Search Results (981)

Background/Objectives: The emergence of drug-resistant Plasmodium falciparum highlights the need for new antiplasmodial compounds with distinct mechanisms of action. Microbial secondary metabolites, particularly from Streptomyces species, remain important sources of bioactive molecules. This study aimed to evaluate antiplasmodial metabolites associated with a Mongolian Streptomyces isolate. Methods: Streptomyces sp. strain D10 was isolated from Mongolian soil samples and extracted with ethyl acetate. Bioassay-guided fractionation was performed, followed by LC–HRMS analysis and GNPS-based spectral dereplication. Antiplasmodial activity was evaluated against P. falciparum 3D7, K1, and Dd2 strains using a SYBR Green I assay. Cytotoxicity was assessed in HSF cells. Stage-specific susceptibility assays were conducted using synchronized 3D7 parasites. Comparative docking analyses against β-hematin and the chloroquine resistance transporter (PfCRT), together with target prediction and molecular docking analyses, were performed to explore potential mechanisms. In vivo efficacy was evaluated using a Plasmodium yoelii 17XNL mouse model. Results: Fractionation yielded an active fraction (C2), and LC–HRMS and GNPS-based dereplication suggested a bile acid-like metabolite, with ursodeoxycholic acid (UDCA) returned as a putative spectral library candidate associated with fraction C2. Fraction C2 and UDCA showed comparable antiplasmodial activity against P. falciparum 3D7 (IC₅₀ = 6.55 ± 3.00 and 4.68 ± 0. 65 µg/mL, respectively) without detectable cytotoxicity up to 200 µg/mL. Activity was retained against multidrug-resistant K1 and Dd2 strains. Stage-specific assays demonstrated inhibitory activity across ring, trophozoite, and schizont stages without significant stage-dependent differences. Comparative docking analyses suggested interaction profiles distinct from chloroquine in β-hematin and PfCRT models. Additional docking analyses identified PfGluPho, PfMAPK, and PfPFT-β as potential targets. In vivo, UDCA reduced parasitemia in a dose-dependent manner without significant toxicity. Conclusions: UDCA exhibited moderate antiplasmodial activity across in vitro, in silico, and in vivo evaluations with a favorable selectivity profile, supporting further investigation of bile acid-like metabolites as potential antimalarial scaffolds. Full article

A series of substituted pyrrolo[2,3-d]pyrimidines was designed, synthesized, and evaluated in vitro against two protozoan parasites: Plasmodium falciparum and Trypanosoma brucei brucei. Pharmacological studies revealed antiprotozoal activity with IC₅₀ values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new compounds was assessed using human HepG2 cells. Among them, the pyrrolopyrimidine derivative 1d emerged as the most potent antimalarial compound, exhibiting a selectivity index (SI) of 600.81 against the P. falciparum chloroquine-resistant W2 strain. For the chloroquine-sensitive 3D7 strain, the most notable selectivity index (SI) was observed for pyrrolo[2,3-d]pyrimidine 1c, with a value of approximately 123. Furthermore, compound 1b demonstrated the most interesting activity against Trypanosoma brucei brucei, with an SI of 39.52, marking it as a promising trypanocidal agent. FRET melting assays confirmed that these nitrogen-containing heterocyclic compounds bind to telomeric G-quadruplexes in P. falciparum and Trypanosoma. However, no clear correlation was found between G-quadruplex binding and antiparasitic activity or selectivity, suggesting that G-quadruplex targeting is unlikely to be the main mechanism underlying cytotoxicity. Full article

Background: Systemic lupus erythematosus (SLE) is associated with an increased burden of cardiovascular disease (CVD), driven by dyslipidemia, hypertension, obesity, inflammation, and treatment. These factors can impact patient quality of life (QoL) by limiting physical activity. Objectives: To characterize lipid abnormalities as CVD risk factors in a Saudi SLE cohort and assess associations between lipid profile, SLE features, treatment, and patient-reported outcomes of physical activity. Methods: A cohort of adult SLE patients followed at King Saud University Medical City since 2021 was analyzed. Demographics, lipid profiles, blood pressure, BMI, SLEDAI-2K, SDI, disease duration, and treatment data were collected. Physical function and quality of life were assessed using the LupusQoL and PROMIS Physical Function T scores. Univariate and multivariate logistic regression analyses were conducted to identify associations between lipid abnormalities, SLE-related factors, and QoL physical activity measures. Results: A cohort of 169 patients (88.2% female, mean age 39.3 ± 12.4 years) was evaluated to assess the presence of dyslipidemia (23.7%), obesity (BMI ≥ 25, 66.3%), and hypertension (≥130/80 mmHg, 26.0%). Mean SLE duration was 9.2 ± 7.7 years and mean SLEDAI-2K was 11.0 ± 7.0. Among these patients, 52.7% used steroids, 88.2% used antimalarial drugs, and 53.8% used immunosuppressives. Dyslipidemia was associated with lower LupusQoL physical scores (adjusted OR 0.986; 95% CI 0.972–1.000; p = 0.0446). No significant associations were found between lipid levels and the PROMIS Physical Function T score. Conclusions: In this Saudi SLE cohort, dyslipidemia and other modifiable CVD risks were common. Dyslipidemia correlated with poorer LupusQoL-specific physical scores, which highlights the importance of lifestyle changes in patients with SLE. Full article

Artesunate (ARU), a key derivative of artemisinin (ART), exhibits excellent water solubility and antimalarial activity due to its incorporation of a succinic acid group. However, the synthesis process of ARU often leaves behind ART with a highly similar structure and properties, making traditional separation methods ineffective for efficient separation. Developing selective separation technologies holds significant importance. Based on previous studies, in work involving the preparation of bidentate MOFs with different ligands, bidentate MOFs containing thiol/amino groups have been found to exhibit outstanding adsorption capacity and selectivity for ARU molecules. Among these, -NH₂ forms hydrogen bonds with -COOH in ARU, while -SH interacts non-specifically with Aru, significantly enhancing the adsorption effect. This study employed a delayed inversion method to prepare a sulfhydryl-amino UiO-66/PVDF hybrid membrane (UiO-66-SH/NH₂/PVDF) by adjusting the composition of the coagulation bath, which was used for efficient separation of ART/ARU. The effects of ethanol ratio in the coagulation bath on membrane structure and performance were systematically investigated. Results showed that increasing the ethanol ratio delays phase transition, promotes MOF material enrichment on membrane pore surfaces, and forms more abundant pore structures. When the ethanol-to-water volume ratio was 1:1, the UiO-66-SH/NH₂/PVDF membrane exhibited optimal pore structure and highest water flux. Static permeation experiments demonstrated that the membrane achieved effective separation of ARU and ART for 8 h, maintaining stable selective adsorption performance after five cycles. This study reveals the critical role of morphology regulation in separating structural analogs, providing new materials and theoretical foundations for efficient separation of artemisinin-based compounds. Full article

Global cultivation of Artemisia annua L. for the isolation of artemisinin as the current best antimalarial therapeutic mainly takes place on large plantations, but there is an increasing cultivation of the plant for more local use and the supplement market. Phytochemical consistency is a major concern among growers and also regulatory bodies. Long-term cultivation and harvest of field-grown clonal A. annua have not been measured for consistency and between different geographical regions. Here, artemisinin and other phytochemicals were measured in clonal A. annua grown in two different US geographical locations. Five Florida (FL) and nine Massachusetts (MA) crops were analyzed for artemisinin and flavonoids. TLC (thin layer chromatography) profiles and mass spectrometry analysis were also compared. Artemisinin content dropped by about 10% after transfer from MA to FL, but the flavonoid content increased 2.6-fold. Artemisinin and flavonoid profiles were relatively consistent within each location, but flavonoids differed significantly between the two locations. We also analyzed the artemisinin content of several US commercial A. annua and artemisinin supplements. Despite manufacturer claims, about half the samples contained no detectable artemisinin. Together, this study enhances the knowledge about A. annua field crops and Artemisia/artemisinin supplements being used globally and in the US for therapeutic purposes. Full article

Background/Objectives: The widespread emergence of chloroquine-resistant Plasmodium falciparum continues to drive the search for new quinoline-based antimalarial agents capable of retaining efficacy against resistant parasites. This study aimed to evaluate a series of synthetic quinoline derivatives incorporating arylnitro and aminochalcone moieties for their antiplasmodial activity and selectivity. Methods: A series of eighteen synthetic quinoline derivatives were evaluated for in vitro antiplasmodial activity against P. falciparum strains (3D7, K1, and Dd2), along with cytotoxicity in mammalian cells and hemolytic activity in human red blood cells. Structure–activity relationship analysis was performed, and molecular docking studies were conducted against β-hematin and the chloroquine resistance transporter (PfCRT). Results: Several compounds exhibited sub-micromolar activity against the chloroquine-sensitive 3D7 strain. The most potent compound (Compound 14), a nitro-substituted N-alkylated quinoline bearing a CF₃-enriched aromatic chalcone framework, demonstrated high potency and selectivity (IC₅₀ = 0.13 μM; SI = 1132.92). Importantly, this compound retained substantial activity against multidrug-resistant K1 and Dd2 strains, displaying lower resistance indices than chloroquine. Structure–activity relationship analysis revealed that nitro substitution, N-alkylation, and halogen/CF₃-rich aromatic features critically influence potency and selectivity. Docking studies suggested that Compound 14 engages both β-hematin and PfCRT more extensively than chloroquine. Conclusions: These findings identify Compound 14 as a promising lead scaffold for further optimization toward next-generation antimalarial agents. Full article

Chalcones featuring α,β–unsaturated carbonyl group are associated with an extensive range of pharmacological properties. The synthesized derivatives of benzimidazole–chalcone are prominent classes of bioactive compounds that have demonstrated significant applications. Recently, there has been an encouraged demand for synthesizing aromatic N–heterocyclic α,β–unsaturated hybrids that comprise benzimidazole–chalcones, which could be evaluated for activities against several diseases. The current review presents the synthetic approaches of the recently prepared benzimidazole–chalcone compounds and their biological applications. The biological activity studies include cytotoxicity against several cancer cells, antibacterial, antifungal, antileishmanial, antimalarial, antiviral and antidiabetic activities. The in silico studies of hybridized benzimidazole–chalcones are also discussed. Therefore, the review shows the significance of benzimidazole–chalcone derivatives and their potential as effective bioactive agents. Full article

Background/Objectives: Hospitalisations in systemic lupus erythematosus (SLE) reflect disease severity, accumulated damage, and the burden of comorbidity, remaining a major determinant of healthcare utilisation. Recent evidence suggests a shift from flare-driven admissions toward complications related to infections, comorbidities, and long-term treatment effects. We aimed to analyse the causes, characteristics, and outcomes of hospital admissions in patients with systemic lupus erythematosus (SLE) over a 30-year period in a tertiary referral centre in Catalonia (Spain) and to evaluate changes over time and prognostic factors associated with adverse outcomes. Methods: A retrospective observational study was conducted including all SLE patients admitted to the Department of Autoimmune Diseases at Hospital Clínic de Barcelona between June 1995 and December 2024. Admissions lasting less than 48 h or lacking clinical documentation were excluded. Variables analysed included demographics, disease duration, comorbidities, cause of admission, treatments, and outcomes. A composite outcome was defined as intensive care unit (ICU) admission, 30-day readmission, or prolonged hospital stay. Statistical analyses included univariate and multivariate regression models. Results: Among the 1216 hospital admissions, SLE flares and infections were the most frequent causes. Over the study period, admissions due to infections increased significantly and, in the last five years, exceeded those related to disease flares (33.7% vs. 26.1%). Patients hospitalized for flares were younger and had a shorter disease duration, whereas infection-related admissions were more common among older patients, those with overlap syndromes, and those with higher damage scores. Vascular events and SLE flares were independently associated with poorer outcomes. Although antimalarial use increased over time, it remained suboptimal, largely due to drug toxicity and newly diagnosed cases (from 45.2% to 69.7%; p < 0.001). Treatment strategies also evolved, with a shift toward lower glucocorticoid doses (from 14.5% to 38.3%; p < 0.001), and mycophenolate mofetil replacing cyclophosphamide as the preferred immunosuppressive agent. Conclusions: Hospitalisation patterns in SLE have shifted over time, with infections emerging as the leading cause of admission. This trend reflects an evolving patient profile characterized by older age, greater accumulated damage, comorbidities, and increased exposure to immunosuppressive therapies. These findings underscore the need for optimized infection prevention strategies and individualized treatment approaches to improve outcomes in contemporary SLE care. Full article

Malaria is one of the major global public health issues. An estimated 282 million malaria cases occurred worldwide in 2024, and the overall prevention and control progress has stagnated or even reversed in some regions. Mass drug administration (MDA), as a potential strategy to accelerate malaria elimination, has regained attention. This paper reviews the evidence base, controversial focuses, and application strategies of MDA in malaria prevention and control. It aims to promote its scientific application in the elimination phase. MDA plays an important role in malaria prevention and control. However, this strategy is accompanied by core limitations such as long-term drug resistance risks, insufficient implementation sustainability, and a high failure rate of regional adaptation. It also faces challenges from multiple common malaria species, as well as the newly discovered Plasmodium knowlesi. We therefore propose an “MDA+” collaborative strategy integrating vaccines, digital monitoring, and cross-border cooperation, so as to optimize resource allocation, achieve full coverage control over various malaria parasites, and advance the global malaria elimination process. Full article

Background: The Democratic Republic of the Congo accounts for approximately 12–13% of the global malaria burden. While international guidelines oppose the use of Artemisia annua infusions due to risks of sub-therapeutic dosing and resistance selection, the plant remains widely used in resource-limited regions. This study evaluates the clinical acceptability and perceptions of healthcare providers regarding the integration of Artemisia annua tea into formal malaria control in the Maniema province. Methods: A cross-sectional survey was conducted among 337 healthcare professionals in the Kalima health district using the KoboCollect digital platform. Multivariate logistic regression was employed to identify the primary socio-professional determinants of clinical acceptability. Results: The overall clinical acceptability of Artemisia annua integration was 81.0%, with 82.8% of providers perceiving the preparation as effective. Rural residency was the strongest predictor of adherence (AOR = 6.847; p = 0.003), reflecting a pragmatic response to frequent ACT stockouts and high treatment costs. Despite high acceptability, 49.0% of providers identified the lack of clinical evidence as a major barrier, and 91.4% demanded formal training on standardized dosage and biological mechanisms. Conclusions: A significant “policy–practice gap” exists between international guidelines and field realities in the DRC. Healthcare providers demonstrate high readiness for integration but emphasize the absolute necessity of galenic standardization to mitigate resistance risks. To address these concerns, a complementary genomic investigation is currently underway in the same study area, comparing PfKelch13 mutation prevalence among Artemisia tea users versus ACT-treated patients. This molecular surveillance will provide essential evidence to define safety parameters for future phytopharmaceutical integration. Full article

Background: In 2018, malaria remained a leading cause of morbidity and mortality in the Democratic Republic of the Congo, accounting for 44% of all outpatient visits and 22% of deaths. This led to the development of the strategic plan for 2020–2023. To meet the objectives of this renewed plan, a monitoring and evaluation program focusing on performance indicators was established. This study aimed to assess the malaria control performance indicators in Kinshasa. Methods: A descriptive cross-sectional study used the National Malaria Control Program dataset of the period 2020–2023 to analyze malaria data from 23 HZ (Health Zone) in Kinshasa. Diagnostic, therapeutic, and preventive use of LLINs (long-lasting insecticidal nets) and sulfadoxine–pyrimethamin-based IPT (intermittent preventive treatment among pregnant women) indicators were evaluated following the targeted thresholds established in the strategic plan for 2020–2023. Results: Malaria was present in all studied HZ from 2020 to 2023, with a heterogeneous distribution. The malaria incidence during the study period was 30%, with an upward trend in both suspected and confirmed cases, peaking in 2022 and showing no further fluctuations thereafter. The proportion of LLINs distributed to pregnant women during antenatal care visits was 62%, 61%, 45%, and 88% in 2020, 2021, 2022, and 2023, respectively. A total of 83.1% of suspected malaria cases were diagnosed using RDT (Rapid Diagnosis Test), and confirmed malaria cases received antimalarial treatment. Conclusions: The objectives of the 2020–2023 strategic plan were only partially achieved, and no HZ reached 100% diagnosis by RDT, with only four HZs reaching at least 95% of the target. Thirty-four HZs were able to benefit from 95% treatment with antimalarial drugs. Full article

Background: Malaria parasites import essential nutrients from plasma into their host erythrocytes through the plasmodial surface anion channel (PSAC), a conserved ion and nutrient channel on the infected cell surface. A parasite-encoded ternary complex consisting of CLAG3, RhopH2, and RhopH3 determines PSAC activity, but the precise contributions of each member to formation of the nutrient uptake pore remains uncertain. Methods: Here, we devised a two-step CRIPSR transfection strategy to examine an amphipathic CLAG3 helix, termed α-helix 44 (α-H44), as a candidate pore-lining domain. Results: A CLAG3 truncation protein without α-H44 phenocopies a CLAG3 knockout line, suggesting a critical role of α-H44 in formation of the nutrient channel; CLAG3 restoration using a recodonized α-H44 restores PSAC activity fully. A saturation mutagenesis library that splits the helix into four sequential segments was devised and implemented. Two engineered mutants exhibit distinct PSAC phenotypes; their cultures failed to expand in a modified medium that approximates in vivo nutrient availability. Conclusions: These studies support a α-H44 role in channel permeation and block by a strain-specific inhibitor. Our strategy will enable saturation mutagenesis to determine how PSAC achieves its unique ion and nutrient selectivity and should help guide drug discovery against this antimalarial target. Full article

Dihydroartemisinin (DHA), the active metabolite of artemisinin derivatives, is a clinically established antimalarial agent that has recently gained significant attention for its anticancer properties. This review systematically examines the molecular mechanisms underlying DHA’s antitumor effects and explores innovative strategies to enhance its bioavailability and therapeutic efficacy. DHA demonstrates substantial potential in combination therapies with conventional clinical agents, with its broad anticancer applications being strongly supported by both preclinical and clinical evidence. Furthermore, this article outlines future research directions, discusses challenges in clinical translation, and summarizes current scientific approaches addressing these limitations. Collectively, this review highlights DHA’s promising role in cancer treatment and provides a foundation for developing improved therapeutic strategies. Full article

Sclerotinia sclerotiorum (Lib.) de Bary is a globally distributed necrotrophic fungal pathogen capable of infecting a wide range of crops. While conventional chemical fungicides offer effective control, their long-term use leads to increased fungicide resistance and poses risks to the environment and human health due to pesticide residues, underscoring the urgent need to develop novel fungicides. Artemisinin, first identified in Artemisia annua, is renowned for its antimalarial activity. Here, we demonstrate that artemisinin exhibites effective antifungal activity against Sclerotinia sclerotiorum with an EC₅₀ value of 0.1 mg/mL. Treatment with artemisinin caused the mycelia surface to collapse and shrivel, accompanied by enhanced membrane permeability. Pretreating Brassica napus and Arabidopsis leaves with artemisinin increased resistance to S. sclerotiorum infection. Proteomic analysis revealed that artemisinin treatment markedly downregulated the expression of key functional proteins in S. sclerotiorum, including enzymes involved in oxalic acid biosynthesis, cell wall-associated proteins, and secreted proteins. In conclusion, artemisinin exhibits notable inhibitory effects against S. sclerotiorum and may hold potential for development as a novel fungicide. Full article

Malaria, caused by Plasmodium parasites, remains a global health crisis, necessitating novel therapeutic strategies targeting host–parasite interactions. During liver-stage infection, parasites exploit host vesicular trafficking machinery, particularly SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins that mediate membrane fusion. Using a CRISPR/Cas9 knockout system in HeLa cells combined with advanced microscopy of Plasmodium berghei-infected HeLa cells, we identified specific endolysosomal SNAREs including Vesicle-Associated Membrane Protein 7 (VAMP7), Vesicle-Associated Membrane Protein 8 (VAMP8), Vesicle Transport Through Interaction With T-SNAREs 1B (Vti1B), and Syntaxin 7 (Stx7) to be recruited to the parasitophorous vacuole membrane (PVM) with distinct temporal profiles. This demonstrates the parasite’s precise manipulation of host endolysosomal trafficking pathways. VAMP7 and Vti1B were localized to the PVM within 30 min post-infection, suggesting potential roles during invasion, while VAMP8 and Stx7 appeared later around 24 h post infection (hpi), coinciding with increased nutrient acquisition. Single gene deletions showed minimal impact, but combinatorial knockouts (KO) revealed critical redundancy. VAMP7-VAMP8 as well as VAMP7–Vti1B double KO significantly reduced parasite infection and growth, with Vti1B playing a dominant role. Triple KO phenotypes mirrored VAMP7-Vti1B disruption, underscoring Vti1B’s dominant role. SNARE depletion also impaired the lysosome–PVM association and LAMP1 positive vesicle recruitment. Our findings indicate Plasmodium hijacks a coordinated host SNARE network to fuse lysosomes with the PVM for nutrient uptake. Targeting Vti1B-containing complexes disrupts this pathway without host cell toxicity, offering a promising host-directed antimalarial approach. Full article