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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 -
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