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Sub-lethal concentrations of artemisinin alter pH of the digestive vacuole of the malaria parasite, Plasmodium falciparum

Ibrahim N, Roslee A, Azlan M, Abu-Bakar N

Trop Biomed, 2020 Mar 01;37(1):1-14.
PMID: 33612713

An appropriate pH maintenance within a membrane-enclosed organelle is vital for the occurrence of biological processes. Artemisinin (ART), a potent antimalarial drug has been reported to target the digestive vacuole (DV) of Plasmodium falciparum, which might alter the pH of the organelle, thereby impairing the hemoglobin degradation and subsequent heme detoxification. Hence, a flow cytometry-based technique using fluorescein isothiocyanate-dextran (FITC-dextran) as a ratiometric pH probe was employed to measure the pH of the DV of the malaria parasite treated with ART. Based on the pH calibration curve generated, the steady-state pH of the acidic DV of the non-treated parasites was 5.42 ± 0.11, indicating that FITC-dextran is suitable for detection of physiological pH of the organelle. The alteration of the DV pH occurred when the parasites were treated with ART even at the sub-lethal concentrations (15 and 30 nM) used. The similar effect was shown by the parasites treated with a standard proton pump inhibitor, concanamycin A. This suggests that ART might have altered the DV pH at lower levels than the level needed to kill the parasite. This study has important implications in designing new ART treatment strategies and in generating new endoperoxide-based antimalarial drugs pertaining to the interruption of the pH regulation of the malaria parasite's DV.
Review: the Multiple Roles of Monocytic Microparticles

Halim AT, Ariffin NA, Azlan M

Inflammation, 2016 Aug;39(4):1277-84.
PMID: 27216803 DOI: 10.1007/s10753-016-0381-8

Monocytic microparticles (mMP) are microparticles derived from human monocytes either under in vivo or in vitro conditions. The size of mMP is between 0.1 and 1.0 μm. Apart from the size range, mMPs are also identified based on phosphatidylserine and CD14 expression on their surface, though this is not always the case. Monocytic MP are critical players in inflammation, endothelial cell function, and blood coagulation. They exhibit dual function by either helping the progression of such conditions or limiting it, depending on certain factors. Furthermore, the numbers of mMP are elevated in some autoimmune diseases, infectious diseases, and metabolic disorders. However, it is unknown whether mMP play an active role in these diseases or are simply biomarkers. The mechanism of mMP modulation is yet to be identified. In this review, we highlight the mechanism of mMP formation and the roles that they play in inflammation, blood coagulation, and different disease settings.
Fulltext The role of monocytes in malaria infection

Xuan KM, Bakar NA, Fadzli Mustaffa KM, Azlan M

Cent Eur J Immunol, 2023;48(1):54-62.
PMID: 37206586 DOI: 10.5114/ceji.2023.126650

Malaria remains one of the most common human infections worldwide. In endemic areas, malaria is a leading cause of morbidity and mortality and it imposes significant socioeconomic burdens on the people affected. Monocytes are part of the immune system controlling parasite burden and protecting the host against malaria infection. Monocytes play their protective roles against malaria via phagocytosis, cytokine production and antigen presentation. Though monocytes are crucial for clearance of malaria infection, they have also been shown to cause adverse clinical outcomes. In this review, we discuss recent findings regarding the role of monocytes in malaria via mechanisms such as parasite detection and clearance, pro-inflammatory activities, and activation of other immune components. We also highlight the role of different monocyte subsets, and other myeloid cells that are involved in malaria infection. However, more investigations are required in order to explore the exact roles of these monocytes in malaria infection.
Fulltext Immunogenicity of recombinant Mycobacterium bovis bacille Calmette-Guèrin clones expressing T and B cell epitopes of Mycobacterium tuberculosis antigens

Mohamud R, Azlan M, Yero D, Alvarez N, Sarmiento ME, Acosta A, et al.

BMC Immunol, 2013;14 Suppl 1:S5.
PMID: 23458635 DOI: 10.1186/1471-2172-14-S1-S5

Recombinant Mycobacterium bovis bacille Calmette-Guèrin (rBCG) expressing three T cell epitopes of Mycobacterium tuberculosis (MTB) Ag85B antigen (P1, P2, P3) fused to the Mtb8.4 protein (rBCG018) or a combination of these antigens fused to B cell epitopes from ESAT-6, CFP-10 and MTP40 proteins (rBCG032) were used to immunize Balb/c mice. Total IgG responses were determined against Mtb8.4 antigen and ESAT-6 and CFP-10 B cell epitopes after immunization with rBCG032. Mice immunized with rBCG032 showed a significant increase in IgG1 and IgG2a antibodies against ESAT-6 and MTP40 (P1) B cell epitopes and IgG3 against both P1 and P2 B cell epitopes of MPT40. Splenocytes from mice immunized with rBCG018 proliferated against Ag85B P2 and P3 T cell epitopes and Mtb8.4 protein whereas those from mice-immunized with rBCG032 responded against all Ag85B epitopes and the ESAT-6 B cell epitope. CD4⁺ and CD8⁺ lymphocytes from mice immunized with rBCG018 produced primarily Th1 type cytokines in response to the T cell epitopes. Similar pattern of recognition against the T cell epitopes were obtained with rBCG032 with the additional recognition of ESAT-6, CFP-10 and one of the MTP40 B cell epitopes with the same pattern of cytokines. This study demonstrates that rBCG constructs expressing either T or T and B cell epitopes of MTB induced appropriate immunogenicity against MTB.
Fulltext Draft Genome Sequence of the Extended-Spectrum β-Lactamase-Producing Escherichia coli Isolate INF13/18/A, Recovered from Kelantan, Malaysia

Wan Makhtar WR, Mohd Azlan M, Hassan NH, Aziah I, Samsurizal NH, Yusof NY

Microbiol Resour Announc, 2020 Aug 13;9(33).
PMID: 32817162 DOI: 10.1128/MRA.01497-19

We describe here the draft genome sequence and basic characteristics of Escherichia coli isolate INF13/18/A, which was isolated from Universiti Sains Malaysia (USM) Hospital. This isolate was identified as an extended-spectrum β-lactamase-producing Escherichia coli strain harboring the antimicrobial resistance genes TEM, CTX-M-1, and CTX-M-9.
Fulltext Mesenchymal Stem Cells: Current Concepts in the Management of Inflammation in Osteoarthritis

Nurul AA, Azlan M, Ahmad Mohd Zain MR, Sebastian AA, Fan YZ, Fauzi MB

Biomedicines, 2021 Jul 07;9(7).
PMID: 34356849 DOI: 10.3390/biomedicines9070785

Osteoarthritis (OA) has traditionally been known as a "wear and tear" disease, which is mainly characterized by the degradation of articular cartilage and changes in the subchondral bone. Despite the fact that OA is often thought of as a degenerative disease, the catabolic products of the cartilage matrix often promote inflammation by activating immune cells. Current OA treatment focuses on symptomatic treatment, with a primary focus on pain management, which does not promote cartilage regeneration or attenuate joint inflammation. Since articular cartilage have no ability to regenerate, thus regeneration of the tissue is one of the key targets of modern treatments for OA. Cell-based therapies are among the new therapeutic strategies for OA. Mesenchymal stem cells (MSCs) have been extensively researched as potential therapeutic agents in cell-based therapy of OA due to their ability to differentiate into chondrocytes and their immunomodulatory properties that can facilitate cartilage repair and regeneration. In this review, we emphasized current knowledge and future perspectives on the use of MSCs by targeting their regeneration potential and immunomodulatory effects in the treatment of OA.
Fulltext Extracellular Vesicles from Mesenchymal Stem Cells as Potential Treatments for Osteoarthritis

Mohd Noor NA, Abdullah Nurul A, Ahmad Mohd Zain MR, Wan Nor Aduni WK, Azlan M

Cells, 2021 05 22;10(6).
PMID: 34067325 DOI: 10.3390/cells10061287

Osteoarthritis (OA) is a chronic degenerative disorder of the joint and its prevalence and severity is increasing owing to ageing of the population. Osteoarthritis is characterized by the degradation of articular cartilage and remodeling of the underlying bone. There is little understanding of the cellular and molecular processes involved in pathophysiology of OA. Currently the treatment for OA is limited to painkillers and anti-inflammatory drugs, which only treat the symptoms. Some patients may also undergo surgical procedures to replace the damaged joints. Extracellular vesicles (EV) play an important role in intercellular communications and their concentration is elevated in the joints of OA patients, although their mechanism is unclear. Extracellular vesicles are naturally released by cells and they carry their origin cell information to be delivered to target cells. On the other hand, mesenchymal stem cells (MSCs) are highly proliferative and have a great potential in cartilage regeneration. In this review, we provide an overview of the current OA treatments and their limitations. We also discuss the role of EV in OA pathophysiology. Finally, we highlight the therapeutic potential of MSC-derived EV in OA and their challenges.
Fulltext Three-year follow-up of a Traumatic Hemipelvectomy Survivor: A Case Report

Wan KL, Azlan MS, Syed-Azmi AS, Lattish R, Faisham WI

Malays Orthop J, 2021 Nov;15(3):143-146.
PMID: 34966511 DOI: 10.5704/MOJ.2111.024

The management of a patient with traumatic hemipelvectomy is complex. We report the acute management and rehabilitation of a 21-year-old patient as well as her prosthesis modification. She was able to return to society as a K3 level ambulator.
Fulltext Apoptosis Activity of the Mouse Macrophage Cell Line J774A.1 Infected with a Recombinant BCG consisting the C-Terminus of Merozoite Surface Protein-1 of Plasmodium falciparum

Zulkipli AF, Zakaria NM, Abdikarim MH, Azlan M, Abdullah N, Nor NM, et al.

Trop Life Sci Res, 2018 Jul;29(2):53-76.
PMID: 30112141 MyJurnal DOI: 10.21315/tlsr2018.29.2.5

Macrophage apoptosis exerts an efficient mechanism in controlling intracellular infection during innate immune response against various pathogens including malaria parasites. This study was carried out to determine the apoptosis activity in mouse macrophage cell line J774A.1 infected with a Mycobacterium bovis bacille Calmette-Guerin (BCG) clone and a recombinant BCG clone expressing the C-terminus of merozoite surface protein-1 (BCG-MSP1C) of Plasmodium falciparum for 48 h. In this study, a parent BCG cells was used as a control. The nuclear staining with Hoechst 33342 showed that the BCG-MSP1C cells was capable of increasing the nuclear condensation and morphological stages of apoptosis in the infected cells compared to the BCG-infected cells and the lipopolysaccharide (LPS)-stimulated cells. The flow cytometric analysis using Annexin-V and Propidium iodide (PI) staining confirmed that the BCG-MSP1C cells significantly increased the percentage of early apoptotic activity in the infected macrophage higher than the one stimulated by the parent BCG cells and LPS. This apoptotic response corresponded with the reduction of the anti-apoptotic Bcl-2 protein expression and higher p53 expression. The colorimetric assay demonstrated that the BCG cells capable of stimulating higher production of caspase-1, -3, -8 and -9 while the BCG-MSP1C cells stimulated the expression of caspase-1 and -9 in the infected macrophages, suggesting the involvement of mitochondrial-mediated (intrinsic) pathway of apoptosis. In conclusion, both the BCG and BCG-MSP1C cells are capable of inducing macrophage apoptosis activity in the mouse macrophage cell line J774A.1. This mechanism is important for the elimination of pathogens such as malaria parasite during the phagocytosis activity of macrophage. However, the BCG-MSP1C cells showed higher apoptosis activity than those produced by the parent BCG cells.
Fulltext Invasion and Metastasis Suppression by Anti-Neonatal Nav1.5 Antibodies in Breast Cancer

Sharudin NA, Murtadha Noor Din AH, Azahar II, Mohd Azlan M, Yaacob NS, Sarmiento ME, et al.

Asian Pac J Cancer Prev, 2022 Sep 01;23(9):2953-2964.
PMID: 36172657 DOI: 10.31557/APJCP.2022.23.9.2953

BACKGROUND: Detectable neonatal Nav1.5 (nNav1.5) expression in tumour breast tissue positive for lymph node metastasis and triple-negative subtype serves as a valid tumour-associated antigen to target and prevent breast cancer invasion and metastasis. Therapeutic antibodies against tumour antigens have become the predominant class of new drugs in cancer therapy because of their fewer adverse effects and high specificity.
OBJECTIVE: This study was designed to investigate the therapeutic and anti-metastatic potential of the two newly obtained anti-nNav1.5 antibodies, polyclonal anti-nNav1.5 (pAb-nNav1.5) and monoclonal anti-nNav1.5 (mAb-nNav1.5), on breast cancer invasion and metastasis.
METHODS: MDA-MB-231 and 4T1 cells were used as in vitro models to study the effect of pAb-nNav1.5 (59.2 µg/ml) and mAb-nNav1.5 (10 µg/ml) (24 hours treatment) on cell invasion. 4T1-induced mammary tumours in BALB/c female mice were used as an in vivo model to study the effect of a single dose of intravenous pAb-nNav1.5 (1 mg/ml) and mAb-nNav1.5 (1 mg/ml) on the occurrence of metastasis. Real-time PCR and immunofluorescence staining were conducted to assess the effect of antibody treatment on nNav1.5 mRNA and protein expression, respectively. The animals' body weight, organs, lesions, and tumour mass were also measured and compared.
RESULTS: pAb-nNav1.5 and mAb-nNav1.5 treatments effectively suppressed the invasion of MDA-MB-231 and 4T1 cells in the 3D spheroid invasion assay. Both antibodies significantly reduced nNav1.5 gene and protein expression in these cell lines. Treatment with pAb-nNav1.5 and mAb-nNav1.5 successfully reduced mammary tumour tissue size and mass and prevented lesions in vital organs of the mammary tumour animal model whilst maintaining the animal's healthy weight. mRNA expression of nNav1.5 in mammary tumour tissues was only reduced by mAb-nNav1.5.
CONCLUSION: Overall, this work verifies the uniqueness of targeting nNav1.5 in breast cancer invasion and metastasis prevention, but more importantly, humanised versions of mAb-nNav1.5 may be valuable passive immunotherapeutic agents to target nNav1.5 in breast cancer.
A study of hospitalized COVID-19 patients with AKI in a setting of multiracial developing country

Ooi SH, Ng KP, Sthaneshwar P, Lim SK, Khor PY, Lim JY, et al.

BMC Nephrol, 2024 Apr 05;25(1):122.
PMID: 38580977 DOI: 10.1186/s12882-024-03498-x

BACKGROUND: The commonest indication for hospitalization in COVID-19 patients is hypoxemia or severe respiratory symptoms. However, COVID-19 disease may result in extrapulmonary complications including kidney-related pathology. The reported incidence of renal involvement related to COVID infection varies based on geographical location.
OBJECTIVE: This study aimed to assess the incidence rate of AKI in hospitalized COVID-19 patients and identify risk factors and prognostic predictors.
METHOD: In this retrospective study, we recruited hospitalized COVID-19 patients from January 2021 until June 2021 at the University Malaya Medical Center. The inclusion criteria were hospitalized for ≥ 48 h with confirmed COVID-19 infection and at least 18 years old. Patient demographic and clinical data were collected from electronic medical records. The staging of AKI was based on criteria as per KDIGO guidelines.
RESULTS: One thousand five hundred twenty-nine COVID patients fulfilled the inclusion criteria with a male-to-female ratio of 759 (49.6%) to 770 (50.3%). The median age was 55 (IQR: 36-66). 500 patients (32.7%) had diabetes, 621 (40.6%) had hypertension, and 5.6% (n = 85) had pre-existing chronic kidney disease (CKD). The incidence rate of AKI was 21.1% (n = 323). The percentage of COVID patients in different AKI stages of 1,2 and 3 were 16.3%, 2.1%, and 2.7%, respectively. Fifteen hospitalized patients (0.98%) required renal replacement therapy. 58.8% (n = 190) of AKI group had complete recovery of kidney function. Demographic factors included age (p
Fulltext Differential polarization and the expression of efferocytosis receptor MerTK on M1 and M2 macrophages isolated from coronary artery disease patients

Mohd Idrus FN, Ahmad NS, Hoe CH, Azlan M, Norfuad FA, Yusof Z, et al.

BMC Immunol, 2021 03 24;22(1):21.
PMID: 33761885 DOI: 10.1186/s12865-021-00410-2

BACKGROUND: Differential polarization of macrophage into M1 and M2 mediates atherosclerotic plaque clearance through efferocytosis. Higher expression of Mer proto-oncogene tyrosine kinase (MerTK) on M2 macrophage helps in maintaining macrophage efferocytic efficiency. In healthy individuals, macrophage polarization into M1 and M2 occurs in tissues in concomitance with the acquisition of functional phenotypes depending on specific microenvironment stimuli. However, whether the macrophage differential polarization and MerTK expression vary in coronary artery disease (CAD) patients remain unknown.
OBJECTIVE: This study aimed to elucidate the polarization of M1 and M2 macrophage from CAD patients as well as to investigate the expression of MerTK in these macrophage phenotypes.
METHODS: A total of 14 (n) CAD patients were recruited and subsequently grouped into "no apparent CAD", "non-obstructive CAD" and "obstructive CAD" according to the degree of stenosis. Thirty ml of venous blood was withdrawn to obtain monocyte from the patients. The M1 macrophage was generated by treating the monocyte with GMCSF, LPS and IFN-γ while MCSF, IL-4 and IL-13 were employed to differentiate monocyte into M2 macrophage. After 7 days of polarization, analysis of cell surface differentiation markers (CD86+/CD80+ for M1 and CD206+/CD200R+ for M2) and measurement of MerTK expression were performed using flow cytometry.
RESULTS: Both M1 and M2 macrophage expressed similar level of CD86, CD80 and CD206 in all groups of CAD patients. MerTK expression in no apparent CAD patients was significantly higher in M2 macrophage compared to M1 macrophage [12.58 ± 4.40 vs. 6.58 ± 1.37, p = 0.040].
CONCLUSION: Differential polarization of macrophage into M1 and M2 was highly dynamic and can be varied due to the microenvironment stimuli in atherosclerotic plaque. Besides, higher expression of MerTK in patients with the least coronary obstructive suggest its vital involvement in efferocytosis.

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