod Biol 2016 Mar 30;198:35-39. Epub 2015 Dec 30.

Department of Obstetrics and Gynaecology, University Malaya, 59100 Kuala Lumpur, Malaysia.

Objective: To evaluate the uterotonic effect of carbetocin compared with oxytocin in emergency cesarean delivery.

Study Design: Participants were randomized to intravenous bolus injection of 100mcg carbetocin or 10IU oxytocin after cesarean delivery of the baby. The primary outcome is any additional uterotonic which may be administered by the blinded provider for perceived inadequate uterine tone with or without hemorrhage in the first 24hours after delivery. Secondary outcomes include operating time, perioperative blood loss, change in hemoglobin and hematocrit levels, blood transfusion and reoperation for postpartum hemorrhage.

Results: Additional uterotonic rates were 107/276 (38.8%) vs. 155/271 (57.2%) [RR 0.68 95% CI 0.57-0.81 p<0.001; NNTb 6 95% CI 3.8-9.8], mean operating time 45.9±16.0 vs. 44.5±13.1minutes p=0.26, mean blood loss 458±258 vs. 446±281ml p=0.6, severe postpartum hemorrhage (≥1000ml) rates 15/276 (5.4%) vs. 10/271 (3.7%) p=0.33 and blood transfusion rates 6/276 (2.2%) vs. 10/271 (3.7%); p=0.30 for carbetocin and oxytocin arms respectively. There was only one case of re-operation (oxytocin arm). In the cases that needed additional uterotonic 98% (257/262) was started intraoperatively and in 89% (234/262) the only additional uterotonic administered was an oxytocin infusion over 6hours.

Conclusion: Fewer women in the carbetocin arm needed additional uterotonics but perioperative blood loss, severe postpartum hemorrhage, blood transfusion and operating time were not different.
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http://dx.doi.org/10.1016/j.ejogrb.2015.12.017DOI Listing
March 2016

Polyphenols from the extract and fraction of T. indica seeds protected HepG2 cells against oxidative stress.

BMC Complement Altern Med 2015 Dec 18;15:438. Epub 2015 Dec 18.

Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.

Background: Tamarindus indica L. (T. indica) or locally known as "asam jawa" belongs to the family Leguminosae. T. indica seeds as by-products from the fruits were previously reported to contain high polyphenolic content. However, identification of their bioactive polyphenols using recent technologies is less well researched but nonetheless important. Hence, it was the aim of this study to provide further information on the polyphenolic content and antioxidant activities as well as to identify and quantify its bioactive polyphenols.

Methods: T. indica seeds were extracted with methanol and were then fractionated with different compositions of hexane, ethyl acetate and methanol. Polyphenolic contents were measured using Folin-Ciocalteu assay while antioxidant activities were measured using DPPH radical scavenging and ferric reducing (FRAP) activities. The cytotoxic activities of the crude extract and the active fraction were evaluated in HepG2 cells using MTT assay. The cells were then pre-treated with the IC20 concentrations and induced with H2O2 before measuring their cellular antioxidant activities including FRAP, DPPH, lipid peroxidation, ROS generation and antioxidant enzymes, SOD, GPx and CAT. Analyses of polyphenols in the crude extract and its active fraction were done using UHPLC and NMR.

Results: Amongst the 7 isolated fractions, fraction F3 showed the highest polyphenolic content and antioxidant activities. When HepG2 cells were treated with fraction F3 or the crude extract, the former demonstrated higher antioxidant activities. F3 also showed stronger inhibition of lipid peroxidation and ROS generation, and enhanced activities of SOD, GPx and CAT of HepG2 cells following H2O2-induced oxidative damage. UHPLC analyses revealed the presence of catechin, procyanidin B2, caffeic acid, ferulic acid, chloramphenicol, myricetin, morin, quercetin, apigenin and kaempferol, in the crude seed extract of T. indica. UHPLC and NMR analyses identified the presence of caffeic acid in fraction F3. Our studies were the first to report caffeic acid as the active polyphenol isolated from T. indica seeds which likely contributed to the potent antioxidant defense system of HepG2 cells.

Conclusion: Results from this study indicate that caffeic acid together with other polyphenols in T. indica seeds can enhance the antioxidant activities of treated HepG2 cells which can provide protection against oxidative damage.
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http://dx.doi.org/10.1186/s12906-015-0963-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683930PMC
December 2015

Investigation into the effects of antioxidant-rich extract of Tamarindus indica leaf on antioxidant enzyme activities, oxidative stress and gene expression profiles in HepG2 cells.

PeerJ 2015 1;3:e1292. Epub 2015 Oct 1.

Department of Molecular Medicine, Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.

The leaf extract of Tamarindus indica L. (T. indica) had been reported to possess high phenolic content and showed high antioxidant activities. In this study, the effects of the antioxidant-rich leaf extract of the T. indica on lipid peroxidation, antioxidant enzyme activities, H2O2-induced ROS production and gene expression patterns were investigated in liver HepG2 cells. Lipid peroxidation and ROS production were inhibited and the activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase was enhanced when the cells were treated with the antioxidant-rich leaf extract. cDNA microarray analysis revealed that 207 genes were significantly regulated by at least 1.5-fold (p < 0.05) in cells treated with the antioxidant-rich leaf extract. The expression of KNG1, SERPINC1, SERPIND1, SERPINE1, FGG, FGA, MVK, DHCR24, CYP24A1, ALDH6A1, EPHX1 and LEAP2 were amongst the highly regulated. When the significantly regulated genes were analyzed using Ingenuity Pathway Analysis software, "Lipid Metabolism, Small Molecule Biochemistry, Hematological Disease" was the top biological network affected by the leaf extract, with a score of 36. The top predicted canonical pathway affected by the leaf extract was the coagulation system (P < 2.80 × 10(-6)) followed by the superpathway of cholesterol biosynthesis (P < 2.17 × 10(-4)), intrinsic prothrombin pathway (P < 2.92 × 10(-4)), Immune Protection/Antimicrobial Response (P < 2.28 × 10(-3)) and xenobiotic metabolism signaling (P < 2.41 × 10(-3)). The antioxidant-rich leaf extract of T. indica also altered the expression of proteins that are involved in the Coagulation System and the Intrinsic Prothrombin Activation Pathway (KNG1, SERPINE1, FGG), Superpathway of Cholesterol Biosynthesis (MVK), Immune protection/antimicrobial response (IFNGR1, LEAP2, ANXA3 and MX1) and Xenobiotic Metabolism Signaling (ALDH6A1, ADH6). In conclusion, the antioxidant-rich leaf extract of T. indica inhibited lipid peroxidation and ROS production, enhanced antioxidant enzyme activities and significantly regulated the expression of genes and proteins involved with consequential impact on the coagulation system, cholesterol biosynthesis, xenobiotic metabolism signaling and antimicrobial response.
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http://dx.doi.org/10.7717/peerj.1292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636403PMC
November 2015

Topical trans-resveratrol ameliorates steroid-induced anterior and posterior segment changes in rats.

Exp Eye Res 2016 Feb 28;143:9-16. Epub 2015 Sep 28.

Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia.

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.
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http://dx.doi.org/10.1016/j.exer.2015.09.014DOI Listing
February 2016

Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets.

J Pediatr Endocrinol Metab 2015 Sep;28(9-10):1009-17

Hypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and, dentin matrix protein-1 (DMP1) and ecto-nucleotide pyro phosphatase/phosphodiesterase 1 (ENPP1) genes, respectively. Mutations in these genes are believed to cause elevation of circulating FGF23 protein. Increase in FGF23 disrupts phosphate homeostasis, leading to HR. This review aims to summarize phosphate homeostasis and focuses on the genes and mutations related to XLH, ADHR, and ARHR. A compilation of XLH mutation hotspots based on the PHEX gene database and mutations found in the FGF23, DMP1, and ENPP1 genes are also made available in this review.
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http://dx.doi.org/10.1515/jpem-2014-0366DOI Listing
September 2015

Anterior and posterior segment changes in rat eyes with chronic steroid administration and their responsiveness to antiglaucoma drugs.

Eur J Pharmacol 2015 Feb 4;749:73-80. Epub 2014 Dec 4.

Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia; Faculty of Medicine, Brain and Neuroscience Communities of Research, Universiti Teknologi MARA (UiTM), Shah Alam, Selangor, Malaysia.

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.
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http://dx.doi.org/10.1016/j.ejphar.2014.11.029DOI Listing
February 2015

Liposomes in topical ophthalmic drug delivery: an update.

Drug Deliv 2016 May 12;23(4):1075-91. Epub 2014 Aug 12.

a Faculty of Medicine , Universiti Teknologi MARA, Sungai Buloh Campus , Sungai Buloh , Selangor , Malaysia .

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.
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http://dx.doi.org/10.3109/10717544.2014.943336DOI Listing
May 2016

Role of adenosine receptors in resveratrol-induced intraocular pressure lowering in rats with steroid-induced ocular hypertension.

Clin Exp Ophthalmol 2015 Jan-Feb;43(1):54-66. Epub 2014 Nov 20.

Faculty of Medicine, Brain and Neuroscience Communities of Research, Universiti Teknologi MARA (UiTM), Shah Alam, Selangor.

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.
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http://dx.doi.org/10.1111/ceo.12375DOI Listing
July 2015