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BACKGROUND: Transcriptomics has been used to evaluate immune responses during malaria in diverse cohorts worldwide. However, the high heterogeneity of cohorts and poor generalization of transcriptional signatures reported in each study limit their potential clinical applications. METHODS: We compiled 28 public data sets containing 1556 whole-blood or peripheral blood mononuclear cell transcriptome samples. We estimated effect sizes with Hedge's g value and the DerSimonian-Laird random-effects model for meta-analyses of uncomplicated malaria. Random forest models identified gene signatures that discriminate malaria from bacterial infections or malaria severity. Parasitological, hematological, immunological, and metabolomics data were used for validation. RESULTS: We identified 3 gene signatures: the uncomplicated Malaria Meta-Signature, which discriminates Plasmodium falciparum malaria from uninfected controls; the Malaria or Bacteria Signature, which distinguishes malaria from sepsis and enteric fever; and the cerebral Malaria Meta-Signature, which characterizes individuals with cerebral malaria. These signatures correlate with clinical hallmark features of malaria. Blood transcription modules indicate immune regulation by glucocorticoids, whereas cell development and adhesion are associated with cerebral malaria. CONCLUSIONS: Transcriptional meta-signatures reflecting immune cell responses provide potential biomarkers for translational innovation and suggest critical roles for metabolic regulators of inflammation during malaria.

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Cerebral malaria (CM) pathogenesis is described as a multistep mechanism. In this context, monocytes have been implicated in CM pathogenesis by increasing the sequestration of infected red blood cells to the brain microvasculature. In disease, endothelial activation is followed by reduced monocyte rolling and increased adhesion. Nowadays, an important challenge is to identify potential pro-inflammatory stimuli that can modulate monocytes behavior. Our group have demonstrated that bradykinin (BK), a pro-inflammatory peptide involved in CM, is generated during the erythrocytic cycle of P. falciparum and is detected in culture supernatant (conditioned medium). Herein we investigated the role of BK in the adhesion of monocytes to endothelial cells of blood brain barrier (BBB). To address this issue human monocytic cell line (THP-1) and human brain microvascular endothelial cells (hBMECs) were used. It was observed that 20% conditioned medium from P. falciparum infected erythrocytes (Pf-iRBC sup) increased the adhesion of THP-1 cells to hBMECs. This effect was mediated by BK through the activation of B2 and B1 receptors and involves the increase in ICAM-1 expression in THP-1 cells. Additionally, it was observed that angiotensin-converting enzyme (ACE) inhibitor, captopril, enhanced the effect of both BK and Pf-iRBC sup on THP-1 adhesion. Together these data show that BK, generated during the erythrocytic cycle of P. falciparum, could play an important role in adhesion of monocytes in endothelial cells lining the BBB.

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The study of animal behavior has been carried out for many years in order to understand physiological and pathological factors, so that work with animals could be developed to evaluate animal well-being. The Arouca Law emerged in Brazil, which regulates the use of animals in teaching and research. To further assist in the development and analysis of changes that can cause pain in animals, researchers developed the Grimace Scale, which shows, through assessment, facial changes in animals, allowing researchers to have ways of controlling the animals' distress. Therefore, this work aimed to show the clinical scores and changes of mice when infected with rabies, SARS-COV-2 and cerebral malaria. We showed that animals infected with the pathogens rabies, SARS-COV-2 and cerebral malaria, mainly present weight loss, muscular and postural changes. Finally, understand the importance of recognizing changes in behavior, enabling the relief of pain and suffering in animals used in research. The premise of animal welfare must always prevail over the study.

O estudo do comportamento animal acontece a muitos anos afim de entender os fatores fisiológicos e patológicos, para que os trabalhos com animais sejam desenvolvidos avaliando o bem estar animal, para tanto surge no Brasil a Lei Arouca que regulamenta a utilização de animais em ensino e pesquisa. Para auxiliar ainda no desenvolvimento e análise das alterações que podem causar dor nos animais os pesquisadores desenvolveram a Escala de Grimace, que mostra por meio de avaliação das alterações faciais dos animais, permitindo que os pesquisadores tenham formas de controlar o distresse dos animais. Diante disso, este trabalho teve como objetivo mostrar os escore clínicos e alterações dos camundongos quando infectados com raiva, SARS-COV-2 e Malária cerebral. Evidenciamos que os animais infectados com os patógenos da raiva, SARS-COV-2 e Malária cerebral, apresentam principalmente perda de peso, alteração muscular e postural. Por fim, compreender a importância de reconhecer as alterações de comportamento, possibilitando o alivio da dor e sofrimento dos animais usados em pesquisa. A premissa do bem-estar animal deve sempre prevalecer sobre o estudo.

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Every year, thousands of children, particularly those under 5 years old, die because of cerebral malaria (CM). Following conventional treatment, approximately 25% of surviving individuals have lifelong severe neurocognitive sequelae. Therefore, improved conventional therapies or effective alternative therapies that prevent the severe infection are crucial. Omega-3 (Ω-3) polyunsaturated fatty acids (PUFAs) are known to have antioxidative and anti-inflammatory effects and protect against diverse neurological disorders, including Alzheimer's and Parkinson's diseases. However, little is known regarding the effects of Ω-3 PUFAs against parasitic infections. In this study, C57BL/6 mice received supplemental treatment of a fish oil rich in the Ω-3 PUFA, docosahexaenoic acid (DHA), which was started 15 days prior to infection with Plasmodium berghei ANKA and was maintained until the end of the study. Animals treated with the highest doses of DHA, 3.0 and 6.0 g/kg body weight, had 60 and 80% chance of survival, respectively, while all nontreated mice died by the 7th day postinfection due to CM. Furthermore, the parasite load during the critical period for CM development (5th to 11th day postinfection) was controlled in treated mice. However, after this period all animals developed high levels of parasitemia until the 20th day of infection. DHA treatment also effectively reduced blood-brain barrier (BBB) damage and brain edema and completely prevented brain hemorrhage and vascular occlusion. A strong anti-inflammatory profile was observed in the brains of DHA-treated mice, as well as, an increased number of neutrophil and reduced number of CD8+ T leukocytes in the spleen. Thus, this is the first study to demonstrate that the prophylactic use of DHA-rich fish oil exerts protective effects against experimental CM, reducing the mechanical and immunological events caused by the P. berghei ANKA infection.

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Newly emerging data suggest that several neutrophil defense mechanisms may play a role in both aggravating and protecting against malaria. These exciting findings suggest that the balance of these cells in the host body may have an impact on the pathogenesis of malaria. To fully understand the role of neutrophils in severe forms of malaria, such as cerebral malaria (CM), it is critical to gain a comprehensive understanding of their behavior and functions. This study investigated the dynamics of neutrophil and T cell responses in C57BL/6 and BALB/c mice infected with Plasmodium berghei ANKA, murine models of experimental cerebral malaria (ECM) and non-cerebral experimental malaria, respectively. The results demonstrated an increase in neutrophil percentage and neutrophil-T cell ratios in the spleen and blood before the development of clinical signs of ECM, which is a phenomenon not observed in the non-susceptible model of cerebral malaria. Furthermore, despite the development of distinct forms of malaria in the two strains of infected animals, parasitemia levels showed equivalent increases throughout the infection period evaluated. These findings suggest that the neutrophil percentage and neutrophil-T cell ratios may be valuable predictive tools for assessing the dynamics and composition of immune responses involved in the determinism of ECM development, thus contributing to the advancing of our understanding of its pathogenesis.

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This review will provide a better understanding of a set of signs known as malarial retinopathy. The discovery of this retinopathy in association with cerebral malaria is important because it best distinguishes patients with true cerebral malaria from those with coma due to other causes and incidental Plasmodium falciparum parasitemia. Identifying a comatose patient with malarial retinopathy increases the likelihood of an accurate severe or cerebral malaria diagnosis. As the World Health Organization does not specify that malarial retinopathy is one of the factors included in determining a cerebral malaria diagnosis, there are significant false-positive diagnoses of cerebral malaria. Once a cerebral malaria diagnosis is assigned, other possibilities and treatments are often excluded making an incorrect diagnosis of cerebral malaria potentially fatal. However, Plasmodium falciparum may also contribute to coma in some children with retinopathy-negative cerebral malaria, as this group is still not clinically well characterized, so all children with the WHO definition of cerebral malaria should be treated for severe malaria. Nevertheless, by raising awareness about malarial retinopathy, there could be a greater potential to accurately diagnose cerebral malaria and thus achieve more positive patient outcomes in the future. This literary review aims to raise awareness of the retinopathy by defining what it is to non-experts, explaining its pathology, clarifying the techniques needed to accurately diagnose malarial retinopathy, as well as the barriers that prevent clinicians from providing a proper diagnosis in malaria-endemic regions; and finally, discuss future directions to continue the study of malarial retinopathy.

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BACKGROUND Cerebral malaria (CM) is a severe immunovasculopathy caused for Plasmodium falciparum infection, which is characterised by the sequestration of parasitised red blood cells (pRBCs) in brain microvessels. Previous studies have shown that some terpenes, such as perillyl alcohol (POH), exhibit a marked efficacy in preventing cerebrovascular inflammation, breakdown of the brain-blood barrier (BBB) and brain leucocyte accumulation in experimental CM models. OBJECTIVE To analyse the effects of POH on the endothelium using human brain endothelial cell (HBEC) monolayers co-cultured with pRBCs. METHODOLOGY The loss of tight junction proteins (TJPs) and features of endothelial activation, such as ICAM-1 and VCAM-1 expression were evaluated by quantitative immunofluorescence. Microvesicle (MV) release by HBEC upon stimulation by P. falciparum was evaluated by flow cytometry. Finally, the capacity of POH to revert P. falciparum-induced HBEC monolayer permeability was examined by monitoring trans-endothelial electrical resistance (TEER). FINDINGS POH significantly prevented pRBCs-induced endothelial adhesion molecule (ICAM-1, VCAM-1) upregulation and MV release by HBEC, improved their trans-endothelial resistance, and restored their distribution of TJPs such as VE-cadherin, Occludin, and JAM-A. CONCLUSIONS POH is a potent monoterpene that is efficient in preventing P. falciparum-pRBCs-induced changes in HBEC, namely their activation, increased permeability and alterations of integrity, all parameters of relevance to CM pathogenesis.

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Plasmodium berghei ANKA (PbA) infection in mice resembles several aspects of severe malaria in humans, such as cerebral malaria and acute respiratory distress syndrome. Herein, the effects of N-(coumarin-3-yl)cinnamamide (M220) against severe experimental malaria have been investigated. Treatment with M220 proved to protect cognitive abilities and lung function in PbA-infected mice, observed by an object recognition test and spirometry, respectively. In addition, treated mice demonstrated decreased levels of brain and lung inflammation. The production and accumulation of microglia, and immune cells that produce the inflammatory cytokines TNF and IFN-γ, decreased, while the production of the anti-inflammatory cytokine IL-10 by innate and adaptive immune cells was enhanced. Treatment with M220 promotes immunomodulatory, neuroprotective, and lung function-preserving effects during experimental severe malaria. Therefore, it may be an interesting therapeutic candidate to treat severe malaria effects.

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Malaria is an infectious disease widespread in underdeveloped tropical regions. The most severe form of infection is caused by Plasmodium falciparum, which can lead to development of cerebral malaria (CM) and is responsible for deaths and significant neurocognitive sequelae throughout life. In this context and considering the emergence and spread of drug-resistant P. falciparum isolates, the search for new antimalarial candidates becomes urgent. ß-carbolines alkaloids are good candidates since a wide range of biological activity for these compounds has been reported. Herein, we designed 20 chemical entities and performed an in silico virtual screening against a pool of P. falciparum molecular targets, the Brazilian Malaria Molecular Targets (BRAMMT). Seven structures showed potential to interact with PfFNR, PfPK7, PfGrx1, and PfATP6, being synthesized and evaluated for in vitro antiplasmodial activity. Among them, compounds 3−6 and 10 inhibited the growth of the W2 strain at µM concentrations, with low cytotoxicity against the human cell line. In silico physicochemical and pharmacokinetic properties were found to be favorable for oral administration. The compound 10 provided the best results against CM, with important values of parasite growth inhibition on the 5th day post-infection for both curative (67.9%) and suppressive (82%) assays. Furthermore, this compound was able to elongate mice survival and protect them against the development of the experimental model of CM (>65%). Compound 10 also induced reduction of the NO level, possibly by interaction with iNOS. Therefore, this alkaloid showed promising activity for the treatment of malaria and was able to prevent the development of experimental cerebral malaria (ECM), probably by reducing NO synthesis.

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RESUMEN Plasmodium vivax es la especie más común en la Amazonía peruana y ocasiona el 81% del total de casos de malaria. Presentamos el caso de un paciente adulto varón con malaria cerebral por Plasmodium vivax, que inicia con malestar general y fiebre, luego presenta convulsiones más de dos veces al día con pérdida de consciencia y limitación funcional motora. Se le realiza gota gruesa donde se observa trofozoítos de Plasmodium vivax y depresión de las tres series sanguíneas. Se inicia tratamiento con artesunato y clindamicina por cinco días, se le transfunde un paquete globular, y continua con primaquina por siete días. El paciente muestra mejoría clínica con secuela neurológica en extremidad inferior izquierda.

ABSTRACT Plasmodium vivax causes 81% of all malaria cases and is the most common species in the Peruvian Amazon. We present the case of a male patient with cerebral malaria caused by Plasmodium vivax, who had general malaise and fever, and then presented seizures more than twice a day with loss of consciousness and motor functional limitation. Plasmodium vivax trophozoites were detected by thick blood smear, besides, we also observed low counts of all three blood cell types. Treatment began with artesunate and clindamycin for five days, then one unit of packed red blood cells was transfused; treatment continued with primaquine for seven days. The patient showed clinical improvement with neurological sequelae in one lower limb.

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La malaria representa un grave problema de salud pública en el país, por su morbilidad y mortalidad. Es importante conocer la patogenia y las manifestaciones clínicas de la malaria grave, en especial revisar el ciclo biológico del parásito, ya que la enfermedad comienza con la ruptura del esquizonte maduro, siendo las primeras manifestaciones clínicas: fiebre y anemia. La infección por Plasmodium falciparum es más severa y es mediada por el fenómeno de secuestro en la microvasculatura venosa profunda, mientras que Plasmodium vivax causa una enfermedad debilitante, rara vez mortal, pero en oportunidades se presentan manifestaciones graves que causan la muerte del paciente. Malaria grave se define por la presencia de signos clínicos y de laboratorio de disfunción de órganos vitales como sistema nervioso central, riñón, gastrointestinal, vías respiratorias y alteraciones hemodinámicas; la cual requiere el rápido reconocimiento de la enfermedad y del grado de severidad. Se debe hacer un manejo de índole general y prestar especial atención a la terapia antimalárica oportuna con Artesunato, primera línea en malaria grave, o Arthemeter o Quinina con Clindamicina según los protocolos nacionales e internacionales, para lograr una evolución satisfactoria. En consecuencia, es un reto enfrentar esta entidad y obliga a la constante actualización en las diferentes opciones cónsonas con las diferentes especies de Plasmodium patógeno.

Malaria represents a serious public health problem in the country, due to its morbidity and mortality. It is of most importance to know the pathogenesis and clinical manifestations of severe malaria, particularly to review the biological cycle of the parasite. The disease begins with the rupture of the mature schizont, with the first clinical manifestations being fever and anemia. Plasmodium falciparum infection is more severe and is mediated by the phenomenon of sequestration in the deep venous microvasculature, while Plasmodium vivax causes a debilitating disease, rarely fatal, but sometimes serious manifestations occur that cause the death of the patient. Severe malaria is defined by the presence of clinical and laboratory signs of dysfunction of vital organs such as the central nervous system, kidney, gastrointestinal, respiratory tract, and pathological hemodynamic changes that requires rapid disease recognition and degree of severity. General management and timely antimalarial therapy with Artesunate, first line in severe malaria, or Arthemeter, or Quinine with Clindamycin following national and international protocols, achieve a favorable outcome. Consequently, it is a challenge to face this entity and requires constant updating in the different options consistent with the different species of pathogenic Plasmodium.

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Chloroquine (CQ) was the most effective and widely used drug for the prophylaxis and treatment of severe and non-severe malaria. Although its prophylactic use has led to resistance to P. falciparum in all endemic countries, CQ still remains the drug of choice for the treatment of vivax malaria. Otherwise, the speed in which parasite resistance to available antimalarials rises and spreads in endemic regions points to the urgent need for the development of new antimalarials. Quinoline derivatives have been used as a tool in the search for new drugs and were investigated in the present study in an attempt to produce a HIT compound to avoid the cerebral malarial (CM). Seven compounds were synthesized, including three quinoline derivate salts. The cytotoxicity and antiplasmodial activity were assayed in vitro, highlighting compound 3 as a HIT, which also showed interaction with ferriprotoporphyrin IX similarly to CQ. Physicochemical and pharmacokinetic properties of absorption were found to be favorable when analyzed in silico. The in vivo assays, using the experimental cerebral malaria (ECM) model, showed important values of parasite growth inhibition on the 7th day-post infection (Q15 15 mg/kg: 76.9%, Q30 30 mg/kg: 90,1% and Q50 50 mg/kg: 92,9%). Compound 3 also showed significant protection against the development of CM, besides hepatic and renal parameters better than CQ. In conclusion, this quinoline derivative demonstrated promising activity for the treatment of malaria and was able to avoid the development of severe malaria in mice.

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BACKGROUND: Cerebral malaria is one of the most severe complications attributed to protozoal infection by Plasmodium falciparum, gaining prominence in children mortality rates in endemic areas. This condition has a complex pathogenesis associated with behavioral, cognitive and motor sequels in humans and current antimalarial therapies have shown little effect in those aspects. Natural products with antioxidant and anti-inflammatory properties have become a valuable alternative therapeutic option in the treatment of distinct conditions. In this context, this study investigated the neuroprotective effect of Euterpe oleracea (açai) enriched diet during the development of experimental cerebral malaria induced by the inoculation of Swiss albino mice with Plasmodium berghei ANKA strain. METHODS: After Plasmodium infection, animals were maintained on a feeding with Euterpe oleracea enriched ration and parameters such as survival curve, parasitemia and body weight were routinely monitored. The present study has also evaluated the effect of açai-enriched diet on the blood-brain barrier leakage, histological alterations and neurocognitive impairments in mice developing cerebral malaria. RESULTS: Our results demonstrate that between 7th-19th day post infection the survival rate of the group treated with açai enriched ration was higher when compared with Plasmodium-infected mice in which 100% of mice died until the 11th days post-infection, demonstrating that açai diet has a protective effect on the survival of infected treated animals. The same was observed in the brain vascular extravasation, where Evans blue dye assays showed significantly less dye extravasation in the brains of Plasmodium-infected mice treated with açai enriched ration, demonstrating more preserved blood-brain barrier integrity. Açai-enriched diet also attenuate the histopathological alterations elicited by Plasmodium berghei infection. We also showed a decrease of the neurological impairments arising from the exposure of cerebral parenchyma in the group treated with açai diet, ameliorating motor and neuropsychiatric changes, analyzed through the SHIRPA protocol. CONCLUSION: With these results, we conclude that the treatment with açai enriched ration decreased the mortality of infected animals, as well as protected the blood-brain barrier and the neurocognitive deficits in Plasmodium-infected animals.

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BACKGROUND Cerebral malaria is a lethal complication of Plasmodium falciparum infections in need of better therapies. Previous work in murine experimental cerebral malaria (ECM) indicated that the combination of artemether plus intraperitoneal whole blood improved vascular integrity and increased survival compared to artemether alone. However, the effects of blood or plasma transfusion administered via the intravenous route have not previously been evaluated in ECM. OBJECTIVES To evaluate the effects of intravenous whole blood compared to intravenous plasma on hematological parameters, vascular integrity, and survival in artemether-treated ECM. METHODS Mice with late-stage ECM received artemether alone or in combination with whole blood or plasma administered via the jugular vein. The outcome measures were hematocrit and platelets; plasma angiopoietin 1, angiopoietin 2, and haptoglobin; blood-brain barrier permeability; and survival. FINDINGS Survival increased from 54% with artemether alone to 90% with the combination of artemether and intravenous whole blood. Intravenous plasma lowered survival to 18%. Intravenous transfusion provided fast and pronounced recoveries of hematocrit, platelets, angiopoietins levels and blood brain barrier integrity. MAIN CONCLUSIONS The outcome of artemether-treated ECM was improved by intravenous whole blood but worsened by intravenous plasma. Compared to prior studies of transfusion via the intraperitoneal route, intravenous administration was more efficacious.

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BACKGROUND: Venezuela accounted for 55% of the cases and 73% of the malaria deaths in the Americas in 2019. Bolivar state, in the southeast, contributes > 60% of the country's Plasmodium vivax and Plasmodium falciparum cases every year. This study describes the clinical-epidemiological characteristics of clinical malaria patients in this high-transmission area. METHODS: A prospective study was conducted on patients seeking medical attention in three medical centres in the state capital, Ciudad Bolivar, between June and October 2018. Malaria diagnosis was carried out using microscopy following national standards. Malaria-positive patients were examined for clinical symptoms, and haematological tests were performed at the time of diagnosis. Patients were followed up by telephone to evaluate malaria recurrences. RESULTS: Out of 287 patients, 200 (69.7%) were positive for P. vivax, 69 (24%) for P. falciparum, and 18 (6.3%) had mixed (P. vivax/P. falciparum) infections. Patients' median age was 33 years (IQR 20), 168 (69%) were men, and 40% practiced gold mining as the main occupation. Fever (96.5%), chills (91.3%), and headaches (90.6%) were the most frequent symptoms. At least one symptom associated with severe malaria was observed in 69 out of 161 patients with complete clinical evaluation (42.9%). Plasmodium vivax infections were found in 42 out of 69 (60.9%) severe cases; by contrast, P. falciparum and mixed malaria caused 34.8% (24/69) and 4.4% (3/69) of infections, respectively. Two patients died of cerebral malaria. Mean hemoglobin was lower in the patients infected with P. falciparum than those infected with P. vivax. Regardless of the parasite causing the infection, patients presented high levels of total bilirubin, aminotransferases (AST, ALT), and lactate dehydrogenase (LDH). Out of the 142 patients followed up by phone for three months (49.5% of the 287 patients), 35 (24.7%) reported recurrences. CONCLUSIONS: The high malaria prevalence among young male adults practicing gold mining suggests that this occupation is a significant risk factor. The unexpected high prevalence of P. vivax patients with at least one criteria of severe clinical disease is a matter of concern. Whether it is the result of a lack of timely diagnosis and effective treatment should be explored.

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Cerebral malaria is characterized by permanent cognitive impairments in Plasmodium-infected children. Antimalarial therapies show little effectiveness to avoid neurological deficits and brain tissue alterations elicited by severe malaria. Melatonin is a well-recognized endogenous hormone involved in the control of brain functions and maintenance of blood-brain barrier integrity. The current study has evaluated the effect of melatonin on the histological alterations, blood-brain barrier leakage, and neurocognitive impairments in mice developing cerebral malaria. Swiss mice infected with Plasmodium berghei ANKA strain was used as cerebral malaria model. Melatonin treatment (5 and 10 mg/kg) was performed for four consecutive days after the infection, and data have shown an increased survival rate in infected mice treated with melatonin. It was also observed that melatonin treatment blocked brain edema and prevented the breakdown of blood-brain barrier induced by the Plasmodium infection. Furthermore, hematoxylin and eosin staining revealed that melatonin mitigates the histological alterations in Plasmodium-infected animals. Melatonin was also able to prevent motor and cognitive impairments in infected mice. Taken together, these results show for the first time that melatonin treatment prevents histological brain damages and neurocognitive alterations induced by cerebral malaria.

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Autoantibodies are frequently reported in patients with malaria, but whether they contribute to protection or to pathology is an issue of debate. A large body of evidence indicates that antibodies against host-self components are associated to malaria clinical outcomes such as cerebral malaria, renal dysfunction and anemia. Nonetheless, self-reactive immunoglobulins induced during an infection can also mediate protection. In light of these controversies, we summarize here the latest findings in our understanding of autoimmune responses in malaria, focusing on Plasmodium falciparum and Plasmodium vivax. We review the main targets of self-antibody responses in malaria as well as the current, but still limited, knowledge of their role in disease pathogenesis or protection.

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BACKGROUND: Cerebral malaria is the most severe form of infection with Plasmodium falciparum characterized by a highly inflammatory response. This systematic review aimed to investigate the association between TNF-α levels and cerebral malaria. METHODS: This review followed the Preferred Reporting of Systematic Review and Meta-analyses (PRISMA) guidelines. The search was performed at PubMed, LILACS, Scopus, Web of Science, The Cochrane Library, OpenGrey and Google Scholar. We have included studies of P. falciparum-infected humans with or without cerebral malaria and TNF-α dosage level. All studies were evaluated using a risk of bias tool and the GRADE approach. RESULTS: Our results have identified 2338 studies, and 8 articles were eligible according to this systematic review inclusion criteria. Among the eight articles, five have evaluated TNF- α plasma dosage, while two have evaluated at the blood and one at the brain (post-Morten). Among them, only five studies showed higher TNF-α levels in the cerebral malaria group compared to the severe malaria group. Methodological problems were identified regarding sample size, randomization and blindness, but no risk of bias was detected. CONCLUSION: Although the results suggested that that TNF-α level is associated with cerebral malaria, the evidence is inconsistent and imprecise. More observational studies evaluating the average TNF-alpha are needed.

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Cerebral malaria (CM) is a clinical syndrome involving irreversible and lethal signs of brain injury associated to infection by parasites of the genus Plasmodium. The pathogenesis of CM derives from infection-induced proinflammatory cytokines associated with cytoadherence of parasitized red blood cells to brain microvasculature. Glycoconjugates are very abundant in the surface of Plasmodium spp., and are critical mediators of parasite virulence in host-pathogen interactions. Herein, we show that 6-Diazo-5-oxo-L-norleucine (DON) therapeutically used for blocking hexosamine biosynthetic pathway leads to recovery in experimental murine cerebral malaria. DON-induced protection was associated with decreased parasitism, which severely reduced Plasmodium transmission to mosquitoes. These findings point to a potential use of DON in combination therapies against malaria.