Displaying publications 1 - 20 of 88 in total

Abstract:
Sort:
  1. Fulltext In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors
    Zulkipli NN, Zakaria R, Long I, Abdullah SF, Muhammad EF, Wahab HA, et al.
    Molecules, 2020 Sep 02;25(17).
    PMID: 32887218 DOI: 10.3390/molecules25173991
    Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC50 of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from Centella asiatica, revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC50 values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.
  2. H274Y's Effect on Oseltamivir Resistance: What Happens Before the Drug Enters the Binding Site
    Yusuf M, Mohamed N, Mohamad S, Janezic D, Damodaran KV, Wahab HA
    J Chem Inf Model, 2016 Jan 25;56(1):82-100.
    PMID: 26703840 DOI: 10.1021/acs.jcim.5b00331
    Increased reports of oseltamivir (OTV)-resistant strains of the influenza virus, such as the H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies have been conducted in the attempt to uncover the mechanism of OTV resistance in H274Y NA. However, most of the reported studies on H274Y focused only on the drug-bound system, so the direct effects of the mutation on NA itself prior to drug binding still remain unclear. Therefore, molecular dynamics simulations of NA in apo form, followed by principal component analysis and interaction energy calculations, were performed to investigate the structural changes of the NA binding site as a result of the H274Y mutation. It was observed that the disruption of the NA binding site due to the H274Y mutation was initiated by the repulsive effect of Y274 on the 250-loop, which in turn altered the hydrogen-bonding network around residue 274. The rotated W295 side chain caused the upward movement of the 340-loop. Consequently, sliding box docking results suggested that the binding pathway of OTV was compromised because of the disruption of this binding site. This study also highlighted the importance of the functional group at C6 of the sialic acid mimicry. It is hoped that these results will improve the understanding of OTV resistance and shed some light on the design of a novel anti-influenza drug.
  3. Structurally conserved binding sites of hemagglutinin as targets for influenza drug and vaccine development
    Yusuf M, Konc J, Sy Bing C, Trykowska Konc J, Ahmad Khairudin NB, Janezic D, et al.
    J Chem Inf Model, 2013 Sep 23;53(9):2423-36.
    PMID: 23980878 DOI: 10.1021/ci400421e
    ProBiS is a new method to identify the binding site of protein through local structural alignment against the nonredundant Protein Data Bank (PDB), which may result in unique findings compared to the energy-based, geometry-based, and sequence-based predictors. In this work, binding sites of Hemagglutinin (HA), which is an important target for drugs and vaccines in influenza treatment, have been revisited by ProBiS. For the first time, the identification of conserved binding sites by local structural alignment across all subtypes and strains of HA available in PDB is presented. ProBiS finds three distinctive conserved sites on HA's structure (named Site 1, Site 2, and Site 3). Compared to other predictors, ProBiS is the only one that accurately defines the receptor binding site (Site 1). Apart from that, Site 2, which is located slightly above the TBHQ binding site, is proposed as a potential novel conserved target for membrane fusion inhibitor. Lastly, Site 3, located around Helix A at the stem domain and recently targeted by cross-reactive antibodies, is predicted to be conserved in the latest H7N9 China 2013 strain as well. The further exploration of these three sites provides valuable insight in optimizing the influenza drug and vaccine development.
  4. Fulltext In Vitro and In Silico Analysis of the Anticancer Effects of Eurycomanone and Eurycomalactone from Eurycoma longifolia
    Yunos NM, Wahab HA, Al-Thiabat MG, Sallehudin NJ, Jauri MH
    Plants (Basel), 2023 Jul 31;12(15).
    PMID: 37570981 DOI: 10.3390/plants12152827
    Eurycomanone and eurycomalactone are known quassinoids present in the roots and stems of Eurycoma longifolia. These compounds had been reported to have cytotoxic effects, however, their mechanism of action in a few cancer cell lines have yet to be elucidated. This study was aimed at investigating the anticancer effects and mechanisms of action of eurycomanone and eurycomalactone in cervical (HeLa), colorectal (HT29) and ovarian (A2780) cancer cell lines via Sulforhodamine B assay. Their mechanism of cell death was evaluated based on Hoechst 33342 assay and in silico molecular docking toward DHFR and TNF-α as putative protein targets. Eurycomanone and eurycomalactone exhibited in vitro anticancer effects manifesting IC50 values of 4.58 ± 0.090 µM and 1.60 ± 0.12 µM (HeLa), 1.22 ± 0.11 µM and 2.21 ± 0.049 µM (HT-29), and 1.37 ± 0.13 µM and 2.46 ± 0.081 µM (A2780), respectively. They induced apoptotic cancer cell death in dose- and time-dependent manners. Both eurycomanone and eurycomalactone were also predicted to have good inhibitory potential as demonstrated by the docking into TNF-α with binding affinity of -8.83 and -7.51 kcal/mol, respectively, as well as into DHFR with binding affinity results of -8.05 and -8.87 kcal/mol, respectively. These results support the evidence of eurycomanone and eurycomalactone as anticancer agents via apoptotic cell death mechanism that could be associated with TNF-α and DHFR inhibition as among possible protein targets.
  5. Binding specificity of polypeptide substrates in NS2B/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study
    Yotmanee P, Rungrotmongkol T, Wichapong K, Choi SB, Wahab HA, Kungwan N, et al.
    J Mol Graph Model, 2015 Jul;60:24-33.
    PMID: 26086900 DOI: 10.1016/j.jmgm.2015.05.008
    The pathogenic dengue virus (DV) is a growing global threat, particularly in South East Asia, for which there is no specific treatment available. The virus possesses a two-component (NS2B/NS3) serine protease that cleaves the viral precursor proteins. Here, we performed molecular dynamics simulations of the NS2B/NS3 protease complexes with six peptide substrates (capsid, intNS3, 2A/2B, 4B/5, 3/4A and 2B/3 containing the proteolytic site between P(1) and P(1)' subsites) of DV type 2 to compare the specificity of the protein-substrate binding recognition. Although all substrates were in the active conformation for cleavage reaction by NS2B/NS3 protease, their binding strength was somewhat different. The simulated results of intermolecular hydrogen bonds and decomposition energies suggested that among the ten substrate residues (P(5)-P(5)') the P(1) and P(2) subsites play a major role in the binding with the focused protease. The arginine residue at these two subsites was found to be specific preferential binding at the active site with a stabilization energy of intNS3>2A/2B>4B/5>3/4A>2B/3 in a relative correspondence with previous experimentally derived values.
  6. Molecular insights into 14-membered macrolides using the MM-PBSA method
    Yam WK, Wahab HA
    J Chem Inf Model, 2009 Jun;49(6):1558-67.
    PMID: 19469526 DOI: 10.1021/ci8003495
    Erythromycin A and roxithromycin are clinically important macrolide antibiotics that selectively act on the bacterial 50S large ribosomal subunit to inhibit bacteria's protein elongation process by blocking the exit tunnel for the nascent peptide away from ribosome. The detailed molecular mechanism of macrolide binding is yet to be elucidated as it is currently known to the most general idea only. In this study, molecular dynamics (MD) simulation was employed to study their interaction at the molecular level, and the binding free energies for both systems were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The calculated binding free energies for both systems were slightly overestimated compared to the experimental values, but individual energy terms enabled better understanding in the binding for both systems. Decomposition of results into residue basis was able to show the contribution of each residue at the binding pocket toward the binding affinity of macrolides and hence identified several key interacting residues that were in agreement with previous experimental and computational data. Results also indicated the contributions from van der Waals are more important and significant than electrostatic contribution in the binding of macrolides to the binding pocket. The findings from this study are expected to contribute to the understanding of a detailed mechanism of action in a quantitative matter and thus assisting in the development of a safer macrolide antibiotic.
  7. Fulltext Structural modeling and biochemical characterization of recombinant KPN_02809, a zinc-dependent metalloprotease from Klebsiella pneumoniae MGH 78578
    Wong MT, Choi SB, Kuan CS, Chua SL, Chang CH, Normi YM, et al.
    Int J Mol Sci, 2012;13(1):901-17.
    PMID: 22312293 DOI: 10.3390/ijms13010901
    Klebsiella pneumoniae is a Gram-negative, cylindrical rod shaped opportunistic pathogen that is found in the environment as well as existing as a normal flora in mammalian mucosal surfaces such as the mouth, skin, and intestines. Clinically it is the most important member of the family of Enterobacteriaceae that causes neonatal sepsis and nosocomial infections. In this work, a combination of protein sequence analysis, structural modeling and molecular docking simulation approaches were employed to provide an understanding of the possible functions and characteristics of a hypothetical protein (KPN_02809) from K. pneumoniae MGH 78578. The computational analyses showed that this protein was a metalloprotease with zinc binding motif, HEXXH. To verify this result, a ypfJ gene which encodes for this hypothetical protein was cloned from K. pneumoniae MGH 78578 and the protein was overexpressed in Escherichia coli BL21 (DE3). The purified protein was about 32 kDa and showed maximum protease activity at 30 °C and pH 8.0. The enzyme activity was inhibited by metalloprotease inhibitors such as EDTA, 1,10-phenanthroline and reducing agent, 1,4-dithiothreitol (DTT). Each molecule of KPN_02809 protein was also shown to bind one zinc ion. Hence, for the first time, we experimentally confirmed that KPN_02809 is an active enzyme with zinc metalloprotease activity.
  8. Drug-like and non drug-like pattern classification based on simple topology descriptor using hybrid neural network
    Wan-Mamat WM, Isa NA, Wahab HA, Wan-Mamat WM
    Annu Int Conf IEEE Eng Med Biol Soc, 2009;2009:6424-7.
    PMID: 19964424 DOI: 10.1109/IEMBS.2009.5333747
    An intelligent prediction system has been developed to discriminate drug-like and non drug-like molecules pattern. The system is constructed by using the application of advanced version of standard multilayer perceptron (MLP) neural network called Hybrid Multilayer Perceptron (HMLP) neural network and trained using Modified Recursive Prediction Error (MRPE) training algorithm. In this work, a well understood and easy excess Rule of Five + Veber filter properties are selected as the topological descriptor. The main idea behind the selection of this simple descriptor is to assure that the system could be used widely, beneficial and more advantageous regardless at all user level within a drug discovery organization.
  9. Fulltext Quantitative analysis of electroplated nickel coating on hard metal
    Wahab HA, Noordin MY, Izman S, Kurniawan D
    ScientificWorldJournal, 2013;2013:631936.
    PMID: 23997678 DOI: 10.1155/2013/631936
    Electroplated nickel coating on cemented carbide is a potential pretreatment technique for providing an interlayer prior to diamond deposition on the hard metal substrate. The electroplated nickel coating is expected to be of high quality, for example, indicated by having adequate thickness and uniformity. Electroplating parameters should be set accordingly for this purpose. In this study, the gap distances between the electrodes and duration of electroplating process are the investigated variables. Their effect on the coating thickness and uniformity was analyzed and quantified using design of experiment. The nickel deposition was carried out by electroplating in a standard Watt's solution keeping other plating parameters (current: 0.1 Amp, electric potential: 1.0 V, and pH: 3.5) constant. The gap distance between anode and cathode varied at 5, 10, and 15 mm, while the plating time was 10, 20, and 30 minutes. Coating thickness was found to be proportional to the plating time and inversely proportional to the electrode gap distance, while the uniformity tends to improve at a large electrode gap. Empirical models of both coating thickness and uniformity were developed within the ranges of the gap distance and plating time settings, and an optimized solution was determined using these models.
  10. Refinement of a low-resolution crystal structure to better understand erythromycin interactions on large ribosomal subunit
    Wahab HA, Yam WK, Samian MR, Najimudin N
    J Biomol Struct Dyn, 2008 Aug;26(1):131-46.
    PMID: 18533733
    Macrolides are a group of diverse class of naturally occurring and synthetic antibiotics made of macrocyclic-lactone ring carrying one or more sugar moieties linked to various atoms of the lactone ring. These macrolides selectively bind to a single high affinity site on the prokaryotic 50S ribosomal subunit, making them highly effective towards a wide range of bacterial pathogens. The understanding of binding between macrolides and ribosome serves a good basis in elucidating how they work at the molecular level and these findings would be important in rational drug design. Here, we report refinement of reconstructed PDB structure of erythromycin-ribosome system using molecular dynamics (MD) simulation. Interesting findings were observed in this refinement stage that could improve the understanding of the binding of erythromycin A (ERYA) onto the 50S subunit. The results showed ERYA was highly hydrated and water molecules were found to be important in bridging hydrogen bond at the binding pocket during the simulation time. ERYA binding to ribosome was also strengthened by hydrogen bond network and hydrophobic interactions between the antibiotic and the ribosome. Our MD simulation also demonstrated direct interaction of ERYA with Domains II, V and with C1773 (U1782EC), a residue in Domain IV that has yet been described of its role in ERYA binding. It is hoped that this refinement will serve as a starting model for a further enhancement of our understanding towards the binding of ERYA to ribosome.
  11. Elucidating isoniazid resistance using molecular modeling
    Wahab HA, Choong YS, Ibrahim P, Sadikun A, Scior T
    J Chem Inf Model, 2009 Jan;49(1):97-107.
    PMID: 19067649 DOI: 10.1021/ci8001342
    The continuing rise in tuberculosis incidence and the problem of drug resistance strains have prompted the research on new drug candidates and the mechanism of drug resistance. Molecular docking and molecular dynamics simulation (MD) were performed to study the binding of isoniazid onto the active site of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) in an attempt to address the mycobacterial resistance against isoniazid. Results show that isonicotinic acyl-NADH (INADH) has an extremely high binding affinity toward the wild type InhA by forming stronger interactions compared to the parent drug (isoniazid) (INH). Due to the increase of hydrophobicity and reduction in the side chain's volume of A94 of mutant type InhA, both INADH and the mutated protein become more mobile. Due to this reason, the molecular interactions of INADH with mutant type are weaker than that observed with the wild type. However, the reduced interaction caused by the fluctuation of INADH and the mutant protein only inflected minor resistance in the mutant strain as inferred from free energy calculation. MD results also showed there exists a water-mediated hydrogen bond between INADH and InhA. However, the bridged water molecule is only present in the INADH-wild type complex, reflecting the putative role of the water molecule in the binding of INADH to the wild type protein. The results support the assumption that the conversion of prodrug isoniazid into its active form INADH is mediated by KatG as a necessary step prior to target binding on InhA. Our findings also contribute to a better understanding of INH resistance in mutant type.
  12. Women in Computational Chemistry
    Wahab HA, Amaro RE, Cournia Z
    J Chem Inf Model, 2018 11 26;58(11):2175-2177.
    PMID: 30277769 DOI: 10.1021/acs.jcim.8b00642
  13. Sequence analysis and structure prediction of type II Pseudomonas sp. USM 4-55 PHA synthase and an insight into its catalytic mechanism
    Wahab HA, Ahmad Khairudin NB, Samian MR, Najimudin N
    BMC Struct Biol, 2006;6:23.
    PMID: 17076907
    Polyhydroxyalkanoates (PHA), are biodegradable polyesters derived from many microorganisms such as the pseudomonads. These polyesters are in great demand especially in the packaging industries, the medical line as well as the paint industries. The enzyme responsible in catalyzing the formation of PHA is PHA synthase. Due to the limited structural information, its functional properties including catalysis are lacking. Therefore, this study seeks to investigate the structural properties as well as its catalytic mechanism by predicting the three-dimensional (3D) model of the Type II Pseudomonas sp. USM 4-55 PHA synthase 1 (PhaC1P.sp USM 4-55).
  14. Fulltext Fluorescent Multifunctional Organic Nanoparticles for Drug Delivery and Bioimaging: A Tutorial Review
    Vargas-Nadal G, Köber M, Nsamela A, Terenziani F, Sissa C, Pescina S, et al.
    Pharmaceutics, 2022 Nov 17;14(11).
    PMID: 36432688 DOI: 10.3390/pharmaceutics14112498
    Fluorescent organic nanoparticles (FONs) are a large family of nanostructures constituted by organic components that emit light in different spectral regions upon excitation, due to the presence of organic fluorophores. FONs are of great interest for numerous biological and medical applications, due to their high tunability in terms of composition, morphology, surface functionalization, and optical properties. Multifunctional FONs combine several functionalities in a single nanostructure (emission of light, carriers for drug-delivery, functionalization with targeting ligands, etc.), opening the possibility of using the same nanoparticle for diagnosis and therapy. The preparation, characterization, and application of these multifunctional FONs require a multidisciplinary approach. In this review, we present FONs following a tutorial approach, with the aim of providing a general overview of the different aspects of the design, preparation, and characterization of FONs. The review encompasses the most common FONs developed to date, the description of the most important features of fluorophores that determine the optical properties of FONs, an overview of the preparation methods and of the optical characterization techniques, and the description of the theoretical approaches that are currently adopted for modeling FONs. The last part of the review is devoted to a non-exhaustive selection of some recent biomedical applications of FONs.
  15. Development, optimization and characterization of cisplatin loaded cubosomes for human lung carcinoma
    Umar H, Wahab HA, Ahmed N, Fujimura NA, Amjad MW, Bukhari SNA, et al.
    Drug Dev Ind Pharm, 2024 Mar 20.
    PMID: 38451066 DOI: 10.1080/03639045.2024.2326043
    OBJECTIVES: This study aimed to develop, optimize and evaluate glyceryl monooleate (GMO) based cubosomes as a drug delivery system containing cisplatin for treatment of human lung carcinoma.

    SIGNIFICANCE: The significance of this research was to successfully incorporate slightly water soluble and potent anticancer drug (cisplatin) into cubosomes, which provide slow and sustained release of drug for longer period of time.

    METHODS: The delivery system was developed through top-down approach by melting GMO and poloxamer 407 (P407) at 70 °C and then drop-wise addition of warm deionized water (70 °C) containing cisplatin. The formulation then exposed to probe sonicator for about 2 min. A randomized regular two level full factorial design with help of Design Expert was used for optimization of blank cubosomal formulations. Cisplatin loaded cubosomes were then subjected to physico-chemical characterization.

    RESULTS: The characterization of the formulation revealed that it had a sufficient surface charge of -9.56 ± 1.33 mV, 168.25 ± 5.73 nm particle size, and 60.64 ± 0.11% encapsulation efficiency. The in vitro release of cisplatin from the cubosomes at pH 7.4 was observed to be sustained, with 94.5% of the drug being released in 30 h. In contrast, 99% of cisplatin was released from the drug solution in just 1.5 h. In vitro cytotoxicity assay was conducted on the human lung carcinoma NCI-H226 cell line, the cytotoxicity of cisplatin-loaded cubosomes was relative to that of pure cisplatin solution, while blank (without cisplatin) cubosomes were nontoxic.

    CONCLUSIONS: The obtained results demonstrated the successful development of cubosomes for sustained delivery of cisplatin.

  16. Platinum-based targeted chemotherapies and reversal of cisplatin resistance in non-small cell lung cancer (NSCLC)
    Umar H, Wahab HA, Attiq A, Amjad MW, Bukhari SNA, Ahmad W
    Mutat Res, 2024 Mar 19;828:111856.
    PMID: 38520879 DOI: 10.1016/j.mrfmmm.2024.111856
    Lung cancer is the one of the most prevalent cancer in the world. It kills more people from cancer than any other cause and is especially common in underdeveloped nations. With 1.2 million instances, it is also the most prevalent cancer in men worldwide, making about 16.7% of the total cancer burden. Surgery is the main form of curative treatment for early-stage lung cancer. However, the majority of patients had incurable advanced non-small cell lung cancer (NSCLC) recurrence after curative purpose surgery, which is indicative of the aggressiveness of the illness and the dismal outlook. The gold standard of treatment for NSCLC patients includes drug targeting of specific mutated genes drive in development of lung cancer. Furthermore, patients with advanced NSCLC and those with early-stage illness needing adjuvant therapy should use cisplatin as it is the more active platinum drug. So, this review encompasses the non-small cell lung cancer microenvironment, treatment approaches, and use of cisplatin as a first-line regimen for NSCLC, its mechanism of action, cisplatin resistance in NSCLC and also the prevention strategies to revert the drug resistance.
  17. Fulltext Structure to function prediction of hypothetical protein KPN_00953 (Ycbk) from Klebsiella pneumoniae MGH 78578 highlights possible role in cell wall metabolism
    Teh BA, Choi SB, Musa N, Ling FL, Cun ST, Salleh AB, et al.
    BMC Struct Biol, 2014;14:7.
    PMID: 24499172 DOI: 10.1186/1472-6807-14-7
    Klebsiella pneumoniae plays a major role in causing nosocomial infection in immunocompromised patients. Medical inflictions by the pathogen can range from respiratory and urinary tract infections, septicemia and primarily, pneumonia. As more K. pneumoniae strains are becoming highly resistant to various antibiotics, treatment of this bacterium has been rendered more difficult. This situation, as a consequence, poses a threat to public health. Hence, identification of possible novel drug targets against this opportunistic pathogen need to be undertaken. In the complete genome sequence of K. pneumoniae MGH 78578, approximately one-fourth of the genome encodes for hypothetical proteins (HPs). Due to their low homology and relatedness to other known proteins, HPs may serve as potential, new drug targets.
  18. Mitragynine and its potential blocking effects on specific cardiac potassium channels
    Tay YL, Teah YF, Chong YM, Jamil MFA, Kollert S, Adenan MI, et al.
    Toxicol Appl Pharmacol, 2016 08 15;305:22-39.
    PMID: 27260674 DOI: 10.1016/j.taap.2016.05.022
    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.
  19. Fulltext Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells
    Tay YL, Amanah A, Adenan MI, Wahab HA, Tan ML
    Sci Rep, 2019 12 24;9(1):19757.
    PMID: 31874991 DOI: 10.1038/s41598-019-56106-6
    Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.
  20. Primary health care: hope and challenges for public health in Maldives
    Sulaiman AI, Abu Bakar SH, Wahab HA
    J Community Health, 2014 Jun;39(3):627-31.
    PMID: 24488646 DOI: 10.1007/s10900-013-9809-3
    The government of Maldives considers that the enjoyment of the highest attainable level of health is a basic right of every citizen. Thus it lays emphasis on the accessibility and affordability of health care services. In order to achieve these objectives, it is very important to expand curative services as well as preventive services in the country. The major hurdles faced by the country are result of the inherent structural problem faced by the county which leads to sever diseconomies of scale in the provision of healthcare services. Community and individual involvement and self-reliance are very important to achieve Health for All by the Year 200 AD. Community participation is one of the domains of community capacity building in a small island country. It is one of the mechanisms to empower people to take part in community development. In this paper, the nature, the dimensions of community participation, and its role and scope in implementation of different components of primary health care have been described. The health services in public and curative care have been briefed. Some of the achievements in health sector have also been briefly presented.
Related Terms
Filters
Contact Us

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links