Host resistance to malaria: using mouse models to explore the host response

Malaria is a disease that infects over 500 million people, causing at least 1 million deaths every year, with the majority occurring in developing countries. The current antimalarial arsenal is becoming dulled due to the rapid rate of resistance of the parasite. However, in populations living in malaria-endemic regions there are many examples of genetic-based resistance to the severe effects of the parasite Plasmodium. Defining the genetic factors behind host resistance has been an area of great scientific interest over the last few decades; this review summarizes the current knowledge of the genetic loci involved. Perhaps the lessons learned from the natural variation in both the human populations and experimental mouse models of infection may pave the way for novel resistance-proof antimalarials.     

Medicinal plants as a fight against murine blood-stage malaria

ObjectiveMalaria is an infectious parasitic disease affecting most of countries worldwide. Due to antimalarial drug resistance, researchers are seeking to find another safe efficient source for treatment of malaria. Since many years ago, medicinal plants were widely used for the treatment of several diseases. In general, most application is done first on experimental animals then human. In this article, medicinal plants as antimalarial agents in experimental animals were reviewed from January 2000 until November 2020.Materials and methodsIn this systematic review published articles were reviewed using the electronic databases NCBI, ISI Web of knowledge, ScienceDirect and Saudi digital library to check articles and theses for M.Sc/Ph.D. The name of the medicinal plant with its taxon ID and family, the used Plasmodium species, plant part used and its extract type and the country of harvest were described.Results and conclusionThe reviewed plants belonged to 83 families. Medicinal plants of families Asteraceae, Meliaceae Fabaceae and Lamiaceae are the most abundant for use in laboratory animal antimalarial studies. According to region, published articles from 33 different countries were reviewed. Most of malaria published articles are from Africa especially Nigeria and Ethiopia. Leaves were the most common plant part used for the experimental malaria research. In many regions, research using medicinal plants to eliminate parasites and as a defensive tool is popular.     

Ethnobotany in the Cumbres de Monterrey National Park, Nuevo León, México

The archives of Flora Medicinal, an ancient pharmaceutical laboratory that supported ethnomedical research in Brazil for more than 30 years, were searched for plants with antimalarial use. Forty plant species indicated to treat malaria were described by Dr. J. Monteiro da Silva (Flora Medicinal leader) and his co-workers. Eight species, Bathysa cuspidata, Cosmos sulphureus, Cecropia hololeuca, Erisma calcaratum, Gomphrena arborescens, Musa paradisiaca, Ocotea odorifera, and Pradosia lactescens, are related as antimalarial for the first time in ethnobotanical studies. Some species, including Mikania glomerata, Melampodium divaricatum, Galipea multiflora, Aspidosperma polyneuron, and Coutarea hexandra, were reported to have activity in malaria patients under clinical observation. In the information obtained, also, there were many details about the appropriate indication of each plant. For example, some plants are indicated to increase others' potency. There are also plants that are traditionally employed for specific symptoms or conditions that often accompany malaria, such as weakness, renal failure or cerebral malaria. Many plants that have been considered to lack activity against malaria due to absence of in vitro activity against Plasmodium can have other mechanisms of action. Thus researchers should observe ethnomedical information before deciding which kind of screening should be used in the search of antimalarial drugs.     

Artemisinin-Ginkgo biloba extract combination therapy for Plasmodium yoelii

Malaria remains a widespread life-threatening infectious disease, leading to an estimated 219 million cases and around 435,000 deaths. After an unprecedented success, the antimalarial progress is at a standstill. Therefore, new methods are urgently needed to decrease drug resistant and enhance antimalarial efficacy. According to the alteration of erythrocyte biomechanical properties and the immune evasion mechanism of parasites, drugs, which can improve blood circulation, can be chosen to combine with antimalarial drugs for malaria treatment. Ginkgo biloba extract (GBE), one of drug for vascular disease, was used to combine with artemisinin for Plasmodium yoelii therapy. Artemisinin-GBE combination therapy (AGCT) demonstrated remarkable antimalarial efficacy by decreasing infection rate, improving blood microcirculation and modulating immune system. Besides, the expression of invasion related genes, such as AMA1, MSP1 and Py01365, can be suppressed by AGCT, hindering invasion process of merozoites. This new antimalarial strategy, combining antimalarial drugs with drugs that improve blood circulation, may enhance the antimalarial efficacy and ameliorate restoration ability, proving a potential method for finding ideal compatible drugs to improve malaria therapy     

Structural analyses of the malaria parasite aminoacyl‐tRNA synthetases provide new avenues for antimalarial drug discovery

Malaria is a parasitic illness caused by the genus Plasmodium from the apicomplexan phylum. Five plasmodial species of P. falciparum (Pf), P. knowlesi, P. malariae, P. ovale, and P. vivax (Pv) are responsible for causing malaria in humans. According to the World Malaria Report 2020, there were 229 million cases and ~ 0.04 million deaths of which 67% were in children below 5 years of age. While more than 3 billion people are at risk of malaria infection globally, antimalarial drugs are their only option for treatment. Antimalarial drug resistance keeps arising periodically and thus threatens the main line of malaria treatment, emphasizing the need to find new alternatives. The availability of whole genomes of P. falciparum and P. vivax has allowed targeting their unexplored plasmodial enzymes for inhibitor development with a focus on multistage targets that are crucial for parasite viability in both the blood and liver stages. Over the past decades, aminoacyl‐tRNA synthetases (aaRSs) have been explored as anti‐bacterial and anti‐fungal drug targets, and more recently (since 2009) aaRSs are also the focus of antimalarial drug targeting. Here, we dissect the structure‐based knowledge of the most advanced three aaRSs—lysyl‐ (KRS), prolyl‐ (PRS), and phenylalanyl‐ (FRS) synthetases in terms of development of antimalarial drugs. These examples showcase the promising potential of this family of enzymes to provide druggable targets that stall protein synthesis upon inhibition and thereby kill malaria parasites selectively.     

Whole exome sequencing of a Saudi family and systems biology analysis identifies CPED1 as a putative causative gene to Celiac Disease

Celiac disease (CD) is a gastrointestinal disorder whose genetic basis is not fully understood. Therefore, we studied a Saudi family with two CD affected siblings to discover the causal genetic defect. Through whole exome sequencing (WES), we identified that both siblings have inherited an extremely rare and deleterious CPED1 genetic variant (c.241 A > G; p.Thr81Ala) segregating as autosomal recessive mutation, suggesting its putative causal role in the CD. Saudi population specific minor allele frequency (MAF) analysis has confirmed its extremely rare prevalence in homozygous condition (MAF is 0.0004). The Sanger sequencing analysis confirmed the absence of this homozygous variant in 100 sporadic Saudi CD cases. Genotype-Tissue Expression (GTEx) data has revealed that CPED1 is abundantly expressed in gastrointestinal mucosa. By using a combination of systems biology approaches like protein 3D modeling, stability analysis and nucleotide sequence conservation analysis, we have further established that this variant is deleterious to the structural and functional aspects of CPED1 protein. To the best of our knowledge, this variant has not been previously reported in CD or any other gastrointestinal disease. The cell culture and animal model studies could provide further insight into the exact role of CPED1 p.Thr81Ala variant in the pathophysiology of CD. In conclusion, by using WES and systems biology analysis, present study for the first-time reports CPED1 as a potential causative gene for CD in a Saudi family with potential implications to both disease diagnosis and genetic counseling.     

The chemistry and biology of febrifugine and halofuginone

The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product febrifugine (also known as dichroine B) and its synthetic analogue, halofuginone, possess antimalarial activity. More recently studies have also shown that halofuginone acts as an agent capable of reducing fibrosis, an indication with clinical relevance for several disease states. This review summarizes historical isolation studies and the chemistry performed which culminated in the correct structural elucidation of naturally occurring febrifugine and its isomer isofebrifugine. It also includes the range of febrifugine analogues prepared for antimalarial evaluation, including halofuginone. Finally, a section detailing current opinion in the field of halofuginone’s human biology is included.     

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.     

New 3-methylquinoxaline-2-carboxamide 1,4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents

Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents, obtaining biological values similar to the reference compound, Rifampin (RIF).     

Phytophagous and predaceous mites associated with vegetable crops from Riyadh,Saudi Arabia

This study was conducted to investigate phytophagous and predatory mites associated with vegetable plants in Riyadh, Saudi Arabia. Eight phytophagous and 10 predacious mites were collected from 14 species of vegetable crops covering five major production localities. Out of these 18 mite species, 13 species are new to the mite fauna of Saudi Arabia. In addition, the two species, Tenuipalpus punicae and Agistemus exsertus, are reported for the first time on vegetable crops in Saudi Arabia. For each mite species found, notes on host plant association and occurrence period are given. An illustrated key for the identification of the 18 mite species reported in this study is provided and this can be used to improve the IPM programs by applying the local natural predatory mites in controlling mite pests in Saudi Arabia.     

Compounds Derived from the Bhutanese Daisy,Ajania nubigena,Demonstrate Dual Anthelmintic Activity against Schistosoma mansoni and Trichuris muris

BackgroundWhipworms and blood flukes combined infect almost one billion people in developing countries. Only a handful of anthelmintic drugs are currently available to treat these infections effectively; there is therefore an urgent need for new generations of anthelmintic compounds. Medicinal plants have presented as a viable source of new parasiticides. Ajania nubigena, the Bhutanese daisy, has been used in Bhutanese traditional medicine for treating various diseases and our previous studies revealed that small molecules from this plant have antimalarial properties. Encouraged by these findings, we screened four major compounds isolated from A. nubigena for their anthelmintic properties.Conclusions/SignificanceAmong the four compounds tested, luteolin demonstrated the best broad-spectrum activity against two different helminths—T. muris and S. mansoni—and was effective against juvenile schistosomes, the stage that is refractory to the current gold standard drug, praziquantel. Medicinal chemistry optimisation including cytotoxicity analysis, analogue development and structure-activity relationship studies are warranted and could lead to the identification of more potent chemical entities for the control of parasitic helminths of humans and animals.     

The Importance of Ring Size and Position for the Antiplasmodial Activity of Angiotensin II Restricted Analogs

Malaria is caused by the protozoa Plasmodium and is responsible for approximately one million deaths annually. The antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and falciparum have recently been reported. Here, 12 angiotensin II restricted analogs that contain i ? (i + 2), i ? (i + 3) and i ? (i + 4) lactam bridges were synthesized to analyze their effect on antiplasmodial activity. To accomplish this, peptides containing two amino acid residues (aspartic or glutamic acids and lysine or ornithine), were synthesized by the t-Boc solid phase method, purified by liquid chromatography, and characterized by mass spectrometry, and conformational studies were performed by circular dichroism. The results indicate that some of the analogs had anti-plasmodium activity similar to angiotensin II (88 % activity). Among those, eight compounds exhibited high activity (>70 %), measured by fluorescence microscopy. The analogs with smaller lactam rings and an aspartic acid residue as the bridgehead element had lower levels of lytic activity. The results obtained with the new restricted analogs showed that the insertion position (near the N-terminus), the ring size, and the number of residues between the rings are as important as the components of lactam bridge, regardless of their chirality. The circular dichroism studies suggest that the active analogs, and native angiotensin II, adopt a β-fold conformation in different solutions. In conclusion, this approach provides insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents.     

Distance to semi-natural grassland influences seed production of insect-pollinated herbs

Marginal grassland fragments, such as road verges and field margins, may act as important supplemental habitats for grassland plants in the modern agricultural landscape. However, abundance of pollinators in such fragments has been found to decline with distance to larger natural and semi-natural habitats, and this could have corresponding effects on plant pollination. In this study, we performed a field experiment on road verges with three insect-pollinated grassland herbs to examine the relationship between distance to semi-natural grassland and plant reproductive success in two landscapes with contrasting farming intensities. In Lychnis viscaria and Lotus corniculatus, seed production tended to decrease with increasing distance to semi-natural grassland, but only in the landscape with high farming intensity. Seed production in Armeria maritima spp. maritima decreased with distance in both landscapes. Although many studies have investigated effects of natural habitat on crop pollination, little is known about the impact on pollination in native plants. The results from this study indicate that management of semi-natural grasslands improves not only biodiversity within the actual grassland but also pollination of native plants in the surrounding agricultural landscape.     

Investigation of some medicinal plants traditionally used for treatment of malaria in Kenya as potential sources of antimalarial drugs

Malaria is a major public health problem in many tropical and subtropical countries and the burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for discovery of new antimalarial agents. Herbal medicines for the treatment of various diseases including malaria are an important part of the cultural diversity and traditions of which Kenya′s biodiversity has been an integral part. Two major antimalarial drugs widely used today came originally from indigenous medical systems, that is quinine and artemisinin, from Peruvian and Chinese ancestral treatments, respectively. Thus ethnopharmacology is a very important resource in which new therapies may be discovered. The present review is an analysis of ethnopharmacological publications on antimalarial therapies from some Kenyan medicinal plants.     

The Lessonia nigrescens fishery in northern Chile: “how you harvest is more important than how much you harvest”

In Chile, management of natural resources usually starts right before its imminent collapse or after evident declination. In the northern area of the country, the fishery of brown seaweeds has an enormous social, ecological, and economical importance. More than 11,000 people depend directly or indirectly on the collection and harvesting of this resource. Ecologically, kelps constitute areas for food, reproduction, and refuge for hundreds of invertebrates and fish species. Economically, landings up to 300,000 dry tons per year represent close to US $60 million for the industry. Until 2002, the Chilean brown seaweed fishery was mainly sustained by natural mortality, where plants cast ashore were collected by artisanal fishermen. Since then, three brown seaweed species of economic importance (Lessonia nigrescens, Lessonia trabeculata, and Macrocystis pyrifera) have been intensively harvested in coastal areas between 18° and 32° S. To manage kelp populations along the northern Chilean coast, regulations have been based on the principle “how you harvest is more important than how much you harvest”. This exploitation strategy has been adopted in consensus between fishermen, industries, governmental entities, and scientists. Since L. nigrescens represents more than 70% of total brown seaweed landings, this study tests the effects of L. nigrescens harvesting on the following population variables: (1) abundance, (2) distribution, (3) juvenile recruitment, (4) plant morphology, (5) frequency of reproductive plants, and (6) biodiversity of the macroinvertebrate community associated to kelp holdfasts. Our results show that, despite the enormous harvesting pressure on Lessonia density and biomass, the associated macroinvertebrate richness has been maintained, due to normal plant growth and high recruitment all year round.     

Screening of potential cytotoxic activities of some medicinal plants of Saudi Arabia

Phytochemicals from plant extracts belong to an important source of natural products which have demonstrated excellent cytotoxic activities. However, plants of different origins exhibit diverse chemical composition and bioactivities. Therefore, discovery of plants based new anticancer agents from different parts of the world is always challenging. In this study, methanolic extracts of different parts of 11 plants from Saudi Arabia have been tested in vitro for their anticancer potential on human liver cancer cell line (HepG2). Particularly, for this study, plants from Asteraceae, Resedaceae and Polygonaceae families were chosen on the basis of locally available ethnobotanical data and their medicinal properties. Among 12 tested extract samples, three samples obtained from Artemisia monosperma stem, Ochradenus baccatus aerial parts and Pulicaria glutinosa stem have demonstrated interesting cytotoxic activities with a cell viability of 29.3%, 28.4% and 24.2%, respectively. Whereas, four plant extracts including Calendula arvensis aerial parts, Scorzonera musilii whole plant, A. monosperma leaves show moderate anticancer properties bearing a cell viability ranging from 11.9 to 16.7%. The remaining extracts have shown poor cytotoxic activities. Subsequently, GC-MS analysis of methanolic extracts of four most active plants extracts such as C. comosum, O. baccatus, P. glutinosa and A. monosperma detected the presence of 41 phytomolecules. Among which 3-(4-hydroxyphenyl) propionitrile (1), 8,11-octadecadiynoic acid methyl ester (2), 6,7-dimethoxycoumarin (3) and 1-(2-hydroxyphenyl) ethenone (4) were found to be the lead compounds of C. comosum, O. baccatus P. glutinosa and A. monosperma, respectively.     

Structural studies of vacuolar plasmepsins

Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium spp. (P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes 10 PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), 4 of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50-79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium spp.. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure-function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15 years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.     

Essential oils for the control of reduviid insects

Chagas disease is an important vector-borne disease problem in South America, especially in rural areas where inhabitants are in contact with the reduviid insects that transmit the parasite Trypanosoma cruzi. Today, the main means of interrupting transmission of T. cruzi is to control the vector. Therefore, studies of new agents with activity against these vectors have a priority interest. This review covers recent studies on essential oils from plants that have demonstrated moderate to high activity against the main vectors of Chagas disease. Further, we investigate the constituents of essential oils of plants of the genera Mentha, Thymus, Satureja and Artemisia and their activity on Rhodnius prolixus using an excito-repellency test.     

The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process

Chagas’ disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas’ disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K₃. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K₃ and vitamin C, alone and in combination, against T. cruzi. The vitamin K₃ + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K₃ + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death.