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Background: Emergence of chloroquine (CQ) resistance among different strains of Plasmodium falciparum is the worst catastrophe that has ever perplexed the dedicated efforts to eradicate malaria. This urged the scientists to search for new alternatives or sensitizers to augment its antiplasmodium effect. Materials and Method: In this experiment, the potential of embelin, isolated from Embelia ribes, to inhibit the growth and sensitize CQ action was screened using SYBRE-green-I based drug sensitivity and isobologram assays, respectively. Its effect on red blood cells stability was screened to assess its safety. To explore its molecular mechanism, its effect on plasmodial Hemozoin and the in vitro β-hematin formation was screened as well. Furthermore, its anti-oxidant activity was measured using the conventional in vitro tests and its molecular characters were obtained using Molispiration program. Results: The results showed that its anti-plasmodial effect was weaker than CQ but synergism was obtained when they were combined at ratios lower than 5:5 CQ/embelin. Furthermore, β-hematin formation was inhibited by embelin without showing any synergism after mixing with CQ. Conclusion: Overall, embelin is not ideal to be suggested as a conventional antiplasmodium but it has a potential to ameliorate CQ resistance. Furthermore, its action is not related to its impact on hemozoin formation. Further, investigations are recommended to illustrate its detailed mechanism of action. [ABSTRACT FROM AUTHOR]

Acanthamoeba ,   a free-living amoeba (FLA) found in diverse ecosystems, poses significant health risks globally, particularly in Malaysia. It causes severe infectious diseases, e.g.,  Acanthamoeba  keratitis (AK), primarily affecting individuals who wear contact lenses, along with granulomatous amoebic encephalitis (GAE), a rare but often life-threatening condition among immunocompromised individuals. AK has become increasingly prevalent in Malaysia and is linked to widespread environmental contamination and improper contact lens hygiene. Recent studies highlight  Acanthamoeba 's capacity to serve as a "Trojan horse" for amoeba-resistant bacteria (ARBs), contributing to hospital-associated infections (HAIs). These symbiotic relationships and the resilience of  Acanthamoeba  cysts make treatment challenging. Current diagnostic methods in Malaysia rely on microscopy and culture, though molecular procedures like polymerase chain reaction (PCR) are employed for more precise detection. Treatment options remain limited due to the amoeba's cyst resistance to conventional therapies. However, recent advancements in natural therapeutics, including using plant extracts such as betulinic acid from  Pericampylus glaucus  and chlorogenic acid from  Lonicera japonica , have shown promising in vitro results. Additionally, nanotechnology applications, mainly using gold and silver nanoparticles to enhance drug efficacy, are emerging as potential solutions. Further, in vivo studies and clinical trials must validate these findings. This review highlights the requirement for continuous research, public health strategies, and interdisciplinary collaboration to address the growing threat of  Acanthamoeba  infections in Malaysia while exploring the country's rich biodiversity for innovative therapeutic solutions., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hamid et al.)

Objective: Inflammatory diseases are influenced by oxidative stress. Oxidatively damaged 8-oxoG in DNA is linked to inflammation. The enzyme OGG1 is responsible for repairing the damaged base in the DNA which is linked to pro-inflammatory signaling and severe inflammation. This study aims to explore the potential of targeting OGG1 as a therapeutic strategy in inflammatory disease conditions., Methods: A comprehensive search and review of literature were conducted using appropriate scientific databases such as Google Scholar, Scopus, PubMed, Web of Science, and other references to obtain relevant information that suited the title and content of this article., Results: Compelling pieces of evidence from many previous studies have shown the crucial role of the OGG1/8oxoG pathway in inflammatory disease conditions, leading to severe inflammatory response and death. Therefore, based on these pieces of evidence, targeting this enzyme (OGG1) using specific pharmacological inhibitors or interventions might lead to downregulation and amelioration of severe inflammation to reduce the morbimortality related to several disease conditions., Conclusion: This review highlighted the molecular mechanism of OGG1 activity via the 8-oxo/OGG1 pathway and its role in inflammation and inflammatory disease conditions. Due to the paucity of studies involving OGG1in inflammatory infectious diseases, further research projects are needed to explore the therapeutic potential of various OGG1 inhibitors to serve as novel therapeutic strategies in infectious inflammatory diseases of medical importance in developing countries such as malaria, meningitis, tuberculosis among others.

Andrographolide (AG) has been shown to have several medicinal and pharmaceutical effects, such as antimicrobial, anti-inflammatory, antioxidant, anti-diabetic, and anti-malarial activities. Moreover, studies to assess the pharmacological effect of AG on the metabolic changes of uninfected red blood cells (uRBCs) have not yet been investigated. This study aims to evaluate the pharmacological effects of AG compared to chloroquine (CQ) on the metabolic variations of uRBCs in vitro using a proton nuclear magnetic resonance ( 1 H-NMR)-based metabolomics approach coupled with multivariate data analysis (MVDA). Forty-one metabolites were successfully identified by 1 H-NMR. The results of the unsupervised data analysis principal component analysis (PCA) showed ideal differentiation between AG and CQ. PC1 and PC2 accounted for 71.4% and 17.7% of the explained variation, respectively, with a total variance of 89.10%. Based on S-plot and VIP values, a total of 28 and 32 metabolites were identified as biomarkers in uRBCs-AG and uRBCs-CQ, respectively. In uRBCs treated with AG, ten metabolic pathways were determined to be disturbed, including riboflavin metabolism, d-glutamate and d-glutamine metabolism, phenylalanine metabolism, glutathione metabolism, proline and arginine metabolism, arginine biosynthesis, citrate cycle, glycolysis/gluconeogenesis, and pyruvate metabolism as well as alanine, aspartate, and glutamate metabolism. In contrast, in CQ-treated uRBCs, nine affected metabolic pathways were determined, which involved the same metabolic pathways for uRBCs-AG, except for glutathione metabolism. These findings suggest an evident relationship between AG and CQ associated with metabolic changes in intact RBCs after being exposed to the treatment. The metabolomics results could allow useful comprehensive insights into the underlying mechanism of the action of AG and CQ on red blood cells. Consequently, the 1 H-NMR-based metabolomics approach was successfully utilized to identify the pharmacological effects of AG and CQ on the metabolic variations of uRBCs.

The major route for Toxoplasma gondii ( T. gondii ) infection is through the ingestion of foods contaminated with oocyst from cat faeces. The microscopic detection of T. gondii oocysts in cat faeces is challenging, which contributes to the failure of detecting or differentiating it from other related coccidian parasites. This study aims to detect T. gondii oocysts in cat faeces using two multicopy-target PCR assays and to evaluate their genetic diversity. Cat faecal (200) samples were collected from pet cats (PCs; 100) and free-roaming cats (FRCs; 100) within Klang Valley, Malaysia, and screened for coccidian oocysts by microscopy using Sheather's sucrose floatation. PCR assays were performed on each faecal sample, targeting a B1 gene and a repetitive element (REP) gene to confirm T. gondii oocysts. Additionally, the PCR amplicons from the REP gene were sequenced to further confirm T. gondii -positive samples for phylogenetic analysis. Microscopy detected 7/200 (3.5%) T. gondii -like oocysts, while both the B1 gene and the REP gene detected 17/200 (8.5%) samples positive for T. gondii . All samples that were microscopically positive for T. gondii -like oocysts were also shown to be positive by both B1 and REP genes. The BLAST results sequenced for 16/200 (8.0%) PCR-positive T. gondii samples revealed homology and genetic heterogeneity with T. gondii strains in the GenBank, except for only one positive sample that did not show a result. There was almost perfect agreement (k = 0.145) between the two PCR assays targeting the B1 gene and the REP gene. This is the first report on microscopic, molecular detection and genetic diversity of T. gondii from cat faecal samples in Malaysia. In addition, the sensitivities of either the B1 gene or REP gene multicopy-target PCR assays are suitable for the accurate detection of T. gondii from cat faeces.

Toxoplasmosis is a disease caused by the protozoan parasite Toxoplasma gondii ( T. gondii ). Human toxoplasmosis seroprevalence in Malaysia has increased since it was first reported in 1973 as shown in previous reviews of 1991 and 2007. However, over a decade since the last review, comprehensive data on toxoplasmosis in Malaysia is lacking. This work aimed at reviewing articles on toxoplasmosis research in Malaysia in order to identify the research gaps, create public awareness, and efforts made so far and proffer management options on the disease. The present review examines the available published research articles from 2008 to 2018 related to toxoplasmosis research conducted in Malaysia. The articles reviewed were retrieved from nine credible databases such as Web of Science, Google Scholar, ScienceDirect, PubMed, Scopus, Springer, Wiley online library, Ovid, and Cochrane using the keywords; Malaysia, toxoplasmosis, Toxoplasma gondii , toxoplasma encephalitis, seroprevalence, human immunodeficiency virus (HIV) patients, pregnant women, genotype strain, anti-toxoplasma antibodies, felines, and vaccine. The data highlighted seropositive cases from healthy community members in Pangkor Island (59.7%) and among migrant workers (57.4%) at alarming rates, as well as 42.5% in pregnant women. Data on animal seroprevalence were limited and there was no information on cats as the definitive host. Genetic characterization of Toxoplasma gondii from HIV patients; pregnant women, and domestic cats is lacking. This present review on toxoplasmosis is beneficial to researchers, health workers, animal health professionals, and policymakers. Therefore, attention is required to educate and enlighten health workers and the general public about the risk factors associated with T. gondii infection in Malaysia.

Treatment Failure with chloroquine is one of the challenges that faced the dedicated efforts to eradicate malaria This study aims at investigating the impact of treatment failure with chloroquine on the progression of the disease-induced histo-pathogenic and immunogenic outcomes. To achieve this, Rane's protocol with modifications was applied on a model of Plasmodium berghei ANKA infected ICR mice to determine the dose response curve of chloroquine and to screen the treatment impact on the disease progression. Chloroquine was given at 1, 5, 10, 15 and 20 mg/kg once the parasitemia reached to 20-30% (the experimental initiation point). During the subsequent days, the mice were monitored for changes in the clinical signs, hematology parameters and the progress of the parasitemia until the parasitemia reached to 60-70% (the experimental termination point) or up to 10 days after chloroquine administration in case of achieving a complete eradication of the parasite. At the end, the mice were exsanguinated and their blood and organs were collected for the biochemistry and the histology study. A complete eradication of the parasite was achieved at 20 mg/kg while recrudescence was observed at the lower doses. At 1 mg/kg, the parasite growth was comparable to that of the positive control. The histo-pathogenic and immunogenic changes were stronger in the groups that experienced recrudescence (at 5 and 10 mg/kg). All in all, the study highlights the possibility of having a worsened clinical condition when chloroquine is given at its sub-therapeutic doses during malaria treatment.

Background: The immune modulating potential of IL-35 in multiple human disorders has been reported. Consequent upon the recognition of inflammatory cytokine activation and its preponderance for mediating pathology during malaria infection, the study aimed to characterize the expression and functional contribution(s) of IL-35 in Plasmodium berghei (strain ANKA) infected mice., Methods: Plasmodium berghei infection in male ICR mice was used as the rodent model of choice. The time course of IL-35 expression in the systemic circulation and tissues of P. berghei infected mice as well as their healthy control counterparts was assessed by enzyme linked immunosorbent assay and immunohistochemistry respectively. The effect of modulating IL-35 by recombinant IL-35 protein or neutralizing anti-Epstein-Barr virus-induced gene 3 antibody on the cytokine environment during P. berghei infection was assessed by flow cytometry. Furthermore, the influence of modulating IL-35 on histopathological hallmarks of malaria and disease progression was evaluated., Results: Interleukin-35 was significantly up regulated in serum and tissues of P. berghei infected mice and correlated with parasitaemia. Neutralization of IL-35 significantly enhanced the release of IFN-γ, decreased the expression of IL-6 and decreased parasitaemia patency. Neutralization of IL-35 was also associated with a tendency towards increased survival as well as the absence of pathological features associated with malaria infection unlike recombinant IL-35 protein administration which sustained a normal course of infection and unfavourable malaria associated histological outcomes in P. berghei infected mice., Conclusion: These results indicate the involvement of IL-35 in P. berghei induced malaria infection. IL-35 neutralization strategies may represent viable therapeutic modalities beneficial for the resolution of malaria infection.

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis., Competing Interests: The authors declare no conflict of interest.

Interleukin-33 (IL-33) is an IL-1 family member, which exhibits both pro- and anti-inflammatory properties solely based on the type of the disease itself. Generally, IL-33 is expressed by both endothelial and epithelial cells and mediates its function based on the interaction with various receptors, mainly with ST2 variants. IL-33 is a potent inducer for the Th2 immune response which includes defence mechanism in brain diseases. Thus, in this paper, we review the biological features of IL-33 and the critical roles of IL-33/ST2 pathway in selected neurological disorders including Alzheimer's disease, multiple sclerosis, and malaria infection to discuss the involvement of IL-33/ST2 pathway during these brain diseases and its potential as future immunotherapeutic agents or for intervention purposes.

Emergence of chloroquine (CQ) resistance among different strains of Plasmodium falciparum is the worst incident that has ever faced the dedicated efforts to eradicate malaria. The main cause of CQ resistance is over-activity of the pumping mechanism that ousts CQ outside the DV. This urged the scientists to look for other alternatives or adjuvants that augment its action. CQ The study aimed to test the potential of five coumarin derivatives, namely; umbeliferon, esculetin, scopoletine, herniarin and 3-aminocoumarine to inhibit plasmodium growth and reverse CQ resistance in Plasmodium falciparum K1 and 3D7. They are highly ubiquitous in nature and are famous by their diverse pharmacological effects. SYBRE green-1 based drug sensitivity assay was used to screen the effect of CQ and each coumarin on the parasite growth and isobologram technique was to assess the interaction of the coumarins with CQ. Effect of each coumarin on both RBCs and Vero cells stability as well as on RBCs fragility were screened to exclude any toxic impact on normal cells. On the other hand, their effect on hemozoin formation was screened to investigate about their molecular mechanism. For molecular characterization, Their antioxidant properties were determined using the conventional in vitro tests and their characters were obtained from Molinspiration Simulation Software. Results showed that all of them were safe to human cells, have weak to moderate plasmodial growth inhibitory effect and only umbeliferon, 3- aminocoumarin and esculetin has interacted effectively with CQ. These actions are neither correlated with hemozoin formation inhibition nor to the antioxidant mechanisms. Further studies recommended to investigate the mechanism of their action. Overall, all the tested coumarins are not ideal to be used in the conventional malaria therapy and only umbeliferon, 3-aminocoumarin and esculetin can be suggested to potentiate CQ action.

Atovaquone is an anti-malarial drug used in combination with proguanil (e.g. Malarone(TM)) for the curative and prophylactic treatment of malaria. Atovaquone, a 2-hydroxynaphthoquinone, is a competitive inhibitor of the quinol oxidation (Q(o)) site of the mitochondrial cytochrome bc(1) complex. Inhibition of this enzyme results in the collapse of the mitochondrial membrane potential, disruption of pyrimidine biosynthesis, and subsequent parasite death. Resistance to atovaquone in the field is associated with point mutations in the Q(o) pocket of cytochrome b, most notably near the conserved Pro(260)-Glu(261)-Trp(262)-Tyr(263) (PEWY) region in the ef loop). The effect of this mutation has been extensively studied in model organisms but hitherto not in the parasite itself. Here, we have performed a molecular and biochemical characterization of an atovaquone-resistant field isolate, TM902CB. Molecular analysis of this strain reveals the presence of the Y268S mutation in cytochrome b. The Y268S mutation is shown to confer a 270-fold shift of the inhibitory constant (K(i)) for atovaquone with a concomitant reduction in the V(max) of the bc(1) complex of ∼40% and a 3-fold increase in the observed K(m) for decylubiquinol. Western blotting analyses reveal a reduced iron-sulfur protein content in Y268S bc(1) suggestive of a weakened interaction between this subunit and cytochrome b. Gene expression analysis of the TM902CB strain reveals higher levels of expression, compared with the 3D7 (atovaquone-sensitive) control strain in bc(1) and cytochrome c oxidase genes. It is hypothesized that the observed differential expression of these and other key genes offsets the fitness cost resulting from reduced bc(1) activity.