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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 -
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 -
Bioinformatics (Oxford, England) Jun 2024Nanopore direct RNA sequencing (DRS) enables the detection of RNA N6-methyladenosine (m6A) without extra laboratory techniques. A number of supervised or comparative...
MOTIVATION
Nanopore direct RNA sequencing (DRS) enables the detection of RNA N6-methyladenosine (m6A) without extra laboratory techniques. A number of supervised or comparative approaches have been developed to identify m6A from Nanopore DRS reads. However, existing methods typically utilize either statistical features of the current signals or basecalling-error features, ignoring the richer information of the raw signals of DRS reads.
RESULTS
Here, we propose RedNano, a deep-learning method designed to detect m6A from Nanopore DRS reads by utilizing both raw signals and basecalling errors. RedNano processes the raw-signal feature and basecalling-error feature through residual networks. We validated the effectiveness of RedNano using synthesized, Arabidopsis, and human DRS data. The results demonstrate that RedNano surpasses existing methods by achieving higher area under the ROC curve (AUC) and area under the precision-recall curve (AUPRs) in all three datasets. Furthermore, RedNano performs better in cross-species validation, demonstrating its robustness. Additionally, when detecting m6A from an independent dataset of Populus trichocarpa, RedNano achieves the highest AUC and AUPR, which are 3.8%-9.9% and 5.5%-13.8% higher than other methods, respectively.
AVAILABILITY AND IMPLEMENTATION
The source code of RedNano is freely available at https://github.com/Derryxu/RedNano.
Topics: Arabidopsis; Humans; Sequence Analysis, RNA; Adenosine; Nanopore Sequencing; Deep Learning; RNA; Nanopores
PubMed: 38889266
DOI: 10.1093/bioinformatics/btae375 -
BMC Infectious Diseases Jun 2024Q fever, caused by the zoonotic pathogen Coxiella burnetii, exhibits a worldwide prevalence. In China, Q fever is not recognized as a notifiable disease, and the disease...
BACKGROUND
Q fever, caused by the zoonotic pathogen Coxiella burnetii, exhibits a worldwide prevalence. In China, Q fever is not recognized as a notifiable disease, and the disease is overlooked and underestimated in clinical practice, leading to diagnostic challenges.
CASE PRESENTATION
We present a case series of three patients diagnosed with persistent Q fever between 2022 and 2023. The average age of our three cases was 63.33 years old, consisting of two males and one female. The medical history of the individuals included previous valve replacement, aneurysm followed by aortic stent-graft placement and prosthetic hip joint replacement. At the onset of the disease, only one case exhibited acute fever, while the remaining two cases were devoid of any acute symptoms. The etiology was initially overlooked until metagenomic next-generation sequencing test identified Coxiella burnetii from the blood or biopsy samples. Delayed diagnosis was noted, with a duration ranging from three months to one year between the onset of the disease and its confirmation. The epidemiological history uncovered that none of the three cases had direct exposure to domestic animals or consumption of unpasteurized dairy products. Case 1 and 2 resided in urban areas, while Case 3 was a rural resident engaged in farming. All patients received combination therapy of doxycycline and hydroxychloroquine, and no recurrence of the disease was observed during the follow-up period.
CONCLUSION
Q fever is rarely diagnosed and reported in clinical practice in our country. We should be aware of persistent Q fever in high-risk population, even with unremarkable exposure history. Metagenomic next-generation sequencing holds great potential as a diagnostic tool for identifying rare and fastidious pathogens such as Coxiella burnetii.
Topics: Q Fever; Humans; Male; Middle Aged; Female; China; Coxiella burnetii; Aged; Delayed Diagnosis; Anti-Bacterial Agents; Doxycycline; High-Throughput Nucleotide Sequencing
PubMed: 38886677
DOI: 10.1186/s12879-024-09484-w -
Cell Death & Disease Jun 2024TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (mA) stands as one of the most abundant modifications on the mRNA...
TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (mA) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-β1 with mRNA mA modification, especially the effect of mRNA translation efficiency associated with mA modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-β1 expression in GBC. Overexpression of FOXA1 inhibited TGF-β1-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-β1 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-β1 promoted mA modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-β1. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting mA modification on the CDS region of FOXA1 mRNA. Moreover, TGF-β1 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-β1 in regulating TGF-β1/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through mA modification.
Topics: Hepatocyte Nuclear Factor 3-alpha; Humans; Transforming Growth Factor beta1; Gallbladder Neoplasms; Animals; Epithelial-Mesenchymal Transition; Cell Line, Tumor; Adenosine; Mice, Nude; Mice; Protein Biosynthesis; Neoplasm Metastasis; Gene Expression Regulation, Neoplastic; Cell Movement; RNA, Messenger; Mice, Inbred BALB C; Male
PubMed: 38886389
DOI: 10.1038/s41419-024-06800-9 -
Clinical and Translational Medicine Jun 2024Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal... (Review)
Review
Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N-methyladenosine (mA) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-mA RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the mA modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-mA RNA modifications. In this review, we mainly focus on the roles and implications of non-mA RNA modifications, including N-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2'-O-methylation, N-methyladenosine and N-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-mA RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-mA RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-mA modifiers in blood cancer.
Topics: Humans; Hematologic Neoplasms; RNA Processing, Post-Transcriptional; RNA; Adenosine
PubMed: 38880983
DOI: 10.1002/ctm2.1666 -
Journal of Microorganism Control 2024Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been...
Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been elucidated. In this study, we examined clinical and microbiological characteristics of invasive CPE infection occurring at 8 hospitals in Minami Ibaraki Area between July 2001 to June 2017. Of 7294 Enterobacterales strains isolated from independent cases of bacteremia and/or meningitis, 10 (0.14%) were CPE (8 Enterobacter cloacae-complex, 1 Escherichia coli, and 1 Edwardsiella tarda), all of which had the bla gene and susceptible to gentamicin and trimethoprim/sulfamethoxazole. These strains were isolated from 7 adult and 2 infant bacteremia (1 infant patient developed CPE bacteremia twice) after 2007. The most common portal of entry was intravenous catheters. All of the adult patients were recovered, while the infant patients eventually died. Genomic analyses showed that the 8 E. cloacae-complex strains were classified into 5 groups, each of which was exclusively detected in specific facilities at intervals of up to 3 years, suggesting persistent colonization in the facilities. This study showed that invasive CPE infection in the area was rare, caused by IMP-1-type CPE having susceptibility to various antibiotics, and nonfatal among adult patients.
Topics: Humans; Japan; Bacteremia; Enterobacteriaceae Infections; beta-Lactamases; Male; Female; Anti-Bacterial Agents; Bacterial Proteins; Infant; Microbial Sensitivity Tests; Middle Aged; Adult; Aged; Enterobacter cloacae; Gentamicins; Trimethoprim, Sulfamethoxazole Drug Combination; Aged, 80 and over; Carbapenem-Resistant Enterobacteriaceae
PubMed: 38880620
DOI: 10.4265/jmc.29.2_81