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Medicina (Kaunas, Lithuania) Jun 2024: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater...
: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater Mekong Subregion, including Vietnam, due to the spread of resistant malaria strains. This study was conducted to assess the efficacy of the Dihydroartemisinin (DHA)-Piperaquine (PPQ) regimen in treating uncomplicated malaria and to conduct molecular surveillance of antimalarial drug resistance in Binh Phuoc and Dak Nong provinces. : The study included 63 uncomplicated malaria falciparum patients from therapeutic efficacy studies (TES) treated following the WHO treatment guidelines (2009). Molecular marker analysis was performed on all 63 patients. Methods encompassed Sanger sequencing for mutations and quantitative real-time PCR for the gene. : This study found a marked decrease in the efficacy of the DHA-PPQ regimen, with an increased rate of treatment failures at two study sites. Genetic analysis revealed a significant presence of mutations and amplifications, indicating emerging resistance to artemisinin and its partner drug. : The effectiveness of the standard DHA-PPQ regimen has sharply declined, with rising treatment failure rates. This decline necessitates a review and possible revision of national malaria treatment guidelines. Importantly, molecular monitoring and clinical efficacy assessments together provide a robust framework for understanding and addressing detection drug resistance in malaria.
Topics: Humans; Artemisinins; Quinolines; Vietnam; Antimalarials; Malaria, Falciparum; Male; Female; Adult; Plasmodium falciparum; Drug Resistance; Adolescent; Middle Aged; Drug Therapy, Combination; Young Adult; Protozoan Proteins; Real-Time Polymerase Chain Reaction; Mutation; Piperazines
PubMed: 38929629
DOI: 10.3390/medicina60061013 -
Medicina (Kaunas, Lithuania) May 2024Hydroxychloroquine sulfate (HCQ) is a lysosomotropic agent administered in systemic lupus erythematosus and rheumatoid arthritis that has fewer toxic effects than...
Hydroxychloroquine sulfate (HCQ) is a lysosomotropic agent administered in systemic lupus erythematosus and rheumatoid arthritis that has fewer toxic effects than chloroquine. However, HCQ may still be responsible for retinal toxicity. In this study, we observed structural changes in the retinas of experimental rats after prolonged exposure to HCQ. We investigated several aspects regarding retinal changes, at both the histopathological and ultrastructural levels. We used 96 male albino Wistar rats distributed into four equal groups (n = 24 per group): the first three groups were treated with different doses of HCQ (50, 100, and 200 mg/kg HCQ, injected intraperitoneally in a single dose daily), and the last group (the control group, n = 24) was treated with saline solution administered in the same way (0.4 mL of saline solution). The treated groups received HCQ daily for 4 months, and every month, six animals from each group were sacrificed to assess retinal changes. The eyes were examined via optical (OM) and electronic microscopy (EM). Statistical analysis was deployed, and results regarding retinal morpho-photometry were acquired. We observed structural retinal changes in both high and low doses of HCQ; while high doses determined a significant thinning of the retina, lower doses caused retinal thickening. Morphological retinal changes upon exposure to HCQ are believed to be caused by accumulated HCQ in lysosomes found in retinal ganglion cells and in the inner nuclear and photoreceptor cell layers. Such changes were most evident in the group receiving HCQ intraperitoneally in doses of 100 mg/kg for a longer period (4 months). The present study highlights histopathological and ultrastructural retinal changes induced by chronic HCQ administration, which were strongly connected to the dosage and period of exposure.
Topics: Hydroxychloroquine; Animals; Rats, Wistar; Rats; Retina; Male; Antirheumatic Agents
PubMed: 38929463
DOI: 10.3390/medicina60060846 -
International Journal of Environmental... May 2024Multidrug- and artemisinin-resistant (ART-R) parasites represent a challenge for malaria elimination worldwide. Molecular monitoring in the Kelch domain region gene...
Multidrug- and artemisinin-resistant (ART-R) parasites represent a challenge for malaria elimination worldwide. Molecular monitoring in the Kelch domain region gene allows tracking mutations in parasite resistance to artemisinin. The increase in illegal miners in the Roraima Yanomami indigenous land (YIL) could favor ART-R parasites. Thus, this study aimed to investigate ART-R in patients from illegal gold mining areas in the YIL of Roraima, Brazil. A questionnaire was conducted, and blood was collected from 48 patients diagnosed with or mixed malaria (). The DNA was extracted and the gene was amplified by PCR. The amplicons were subjected to DNA-Sanger-sequencing and the entire amplified fragment was analyzed. Among the patients, 96% (46) were from illegal mining areas of the YIL. All parasite samples carried the wild-type genotypes/ART-sensitive phenotypes. These data reinforce the continued use of artemisinin-based combination therapies (ACTs) in Roraima, as well as the maintenance of systematic monitoring for early detection of parasite populations resistant to ART, mainly in regions with an intense flow of individuals from mining areas, such as the YIL. This is especially true when the achievement of falciparum malaria elimination in Brazil is planned and expected by 2030.
Topics: Artemisinins; Brazil; Plasmodium falciparum; Humans; Antimalarials; Drug Resistance; Malaria, Falciparum; Male; Mining; Adult; Female; Middle Aged; Young Adult; Adolescent; Genotype
PubMed: 38928926
DOI: 10.3390/ijerph21060679 -
International Journal of Molecular... Jun 2024Sulfonamides can be effectively removed from wastewater through a photocatalytic process. However, the mineralization achieved by this method is a long-term and...
Sulfonamides can be effectively removed from wastewater through a photocatalytic process. However, the mineralization achieved by this method is a long-term and expensive process. The effect of shortening the photocatalytic process is the partial degradation and formation of intermediates. The purpose of this study was to evaluate the sensitivity and transformation of photocatalytic reaction intermediates in aerobic biological processes. Sulfadiazine and sulfamethoxazole solutions were used in the study, which were irradiated in the presence of a TiO-P25 catalyst. The resulting solutions were then aerated after the addition of river water or activated sludge suspension from a commercial wastewater treatment plant. The reaction kinetics were determined and fifteen products of photocatalytic degradation of sulfonamides were identified. Most of these products were further transformed in the presence of activated sludge suspension or in water taken from the river. They may have been decomposed into other organic and inorganic compounds. The formation of biologically inactive acyl derivatives was observed in the biological process. However, compounds that are more toxic to aquatic organisms than the initial drugs can also be formed. After 28 days, the sulfamethoxazole concentration in the presence of activated sludge was reduced by 66 ± 7%. Sulfadiazine was practically non-biodegradable under the conditions used. The presented results confirm the advisability of using photocatalysis as a process preceding biodegradation.
Topics: Biodegradation, Environmental; Kinetics; Sulfonamides; Catalysis; Water Pollutants, Chemical; Titanium; Sulfamethoxazole; Photolysis; Wastewater; Sewage; Sulfadiazine; Water Purification
PubMed: 38928394
DOI: 10.3390/ijms25126688 -
International Journal of Molecular... Jun 2024Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell...
Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase ( NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.
Topics: Nitroreductases; Nitroimidazoles; Metronidazole; Prodrugs; Escherichia coli Proteins; Positron-Emission Tomography; Escherichia coli; Catalytic Domain; Protein Engineering; Models, Molecular; Aziridines
PubMed: 38928299
DOI: 10.3390/ijms25126593 -
International Journal of Molecular... Jun 2024It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid...
It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid arthritis. The molecular chaperone HSP60 alone induces inflammatory cytokine IL-6 and the co-chaperone HSP10 alone inhibits IL-6 induction. HSP60 and HSP10 form a complex in the presence of ATP. We analyzed the effects of Mizoribine, which is structurally similar to ATP, on the structure and physiological functions of HSP60-HSP10 using Native/PAGE and transmission electron microscopy. At low concentrations of Mizoribine, no complex formation of HSP60-HSP10 was observed, nor was the expression of IL-6 affected. On the other hand, high concentrations of Mizoribine promoted HSP60-HSP10 complex formation and consequently suppressed IL-6 expression. Here, we propose a novel mechanism of immunosuppressive action of Mizoribine.
Topics: Ribonucleosides; Interleukin-6; Chaperonin 60; Humans; Immunosuppressive Agents; Animals; Mice
PubMed: 38928158
DOI: 10.3390/ijms25126452 -
International Journal of Molecular... Jun 2024Chloroquine (CQ) is a 4-aminoquinoline derivative largely employed in the management of malaria. CQ treatment exploits the drug's ability to cross the erythrocyte...
Chloroquine (CQ) is a 4-aminoquinoline derivative largely employed in the management of malaria. CQ treatment exploits the drug's ability to cross the erythrocyte membrane, inhibiting heme polymerase in malarial trophozoites. Accumulation of CQ prevents the conversion of heme to hemozoin, causing its toxic buildup, thus blocking the survival of Plasmodium parasites. Recently, it has been reported that CQ is able to exert antiviral properties, mainly against HIV and SARS-CoV-2. This renewed interest in CQ treatment has led to the development of new studies which aim to explore its side effects and long-term outcome. Our study focuses on the effects of CQ in non-parasitized red blood cells (RBCs), investigating hemoglobin (Hb) functionality, the anion exchanger 1 (AE1) or band 3 protein, caspase 3 and protein tyrosine phosphatase 1B (PTP-1B) activity, intra and extracellular ATP levels, and the oxidative state of RBCs. Interestingly, CQ influences the functionality of both Hb and AE1, the main RBC proteins, affecting the properties of Hb oxygen affinity by shifting the conformational structure of the molecule towards the R state. The influence of CQ on AE1 flux leads to a rate variation of anion exchange, which begins at a concentration of 2.5 μM and reaches its maximum effect at 20 µM. Moreover, a significant decrease in intra and extracellular ATP levels was observed in RBCs pre-treated with 10 µM CQ vs. erythrocytes under normal conditions. This effect is related to the PTP-1B activity which is reduced in RBCs incubated with CQ. Despite these metabolic alterations to RBCs caused by exposure to CQ, no signs of variations in oxidative state or caspase 3 activation were recorded. Our results highlight the antithetical effects of CQ on the functionality and metabolism of RBCs, and encourage the development of new research to better understand the multiple potentiality of the drug.
Topics: Erythrocytes; Humans; Chloroquine; Hemoglobins; Anion Exchange Protein 1, Erythrocyte; Adenosine Triphosphate; Antimalarials; Caspase 3
PubMed: 38928131
DOI: 10.3390/ijms25126424 -
Antibiotics (Basel, Switzerland) Jun 2024() is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs...
() is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 μM against type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against were identified. Among them, bithionol, a clinically approved antiparasitic agent, showed excellent antibacterial activity and inhibited the growth of three different subtypes of from 0.625 μM to 2.5 μM. We confirmed the bactericidal activity of bithionol by the MBC/MIC ratio being ≤4 and the time-kill curve study and also electron microscopy study. Interestingly, it was found that at 128 μg/mL, bithionol could completely eliminate biofilms after 48h, demonstrating an outstanding antibiofilm capability compared to commonly used antibiotics. Additionally, bithionol could eliminate 99.9% of biofilm bacteria at 64 μg/mL, 99% at 32 μg/mL, and 90% at 16 μg/mL. Therefore, bithionol may be a potential candidate for the treatment of infections due to its significant antimicrobial and antibiofilm activities.
PubMed: 38927195
DOI: 10.3390/antibiotics13060529 -
Biomolecules Jun 2024Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and...
Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and tumorigenesis. However, adaptation to mitochondrial dysfunction can occur through the activation of survival pathways, whose mechanisms are still poorly understood. The yeast is an invaluable model organism for studying how mitochondrial dysfunction can affect stress response and adaptation processes. In this study, we analyzed and compared in the absence and in the presence of osmostress wild-type cells with two models of cells lacking mitochondrial DNA: ethidium bromide-treated cells (ρ) and cells lacking the mitochondrial pyrimidine nucleotide transporter (Δ). Our results revealed that the lack of mitochondrial DNA provides an advantage in the kinetics of stress response. Additionally, wild-type cells exhibited higher osmosensitivity in the presence of respiratory metabolism. Mitochondrial mutants showed increased glycerol levels, required in the short-term response of yeast osmoadaptation, and prolonged oxidative stress. The involvement of the mitochondrial retrograde signaling in osmoadaptation has been previously demonstrated. The expression of , encoding the peroxisomal isoform of citrate synthase and whose up-regulation is prototypical of RTG pathway activation, appeared to be increased in the mutants. Interestingly, selected TCA cycle genes, and , whose expression depends on RTG signaling upon stress, showed a different regulation in ρ and Δ cells. These data suggest that osmoadaptation can occur through different mechanisms in the presence of mitochondrial defects and will allow us to gain insight into the relationships among metabolism, mitochondria-mediated stress response, and cell adaptation.
Topics: Saccharomyces cerevisiae; DNA, Mitochondrial; Saccharomyces cerevisiae Proteins; Mitochondria; Adaptation, Physiological; Oxidative Stress; Glycerol; Ethidium
PubMed: 38927107
DOI: 10.3390/biom14060704 -
Malaria Journal Jun 2024Although Tanzania adopted and has been implementing effective interventions to control and eventually eliminate malaria, the disease is still a leading public health...
High prevalence and risk of malaria among asymptomatic individuals from villages with high prevalence of artemisinin partial resistance in Kyerwa district of Kagera region, north-western Tanzania.
BACKGROUND
Although Tanzania adopted and has been implementing effective interventions to control and eventually eliminate malaria, the disease is still a leading public health problem, and the country experiences heterogeneous transmission. Recent studies reported the emergence of parasites with artemisinin partial resistance (ART-R) in Kagera region with high prevalence (> 10.0%) in two districts of Karagwe and Kyerwa. This study assessed the prevalence and predictors/risk of malaria infections among asymptomatic individuals living in a hyperendemic area where ART-R has emerged in Kyerwa District of Kagera region, north-western Tanzania.
METHODS
This was a community-based cross-sectional survey which was conducted in July and August 2023 and involved individuals aged ≥ 6 months from five villages in Kyerwa district. Demographic, anthropometric, clinical, parasitological, type of house inhabited and socio-economic status (SES) data were collected using electronic capture tools run on Open Data Kit (ODK) software. Predictors/risks of malaria infections were determined by univariate and multivariate logistic regression, and the results were presented as crude (cORs) and adjusted odds ratios (aORs), with 95% confidence intervals (CIs).
RESULTS
Overall, 4454 individuals were tested using rapid diagnostic tests (RDTs), and 1979 (44.4%) had positive results. The prevalence of malaria infections ranged from 14.4% to 68.5% and varied significantly among the villages (p < 0.001). The prevalence and odds of infections were significantly higher in males (aOR = 1.28, 95% CI 1.08 -1.51, p = 0.003), school children (aged 5-≤10 years (aOR = 3.88, 95% CI 3.07-4.91, p < 0.001) and 10-≤15 years (aOR = 4.06, 95% CI 3.22-5.13, p < 0.001)) and among individuals who were not using bed nets (aOR = 1.22, 95% CI 1.03-1.46, p = 0.024). The odds of malaria infections were also higher in individuals with lower SES (aOR = 1.42, 95% CI 1.17-1.72, p < 0.001), and living in houses without windows (aOR = 2.08, 95% CI 1.46-2.96, p < 0.001), partially open (aOR = 1.33, 95% CI 1.11-1.58, p = 0.002) or fully open windows (aOR = 1.30, 95%CI 1.05-1.61, p = 0.015).
CONCLUSION
The five villages had a high prevalence of malaria infections and heterogeneity at micro-geographic levels. Groups with higher odds of malaria infections included school children, males, and individuals with low SES, living in poorly constructed houses or non-bed net users. These are important baseline data from an area with high prevalence of parasites with ART-R and will be useful in planning interventions for these groups, and in future studies to monitor the trends and potential spread of such parasites, and in designing a response to ART-R.
Topics: Tanzania; Male; Prevalence; Female; Humans; Artemisinins; Cross-Sectional Studies; Child; Child, Preschool; Adolescent; Adult; Young Adult; Antimalarials; Middle Aged; Infant; Drug Resistance; Malaria; Aged; Malaria, Falciparum; Risk Factors; Plasmodium falciparum
PubMed: 38926854
DOI: 10.1186/s12936-024-05019-5