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Journal of Ethnopharmacology Aug 2024Malaria eradication has been a major goal of the Indonesian government since 2020. Medicinal plants, such as Strychnos lucida R. Br., are empirically used to treat...
ETHNOPHARMACOLOGICAL RELEVANCE
Malaria eradication has been a major goal of the Indonesian government since 2020. Medicinal plants, such as Strychnos lucida R. Br., are empirically used to treat malaria through traditional preparation methods. However, the safety and efficacy of these plants have not yet been confirmed. Therefore, further investigations are necessary to confirm the safety and efficacy of S. lucida as an antimalarial agent.
AIMS OF THE STUDY
To quantify the concentration of brucine in the S. lucida extract, determine the acute oral toxicity of the standardized extract, and evaluate the in vivo antimalarial potency of S. lucida tablet (SLT).
MATERIALS AND METHODS
Acute oral toxicity of S.lucida extract was determined using the Organization for Economic Co-operation and Development 420 procedure, and the analytical method for brucine quantification was validated using high-performance liquid chromatography. In addition, antimalarial activity was determined using the Peter's four-day suppressive method.
RESULTS
Acute toxicity analysis revealed S. lucida as a low-toxicity compound with a cut-off median lethal dose of 2000-5000 mg/kg body weight [BW], which was supported by the hematological and biochemical profiles of the kidneys, liver, and pancreas (p > 0.05). Extract standardization revealed that S. lucida contained 3.91 ± 0.074% w/w brucine, adhering to the limit specified in the Indonesian Herbal Pharmacopeia. Antimalarial test revealed that SLT inhibited the growth of Plasmodium berghei by 27.74-45.27%. Moreover, SLT improved the hemoglobin and hematocrit levels. White blood cell and lymphocyte counts were lower in the SLT-treated group than in the K (+) group (p < 0.05).
CONCLUSION
Histopathological and biochemical evaluations revealed that S. lucida extract was safe at a dose of 2000 mg/kg BW with low toxicity. SLT inhibited Plasmodium growth and improved the hemoglobin, hematocrit, and red blood cell profiles. Additionally, SLT reduced the lymphocyte and WBC counts and increased the monocyte and thrombocyte counts as part of the immune system response against Plasmodium infection.
Topics: Antimalarials; Animals; Plant Extracts; Mice; Male; Strychnos; Plasmodium berghei; Tablets; Administration, Oral; Strychnine; Female; Malaria; Toxicity Tests, Acute; Lethal Dose 50
PubMed: 38621467
DOI: 10.1016/j.jep.2024.118200 -
International Journal For Parasitology.... Apr 2024Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming...
Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, Plasmodium berghei ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria.
PubMed: 38621317
DOI: 10.1016/j.ijpddr.2024.100539 -
Bioorganic & Medicinal Chemistry Apr 20244,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent...
4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei, although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P. falciparum parasites, with no evidence of hemolytic effects below 100 µM. Moreover, the new compounds were at least 25-fold more potent than primaquine against P. falciparum gametocytes. Thus, the new antiplasmodial hits disclosed herein emerge as valuable templates for the development of multi-stage antiplasmodial drug candidates.
Topics: Humans; Antimalarials; Primaquine; Disclosure; Plasmodium falciparum; Malaria, Falciparum; Plasmodium berghei; Cinnamates
PubMed: 38582046
DOI: 10.1016/j.bmc.2024.117714 -
Life Science Alliance Jun 2024Increasing numbers of antimalarial compounds are being identified that converge mechanistically at inhibition of cytoplasmic translation, regardless of the molecular...
Increasing numbers of antimalarial compounds are being identified that converge mechanistically at inhibition of cytoplasmic translation, regardless of the molecular target or mechanism. A deeper understanding of how their effectiveness as liver stage translation inhibitors relates to their chemoprotective potential could prove useful. Here, we probed that relationship using the -HepG2 liver stage infection model. After determining translation inhibition ECs for five compounds, we tested them at equivalent effective concentrations to compare the parasite response to, and recovery from, a brief period of translation inhibition in early schizogony, followed by parasites to 120 h post-infection to assess antiplasmodial effects of the treatment. We show compound-specific heterogeneity in single parasite and population responses to translation inhibitor treatment, with no single metric strongly correlated to the release of hepatic merozoites for all compounds. We also demonstrate that DDD107498 is capable of exerting antiplasmodial effects on translationally arrested liver stage parasites and uncover unexpected growth dynamics during the liver stage. Our results demonstrate that translation inhibition efficacy does not determine antiplasmodial efficacy for these compounds.
Topics: Animals; Plasmodium berghei; Parasites; Antimalarials; Liver; Merozoites
PubMed: 38575357
DOI: 10.26508/lsa.202302540 -
Current Opinion in Microbiology Jun 2024Malaria blood stage parasites commit to either one of two distinct cellular fates while developing within erythrocytes of their mammalian host: they either undergo... (Review)
Review
Malaria blood stage parasites commit to either one of two distinct cellular fates while developing within erythrocytes of their mammalian host: they either undergo another round of asexual replication or they differentiate into nonreplicative transmissible gametocytes. Depending on the state of infection, either path may support or impair the ultimate goal of human-to-human transmission via the mosquito vector. Malaria parasites therefore evolved strategies to control investments into asexual proliferation versus gametocyte formation. Recent work provided fascinating molecular insight into shared and unique mechanisms underlying the control and environmental modulation of sexual commitment in the two most widely studied malaria parasite species, Plasmodium falciparum and P. berghei. With this review, we aim at placing these findings into a comparative mechanistic context.
Topics: Plasmodium falciparum; Animals; Humans; Plasmodium berghei; Malaria; Erythrocytes
PubMed: 38574448
DOI: 10.1016/j.mib.2024.102469 -
Molecular Microbiology Jun 2024The protozoan parasite Plasmodium, the causative agent of malaria, undergoes an obligatory stage of intra-hepatic development before initiating a blood-stage infection....
The protozoan parasite Plasmodium, the causative agent of malaria, undergoes an obligatory stage of intra-hepatic development before initiating a blood-stage infection. Productive invasion of hepatocytes involves the formation of a parasitophorous vacuole (PV) generated by the invagination of the host cell plasma membrane. Surrounded by the PV membrane (PVM), the parasite undergoes extensive replication. During intracellular development in the hepatocyte, the parasites provoke the Plasmodium-associated autophagy-related (PAAR) response. This is characterized by a long-lasting association of the autophagy marker protein, and ATG8 family member, LC3B with the PVM. LC3B localization at the PVM does not follow the canonical autophagy pathway since upstream events specific to canonical autophagy are dispensable. Here, we describe that LC3B localization at the PVM of Plasmodium parasites requires the V-ATPase and its interaction with ATG16L1. The WD40 domain of ATG16L1 is crucial for its recruitment to the PVM. Thus, we provide new mechanistic insight into the previously described PAAR response targeting Plasmodium liver stage parasites.
Topics: Vacuoles; Plasmodium berghei; Animals; Autophagy-Related Proteins; Microtubule-Associated Proteins; Liver; Mice; Autophagy; Hepatocytes; Vacuolar Proton-Translocating ATPases; Malaria; Protozoan Proteins; Humans
PubMed: 38574236
DOI: 10.1111/mmi.15259 -
The Journal of Veterinary Medical... May 2024Plasmodium parasites within mosquitoes are exposed to various physiological processes, such as blood meal digestion activity, the gonotrophic cycle, and host responses...
Plasmodium parasites within mosquitoes are exposed to various physiological processes, such as blood meal digestion activity, the gonotrophic cycle, and host responses preventing the entry of parasites into the midgut wall. However, when in vitro-cultured ookinetes are injected into the hemocoel of mosquitoes, Plasmodium parasites are not affected by the vertebrate host's blood contents and do not pass through the midgut epithelial cells. This infection method might aid in identifying mosquito-derived factors affecting Plasmodium development within mosquitoes. This study investigated novel mosquito-derived molecules related to parasite development in Anopheles mosquitoes. We injected in vitro-cultured Plasmodium berghei (ANKA strain) ookinetes into female and male Anopheles stephensi (STE2 strain) mosquitoes and found that the oocyst number was significantly higher in males than in females, suggesting that male mosquitoes better support the development of parasites. Next, RNA-seq analysis was performed on the injected female and male mosquitoes to identify genes exhibiting changes in expression. Five genes with different expression patterns between sexes and greatest expression changes were identified as being potentially associated with Plasmodium infection. Two of the five genes also showed expression changes with infection by blood-feeding, indicating that these genes could affect the development of Plasmodium parasites in mosquitoes.
Topics: Animals; Anopheles; Female; Male; Plasmodium berghei; Malaria; Mosquito Vectors; Mice; Host-Parasite Interactions
PubMed: 38569883
DOI: 10.1292/jvms.24-0008 -
International Immunopharmacology May 2024RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk...
RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk of cerebral malaria (CM) among children under the age of 5, it is imperative to develop new vaccines. EVs are potential vaccine candidates as they obtain the ability of brain-targeted delivery and transfer plasmodium antigens and immunomodulators during infections. This study extracted EVs from BALB/c mice infected with Plasmodium yoelii 17XNL (P.y17XNL). C57BL/6J mice were intravenously immunized with EVs (EV-I.V. + CM group) or subcutaneously vaccinated with the combination of EVs and CpG ODN-1826 (EV + CPG ODN-S.C. + CM group) on days 0 and 20, followed by infection with Plasmodium berghei ANKA (P.bANKA) on day 20 post-second immunization. We monitored Parasitemia and survival rate. The integrity of the Blood-brain barrier (BBB) was examined using Evans blue staining.The levels of cytokines and adhesion molecules were evaluated using Luminex, RT-qPCR, and WB. Brain pathology was evaluated by hematoxylin and eosin and immunohistochemical staining. The serum levels of IgG, IgG1, and IgG2a were analyzed by enzyme-linked immunosorbent assay. Compared with those in the P.bANKA-infected group, parasitemia increased slowly, death was delayed (day 10 post-infection), and the survival rate reached 75 %-83.3 % in the EV-I.V. + ECM and EV + CPG ODN-S.C. + ECM groups. Meanwhile, compared with the EV + CPG ODN-S.C. + ECM group, although parasitemia was almost the same, the survival rate increased in the EV-I.V. + ECM group.Additionally, EVs immunization markedly downregulated inflammatory responses in the spleen and brain and ameliorated brain pathological changes, including BBB disruption and infected red blood cell (iRBC) sequestration. Furthermore, the EVs immunization group exhibited enhanced antibody responses (upregulation of IgG1 and IgG2a production) compared to the normal control group. EV immunization exerted protective effects, improving the integrity of the BBB, downregulating inflammation response of brain tissue, result in reduces the incidence of CM. The protective effects were determined by immunological pathways and brain targets elicited by EVs. Intravenous immunization exhibited better performance than subcutaneous immunization, which perhaps correlated with EVs, which can naturally cross BBB to play a better role in brain protection.
Topics: Animals; Malaria, Cerebral; Plasmodium berghei; Mice, Inbred C57BL; Extracellular Vesicles; Erythrocytes; Blood-Brain Barrier; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Malaria Vaccines; Female; Brain; Cytokines; Plasmodium yoelii; Antibodies, Protozoan; Parasitemia; Disease Models, Animal; Immunoglobulin G
PubMed: 38569430
DOI: 10.1016/j.intimp.2024.111982 -
Journal of Parasitology Research 2024The spread of drug resistance is a significant issue, particularly in endemic countries with limited resources. The aim of this study was to evaluate antimalarial and...
BACKGROUND
The spread of drug resistance is a significant issue, particularly in endemic countries with limited resources. The aim of this study was to evaluate antimalarial and antioxidant activity of in order to justify its use in traditional medicine.
METHODS
Evaluation of the antimalarial activity of was carried out according to the model of the suppressive and curative test of Peters' over 4 days in infected mice. Antioxidant parameters and stress were measured after intraperitoneal administration of 1 × 10 infected red blood cells.
RESULTS
At doses of 150 mg/kg, 300 mg/kg, and 600 mg/kg, administration of B. micrantha substantially produced suppression of infection by 67.75%, 73.46%, and 78.99%, respectively, while 84.64% of the untreated group (1% DMSO) had suppression from chloroquine. The curative test significantly decreased the levels of parasitaemia and death in the treated groups. Furthermore, after extract was given to infected mice, a noteworthy increase in total protein, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was observed. On the other hand, hepatic catalase (CAT) and superoxide dismutase (SOD) productions were considerably greater than that of the healthy control. Mice had considerably lower levels of nonenzymatic antioxidant markers such as glutathione, NO, and MDA showing that the liver was protected.
CONCLUSION
The infected groups responded favorably to the ethanol extract of . This result justifies investigation for its use in Cameroon.
PubMed: 38566916
DOI: 10.1155/2024/8821019 -
JACS Au Mar 2024Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance...
Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance against established antimalarial pharmaceuticals leads to an urge toward new antimalarial drugs. Hybridization of two chemically diverse compounds into a new bioactive product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds and also to overcome multidrug resistance. 1,2,3-Triazoles are a significant pharmacophore system among nitrogen-containing heterocycles with various applications, such as antiviral, antimalarial, antibacterial, and anticancer agents. Several marketed drugs possess these versatile moieties, which are used in a wide range of medical indications. While the synthesis of hybrid compounds containing a 1,2,3-triazole unit was described using Cu- and Ru-catalyzed azide-alkyne cycloaddition, an alternative metal-free pathway has never been reported for the synthesis of antimalarial hybrids. However, a metal-free pathway is a green method that allows toxic and expensive metals to be replaced with an organocatalyst. Herein, we present the synthesis of new artemisinin-triazole antimalarial hybrids a facile Ramachary-Bressy-Wang organocatalyzed azide-carbonyl [3 + 2] cycloaddition (organo-click) reaction. The prepared new hybrid compounds are highly potent against chloroquine (CQ)-resistant and multi-drug-resistant strains (IC (Dd2) down to 2.1 nM; IC (K1) down to 1.8 nM) compared to CQ (IC (Dd2) = 165.3 nM; IC (K1) = 302.8 nM). Moreover, the most potent hybrid drug was more efficacious in suppressing parasitemia and extending animal survival in -infected mice (up to 100% animal survival and up to 40 days of survival time) than the reference drug artemisinin, illustrating the potential of the hybridization concept as an alternative and powerful drug-discovery approach.
PubMed: 38559731
DOI: 10.1021/jacsau.3c00716