BACKGROUND: Malaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant\'s malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice.
METHODS: The plant\'s leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences.
RESULTS: No toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract.
CONCLUSIONS: The results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended.

BACKGROUND: 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.
OBJECTIVE: 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).
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).
CONCLUSIONS: 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.

Drug resistance to practically all antimalarial drugs in use necessitate the development of new chemotherapeutics against malaria. In this aspect, traditionally used plants with folklore reputation are the pillar for drug discovery. Cuscuta reflexa being traditionally used in the treatment of malaria in Odisha, India we aimed to experimentally validate its antimalarial potential. Different solvent extracts of C. reflexa or column fractions from a promising solvent extract were evaluated for in vitro anti-plasmodial activity against Plasmodium falciparum strain Pf3D7. Potent fractions were further evaluated for inhibition of parasite growth against different drug resistant strains. Safety of these fractions was determined by in vitro cyto-toxicity, and therapeutic effectiveness was evaluated by suppression of parasitemia and improvement in survival of experimental mice. Besides, their immunomodulatory effect was investigated in Pf-antigen stimulated RAW cells. GCMS fingerprints of active fractions was determined. Column separation of methanol extract which showed the highest in vitro antiplasmodial activity (IC50 = 14.48 μg/ml) resulted in eleven fractions, three of which (F2, F3, and F4) had anti-plasmodial IC50 ranging from ≤ 10 to 2.2 μg/ml against various P. falciparum strains with no demonstration of in vitro cytotoxicity. F4 displayed the highest in vivo parasite suppression, and had a mean survival time similar to artesunate (19.3 vs. 20.6 days). These fractions significantly modulated expression of inflammatory cytokines in Pf-antigen stimulated RAW cells. The findings of the study confirm the antimalarial potential of C. reflexa. Exploration of phyto-molecules in GCMS fingerprints of active fractions is warranted for possible identification of lead anti-malarial phyto-drugs.

Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children, especially under the age of five, in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms. Increased release of circulating miRNA, proteins, lipids and extracellular vesicles has been found in CM patients and experimental mouse models. We compared lipid profiles derived from the plasma of CBA mice infected with Plasmodium berghei ANKA (PbA), which causes CM, to those from Plasmodium yoelii (Py), which does not. We previously showed that platelet-free plasma (18k fractions enriched from plasma) contains a high number of extracellular vesicles (EVs). Here, we found that this fraction produced at the time of CM differed dramatically from those of non-CM mice, despite identical levels of parasitaemia. Using high-resolution liquid chromatography-mass spectrometry (LCMS), we identified over 300 lipid species within 12 lipid classes. We identified 45 and 75 lipid species, mostly including glycerolipids and phospholipids, with significantly altered concentrations in PbA-infected mice compared to Py-infected and uninfected mice, respectively. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to Py infection and controls. These results suggest that experimental CM could be characterised by specific changes in the lipid composition of the 18k fraction containing circulating EVs and can be considered an appropriate model to study the role of lipids in the pathophysiology of CM.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is increasingly gaining recognition as a severe malaria complication because of poor prognostic outcomes, high lethality rate, and limited therapeutic interventions. Unfortunately, invasive clinical studies are challenging to conduct and yields insufficient mechanistic insights. These limitations have led to the development of suitable MA-ARDS experimental mouse models. In patients and mice, MA-ARDS is characterized by edematous lung, along with marked infiltration of inflammatory cells and damage of the alveolar-capillary barriers. Although, the pathogenic pathways have yet to be fully understood, the use of different experimental mouse models is fundamental in the identification of mediators of pulmonary vascular damage. In this review, we discuss the current knowledge on endothelial activation, leukocyte recruitment, leukocyte induced-endothelial dysfunction, and other important findings, to better understand the pathogenesis pathways leading to endothelial pulmonary barrier lesions and increased vascular permeability. We also discuss how the advances in imaging techniques can contribute to a better understanding of the lung lesions induced during MA-ARDS, and how it could aid to monitor MA-ARDS severity.

BACKGROUND: Malaria remains the major health problem responsible for many mortality and morbidity in developing countries. Because of the development of resistance by Plasmodium species, searching effective antimalarial agents becomes increasingly important. Pinocembrin is a flavanone previously isolated as the most active antiplasmodial compound from the leaves of Dodonaea angustifolia. For a better understanding of the antiplasmodial activity, the synthesis of pinocembrin and a great number of analogs was undertaken.
METHODS: Chalcones 5a-r were synthesized via Claisen-Schmidt condensation using 2,4-dibenzyloxy-6-hydroxyacetophenone and aromatic aldehydes as substrates under basic conditions. Cyclization of compounds 5a-r to the corresponding dibenzylated pinocembrin analogs 6a-r was achieved using NaOAc in EtOH under reflux. Catalytic hydrogenation using 10% Pd/C as catalyst in an H-Cube Pro was used for debenzylation to deliver 7a-l. The structures of the synthesized compounds were characterized using various physical and spectroscopic methods, including mp, UV, IR, NMR, MS and HRMS. The synthesized dibenzylated flavanones 6a-d, 6i and 7a were evaluated for their in vivo antiplasmodial activities against Plasmodium berghei infected mice. Molecular docking simulation and drug likeness properties of compounds 7a-l were assessed using AutoDock Vina and SwissADME, respectively.
RESULTS: A series of chalcones 5a-r has been synthesized in yields ranging from 46 to 98%. Treatment of the chalcones 5a-r with NaOAc refluxing in EtOH afforded the dibenzylated pinocembrin analogs 6a-r with yields up to 54%. Deprotection of the dibenzylated pinocembrin analogs delivered the products 7a-l in yields ranging from 78 to 94%. The dibenzylated analogs of pinocembrin displayed percent inhibition of parastaemia in the range between 17.4 and 87.2% at 30 mg/kg body weight. The parastaemia inhibition of 87.2 and 55.6% was obtained on treatment of the infected mice with pinocembrin (7a) and 4\'-chloro-5,7-dibenzylpinocembrin (6e), respectively. The mean survival times of those infected mice treated with these two compounds were beyond 14 days indicating that the samples suppressed P. berghei and reduced the overall pathogenic effect of the parasite. The molecular docking analysis of the chloro derivatives of pinocembrin revealed that compounds 7a-l show docking affinities ranging from - 8.1 to - 8.4 kcal/mol while it was -7.2 kcal/mol for chloroquine.
CONCLUSIONS: Pinocembrin (7a) and 4\'-chloro-5,7-dibenzyloxyflavanone (6e) displayed good antiplasmodial activity. The in silico docking simulation against P. falciparum dihydrofolate reductase-thymidylate synthase revealed that pinocembrin (7a) and its chloro analogs 7a-l showed better binding affinity compared with chloroquine that was used as a standard drug. This is in agreement with the drug-like properties of compounds 7a-l which fulfill Lipinski\'s rule of five with zero violations. Therefore, pinocembrin and its chloro analogs could serve as lead compounds for further antiplasmodial drug development.

Rutin (3, 3\', 4\' 5 and 7-pentahydroxyflavone-3-rhamnoglucoside) is a flavonoid glycoside, found in many edible plants such as buckwheat and berries. Severe malaria is an inflammatory response triggered by oxidative stress that results in multi-organ pathologies and a high mortality rate in children and pregnant women worldwide. Rutin is recommended as a food supplement for the treatment of various diseases due to its anti-oxidative and anti-inflammatory properties, which prompted us to investigate its ameliorative effects in severe malaria pathogenesis against oxidative stress and inflammatory response using in vitro and in vivo bioassays. Rutin was examined in this work for its anti-plasmodial activity against chloroquine-sensitive and resistant Plasmodium falciparum strains, as well as its anti-oxidative and anti-inflammatory activity against LPS-stimulated macrophage cells. The in vitro data were subsequently verified in mice fed orally with rutin alone or in combination with chloroquine in Plasmodium berghei-induced malaria pathogenesis. The anti-plasmodial and anti-inflammatory properties of rutin were demonstrated in in vitro results. Apart from its anti-inflammatory and anti-oxidant effects in malaria pathogenesis, in vivo efficacy studies indicated that oral treatment with rutin reduced parasitaemia, increased mean survival time, and restored haemoglobin and glucose levels in mice at lower dose. Interestingly, both rutin and chloroquine demonstrated synergy in in vitro and in vivo experiments. The findings of the present study thus highlighted the suitability of rutin for further study in the management of drug resistant malaria in combination with standard anti-malarial drugs.

BACKGROUND: New effective, economical and safe antimalarial drugs are urgently needed due to the development of multi-drug-resistant strains of the parasite. Homeopathy uses ultra-diluted doses of various substances to stimulate autoregulatory and self-healing processes to cure various ailments. The aim of the study was to evaluate the in vitro and in vivo antimalarial efficacy of a homeopathic drug, Chininum sulphuricum 30C.
METHODS: In vitro antiplasmodial activity was screened against the P. falciparum chloroquine-sensitive (3D7) strain, and cell viability was assessed against normal human dermal fibroblasts and HepG2 cells. Suppressive, preventive and curative studies were carried out against P. berghei-infected mice in vivo.
RESULTS: Chininum sulphuricum (30C) revealed good antiplasmodial activity in vitro, with 92.79 ± 6.93% inhibition against the 3D7 strain. The cell viability was 83.6 ± 0.6% against normal human dermal fibroblasts and 95.22 ± 5.1% against HepG2 cells. It also exhibited suppressive efficacy with 95.56% chemosuppression on day 7 with no mortality throughout the follow-up period of 28 days. It also showed preventive activity against the disease. Drug treatment was also safe to the liver and kidney function of the host as evidenced by biochemical studies.
CONCLUSIONS: Chininum sulphuricum 30C exhibited considerable antimalarial activity along with safety to the liver and kidney function of the host.
Hintergrund: Es besteht dringender Bedarf an neuen wirkungsvollen, ökonomischen und sicheren Malariamedikamenten angesichts der Entwicklung multiresistenter Stämme des Parasiten. In der Homöopathie werden hochverdünnte Dosen verschiedener Substanzen eingesetzt, um selbstregulierende und selbstheilende Prozesse zur Heilung verschiedener Leiden anzustoßen. Das Ziel dieser Studie war es, die Wirksamkeit des homöopathischen Präparats Chininum sulfuricum 30C gegen Malaria in vitro und in vivo zu beurteilen. Methoden: Die antiplasmodiale Aktivität in vitro wurde an P. falciparum, chloroquinsensitiver Stamm (3D7) getestet, und die Zellvitalität wurde bei normalen humanen Dermis-Fibroblasten sowie HepG2-Zellen untersucht. In vivo wurden suppressive, präventive und kurative Studien bei P.-berghei-infizierten Mäusen durchgeführt. Ergebnisse: Chininum sulfuricum (30C) zeigte in vitro gute antiplasmodiale Aktivitätmit 92,79 ± 6,93% Inhibition des 3D7-Stamms. Die Zellvitalität lag bei 83,6 ± 0,6% bei normalen humanen dermalen Fibroblasten bzw. 95,22 ± 5,1% bei HepG2-Zellen.Außerdem zeigte das Präparat suppressive Wirksamkeit mit 95,56% Chemosuppression an Tag 7 ohne Mortalität im gesamten Nachbeobachtungszeitraum von 28 Tagen. Auch zeigte es präventive Wirksamkeit gegen die Krankheit. Die Behandlung war dabei sicher in Bezug auf die Leber- und Nierenfunktion des Wirts, wie biochemische Studien belegen. Schlussfolgerung: Chininum sulfuricum 30C zeigte erhebliche Aktivität gegen die Malariainfektion und war dabei sicher in Bezug auf die Leber- und Nierenfunktion des Wirts.

Inferring biological processes from population dynamics is a common challenge in ecology, particularly when faced with incomplete data. This challenge extends to inferring parasite traits from within-host infection dynamics. We focus on rodent malaria infections (Plasmodium berghei), a system for which previous work inferred an immune-mediated extension in the length of the parasite development cycle within red blood cells. By developing a system of delay-differential equations to describe within-host infection dynamics and simulating data, we demonstrate the potential to obtain biased estimates of parasite (and host) traits when key biological processes are not considered. Despite generating infection dynamics using a fixed parasite developmental cycle length, we find that known sources of measurement bias in parasite stage and abundance data can affect estimates of parasite developmental duration, with stage misclassification driving inferences about extended cycle length. We discuss alternative protocols and statistical methods that can mitigate such misestimation.

Asymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated in-vitro-differentiated human hepatocyte-like cells (iHLCs) to study LS of P. berghei and found it to be a sub-optimal infection model. Overall, our results present a new mouse ESC-based P. berghei LS infection model that can be utilized to study the impact of host genetic variation on parasite development.