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PloS One 2024Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multi-drug resistance protein 1 (Pfmrp1) gene have previously been reported to confer resistance to...
Increased sensitivity of malaria parasites to common antimalaria drugs after the introduction of artemether-lumefantrine: Implication of policy change and implementation of more effective drugs in fight against malaria.
Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multi-drug resistance protein 1 (Pfmrp1) gene have previously been reported to confer resistance to Artemisinin-based Combination Therapies (ACTs) in Southeast Asia. A total of 300 samples collected from six sites between 2008 and 2019 under an ongoing malaria drug sensitivity patterns in Kenya study were evaluated for the presence of SNPs at Pfmrp1 gene codons: H191Y, S437A, I876V, and F1390I using the Agena MassARRAY® platform. Each isolate was further tested against artemisinin (ART), lumefantrine (LU), amodiaquine (AQ), mefloquine (MQ), quinine (QN), and chloroquine (CQ) using malaria the SYBR Green I-based method to determine their in vitro drug sensitivity. Of the samples genotyped, polymorphism at Pfmrp1 codon I876V was the most frequent, with 59.3% (163/275) mutants, followed by F1390I, 7.2% (20/278), H191Y, 4.0% (6/151), and S437A, 3.3% (9/274). A significant decrease in median 50% inhibition concentrations (IC50s) and interquartile range (IQR) was noted; AQ from 2.996 ng/ml [IQR = 2.604-4.747, n = 51] in 2008 to 1.495 ng/ml [IQR = 0.7134-3.318, n = 40] (P<0.001) in 2019, QN from 59.64 ng/ml [IQR = 29.88-80.89, n = 51] in 2008 to 18.10 ng/ml [IQR = 11.81-26.92, n = 42] (P<0.001) in 2019, CQ from 35.19 ng/ml [IQR = 16.99-71.20, n = 30] in 2008 to 6.699 ng/ml [IQR = 4.976-9.875, n = 37] (P<0.001) in 2019, and ART from 2.680 ng/ml [IQR = 1.608-4.857, n = 57] in 2008 to 2.105 ng/ml [IQR = 1.266-3.267, n = 47] (P = 0.0012) in 2019, implying increasing parasite sensitivity to the drugs over time. However, no significant variations were observed in LU (P = 0.2692) and MQ (P = 0.0939) respectively, suggesting stable parasite responses over time. There was no statistical significance between the mutation at 876 and parasite sensitivity to selected antimalarials tested, suggesting stable sensitivity for the parasites with 876V mutations. These findings show that Kenyan parasite strains are still sensitive to AQ, QN, CQ, ART, LU, and MQ. Despite the presence of Pfmrp1 mutations in parasites among the population.
Topics: Antimalarials; Humans; Plasmodium falciparum; Artemether, Lumefantrine Drug Combination; Malaria, Falciparum; Polymorphism, Single Nucleotide; Multidrug Resistance-Associated Proteins; Kenya; Mefloquine; Amodiaquine; Drug Resistance; Artemisinins; Chloroquine; Quinine; Male; Female
PubMed: 38900782
DOI: 10.1371/journal.pone.0298585 -
Veterinaria Italiana Mar 2024The aim of this study was to determine the concentration of TNF-alpha (TNF-α) in dogs naturally infected with Dirofilaria immitis (D. immitis) and to assess whether...
The aim of this study was to determine the concentration of TNF-alpha (TNF-α) in dogs naturally infected with Dirofilaria immitis (D. immitis) and to assess whether there are any changes in TNF-α concentration and their dependence during therapy for heartworm disease (HWD). For this study, 14 client-owned dogs with HWD were selected. Clinical and parasitological examinations (modified Knott test for circulating microfilariae and SNAP Test IDEXX for circulating D. immitis antigen) had been used for diagnosing D. immitis and HWD. All dogs were treated with an alternative therapy for HWD (oral doxycycline 10 mg/kg b.w., once daily for 6 weeks, then alternately 4 weeks without and 2 weeks with the medication, and oral ivermectin 6-14 µg/kg b.w., every 2 weeks). The dogs blood sera at the moment of HWD diagnosis, during and at the end of therapy were frozen for further quantifying of TNF-α (Canine TNF-alpha ELISA kit, Thermo scientific). At the moment of HWD diagnosis TNF-α was detected in 9 dogs (7.21±12.44 pg/ml). Concentration of TNF-α was not significantly change during the therapy, neither related to the level of D. immitis antigen nor to antigen level changes. The alternative therapy for HWD has no influence on TNF-α concentration dynamics.
Topics: Animals; Dogs; Dirofilariasis; Dog Diseases; Tumor Necrosis Factor-alpha; Dirofilaria immitis; Male; Female; Doxycycline; Ivermectin
PubMed: 38898794
DOI: 10.12834/VetIt.2662.22847.2 -
BMC Infectious Diseases Jun 2024the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series...
BACKGROUND
the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series aims to describe the efficacy and safety of the exchange transfusion combined with artesunate (ET-AS) regimen in severe P. falciparum malaria. Eight patients diagnosed with severe P. falciparum malaria were included. All patients underwent ET using the COBE Spectra system. The aimed for a post-exchange hematocrit of 30%. Half the estimated blood volume was removed and replaced using fresh frozen plasma. The regimen was well-tolerated without complications. The parasite clearance time ranged from 1 ~ 5 days. Five patients with cerebral malaria exhibited full improved consciousness within 3 days, while patient2 with hemolysis improved on day 2. Liver function improved within 1 ~ 6 days, and patient 1 and patient 6 showed improvements renal function on days 18 and 19, respectively. The length of intensive care unit stay range from 2 ~ 10 days, and all patients treated with ET-AS remained in the hospital for 3 ~ 19 days.
CONCLUSIONS
these preliminary results suggest that ET-AS regimens are a safe and effective therapy for severe P. falciparum malaria and can benefit patients in clinical settings.
Topics: Humans; Artesunate; Malaria, Falciparum; Male; Adult; Female; Antimalarials; Middle Aged; Exchange Transfusion, Whole Blood; Artemisinins; Treatment Outcome; Young Adult; Plasmodium falciparum; Aged; Combined Modality Therapy
PubMed: 38898395
DOI: 10.1186/s12879-024-09381-2 -
Molecules (Basel, Switzerland) Jun 2024Ammonium polyphosphate (APP), a pivotal constituent within environmentally friendly flame retardants, exhibits notable decomposition susceptibility and potentially...
Ammonium polyphosphate (APP), a pivotal constituent within environmentally friendly flame retardants, exhibits notable decomposition susceptibility and potentially engenders ecological peril. Consequently, monitoring the APP concentration to ensure product integrity and facilitate the efficacious management of wastewater from production processes is of great significance. A fluorescent assay was devised to swiftly discern APP utilizing 4',6'-diamino-2-phenylindole (DAPI). With increasing APP concentrations, DAPI undergoes intercalation within its structure, emitting pronounced fluorescence. Notably, the flame retardant JLS-PNA220-A, predominantly comprising APP, was employed as the test substrate. Establishing a linear relationship between fluorescence intensity (F-F0) and JLS-PNA220-A concentration yielded the equation y = 76.08x + 463.2 (R = 0.9992), with a LOD determined to be 0.853 mg/L. The method was used to assess the degradation capacity of APP-degrading bacteria. Strain D-3 was isolated, and subsequent analysis of its 16S DNA sequence classified it as belonging to the genus. D-3 demonstrated superior APP degradation capabilities under pH 7 at 37 °C, with degradation rates exceeding 85% over a four-day cultivation period. It underscores the sensitivity and efficacy of the proposed method for APP detection. Furthermore, D-3 exhibits promising potential for remediation of residual APP through environmental biodegradation processes.
Topics: Biodegradation, Environmental; Acinetobacter; Polyphosphates; Indoles; Ammonium Compounds; Flame Retardants
PubMed: 38893541
DOI: 10.3390/molecules29112667 -
Molecules (Basel, Switzerland) May 2024Metronidazole (MTZ) is the most common drug used against () infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported,...
Metronidazole (MTZ) is the most common drug used against () infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in to MTZ. Therefore, research into new therapeutic options against infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC values in the nanomolar range and AGR-2 being the most potent (IC 400 nM). To gain insight into molecular events related to AGR-induced cell death in , we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (, , , and ) and genes involved in metabolism (, , , , , and ), suggesting that disturbing these key metabolic genes alters the survival of the parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against .
Topics: Trichomonas vaginalis; Imidazoles; Humans; Carbamates; Metronidazole; Gene Expression Regulation; Trophozoites
PubMed: 38893461
DOI: 10.3390/molecules29112585 -
Molecules (Basel, Switzerland) May 2024Kallopterolides A-I (-), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were...
Kallopterolides A-I (-), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were isolated from the Caribbean Sea plume . The structures and relative configurations of - were characterized by analysis of HR-MS, IR, UV, and NMR spectroscopic data in addition to computational methods and side-by-side comparisons with published NMR data of related congeners. An investigation was conducted as to the potential of the kallopterolides as plausible in vitro anti-inflammatory, antiprotozoal, and antituberculosis agents.
Topics: Diterpenes; Animals; Anthozoa; Antiprotozoal Agents; Caribbean Region; Molecular Structure; Anti-Inflammatory Agents; Magnetic Resonance Spectroscopy; Antitubercular Agents
PubMed: 38893370
DOI: 10.3390/molecules29112493 -
Molecules (Basel, Switzerland) May 2024m6A methylation, a ubiquitous modification on circRNAs, exerts a profound influence on RNA function, intracellular behavior, and diverse biological processes, including...
m6A methylation, a ubiquitous modification on circRNAs, exerts a profound influence on RNA function, intracellular behavior, and diverse biological processes, including disease development. While prediction algorithms exist for mRNA m6A modifications, a critical gap remains in the prediction of circRNA m6A modifications. Therefore, accurate identification and prediction of m6A sites are imperative for understanding RNA function and regulation. This study presents a novel hybrid model combining a convolutional neural network (CNN) and a bidirectional long short-term memory network (BiLSTM) for precise m6A methylation site prediction in circular RNAs (circRNAs) based on data from HEK293 cells. This model exploits the synergy between CNN's ability to extract intricate sequence features and BiLSTM's strength in capturing long-range dependencies. Furthermore, the integrated attention mechanism empowers the model to pinpoint critical biological information for studying circRNA m6A methylation. Our model, exhibiting over 78% prediction accuracy on independent datasets, offers not only a valuable tool for scientific research but also a strong foundation for future biomedical applications. This work not only furthers our understanding of gene expression regulation but also opens new avenues for the exploration of circRNA methylation in biological research.
Topics: RNA, Circular; Humans; Neural Networks, Computer; Methylation; HEK293 Cells; Computational Biology; Algorithms; Adenosine
PubMed: 38893304
DOI: 10.3390/molecules29112429 -
International Journal of Molecular... Jun 2024Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World...
Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist , which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.
Topics: Giardiasis; Giardia lamblia; Molecular Docking Simulation; Antiprotozoal Agents; United States; United States Food and Drug Administration; Humans; Protozoan Proteins; Molecular Dynamics Simulation
PubMed: 38892424
DOI: 10.3390/ijms25116238 -
BMC Complementary Medicine and Therapies Jun 2024The present study aimed to assess the anti-leishmanial effects of curcumin nanoemulsion (CUR-NE) against Leishmania major (MRHO/IR/75/ER) in both in vitro and in vivo...
The present study aimed to assess the anti-leishmanial effects of curcumin nanoemulsion (CUR-NE) against Leishmania major (MRHO/IR/75/ER) in both in vitro and in vivo experiments. CUR-NE was successfully prepared via the spontaneous emulsification method. The in vitro effect of various concentrations of CUR-NE against L. major promastigotes was assessed using the flow cytometry method. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 10L. major promastigotes. Mice were treated with topical CUR-NE (2.5 mg/ml), intra-lesion injection of CUR-NE (2.5 mg/ml), topical CUR suspension (CUR-S, 2.5 mg/ml), topical NE without CUR (NE-no CUR), amphotericin B as the positive control group, and infected untreated mice as the negative control group. In vitro exposure of promastigotes to CUR-NE showed a dose-dependent anti-leishmanial effect, with a 67.52 ± 0.35% mortality rate at a concentration of 1250 µg/ml and an IC50 of 643.56 µg/ml. In vivo experiments showed that topical CUR-NE and CUR-S significantly decreased the mean lesion size in mice after four weeks from 4.73 ± 1.28 to 2.78 ± 1.28 mm and 4.45 ± 0.88 to 3.23 ± 0.59 mm, respectively (p = 0.001). Furthermore, CUR-NE significantly decreased the parasite load in treated mice compared with the negative control group (p = 0.001). Results from the current study demonstrated the promising activity of CUR-NE against L. major in both in vitro and in vivo experiments. Moreover, CUR-NE was more efficient than CUR-S in healing and reducing parasite burden in mouse models. Future studies should aim to identify molecular mechanisms as well as the pharmacologic and pharmacokinetic aspects of CUR-NE.
Topics: Animals; Curcumin; Mice, Inbred BALB C; Leishmania major; Mice; Emulsions; Leishmaniasis, Cutaneous; Antiprotozoal Agents; Female; Nanoparticles
PubMed: 38890586
DOI: 10.1186/s12906-024-04522-1 -
Communications Biology Jun 2024Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA...
Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.
Topics: Plasmodium falciparum; Lysine-tRNA Ligase; Protein Kinase Inhibitors; Anaplastic Lymphoma Kinase; Antimalarials; Structure-Activity Relationship; Humans; Protozoan Proteins
PubMed: 38890421
DOI: 10.1038/s42003-024-06455-4