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Using Origin2022Pro, PAST4.09, GraphPad, and ArcGIS, this study analyzed the big data of the fourth national survey of traditional Chinese medicine resources in Jilin province from five dimensions: differences in resource quantity, taxonomic group, family, and genus, regional distribution, and spatiotemporal distribution, aiming to fully elucidate the biodiversity of medicinal plants in Jilin province. The results indicated that 2 241 species of medicinal plants existed in Jilin province, belonging to 881 genera of 243 families, with 20 dominant families and 3 dominant genera. There were 1 901 species of medicinal plants(belonging to 778 genera of 227 families) in the eastern mountainous region, 1 503 species(belonging to 690 genera of 225 families) in the mid-mountainous areas of the central mountainous region, and 811 species(belonging to 436 genera of 136 families) in the western plain region. The biodiversity of medicinal plants in Jilin province was high and presented a trend of high in the east and low in the west. The medicinal plant resources were mainly concentrated in the eastern mountainous region, and the number of medicinal plant groups had significant diffe-rences between regions, following the trend of western region > central region > eastern region. The species richness was in the order of eastern region > western region > central region. The species diversity structure in the central region was similar to that in the eastern and western regions, while it was significantly different between the western and eastern regions. Compared with the third national survey of traditional Chinese medicine resources, the fourth survey showed an increase of 1 417 species, a decrease of 580 species, and 824 common species, indicating significant changes in the biodiversity of medicinal plants in Jilin province. The reasons for these changes need to be further explored. This article elucidates the background and biodiversity changes of medicinal plant resources in Jilin province, laying a foundation for the protection, utilization, and industrial development of traditional Chinese medicine resources in Jilin province.
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Biodiversidad , Medicina Tradicional China , Plantas Medicinales , Plantas Medicinales/química , Plantas Medicinales/clasificación , Plantas Medicinales/crecimiento & desarrollo , China , Encuestas y CuestionariosRESUMEN
COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1, that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.
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Complejo del Señalosoma COP9 , Humanos , Complejo del Señalosoma COP9/metabolismo , Complejo del Señalosoma COP9/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Simulación de Dinámica Molecular , Colorantes Fluorescentes/química , Células HCT116 , Antineoplásicos/farmacología , Antineoplásicos/química , Descubrimiento de Drogas/métodos , Relación Estructura-Actividad , Péptido Hidrolasas , Péptidos y Proteínas de Señalización IntracelularRESUMEN
Metalloenzymes are attractive research targets in fields of chemistry, biology, and medicine. Given that metalloenzymes can manifest conservation of metal-coordination and ligand binding modes, the excavation and expansion of metalloenzyme-specific knowledge is of interest in bridging metalloenzyme-related fields. Building on our previous metalloenzyme-ligand association database, MeLAD, we have expanded the scope of metalloenzyme-specific knowledge and services, by forming a versatile platform, termed the Metalloenzyme Data Bank and Analysis (MeDBA). The MeDBA provides: (i) manual curation of metalloenzymes into different categories, that this M-I, M-II and M-III; (ii) comprehensive information on metalloenzyme activities, expression profiles, family and disease links; (iii) structural information on metalloenzymes, in particular metal binding modes; (iv) metalloenzyme substrates and bioactive molecules acting on metalloenzymes; (v) excavated metal-binding pharmacophores and (vi) analysis tools for structure/metal active site comparison and metalloenzyme profiling. The MeDBA is freely available at https://medba.ddtmlab.org.
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Bases de Datos de Proteínas , Metaloproteínas , Dominio Catalítico , Ligandos , Metaloproteínas/metabolismo , Metales , EnzimasRESUMEN
The study of short-term dynamics of soil moisture in the dry-hot valley area during rainfall process will help identify soil hydrological function. In this study, we analyzed the short-term responses of soil moisture to rainfall in Huajiang dry-hot valley of Guizhou, using in-situ monitoring method to yield high-frequency soil moisture monitoring data of different slope positions. The results showed that, during the whole monitoring period, soil moisture at each layer was at a moderate variation level (15.2%≤coefficient of variation CV≤29.7%), for both upper slope and middle slope. The fluctuation range of soil moisture of the upper slope (CV=21.1%) was greater than that of the middle slope (CV=19.1%), and that of the 0-5 cm soil layer (CV=26.2%) was greater than 20-40 cm layer (CV=16.5%). Compared with the middle slope, soil moisture of the upper slope had a faster response to rainfall. The supplement amount of rainfall was bigger and the supplement speed of rainfall was faster at the upper slope than that at the middle slope. The difference between the supplement speed and the depletion speed of soil moisture of the upper slope (2.3%·h-1) was greater than that of the middle slope (1.8%·h-1). With the increase of soil depth, the responses of soil moisture to rainfall in subsoil layer was earlier or synchronous with that in topsoil layer. When the supplement amount of soil moisture decreased and the supplement speed slowed down, the depletion speed slowed down. Compared with the middle slope, soil at the upper slope had greater water infiltration capacity and better water retention capacity. The responses of soil moisture to rainfall in dry-hot valley were influenced by micro-environment and microclimate, and the rapid recharge of dominant flow at rock-soil interface accelerated the response speed of subsoil moisture to rainfall, which made the slopes in this area easier to form mixed runoff generation mechanism.
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Lluvia , Suelo , China , Hidrología , Agua , Movimientos del AguaRESUMEN
Drug repositioning is an attractive strategy for discovering new therapeutic uses for approved or investigational drugs, with potentially shorter development timelines and lower development costs. Various computational methods have been used in drug repositioning, promoting the efficiency and success rates of this approach. Recently, deep learning (DL) has attracted wide attention for its potential in target prediction and drug repositioning. Here, we provide an overview of the basic principles of commonly used DL architectures and their applications in target prediction and drug repositioning, and discuss possible ways of dealing with current challenges to help achieve its expected potential for drug repositioning.
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Aprendizaje Profundo , Reposicionamiento de Medicamentos , Biología ComputacionalRESUMEN
Metalloenzymes have critical roles in a wide range of biological processes and are directly involved in many human diseases; hence, they are considered as important targets for therapeutic intervention. The specific characteristics of metal ion(s)-containing active sites make exploitation of metal-binding pharmacophores (MBPs) critical to inhibitor development targeting metalloenzymes. This Perspective focuses on boron-containing MBPs, which display unique binding modes with metalloenzyme active sites, particularly via mimicking native substrates or tetrahedral transition states. The design concepts regarding boron-containing MBPs are highlighted through the case analyses on five distinct classes of clinically relevant nucleophilic metalloenzymes from medicinal chemistry perspectives. The challenges (e.g., selectivity) faced by some boron-containing MBPs and possible strategies (e.g., bioisosteres) for metalloenzyme inhibitor transformation are also discussed.
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Boro/química , Inhibidores Enzimáticos/farmacología , Metaloproteínas/antagonistas & inhibidores , Metales/química , Inhibidores Enzimáticos/química , Estructura MolecularRESUMEN
Chiral 3-substituted benzoxaboroles were designed as carbapenemase inhibitors and efficiently synthesised via asymmetric Morita-Baylis-Hillman reaction. Some of the benzoxaboroles were potent inhibitors of clinically relevant carbapenemases and restored the activity of meropenem in bacteria harbouring these enzymes. Crystallographic analyses validate the proposed mechanism of binding to carbapenemases, i.e. in a manner relating to their antibiotic substrates. The results illustrate how combining a structure-based design approach with asymmetric catalysis can efficiently lead to potent ß-lactamase inhibitors and provide a starting point to develop drugs combatting carbapenemases.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Proteínas Bacterianas/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , beta-Lactamasas/farmacología , Antibacterianos/química , Benzoxazoles/química , Técnicas de Química Sintética , EstereoisomerismoRESUMEN
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 µM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
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Inhibidores Enzimáticos/uso terapéutico , Indazoles/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Triptófano Oxigenasa/antagonistas & inhibidores , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Encéfalo/patología , Línea Celular Tumoral , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Indazoles/síntesis química , Indazoles/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Unión Proteica , Relación Estructura-Actividad , Triptófano Oxigenasa/metabolismoRESUMEN
The production of ß-lactamases represents the main cause of resistance to clinically important ß-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum ß-lactamase inhibitors to combat ß-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-ß-lactamases (SBLs) and metallo-ß-lactamases (MBLs). The most potent inhibitor 9f displayed an IC50 value of 86 nM to KPC-2 SBL and micromolar inhibitory activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent toxicity in HEK293T cells.
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Compuestos de Boro/farmacología , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/farmacología , Sitios de Unión , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Células HEK293 , Humanos , Concentración 50 Inhibidora , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/metabolismo , Meropenem/farmacología , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Inhibidores de beta-Lactamasas/químicaRESUMEN
Adonis amurensis Regel et Radde is an important cardiac folk medicinal plant which endemic to Northeast Asia. We determined the first complete chloroplast genome of A. amurensis using genome skimming approach. The cp genome was 157,032 bp long, with a large single-copy region (LSC) of 86,218 bp and a small single-copy region (SSC) of 18,212 bp separated by a pair of inverted repeats (IRs) of 26,301 bp. It encodes 129 genes, including 84 protein-coding genes, 37 tRNA genes, and 8 ribosomal RNA genes. We also reconstructed the phylogeny of Adonideae and Isopyreae using maximum likelihood (ML) method, including our data and previously reported cp genomes of related taxa. The phylogenetic analysis indicated that A. amurensis is close related with Adonis sutchuenensis.
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Prunus pensylvanica is one of the two native cherry species of North America. We determined the first complete chloroplast genome of P. pensylvanica using genome-skimming approach. The cp genome was 157,953 bp long, with a large single-copy region (LSC) of 86,030 bp and a small single-copy region (SSC) of 19,135 bp separated by a pair of inverted repeats (IRs) of 26,394 bp. It encodes 129 genes, including 84 protein-coding genes, 37 tRNA genes, and 8 ribosomal RNA genes. We also reconstructed the phylogeny of Prunus sensu lato using maximum likelihood (ML) method, including our data and previously reported cp genomes of related taxa. The phylogenetic analysis indicated that P. pensylvanica is closely related to P. emarginata.
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Near-infrared hypserspectral imaging technology was applied for the discrimination of a variety of life states, the judgment of being alive or death. Discrimination models were built based on spectral data of Pieris rapaes acquired during different life states. The wavelengths from 951.5 to 1649.2 nm were used for analysis after the removal of spectral region with obvious noises at the beginning and the end. And the spectra data of 951.5-1649.2 nm were preprocessed by different pretreatment methods. To discriminate the state of being alive or death of Pieris rapaes, discrimination models were built based on the spectral data processed by different pretreatment methods. Results showed that the discriminant accuracy can approach or attain 100%. Thus the method was proved to be useful for the discrimination of the state of being alive or death of Pieris rapaes. After the spectral data were preprocessed by moving average (MA) algorithm, 17 characteristic wavelengths were extracted based on weighted regression coefficient (Bw) and 20 were extracted based on successive projections algorithm (SPA) to identify the state of being alive or death of Pieris rapaes. Four classification methods based on characteristic wavelengths, including partial least squares-discriminant analysis (PLS-DA), K-nearest neighbor algorithm (KNN), back propagation neural network (BPNN) and support vector machine (SVM) were used to build discriminant models for identifying the state of being alive or death of Pieris rapaes. The discriminant accuracy all can approach or attain 100%.
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Ericaceae/crecimiento & desarrollo , Espectroscopía Infrarroja Corta , Algoritmos , Análisis Discriminante , Análisis de los Mínimos Cuadrados , Modelos Teóricos , Redes Neurales de la Computación , Máquina de Vectores de SoporteRESUMEN
In this study, ITS2 barcode was used to identify Bupleurum chinense and B. longiradiatum. The ITS2 regions of 48 samples were amplified and sequenced. The sequences obtained above were aligned and the K2P distances were calculated. We used three methods, BLAST1, nearest distance and phylogenetic tree (NJ-tree), to test the identification ability. The results showed that the maximum intraspecific genetic distance of B. chinense was 0.013, and the minimum interspecific genetic distance between B. chinense and B. longiradiatum was 0.049. The NJ-tree can easily identify B. chinense and B. longiradiatum. Therefore, the ITS2 barcode is suitable to identify B. chinense and B. longiradiatum.
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Bupleurum/clasificación , Código de Barras del ADN Taxonómico/métodos , ADN de Plantas/genética , ADN Espaciador Ribosómico/genética , Medicamentos Herbarios Chinos/clasificación , Bupleurum/genética , Medicamentos Herbarios Chinos/química , Datos de Secuencia Molecular , Filogenia , Control de CalidadRESUMEN
In order to identify Cimicifugae Rhizoma from its adulterants and to ensure its safe use, the internal transcribed spacer 2 (ITS2) sequence of Cimicifugae Rhizoma and its adulterants were amplified and bidirectionally sequenced by DNA barcoding technology. Sequence assembly and consensus sequence generation were performed by the CodonCode Aligner V3.7.1. The genetic distances were computed by MEGA 5.0. Identification analyses were performed using neighbor-joining (NJ) methods. The length of ITS2 sequence of the three origin plants of Cimicifugae Rhizoma include Cimicifuga heracleifolia, C. foetida, C. dahurica was 217, 219 and 219 bp, respectively. Their intraspecific genetic distance was much lower than the interspecific genetic distance with their closely related species. The NJ tree of ITS2 indicated that the three origin plants of Cimicifugae Rhizoma formed a monophyletic clade, Cimicifugae Rhizoma and its adulterants could be distinguished clearly. The authors proposed that ITS2 sequence was suitable for the authentication of Cimicifugae Rhizoma and its adulterants.
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Cimicifuga/clasificación , Código de Barras del ADN Taxonómico/métodos , ADN de Plantas/genética , ADN Espaciador Ribosómico/genética , Medicamentos Herbarios Chinos/clasificación , Secuencia de Bases , China , Cimicifuga/genética , Contaminación de Medicamentos/prevención & control , Medicamentos Herbarios Chinos/química , Datos de Secuencia Molecular , Filogenia , Control de Calidad , Rizoma/clasificación , Rizoma/genéticaRESUMEN
A phytochemical study of secondary metabolites produced by Schisandra chinensis has led to the isolation of six novel highly oxygenated nortriterpenoids, wuweizidilactones A-F (1-6). Compounds 3-6 possess an unprecedented 3,4-seco-18(13-->14)-abeo-artane skeleton. Interestingly, structures 3-6 have a beta-oriented methyl group at the C-14 position. This structural feature corroborates the biogenetic pathway proposed for the formation of 18-norschiartane-type compounds 1 and 2. The structures of these novel metabolites were established on the basis of their detailed spectroscopic analysis. The structure of 1 was also confirmed by single-crystal X-ray diffraction analysis. For the first time, the absolute configuration of these nortriterpenoids was determined by using a modified Mosher method.