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Telemedicine Journal and E-health : the... May 2024n p p p
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Topics: Humans; Malaria; Female; Smartphone; Mobile Applications; Male; Antimalarials; Adult; Middle Aged; Spain; Travel; Medication Adherence; Young Adult
PubMed: 38215269
DOI: 10.1089/tmj.2023.0200 -
Anti-cancer Drugs Apr 2024The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly...
The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly understood. In our previous studies, we highlighted the association between isoprenylcysteine carboxylmethyltransferase (ICMT) and chemoresistance in NPC. In this current research, we revealed that both 5-FU and cisplatin-resistant NPC cells exhibited elevated mitochondrial function and increased expression of mitochondrial genes, independent of ICMT. Our investigations further showed that classic mitochondrial inhibitors, such as oligomycin, antimycin, and rotenone, were notably more effective in reducing viability in chemo-resistant NPC cells compared to parental cells. Moreover, we identified two antimicrobial drugs, tigecycline and atovaquone, recognized as mitochondrial inhibitors, as potent agents for decreasing chemo-resistant NPC cells by targeting mitochondrial respiration. Remarkably, tigecycline and atovaquone, administered at tolerable doses, inhibited chemo-resistant NPC growth in mouse models and extended overall survival rates. This work unveils the efficacy of mitochondrial inhibition as a promising strategy to overcome chemo-resistance in NPC. Additionally, our findings highlight the potential repurposing of clinically available drugs like tigecycline and atovaquone for treating NPC patients who develop chemoresistance.
Topics: Animals; Mice; Humans; Nasopharyngeal Carcinoma; Drug Resistance, Neoplasm; Atovaquone; Tigecycline; Cell Line, Tumor; Cisplatin; Mitochondria; Nasopharyngeal Neoplasms
PubMed: 38215016
DOI: 10.1097/CAD.0000000000001566 -
Cell Death & Disease Jan 2024Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells....
Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
Topics: Humans; Animals; Mice; Atovaquone; Electron Transport Complex III; Neoplasms; CD8-Positive T-Lymphocytes; Immunotherapy; B7-H1 Antigen; Tumor Microenvironment
PubMed: 38212297
DOI: 10.1038/s41419-023-06405-8 -
The Journal of Infectious Diseases Jan 2024Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights...
Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights the need for new and more effective treatments. Here we demonstrate that the 8-aminoquinoline antimalarial drug tafenoquine inhibits the growth of different Babesia species in vitro, is highly effective against Babesia microti and Babesia duncani in mice and protects animals from lethal infection caused by atovaquone-sensitive and -resistant B. duncani strains. We further show that a combination of tafenoquine and atovaquone achieves cure with no recrudescence in both models of human babesiosis. Interestingly, elimination of B. duncani infection in animals following drug treatment also confers immunity to subsequent challenge. Altogether, the data demonstrate superior efficacy of tafenoquine plus atovaquone combination over current therapies for the treatment of human babesiosis and highlight its potential in providing protective immunity against Babesia following parasite clearance.
Topics: Humans; Animals; Mice; Babesiosis; Atovaquone; Babesia; Models, Theoretical; Aminoquinolines
PubMed: 38169301
DOI: 10.1093/infdis/jiad315 -
Biomaterials Mar 2024Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair...
Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair abilities of cancer cells. Mitochondria, as the pivotal player in ferroptosis, exhibit tremendous therapeutic potential by targeting the intramitochondrial anti-ferroptotic pathway mediated by dihydroorotate dehydrogenase (DHODH). In this study, an albumin-based nanomedicine was developed to induce augmented ferroptosis in triple-negative breast cancer (TNBC) by depleting glutathione (GSH) and inhibiting DHODH activity. The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). SRF is an FDA-approved ferroptosis inducer and ATO is the only drug used in clinical that targets mitochondria. By combining the effects of SRF and ATO, ATO/SRF@BSA promoted the accumulation of lipid peroxides within mitochondria by inhibiting the glutathione peroxidase 4 (GPX4)-GSH pathway and downregulating the DHODH-coenzyme Q (CoQH) defense mechanism, triggers a burst of lipid peroxides. Simultaneously, ATO/SRF@BSA suppressed cancer cell self-repair and enhanced cell death by inhibiting the synthesis of adenosine triphosphate (ATP) and pyrimidine nucleotides. Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.
Topics: Humans; Dihydroorotate Dehydrogenase; Triple Negative Breast Neoplasms; Ferroptosis; Lipid Peroxides; Serum Albumin, Bovine; Atovaquone; Glutathione; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38154441
DOI: 10.1016/j.biomaterials.2023.122447 -
Acta Parasitologica Mar 2024The study aimed to investigate genetic diversity in Babesia gibsoni, the causative agent of canine babesiosis, and to assess the presence of atovaquone-resistant...
PURPOSE
The study aimed to investigate genetic diversity in Babesia gibsoni, the causative agent of canine babesiosis, and to assess the presence of atovaquone-resistant isolates in naturally infected dogs.
METHODS
A total of 24 blood samples confirmed for B. gibsoni infection was subjected to PCR amplification and sequencing based on cytb gene. Genetic characterization of B. gibsoni as well as attempts to detect the point mutation rendering atovaquone resistance was carried out based on the analysis of nucleotide sequence of cytb gene using bioinformatics software.
RESULTS
The findings indicated that the B. gibsoni isolates in the investigation exhibited a high nucleotide identity with the Asian genotype, ranging from 98.41 to 98.69%. Notably, none of the isolates carried cytb gene variants associated with atovaquone resistance. Phylogenetic analysis revealed clustering of most isolates with those from Japan and China, except for one isolate forming a distinct subclade. Haplotype network analysis indicated a high diversity with 22 distinct haplotypes among the B. gibsoni isolates, emphasizing the genetic variability within the studied population.
CONCLUSION
In conclusion, the cytb gene exhibited remarkable conservation among the twenty-four B. gibsoni isolates studied and the study represents the first genetic diversity assessment of B. gibsoni using the cytb gene in dogs from India. These findings shed light on the genetic characteristics of B. gibsoni in the region and provide valuable insight for addressing the challenges posed by this life-threatening disease in dogs.
Topics: Dogs; Animals; Babesia; Babesiosis; Dog Diseases; Genetic Variation; India; Phylogeny; Cytochromes b; Haplotypes; Atovaquone; Drug Resistance; Genotype; Polymerase Chain Reaction
PubMed: 38133744
DOI: 10.1007/s11686-023-00757-z -
Methods in Molecular Biology (Clifton,... 2024Atovaquone is an FDA-approved antiparasitic and antifungal therapeutic that is currently used as a prophylactic agent to prevent Pneumocystis carinii pneumonia (PCP)...
Atovaquone is an FDA-approved antiparasitic and antifungal therapeutic that is currently used as a prophylactic agent to prevent Pneumocystis carinii pneumonia (PCP) infections in acute myeloid leukemia (AML) patients after receiving hematopoietic stem cell transplantation (HSCT). Recent studies have shown that atovaquone has shown potential as an anticancer agent. The high variability in atovaquone bioavailability prompts the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients. Briefly, an organic-based solvent system is used to precipitate protein and extract the atovaquone content from each patient-derived plasma sample. After completing a second stage of sample dilution (5000-fold overall), a 2 μL volume of the plasma extract is analyzed using the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based bioanalytical method described.
Topics: Humans; Child; Atovaquone; Pneumonia, Pneumocystis; Tandem Mass Spectrometry; Chromatography, Liquid; Antifungal Agents; Leukemia, Myeloid, Acute; Plant Extracts
PubMed: 38036811
DOI: 10.1007/978-1-0716-3541-4_7 -
Nanoscale Advances Nov 2023Inherent barrier properties of the skin impose significant challenges to the transdermal delivery of drugs to systemic circulation. Here, the transdermal permeation and...
Inherent barrier properties of the skin impose significant challenges to the transdermal delivery of drugs to systemic circulation. Here, the transdermal permeation and deposition of an anti-malarial prophylactic atovaquone solid drug nanoformulation is radiometrically evaluated following application of a solid microneedle format.
PubMed: 38024306
DOI: 10.1039/d3na00454f -
Microbiology Spectrum Jan 2024This study is the first of its kind that suggests exosomes as a nano-carrier loaded with atovaquone (ATQ), which could be considered as a new strategy for improving the...
This study is the first of its kind that suggests exosomes as a nano-carrier loaded with atovaquone (ATQ), which could be considered as a new strategy for improving the effectiveness of ATQ against acute and chronic phases of .
Topics: Atovaquone; Toxoplasma; Exosomes; Macrophages
PubMed: 38014940
DOI: 10.1128/spectrum.03080-23 -
Animals : An Open Access Journal From... Nov 2023Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus , mainly . The even wider diffusion...
Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus , mainly . The even wider diffusion of the disease, probably because of the increase in the areas covered by their mosquito vectors, may pose new risks for avian species lacking natural resistance (especially those from artic or sub-artic environments) or those hosted in structures like zoos and wildlife rescue centers. With that premise, this study describes the efficacy and safety of a therapeutic protocol to treat avian malaria in three snowy owls () hosted in a wildlife rescue center in Apulia, south of Italy, and affected by avian malaria by . The protocol consisted of administering 10/4 mg/kg atovaquone/proguanil per os once a day for three consecutive days, repeating this seven days later. Seven days after the end of the treatment, was not detected in the birds' blood and no adverse effects were observed during the 60 days of monitoring after the end of the treatment. Therefore, a therapeutic regimen of 10/4 mg/kg/day may be considered safe and effective in a valuable and endangered species such as .
PubMed: 38003076
DOI: 10.3390/ani13223457