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BioRxiv : the Preprint Server For... Jun 2024Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually...
Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually counting parasite-infected red blood cells (iRBCs), a time-consuming process, which can be inconsistent between individuals and labs. We have developed an easy-to-use machine learning (ML)-based software, Malaria Screener R, to expedite and standardize such studies by automating the counting of iRBCs in rodents. This software can process Giemsa-stained blood smear images captured by any camera-equipped microscope. It features an intuitive graphical user interface that facilitates image processing and visualization of the results. The software has been developed as a desktop application that processes images on standard Windows and Mac OS computers. A previous ML model created by the authors designed to count -infected human RBCs did not perform well counting -infected mouse RBCs. We leveraged that model by loading the pre-trained weights and training the algorithm with newly collected data to target and mouse iRBCs. This new model reliably measured both and parasitemia (R = 0.9916). Additional rounds of training data to incorporate variances due to length of Giemsa staining, microscopes etc, have produced a generalizable model, meeting WHO Competency Level 1 for the sub-category of parasite counting using independent microscopes. Reliable, automated analyses of blood-stage parasitemia will facilitate rapid and consistent evaluation of novel vaccines and antimalarials across labs in an easily accessible malaria model.
PubMed: 38895284
DOI: 10.1101/2024.06.05.597554 -
ACS Medicinal Chemistry Letters Jun 2024and are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal...
and are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal therapy highlights the need for new drugs. In our previous work, we demonstrated that an analogue of the clinically used antimalarial mefloquine, (8-chloro-2-(4-chlorophenyl)quinolin-4-yl)(piperidin-2-yl)methanol (), has both antifungal activity and the ability to penetrate the central nervous system. Herein we describe the synthesis and antifungal assay of all four stereoisomers of . All four stereoisomers retain potent antifungal activity with the enantiomers having MIC values of 1 and 4 μg/mL against and respectively, and enantiomers, MIC values of 2 and 8 μg/mL, respectively. These results indicate that the stereochemistry of the piperidine methanol group is not critical for the antifungal properties of and gives guidance to future medicinal chemistry optimization efforts.
PubMed: 38894917
DOI: 10.1021/acsmedchemlett.4c00031 -
International Journal of Molecular... Jun 2024Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are... (Review)
Review
Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.
Topics: Protein Processing, Post-Translational; Life Cycle Stages; Humans; Animals; Protozoan Proteins; Plasmodium; Malaria; Host-Parasite Interactions
PubMed: 38892332
DOI: 10.3390/ijms25116145 -
Advances in Rheumatology (London,... Jun 2024To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
OBJECTIVE
To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
METHODS
Two methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.
RESULTS
All SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.
CONCLUSION
This consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.
Topics: Lupus Nephritis; Humans; Immunosuppressive Agents; Brazil; Societies, Medical; Creatinine; Proteinuria; Mycophenolic Acid; Antibodies, Monoclonal, Humanized; Rheumatology; Rituximab; Biopsy; Cyclophosphamide; Leflunomide; Glucocorticoids; Hydroxychloroquine; Azathioprine; Remission Induction; Cyclosporine; Evidence-Based Medicine; Consensus; Disease Progression; Kidney Failure, Chronic; Randomized Controlled Trials as Topic
PubMed: 38890752
DOI: 10.1186/s42358-024-00386-8 -
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 -
Nature Communications Jun 2024With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833),...
With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
Topics: Plasmodium falciparum; Acetamides; Protozoan Proteins; Antimalarials; Animals; Carrier Proteins; Mutation; Malaria, Falciparum; Humans; Drug Resistance; Life Cycle Stages
PubMed: 38890312
DOI: 10.1038/s41467-024-49491-8 -
BMJ Case Reports Jun 2024We introduce the case of a male patient in his 60s who was admitted to our emergency department with a persisting sore throat for the last 3 weeks and dysphagia....
We introduce the case of a male patient in his 60s who was admitted to our emergency department with a persisting sore throat for the last 3 weeks and dysphagia. Fibre-endoscopic evaluation revealed an asymmetry at the base of the tongue. In combination with elevated white cell count and C reactive protein, a computerized tomography showed a superinfected thyroglossal duct cyst. Intravenous antibiotics were initiated, and the patient was taken to the operating room for cervicotomy. The microbiological swab taken intraoperatively detected Additional imaging revealed disseminated nocardiosis with cerebral and pulmonary manifestations.The patient was treated with oral trimethoprim/sulfamethoxazole and, over time, showed complete remission of central nervous system lesions and improvement of pulmonary involvement. Following this, the treatment was stopped 8 months after the initial diagnosis. In this report, we discuss treatment standards and outcomes of nocardiosis based on our management strategies of our patient.
Topics: Humans; Male; Nocardia Infections; Thyroglossal Cyst; Middle Aged; Anti-Bacterial Agents; Trimethoprim, Sulfamethoxazole Drug Combination; Diagnosis, Differential; Tomography, X-Ray Computed; Nocardia
PubMed: 38890116
DOI: 10.1136/bcr-2024-259725 -
Tissue & Cell Jun 2024Hydroxychloroquine (HCQ), an antimalarial drug widely used in treating rheumatoid disorders. Many side effects have been reported with HCQ administration indicating its...
Effects of prolonged hydroxychloroquine use on the pancreatic tissue and expected ameliorative effect of lactoferrin in rats (biochemical, histological, and morphometric study).
Hydroxychloroquine (HCQ), an antimalarial drug widely used in treating rheumatoid disorders. Many side effects have been reported with HCQ administration indicating its hazardous effects on various organs. No previous studies reported the effect of long-term administration of oral HCQ on pancreatic tissue. Our study assessed pancreatic tissues functional and histopathological alterations following prolonged oral administration of HCQ. We also investigated the possible ameliorative effects of the lactoferrin (LF) coadministration with HCQ in adult male albino rats. Forty adult male Wister albino rats were divided into: negative control, LF positive control (2 g/kg), HCQ-treated (200 mg/kg), and HCQ+LF treated. Biochemical, histological, immunohistochemical, and morphometric analyses of the pancreatic tissues were conducted. Our findings revealed that prolonged oral administration of HCQ induced significant disruption of the pancreatic acinar architecture, enlarged congested islets of Langerhans, and elevated plasma insulin, amylase, and lipase levels. Interestingly, LF administration ameliorated the deleterious effects of prolonged HCQ administration on pancreatic tissue of adult male albino rats. In conclusion, prolonged oral administration of HCQ induced pancreatic tissue damage in rats, while LF attenuates HCQ-induced pancreatic injury. Our results emphasized the necessity of prescribing HCQ with caution, considering both dosage and treatment duration.
PubMed: 38889555
DOI: 10.1016/j.tice.2024.102439 -
Journal of Hazardous Materials Aug 2024In this study, oversized microplastics (OMPs) were intentionally introduced into soil containing manure-borne doxycycline (DOX). This strategic approach was used to...
Multiomics analysis of the effects of manure-borne doxycycline combined with oversized fiber microplastics on pak choi growth and the risk of antibiotic resistance gene transmission.
In this study, oversized microplastics (OMPs) were intentionally introduced into soil containing manure-borne doxycycline (DOX). This strategic approach was used to systematically examine the effects of combined OMP and DOX pollution on the growth of pak choi, analyze alterations in soil environmental metabolites, and explore the potential migration of antibiotic resistance genes (ARGs). The results revealed a more pronounced impact of DOX than of OMPs. Slender-fiber OMPs (SF OMPs) had a more substantial influence on the growth of pak choi than did coarse-fiber OMPs (CF OMPs). Conversely, CF OMPs had a more significant effect on the migration of ARGs within the system. When DOX was combined with OMPs, the negative effects of DOX on pak choi growth were mitigated through the synthesis of indole through the adjustment of carbon metabolism and amino acid metabolism in pak choi roots. In this process, Pseudohongiellaceae and Xanthomonadaceae were key bacteria. During the migration of ARGs, the potential host bacterium Limnobacter should be considered. Additionally, the majority of potential host bacteria in the pak choi endophytic environment were associated with tetG. This study provides insights into the intricate interplay among DOX, OMPs, ARGs, plant growth, soil metabolism, and the microbiome.
Topics: Doxycycline; Anti-Bacterial Agents; Manure; Soil Pollutants; Microplastics; Drug Resistance, Microbial; Soil Microbiology; Bacteria; Genes, Bacterial; Drug Resistance, Bacterial; Multiomics
PubMed: 38889467
DOI: 10.1016/j.jhazmat.2024.134931 -
EXCLI Journal 2024Malaria has developed as a serious worldwide health issue as a result of the introduction of resistant species strains. Because of the common chemo resistance to most... (Review)
Review
Malaria has developed as a serious worldwide health issue as a result of the introduction of resistant species strains. Because of the common chemo resistance to most of the existing drugs on the market, it poses a severe health problem and significant obstacles in drug research. Malaria treatment has evolved during the last two decades in response to drug sensitivity and a return of the disease in tropical areas. is now highly resistant to the majority of antimalarial drugs. The parasite resistance drew focus to developing novel antimalarials to combat parasite resistance. The requirement for many novel antimalarial drugs in the future year necessitates adopting various drug development methodologies. Different innovative strategies for discovering antimalarial drugs are now being examined here. This review is primarily concerned with the description of newly synthesized antimalarial compounds, i.e. Tafenoquine, Cipargamin, Ferroquine, Artefenomel, DSM265, MMV390048 designed to improve the activity of pure antimalarial enantiomers. In this review, we selected the representative malarial drugs in clinical trials, classified them with detailed targets according to their action, discussed the relationship within the human trials, and generated a summative discussion with prospective expectations.
PubMed: 38887396
DOI: 10.17179/excli2023-6856