Malaria Drug Research Articles

Computational approach for decoding malaria drug targets from single-cell transcriptomics and finding potential drug molecule

Malaria is a deadly disease caused by Plasmodium parasites. While potent drugs are available in the market for malaria treatment, over the years, Plasmodium parasites have successfully developed resistance against many, if not all, front-line drugs. This poses a serious threat to global malaria eradication efforts, and the continued discovery of new drugs is necessary to tackle this debilitating disease. With recent unprecedented progress in machine learning techniques, single-cell transcriptomic in Plasmodium offers a powerful tool for identifying crucial proteins as a drug target and subsequent computational prediction of potential drugs. In this study, We have implemented a mutual-information-based feature reduction algorithm with a classification algorithm to select important proteins from transcriptomic datasets (sexual and asexual stages) for Plasmodium falciparum and then constructed the protein-protein interaction (PPI) networks of the proteins. The analysis of this PPI network revealed key proteins vital for the survival of Plasmodium falciparum. Based on the function and identification of a few strong binding sites on a couple of these key proteins, we computationally predicted a set of potential drug molecules using a deep learning-based technique. Lead drug molecules that satisfy ADMET and drug-likeliness properties are finally reported out of the generated drugs. The study offers a general computational pipeline to identify crucial proteins using scRNA-seq data sets and further development of potential new drugs.

Determinants of Prevalence and Factors Associated with Anemia among Pregnant Women in Gambia: A Multivariate Analysis using DHS Data

Background Anemia is a prevalent public health concern in The Gambia and other developing nations. While previous studies relied on binary logistic regression, the Multinomial Survey Logistic Regression Model was developed to address complexities in survey design, including sampling weights, stratification, and clustering. Multiple Imputation with Chained Equations (MICE) was employed to address missing data in variables such as anemia level, contraceptive use, and malaria drug intake during pregnancy. Aim/Objective This study aims to determine the prevalence and factors of anemia among pregnant women across eight local government areas in The Gambia. The research focuses on Kanifing, Kuntaur, Mansakonko, Kerewan, Janjanbureh, Basse, Brikama, and Banjul. Given the limited research on anemia among pregnant women in The Gambia, there is a need for further investigation into this topic. Methods MICE were utilized to address missing data due to their validity in handling uncertainty. This method generates multiple reasonable datasets for imputation and analyzes them accurately. A survey logistic regression model was employed to assess data fitness, considering the complex sample design. Anemia levels were measured among 11,865 pregnant women aged 15 to 49 using a systematic questionnaire. The multinomial survey logistic regression model was utilized to account for sampling weights, stratification, and clustering, relaxing the premise of observation independence violated by conventional logistic regression. Results The study involved 11,865 expectant mothers, revealing mild, moderate, and severe cases of anemia with a prevalence of 44.6%. Factors associated with anemia included place of residence, local government area, contraceptive use, age, literacy level, and current pregnancy status. Conclusion Socio-economic, demographic, and environmental factors significantly impact anemia levels among reproductive women in The Gambia. Addressing factors such as place of residence, local government areas, contraceptive use, literacy level, and current pregnancy status is crucial in mitigating anemia risk. Government initiatives, such as improving access to sanitation facilities and offering free check-ups, could effectively address this public health concern.

An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds.

A revamped in vitro compound identification and activity profiling approach is required to meet the large unmet need for new anti-malarial drugs to combat parasite drug resistance. Although compound hit identification utilizing high-throughput screening of large compound libraries is well established, the ability to rapidly prioritize such large numbers for further development is limited. Determining the speed of action of anti-malarial drug candidates is a vital component of malaria drug discovery, which currently occurs predominantly in lead optimization and development. This is due in part to the capacity of current methods which have low throughput due to the complexity and labor intensity of the approaches. Here, we provide an adaptable screening paradigm utilizing automated high content imaging, including the development of an automated schizont maturation assay, which collectively can identify anti-malarial compounds, classify activity into fast and slow acting, and provide an indication of the parasite stage specificity, with high-throughput capability. By frontloading these critical biological parameters much earlier in the drug discovery pipeline, it has the potential to reduce lead compound attrition rates later in the development process. The capability of the approach in its alternative formats is demonstrated using three Medicines for Malaria Venture open access compound "boxes," namely Pathogen Box (malaria set-125 compounds), Global Health Priority Box [Malaria Box 2 (80 compounds) and zoonotic neglected diseases (80 compounds)], and the Pandemic Response Box (400 compounds). From a total of 685 compounds tested, 79 were identified as having fast ring-stage-specific activity comparable to that of artemisinin and therefore of high priority for further consideration and development.

Ligand-based pharmacophore modeling, virtual screening, and molecular dynamics simulations of Pfhsp90 fingerprints in Plasmodium malaria treatment

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted the WHO to recommend prevention strategies such as using antimalarial drugs. However, these strategies have been ineffective because of antimalarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACT clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious antimalarial drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drug target, this study uses it to discover more efficacious antimalarial drugs. An in silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using a molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC20 database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and nine of them satisfied the requirements. The nine ZINC20 compounds were docked with PfHsp90 using the PyRx software version 0.8 to understand their interactions. From the molecular docking results, ZINC09060002 (−8.2 kcal/mol), ZINC72133064 (−7.8 kcal/mol), ZINC72163401 (−7.7 kcal/mol), ZINC72358537 (−8.1 kcal/mol), and ZINC72358557 (−7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (−7.5 kcal/mol). The stability of these molecularly docked protein–inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 and 400 ng/mL. In this regard, the three PfHsp90 inhibitors can be further developed as potential antimalarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.

Ternary structure of Plasmodium vivaxN-myristoyltransferase with myristoyl-CoA and inhibitor IMP-0001173.

Plasmodium vivax is a major cause of malaria, which poses an increased health burden on approximately one third of the world's population due to climate change. Primaquine, the preferred treatment for P. vivax malaria, is contraindicated in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic cause of hemolytic anemia, that affects ∼2.5% of the world's population and ∼8% of the population in areas of the world where P. vivax malaria is endemic. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducted a structure-function analysis of P.vivax N-myristoyltransferase (PvNMT) as part of efforts to develop alternative malaria drugs. PvNMT catalyzes the attachment of myristate to the N-terminal glycine of many proteins, and this critical post-translational modification is required for the survival of P. vivax. The first step is the formation of aPvNMT-myristoyl-CoA binary complex that can bind to peptides. Understanding how inhibitors prevent protein binding will facilitate the development of PvNMT as a viable drug target. NMTs are secreted in all life stages of malarial parasites, making them attractive targets, unlike current antimalarials that are only effective during the plasmodial erythrocytic stages. The 2.3 Å resolution crystal structure of the ternary complex of PvNMT with myristoyl-CoA and a novel inhibitor is reported. One asymmetric unit contains two monomers. The structure reveals notable differences between the PvNMT and human enzymes and similarities to other plasmodial NMTs that can be exploited to develop new antimalarials.

Anaphylactic Reaction to Penicillin in Malaria-Infected Patients: A Case Study and Implications for Clinical Management

Malaria remains a significant global health challenge, often necessitating a combination of antimalarial and antibiotic treatments to manage both the primary infection and secondary bacterial complications. This review focuses on a critical case study involving a 35-year-old male with recurrent malaria who experienced a severe anaphylactic reaction to penicillin, highlighting the complex interplay between malaria management and drug allergies. The patient, already compromised by malaria, developed anaphylaxis shortly after receiving penicillin for a suspected bacterial infection. Despite immediate treatment, including epinephrine, antihistamines, and corticosteroids, the patient’s condition worsened due to the exacerbation of symptoms of malaria, leading to a fatal outcome. This case underscores the diagnostic and management challenges of drug allergies in malaria-infected patients, emphasizing the need for improved allergy assessment protocols, better training for healthcare providers, and enhanced patient education. The review advocates for the development of comprehensive allergy management strategies, improved allergy history documentation, and ongoing research to refine drug allergy testing and treatment protocols. Effective management of drug allergies, particularly in complex infection scenarios, is essential for optimizing patient safety and treatment efficacy. Keywords: Anaphylaxis, Penicillin Allergy, Malaria, Drug Reactions, Allergy Management, Clinical Protocols.

I isolate compounds in local plants in search of new malaria drugs

I isolate compounds in local plants in search of new malaria drugs

The Role of the Plasmodium falciparum Chloroquine Resistance Transporter Gene in Malaria Drug Resistance and its implication on malaria control in Africa

The Role of the Plasmodium falciparum Chloroquine Resistance Transporter Gene in Malaria Drug Resistance and its implication on malaria control in Africa

The characteristic structural and functional dynamics of P. falciparum DHFR binding with pyrimidine chemotypes implicate malaria therapy design

Dihydrofolate reductase (DHFR) enzyme regulates de-novo folate synthesis in Plasmodium falciparum, hence a critical malaria drug target. Pyrimethamine inhibits DHFR, but resistance and lack of cross-species activity are key challenges. Therefore, this study is set to investigate more potent nitrogenous heterocyclic compounds against DHFR. Docking and MD simulations were employed to gain insight into the compounds’ binding free energies and conformational stabilities, while cross-species activity was determined using sequence alignment. Among the 500 screened compounds, PMD_01 (−12.2 kcal/mol), PMD_02 (−11.1 kcal/mol), PMD_03 (−10.7 kcal/mol), and PMD_04 (−10.7 kcal/mol) have the highest binding affinities against pfDHFR compared to pyrimethamine (−7.9 kcal/mol). Critical amino acids for binding interactions in the active site of pfDHFR include Leu45, Thr107, Ile164, and Thr170. PMD-bound systems showed higher binding free energy than pyrimethamine, except PMD_03. Hydrogen bonding interactions with Gly159, Ser101, Ser104, Ser160, Ile157, and Lys48 played significant roles in the binding interaction of these compounds as opposed to Asp53 in pyrimethamine. The four systems converged around 1.90 Å RMSD and showed more stability than pyrimethamine-bound and unbound pfDHFR. The pocket's residues across the four plasmodia were highly conserved, but Phe116 and Ile164 replaced Met in P. knowlesi and Tyr in the other species. PMD_01, PMD_02, PMD_03, and PMD_04 showed promising inhibition against pfDHFR and are, thus, potential antimalarial agents against plasmodia DHFR homologues.

Identification of the histone acetyltransferase gene family in the Artemisia annua genome.

As the most effective therapeutic drug for malaria, artemisinin can only be extracted from Artemisia annua L., which is sensitive to the surrounding growing habitat. Histone acetyltransferases (HATs) contain acetyl groups, which modulate mRNA transcription and thereby regulate plant environmental adaptation. Comprehensive analyses of HATs have been performed in many plants, but systematic identification of HATs in medicinal plants is lacking. In the present study, we identified 11 AaHATs and characterized these genes into four classes according to their conserved protein structures. According to the phylogenetic analysis results, potential functions of HAT genes from Arabidopsis thaliana, Oryza sativa, and A. annua were found. According to our results, AaHAT has a highly conserved evolutionary history and is rich in highly variable regions; thus, AaHAT has become a comparatively ideal object of medical plant identification and systematic study. Moreover, motifs commonly present in histone acetyltransferases in the A. annua genome may be associated with functional AaHATs. AaHATs appear to be related to gene-specific functions. AaHATs are regulated by cis-elements, and these genes may affect phytohormone responsiveness, adaptability to stress, and developmental growth. We performed expression analyses to determine the potential roles of AaHATs in response to three environmental stresses. Our results revealed a cluster of AaHATs that potentially plays a role in the response of plants to dynamic environments.

Distribution of Malaria Infection Among Different Genotypes in Three Senatorial Zones of Taraba State Nigeria

Malaria infection is recognized as a severe public health problem linked to most cases of morbidity and mortality in malaria endemic areas. The study was used to determine the distribution of malaria infection among the different genotypes in three senatorial zones in Taraba state. The study employed a community and laboratory based cross sectional study. The electrophoresis machine was used to determine the genotypes of the research subjects while Rapid diagnostic technique and the gold standard microscopy was used to determine the prevalence of malaria infection. The haematology auto-analyzer (Sysmex XTI 2000) was used to determine the haematological parameters of the subjects. A total of 3084 blood samples was obtained by venepuncture. The distribution of the genotypes are AA 1721 (55.8%), AS 966 (31.3%) and SS 397 (12.9%). The overall prevalence of malaria was 620 (20.1%). Malaria infection was highest in the southern senatorial zone (29.1%) than in the north and central zones (p<0.05). Infection was high with the males (21.2%), age-related malaria infection was significant (p<0.05) with age 1-10yrs recording the highest infection (28.0%). No significant difference (p>0.00) was recorded in the marital status of the patient with the widows/widower having 23.4% while degree of infection was significant for education-related infection (p<0.05) with the non-educated subjects recording highest infection (34.4%). Occupational related prevalence was significant (p<0.05) with high infection among traders (162 (28.7%). Significant difference was recorded in the marital status with the widow/widower recording a high prevalence of malaria 112 (23.4%). Our finding in the current study confirm that malaria remains a major challenge and there is need for periodic prophylactic administration of malaria drugs in the treatment regime of sickle cell anaemia patients. Keywords: Malaria infection, genotypes, distribution, senatorial zones, Taraba State, Nigeria

Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development.

Malaria drug research and development efforts have resurged in the last decade following the decelerating rate of mortality and malaria cases in endemic regions. The inefficiency of malaria interventions is largely driven by the spreading resistance of the Plasmodium falciparum parasite to current drug regimens and that of the malaria vector, the Anopheles mosquito, to insecticides. In response to the new eradication agenda, drugs that act by breaking the malaria transmission cycle (transmission-blocking drugs), which has been recognized as an important and additional target for intervention, are being developed. These drugs take advantage of the susceptibility of Plasmodium during population bottlenecks before transmission (gametocytes) and in the mosquito vector (gametes, zygotes, ookinetes, oocysts, sporozoites). To date, compounds targeting stage V gametocytes predominate in the chemical library of transmission-blocking drugs, and some of them have entered clinical trials. The targeting of Plasmodium mosquito stages has recently renewed interest in the development of innovative malaria control tools, which hold promise for the application of compounds effective at these stages. In this review, we highlight the major achievements and provide an update on the research of transmission-blocking drugs, with a particular focus on their chemical scaffolds, antiplasmodial activity, and transmission-blocking potential.

Haematological Derangements Due to Plasmodium falciparum Among Sickle Cell Anaemia Patients in Taraba State Nigeria

Malaria infection is recognized as a severe public health problem linked to most cases of morbidity and mortality in malaria endemic areas. The study was used to determine the hematological derangement of plasmodium falciparum among sickle cell anaemia patients in Taraba state. The study employed a community and laboratory based cross sectional study. The findings shows that malaria infection was highest in the southern senatorial zone (29.1%) than in the north and central zones (p<0.05). Infection was high with the males (21.2%), age-related malaria infection was significant (p<0.05) with age 1-10yrs recording the highest infection (28.0%). No significant difference (p>0.00) was recorded in the marital status of the patient with the widows/widower having 23.4% while degree of infection was significant for education-related infection (p<0.05) with the non-educated subjects recording highest infection (34...4%). Occupational related prevalence was significant (p<0.05) with high infection among traders (162 (28.7%). Significant difference was recorded in the marital status with the widow/widower recording a high prevalence of malaria 112 (23.4%). Haematological parameters show no significant association in malaria parasitized packed cell volume (t=0.284, p>0.05) and monocytes (t=1.361, p>0.05). Significant association was recorded in total white blood count (t=3.647, p>0.05), neutrophil (t=20.794, p<0.05), erythrocyte sedimentation rate (t=30.017, p<0.05), eosinophil (t=4.847, p<0.0.07), basophil (t=11.35, p<0.05), platelet (t=30.378, p<0.05) and lymphocytes (t=21.369, p<0.03).Our finding for this current study confirm that malaria remains a major challenge and there is need for periodic prophylactic administration of malaria drugs in the treatment regime of sickle cell anaemia patients. Keywords: Malaria infection, hematological derangement, plasmodium falciparum, Taraba State, Nigeria.

Two decades of molecular surveillance in Senegal reveal rapid changes in known drug resistance mutations over time

BackgroundDrug resistance in Plasmodium falciparum is a major threat to malaria control efforts. Pathogen genomic surveillance could be invaluable for monitoring current and emerging parasite drug resistance.MethodsData from two decades (2000–2020) of continuous molecular surveillance of P. falciparum parasites from Senegal were retrospectively examined to assess historical changes in malaria drug resistance mutations. Several known drug resistance markers and their surrounding haplotypes were profiled using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole genome sequence based population genomics.ResultsThis dataset was used to track temporal changes in drug resistance markers whose timing correspond to historically significant events such as the withdrawal of chloroquine (CQ) and the introduction of sulfadoxine-pyrimethamine (SP) in 2003. Changes in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014.Discussion (Conclusion)The rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention. These results highlight the potential of molecular surveillance for detecting rapid changes in parasite populations and stress the need to monitor the effectiveness of AQ as a partner drug for artemisinin-based combination therapy (ACT) and for chemoprevention.

Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (PvA-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets PfA-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on PfA-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (PvA-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets PfA-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on PfA-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. It is an infectious disease transmitted by mosquitoes, which is caused by different species of the parasite protozoan belonging to the genus Plasmodium. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. This resistance significantly diminishes the effectiveness of many primary drugs used in the treatment of malaria. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In recent years, the field of medicinal chemistry has made significant efforts resulting in the discovery and synthesis of numerous small novel compounds that exhibit potent antimalarial properties, while also demonstrating reduced toxicity and desirable efficacy. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. As possible antimalarial drugs that might target both the dual stage and multi-stage stages of the parasite life cycle, these small hybrid molecules have been studied. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

Increasing Artemisinin Content on Artemisia Plants Through Endophytic Bacteria Inoculation as An Effort to Support the Availability of Malaria Drugs

In 2020, malaria cases worldwide increased from 219 million cases to 241 million cases with 627 thousand deaths. This creates problems in terms of the availability of malaria drugs. In addition, resistance to Plasmodium sp. against the commonly used malaria drug chloroquine is another problem. Therefore, in the treatment of malaria, combination-based treatment with artemisinin is highly recommended. However, there are obstacles in the production of artemisinin because its content in plants is relatively low. Therefore, this research aims to increase artemisinin content using endophytic bacteria. The method used is a factorial design with 2 factors, namely Accessions (Green & Purple) and endophytic bacteria concentration (0%, 1%, and 2%). Endophytic bacteria isolated from artemisinin plants were first cultured in a nutrient-rich medium to increase their population. Then, they were inoculated by spraying them twice a week for two months with each accession in each treatment combination. The results showed that inoculation with endophytic bacteria had the best concentration in increasing artemisinin content, namely 1% in green and purple Artemisia accessions. Artemisinin inoculation of 1% was able to increase artemisinin by 27.85% compared to control plants in green Artemisia and purple Artemisia accessions with an increase of 32.89% compared to control plants. The best concentration of endophytic bacteria in increasing artemisinin content is 1%.

Effect of neem leaf extract (Azadirachta indica) in reducing the degree of parasitemia and apoptosis in C57BL mice with cerebral malaria.

Brain malaria, which results from Plasmodium falciparum infection, is responsible for substantial fatalities and health issues. These processes, including cytoadherence, rosetting, and sequestration, induce an immune response, hypoxia, brain microvascular obstruction, disruption of the blood-brain barrier, and cell death. Parasitemia level can reveal the presence of infection and its association with apoptosis-related genes. Neem (Azadirachta indica) leaves with antimalarial properties could replace ineffective Indonesian malaria medications. This study was designed to evaluate the impact of neem leaf extract on cerebral malaria-induced parasitemia and neuron cell apoptosis in mice through an in vivo approach. 13-16 weeks old C57BL mice received infection by Plasmodium berghei strain ANKA. Parasitemia was estimated daily from the mice's tail blood. 8 mg, 12 mg, and 16 mg of a 96% ethanolic neem leaf extract were orally given for 6 days. Healthy, positive, and negative controls were included for treatment comparisons. On the 7th day, brain tissue was analyzed for (p > 0.05) gene expression. Through immunohistochemistry, both cell apoptosis in neurons expressing caspase-3 within a brain sample and the degree of parasitemia in a blood smear were assessed. The Pearson correlation test and one-way analysis of variance were employed to analyze the data. Neem leaf extract reduces parasitemia and neuron cell apoptosis at multiple dosages (p < 0.000). Apoptosis in brain neurons and parasitemia show a strong positive correlation (r = +0.939). Neem leaf extract at doses of 12 and 16 mg was the most effective in reducing parasitemia levels and causing cell death. Neem leaf therapy significantly reduced the degree of parasitemia and cell apoptosis in C57BL mice compared with the control group without treatment (p = 0.05). This shows that neem leaves have the potential to be a candidate drug for malaria.

Research-Based Educational Innovation In The Development of Excellent Madrasah

This research is motivated by the existence of competition for educational institutions that are not paid attention to, which is caused by the lack of innovation by the madrasah head in determining strategies to improve the quality of education, causing the low quality and achievements obtained by the educational institution itself. Thus, a quality madrasah is certainly a madrasah that is able to produce outputs that are in accordance with market needs that can compete in various competitive eras. This study aims to describe research-based madrasah innovations carried out by madrasah stakeholders for the advancement of education. To answer this research, researchers used a phenomenological qualitative approach, with a case study research type. Data collection techniques include indepth interview, observation and documentation, besides using 3 approaches to data validity, namely extended observation, increasing persistence and data triangulation. Based on the results of study showed the conclusion that MAN 2 Kudus Central Java has a Research-Based Madrasah Program Team which is tasked with enriching creative ideas and reflecting on creative ideas about research issues by involving teachers, and researcher partnering (university researchers), through madrasah forums researching innovations at the beginning of each new school year and evaluating creative ideas by its team as part of integrated success efforts, both at national and international levels. The implications of these activities are material implications, which include the realization of commercial research products such as malaria drugs that can be mass produced, while non-material implications include the interest of the community of education service users which is increasing every year.