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Fulltext Role of Different Pfcrt and Pfmdr-1 Mutations in Conferring Resistance to Antimalaria Drugs in Plasmodium falciparum

Ibraheem ZO, Abd Majid R, Noor SM, Sedik HM, Basir R

Malar Res Treat, 2014;2014:950424.
PMID: 25506039 DOI: 10.1155/2014/950424

Emergence of drugs resistant strains of Plasmodium falciparum has augmented the scourge of malaria in endemic areas. Antimalaria drugs act on different intracellular targets. The majority of them interfere with digestive vacuoles (DVs) while others affect other organelles, namely, apicoplast and mitochondria. Prevention of drug accumulation or access into the target site is one of the mechanisms that plasmodium adopts to develop resistance. Plasmodia are endowed with series of transporters that shuffle drugs away from the target site, namely, pfmdr (Plasmodium falciparum multidrug resistance transporter) and pfcrt (Plasmodium falciparum chloroquine resistance transporter) which exist in DV membrane and are considered as putative markers of CQ resistance. They are homologues to human P-glycoproteins (P-gh or multidrug resistance system) and members of drug metabolite transporter (DMT) family, respectively. The former mediates drifting of xenobiotics towards the DV while the latter chucks them outside. Resistance to drugs whose target site of action is intravacuolar develops when the transporters expel them outside the DVs and vice versa for those whose target is extravacuolar. In this review, we are going to summarize the possible pfcrt and pfmdr mutation and their role in changing plasmodium sensitivity to different anti-Plasmodium drugs.
Fulltext Impact of gentamicin coadministration along with high fructose feeding on progression of renal failure and metabolic syndrome in Sprague-Dawley rats

Ibraheem ZO, Basir R, Aljobory AKh, Ibrahim OE, Alsumaidaee A, Yam MF

Biomed Res Int, 2014;2014:823879.
PMID: 25045706 DOI: 10.1155/2014/823879

The current study evaluates the impact of high fructose feeding in rat model of gentamicin induced nephrotoxicity. Sprague-Dawley rats weighing 180-200 g were randomized into four groups; (C) received standard rodents chow with free access to ad libitum drinking water for 8 weeks and was considered as control, (F) received standard rodents chow with free access to drinking water supplemented with 20% (W/V) fructose for the same abovementioned period, (FG) was fed as group F and was given 80 mg/kg (body weight)/day gentamicin sulphate intraperitoneally during the last 20 days of the feeding period, and (G) was given gentamicin as above and fed as group C. Renal function was assessed at the end of the treatment period through measuring serum creatinine, uric acid and albumin, creatinine clearance, absolute and fractional excretion of both sodium and potassium, twenty-four-hour urinary excretion of albumin, and renal histology. For metabolic syndrome assessment, fasting plasma glucose and insulin were measured and oral glucose tolerance test was performed throughout the treatment period. Results showed that gentamicin enhances progression of fructose induced metabolic syndrome. On the other hand, fructose pretreatment before gentamicin injection produced a comparable degree of renal dysfunction to those which were given fructose-free water but the picture of nephrotoxicity was somewhat altered as it was characterized by higher extent of glomerular congestion and protein urea. Overall, more vigilance is required when nephrotoxic drugs are prescribed for patients with fructose induced metabolic syndrome.
Effect of high saturated free fatty acids feeding on progression of renal failure in rat model of experimental nephrotoxicity

Ibraheem ZO, Sattar MA, Abdullah NA, Rathore HA, Johns EJ

Bosn J Basic Med Sci, 2012 Feb;12(1):26-32.
PMID: 22364300

The current study evaluates the impact of high saturated fat feeding in rat model of experimental nephrotoxicity induced by gentamicin. Sprague-Dawley rats weighing 200 g were randomized into four groups; the first one received the standard rodents chow for 8 weeks and was treated as control, the second group (HFD)received an experimental high fat diet rich in palm kernel oil (40% of Calories as fat) for the same period. The third group (HFDG) was given 80 mg/kg (body weight)/day gentamicin sulphate intraperitoneally during the last 24 days of the feeding period while the fourth group was given gentamicin as above along with the standard rodents chow. Renal function was assessed through measuring serum creatinine, creatinine clearance and absolute and fractional excretion of both sodium and potassium. At the end, rats underwent a surgical procedure for blood pressure measurement. Renal function study showed a stronger nephrotoxicity for HFDG group. Hypertension was observed in HFD group while the pressure declined after gentamicin co-administration. Overall, changing the feeding behavior toward using more SAFFAs for rats injected with gentamicin promotes the progression of renal failure.
Orthosiphon stamineus: traditional uses, phytochemistry, pharmacology, and toxicology

Ameer OZ, Salman IM, Asmawi MZ, Ibraheem ZO, Yam MF

J Med Food, 2012 Aug;15(8):678-90.
PMID: 22846075 DOI: 10.1089/jmf.2011.1973

Orthosiphon stamineus Benth. (Lambiaceae) is an important plant in traditional folk medicine. This review is a comprehensive summary of the currently available chemical, pharmacological, and toxicological investigations as well as the traditional and therapeutic uses of this plant. Different in vitro and in vivo models have been addressed along with a survey of all phytochemicals identified in this plant, including flavonoids, terpenoids, and essential oils. Previous studies revealed that O. stamineus possesses several pharmacological activities, which are attributed to its phytochemical content. It was found that O. stamineus exhibits diuretic, hypouricemic, renal protective, antioxidant, anti-inflammatory, hepatoprotective, gastroprotective, antihypertensive, antidiabetic, antihyperlipidemic, antimicrobial, and anorexic activities. In conclusion, O. stamineus has wide traditional and pharmacological uses in various pathophysiological conditions. Therefore, it is an attractive subject for further experimental and clinical investigations.
The Potential of β Carbolin Alkaloids to Hinder Growth and Reverse Chloroquine Resistance in Plasmodium falciparum

Ibraheem ZO, Abdul Majid R, Mohd Noor S, Mohd Sidek H, Basir R

Iran J Parasitol, 2015 Oct-Dec;10(4):577-83.
PMID: 26811724

Nowadays, scourge of malaria as a fatalistic disease has increased due to emergence of drug resistance and tolerance among different strains of Plasmodium falciparum. Emergence of chloroquine (CQ) resistance has worsened the calamity as CQ is still considered the most efficient, safe and cost effective drug among other antimalarials. This urged the scientists to search for other alternatives or sensitizers that may be able to augment CQ action and reverse its resistance.
Liver functions in combined models of the gentamicin induced nephrotoxicity and metabolic syndrome induced by high fat or fructose diets: a comparative study

Ibraheem ZO, Farhan SS, Al Sumaidaee A, Al Sufi L, Bashir A, Balwa A, et al.

Toxicol Res, 2021 Apr;37(2):221-235.
PMID: 33868979 DOI: 10.1007/s43188-020-00059-w

Metabolic syndrome is one of the major risk factors that lead to various serious complications like cardiovascular abnormalities, hyperlipidemia and diabetes. Its co-incidence with other organs dysfunction results in further deterioration of the condition or precipitation of other dysfunctions. This study aimed at studying the changes in the hepatic functions after the co-incidence of the high fat or fructose diets induced metabolic syndrome along with the gentamicin induced nephrotoxicity. Briefly, six groups of male Sprague Daley rats (n = 10-12) were fed with different feeding protocols; viz; standard rodent's chow, an experimental high fat or high fructose diets feedings. For each, two groups were allocated that one of them was injected with normal saline and the other with 80 mg/kg/day I.P gentamicin during the last 24 days of the feeding period. The rats were monitored for changes in the metabolic data, glycemic control, lipid profile, renal and hepatic functions, oxidative stress and the inflammatory response. The study revealed stronger hepatic changes in the renal failure groups fed with the high fat diet rather than that in the groups fed with the high fructose diet. Although, the latter experienced a stronger deterioration in the glycemic control. The study suggests that the incidence of the hepatic changes is more linked to the incidence of the deterioration in the lipids profile that was observed after the high fat diet feeding. Overall, the co-incidence of the high fat diet induced metabolic syndrome along with the renal failure constitutes a risk factor for the hepatic dysfunction.
Fulltext Cosmos caudatus extract/fractions reduce smooth muscle cells migration and invasion in vitro : A potential benefit of suppressing atherosclerosis

Moshawih S, Cheema MS, Ibraheem ZO, Tailan ND, Hakim MN

Porto Biomed J, 2017;2(6):293-300.
PMID: 32258785 DOI: 10.1016/j.pbj.2017.03.008

HIGHLIGHTS: Cosmos caudatus Ethanolic extract fractionation by n-butanol produced a phenolics-saponin rich fraction.Cosmos caudatus butanol fraction was the most potent in all antioxidant and MTT assays.High concentrations of all fractions increased cells migration and invasion in vitro.Butanol fraction intermediate concentration maximally inhibited VSMC migration and invasion.Mild concentrations of crude and butanol fractions showed the best invasion inhibition index.
BACKGROUND: Cosmos caudatus Kunth is a medicinal herb used traditionally in Latin America and South East Asia to retard aging, rigidify bones and for several cardiovascular uses.
OBJECTIVE: Is to assess C. caudatus extract/fractions' antioxidant and vascular smooth muscle cells (VSMC) migration and invasion inhibition capacity in vitro.
METHODS: Cosmos caudatus shoots were extracted by cold maceration in 50% ethanol to produce crude (CEE), and then the extract was fractionated to butanol (Bu.F), and aqueous fractions (Aq.f). Phenolics and saponins were quantified in extract and fractions by colorimetric methods and their antioxidant capacity was assayed in four different tests. Cytotoxic effect and safety level concentrations were determined for the fractions by using MTT assay. Migration and invasion inhibitory potential were measured in vitro at three different concentrations equivalent to (IC10, IC25, and IC50). Finally, invasion inhibitory index was calculated to obtain the best fraction(s) that show(s) the highest ratio of cell invasion inhibition to the total cell migration inhibition.
RESULTS: Butanol fraction yield was the lowest; nevertheless, its phytochemical contents, antioxidant activities as well as its potency were the highest. Unlike other fractions, Bu.F was strongly correlated with all antioxidant assays experimented. In addition, it has the highest inhibitory effect at IC25 against VSMCs migration and invasion that accounts for 53.93% and 59.94% respectively. Unexpectedly, Bu.F and CEE at IC10 displayed the highest invasion inhibitory index (approx. 68%).
CONCLUSION: Butanol fraction of C. caudatus offers a potentiality for the discovery of new leads for preventing atherosclerosis.
Antioxidant and cardio protective effect of palm oil leaves extract (standardized ethanolic fraction) in rats' model of saturated fats induced metabolic disorders

Ibraheem ZO, Satar M, Abdullah NA, Rathore H, Tan YC, Uldin F, et al.

Pak J Pharm Sci, 2014 Jan;27(1):1-9.
PMID: 24374430

Recently, it is suggested to use POLE (palm oil leaf extract) as a nutraceutical health product in food industry due to its newly discovered content of polyphenols and antioxidant vitamins. In the experiment, the antioxidant and anti-lipid-peroxidation activities of the extract were confirmed using; DPPH (1-diphenyl-2-picryl-hydrazil) radical scavenging activity, ferric ion induced lipid peroxidation inhibition, reducing power and hydrogen peroxide scavenging activity assays. The cardio-protective activity was studied in vivo using a model of metabolic syndrome induced by high fat diet. Lipid profile, obesity indices, renal tubular handling of water and electrolytes, blood pressure and arterial stiffness were measured at the end of the treatment period. Sprague Dawley rats weighing 150-200 g were divided into six groups, viz; group C; was treated as a negative control and fed with standard rodents chow, group H; was treated as a positive control and fed with an experimental diet enriched with saturated free fatty acids for 8 weeks, groups HP0.5, HP1 and HP2 which were fed with 0.5,1 and 2 g/kg (body weight) /day of POLE orally during the last 24 days of the high fat diet feeding period and group P; fed with highest dose of POLE. Results revealed that POLE possesses a cardio-protective effect which is ascribed to its content of polyphenols.
Fulltext In Vitro Antiplasmodium and Chloroquine Resistance Reversal Effects of Andrographolide

Ibraheem ZO, Majid RA, Sidek HM, Noor SM, Yam MF, Abd Rachman Isnadi MF, et al.

Evid Based Complement Alternat Med, 2019;2019:7967980.
PMID: 31915453 DOI: 10.1155/2019/7967980

The emergence of drug-resistant strains of Plasmodium falciparum is the worst catastrophe that has ever confronted the dedicated efforts to eradicate malaria. This urged for searching other alternatives or sensitizers that reverse chloroquine resistance. In this experiment, the potential of andrographolide to inhibit plasmodial growth and reverse CQ resistance was tested in vitro using the SYBRE green-1-based drug sensitivity assay and isobologram technique, respectively. Its safety level toward mammalian cells was screened as well against Vero cells and RBCs using MTT-based drug sensitivity and RBC hemolysis assays, respectively. Its effect against hemozoin formation was screened using β-hematin formation and heme fractionation assays. Its molecular characters were determined using the conventional tests for the antioxidant effect measurement and the in silico molecular characterization using the online free chemi-informatic Molinspiration software. Results showed that andrographolide has a moderate antiplasmodium effect that does not entitle it to be a substituent for chloroquine. Furthermore, andrographolide ameliorated the sensitivity of the parasite to chloroquine. Besides, it showed an indirect inhibitory effect against hemozoin formation within the parasite and augmented the chloroquine-induced inhibition of hemozoin formation. The study suggests that its chloroquine resistance reversal effect may be due to inhibition of chloroquine accumulation or due to its impact on the biological activity of the parasite. Overall, this in vitro study is a clue for the reliability of andrographolide to be added with chloroquine for reversal of chloroquine resistance and tolerance, but further in vivo studies are recommended to confirm this notion. In spite of its prominent and safe in vitro and in vivo growth inhibitory effect and its in vitro chloroquine resistance reversing effect, it is inapplicable to implement it in malaria chemotherapy to substitute chloroquine or to reverse its resistance.
Fulltext Investigation of Andrographolide Effect on Non-Infected Red Blood Cells Using the 1H-NMR-Based Metabolomics Approach

Alapid AAI, Abd Majid R, Ibraheem ZO, Mediani A, Ismail IS, Unyah NZ, et al.

Metabolites, 2021 Jul 28;11(8).
PMID: 34436427 DOI: 10.3390/metabo11080486

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 (1H-NMR)-based metabolomics approach coupled with multivariate data analysis (MVDA). Forty-one metabolites were successfully identified by 1H-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 1H-NMR-based metabolomics approach was successfully utilized to identify the pharmacological effects of AG and CQ on the metabolic variations of uRBCs.
Fulltext Andrographolide effect on both Plasmodium falciparum infected and non infected RBCs membranes

Zaid OI, Abd Majid R, Sabariah MN, Hasidah MS, Al-Zihiry K, Yam MF, et al.

Asian Pac J Trop Med, 2015 Jul;8(7):507-12.
PMID: 26276279 DOI: 10.1016/j.apjtm.2015.06.007

OBJECTIVE: To explore whether its antiplasmodium effect of andrographolide is attributed to its plausible effect on the plasma membrane of both Plasmodium falciparum infected and non-infected RBCs.
METHODS: Anti-plasmodium effect of andrographolide against Plasmodium falciparum strains was screened using the conventional malaria drug sensitivity assay. The drug was incubated with uninfected RBCs to monitor its effect on their morphology, integrity and osmotic fragility. It was incubated with the plasmodium infected RBCs to monitor its effect on the parasite induced permeation pathways. Its effect on the potential of merozoites to invade new RBCs was tested using merozoite invasion assay.
RESULTS: It showed that at andrographolide was innocuous to RBCs at concentrations approach its therapeutic level against plasmodia. Nevertheless, this inertness was dwindled at higher concentrations.
CONCLUSIONS: In spite of its success to inhibit plasmodium induced permeation pathway and the potential of merozoites to invade new RBCs, its anti-plasmodium effect can't be attributed to these functions as they were attained at concentrations higher than what is required to eradicate the parasite. Consequently, other mechanisms may be associated with its claimed actions.
Fulltext Anti-plasmodial and Chloroquine Resistance Suppressive Effects of Embelin

Zaid OI, Majid RA, Hasidah MS, Sabariah MN, Al-Zihiry K, Rahi S, et al.

Pharmacogn Mag, 2017 Jan;13(Suppl 1):S48-S55.
PMID: 28479726 DOI: 10.4103/0973-1296.203982

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. Abbreviation used: CQ-DV-PBS-HEPES: Chloroquine-Digestive vacuole-Phosphate-buffer-saline-4-(2-hydroxyethyl-1-piperazin-ethan-sulphoni-acid), EDTA: Ethylen-diamin-tetra-acetic-acid, g.m.wt: Gram molecular weight, cMCM: Complete-malaria-culture-medium, Hct: Hematocrite, PRBCs: Parasitized-redblood-cells, nRBCs: Normal-red-blood-cells, RT: Room temperature, IC: Inhibitory concentration, FIC: Fractional inhibitory concentration, iCM: Incomplete-culturemedium, BSA: Bovin serum albumin, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, DPPH: 2,2-diphenyl-1- picrylhydrazy, BHT: Butylatedhydroxyl-toleuen, PSA: Polar surface area, ClogP: Log partition coefficient (octanol/water), GPCR: G-protein-coupled-receptors, DMSO: Dimethylsulphoxide, NaOH: Sodium hydroxide.
Fulltext Prediction of Strength Properties of Concrete Containing Waste Marble Aggregate and Stone Dust-Modeling and Optimization Using RSM

Zamir Hashmi SR, Khan MI, Khahro SH, Zaid O, Shahid Siddique M, Md Yusoff NI

Materials (Basel), 2022 Nov 14;15(22).
PMID: 36431509 DOI: 10.3390/ma15228024

Carbon footprint reduction, recompense depletion of natural resources, as well as waste recycling are nowadays focused research directions to achieve sustainability without compromising the concrete strength parameters. Therefore, the purpose of the present study is to utilize different dosages of marble waste aggregates (MWA) and stone dust (SD) as a replacement for coarse and fine aggregate, respectively. The MWA with 10 to 30% coarse aggregate replacement and SD with 40 to 50% fine aggregate replacement were used to evaluate the physical properties (workability and absorption), durability (acid attack resistance), and strength properties (compressive, flexural, and tensile strength) of concrete. Moreover, statistical modeling was also performed using response surface methodology (RSM) to design the experiment, optimize the MWA and SD dosages, and finally validate the experimental results. Increasing MWA substitutions resulted in higher workability, lower absorption, and lower resistance to acid attack as compared with controlled concrete. However, reduced compressive strength, flexural strength, and tensile strength at 7-day and 28-day cured specimens were observed as compared to the controlled specimen. On the other hand, increasing SD content causes a reduction in workability, higher absorption, and lower resistance to acid attack compared with controlled concrete. Similarly, 7-day and 28-day compressive strength, flexural strength, and tensile strength of SD-substituted concrete showed improvement up to 50% replacement and a slight reduction at 60% replacement. However, the strength of SD substituted concrete is higher than controlled concrete. Quadratic models were suggested based on a higher coefficient of determination (R2) for all responses. Quadratic RSM models yielded R2 equaling 0.90 and 0.94 for compressive strength at 7 days and 28 days, respectively. Similarly, 0.94 and 0.96 for 7-day and 28-day flexural strength and 0.89 for tensile strength. The optimization performed through RSM indicates that 15% MWA and 50% SD yielded higher strength compared to all other mixtures. The predicted optimized data was validated experimentally with an error of less than 5%.
Progression of malaria induced pathogenicity during chloroquine therapy

Zaid OI, Abd Majid R, Sidek HM, Noor SM, Abd Rachman-Isnadi MF, Bello RO, et al.

Trop Biomed, 2020 Mar 01;37(1):29-49.
PMID: 33612716

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.

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