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Journal of Pharmaceutical Analysis Feb 2024Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors...
Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. and studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation and . Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.
PubMed: 38464783
DOI: 10.1016/j.jpha.2023.05.014 -
Research Square Feb 2024Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed (Pv)...
Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed (Pv) and (Pf) transmission dynamics, resistance markers, and Pf deletions in Nueva Jerusalén (NJ), a remote, indigenous community in the Peruvian Amazon with high population mobility. We collected samples from November 2019 to May 2020 by active (ACD) and passive case detection (PCD) in NJ. Parasites were identified with microscopy and PCR. Then, we analyzed a representative set of positive-PCR samples (Pv = 68, Pf = 58) using highly-multiplexed deep sequencing assays (AmpliSeq) and compared NJ parasites with ones from other remote Peruvian areas using population genetics indexes. The ACD intervention did not reduce malaria cases in the short term, and persistent malaria transmission was observed (at least one Pv infection was detected in 96% of the study days). In Nueva Jerusalen, the Pv population had modest genetic diversity (He = 0.27). Pf population had lower diversity (He = 0.08) and presented temporal clustering, one of these clusters linked to an outbreak in February 2020. Moreover, Pv and Pf parasites from NJ exhibited variable levels of differentiation (Pv Fst = -0.52 & Pf Fst = 0.11-0.58) with parasites from other remote areas. No artemisin resistance mutations but chloroquine (57%) and sulfadoxine-pyrimethamine (35-67%) were detected in NJ's Pf parasites. Moreover, gene deletions were common (32-50% of parasites with one or both genes deleted). The persistent Pv transmission and the detection of a Pf outbreak with parasites genetically distinct from the local ones highlight the need for tailored interventions focusing on mobility patterns and imported infections in remote areas to eliminate malaria in the Peruvian Amazon.
PubMed: 38464169
DOI: 10.21203/rs.3.rs-3979991/v1 -
Frontiers in Epidemiology 2024Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and...
INTRODUCTION
Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and prophylaxis respectively. The genetic basis of development of drug resistance involves single nucleotide polymorphisms in genes encoding proteins for multiple cellular and metabolic processes. The prevalence of single nucleotide polymorphisms in nine genes linked to ACT and SP resistance in the malaria parasite population was determined.
METHODS
Archived filter paper blood blot samples from patients aged 9 years and below with uncomplicated malaria reporting at 10 sentinel sites located in three ecological zones for the Malaria Therapeutic Efficacy Studies were used. The samples used were collected from 2007-2018 malaria transmission seasons and mutations in the genes were detected using PCR and Sanger sequencing.
RESULTS
In all 1,142 samples were used for the study. For falcipain-2 gene () Sanger sequencing was successful for 872 samples and were further analysed. The prevalence of the mutants was 45% (392/872) with markers V51I and S59F occurring in 15.0% (128/872) and 3.0% (26/872) of the samples respectively. Prevalence of other gene mutations: coronin () was 44.8% (37/90); cysteine desulfurase () was 73.9% (68/92); apicoplast ribosomal protein S10 () was 36.8% (35/95); ferredoxin () was 8.8% (8/91); multidrug resistance protein-1 () was 95.2.0% (80/84); multidrug resistance protein-2 () was 91.4% (32/35); dihydrofolate reductase () was 99.0% (84/85); dihydropteroate synthase () was 72% (68/95).
DISCUSSION
The observation of numerous mutations in these genes of interest in the Ghanaian isolates, some of which have been implicated in delayed parasite clearance is of great interest. The presence of these genotypes may account for the decline in the efficacies of ACT regimens being used to treat uncomplicated malaria in the country. The need for continuous monitoring of these genetic markers to give first-hand information on parasite susceptibility to antimalarial drugs to inform policy makers and stakeholders in malaria elimination in the country is further discussed.
PubMed: 38456076
DOI: 10.3389/fepid.2024.1279835 -
PloS One 2024Accurate bike-sharing demand prediction is crucial for bike allocation rebalancing and station planning. In bike-sharing systems, the bike borrowing and returning...
Accurate bike-sharing demand prediction is crucial for bike allocation rebalancing and station planning. In bike-sharing systems, the bike borrowing and returning behavior exhibit strong spatio-temporal characteristics. Meanwhile, the bike-sharing demand is affected by the arbitrariness of user behavior, which makes the distribution of bikes unbalanced. These bring great challenges to bike-sharing demand prediction. In this study, a usage pattern similarity-based dual-network for bike-sharing demand prediction, called FF-STGCN, is proposed. Inter-station flow features and similar usage pattern features are fully considered. The model includes three modules: multi-scale spatio-temporal feature fusion module, bike usage pattern similarity learning module, and bike-sharing demand prediction module. In particular, we design a multi-scale spatio-temporal feature fusion module to address limitations in multi-scale spatio-temporal accuracy. Then, a bike usage pattern similarity learning module is constructed to capture the underlying correlated features among stations. Finally, we employ a dual network structure to integrate inter-station flow features and similar usage pattern features in the bike-sharing demand prediction module to realize the final prediction. Experiments on the Citi Bike dataset have demonstrated the effectiveness of our proposed model. The ablation experiments further confirm the indispensability of each module in the proposed model.
Topics: Bicycling; Transportation; Learning; Pyrimethamine
PubMed: 38451911
DOI: 10.1371/journal.pone.0298684 -
Tropical Parasitology 2024Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine)...
Prevalence of polymorphisms in marker genes associated with antimalarial drug resistance in following 10 years of artemisinin-based combination therapy implementation in urban Kolkata.
CONTEXT
Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine) was introduced in place of chloroquine (CQ) for the treatment of uncomplicated falciparum malaria in 2010. Periodical monitoring of polymorphisms in antimalarial drug resistance marker genes will be useful for assessing drug pressure, mapping and monitoring of drug resistance status; and will be helpful for searching alternative treatments.
OBJECTIVES
This study was conducted to study the polymorphisms in antimalarial drug resistance marker genes among clinical isolates collected from Kolkata after 10 years of artemisinin-based combination therapie (ACT) implementation.
MATERIALS AND METHODS
Blood samples were collected from mono-infected patients and polymorphisms in CQ resistance transporter , multidrug resistance , dihydrofolate reductase , dihydropteroate synthetase , and propeller genes were analysed by polymerase chain reaction and DNA sequencing.
RESULTS
In gene, C72S, and K76T mutation was recorded in 100% isolates and no mutations was detected in any of the targeted codons of gene. A double mutant haplotype SVMNT and wildtype haplotype NYD in were prevalent in 100% of study isolates. Triple mutant haplotype ANRNI-SGKAA was recorded. No polymorphism in gene was documented in any of the isolates.
CONCLUSIONS
Observed wild codon N86 along with Y184 and D1246 of gene might be an indication of the reappearance of CQ sensitivity. The absence of quadruple and quintuple haplotypes in gene along with the wild haplotype of pfK13 is evidence of ACT effectivity. Hence, similar studies with large sample size are highly suggested for monitoring the drug resistance status of .
PubMed: 38444799
DOI: 10.4103/tp.tp_43_23 -
Cureus Jan 2024Introduction Congenital toxoplasmosis (CT), despite being mostly subclinical at birth, can cause disabling disease in the fetus and lead to long-term sequelae. It is an...
Introduction Congenital toxoplasmosis (CT), despite being mostly subclinical at birth, can cause disabling disease in the fetus and lead to long-term sequelae. It is an important cause of chorioretinitis in infants and adolescents. Data on postnatal treatment are controversial, and there is a lack of universal guidelines. Methods A cross-sectional study of newborns with suspected CT was conducted between January 2007 and December 2021. Results Seventy-one patients with suspected CT were included. During pregnancy, 64 (90.1%) of the mothers underwent therapy, of which 59 (83.1%) with spiramycin. Amniocentesis identified one positive polymerase chain reaction assay. Most newborns were asymptomatic with normal laboratory, ophthalmological, and hearing screening. There was one case of hyperproteinorrachia. Fifty-seven patients (80.3%) started treatment: 42 (73.7%) with spiramycin, seven (12.3%) with pyrimethamine, sulfadiazine, and folinic acid (P+S+FA), and eight (14%) with P+S+FA intercalated with spiramycin. Adverse effects were found in 11 (19.3%) cases, mainly neutropenia. After investigation, we found three confirmed CT cases corresponding to 4.2% of suspected cases and an incidence of 0.4 per 10,000 births. All had normal clinical and laboratory exams in the neonatal period and started P+S+FA, fulfilling 12 months of therapy. During the follow-up, all presented normal psychomotor development without any long-term sequelae. Conclusion The lower incidence in our study, compared to the incidence in Europe, may be related to the decline in the prevalence of toxoplasmosis as well as the effectiveness of measures to prevent primary infection and a well-established program of antenatal screening, followed by the early initiation of treatment during pregnancy to prevent vertical transmission.
PubMed: 38406029
DOI: 10.7759/cureus.52971 -
RSC Advances Feb 2024The current work is about the modification of primary amine functionalized drugs, pyrimethamine and 4-amino--(2,3-dihydrothiazol-2-yl)benzenesulfonamide, condensation...
A synthetic approach towards drug modification: 2-hydroxy-1-naphthaldehyde based imine-zwitterion preparation, single-crystal study, Hirshfeld surface analysis, and computational investigation.
The current work is about the modification of primary amine functionalized drugs, pyrimethamine and 4-amino--(2,3-dihydrothiazol-2-yl)benzenesulfonamide, condensation reaction with 2-hydroxy-1-naphthaldehyde to produce new organic zwitterionic compounds ()-1-(((4-(-(2,3-dihydrothiazol-2-yl)sulfamoyl)phenyl)iminio)methyl)naphthalen-2-olate (DSPIN) and ()-1-(((4-amino-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl)iminio)methyl)naphthalen-2-olate (ACPIN) in methanol as a solvent. The crystal structures of both compounds were confirmed to be imine-based zwitterionic products single-crystal X-ray diffraction (SC-XRD) analysis which indicated that the stabilization of both crystalline compounds is achieved various noncovalent interactions. The supramolecular assembly in terms of noncovalent interactions was explored by the Hirshfeld surface analysis. Void analysis was carried out to predict the crystal mechanical response. Compound geometries calculated in the DFT (Density Functional Theory) study showed reasonably good agreement with the experimentally determined structural parameters. Frontier molecular orbital (FMO) analysis showed that the DSPIN HOMO/LUMO gap is by 0.15 eV smaller than the ACPIN HOMO/LUMO gap due to some destabilization of the DSPIN HOMO and some stabilization of its LUMO. The results of the charge analysis implied formation of intramolecular hydrogen bonds and suggested formation of intermolecular hydrogen bonding and dipole-dipole and dispersion interactions.
PubMed: 38390507
DOI: 10.1039/d3ra08727a -
MedRxiv : the Preprint Server For... Feb 2024Genomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted...
Genomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted genomic surveillance of malaria by sequencing 241 genomes from regions with varying levels of malaria transmission across Zambia. We found genomic evidence of high levels of within-host polygenomic infections, regardless of epidemiological characteristics, underscoring the extensive and ongoing endemic malaria transmission in the country. We identified country-level clustering of parasites from Zambia and neighboring countries, and distinct clustering of parasites from West Africa. Within Zambia, our identity by descent (IBD) relatedness analysis uncovered spatial clustering of closely related parasite pairs at the local level and rare cases of long-distance sharing. Genomic regions with large shared IBD segments and strong positive selection signatures identified genes involved in sulfadoxine-pyrimethamine and artemisinin combination therapies drug resistance, but no signature related to chloroquine resistance. Together, our findings enhance our understanding of transmission nationwide in Zambia and highlight the urgency of strengthening malaria control programs and surveillance of antimalarial drug resistance.
PubMed: 38370674
DOI: 10.1101/2024.02.09.24302570 -
Scientific Reports Feb 2024We explored whether isotope ratio mass spectrometry (IRMS) is useful to investigate the origin of falsified antimalarials. Forty-four falsified and genuine antimalarial...
We explored whether isotope ratio mass spectrometry (IRMS) is useful to investigate the origin of falsified antimalarials. Forty-four falsified and genuine antimalarial samples (artesunate, artemether-lumefantrine, dihydroartemisinin-piperaquine and sulphamethopyrazine-pyrimethamine) were analyzed in bulk for carbon (C), nitrogen (N), and oxygen (O) element concentrations and stable isotope ratios. The insoluble fraction ("starch") was extracted from 26 samples and analyzed. Samples of known geographical origin maize, a common source of excipient starch, were used to produce a comparison dataset to predict starch source. In both an initial (n = 18) and a follow-on set of samples that contained/claimed to contain artesunate/artemether (n = 26), falsified antimalarials had a range of C concentrations less than genuine comparator antimalarials and δC values higher than genuine comparators. The δC values of falsified antimalarials suggested that C plant-based organic material (e.g., starch derived from maize) had been included. Using the known-origin maize samples, predictions for growth water δO values for the extracted "starch" ranged from - 6.10 to - 1.62‰. These findings suggest that IRMS may be a useful tool for profiling falsified antimalarials. We found that C ingredients were exclusively used in falsified antimalarials versus genuine antimalarials, and that it may be possible to predict potential growth water δO values for the starch present in falsified antimalarials.
Topics: Antimalarials; Artesunate; Pilot Projects; Artemether; Artemether, Lumefantrine Drug Combination; Mass Spectrometry; Isotopes; Starch; Water
PubMed: 38369604
DOI: 10.1038/s41598-024-54168-9 -
The Lancet. Global Health Mar 2024Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on...
BACKGROUND
Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles.
METHODS
In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions.
FINDINGS
Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug.
INTERPRETATION
Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount.
FUNDING
Bill & Melinda Gates Foundation and the Swiss National Science Foundation.
Topics: Child; Humans; Infant; Antimalarials; Pharmaceutical Preparations; Public Health; Seasons; Malaria; Drug Combinations; Chemoprevention
PubMed: 38365418
DOI: 10.1016/S2214-109X(23)00550-8