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EMBO Reports Oct 2023The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and...
The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA-approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide-induced systemic inflammation and Parkinson's disease-like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3-driven diseases and migth expand its clinical use considerably.
PubMed: 37621232
DOI: 10.15252/embr.202357101 -
Neurology International Jul 2023A 58-year-old woman with a history of systemic lupus erythematosus (SLE) who was taking prednisolone and mycophenolate mofetil presented with gait disturbances that...
A 58-year-old woman with a history of systemic lupus erythematosus (SLE) who was taking prednisolone and mycophenolate mofetil presented with gait disturbances that progressively worsened over a period of 3 months. Her blood test and cerebrospinal fluid (CSF) examination results did not indicate active SLE. Initial brain magnetic resonance imaging (MRI) revealed a small spotty lesion in the left cerebellar peduncle. The clinical course was consistent with rapidly progressive cerebellar syndrome (RPCS), which sometimes involves neuronal antibodies. The line blot assay detected anti-Yo antibodies, but no malignancy was found. Immunohistological techniques using rat brain sections yielded a negative result for anti-Yo antibodies. The second MRI revealed a focal lesion and surrounding spotty lesion in the left cerebellar peduncle, which was consistent with the punctate pattern observed in progressive multifocal leukoencephalopathy (PML). The CSF JCV-DNA test indicated the presence of cerebellar PML. Immunosuppressants were reduced, and mefloquine and mirtazapine were initiated. After approximately 2 years and 1 month, the CSF JCV-DNA results became negative. Cerebellar PML may exhibit a clinical course that is consistent with RPCS. The punctate pattern should be recognized as an early manifestation of PML. The CSF JCV-DNA copy number may serve as a useful indicator of PML stabilization.
PubMed: 37606392
DOI: 10.3390/neurolint15030059 -
PLoS Neglected Tropical Diseases Aug 2023Echinococcus multilocularis and E. granulosus s.l. are the causative agents of alveolar and cystic echinococcosis, respectively. Drug treatment options for these severe...
Echinococcus multilocularis and E. granulosus s.l. are the causative agents of alveolar and cystic echinococcosis, respectively. Drug treatment options for these severe and neglected diseases are limited to benzimidazoles, which are not always efficacious, and adverse side effects are reported. Thus, novel and improved treatments are needed. In this study, the previously established platform for E. multilocularis in vitro drug assessment was adapted to E. granulosus s.s. In a first step, in vitro culture protocols for E. granulosus s.s. were established. This resulted in the generation of large amounts of E. granulosus s.s. metacestode vesicles as well as germinal layer (GL) cells. In vitro culture of these cells formed metacestode vesicles displaying structural characteristics of metacestode cysts generated in vivo. Next, drug susceptibilities of E. multilocularis and E. granulosus s.s. protoscoleces, metacestode vesicles and GL cells were comparatively assessed employing established assays including (i) metacestode vesicle damage marker release assay, (ii) metacestode vesicle viability assay, (iii) GL cell viability assay, and (iv) protoscolex motility assay. The standard drugs albendazole, buparvaquone, mefloquine, MMV665807, monepantel, niclosamide and nitazoxanide were included. MMV665807, niclosamide and nitazoxanide were active against the parasite in all four assays against both species. MMV665807 and monepantel were significantly more active against E. multilocularis metacestode vesicles, while albendazole and nitazoxanide were significantly more active against E. multilocularis GL cells. Albendazole displayed activity against E. multilocularis GL cells, but no effects were seen in albendazole-treated E. granulosus s.s. GL cells within five days. Treatment of protoscoleces with albendazole and monepantel had no impact on motility. Similar results were observed for both species with praziquantel and its enantiomers against protoscoleces. In conclusion, in vitro culture techniques and drug screening methods previously established for E. multilocularis were successfully implemented for E. granulosus s.s., allowing comparisons of drug efficacy between the two species. This study provides in vitro culture techniques for the reliable generation of E. granulosus s.s. metacestode vesicles and GL cell cultures and describes the validation of standardized in vitro drug screening methods for E. granulosus s.s.
Topics: Animals; Echinococcus granulosus; Albendazole; Niclosamide; Drug Evaluation, Preclinical; Echinococcus multilocularis
PubMed: 37540716
DOI: 10.1371/journal.pntd.0011343 -
Proceedings of the National Academy of... Aug 2023multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is...
multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance to antimalarial drugs. To understand the mechanisms of PfMDR1, we determined the cryo-electron microscopy structures of this transporter in different states. The transporter in the apo state shows an inward-facing conformation with a large cavity opening to the cytoplasm. Upon ATP binding and dimerization of the nucleotide-binding domains (NBDs), PfMDR1 displays an outward-facing conformation with a cavity toward the DV lumen. Drug resistance-associated mutations were investigated in both structures for their effects, and Y184F was identified as an allosteric activity-enhancing mutation. The amphiphilic substrate-binding site of PfMDR1 was revealed by the complex structure with the antimalarial drug mefloquine and confirmed by mutagenesis studies. Remarkably, a helical structure was found to hinder NBD dimerization and inhibit PfMDR1 activity. The location of this regulatory domain in the N terminus is different from the well-studied R domain in the internal linker region of other ABC transporter family members. The lack of the phosphorylation site of this domain also suggests a different regulation mechanism.
Topics: Humans; Plasmodium falciparum; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cryoelectron Microscopy; Antimalarials; Membrane Transport Proteins; ATP-Binding Cassette Transporters; Adenosine Triphosphate; Multidrug Resistance-Associated Proteins; Drug Resistance; Malaria, Falciparum
PubMed: 37527341
DOI: 10.1073/pnas.2219905120 -
Nature Communications Jul 2023Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs)...
Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance. Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.
Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Folic Acid Antagonists
PubMed: 37516752
DOI: 10.1038/s41467-023-39914-3 -
PLoS Neglected Tropical Diseases Jun 2023Malaria is caused by parasite of the genus Plasmodium and is still one of the most important infectious diseases in the world. Several biological characteristics of...
Malaria is caused by parasite of the genus Plasmodium and is still one of the most important infectious diseases in the world. Several biological characteristics of Plasmodium vivax contribute to the resilience of this species, including early gametocyte production, both of which lead to efficient malaria transmission to mosquitoes. This study evaluated the impact of currently used drugs on the transmission of P. vivax. Participants received one of the following treatments for malaria: i) chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 7 days]; ii) Chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with one-dose of Tafenoquine [300 mg on day 1]; and iii) Artesunate and Mefloquine [100 mg and 200 mg on day 1, 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 14 days]. Patient blood was collected before treatment and 4 h, 24 h, 48 h and 72 h after treatment. The blood was used to perform a direct membrane feeding assay (DMFA) using Anopheles darlingi mosquitoes. The results showed 100% inhibition of the mosquito infection after 4 h using ASMQ+PQ, after 24 h for the combination of CQ+PQ and 48 h using CQ+TQ. The density of gametocytes declined over time in all treatment groups, although the decline was more rapid in the ASMQ+PQ group. In conclusion, it was possible to demonstrate the transmission-blocking efficacy of the malaria vivax treatment and that ASMQ+PQ acts faster than the two other treatments.
Topics: Animals; Humans; Antimalarials; Primaquine; Malaria, Vivax; Anopheles; Chloroquine; Malaria; Plasmodium vivax
PubMed: 37327209
DOI: 10.1371/journal.pntd.0011425 -
Clinical Epigenetics Jun 2023The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several...
BACKGROUND & AIMS
The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several factors, including pre-existing conditions such as viral hepatitis and cirrhosis, which are commonly associated with HCC.
METHODS
We conducted an analysis of epigenomics in SARS-CoV-2 infection and HCC patients, and identified common pathogenic mechanisms using weighted gene co-expression network analysis (WGCNA) and other analyses. Hub genes were identified and analyzed using LASSO regression. Additionally, drug candidates and their binding modes to key macromolecular targets of COVID-19 were identified using molecular docking.
RESULTS
The epigenomic analysis of the relationship between SARS-CoV-2 infection and HCC patients revealed that the co-pathogenesis was closely linked to immune response, particularly T cell differentiation, regulation of T cell activation and monocyte differentiation. Further analysis indicated that CD4 T cells and monocytes play essential roles in the immunoreaction triggered by both conditions. The expression levels of hub genes MYLK2, FAM83D, STC2, CCDC112, EPHX4 and MMP1 were strongly correlated with SARS-CoV-2 infection and the prognosis of HCC patients. In our study, mefloquine and thioridazine were identified as potential therapeutic agents for COVID-19 in combined with HCC.
CONCLUSIONS
In this research, we conducted an epigenomics analysis to identify common pathogenetic processes between SARS-CoV-2 infection and HCC patients, providing new insights into the pathogenesis and treatment of HCC patients infected with SARS-CoV-2.
Topics: Humans; Carcinoma, Hepatocellular; COVID-19; SARS-CoV-2; DNA Methylation; Molecular Docking Simulation; Liver Neoplasms; Microtubule-Associated Proteins; Cell Cycle Proteins; Epoxide Hydrolases
PubMed: 37309005
DOI: 10.1186/s13148-023-01515-8 -
Malaria Journal Jun 2023Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In...
BACKGROUND
Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether-lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission.
METHODS
230 microscopically confirmed P. falciparum isolates were collected from Assosa (high transmission area) and Gida Ayana (low transmission area) sites, of which 225 of them tested positive by PCR. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes and pfmdr1 SNPs. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A P-value of less or equal to 0.05 was considered significant.
RESULTS
Of the 225 samples, 95.5%, 94.4%, 86.7%, 91.1%, and 94.2% were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. The mutant pfcrt haplotypes were detected among 33.5% (52/155) and 80% (48/60) of isolates collected from the Assosa and Gida Ayana sites, respectively. Plasmodium falciparum with chloroquine-resistant haplotypes was more prevalent in the Gida Ayana area compared with the Assosa area (COR = 8.4, P = 0.00). Pfmdr1-N86Y wild type and 184F mutations were found in 79.8% (166/208) and 73.4% (146/199) samples, respectively. No single mutation was observed at the pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codons N86Y-Y184F-D1246Y were identified with the dominant NFD 61% (122/200). There was no difference in the distribution of pfmdr1 SNPs, haplotypes, and CNV between the two study sites (P > 0.05).
CONCLUSION
Plasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. The NFD haplotype was the predominant haplotype of the N86Y-Y184F-D1246Y. A continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.
Topics: Humans; Antimalarials; Ethiopia; Artemether, Lumefantrine Drug Combination; Artemether; Malaria, Falciparum; Chloroquine; Malaria; Lumefantrine; Plasmodium falciparum; Polymorphism, Single Nucleotide; Multidrug Resistance-Associated Proteins; Protozoan Proteins; Drug Resistance
PubMed: 37270589
DOI: 10.1186/s12936-023-04602-6 -
Arabian Journal of Chemistry Sep 2023The coronavirus pandemic led to the announcement of a worldwide health emergency. The SARS-CoV-2 Omicron variant, which swiftly spread worldwide, has fueled existing...
The coronavirus pandemic led to the announcement of a worldwide health emergency. The SARS-CoV-2 Omicron variant, which swiftly spread worldwide, has fueled existing challenges. Appropriate medication is necessary to avoid severe SARS-CoV-2 disease. The human TMPRSS2 and SARS-CoV-2 Omicron spike protein, which are required for viral entry into the host phase, were identified as the target proteins through computational screening. Structure-based virtual screening; molecular docking; absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis; and molecular dynamics simulation were the methods applied for TMPRSS2 and spike protein inhibitors. Bioactive marine invertebrates from Indonesia were employed as test ligands. Camostat and nafamostat (co-crystal) were utilized as reference ligands against TMPRSS2, whereas mefloquine was used as a reference ligand against spike protein. Following a molecular docking and dynamics simulation, we found that acanthomanzamine C has remarkable effectiveness against TMPRSS2 and spike protein. Compared to camostat (-8.25 kcal/mol), nafamostat (-6.52 kcal/mol), and mefloquine (-6.34 kcal/mol), acanthomanzamine C binds to TMPRSS2 and spike protein with binding energies of -9.75 kcal/mol and -9.19 kcal/mol, respectively. Furthermore, slight variances in the MD simulation demonstrated consistent binding to TMPRSS2 and spike protein after the initial 50 ns. These results are highly valuable in the search for a treatment for SARS-CoV-2 infection.
PubMed: 37234226
DOI: 10.1016/j.arabjc.2023.104984 -
Travel Medicine and Infectious Disease 2023Hair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a...
BACKGROUND
Hair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a methodology to determine hair concentrations of atovaquone, proguanil and mefloquine in travellers using chemoprophylaxis.
METHODS
A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous analysis of the antimalarial drugs -atovaquone (ATQ), proguanil (PRO) and mefloquine (MQ), in human hair. The hair samples from five volunteers were used for this proof-of-concept analysis. Three volunteers were taking daily atovaquone/proguanil (ATQ/PRO) chemoprophylaxis and two volunteers were using weekly mefloquine (MQ) chemoprophylaxis.
RESULTS
With this proof-of-principle analysis, we could show that ATQ/PRO and MQ are integrated into the hair matrix. Chemoprophylaxis could be quantified with the established method. In hair segments, maximal concentrations of 3.0 ng/mL/20 mg hair proguanil, 1.3 ng/mL/20 mg hair atovaquone and 78.3 ng/mL/20 mg hair mefloquine were measured. Moreover, malaria drug concentration changes correlated with the time interval since finishing the chemoprophylaxis regimen.
CONCLUSIONS
The validated method was used successfully for the analysis of antimalarial-drug positive hair samples containing atovaquone, proguanil or mefloquine. This research shows that hair can be used for adherence monitoring of chemoprophylaxis and paves the way for larger studies and optimized procedures.
Topics: Humans; Antimalarials; Proguanil; Atovaquone; Mefloquine; Chromatography, Liquid; Drug Therapy, Combination; Travel; Tandem Mass Spectrometry; Drug Combinations
PubMed: 37209974
DOI: 10.1016/j.tmaid.2023.102590