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Journal of Experimental Pharmacology 2024Malaria is causing high mortality and morbidity due to resistance to currently available anti-malarial drugs and mosquito's resistance to insecticides. Thus, there is a...
BACKGROUND
Malaria is causing high mortality and morbidity due to resistance to currently available anti-malarial drugs and mosquito's resistance to insecticides. Thus, there is a critical need to search for novel anti-malarial drugs from natural sources. Therefore, this study investigated in vivo antimalarial activities of two Ethiopian medicinal plants, Pax and Thonn, in infected Swiss albino mice.
METHODS
Soxhlet extraction method using 80% methanol as a solvent was used to prepare crude extracts of the two plants. Acute oral toxicity and 4-day suppressive in vivo antimalarial activity tests were performed on healthy female mice and infected male mice, respectively. Antimalarial activity of the crude extracts at doses of 100, 200, and 400 mg/kg and the standard drug, chloroquine were used to assesse in infected Swiss albino mice. Parasitemia level, packed cell volume, body weight, and rectal temperature of the mice were determined before infection (day 0) and after treatment (day 4). Survival time was determined by recording the date on which the mice died, considering the date of infection as day 0. The recorded data were analyzed using ANOVA and SPSS version 24.
RESULTS
The result of the acute toxicity study revealed that the crude extracts were non-toxic at doses up to 2 g/kg. The extract of suppressed parasitemia level by 66.28, 63.44 and 63.14% at 400, 200, and 100mg/kg, levels while extract suppressed parasitemia level by 45.29% at a dose of 400mg/kg. The remaining two dose levels of extract suppressed parasitemia level by < 30%.
CONCLUSION
and showed anti-plasmodial activities. exhibited a more pronounced anti-plasmodial effect than . The activities of both plants observed in this study support their traditional use as antimalarial drugs. Further studies on these plants using solvent fractions are required to identify their active ingredients.
PubMed: 38826847
DOI: 10.2147/JEP.S457659 -
Frontiers in Cellular and Infection... 2023Coronavirus disease 2019 (COVID-19) and malaria, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and parasites, respectively, share geographical...
Coronavirus disease 2019 (COVID-19) and malaria, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and parasites, respectively, share geographical distribution in regions where the latter disease is endemic, leading to the emergence of co-infections between the two pathogens. Thus far, epidemiologic studies and case reports have yielded insufficient data on the reciprocal impact of the two pathogens on either infection and related diseases. We established novel co-infection models to address this issue experimentally, employing either human angiotensin-converting enzyme 2 (hACE2)-expressing or wild-type mice, in combination with human- or mouse-infective variants of SARS-CoV-2, and the rodent malaria parasite. We now show that a primary infection by a viral variant that causes a severe disease phenotype partially impairs a subsequent liver infection by the malaria parasite. Additionally, exposure to an attenuated viral variant modulates subsequent immune responses and provides protection from severe malaria-associated outcomes when a blood stage infection was established. Our findings unveil a hitherto unknown host-mediated virus-parasite interaction that could have relevant implications for disease management and control in malaria-endemic regions. This work may contribute to the development of other models of concomitant infection between and respiratory viruses, expediting further research on co-infections that lead to complex disease presentations.
Topics: Humans; Mice; Animals; SARS-CoV-2; COVID-19; Rodentia; Coinfection; Malaria; Disease Models, Animal
PubMed: 38156320
DOI: 10.3389/fcimb.2023.1307553 -
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 -
Nature Communications Jan 2024Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental...
Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.
Topics: Animals; Mice; Acute Lung Injury; Extracellular Traps; Lung; Malaria; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Protein Tyrosine Phosphatases; Immediate-Early Proteins
PubMed: 38286811
DOI: 10.1038/s41467-024-45210-5 -
Journal of Parasitology Research 2024Comorbidities that involve infectious and noninfectious diseases, such as malaria and cancer, have been described. Cancer and malaria induce changes in the nociceptive...
Comorbidities that involve infectious and noninfectious diseases, such as malaria and cancer, have been described. Cancer and malaria induce changes in the nociceptive and inflammatory responses through similar pathophysiological mechanisms. However, it is unclear whether malaria and antimalarial treatment can change the inflammatory and nociceptive responses induced by solid cancer. Therefore, the present study experimentally evaluated the effect of infection by strain ANKA and chloroquine treatment on the nociceptive and inflammatory responses induced by the solid Ehrlich tumor in male BALB/c mice. On the 1 experimental day, mice were infected with and injected with tumor cells in the left hind paw. From the 7 to the 9 experimental day, mice were treated daily with chloroquine. The parasitemia was evaluated on the 7 and 10 days after infection. On the 11 experimental day, mice were evaluated on the von Frey filament test, the hot plate test, and the paw volume test. At the end of the experimental tests on the 11th day, the peripheral blood of all mice was collected for dosing of IL-1 and TNF-. The blood parasitemia significantly increased from the 7 to the 10 day. The chloroquine treatment significantly decreased the parasitemia on the 10 day. The presence of the tumor did not significantly change the parasitemia on the 7 and 10 days in mice treated and nontreated with chloroquine. On the 11 day, the mechanical and thermal nociceptive responses significantly increased in mice with tumors. The treatment with antimalarial significantly reduced the mechanical nociceptive response induced by tumors. The hyperalgesia induced by tumors did not change with malaria. The mechanical and thermal hyperalgesia induced by the tumor was significantly reduced in mice treated and healed from malaria. On the 11 day, the volume of the paw injected by the tumor was significantly increased. The mice treated with chloroquine, infected with malaria, or healed of malaria showed reduced paw edema induced by the tumor. Mice with tumors did not show a change in IL- and TNF- serum levels. Mice with tumors showed a significant increase in serum levels of IL-1 but not TNF- when treated with chloroquine, infected with malaria, or healed of malaria. In conclusion, the results show that malaria infection and chloroquine treatment can influence, in synergic form, the nociceptive and inflammatory responses induced by the solid tumor. Moreover, the mechanical antinociception, the thermal hyperalgesia, and the antiedema effect observed in mice treated with chloroquine and healed from malaria can be related to the increase in the serum level of IL-1.
PubMed: 38774541
DOI: 10.1155/2024/3771926 -
ELife Dec 2023Lipophorin is an essential, highly expressed lipid transport protein that is secreted and circulates in insect hemolymph. We hijacked the gene to make it co-express a...
Lipophorin is an essential, highly expressed lipid transport protein that is secreted and circulates in insect hemolymph. We hijacked the gene to make it co-express a single-chain version of antibody 2A10, which binds sporozoites of the malaria parasite . The resulting transgenic mosquitoes show a markedly decreased ability to transmit expressing the circumsporozoite protein to mice. To force the spread of this antimalarial transgene in a mosquito population, we designed and tested several CRISPR/Cas9-based gene drives. One of these is installed in, and disrupts, the pro-parasitic gene and also cleaves wild-type causing the anti-malarial modified version to replace the wild type and hitch-hike together with the drive. Although generating drive-resistant alleles and showing instability in its gRNA-encoding multiplex array, the -based gene drive reached high levels in caged mosquito populations and efficiently promoted the simultaneous spread of the antimalarial allele. This combination is expected to decrease parasite transmission via two different mechanisms. This work contributes to the design of novel strategies to spread antimalarial transgenes in mosquitoes, and illustrates some expected and unexpected outcomes encountered when establishing a population modification gene drive.
Topics: Animals; Mice; Anopheles; Gene Drive Technology; Antimalarials; Mosquito Vectors; RNA, Guide, CRISPR-Cas Systems; Plasmodium falciparum; Plasmodium berghei; Lipoproteins
PubMed: 38051195
DOI: 10.7554/eLife.93142 -
Journal of Vector Borne Diseases Apr 2024The persistent threat of drug resistant malaria demands new cures. Low prevalence of malaria in the Indian state of Kerala compared with other proximal states made us...
BACKGROUND OBJECTIVES
The persistent threat of drug resistant malaria demands new cures. Low prevalence of malaria in the Indian state of Kerala compared with other proximal states made us explore if there is any traditional practice in Kerala which may confer protection against malaria. In this context, our attention was drawn to 'Pathimugam' i.e., Ceasalpinia sappan whose heartwood is used to prepare a red aqueous extract which is a uniquely popular drink in Kerala.
METHODS
Aqueous and methanolic extracts of various organs of C. sappan were prepared and tested against Plasmodium falciparum grown in vitro culture using SYBR Green-I assay. The cytotoxicity of active extracts/fractions was studied using mammalian HeLa cell line. in vivo efficacy was determined using P. berghei ANKA infected mice.
RESULTS
The highest antiplasmodial activities in the alcoholic and aqueous extracts were observed in leaf methanolic extract (IC50 2 μg/ml) and heartwood aqueous extract (IC50 12.5 μg/ml). Ceasalpinia sappan extracts were equipotent against both chloroquine-sensitive Pf3D7 and resistant PfINDO strains and showed suppression of percentage parasitemia in P. berghei infected mice. Activity- guided chromatographic fractionation of aqueous wood extract led to the fortification of antiplasmodial activity (IC50 5 μg/ml).
INTERPRETATION CONCLUSION
Our results establish the antiplasmodial potential of C. sappan and suggest that its regular use might have prophylactic or curative actions that may assist in keeping check on malaria in the Indian state of Kerala.
PubMed: 38634464
DOI: 10.4103/JVBD.JVBD_18_24 -
MBio Apr 2024Remodeling the erythrocyte membrane and skeleton by the malarial parasite is closely associated with intraerythrocytic development. However, the mechanisms underlying...
UNLABELLED
Remodeling the erythrocyte membrane and skeleton by the malarial parasite is closely associated with intraerythrocytic development. However, the mechanisms underlying this association remain unclear. In this study, we present evidence that erythrocytic α-spectrin, but not β-spectrin, was dynamically ubiquitinated and progressively degraded during the intraerythrocytic development of from the ring to the schizont stage. We further observed an upregulated expression of phosphatidylinositol 3-kinase (PfPI3K) in the infected red blood cells during the intraerythrocytic development of the parasite. The data indicated that PfPI3K phosphorylated and activated erythrocytic ubiquitin-protein ligase, leading to increased α-spectrin ubiquitination and degradation during development. We further revealed that inhibition of the activity of PfPI3K impaired development and infectivity in mice. These findings collectively unveil an important mechanism of PfPI3K-ubiquitin-mediated degradation of α-spectrin during the intraerythrocytic development of species. Proteins in the PfPI3K regulatory pathway are novel targets for effective treatment of severe malaria.
IMPORTANCE
is the causative agent of severe malaria that causes millions of deaths globally. The parasite invades human red blood cells and induces a cascade of alterations in erythrocytes for development and proliferation. Remodeling the host erythrocytic cytoskeleton is a necessary process during parasitization, but its regulatory mechanisms remain to be elucidated. In this study, we observed that erythrocytic α-spectrin is selectively degraded after invasion, while β-spectrin remained intact. We found that the α-spectrin chain was profoundly ubiquitinated by E3 ubiquitin ligase and degraded by the 26S proteasome. E3 ubiquitin ligase activity was regulated by phosphatidylinositol 3-kinase (PfPI3K) signaling. Additionally, blocking the PfPI3K-ubiquitin-proteasome pathway in -infected red blood cells reduced parasite proliferation and infectivity. This study deepens our understanding of the regulatory mechanisms of host and malarial parasite interactions and paves the way for the exploration of novel antimalarial drugs.
Topics: Humans; Animals; Mice; Plasmodium falciparum; Spectrin; Erythrocytes; Malaria, Falciparum; Ubiquitin; Phosphatidylinositol 3-Kinase; Ubiquitin-Protein Ligases
PubMed: 38470053
DOI: 10.1128/mbio.03510-23 -
BioMed Research International 2023Emergence of resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need...
BACKGROUND
Emergence of resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need for the development of new and effective antimalarial agents. (L.) link extract has exhibited antiplasmodial activity in many pharmacological studies. To our knowledge, data on its antimalarial efficacy is still very limited. A recent study demonstrated that polar extracts from the plant roots inhibit proliferation in a mouse model. This study further describes the efficacy and safety of a methanolic root extract of the plant as an antimalarial agent by demonstrating its effect on hematological, biochemical, and histological parameters of -infected BALB/c mice.
METHODS
Rane's test, a curative approach, was used to evaluate the antimalarial efficacy of methanolic root extract in -infected BALB/c mice. The effect of the extract on both hematological and biochemical parameters was evaluated using automated analyzers. Kidney, liver, lung, spleen, and brain tissues were harvested from euthanized mice and examined for changes in organ architecture.
RESULTS
This study demonstrates that methanolic root extract of significantly inhibited parasitemia in BALB/c mice ( < 0.01). Infected mice that were treated with the extract depicted a significantly low level of total leucocytes ( < 0.01), red blood cell distribution width ( < 0.01), and a significantly high hemoglobin concentration ( < 0.001) compared to the infected animals that were administered with the vehicle only. The infected animals that were treated with the extract exhibited a significantly low level of urea, creatinine, bilirubin, and alkaline phosphatase ( < 0.05), compared to the infected animals that were given the vehicle only. The level of sodium, potassium and chloride ions, lymphocytes, granulocytes, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein, albumin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total platelets, mean platelet volume (MPV), and platelet distribution width of the infected animals treated with the extract was not significantly different from those of the infected animals that were given the vehicle only ( > 0.05). The extract alleviated organ pathological changes in the infected mice. The extract did not induce any remarkable adverse effect on the growth, hematological, and biochemical parameters of uninfected animals ( > 0.05). In addition, administration of the extract did not alter the gross appearance and histological architecture of the organs, implying that the extract was well tolerated in mice.
CONCLUSIONS
methanolic root extract exhibited good antimalarial activity against and may be safe in mice.
Topics: Mice; Animals; Antimalarials; Plasmodium berghei; Senna Plant; Mice, Inbred BALB C; Alkaline Phosphatase; Plant Extracts
PubMed: 37583959
DOI: 10.1155/2023/8296195 -
The Journal of Veterinary Medical... Sep 2023Malaria needs new strategies for its control. Plasmodium spp., the causative agent of malaria, is transmitted by mosquitoes. These parasites develop into oocysts and...
Malaria needs new strategies for its control. Plasmodium spp., the causative agent of malaria, is transmitted by mosquitoes. These parasites develop into oocysts and sporozoites in the body of the mosquitoes. A deeper understanding of oocysts that produce the infectious form of the parasite, sporozoites, can facilitate the development of novel countermeasures. However, the isolation of Plasmodium oocysts is challenging as these are formed between midgut epithelial cells and basal lamina after gametocytes enter the mosquito's body through blood feeding. Further research on oocysts has been impeded by issues related to oocyst isolation. Therefore, in this study, we injected Plasmodium into mosquitoes-an artificial and unique method-and aimed to clarify how oocysts were formed in mosquitoes after Plasmodium injection and whether free oocysts were formed from the mosquito tissue. Plasmodium berghei (ANKA strain) ookinetes cultured in vitro were injected into the thoracic body cavity (hemocoel) of female and male Anopheles stephensi mosquitoes. Oocysts were formed in the body of female and male mosquitoes at 14 days post injection. In addition, oocysts formed as a result of injection developed into sporozoites, which were infectious to mice. These findings suggest that P. berghei can complete its developmental stage in mosquitoes by injection. Some of the oocysts formed were free from mosquito tissue, and it was possible to collect oocysts with minimal contamination of mosquito tissue. These free oocysts can be used for investigating oocyst proteins and metabolism.
Topics: Male; Female; Animals; Mice; Oocysts; Anopheles; Malaria; Plasmodium berghei
PubMed: 37407494
DOI: 10.1292/jvms.23-0099