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Mechanisms of Blood Brain Barrier Disruption by Different Types of Bacteria, and Bacterial-Host Interactions Facilitate the Bacterial Pathogen Invading the Brain

Al-Obaidi MMJ, Desa MNM

Cell Mol Neurobiol, 2018 Oct;38(7):1349-1368.
PMID: 30117097 DOI: 10.1007/s10571-018-0609-2

This review aims to elucidate the different mechanisms of blood brain barrier (BBB) disruption that may occur due to invasion by different types of bacteria, as well as to show the bacteria-host interactions that assist the bacterial pathogen in invading the brain. For example, platelet-activating factor receptor (PAFR) is responsible for brain invasion during the adhesion of pneumococci to brain endothelial cells, which might lead to brain invasion. Additionally, the major adhesin of the pneumococcal pilus-1, RrgA is able to bind the BBB endothelial receptors: polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1), thus leading to invasion of the brain. Moreover, Streptococcus pneumoniae choline binding protein A (CbpA) targets the common carboxy-terminal domain of the laminin receptor (LR) establishing initial contact with brain endothelium that might result in BBB invasion. Furthermore, BBB disruption may occur by S. pneumoniae penetration through increasing in pro-inflammatory markers and endothelial permeability. In contrast, adhesion, invasion, and translocation through or between endothelial cells can be done by S. pneumoniae without any disruption to the vascular endothelium, upon BBB penetration. Internalins (InlA and InlB) of Listeria monocytogenes interact with its cellular receptors E-cadherin and mesenchymal-epithelial transition (MET) to facilitate invading the brain. L. monocytogenes species activate NF-κB in endothelial cells, encouraging the expression of P- and E-selectin, intercellular adhesion molecule 1 (ICAM-1), and Vascular cell adhesion protein 1 (VCAM-1), as well as IL-6 and IL-8 and monocyte chemoattractant protein-1 (MCP-1), all these markers assist in BBB disruption. Bacillus anthracis species interrupt both adherens junctions (AJs) and tight junctions (TJs), leading to BBB disruption. Brain microvascular endothelial cells (BMECs) permeability and BBB disruption are induced via interendothelial junction proteins reduction as well as up-regulation of IL-1α, IL-1β, IL-6, TNF-α, MCP-1, macrophage inflammatory proteins-1 alpha (MIP1α) markers in Staphylococcus aureus species. Streptococcus agalactiae or Group B Streptococcus toxins (GBS) enhance IL-8 and ICAM-1 as well as nitric oxide (NO) production from endothelial cells via the expression of inducible nitric oxide synthase (iNOS) enhancement, resulting in BBB disruption. While Gram-negative bacteria, Haemophilus influenza OmpP2 is able to target the common carboxy-terminal domain of LR to start initial interaction with brain endothelium, then invade the brain. H. influenza type b (HiB), can induce BBB permeability through TJ disruption. LR and PAFR binding sites have been recognized as common routes of CNS entrance by Neisseria meningitidis. N. meningitidis species also initiate binding to BMECs and induces AJs deformation, as well as inducing specific cleavage of the TJ component occludin through the release of host MMP-8. Escherichia coli bind to BMECs through LR, resulting in IL-6 and IL-8 release and iNOS production, as well as resulting in disassembly of TJs between endothelial cells, facilitating BBB disruption. Therefore, obtaining knowledge of BBB disruption by different types of bacterial species will provide a picture of how the bacteria enter the central nervous system (CNS) which might support the discovery of therapeutic strategies for each bacteria to control and manage infection.
Efficacy of modified Leeming-Notman media in a resazurin microtiter assay in the evaluation of in-vitro activity of fluconazole against Malassezia furfur ATCC 14521

Far FE, Al-Obaidi MMJ, Desa MNM

J Mycol Med, 2018 Sep;28(3):486-491.
PMID: 29753721 DOI: 10.1016/j.mycmed.2018.04.007

BACKGROUND: Malassezia furfur is lipodependent yeast like fungus that causes superficial mycoses such as pityriasis versicolor and dandruff. Nevertheless, there are no standard reference methods to perform susceptibility test of Malassezia species yet.
AIMS: Therefore, in this study, we evaluated the optimized culture medium for growth of this lipophilic yeast using modified leeming-Notman agar and colorimetric resazurin microtiter assay to assess antimycotic activity of fluconazole against M. furfur.
RESULTS: The result showed that these assays were more adjustable for M. furfur with reliable and reproducible MIC end-point, by confirming antimycotic activity of fluconazole with MIC of 2μg/ml.
CONCLUSION: We conclude that this method is considered as the rapid and effective susceptibility testing of M. furfur with fluconazole antifungal activity.
Fulltext Identifying protein biomarkers in predicting disease severity of dengue virus infection using immune-related protein microarray

Soe HJ, Yong YK, Al-Obaidi MMJ, Raju CS, Gudimella R, Manikam R, et al.

Medicine (Baltimore), 2018 Feb;97(5):e9713.
PMID: 29384851 DOI: 10.1097/MD.0000000000009713

Dengue virus is one of the most widespread flaviviruses that re-emerged throughout recent decades. The progression from mild dengue to severe dengue (SD) with the complications such as vascular leakage and hemorrhage increases the fatality rate of dengue. The pathophysiology of SD is not entirely clear. To investigate potential biomarkers that are suggestive of pathogenesis of SD, a small panel of serum samples selected from 1 healthy individual, 2 dengue patients without warning signs (DWS-), 2 dengue patients with warning signs (DWS+), and 5 patients with SD were subjected to a pilot analysis using Sengenics Immunome protein array. The overall fold changes of protein expressions and clustering heat map revealed that PFKFB4, TPM1, PDCL3, and PTPN20A were elevated among patients with SD. Differential expression analysis identified that 29 proteins were differentially elevated greater than 2-fold in SD groups than DWS- and DWS+. From the 29 candidate proteins, pathways enrichment analysis also identified insulin signaling and cytoskeleton pathways were involved in SD, suggesting that the insulin pathway may play a pivotal role in the pathogenesis of SD.
Evaluation of Clinical Efficacy of Biodegradable Chip Containing Salvadora persica (miswak) Extract in Chitosan Base as an Adjunct to Scaling and Root Planing in the Management of Periodontitis

Al-Bayaty FH, Kamaruddin AA, Ismail MA, Al-Obaidi MMJ

Sultan Qaboos Univ Med J, 2024 Aug;24(3):360-366.
PMID: 39234330 DOI: 10.18295/squmj.6.2024.030

OBJECTIVES: This study attempted to develop 2 biodegradable periodontal chips containing Salvadora persica (miswak) or benzyl isothiocyanate (BITC) extracts and evaluate their clinical effectiveness in managing periodontitis.
METHODS: This clinical trial was conducted at the Faculty of Dentistry, Universiti Teknologi MARA Shah Alam, Selangor, Malaysia, from September 2010 to April 2012. Periodontal chips were formulated using S. persica, benzyl isothiocyanate (BITC) and chitosan extracts. All patients were treated with full mouth scaling and root planing at baseline. Thereafter, the periodontal pockets (≥5 mm in length) were divided into 4 groups: the control group; group 2 (plain chitosan chip); group 3 (S. persica extract); and group 4 (BITC extract). Plaque index (PI), bleeding on probing (BOP), periodontal probing pocket depth and clinical attachment levels were recorded at days 0 and 60 only.
RESULTS: A total of 12 patients participated in this study. Overall, 240 periodontal pockets were evaluated. The study revealed significant improvements in PI, BOP and reduction in periodontal pocket depth in all 4 groups (P <0.05). The improvement in clinical attachment level was significantly higher (P <0.001) among the group that received S. persica chips compared to the control and other chip-treated groups.
CONCLUSION: Periodontal chips containing S. persica can be used as adjuncts to treat patients with periodontitis.
Japanese encephalitis virus disrupts blood-brain barrier and modulates apoptosis proteins in THBMEC cells

Al-Obaidi MMJ, Bahadoran A, Har LS, Mui WS, Rajarajeswaran J, Zandi K, et al.

Virus Res, 2017 04 02;233:17-28.
PMID: 28279803 DOI: 10.1016/j.virusres.2017.02.012

Japanese encephalitis (JE) is a neurotropic flavivirus that causes inflammation in central nervous system (CNS), neuronal death and also compromises the structural and functional integrity of the blood-brain barrier (BBB). The aim of this study was to evaluate the BBB disruption and apoptotic process in Japanese encephalitis virus (JEV)-infected transfected human brain microvascular endothelial cells (THBMECs). THBMECs were overlaid by JEV with different MOIs (0.5, 1.0, 5.0 and 10.0) and monitored by electrical cell-substrate impedance sensing (ECIS) in a real-time manner in order to observe the barrier function of THBMECs. Additionally, the level of 43 apoptotic proteins was quantified in the virally infected cells with different MOIs at 24h post infection. Infection of THBMEC with JEV induced an acute reduction in transendothelial electrical resistance (TEER) after viral infection. Also, significant up-regulation of Bax, BID, Fas and Fasl and down-regulation of IGFBP-2, BID, p27 and p53 were observed in JEV infected THBMECs with 0.5 and 10 MOIs compared to uninfected cells. Hence, the permeability of THBMECs is compromised during the JEV infection. In addition high viral load of the virus has the potential to subvert the host cell apoptosis to optimize the course of viral infection through deactivation of pro-apoptotic proteins.
Characterization of resistance to selected antibiotics and Panton-Valentine leukocidin-positiveStaphylococcus aureusin a healthy student population at a Malaysian University

Suhaili Z, Rafee P', Mat Azis N, Yeo CC, Nordin SA, Abdul Rahim AR, et al.

Germs, 2018 Mar;8(1):21-30.
PMID: 29564245 DOI: 10.18683/germs.2018.1129

Introduction: This study aims to assess the antimicrobial susceptibility profiles ofStaphylococcus aureusstrains isolated from university students and to determine the prevalence of constitutive and inducible clindamycin resistance, the latter being able to cause therapeutic failure due to false in vitro clindamycin susceptibility.
Methods: S. aureus
strains were isolated from the nasal swabs of 200 health sciences students of a Malaysian university. Twelve classes of antibiotics were used to evaluate the antimicrobial susceptibility profiles with the macrolide-lincosamide-streptogramin B (MLSB) phenotype for inducible clindamycin resistance determined by the double-diffusion test (D-test). Carriage of resistance and virulence genes was performed by PCR onS. aureusisolates that were methicillin resistant, erythromycin resistant and/or positive for the leukocidin gene,pvl(n=15).
Results: Forty-nine isolates were viable and identified asS. aureuswith four of the isolates characterized as methicillin-resistantS. aureus(MRSA; 2.0%). All isolates were susceptible to the antibiotics tested except for penicillin (resistance rate of 49%), erythromycin (16%), oxacillin (8%), cefoxitin (8%) and clindamycin (4%). Of the eight erythromycin-resistant isolates, iMLSBwas identified in five isolates (three of which were also MRSA). The majority of the erythromycin-resistant isolates harbored themsrAgene (four iMLSB) with the remaining iMLSBisolate harboring theermCgene.
Conclusion: The presence of MRSA isolates which are also iMLSBin healthy individuals suggests that nasal carriage may play a role as a potential reservoir for the transmission of these pathogens.
Fulltext Retraction Note: Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats

Ibrahim MY, Hashim NM, Dhiyaaldeen SM, Al-Obaidi MMJ, El-Ferjani RM, Adam H, et al.

Sci Rep, 2020 04 17;10(1):6792.
PMID: 32303687 DOI: 10.1038/s41598-020-63217-y

This paper has been retracted.