The antimalarial effect of curcumin is mediated by the inhibition of glycogen synthase kinase-3β

Curcumin, a bioactive compound in Curcuma longa, exhibits various pharmacological activities, including antimalarial effects. In silico docking simulation studies suggest that curcumin possesses glycogen synthase kinase-3β (GSK3β)-inhibitory properties. The involvement of GSK3 in the antimalarial effects in vivo is yet to be demonstrated. In this study, we aimed to evaluate whether the antimalarial effects of curcumin involve phosphorylation of host GSK3β. Intraperitoneal administration of curcumin into Plasmodium berghei NK65-infected mice resulted in dose-dependent chemosuppression of parasitemia development. At the highest dose tested (30 mg/kg body weight), both therapeutic and prophylactic administrations of curcumin resulted in suppression exceeding 50% and improved median survival time of infected mice compared to control. Western analysis revealed a 5.5-fold (therapeutic group) and 1.8-fold (prophylactic group) increase in phosphorylation of Ser 9 GSK3β and 1.6-fold (therapeutic group) and 1.7-fold (prophylactic group) increase in Ser 473 Akt in liver of curcumin-treated infected animals. Following P. berghei infection, levels of pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-10, and IL-4 were elevated by 7.5-, 35.0-, 33.0-, and 2.2-fold, respectively. Curcumin treatment (therapeutic) caused a significant decrease (by 6.0- and 2.0-fold, respectively) in serum TNF-α and IFN-γ level, while IL-10 and IL-4 were elevated (by 1.4- and 1.8-fold). Findings from the present study demonstrate for the first time that the antimalarial action of curcumin involved inhibition of GSK3β

Antiplasmodial and chloroquine chemosensitizing and resistance reversal effects of coumarin derivatives against Plasmodium falciparum 3D7 and K1

Background 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

Anti-malarial and anti-inflammatory effects of Gleichenia truncata mediated through inhibition of GSK3ß

Gleichenia truncata is a highland fern from the Gleicheniaceae family known for its traditional use among indigenous communities in Asia to treat fever. The scientific basis of its effect has yet to be documented. A yeast-based kinase assay conducted in our laboratory revealed that crude methanolic extract (CME) of G. truncata exhibited glycogen synthase kinase-3 (GSK3)-inhibitory activity. GSK3β is now recognized to have a pivotal role in the regulation of inflammatory response during bacterial infections. We have also previously shown that lithium chloride (LiCl), a GSK3 inhibitor suppressed development of Plasmodium berghei in a murine model of malarial infection. The present study is aimed at evaluating G. truncata for its anti-malarial and anti-inflammatory effects using in vivo malarial and melioidosis infection models respectively. In a four-day suppressive test, intraperitoneal injections of up to 250 mg/kg body weight (bw) G. truncata CME into P.berghei-infected mice suppressed parasitaemia development by >60%. Intraperitoneal administration of 150 mg/kg bw G. truncata CME into Burkholderia pseudomallei-infected mice improved survivability by 44%. G. truncata CME lowered levels of pro-inflammatory cytokines (TNF-α, IFN-γ) in serum and organs of B. pseudomallei-infected mice. In both infections, increased phosphorylations (Ser9) of GSK3β were detected in organ samples of animals administered with G. truncata CME compared to controls. Taken together, results from this study strongly suggest that the anti-malarial and anti-inflammatory effects elicited by G. truncata in part were mediated through inhibition of GSK3β. The findings provide scientific basis for the ethnomedicinal use of this fern to treat inflammation-associated symptoms

The relationship between customer satisfaction and service quality towards TM global products at Petaling Jaya / Nor Hasidah Hashim

Purpose – The purpose of this study is to identify the factors customer satisfaction towards global products. Design/Methodology/Approach – A total 132 respondents were participated in answering questionnaires. Findings – The findings of the study indicate that there is a significant influence between interaction and customer satisfaction. The other variable also has a relationship with customer satisfaction but it will not give as much influence as interaction. Practical Implications – The findings of the paper may have serious implications for the customer satisfaction in Telekom Malaysia Berhad. Originality/Value – The papers draw attention to a rather neglected issue between customer satisfaction and service quality in Telekom Malaysia Berhad

Andrographolide effect on both Plasmodium falciparum infected and non infected RBCs membranes

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

Anti-malarial and anti-inflammatory effects of Gynura procumbens are mediated by kaempferol via inhibition of glycogen synthase kinase-3ß (GSK3ß)

Gynura procumbens is a medicinal plant, traditionally used to treat inflammation and fever. A yeast-based assay detected GSK3â-inhibitory activity in the aqueous extract of G. procumbens. GSK3â is now known to have a central role in the modulation of host inflammatory response during bacterial infections. In this study, we investigated the involvement of GSK3â in the anti-malarial and anti-inflammatory effects of an aqueous extract of G. procumbens. Our results showed that G. procumbens inhibited growth of P. falciparum 3D7. Consecutive four-day administration of 250 mg/kg body weight (b.w.) G. procumbens resulted in strong chemosuppression and improved survivability in P. berghei-infected mice. B. pseudomallei-infected mice treated with G. procumbens (50 mg/kg b.w.) showed increased survivability. TNF-á and IFN-ã levels in liver and serum of B. pseudomallei-infected mice were lowered by G. procumbens treatment. IL-10 level was higher in serum of G. procumbens-administered infected mice. G. procumbens treatment of P. berghei-and B. pseudomallei-infected animals each resulted in increased hepatic GSK3â (Ser9) phosphorylation. It is noteworthy that kaempferol (one of the compounds in G. procumbens) also inhibited the growth of P. falciparum 3D7; showed strong chemosuppression and improved survivability in P. berghei-infected mice at 5 mg/kg b.w. B. pseudomallei-infected mice treated with kaempferol (10 mg/kg b.w.) showed improved survivability. Concomitantly, the described effects due to kaempferol also involved enhanced GSK3â (Ser9) phosphorylation as observed with G. procumbens. In summary, the observed anti-malarial and anti-inflammatory effects of G. procumbens involved inhibition of GSK3â and kaempferol may in part be responsible for the pharmacological effects

Comparative study on mitogen activated protein kinase of Plasmodium species by using in silico method / Mohd Fakharul Zaman Raja Yahya and Hasidah Mohd Sidek

Malaria parasites, Plasmodium can infect a wide range of hosts including humans and rodents. There are two copies of mitogen activated protein kinases (MAPKs) in Plasmodium, namely MAPK1 and MAPK2. The MAPKs have been studied extensively in the human Plasmodium, P. falciparum. However, the MAPKs from other Plasmodium species have not been characterized and it is therefore the premise of presented study to characterize the MAPKs from other Plasmodium species-P. vivax, P. knowlesi, P. berghei, P. chabaudi and P.yoelli using a series of publicly available bioinformatic tools. In silico data indicates that all Plasmodium MAPKs are nuclear-localizedandcontain both a nuclear localization signal (NLS) anda Leucine-rich nuclear export signal (NES). The activation motifs ofTDYand TSH werefound to befully conserved in Plasmodium MAPK1 and MAPK2, respectively