Anti-malaria Agent Research Articles

Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.

Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1β, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

Investigation of the Anti-Plasmodial Properties of N-2-Oxo Pyrrolidine Pentanamide-Based Sulfonamides: Experimental and Theoretical Approach

The study aimed to investigate novel pyrrolidine-pentanamide derivatives of sulfonamides as potential anti-malaria agents through a comprehensive approach involving experimental, theoretical, and in silico evaluations. The compounds were synthesized using standard methods and characterized using NMR, FT-IR, and HRMS techniques. The molecular properties of the compounds were investigated using density functional theory (DFT) at the B3LYP-D3 meta-functional/GenECP theoretical level. The calculated vibrational frequencies of the compounds showed good agreement with experimental results, validating the accuracy of the theoretical approach in capturing the behavior of different functional groups. Molecular docking simulations were performed to assess the binding affinity of the compounds to the amino acid residues binding sites of two target proteins: farnesyl pyrophosphate synthase (PDB ID: 1RQJ) and Plasmodium falciparum 80S ribosome (PDB ID: 3J7A). Substantially, the results of the docking simulations demonstrated that three compounds, namely 3-Methyl-2-(4-methylphenylsulfonamido)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pentanamide (MMOPEP), 3-Methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2-(phenylsulfonamido)pentanamide (MOPEPP), and 3-Methyl-2-(4-nitrophenylsulfonamido)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pentanamide (MNOPEP), exhibited tight binding to the target proteins. These compounds showed favorable docking scores compared to standard drugs, indicating their potential as anti-malaria agents. Additionally, the high electrophilicity index recorded for the three compounds further supports their suitability as anti-malaria agents. The results collectively suggest that the pyrrolidine-pentanamide derivatives of sulfonamides have promising interactions with the target proteins, indicating their potential effectiveness against malaria. This study provides valuable insights into the molecular properties and binding affinities of the synthesized compounds, contributing to the development of new anti-malaria therapies.

Antioxidant and Antimalarial Activities of Methanol Extract of Picralima nitida Root Bark

Ethnomedically, the root, stem bark, seed or leaves of Picralima nitida are relevant in local preparations as antimalaria, antipyretic, antihypertensive and gastrointestinal agents. This study was therefore designed to determine the antimalarial and antioxidant effects of the methanol extract of the root bark of Picralima nitida using standard procedures. The antioxidant activity of the methanol root bark extract was evaluated using 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging method and ferric reducing antioxidant power (FRAP) assay. The antimalarial activity of the methanol root bark extract was investigated using the 4-day suppressive test in mice infected with Plasmodium berghei. The extract showed a concentration-dependent antioxidant activity with 50% inhibitory concentration (IC50) for free radical scavenging activity of 10.19 µg/mL, while the FRAP value was 0.17 ± 0.00 mM FSE/g Extract. The extract demonstrated significant antimalarial activity with 68.33% and 67.27% parasitaemia suppression at doses of 400 mg/kg and 800 mg/kg, respectively. The present study has shown that the root bark extract of P. nitida has antioxidant and antimalarial activities. This study does not only validate the claimed ethnomedicinal use of the plant as antimalaria but also has shown the plant as a potential source of active antimalarial agent.

Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate.

Liver, as an immune and detoxification organ, represents an important line of defense against bacteria and infection and a vulnerable organ that is easily injured during sepsis. Artesunate (ART) is an anti-malaria agent, that also exhibits broad pharmacological activities including anti-inflammatory, immune-regulation and liver protection. In this study, we investigated the cellular responses in liver to sepsis infection and ART hepatic-protective mechanisms against sepsis. Cecal ligation and puncture (CLP)-induced sepsis model was established in mice. The mice were administered ART (10 mg/kg, i.p.) at 4 h, and sacrificed at 12 h after the surgery. Liver samples were collected for preparing single-cell RNA transcriptome sequencing (scRNA-seq). The scRNA-seq analysis revealed that sepsis-induced a dramatic reduction of hepatic endothelial cells, especially the subtypes characterized with proliferation and differentiation. Macrophages were recruited during sepsis and released inflammatory cytokines (Tnf, Il1b, Il6), chemokines (Ccl6, Cd14), and transcription factor (Nfkb1), resulting in liver inflammatory responses. Massive apoptosis of lymphocytes and abnormal recruitment of neutrophils caused immune dysfunction. ART treatment significantly improved the survival of CLP mice within 96 h, and partially relieved or reversed the above-mentioned pathological features, mitigating the impact of sepsis on liver injury, inflammation, and dysfunction. This study provides comprehensive fundamental proof for the liver protective efficacy of ART against sepsis infection, which would potentially contribute to its clinical translation for sepsis therapy. Single cell transcriptome reveals the changes of various hepatocyte subtypes of CLP-induced liver injury and the potential pharmacological effects of artesunate on sepsis.

Medicinal plant-derived mtDNA via nanovesicles induces the cGAS-STING pathway to remold tumor-associated macrophages for tumor regression

Plant-derived nanovesicles (PDNVs) have been proposed as a major mechanism for the inter-kingdom interaction and communication, but the effector components enclosed in the vesicles and the mechanisms involved are largely unknown. The plant Artemisia annua is known as an anti-malaria agent that also exhibits a wide range of biological activities including the immunoregulatory and anti-tumor properties with the mechanisms to be further addressed. Here, we isolated and purified the exosome-like particles from A. annua, which were characterized by nano-scaled and membrane-bound shape and hence termed artemisia-derived nanovesicles (ADNVs). Remarkably, the vesicles demonstrated to inhibit tumor growth and boost anti-tumor immunity in a mouse model of lung cancer, primarily through remolding the tumor microenvironment and reprogramming tumor-associated macrophages (TAMs). We identified plant-derived mitochondrial DNA (mtDNA), upon internalized into TAMs via the vesicles, as a major effector molecule to induce the cGAS-STING pathway driving the shift of pro-tumor macrophages to anti-tumor phenotype. Furthermore, our data showed that administration of ADNVs greatly improved the efficacy of PD-L1 inhibitor, a prototypic immune checkpoint inhibitor, in tumor-bearing mice. Together, the present study, for the first time, to our knowledge, unravels an inter-kingdom interaction wherein the medical plant-derived mtDNA, via the nanovesicles, induces the immunostimulatory signaling in mammalian immune cells for resetting anti-tumor immunity and promoting tumor eradication.Graphical

Synthesis, antimalarial activity assay and molecular docking study of N-substituted chloro-pyrazolines

Purpose: To synthesize chloro-pyrazolines (A–D), determine their antimalarial activity against Plasmodium falciparum strain 3D7 in vitro, and understand the interaction between falcipain-2 active sites and synthesized compounds by molecular docking simulation.Methods: Chloro-pyrazolines (A–D) were synthesized via cyclo-condensation of 4-chloro chalcone derivatives using several types of hydrazines, i.e., formylhydrazine, benzoylhydrazine, phenylhydrazine and chlorophenylhydrazine. The compounds were analyzed and subjected to antimalarial assay against P. falciparum 3D7. Molecular docking was performed using AutoDock Tools and AutoDock Vina, while each docked compound was visualized using Discovery Studio Visualizer.Results: Pyrazolines A–D yield was 87.09, 61.71, 50.24 and 57.64 %, respectively. Antimalarial assay showed half-maximal inhibitory concentration (IC50) values of 16.46 and 5.55 μM for pyrazoline A and B, respectively, and ≥ 100 μM for pyrazoline C and D. Molecular docking study revealed that pyrazolines A–D had good interaction with the active site of falcipain-2 receptor.Conclusion: A series of N-substituted chloro-pyrazolines has successfully been synthesized with moderate yield. Pyrazoline B has the highest antimalarial activity against P. falciparum 3D7 with IC50 of 5.55 μM. This finding is supported by molecular docking and indicates that the benzoyl substituent increases the antimalarial activity of pyrazoline B. Pyrazoline B has potentials for clinical application as an antimalaria agent.

Antimalarial potential of naphthalene-sulfonic acid derivatives: Molecular electronic properties, vibrational assignments, and in-silico molecular docking studies

The need to discover, design and develop novel anti-malaria agent that are capable of treating and providing prophylaxis cover for malaria infections has become paramount. Herein, four novel derivatives of naphthalene-2-sulfonic acid: 5-amino-3-((4-formylphenyl)diazenyl)-4-hydroxynaphthalene-2,7-disulfonic acid (AZDH1), 7-amino-3-((4-formylphenyl)diazenyl)-4-hydroxynaphathalene-2-sulfonic acid (AZDH2), 6-amino-3-((4-formylphenyl)diazenyl)-4-hydroxynaphthalene-2-sulfonic acid (AZDH3), 5-((4-formylphenyl)diazenyl)-6-nitronapthalene-2-sulfonic acid (AZDH4) have been synthesized and characterized using FT-IR, UV-vis, and NMR spectroscopic techniques. The studied compounds were modeled for their molecular electronic structural properties and antimalarial activity using first principle density functional theory (DFT) at the B3LYP/6-31++G(d, p) level of theory and in-silico molecular docking. The influence of solvation on the vibrational and excited states characteristics of the studied compounds were conducted with the intentions of assessing possible hydration and changes in absorptivity of –OH, -NH2, -SO3, and C=O functional groups in different media. The molecular docking results show that the combination of the four compounds when docked with proteins: 1RQJ, 3J7A and 6MUW revealed a mean binding affinity of −9.4, −7.6 and −8.4 kcal/mol, respectively. Because the high binding affinities indicate a high reactivity compared to the standard (artesunate), it can be said that the studied compounds are capable of inducing a protective influence against the P. berghei- exerting inflammatory response by inhibiting NF-κB nuclear translocation that results to endothelial cell activation and the subsequent expression of ICAM-1 through an autonomous mechanism that kills the plasmodium parasite.

Plants as Sources of Natural and Recombinant Antimalaria Agents.

Malaria is one of the severe infectious diseases that has victimized about half a civilization billion people each year worldwide. The application of long-lasting insecticides is the main strategy to control malaria; however, a surge in antimalarial drug development is also taking a leading role to break off the infections. Although, recurring drug resistance can compromise the efficiency of both conventional and novel antimalarial medicines. The eradication of malaria is significantly contingent on discovering novel potent agents that are low cost and easy to administer. In this context, plant metabolites inhibit malaria infection progression and might potentially be utilized as an alternative treatment for malaria, such as artemisinin. Advances in genetic engineering technology, especially the advent of molecular farming, have made plants more versatile in producing protein drugs (PDs) to treat infectious diseases, including malaria. These recent developments in genetic modifications have enabled the production of native pharmaceutically active compounds and the accumulation of diverse heterologous proteins such as human antibodies, booster vaccines, and many PDs to treat infectious diseases and genetic disorders. This review will discuss the pivotal role of a plant-based production system that expresses natural antimalarial agents or host protein drugs to cure malaria infections. The potential of these natural and induced compounds will support modern healthcare systems in treating malaria infections, especially in developing countries to mitigate human fatalities.

Antibacterial activity of Escherichia coli from squid ink (Loligo sp.) n-Hexane extracts

Squid is one of the export commodities in Indonesia. In general, the use of squid meat, while the ink is only as waste. In fact, Squid ink contain bioactive compound that potential as anti-inflammatory, antihypertensive, anti-diabetic,anti-microbial and anti-malaria agents. The purpose of the study is to determine the types of secondary metabolite compounds contained in n-hexane extract of Loligo sp. ink using maceration method to determine its antibacterial activity against Escherichia coli. The results of secondary metabolite compounds obtained from the n-hexane extract of Loligo sp. ink are alkaloid, saponins, glycosides and phenol. The results of antibacterial test against E. coli using the disc method obtained the average of inhibition zone diameter at the concentration of 4% is 6.3 mm (intermediate), concentration of 8% is 7.83 mm (intermediate), concentration of 16% is 14.5 mm (susceptible) and concentration of 32% is 10.83 mm (intermediate). The antibacterial activity in n-hexane extract of Loligo sp. ink is optimal at the concentration of 16% against E. coli bacteria.

Willingness to Treat with Therapies of Unknown Effectiveness in Severe COVID-19: A Survey of Intensivist Physicians.

RationaleLittle is known about how physicians develop their beliefs about new treatments or update their beliefs in the face of new clinical evidence. These issues are particularly salient in the context of the coronavirus disease (COVID-19) pandemic, which created rapid demand for novel therapies in the absence of robust evidence.ObjectivesTo identify psychological traits associated with physicians’ willingness to treat with unproven therapies and willingness to update their treatment preferences in the setting of new evidence in the context of COVID-19.MethodsWe administered a longitudinal e-mail survey to United States physicians board certified in intensive care medicine in April and May 2020 (phase one) and October and November 2020 (phase two). We assessed five psychological traits potentially related to evidence uptake: need for cognition, evidence skepticism, need for closure, risk tolerance, and research engagement. We then examined the relationship between these traits and physician preferences for pharmacological treatment for a hypothetical patient with severe COVID-19 pneumonia.ResultsThere were 592 responses to the phase one survey, conducted prior to publication of trial data. At this time physicians were most willing to treat with macrolide antibiotics (50.5%), followed by antimalaria agents (36.1%), corticosteroids (24.5%), antiretroviral agents (22.6%), and angiotensin inhibitors (4.4%). Greater evidence skepticism (relative risk [RR], 1.40; 95% confidence interval [CI], 1.30–1.52; P < 0.001), greater need for closure (RR, 1.19; 95% CI, 1.06–1.34; P = 0.003), and greater risk tolerance (RR, 1.17; 95% CI, 1.08–1.26; P < 0.001) were associated with an increased willingness to treat, whereas greater need for cognition (RR, 0.85; 95% CI, 0.75–0.96, P = 0.010) and greater research engagement (RR, 0.91; 95% CI, 0.88–0.95; P < 0.0001) were associated with decreased willingness to treat. In phase two, most physicians updated their beliefs after publication of trial data about antimalarial agents and corticosteroids. Physicians with greater evidence skepticism were more likely to persist in their beliefs.ConclusionsPsychological traits associated with clinical decisions in the setting of uncertain evidence may provide insight into strategies to better align clinical practice with published evidence.

Therapeutic and Industrial Applications of Curdlan With Overview on Its Recent Patents.

Curdlan is an exopolysaccharide, which is composed of glucose linked with β-(1,3)-glycosidic bond and is produced by bacteria, such as Alcaligenes spp., Agrobacterium spp., Paenibacillus spp., Rhizobium spp., Saccharomyces cerevisiae, Candida spp., and fungal sources like Aureobasidium pullulan, Poria cocos, etc. Curdlan has been utilized in the food and pharmaceutical industries for its prebiotic, viscosifying, and water-holding properties for decades. Recently, the usefulness of curdlan has been further explored by the pharmaceutical industry for its potential therapeutic applications. Curdlan has exhibited immunoregulatory and antitumor activity in preclinical settings. It was observed that curdlan can prevent the proliferation of malarial merozoites in vivo; therefore, it may be considered as a promising therapy for the treatment of end-stage malaria. In addition, curdlan has demonstrated potent antiviral effects against human immunodeficiency virus (HIV) and Aedes aegypti virus. It has been suggested that the virucidal properties of curdlans should be extended further for other deadly viruses, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2/COVID-19). The prebiotic property of curdlan would confer beneficial effects on the host by promoting the growth of healthy microbiota in the gut and consequently help to reduce gastrointestinal disorders. Therefore, curdlan can be employed in the manufacture of prebiotics for the management of various gastrointestinal dysbiosis problems. Studies on the mechanism of action of curdlan-induced suppression in microbial and tumor cells at the cellular and molecular levels would not only enhance our understanding regarding the therapeutic effectiveness of curdlan but also help in the discovery of new drugs and dietary supplements. The primary focus of this review is to highlight the therapeutic interventions of curdlan as an anticancer, anti-malaria, antiviral, and antibacterial agent in humans. In addition, our review provides the latest information about the chemistry and biosynthesis of curdlan and its applications for making novel dairy products, functional foods, and nutraceuticals and also details about the recent patents of curdlan and its derivatives.

Exploring the potentials of selected bioactive compounds isolated from Piper guineense Schumach. &amp; Thonn. leaf toward identification of novel pfDHFR and pfDHODH inhibitors as antimalaria agents

Exploring the potentials of selected bioactive compounds isolated from Piper guineense Schumach. &amp; Thonn. leaf toward identification of novel pfDHFR and pfDHODH inhibitors as antimalaria agents

ROLE OF HYPERTENSION, CARDIOVASCULAR DISEASE AND CARDIOVASCULAR RISK FACTORS ON OUTCOME IN HOSPITALIZED COVID-19 PATIENTS

Objective: Emerging data show that hypertension as well as other cardiovascular risk factors may have a major role on outcome in terms of death on patients with COVID-19. We analysed a population of 258 consecutive patients admitted to General Medicine ward of the Hospital of Montichiari (Brixia, Italy) from 29 February to 30 April 2020. Design and method: A group of 258 consecutive patients (173 males and 85 females, aged 71 ± 14) was enrolled. In 168 patients, high-flow oxygen was required (Venturi mask), 20 patients needed orotracheal intubation and 11 were given continuous positive pressure oxygen therapy (CPAP). Patients were treated with the best approach according to available evidence during pandemic period: anti-malaria agents, anti-viral drugs, antibiotics (azithromycin and others), tocilizumab and low molecular weight heparin (LMWH). As of June 10th, 65 deaths had been observed. Survival curves were calculated according to Kaplan-Meier method. Comparison between groups was performed with Breslow and Mantel-Cox test. Results: As shown in the table, a significant raise in mortality was observed in patients older than 65 years (p &lt; 0.001), of male sex (p &lt; 0.001), hypertensives (p &lt; 0.001) as well as in patients with heart disease (picture 1; p &lt; 0.001), COPD (picture 2; p = 0.004), diabetes (p &lt; 0.001) and neoplasms (p = 0.03) compared with patients with no comorbidities or different diseases, both at discharge and at standard follow-up. The number of comorbidities impacted on survival as well. Conclusions: Hypertension, heart disease and cardiovascular risk factors play a significant role as a negative prognostic factor in patients affected by SARS-CoV-2 pneumonia. This confirms previous observations (Pol Arch Intern Med 2020;130(4):304–309) and outlines the importance of prevention of contagion in population with cardiovascular risk factors or established cardiovascular disease.

Synthesis and antimalarial activity of some triphenyltin(IV) aminobenzoate compounds against Plasmodium falciparum

Abstract This paper presents antimalarial activity of several triphenyltin(IV) aminobenzoate compounds synthesized from the reaction of triphenyltin(IV) hydroxide with 2-, 3-, and 4-aminobenzoic acid. The activity of the compounds as anti-malaria agents was evaluated using Plasmodium falciparum, and demonstrated that the compounds have about the same IC50 with that of chloroquine (2×10−3 μg/mL) applied as the positive control. The result also showed that the Plasmodium is non-resistent to the compounds synthesized, which is the opposite to chloroquine.

Intervention of standardized ethanol leaf extract of Annickia polycarpa, (DC.) Setten and Maas ex I.M. Turner. (Annonaceae), in Plasmodium berghei infested mice produced anti-malaria action and normalized gross hematological indices

Ethnopharmacological relevanceMalaria is a global public health burden due to large number of annual infections and casualties caused by its hematological complications. The bark of Annickia polycarpa is an effective anti-malaria agent in African traditional medicine. However, there is no standardization parameters for A. polycarpa. The anti-malaria properties of its leaf are also not known. Aim of the studyTo standardize the ethanol leaf extract of A. polycarpa (APLE) and investigate its anti-malaria properties and the effect of its treatment on hematological indices in Plasmodium berghei infected mice in the Rane's test. Materials and methodsMalaria was induced by inoculating female ICR mice with 1.0 × 107P. berghei-infected RBCs in 0.2 mL (i.p.) of blood. Treatment was commenced 3 days later with APLE 50, 200, 400 mg/kg p.o., Quinine 30 mg/kg i.m. (Standard drug) or sterile water (Negative control) once daily per group for 4 successive days. Anti-malarial activity and gross malaria indices such as hyperparasitemia, mean change in body weight and mean survival time (MST) were determined for each group. Changes in white blood cells (WBCs), red blood cells (RBCs), platelets (PLT) counts, hemoglobin (HGB) concentration, hematocrit (HCT) and mean corpuscular volume (MCV) were also measured in the healthy mice before infection as baseline and on day 3 and 8 after inoculation using complete blood count. Standardization was achieved by UHPLC-MS chemical fingerprint analysis and quantitative phytochemical tests. ResultsAPLE, standardized to its total alkaloids, phenolics and saponin contents, produced significant (P < 0.05) dose-dependent clearance of mean hyperparasitemia of 22.78 ± 0.93% with the minimum parasitemia level of 2.01 ± 0.25% achieved at 400 mg/kg p.o. on day 8. Quinine 30 mg/kg i.m. achieved a minimum parasitemia level of 6.15 ± 0.92%. Moreover, APLE (50–400 mg/kg p.o.) evoked very significant anti-malaria activity of 89.22–95.50%. Anti-malaria activity of Quinine 30 mg/kg i.m. was 86.22%. APLE also inverse dose-dependently promotes weight gain with the effect being significant (P < 0.05) at 50 mg/kg p.o. Moreover, APLE dose-dependently increased the MST of malaria infested mice with 100% survival at 400 mg/kg p.o. Quinine 30 mg/kg i.m. also produce 100% survival rate but did not promote (P > 0.05) weight gain. Hematological studies revealed the development of leukocytopenia, erythrocytosis, microcytic anemia and thrombocytopenia in the malaria infected mice which were reverted with the treatment of APLE 50–400 mg/kg p.o. or Quinine 30 mg/kg i.m. but persisted in the negative control. The UHPLC-MS fingerprint analysis of APLE led to identification of one oxoaporphine and two aporphine alkaloids (1–3). Alkaloids 1 and 3 are being reported in this plant for the first time. ConclusionThese results indicate that APLE possessed significant anti-malaria, immunomodulatory, erythropoietic and hematinic actions against malaria infection. APLE also has the ability to revoke deleterious physiological alteration produced by malaria and hence, promote clinical cure. These properties of APLE are due to its constituents especially, aporphine and oxoaporphine alkaloids.

Antrocaryon micraster (A. Chev. And Guillaumin) stem bark extract demonstrated anti-malaria action and normalized hematological indices in Plasmodium berghei infested mice in the Rane's test

Ethnopharmacological relevanceMalaria is caused by infection with some species of Plasmodium parasite which leads to adverse alterations in physical and hematological features of infected persons and ultimately results in death. Antrocaryon micraster is used to treat malaria in Ghanaian traditional medicine. However, there is no scientific validation of its anti-malaria properties. The plant does not also have any chemical fingerprint or standardization parameters. Aim of the studyThis study sought to evaluate the anti-malaria activity of standardized A. micraster stem bark extract (AMSBE) and its effect on mean survival time (MST) and body weight reduction of Plasmodiumberghei infested mice. And to study the effect of treatment of AMSBE on hematological indices of the P. berghei infested mice in order to partly elucidate its anti-malarial mechanism of action. Materials and methodsMalaria was induced in female ICR mice by infecting them with 0.2 mL of blood (i.p.) containing 1.0 × 107P. berghei-infested RBCs from a donor mouse and leaving them without treatment for 3 days. AMSBE or Lonart (standard control) was then orally administered at 50, 200 and 400 mg/kg or 10 mg/kg once daily for 4 consecutive days. The untreated control received sterile water. Malaria parasitemia reduction, anti-malarial activity, mean change in body weight and MST of the parasitized mice were evaluated. Furthermore, changes in white blood cells (WBCs), red blood cells (RBCs), platelets count, hemoglobin (HGB), hematocrit (HCT) and mean corpuscular volume (MCV) were also determined in the healthy animals before infection as baseline and on days 3, 5 and 8 after infection by employing complete blood count. Standardization of AMSBE was achieved by quantification of its constituents and chemical fingerprint analysis using UHPLC-MS. ResultsAdministration of AMSBE, standardized to 41.51% saponins and 234.960 ± 0.026 mg/g of GAE phenolics, produced significant (P < 0.05) reduction of parasitemia development, maximum anti-malaria activity of 46.01% (comparable to 32.53% produced by Lonart) and significantly (P < 0.05) increased body weight and MST of P. berghei infected mice compared to the untreated control. Moreover, there were significant (P > 0.05) elevation in WBCs, RBCs, HGB, HCT and platelets in the parasitized-AMSBE (especially at 400 mg/kg p.o.) treated mice compared to their baseline values. Whereas, the non-treated parasitized control recorded significant reduction (P < 0.05) in all the above-mentioned parameters compared to its baseline values. The UHPLC-MS fingerprint of AMSBE revealed four compounds with their retention times, percentage composition in their chromatograms and m/z of the molecular ions and fragments in the spectra. ConclusionsThese results show that A. micraster stem bark possessed significant anti-malaria effect and also has the ability to abolish body weight loss, leucopenia, anemia and thrombocytopenia in P. berghei infected mice leading to prolonged life span. The UHPLC-MS fingerprint developed for AMSBE can be used for rapid authentication and standardization of A. micraster specimens and herbal preparations produced from its hydroethanolic stem bark extract to ensure consistent biological activity. The results justify A. micraster's use as anti-malaria agent.

Antiplasmodial Combined Formulation of Artemisinin with Peschiera fuchsiaefolia Bis-Indole Alkaloids

Antimalarial agents used as monotherapy are increasingly ineffective due to the emergence of Plasmodium resistant strains. Artemisinin (Arte), extracted from Artemisia annua, presents a good efficiency against the Plasmodium strains and is currently used to treat malaria. To avoid the appearance of new resistant strains to artemisinin, the use of Artemisinin-based Combination Therapy (ACT) with another antimalaria agent was recommended by WHO to provide an effective cure and delayed resistance. Although combined formulations of various drugs with Artemisinin have been developed, their release is immediate, and they require multiple doses with side detrimental effects and effectiveness still desired. To improve its efficiency, controlled release formulations were developed to ensure long-term antiplasmodial activity by associating Artemisinin with a natural antimalarial agent extracted from Peschiera fuchsiaefolia (Pf). The Pf extract (containing mostly low soluble alkaloids) was complexed with carboxymethylcellulose to improve its solubility and stability. Two formulation types are reported. As bilayer tablet dosage form, the kinetic release pattern was an immediate release of Artemisinin, followed by a slow sustained release of Pf for 12 h. As monolithic tablet, the release profile shows a simultaneous sustained release of the two active agents, about of 10 h for Arte and 12 h for Pf.

The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma.

Primary effusion lymphoma (PEL), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), presents as a lymphomatous effusion in body cavities and has a poor prognosis. The anti-malaria drug, artesunate, possesses anti-neoplastic potential. Therefore, we aimed to investigate its effect on KSHV-infected PEL cell lines. Artesunate inhibited cell growth and viability of PEL cells, but its effect on peripheral blood mononuclear cells was less pronounced. Artesunate induced G1 phase arrest by downregulating cyclin D1/D2, CDK2/6 and c-Myc. Artesunate increased reactive oxygen species and DNA damage, but did not affect the expression of latent and lytic genes of KSHV. It exhibited cytotoxicity through caspase-dependent and -independent pathways and reduced Bcl-xL, survivin, XIAP and c-IAP1/2 levels. Furthermore, artesunate suppressed NF-κB and AP-1 by inhibiting IκB kinase and IκBα phosphorylation as well as JunB expression. Finally, artesunate treatment attenuated PEL development in mice. Our data support that artesunate is a potential drug for PEL treatment.

Anti-HCV and anti-malaria agent, potential candidates to repurpose for coronavirus infection: Virtual screening, molecular docking, and molecular dynamics simulation study

AimsCoronavirus disease 2019 (COVID-19) has appeared in Wuhan, China but the fast transmission has led to its widespread prevalence in various countries, which has made it a global concern. Another concern is the lack of definitive treatment for this disease. The researchers tried different treatment options which are not specific. The current study aims to identify potential small molecule inhibitors against the main protease protein of SARS-CoV-2 by the computational approach. Main methodsIn this study, a virtual screening procedure employing docking of the two different datasets from the ZINC database, including 1615 FDA approved drugs and 4266 world approved drugs were used to identify new potential small molecule inhibitors for the newly released crystal structure of main protease protein of SARS-CoV-2. In the following to validate the docking result, molecular dynamics simulations were applied on selected ligands to identify the behavior and stability of them in the binding pocket of the main protease in 150 nanoseconds (ns). Furthermore, binding energy using the MMPBSA approach was also calculated. Key findingsThe result indicates that simeprevir (Hepatitis C virus NS3/4A protease inhibitor) and pyronaridine (antimalarial agent) could fit well to the binding pocket of the main protease and because of some other beneficial features including broad-spectrum antiviral properties and ADME profile, they might be a promising drug candidate for repurposing to the treatment of COVID-19. SignificanceSimeprevir and pyronaridine were selected by the combination of virtual screening and molecular dynamics simulation approaches as a potential candidate for treatment of COVID-19.

Possible Impact of Select Trace Mineral Deficiency in HIV Seropositive Pregnant Women with/without Malaria Co-infection in NAUTH, Nnewi, Nigeria

Aims: To evaluate the impact of HIV and malaria on serum Zinc (zn), Selenium (se) and Magnesium (mg) in HIV seropositive pregnant women in Nnewi, Nigeria.&#x0D; Study Design: This is a case-control study.&#x0D; Place and Duration of Study: Prevention of Mother to Child transmission (PMTCT) of HIV Clinic of Nnamdi Azikiwe University Teaching Hospital, Nnewi, (NAUTH), Nigeria, between December, 2017 and April, 2018.&#x0D; Methodology: We included 122 consented female participants; 32 HIV seropositive pregnant women with malaria parasitaemia, 30 HIV seropositive pregnant women without malaria parasitaemia, 30 Malaria infected pregnant women, 30 pregnant women without HIV or malaria parasitaemia, aged between 18 and 42 years. Screening for HIV antibodies and malaria parasite was double screened using National algorithm, rapid detection technique (RDT) and Giemsa staining microscopy technique respectively. Micronutrient levels were determined using atomic absorption spectrophotometry (AAS).&#x0D; Results: When the mean zn, sel and mg levels were compared between the test and control groups, significant decreases in serum zn (37.34 ± 6.7, 36.70 ± 4.39), sel (29.93 ± 6.02, 28.00 ± 5.04) and mg (2.41 ± 0.46, 2.33 ± 0.14) were observed in HIV seropositive pregnant participants with/without malaria co-infection when compared with their corresponding controls Zn (45.1 ± 7.83, 50.36 ± 8.73); Sel (31.46 ± 6.19, 31.96 ± 6.81); Mg (2.62 ± 0.30) and (P &lt; .05 respectively). Body mass index (BMI) was significantly decreased while diastolic blood pressure (DBP) and systolic blood pressure (SBP) were significantly increased in HIV seropositive pregnant women with malaria compared with their seronegative counterparts (P &lt; .05 respectively).&#x0D; Conclusion: The significant loss in BMI with derangement in serum zn, sel and mg levels in HIV seropositive pregnant women with/without malaria co-infection indicates high degree of malnutrition while the increased blood pressure suggests high blood pressure which might predispose the pregnant mothers to pre-eclampsia if not properly managed. Adequate micronutrient supplementation and effective anti malaria agent is strictly advocated in the routine management of HIV infected mothers during pregnancy to reduce the severity of the co-infection and adverse pregnancy complications especially in areas of malaria endemic transmissions.