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1.
Brief Bioinform ; 25(3)2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38647153

RESUMEN

Computational drug repositioning, which involves identifying new indications for existing drugs, is an increasingly attractive research area due to its advantages in reducing both overall cost and development time. As a result, a growing number of computational drug repositioning methods have emerged. Heterogeneous network-based drug repositioning methods have been shown to outperform other approaches. However, there is a dearth of systematic evaluation studies of these methods, encompassing performance, scalability and usability, as well as a standardized process for evaluating new methods. Additionally, previous studies have only compared several methods, with conflicting results. In this context, we conducted a systematic benchmarking study of 28 heterogeneous network-based drug repositioning methods on 11 existing datasets. We developed a comprehensive framework to evaluate their performance, scalability and usability. Our study revealed that methods such as HGIMC, ITRPCA and BNNR exhibit the best overall performance, as they rely on matrix completion or factorization. HINGRL, MLMC, ITRPCA and HGIMC demonstrate the best performance, while NMFDR, GROBMC and SCPMF display superior scalability. For usability, HGIMC, DRHGCN and BNNR are the top performers. Building on these findings, we developed an online tool called HN-DREP (http://hn-drep.lyhbio.com/) to facilitate researchers in viewing all the detailed evaluation results and selecting the appropriate method. HN-DREP also provides an external drug repositioning prediction service for a specific disease or drug by integrating predictions from all methods. Furthermore, we have released a Snakemake workflow named HN-DRES (https://github.com/lyhbio/HN-DRES) to facilitate benchmarking and support the extension of new methods into the field.


Asunto(s)
Benchmarking , Reposicionamiento de Medicamentos , Reposicionamiento de Medicamentos/métodos , Humanos , Biología Computacional/métodos , Programas Informáticos , Algoritmos
2.
Org Biomol Chem ; 22(13): 2678, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38483197

RESUMEN

Correction and removal of expression of concern for 'Total synthesis of tubulysin U and N14-desacetoxytubulysin H' by Bohua Long et al., Org. Biomol. Chem., 2020, 18, 5349-5353, https://doi.org/10.1039/D0OB01109F.

3.
Bioorg Chem ; 147: 107317, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38583252

RESUMEN

By inducing steric activation of the 10CH bond with a 12-acyl group to form a key imine oxime intermediate, 20 novel (10S)-10,12-disubstituted aloperine derivatives were successfully synthesized and assessed for their antiviral efficacy against HCoV-OC43. Of them, compound 3i exhibited the moderate activities against HCoV-OC43, as well as against the SARS-CoV-2 variant EG.5.1 with the comparable EC50 values of 4.7 and 4.1 µM. A mechanism study revealed that it inhibited the protease activity of host TMPRSS2 by binding to an allosteric site, rather than the known catalytic center, different from that of camostat. Also, the combination of compound 3i and molnupiravir, as an RdRp inhibitor, showed an additive antiviral effect against HCoV-OC43. The results provide a new binding mode and lead compound for targeting TMPRSS2, with an advantage in combating broad-spectrum coronavirus.


Asunto(s)
Sitio Alostérico , Antivirales , Coronavirus Humano OC43 , Quinolizidinas , Serina Endopeptidasas , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Serina Endopeptidasas/metabolismo , Humanos , Coronavirus Humano OC43/efectos de los fármacos , Coronavirus Humano OC43/química , Quinolizidinas/química , Quinolizidinas/farmacología , Quinolizidinas/síntesis química , Sitio Alostérico/efectos de los fármacos , Relación Estructura-Actividad , Descubrimiento de Drogas , SARS-CoV-2/efectos de los fármacos , Estructura Molecular , Pruebas de Sensibilidad Microbiana , Relación Dosis-Respuesta a Droga
4.
Bioorg Chem ; 142: 106925, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37890213

RESUMEN

Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet. Primary mechanism study revealed that upregulation of peroxisome proliferator-activated receptors α (PPARα)-carnitine palmitoyltransferase 1A (CPT1A) pathway mediated the efficacy of 7n. Our study provides powerful information for developing this kind of compound into a new class of anti-NAFLD candidates, and compound 7n is worthy of further investigation as an ideal lead compound.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Matrinas , Triglicéridos/metabolismo , Hígado/metabolismo , PPAR alfa/metabolismo , Ratones Endogámicos C57BL
5.
J Hematop ; 17(2): 63-69, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38652382

RESUMEN

Langerhans cell histiocytosis (LCH) of the stomach is rare. Moreover, it is usually found in pediatric patients with systemic diseases and may be associated with a poor prognosis. Solitary gastric LCH in adults is extremely rare and is often misdiagnosed or missed. The aim of our study was to review cases of gastric LCH and explore the characteristics of the disease further. A retrospective study of all patients admitted with solitary gastric LCH was conducted between 2013 and 2023. Clinical manifestations, endoscopic and pathological features, immunophenotypes, and molecular changes were collected from medical records. We examined four cases (one female, three males) of gastric LCH. The affected patients were between 33 and 70 years of age. Endoscopically, three patients presented with a solitary polyp or elevated lesions, whereas one patient showed no abnormalities. Under a microscope, all cases showed abnormal proliferation of histiocytoid cells infiltrating in a nested or sheet-like fashion. The tumor cells were medium-sized, with a slightly eosinophilic cytoplasm, irregular or renal-shaped nuclei, folded nuclear membranes, visible nuclear grooves, and the infiltration of inflammatory cells in the background. Immunohistochemically, all lesions expressed CD1a, S-100, langerin, and cyclinD1. One case showed diffuse BRAF V600E positivity. Follow-up data were available for all patients from 4 to 36 months, and all patients were alive without recurrence or progress at the time of manuscript preparation. Combined with previously reported data, solitary adult gastric LCH is more common in male patients, most of whom are asymptomatic or exhibit only mild gastrointestinal symptoms, with a good prognosis. Endoscopy often reveals solitary polyps or protruding lesions; rare cases may progress to multifocal/multisystem lesions, necessitating long-term close follow-up.


Asunto(s)
Histiocitosis de Células de Langerhans , Humanos , Histiocitosis de Células de Langerhans/patología , Histiocitosis de Células de Langerhans/diagnóstico , Masculino , Femenino , Adulto , Anciano , Persona de Mediana Edad , Gastropatías/patología , Gastropatías/diagnóstico , Estudios Retrospectivos
6.
Comput Biol Med ; 175: 108536, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38701592

RESUMEN

In response to the shortcomings in data quality and coverage for neurological and psychiatric disorders (NPDs) in existing comprehensive databases, this paper introduces the DTNPD database, specifically designed for NPDs. DTNPD contains detailed information on 30 NPDs types, 1847 drugs, 514 drug targets, 64 drug combinations, and 61 potential target combinations, forming a network with 2389 drug-target associations. The database is user-friendly, offering open access and downloadable data, which is crucial for network pharmacology studies. The key strength of DTNPD lies in its robust networks of drug and target combinations, as well as drug-target networks, facilitating research and development in the field of NPDs. The development of the DTNPD database marks a significant milestone in understanding and treating NPDs. For accessing the DTNPD database, the primary URL is http://dtnpd.cnsdrug.com, complemented by a mirror site available at http://dtnpd.lyhbio.com.


Asunto(s)
Trastornos Mentales , Enfermedades del Sistema Nervioso , Humanos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Bases de Datos Farmacéuticas , Bases de Datos Factuales
7.
Drug Des Devel Ther ; 18: 747-766, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38495630

RESUMEN

Purpose: Type 2 diabetes mellitus (T2DM) is associated with reduced insulin uptake and glucose metabolic capacity. Potentilla discolor Bunge (PDB) has been used to treat T2DM; however, the fundamental biological mechanisms remain unclear. This study aimed to understand the active ingredients, potential targets, and underlying mechanisms through which PDB treats T2DM. Methods: Components and action targets were predicted using network pharmacology and molecular docking analyses. PDB extracts were prepared and validated through pharmacological intervention in a Cg>InRK1409A diabetes Drosophila model. Network pharmacology and molecular docking analyses were used to identify the key components and core targets of PDB in the treatment of T2DM, which were subsequently verified in animal experiments. Results: Network pharmacology analysis revealed five effective compounds made up of 107 T2DM-related therapeutic targets and seven protein-protein interaction network core molecules. Molecular docking results showed that quercetin has a strong preference for interleukin-1 beta (IL1B), IL6, RAC-alpha serine/threonine-protein kinase 1 (AKT1), and cellular tumor antigen p53; kaempferol exhibited superior binding to tumor necrosis factor and AKT1; ß-sitosterol demonstrated pronounced binding to Caspase-3 (CASP3). High-performance liquid chromatography data quantified quercetin, kaempferol, and ß-sitosterol at proportions of 0.030%, 0.025%, and 0.076%, respectively. The animal experiments revealed that PDB had no effect on the development, viability, or fertility of Drosophila and it ameliorated glycolipid metabolism disorders in the diabetes Cg>InRK1409A fly. Furthermore, PDB improved the body size and weight of Drosophila, suggesting its potential to alleviate insulin resistance. Moreover, PDB improved Akt phosphorylation and suppressed CASP3 activity to improve insulin resistance in Drosophila with T2DM. Conclusion: Our findings suggest that PDB ameliorates diabetes metabolism disorders in the fly model by enhancing Akt activity and suppressing CASP3 expression. This will facilitate the development of key drug targets and a potential therapeutic strategy for the clinical treatment of T2DM and related metabolic diseases.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Potentilla , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Caspasa 3 , Quempferoles , Drosophila , Simulación del Acoplamiento Molecular , Farmacología en Red , Proteínas Proto-Oncogénicas c-akt , Quercetina
8.
Am J Chin Med ; 52(2): 433-451, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38577825

RESUMEN

Myocardial ischemia/reperfusion (I/R) injury is the leading cause of death worldwide. Ginsenoside Rd (GRd) has cardioprotective properties but its efficacy and mechanism of action in myocardial I/R injury have not been clarified. This study investigated GRd as a potent therapeutic agent for myocardial I/R injury. Oxygen-glucose deprivation and reperfusion (OGD/R) and left anterior descending (LAD) coronary artery ligation were used to establish a myocardial I/R injury model in vitro and in vivo. In vivo, GRd significantly reduced the myocardial infarct size and markers of myocardial injury and improved the cardiac function in myocardial I/R injury mice. In vitro, GRd enhanced cell viability and protected the H9c2 rat cardiomyoblast cell line from OGD-induced injury GRd. The network pharmacology analysis predicted 48 potential targets of GRd for the treatment of myocardial I/R injury. GO and KEGG enrichment analysis indicated that the cardioprotective effects of GRd were closely related to inflammation and apoptosis mediated by the PI3K/Akt signaling pathway. Furthermore, GRd alleviated inflammation and cardiomyocyte apoptosis in vivo and inhibited OGD/R-induced apoptosis and inflammation in cardiomyocytes. GRd also increased PI3K and Akt phosphorylation, suggesting activation of the PI3K/Akt pathway, whereas LY294002, a PI3K inhibitor, blocked the GRd-induced inhibition of OGD/R-induced apoptosis and inflammation in H9c2 cells. The therapeutic effect of GRd in vivo and in vitro against myocardial I/R injury was primarily dependent on PI3K/Akt pathway activation to inhibit inflammation and cardiomyocyte apoptosis. This study provides new evidence for the use of GRd as a cardiovascular drug.


Asunto(s)
Ginsenósidos , Daño por Reperfusión Miocárdica , Ratas , Ratones , Animales , Daño por Reperfusión Miocárdica/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Apoptosis , Miocitos Cardíacos/metabolismo
9.
J Tradit Complement Med ; 14(4): 424-434, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39035690

RESUMEN

Background and aim: Type-2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) induced by hyperglycaemia and insufficient insulin secretion. We employed a diabetic fly model to examine the effect and molecular mechanism of Atractylodes macrocephala Koidz. and Cuscuta chinensis Lam. (AMK-CCL) extract as traditional Chinese medicine in treating IR and T2DM. Experimental procedure: The contents of the active ingredients (rhamnose, xylose, mannose, and hyperoside) in AMK-CCL extract were determined by high-performance liquid chromatography. Wild-type (Cg-GAL4/+) or diabetic (Cg > InRK1409A) Drosophila flies were divided into the control group or metformin group and AMK-CCL (0.0125, 0.025, 0.05, 0.1 g/ml) groups. Food intake, haemolymph glucose and trehalose, protein, weight, triglycerides (TAG), and glycogen were measured to assess glycolipid metabolism. Phosphatidylinositol-3-kinase (PI3K)/Akt signalling was detected using fluorescent reporters [tGPH, Drosophila forkhead box O (dFoxO)-green fluorescent protein (GFP), Glut1-GFP, 2-NBDG] in vivo. Glut1/3 mRNA levels and Akt phosphorylation levels were detected by quantitative polymerase chain reaction and western blotting, respectively, in vitro. Results: AMK-CCL extract contained 0.038 % rhamnose, 0.017 % xylose, 0.69 % mannose, and 0.039 % hyperoside. AMK-CCL at 0.0125 g/mL significantly suppressed the increase in circulating glucose, and the decrease in body weight, TAG, and glycogen contents of diabetic flies. AMK-CCL improved PI3K activity, Akt phosphorylation, Glut1/3 expression, and glucose uptake in diabetic flies, and also rescued diabetes-induced dFoxO nuclear localisation. Conclusions: These findings indicate that AMK-CCL extract ameliorates IR-induced diabetes via the PI3K/Akt signalling pathway, providing an experimental basis for clinical treatment.

11.
Biomed Pharmacother ; 172: 116220, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38308968

RESUMEN

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. APPROACH AND RESULTS: We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved ß-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. CONCLUSIONS: Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dislipidemias , Hiperglucemia , Ratones , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , PPAR gamma/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Dislipidemias/tratamiento farmacológico , Hígado/metabolismo , Hiperglucemia/tratamiento farmacológico , Colesterol/metabolismo , Tejido Adiposo Blanco/metabolismo
12.
Acta Pharm Sin B ; 14(6): 2567-2580, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38828157

RESUMEN

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed -1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes. Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses. Because the FSE mechanism is essential in all coronaviruses, carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA. This finding may open a new direction in antiviral drug discovery for coronavirus variants.

13.
Genome Biol ; 25(1): 145, 2024 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-38831386

RESUMEN

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (SRT) have led to groundbreaking advancements in life sciences. To develop bioinformatics tools for scRNA-seq and SRT data and perform unbiased benchmarks, data simulation has been widely adopted by providing explicit ground truth and generating customized datasets. However, the performance of simulation methods under multiple scenarios has not been comprehensively assessed, making it challenging to choose suitable methods without practical guidelines. RESULTS: We systematically evaluated 49 simulation methods developed for scRNA-seq and/or SRT data in terms of accuracy, functionality, scalability, and usability using 152 reference datasets derived from 24 platforms. SRTsim, scDesign3, ZINB-WaVE, and scDesign2 have the best accuracy performance across various platforms. Unexpectedly, some methods tailored to scRNA-seq data have potential compatibility for simulating SRT data. Lun, SPARSim, and scDesign3-tree outperform other methods under corresponding simulation scenarios. Phenopath, Lun, Simple, and MFA yield high scalability scores but they cannot generate realistic simulated data. Users should consider the trade-offs between method accuracy and scalability (or functionality) when making decisions. Additionally, execution errors are mainly caused by failed parameter estimations and appearance of missing or infinite values in calculations. We provide practical guidelines for method selection, a standard pipeline Simpipe ( https://github.com/duohongrui/simpipe ; https://doi.org/10.5281/zenodo.11178409 ), and an online tool Simsite ( https://www.ciblab.net/software/simshiny/ ) for data simulation. CONCLUSIONS: No method performs best on all criteria, thus a good-yet-not-the-best method is recommended if it solves problems effectively and reasonably. Our comprehensive work provides crucial insights for developers on modeling gene expression data and fosters the simulation process for users.


Asunto(s)
Perfilación de la Expresión Génica , Análisis de la Célula Individual , Análisis de la Célula Individual/métodos , Perfilación de la Expresión Génica/métodos , Humanos , Programas Informáticos , Simulación por Computador , Transcriptoma , Biología Computacional/métodos , Análisis de Secuencia de ARN/métodos , RNA-Seq/métodos , RNA-Seq/normas
14.
Cell Death Dis ; 15(1): 70, 2024 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-38238297

RESUMEN

Glucocorticoid (GC) is essential for maintaining immune homeostasis. While GC is known to regulate the expression of genes related to inflammation in immune cells, the effects of GC, especially in the presence of inflammation, on non-immune cells remain largely unexplored. In particular, the impact of GC on inflammatory cytokine-induced immune modulatory responses of tissue stromal cells is unknown, though it has been widely used to modulate tissue injuries. Here we found that GC could enhance the expression of TSG6, a vital tissue repair effector molecule, in IFNγ and TNFα treated human umbilical cord (UC)-MSCs. NF-κB activation was found to be required for GC-augmented TSG6 upregulation. STAT3, but not STAT1, was also found to be required for the TSG6 upregulation in MSCs exposed to IFNγ, TNFα and GC. Moreover, the phosphorylation (activation) of STAT3 was attenuated when NF-κB was knocked down. Importantly, human UC-MSCs pretreated with a cocktail containing GC, IFNγ, and TNFα could significantly enhance the therapeutic effect of human UC-MSCs in an acute lung injury mouse model, as reflected by reduced infiltration of immune cells and down-regulation of iNOS in macrophages in the lung. Together, the findings reveal a novel link between GR, NF-κB and STAT3 in regulating the immunomodulatory and regenerative properties of MSCs, providing novel information for the understanding and treatment of inflammatory conditions.


Asunto(s)
Células Madre Mesenquimatosas , FN-kappa B , Ratones , Animales , Humanos , FN-kappa B/metabolismo , Citocinas/metabolismo , Glucocorticoides/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Factor de Transcripción STAT3/metabolismo
15.
Artículo en Zh | WPRIM | ID: wpr-260068

RESUMEN

Very low density lipoprotein receptor (VLDLR) is thought to participate in the patho-genesis of atherosclerosis induced by VLDL and β-VLDL. The present study was undertaken to elu-cidate the effects of VLDL and β-VLDL on VLDLR expression and its signaling pathway. RAW264.7 cells were incubated with VLDL and β-VLDL. The expression of VLDLR mRNA was detected by RT-PCR. The transcriptional activity of VLDLR gene was detected in recombinant plasmid pGL4.2VR-luciferase transfected RAW264.7. Western blot assay was used to detect the changes of phosphorylated ERK1/2 protein. Inhibitors or activators were used to observe the signal pathway in-volving VLDLR expression regulation. The results showed that VLDL and β-VLDL stimulated ERKI/2 activity in a PKC-dependent manner. VLDL or β-VLDL-induced VLDLR expression on macrophages was extremely abolished by inhibitors ERKI/2 or PKC. Our findings revealed that VLDL or β-VLDL-induced VLDLR expression via PKC/ERK cascades and the effect was linked to the transcriptional activation of VLDLR gene promoter.

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