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1.
J Ethnopharmacol ; 321: 117513, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38040131

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Penthorum chinense Pursh (PCP) has acknowledged as an edible herbal medicinal plant for the prevention and treatment of alcoholic liver injury (ALI). However, only few of researches focus on the chemical material basis and potential mechanisms of PCP against ALI. AIM OF THE STUDY: Herein, we explored the therapeutic effects of PCP extract against ALI based on the integration of network pharmacology, molecular docking, and experiment validation. METHODS: Based on the standard quality control of PCP herbs by UPLC fingerprint and quantitative determination, 80% ethanol extract fraction of PCP containing more polyphenols, compared to aqueous extract fraction of PCP, were chosen for further experiments. After oral administration of PCP ethanol extract, serum pharmacochemistry based on UPLC-Q-Exactive-MS analysis was implemented to evaluate the potential effective compounds. These absorbed prototypes in PCP were used to construct network pharmacology and predict the potential mechanisms of PCP extract against ALI. Then, the predicted targets and biological mechanisms of PCP extract were validated using animal experiments and molecular docking analysis. RESULTS: Although totally 19 polyphenol compounds were identified in PCP ethanol extract by UPLC-MS analysis, only 18 absorbed prototypes were found in the serum collected from mice at 1 h post-administration with PCP extract. These candidate active compounds were further screened into 13 compounds to construct network pharmacology and 433 targets were identified as PCP targets. GO and KEGG pathway enrichment analyses indicated that the effects of PCP extract would involve in Ras signaling pathway. The animal experiments on chronic ALI model mice shown that the oral administration of PCP can alleviate ALI by attenuating hepatic oxidative stress, inflammation and down-regulating the target proteins in Ras/Raf/MEK/ERK pathway. Molecular docking analysis revealed the good binding ability between the three polyphenols (i.e. quercetin, apigenin, thonningianin B) in PCP with the top contribution in network pharmacology, and these target proteins (Ras, Raf, MEK1/2, and ERK1/2). CONCLUSION: Our results clarified that PCP ethanol extract could effectively alleviate ALI by down-regulating Ras/Raf/MEK/ERK signaling pathway promisingly. Quercetin, apigenin, and thonningianin B may be the active compounds of PCP, attributing to the intervention benefits of PCP against ALI.


Assuntos
Medicamentos de Ervas Chinesas , Saxifragales , Camundongos , Animais , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Polifenóis/metabolismo , Sistema de Sinalização das MAP Quinases , Quercetina/farmacologia , Cromatografia Líquida , Apigenina/farmacologia , Simulação de Acoplamento Molecular , Farmacologia em Rede , Espectrometria de Massas em Tandem , Etanol/farmacologia , Saxifragales/química , Fígado , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Medicamentos de Ervas Chinesas/farmacologia
2.
Chin J Nat Med ; 20(11): 830-845, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36427917

RESUMO

Atherosclerosis (AS) is an invisible killer among cardiovascular diseases (CVD), which has seriously threatened the life of quality. The complex pathogenesis of AS involves multiple interrelated events and cell types, such as macrophages, endothelial cells, vascular smooth muscle cells and immune cells. Currently, the efficacy of recommended statin treatment is not satisfactory. Natural products (NPs) have attracted increasing attention with regard to their broad structural diversity and biodiversity, which makes them a promising library in the demand for lead compounds with cardiovascular protective bio-activity. NPs can preclude the development of AS by regulating lipid metabolism, ameliorating inflammation, stabilizing plaques, and remodeling the gut microbiota, which lays a foundation for the application of NPs in clinical therapeutics.


Assuntos
Aterosclerose , Produtos Biológicos , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Produtos Biológicos/metabolismo , Células Endoteliais/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo
3.
J Ocul Pharmacol Ther ; 38(9): 645-653, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36264174

RESUMO

Purpose: We systematically retrospected and analyzed the general characteristics of ophthalmic drug clinical trials (CTs) registered in China from January 2014 to December 2021. Methods: Data were retrieved from the Drug Trial Registration and Information Publication Platform and then standardized and statistically classified using bibliometric analysis. Results: We identified 201 drug CTs for eye diseases, including 24 international multicenter trials. The number of drug CTs for eye diseases has considerably increased since 2017 in parallel with new policies to encourage innovation in drugs and medical devices in China. The drug types consist of biologicals (48.26%), chemicals (45.77%), and traditional Chinese medicine/natural medicines (5.97%). The main indications were age-related macular degeneration (AMD; n = 47, 23.38%), macular edema (n = 32, 15.92%), and diabetic retinopathy (n = 19, 9.45%). The trials included those in phase I (n = 67, 33.33%), phase II (n = 33, 16.42%), and phase III (n = 72, 35.82%). The phase I trials comprised 24 innovative drug treatments for AMD and 6 novel drug treatments for neuromyelitis optica spectrum disorders, with 39 biologicals and 27 chemicals. The trials mostly followed a randomized (84.08%) or masked (67.16%) design, with 90.37% of the latter being double-masked trials. Conclusion: Research and development of ophthalmic drugs have substantially increased in recent years and are influenced by regulatory policies. Among these drugs, biologicals for AMD are the most prevalent, followed by biologicals for macular edema. Randomized double-masked research designs are often used and represent high-quality evidence.


Assuntos
Retinopatia Diabética , Degeneração Macular , Edema Macular , Humanos , Edema Macular/tratamento farmacológico , Degeneração Macular/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , China
4.
Curr Protein Pept Sci ; 23(10): 684-696, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36121086

RESUMO

As an important pectin enzyme, pectin methylesterase (PME) can hydrolyze methyl esters, release methanol and reduce esterification. It is essential in regulating pollen tube development, root extension, and fruit ripening. Pectin methylesterase inhibitors (PMEI) can specifically bind PME and inhibit its activity, which jointly determines the esterification degree of pectin. PMEI has important application prospects in plant pest control, fruits and vegetable processing fields. In this paper, the gene families, crystal structures, molecular recognition, and applications in plants and industry are reviewed for the PME and PMEI systems. Finally, the semi-rational design of PMEI is discussed and discussed prospected.


Assuntos
Hidrolases de Éster Carboxílico , Pectinas , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Pectinas/química , Pectinas/metabolismo , Plantas/metabolismo , Inibidores Enzimáticos/química
5.
Zhongguo Zhong Yao Za Zhi ; 47(17): 4682-4690, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36164875

RESUMO

This paper clarified the scientific connotation of the changes in cold and heat properties of Arisaematis Rhizoma and Arisaema Cum Bile through investigating the changes of substance and energy metabolism after drug intervention in the rats with normal and cold/heat syndrome, so as to improve the method of evaluating the drug properties of Chinese medicine. After one week of adaptive feeding, healthy male SD rats were randomly divided into three parts: normal rats, heat syndrome rat models, and cold syndrome rat models. Through ice water bath and oral euthyrox(120 µg·kg~(-1)), the models of cold syndrome and heat syndrome were induced, respectively. The models were made at 9:00 am. and administrated by gavage at 3:00 pm. every day. All administration groups were administrated with Arisaematis Rhizoma and Arisaema Cum Bile decoction, respectively, and the blank group was given the same dose of normal saline. After continuous administration for 15 d, the rats were anesthetized by chloral hydrate, blood was taken from abdominal aorta, and the hearts and livers were removed and stored at-80 ℃. The changes in the body weight and anal temperature of rats during administration were detected, and the liver coefficient of rats was detected after removing the liver. Enzyme-linked immunosorbent assay(ELISA) was adopted to detect the expression level of the indexes related to substance and energy metabolism in liver and heart of rat, and Western blot was used to detect the expression of key proteins in AMPK/mTOR signaling pathway for further verification. The results showed that Arisaematis Rhizoma enhanced the expression level of enzymes related to substance and energy metabolism in the normal and cold and heat syndrome rat models, and increased anal temperature, which exhibited warm(hot) drug property. Arisaema Cum Bile inhibited the level of substance and energy metabolism in rats, and reduced anal temperature, which showed cold(cool) drug property. Chinese Pharmacopoeia has recorded "Arisaematis Rhizoma has warm property and Arisaema Cum Bile has cool property", which is consistent with the phenomenon in this study. Therefore, it is feasible to evaluate the drug properties of Chinese medicine based on the substance and energy metabolism of normal and cold/heat syndrome model rats, which completes the method of evaluating drug properties of Chinese medicine.


Assuntos
Arisaema , Resposta ao Choque Frio , Medicamentos de Ervas Chinesas , Golpe de Calor , Proteínas Quinases Ativadas por AMP , Animais , Arisaema/química , Bile , Hidrato de Cloral , Resposta ao Choque Frio/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolismo Energético , Golpe de Calor/terapia , Temperatura Alta , Masculino , Ratos , Ratos Sprague-Dawley , Solução Salina , Síndrome , Serina-Treonina Quinases TOR , Tiroxina , Água
6.
Nanomedicine ; 32: 102322, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33186694

RESUMO

The construction of a functional drug delivery system to reverse the multidrug resistance (MDR) of bone tumors in cases of failed chemotherapy remains a challenge. Herein, we demonstrate a selenium-doped calcium phosphate (Se-CaP) biomineral with high biocompatibility, biodegradability and pH-sensitive drug release properties. Se-CaP may not only serve as an effective drug-carrier to enhance the uptake of doxorubicin (DOX), but may also synchronously induce caspases-mediated apoptosis of osteosarcoma by generating intracellular reactive oxygen species (ROS). Furthermore, in vitro and in vivo studies obviously demonstrate that Se-CaP can reverse the MDR of osteosarcoma by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (ABCB1 and ABCC1). Finally, DOX-loaded Se-CaP can significantly inhibit DOX-resistant MG63 (MG63/DXR) tumor growth in nude mice. Considering its biomimetic chemical properties, the Se-CaP biomineral, with the multiple functions mentioned above, could be a promising candidate for treating bone tumors with MDR characteristics.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Fosfatos de Cálcio/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Minerais/química , Selênio/química , Neoplasias Ósseas/patologia , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Microesferas , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
7.
New Phytol ; 225(2): 807-822, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486533

RESUMO

In flowering plants, pollen wall is a specialized extracellular cell-wall matrix surrounding male gametophytes and acts as a natural protector of pollen grains against various environmental and biological stresses. The formation of pollen wall is a complex but well-regulated process, which involves the action of many different genes. However, the genetic and molecular mechanisms underlying this process remain largely unknown. In this study, we isolated and characterized a novel rice male sterile mutant, defective pollen wall3 (dpw3), which displays smaller and paler anthers with aborted pollen grains. DPW3 encodes a novel membrane-associated alpha integrin-like protein conserved in land plants. DPW3 is ubiquitously expressed in anther developmental stages and its protein is localized to the plasma membrane, endoplasmic reticulum (ER) and Golgi. Anthers of dpw3 plants exhibited unbalanced anther cuticular profile, abnormal Ubisch bodies, disrupted callose deposition, defective pollen wall formation such as abnormal microspore plasma membrane undulation and defective primexine formation, resulting in pollen abortion and complete male sterility. Our findings revealed a novel and vital role of alpha integrin-like proteins in plant male reproduction.


Assuntos
Cadeias alfa de Integrinas/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Pólen/metabolismo , Sequência de Bases , Membrana Celular/metabolismo , Sequência Conservada , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica de Plantas , Complexo de Golgi/metabolismo , Oryza/ultraestrutura , Fenótipo , Filogenia , Epiderme Vegetal/metabolismo , Pólen/genética , Pólen/ultraestrutura , Nicotiana/citologia
8.
J Exp Bot ; 69(8): 1955-1966, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29394372

RESUMO

Jasmonates are plant hormones that induce the accumulation of many secondary metabolites, such as rutin in buckwheat, via regulation of jasmonate-responsive transcription factors. Here, we report on the identification of a clade of jasmonate-responsive subgroup 4 MYB transcription factors, FtMYB13, FtMYB14, FtMYB15, and FtMYB16, which directly repress rutin biosynthesis in Fagopyrum tataricum. Immunoblot analysis showed that FtMYB13, FtMYB14, and FtMYB15 could be degraded via the 26S proteasome in the COI1-dependent jasmonate signaling pathway, and that this degradation is due to the SID motif in their C-terminus. Yeast two-hybrid and bimolecular fluorescence complementation assays revealed that FtMYB13, FtMYB14, and FtMYB15 interact with the importin protein Sensitive to ABA and Drought 2 (FtSAD2) in stem and inflorescence. Furthermore, the key repressor of jasmonate signaling FtJAZ1 specifically interacts with FtMYB13. Point mutation analysis showed that the conserved Asp residue of the SID domain contributes to mediating protein-protein interaction. Protoplast transient activation assays demonstrated that FtMYB13, FtMYB14, and FtMYB15 directly repress phenylalanine ammonia lyase (FtPAL) gene expression, and FtSAD2 and FtJAZ1 significantly promote the repressing activity of FtMYBs. These findings may ultimately be promising for further engineering of plant secondary metabolism.


Assuntos
Ciclopentanos/metabolismo , Fagopyrum/metabolismo , Oxilipinas/metabolismo , Proteínas de Plantas/metabolismo , Rutina/biossíntese , Fatores de Transcrição/metabolismo , Fagopyrum/química , Fagopyrum/genética , Regulação da Expressão Gênica de Plantas , Família Multigênica , Fenilalanina Amônia-Liase/genética , Fenilalanina Amônia-Liase/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/genética , Ligação Proteica , Domínios Proteicos , Fatores de Transcrição/química , Fatores de Transcrição/genética
9.
Plant Cell Rep ; 37(3): 393-410, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29150823

RESUMO

KEY MESSAGE: The dynamics of metabolites from leaves to roots of Panax ginseng during development has revealed the tissue-specific and year-specific metabolic networks. Being an essential Oriental medicinal plant, ginseng (Panax ginseng Meyer) is a slow-growing perennial herb-accumulating pharmaceutically active metabolites such as ginsenosides in roots during growth. However, little is known about how ginseng plants survive in the harsh environments such as winter cold and summer heat for a longer period and accumulates those active metabolites as the plant grows. To understand the metabolic kinetics in both source and sink organs such as leaves and roots of ginseng plant, respectively, and to assess the changes in ginsenosides biosynthesis during ginseng growth, we investigated the metabolic profiles from leaves and roots of 1-, 4-, and 6-year-old field-grown ginseng plants. Using an integrated non-targeted metabolomic approach, we identified in total 348 primary and secondary metabolites, which provided us for the first time a global metabolomic assessment of ginseng during growth, and morphogenesis. Strikingly, the osmoprotectants and oxidized chemicals were highly accumulated in 4- and 6-year-old ginseng leaves suggested that ginseng develop a wide range of metabolic strategies to adapt unfavorable conditions as they mature. In 6-year-old plants, ginsenosides were decreased in leaves but increased in roots up to 1.2- to sixfold, supporting the view that there is a long-distance transport of ginsenosides from leaves to roots as ginseng plants mature. Our findings provide insights into the metabolic kinetics during the development of ginseng plant and this could complement the pharmacological importance of ginseng and its compounds according to their age.


Assuntos
Adaptação Fisiológica , Redes e Vias Metabólicas , Metabolômica/métodos , Panax/metabolismo , Cinética , Panax/crescimento & desenvolvimento , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Medicinais/crescimento & desenvolvimento , Plantas Medicinais/metabolismo
10.
Proc Natl Acad Sci U S A ; 114(46): 12327-12332, 2017 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-29087306

RESUMO

Plants employ dynamic molecular networks to control development in response to environmental changes, yet the underlying mechanisms are largely unknown. Here we report the identification of two rice leucine-rich repeat receptor-like kinases, Thermo-Sensitive Genic Male Sterile 10 (TMS10) and its close homolog TMS10-Like (TMS10L), which redundantly function in the maintenance of the tapetal cell layer and microspore/pollen viability under normal temperature conditions with TMS10 playing an essential role in higher temperatures (namely, 28 °C). tms10 displays male sterility under high temperatures but male fertility under low temperatures, and the tms10 tms10l double mutant shows complete male sterility under both high and low temperatures. Biochemical and genetic assays indicate that the kinase activity conferred by the intracellular domain of TMS10 is essential for tapetal degeneration and male fertility under high temperatures. Furthermore, indica or japonica rice varieties that contain mutations in TMS10, created by genetic crosses or genome editing, also exhibit thermo-sensitive genic male sterility. These findings demonstrate that TMS10 and TMS10L act as a key switch in postmeiotic tapetal development and pollen development by buffering environmental temperature changes, providing insights into the molecular mechanisms by which plants develop phenotypic plasticity via genotype-environment temperature interaction. TMS10 may be used as a genetic resource for the development of hybrid seed production systems in crops.


Assuntos
Regulação da Expressão Gênica de Plantas , Oryza/genética , Infertilidade das Plantas/genética , Proteínas de Plantas/genética , Proteínas Quinases/genética , Sementes/genética , Adaptação Fisiológica/genética , Cruzamentos Genéticos , Interação Gene-Ambiente , Mutação , Oryza/classificação , Oryza/metabolismo , Filogenia , Proteínas de Plantas/metabolismo , Pólen , Polinização , Proteínas Quinases/metabolismo , Transdução de Sinais , Temperatura
11.
J Mol Graph Model ; 78: 96-109, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29055187

RESUMO

As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors. Then, the molecular recognition mechanism of PFV IN by its substrate viral DNA and six naphthyridine derivatives (NRDs) inhibitors was investigated through molecular docking, molecular dynamics simulations and water-mediated interactions analyses. The functional partition of NRDs IN inhibitors could be divided into hydrophobic and hydrophilic ones, and the Mg2+ ions, water molecules and conserved DDE motif residues all interacted with the hydrophilic partition, while the bases in viral DNA and residues like Tyr212, Pro214 interacted with the hydrophobic one. Finally, the free energy landscape (FEL) and cluster analyses were performed to explore the molecular motion of PFV IN-DNA system. It is found that the association with NRDs inhibitors would obviously decrease the motion amplitude of PFV IN-DNA, which may be one of the most potential mechanisms of IN inhibitors. This work will provide a theoretical basis for the inhibitor design based on the structure of HIV-1 IN.


Assuntos
DNA Viral/química , Inibidores de Integrase de HIV/química , Integrase de HIV/química , Conformação Proteica/efeitos dos fármacos , Sítios de Ligação , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/efeitos dos fármacos , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/patogenicidade , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica
12.
Protoplasma ; 254(5): 1909-1922, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28154963

RESUMO

Panax ginseng Meyer, commonly known as ginseng, is considered one of the most important herbs with pharmaceutical values due to the presence of ginsenosides and is cultivated for its highly valued root for medicinal purposes. Recently, it has been recognized that ginseng fruit contains high contents of triterpene such as ginsenoside Re as pharmaceutical compounds. However, it is unclear how carpel, the female reproductive tissue of flowers, is formed during the three-year-old growth before fruit is formed in ginseng plants. Here, we report P. ginseng carpel development at the cytological level, starting from the initial stage of ovule development to seed development. The carpel of P. ginseng is composed of two free stigmas, two free styles, and one epigynous bilocular ovary containing one ovule in each locule. Based on our cytological study, we propose that the female reproductive development in P. ginseng can be classified into seven stages: early phase of ovule development, megasporogenesis, megagametogenesis, pre-fertilization, fertilization, post-fertilization, and seed development. We also describe the correlation of the female and male gametophyte development and compare morphological differences in carpel development between ginseng and other higher plants. One unique feature for ginseng seed development is that it takes 40 days for the embryo to develop to the early torpedo stage and that the embryo is small relative to the seed size, which could be a feature of taxonomic importance. This study will provide an integral tool for the study of the reproductive development and breeding of P. ginseng.


Assuntos
Panax/metabolismo , Flores/metabolismo , Ginsenosídeos/metabolismo , Triterpenos/metabolismo
13.
Plant Physiol ; 173(1): 240-255, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27246096

RESUMO

Aliphatic and aromatic lipids are both essential structural components of the plant cuticle, an important interface between the plant and environment. Although cross links between aromatic and aliphatic or other moieties are known to be associated with the formation of leaf cutin and root and seed suberin, the contribution of aromatic lipids to the biosynthesis of anther cuticles and pollen walls remains elusive. In this study, we characterized the rice (Oryza sativa) male sterile mutant, defective pollen wall 2 (dpw2), which showed an abnormal anther cuticle, a defective pollen wall, and complete male sterility. Compared with the wild type, dpw2 anthers have increased amounts of cutin and waxes and decreased levels of lipidic and phenolic compounds. DPW2 encodes a cytoplasmically localized BAHD acyltransferase. In vitro assays demonstrated that recombinant DPW2 specifically transfers hydroxycinnamic acid moieties, using ω-hydroxy fatty acids as acyl acceptors and hydroxycinnamoyl-CoAs as acyl donors. Thus, The cytoplasmic hydroxycinnamoyl-CoA:ω-hydroxy fatty acid transferase DPW2 plays a fundamental role in male reproduction via the biosynthesis of key components of the anther cuticle and pollen wall.


Assuntos
Aciltransferases/metabolismo , Oryza/enzimologia , Oryza/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Pólen/enzimologia , Pólen/crescimento & desenvolvimento , Sequência de Aminoácidos , Parede Celular/metabolismo , Clonagem Molecular , Regulação da Expressão Gênica de Plantas , Metabolismo dos Lipídeos , Lipídeos de Membrana/metabolismo , Modelos Biológicos , Mutação/genética , Oryza/genética , Oryza/ultraestrutura , Fenóis/metabolismo , Fenótipo , Pólen/ultraestrutura , Transporte Proteico , Proteínas Recombinantes/metabolismo , Análise de Sequência de Proteína , Ceras/metabolismo
14.
J Chem Inf Model ; 56(6): 1152-63, 2016 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-27186994

RESUMO

Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse. The lack of an experimental three-dimensional CB2 structure has hindered not only the development of studies of conformational differences between the inactive and active CB2 but also the rational discovery of novel functional compounds targeting CB2. In this work, we constructed models of both inactive and active CB2 by homology modeling. Then we conducted two comparative 100 ns molecular dynamics (MD) simulations on the two systems-the active CB2 bound with both the agonist and G protein and the inactive CB2 bound with inverse agonist-to analyze the conformational difference of CB2 proteins and the key residues involved in molecular recognition. Our results showed that the inactive CB2 and the inverse agonist remained stable during the MD simulation. However, during the MD simulations, we observed dynamical details about the breakdown of the "ionic lock" between R131(3.50) and D240(6.30) as well as the outward/inward movements of transmembrane domains of the active CB2 that bind with G proteins and agonist (TM5, TM6, and TM7). All of these results are congruent with the experimental data and recent reports. Moreover, our results indicate that W258(6.48) in TM6 and residues in TM4 (V164(4.56)-L169(4.61)) contribute greatly to the binding of the agonist on the basis of the binding energy decomposition, while residues S180-F183 in extracellular loop 2 (ECL2) may be of importance in recognition of the inverse agonist. Furthermore, pharmacophore modeling and virtual screening were carried out for the inactive and active CB2 models in parallel. Among all 10 hits, two compounds exhibited novel scaffolds and can be used as novel chemical probes for future studies of CB2. Importantly, our studies show that the hits obtained from the inactive CB2 model mainly act as inverse agonist(s) or neutral antagonist(s) at low concentration. Moreover, the hit from the active CB2 model also behaves as a neutral antagonist at low concentration. Our studies provide new insight leading to a better understanding of the structural and conformational differences between two states of CB2 and illuminate the effects of structure on virtual screening and drug design.


Assuntos
Descoberta de Drogas , Simulação de Dinâmica Molecular , Receptor CB2 de Canabinoide/química , Receptor CB2 de Canabinoide/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ligantes , Conformação Proteica , Homologia de Sequência de Aminoácidos , Termodinâmica , Interface Usuário-Computador
15.
Bioorg Med Chem Lett ; 26(3): 721-725, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26776360

RESUMO

The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor. However, there is limited information on the structure-activity relationship of this series of compounds. Moreover, there are few scaffolds reported as chelating groups for Fe(II) ion in Jumonji demethylase inhibitors development. To further elaborate the structure-activity relationship of selective JMJD3 inhibitors and to explore the novel chelating groups for Fe(II) ion, we initialized a medicinal chemistry modification based on the GSK-J1 structure. Finally, we found that several compounds bearing different chelating groups showed similar activities with respect to GSK-J1 and excellent metabolic stability in liver microsomes. The ethyl ester prodrugs of these inhibitors also showed a better activity than GSK-J4 for inhibition of TNF-α production in LPS-stimulated murine macrophage cell line Raw 264.7 cells. Taking together, the current study not only discovered alternative potent JMJD3 inhibitors, but also can benefit other researchers to design new series of Jumonji demethylase inhibitors based on the identified chelating groups.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Compostos Ferrosos/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Pirimidinas/química , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Compostos Ferrosos/síntese química , Compostos Ferrosos/química , Meia-Vida , Humanos , Concentração Inibidora 50 , Íons/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Nitrogênio/química , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
16.
Int J Clin Exp Med ; 7(12): 5842-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25664117

RESUMO

OBJECTIVE: To explore the effect of high temperature yoga exercise on improving physical and psychological well-being of overweight middle-aged and young women. DESIGN: 50 overweight middle-aged and young women from yoga clubs were selected. The indexes of their constitution, physiological functions, psychological adaptation were measured and compared before and after one year of uninterrupted high temperature yoga exercise. RESULTS: The indexes of the subjects' constitution and physiological functions were remarkably uplifted (P < 0.05); their psychological adaptation was improved as well. CONCLUSION: Aerobics represented by high temperature yoga can improve body shape, lower lipid, reduce weight, and exert an evident therapeutic effect on improving physiological functions and boosting psychological well-being.

17.
Nat Commun ; 4: 1445, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23385589

RESUMO

Programmed cell death is essential for the development of multicellular organisms, yet pathways of plant programmed cell death and its regulation remain elusive. Here we report that ETERNAL TAPETUM 1, a basic helix-loop-helix transcription factor conserved in land plants, positively regulates programmed cell death in tapetal cells in rice anthers. eat1 exhibits delayed tapetal cell death and aborted pollen formation. ETERNAL TAPETUM 1 directly regulates the expression of OsAP25 and OsAP37, which encode aspartic proteases that induce programmed cell death in both yeast and plants. Expression and genetic analyses revealed that ETERNAL TAPETUM 1 acts downstream of TAPETUM DEGENERATION RETARDATION, another positive regulator of tapetal programmed cell death, and that ETERNAL TAPETUM 1 can also interact with the TAPETUM DEGENERATION RETARDATION protein. This study demonstrates that ETERNAL TAPETUM 1 promotes aspartic proteases triggering plant programmed cell death, and reveals a dynamic regulatory cascade in male reproductive development in rice.


Assuntos
Ácido Aspártico Proteases/metabolismo , Oryza/citologia , Oryza/enzimologia , Proteínas de Plantas/química , Pólen/citologia , Pólen/enzimologia , Sequência de Aminoácidos , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Morte Celular , Cromossomos de Plantas/genética , Regulação da Expressão Gênica de Plantas , Genes de Plantas/genética , Modelos Biológicos , Dados de Sequência Molecular , Mutação/genética , Especificidade de Órgãos , Oryza/genética , Oryza/ultraestrutura , Fenótipo , Filogenia , Mapeamento Físico do Cromossomo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pólen/ultraestrutura , Ligação Proteica , Reprodução , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo
18.
Dev Cell ; 22(6): 1127-37, 2012 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-22698279

RESUMO

In flowering plants, formation of the haploid male gametophytes in anthers requires the interaction between reproductive cells and the neighboring somatic cells, yet the underlying mechanism remains poorly understood. Here, we reveal the crucial role of a fasciclin glycoprotein, MICROSPORE AND TAPETUM REGULATOR1 (MTR1), in controlling the development of sporophytic and reproductive cells in rice (Oryza sativa). MTR1 is specifically expressed in the male reproductive cells, yet its mutant exhibits defects in both tapetum and microspore development, causing complete male sterility. We also demonstrate that the fasciclin domains, N-glycolation, and N-terminal signal peptide-mediated plasma membrane localization of MTR1 are required for normal anther development and pollen fertility. Our findings show that rice male reproductive cells secrete the MTR1 protein to control the development of reproductive cells and their adjacent somatic cells, thus providing novel insights into the mechanism of plant male reproductive development.


Assuntos
Oryza/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Pólen/crescimento & desenvolvimento , Sequência de Aminoácidos , Sequência de Bases , Flores/genética , Flores/crescimento & desenvolvimento , Flores/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação da Expressão Gênica de Plantas/fisiologia , Dados de Sequência Molecular , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Pólen/genética , Pólen/metabolismo , Estrutura Terciária de Proteína/fisiologia
19.
Zhongguo Zhong Yao Za Zhi ; 30(17): 1317-20, 2005 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-16323537

RESUMO

Traditional Chinese medicine with embryo toxicity has been named as abstinence medicine in cyesis in ancient times. Embryo toxicity is one of the key theories of traditional Chinese medicine. Based on history retrospective study and rhodern research, the paper expounded that the developing course of embryo toxicity of traditional Chinese medicine is from cyesis abstinence to inheritance toxicity and reproductive development toxicity, and overviewed the research of active components of traditional Chinese medicine in the domains of inheritance toxicity and reproductive development toxicity. Meanwhile, it pointed out that the main problem in the domain is about the definition of conception and category of traditional Chinese medicine with embryo toxicity and the foundation of relative assessment system. In the end, some suggestions were given to solve the problem including the control of poisonous traditional Chinese medicines, right processing, reasonable compatibility, extensional application, and utilizing modem science and technology.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Embrião de Mamíferos/efeitos dos fármacos , Metais Pesados/toxicidade , Animais , Medicamentos de Ervas Chinesas/química , Desenvolvimento Embrionário/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Metais Pesados/análise , Estudos Retrospectivos , Tecnologia Farmacêutica
20.
Wei Sheng Yan Jiu ; 31(4): 249-51, 2002 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-12600031

RESUMO

To observe the effects of silkworm pupa oil on serum lipids level and platelet function in rats, according to serum TG, TC level, 40 male Wistar rats are divided into four groups (normal control group, high fat control group, silkworm pupa oil group and silkworm pupa oil + VE group). The rats are fed different diets and six weeks later, serum lipids level and platelet function are measured. The results show that (1) Compared with high fat control group, serum TC, TG, LDL-C level, AI value, Platelet aggregability, plasma TXB2 level and T/P ratio decrease significantly while HDL-C level and 6-k-PGF1 level increase in silkworm pupa oil group; (2) Serum TC, LDL-C level, T/P ratio and platelet aggregability are significantly lower in silkworm pupa oil + VE group than in silkworm pupa oil group. It is suggested that silkworm pupa oil rich in alpha-linolenic acid can reduce serum lipids level and inhibit platelet aggregation, which is more effective with the supplementation with VE.


Assuntos
Bombyx/química , Hipolipemiantes/farmacologia , Lipídeos/sangue , Inibidores da Agregação Plaquetária/farmacologia , Ácido alfa-Linolênico/farmacologia , Animais , Masculino , Óleos/farmacologia , Pupa/química , Ratos , Ratos Wistar , Vitamina E/farmacologia
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