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1.
Cell ; 187(12): 2969-2989.e24, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38776919

RESUMO

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.


Assuntos
Fungos , Microbioma Gastrointestinal , Micobioma , Animais , Humanos , Masculino , Camundongos , Fezes/microbiologia , Fungos/genética , Fungos/classificação , Fungos/isolamento & purificação , Genoma Fúngico/genética , Genômica , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/genética , Metagenoma , Filogenia , Feminino , Adulto , Pessoa de Meia-Idade
2.
J Biol Chem ; 300(1): 105565, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38103642

RESUMO

The biochemical SRX (super-relaxed) state of myosin has been defined as a low ATPase activity state. This state can conserve energy when the myosin is not recruited for muscle contraction. The SRX state has been correlated with a structurally defined ordered (versus disordered) state of muscle thick filaments. The two states may be linked via a common interacting head motif (IHM) where the two heads of heavy meromyosin (HMM), or myosin, fold back onto each other and form additional contacts with S2 and the thick filament. Experimental observations of the SRX, IHM, and the ordered form of thick filaments, however, do not always agree, and result in a series of unresolved paradoxes. To address these paradoxes, we have reexamined the biochemical measurements of the SRX state for porcine cardiac HMM. In our hands, the commonly employed mantATP displacement assay was unable to quantify the population of the SRX state with all data fitting very well by a single exponential. We further show that mavacamten inhibits the basal ATPases of both porcine ventricle HMM and S1 (Ki, 0.32 and 1.76 µM respectively) while dATP activates HMM cooperatively without any evidence of an SRX state. A combination of our experimental observations and theories suggests that the displacement of mantATP in purified proteins is not a reliable assay to quantify the SRX population. This means that while the structurally defined IHM and ordered thick filaments clearly exist, great care must be employed when using the mantATP displacement assay.


Assuntos
Trifosfato de Adenosina , Ensaios Enzimáticos , Miosina não Muscular Tipo IIA , Suínos , ortoaminobenzoatos , Animais , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Motivos de Aminoácidos , Benzilaminas/farmacologia , Ensaios Enzimáticos/métodos , Ensaios Enzimáticos/normas , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/enzimologia , Ventrículos do Coração/metabolismo , Contração Miocárdica , Subfragmentos de Miosina/química , Subfragmentos de Miosina/metabolismo , Miosina não Muscular Tipo IIA/química , Miosina não Muscular Tipo IIA/metabolismo , ortoaminobenzoatos/metabolismo , Uracila/análogos & derivados , Uracila/farmacologia
3.
Acta Pharmacol Sin ; 45(6): 1201-1213, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38491160

RESUMO

The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.


Assuntos
Via de Sinalização Hippo , Interleucina-6 , Regeneração Hepática , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases , Receptor Tipo 2 de Angiotensina , Transdução de Sinais , Animais , Masculino , Camundongos , Acetaminofen , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Interleucina-6/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/fisiologia , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Proteínas de Sinalização YAP/metabolismo
4.
Molecules ; 29(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731415

RESUMO

Investigations have shown that storage bugs seriously harm grains during storage. In the interim, essential oils (EOs) have been proven to be a good botanical pesticide. The anti-Lasioderma serricorne properties of Elsholtzia ciliata essential oil, which was obtained by steam distillation, were evaluated using DL-limonene, carvone, and their two optical isomer components using contact, repelling, and fumigation techniques. Simultaneously, the fumigation, contact, and repellent activities of carvone and its two optical isomers mixed with DL-limonene against L. serruricorne were evaluated. The results showed that E. ciliata, its main components (R-carvone, DL-limonene), and S-carvone exhibited both fumigations (LC50 = 14.47, 4.42, 20.9 and 3.78 mg/L) and contact (LD50 = 7.31, 4.03, 28.62 and 5.63 µg/adult) activity against L.serricorne. A binary mixture (1:1) of R-carvone and DL-limonene displayed an obvious synergistic effect. A binary mixture (1:1) of carvone and its two optical isomers exhibited an obvious synergistic effect, too. Furthermore, the repellent activity of the EO, carvone, and its two optical isomers, DL-limonene, and a combination of them varied. To stop insect damage during storage, E. ciliata and its components can be utilized as bio-insecticides.


Assuntos
Inseticidas , Lamiaceae , Óleos Voláteis , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Lamiaceae/química , Animais , Inseticidas/química , Inseticidas/farmacologia , Limoneno/química , Limoneno/farmacologia , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , Monoterpenos Cicloexânicos/química , Monoterpenos Cicloexânicos/farmacologia , Sinergismo Farmacológico , Fumigação
5.
J Mol Cell Cardiol ; 175: 1-12, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36470336

RESUMO

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ∼1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.


Assuntos
Miocárdio , Ribonucleotídeo Redutases , Camundongos , Animais , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Contração Miocárdica , Ribonucleotídeo Redutases/metabolismo , Ribonucleotídeo Redutases/farmacologia , Camundongos Transgênicos , Trifosfato de Adenosina/metabolismo , Miosinas/metabolismo
6.
Opt Lett ; 48(20): 5371-5374, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37831870

RESUMO

In this paper, we demonstrated the design and experimental results of the near-infrared lab-on-a-chip optical biosensor platform that monolithically integrates the MRR and the on-chip spectrometer on the silicon-on-insulator (SOI) wafer, which can eliminate the external optical spectrum analyzer for scanning the wavelength spectrum. The symmetric add-drop MRR biosensor is designed to have a free spectral range (FSR) of ∼19 nm and a bulk sensitivity of ∼73 nm/RIU; then the drop-port output resonance peaks are reconstructed from the integrated spatial-heterodyne Fourier transform spectrometer (SHFTS) with the spectral resolution of ∼3.1 nm and the bandwidth of ∼50 nm, which results in the limit of detection of 0.042 RIU.

7.
Molecules ; 28(8)2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37110706

RESUMO

Cytochrome P450 1A is one of the vital subfamilies of heme-containing cytochrome P450 enzymes belonging to an important exogenous metabolizing CYP in human. The abnormal of endoplasmic reticulum (ER) may directly affect the functional activity of ER-located CYP1A and be associated with the occurrence and development of various diseases. In the present study, we constructed a selective two-photon fluorescent probe ERNM for rapid and visual detection of endogenous CYP1A that was localized in the ER. ERNM could target the ER and detect the enzymatically active CYP1A in living cells and tissues. The monitoring ability of ERNM for the fluctuations in functionality level of CYP1A was confirmed using ER stressed A549 cell. Based on the ER-targeting two-photon probe for CYP1A, the close association of ER state and the functional activity of ER-locating CYP1A was confirmed, which would promote the deep understanding of the biofunction of CYP1A in various ER-related diseases.


Assuntos
Diagnóstico por Imagem , Corantes Fluorescentes , Humanos , Células HeLa , Retículo Endoplasmático , Estresse do Retículo Endoplasmático
8.
Gut ; 71(11): 2205-2217, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35173042

RESUMO

OBJECTIVE: Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice. DESIGN: Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo. RESULTS: The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1-F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice. CONCLUSION: This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Sesquiterpenos , Animais , Antibacterianos/uso terapêutico , Candida parapsilosis , Colite/tratamento farmacológico , Colite/metabolismo , Modelos Animais de Doenças , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-10 , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico
9.
J Fluoresc ; 32(4): 1601-1610, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35587852

RESUMO

Four fluorimetric probes had been developed to rapidly detect 2,4,6-trinitrophenol (TNP). They were designed and synthesized on the basis of 1,3,4-thiadiazole framework combining calculation with experiment. Among them, SK-1 displayed strong blue emission with fluorescence quantum yield as high as 63.6% in solution. Further evaluation demonstrated that SK-1 displays good selectivity and high sensitivity for rapid and visual detection of TNP. It brought significant changes in both colour and fluorescence emission spectrum. The detection limit was as low as 38 nM. Quenching mechanism was confirmed as photo-induced electron transfer (PET) by nuclear magnetic titration and DFT calculations. What's more, application in real water samples and solid phase paper tests illustrated the practical significance of detection of TNP in both vapor and solution.


Assuntos
Espectrometria de Fluorescência , Teoria da Densidade Funcional , Picratos , Tiadiazóis
10.
Breed Sci ; 72(2): 169-180, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36275938

RESUMO

Wheat landraces have abundant genetic variation at the Glu-1 loci, which is desirable germplasms for genetic enhancement of modern wheat varieties, especially for quality improvement. In the current study, we analyzed the allelic variations of the Glu-1 loci of 597 landraces and 926 commercial wheat varieties from the four major wheat-growing regions in China using SDS-PAGE. As results, alleles Null, 7+8, and 2+12 were the dominant HMW-GSs in wheat landraces. Compared to landraces, the commercial varieties contain higher frequencies of high-quality alleles, including 1, 7+9, 14+15 and 5+10. The genetic diversity of the four commercial wheat populations (alleles per locus (A) = 7.33, percent polymorphic loci (P) = 1.00, effective number of alleles per locus (Ae) = 2.347 and expected heterozygosity (He) = 0.563) was significantly higher than that of the landraces population, with the highest genetic diversity found in the Southwestern Winter Wheat Region population. The genetic diversity of HMW-GS is mainly present within the landraces and commercial wheat populations instead of between populations. The landraces were rich in rare subunits or alleles may provide germplasm resources for improving the quality of modern wheat.

11.
J Environ Sci Health B ; 57(9): 739-744, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35930275

RESUMO

In order to find and develop new botanical pesticides against storage pests, components of the essential oil (EO) from Zanthoxylum bungeanum were identified by GC-MS and their insecticidal activity against the stored product pests were studied. The EO was obtained by steam distillation. Results showed that EO was rich in limonene (23.67), linalool (21.76) and linalyl anthranilate (10.87). In contact assays, linalool exhibited strongest toxicity to red flour beetle adult (LD50 = 17.06 µg/adult) and larvae (LD50 = 16.42 µg/larvae), and linalool was the most active one against the Lasioderma serricorne (LD50 = 15.36 µg/larvae). Then limonene and linalool showed different levels of fumigant activities against the two insect species. Synergism effect existed in the proportion of contact assays against Tribolium castaneum adults, and additive was observed in the proportion of 7:1 against T. castaneum larvae. This work provides important information for the development and utilization of Z. bungeanum and suggests that the EO of Z. bungeanum has the potential to serve as bio-insecticides for controlling pest damage in stored products.


Assuntos
Besouros , Repelentes de Insetos , Inseticidas , Óleos Voláteis , Zanthoxylum , Monoterpenos Acíclicos , Animais , Insetos , Inseticidas/análise , Inseticidas/toxicidade , Limoneno , Óleos Voláteis/toxicidade , Vapor , ortoaminobenzoatos
12.
J Environ Sci Health B ; 56(4): 423-430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678144

RESUMO

In this work, we investigated the bioactivities of the essential oil (EO) extracted from the Rhododendron thymifolium and its principal germacrone against Lasioderma serricorne and Tribolium castaneum. The EO was obtained by steam distillation. Germacrone was obtained by cryogenic crystallization. The bioactivity of EO and germacrone was tested via contact and repellent activity assays. The results showed that EO and germacrone possessed contact and repellent activities against two species of insects. EO exhibited obvious contact activity against the L. serricorn adults, larvae and T. castaneum larvae with LD50 values of 29.15 µg/adult, 42.73 µg/larva, 19.65 µg/larva respectively. Germacrone exhibited excellent contact activity against the L. serricorne adults, larvae and the T. castaneum larvae with LD50 values of 17.18 µg/adult, 20.94 µg/larva, 20.93 µg/larva respectively. And at the highest testing concentrations (78.63 and 15.73 nL/cm2), the repellent activity of EO and germacrone on two target insects was comparable to that of the positive control (DEET) after 30 h exposure. In especially, in the treatment of the 120 h after the repellent activity of EO and germacrone against T.castaneum adults and larvae were still very significant and showed the same level percentage repellency as DEET. Meanwhile, germacrone exhibited inhibition of acetylcholinesterase activity with IC50 values of 3%. The results indicated that the EO of R. thymifolium and germacrone had the potential to be developed as natural insecticides and repellents for the control of T. castaneum and L. serricorne.


Assuntos
Inibidores da Colinesterase/farmacologia , Besouros/efeitos dos fármacos , Inseticidas/farmacologia , Óleos Voláteis/farmacologia , Rhododendron/química , Animais , Inibidores da Colinesterase/química , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , Inseticidas/química , Dose Letal Mediana , Óleos Voláteis/química , Sesquiterpenos de Germacrano/farmacologia , Tribolium/química , Tribolium/efeitos dos fármacos
13.
J Cell Physiol ; 235(10): 7449-7464, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32064615

RESUMO

Colorectal cancer (CRC) is one of the most prevalent tumors worldwide. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators in postgenomic biology. Numerous lncRNAs have been identified as diagnostic biomarkers and therapeutic targets. However, the molecular mechanisms underlying the role of lncRNAs in CRC progression are not fully understood. Differentially expressed lncRNAs and messenger RNAs were investigated using a microarray approach in five paired primary CRC tumor tissues and the corresponding nontumor tissues and confirmed in an additional 116 paired tissues and 21 inflammatory bowel disease tissues and 15 adjacent normal tissues by a quantitative real-time polymerase chain reaction. We also performed comprehensive transcriptome profiling analysis on Gene Expression Omnibus and The Cancer Genome Atlas datasets. We identified LINC02595 and evaluated its clinical significance as a plasma biomarker. The function of LINC02595 was evaluated using a panel of in vivo and vitro assays, including cell counting kit-8, colony formation, cell cycle, apoptosis, RNA fluorescence in situ hybridization, luciferase reporter, immunohistochemistry, and CRC xenografts. We found that LINC02595 is upregulated in tumor tissues and blood samples of patients with CRC and CRC cell lines. Functional research found that LINC02595 promotes CRC cell growth, influences the cell cycle, and reduces apoptosis in vitro and vivo. Mechanistically, LINC02595 promoted BCL2-like 1 (BCL2L1) expression through miR-203b-3p sponging. Our research demonstrated that LINC02595 is an oncogene in CRC and established the presence of a LINC02595-miR-203b-BCL2L1 axis in CRC, which might provide a new diagnostic biomarker and therapeutic targets for the treatment of this disease.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteína bcl-X/genética , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Células CACO-2 , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , RNA Mensageiro/genética , Transdução de Sinais/genética , Regulação para Cima/genética
14.
J Transl Med ; 18(1): 235, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532255

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been increasingly applied in the treatment of several kinds of malignancies. Some clinical demographic characteristics were reported to be associated with the ICIs efficacy. The purpose of our current meta-analysis was to clearly evaluated the relationship between BMI and ICIs efficacy for cancer patients receiving immunotherapy. METHODS: A systematic search of Pubmed, EMBASE and conference proceedings was performed to investigate the influence of BMI on ICIs efficacy. Pooled analysis for overall survival (OS), progression-free survival (PFS) and immune-related adverse effects (IRAEs) were analyzed in current study. RESULTS: A total of 13 eligible studies comprising 5279 cancer patients treated with ICIs were included in the analysis. The pooled analysis showed there is positive association between high BMI and improved OS and PFS among patients with ICIs treatment (OS: HR = 0.62, 95% CI 0.55-0.71, P < 0.0001; I2 = 26.3%, P = 0.202); PFS: HR = 0.71, 95% CI 0.61-0.83, P < 0.0001; I2 = 0%, P = 0.591). There is no significant difference between the incidence of all grade IRAEs between obese, overweight patients and normal patients (Overweight vs Normal: pooled RR = 1.28, 95% CI 0.76- 2.18, P = 0.356; Obese vs Normal: pooled RR = 1.36, 95% CI 0.85- 2.17, P = 0.207). CONCLUSION: An improved OS and PFS were observed in patients with high BMI after receiving ICIs treatment compared with patients of low BMI. No significant association between BMI and incidence of IRAEs was found in cancer patients after ICIs treatment.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Índice de Massa Corporal , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias/complicações , Neoplasias/tratamento farmacológico
15.
Exp Cell Res ; 382(2): 111468, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201812

RESUMO

Database screening indicated that microRNAs (miRNAs) are involved in pathogenesis of endometrial cancer. Among these miRNAs, miR-449a might be involved in tumorigenesis and lower expression of miR-449a was associated with poor prognosis. However, the role of miR-449a and its underlying molecular mechanism in endometrial cancer (EC) has not been investigated. In this study, our analysis found that miR-449a expression is inversely correlated with the stage of EC. Downregulation of miR-449a was correlated with tumor progression and poor prognosis in the EC patients. Results of functional analyses revealed that overexpression of miR-449a in human EC cells alleviated cell proliferation, invasion and metastasis. Conversely, loss of miR-449a in EC cancer cells facilitated all these cellular activities. Moreover, we identified N-myc downstream-regulated gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression of NDRG1 in 87 EC specimens were inversely correlated with that of miR-449a. Additionally, further studies show that the down-regulation of NDRG1 expression inhibited proliferation and metastasis of EC cells through the PTEN/AKT pathway. Therefore, these results suggest that miR-449a suppresses the growth and metastasis of EC by directly targeting the NDRG1 gene and that the activation of miR-449a may represent an effective therapeutic strategy in EC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Neoplasias do Endométrio/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Sequência de Bases , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Prognóstico
16.
Bioorg Chem ; 83: 129-134, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30352358

RESUMO

Cephalotrichum microsporum (SYP-F 7763) was a fungus isolated from the rhizosphere soil of traditional Chinese medicine Panax notoginseng. The EtOAc extract of Cephalotrichum microsporum cultivated on sterilized moistened-rice medium was separated by various chromatographic techniques, which yielded 11 metabolites (1-11) of this fungus. On the basis of the widely spectroscopic data, the chemical structures of isolated metabolites were determined, most of which were α-pyrones, including 5 compounds (4-7, and 10) unreported. In the anti-bacterial bioassay, compound 1 displayed significant inhibitory effects on three pathogenic bacteria, MR S. aureus, S. aureus, and B. cereus. α-Pyrones 2, 3, and 5-7 also displayed moderate inhibitory effects on MR S. aureus, S. aureus, and B. subtilis, which could be the major anti-bacterial constituents of Cephalotrichum microsporum. Additionally, compounds 1, 4, and 5 displayed significant cytotoxicity on five human cancer cell lines, with the IC50 values < 20 µM, which are more effective than positive control 5-fluorouracil. Therefore, α-pyrones were important secondary metabolites of Cephalotrichum microsporum, which displayed anti-bacterial and anti-tumor activities.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bacillus/efeitos dos fármacos , Pironas/farmacologia , Staphylococcus/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pironas/química , Pironas/metabolismo , Relação Estrutura-Atividade
17.
Pharmacology ; 104(1-2): 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947229

RESUMO

BACKGROUND: Ocotillol, RT5 and F11, the main active components of ocotillol type ginsenosides, have attracted a lot of attention due to their beneficial effects on neurodegenerative disease models of Alzheimer's disease. Pharmacokinetic (PK) is a bridge linking the herbal medicines and their pharmacological responses. However, few data are available regarding PK behaviors of ocotillol type ginsenosides. METHODS: The liquid chromatography-tandem mass spectrometry methods were developed and validated to calculate the concentrations of 3 ginsenosides in different biological matrices. Rat and beagle dog plasma samples were deproteinized with methanol and separated on Shim-pack GIST C18 column. All of the analytes were detected in positive ion mode using multiple reaction monitoring. RESULTS: The methods showed good linearity (r > 0.996) in the established concentration range. All validated data, such as specificity, intra- and inter-day precision, accuracy, extraction recovery, matrix effect, and stability were within required limits. The values of Cmax and AUC(0-t) indicated ocotillol type ginsenosides had low systemic exposure and poor absorption into blood. T1/2 and MRT(0-t) demonstrated the elimination process of ocotillol type ginsenosides might be slow. Double peaks were observed in the mean plasma concentration versus time profiles of ocotillol, RT5, and F11 after oral intake. CONCLUSIONS: This was the first PK investigation of the ocotillol type ginsenosides in rats and beagle dogs. The results we found here were helpful to our understanding of the absorption mechanism of ocotillol type ginsenosides and provided the scientific basis for further pre-clinical research.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ginsenosídeos/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Panax/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Ginsenosídeos/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Padrões de Referência , Reprodutibilidade dos Testes , Distribuição Tecidual
18.
Proc Natl Acad Sci U S A ; 113(35): E5163-71, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27535938

RESUMO

Asian cultivated rice consists of two subspecies: Oryza sativa subsp. indica and O. sativa subsp. japonica Despite the fact that indica rice accounts for over 70% of total rice production worldwide and is genetically much more diverse, a high-quality reference genome for indica rice has yet to be published. We conducted map-based sequencing of two indica rice lines, Zhenshan 97 (ZS97) and Minghui 63 (MH63), which represent the two major varietal groups of the indica subspecies and are the parents of an elite Chinese hybrid. The genome sequences were assembled into 237 (ZS97) and 181 (MH63) contigs, with an accuracy >99.99%, and covered 90.6% and 93.2% of their estimated genome sizes. Comparative analyses of these two indica genomes uncovered surprising structural differences, especially with respect to inversions, translocations, presence/absence variations, and segmental duplications. Approximately 42% of nontransposable element related genes were identical between the two genomes. Transcriptome analysis of three tissues showed that 1,059-2,217 more genes were expressed in the hybrid than in the parents and that the expressed genes in the hybrid were much more diverse due to their divergence between the parental genomes. The public availability of two high-quality reference genomes for the indica subspecies of rice will have large-ranging implications for plant biology and crop genetic improvement.


Assuntos
Cromossomos de Plantas/genética , Variação Genética , Genoma de Planta/genética , Oryza/genética , Mapeamento Cromossômico/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas/genética , Mutação INDEL , Oryza/classificação , Polimorfismo de Nucleotídeo Único , Especificidade da Espécie
19.
J Biol Chem ; 292(45): 18608-18617, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-28924049

RESUMO

The plasma protein von Willebrand factor (VWF) is essential for hemostasis initiation at sites of vascular injury. The platelet-binding A1 domain of VWF is connected to the VWF N-terminally located D'D3 domain through a relatively unstructured amino acid sequence, called here the N-terminal linker. This region has previously been shown to inhibit the binding of VWF to the platelet surface receptor glycoprotein Ibα (GpIbα). However, the molecular mechanism underlying the inhibitory function of the N-terminal linker has not been elucidated. Here, we show that an aspartate at position 1261 is the most critical residue of the N-terminal linker for inhibiting binding of the VWF A1 domain to GpIbα on platelets in blood flow. Through a combination of molecular dynamics simulations, mutagenesis, and A1-GpIbα binding experiments, we identified a network of salt bridges between Asp1261 and the rest of A1 that lock the N-terminal linker in place such that it reduces binding to GpIbα. Mutations aimed at disrupting any of these salt bridges activated binding unless the mutated residue also formed a salt bridge with GpIbα, in which case the mutations inhibited the binding. These results show that interactions between charged amino acid residues are important both to directly stabilize the A1-GpIbα complex and to indirectly destabilize the complex through the N-terminal linker.


Assuntos
Ácido Aspártico/química , Velocidade do Fluxo Sanguíneo , Plaquetas/metabolismo , Modelos Moleculares , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Fator de von Willebrand/metabolismo , Substituição de Aminoácidos , Sítios de Ligação , Adesão Celular , Deleção de Genes , Humanos , Microesferas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Mutação Puntual , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Eletricidade Estática , Fator de von Willebrand/antagonistas & inibidores , Fator de von Willebrand/química , Fator de von Willebrand/genética
20.
Int J Med Sci ; 14(12): 1276-1283, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29104485

RESUMO

Background: Cell recognition molecule L1 (L1) plays an important role in cancer cell differentiation, proliferation, migration and survival, but its mechanism remains unclear. Methodology/Principal: Our previous study has demonstrated that L1 enhanced cell survival and migration in neural cells by regulating cell surface glycosylation. In the present study, we show that L1 affected cell migration and survival in CHO (Chinese hamster ovary) cell line by modulation of sialylation and fucosylation at the cell surface via the PI3K (phosphoinositide 3-kinase) and Erk (extracellularsignal-regulated kinase) signaling pathways. Flow cytometry analysis indicated that L1 modulated cell surface sialylation and fucosylation in CHO cells. Activated L1 upregulated the protein expressions of ST6Gal1 (ß-galactoside α-2,6-sialyltransferase 1) and FUT9 (Fucosyltransferase 9) in CHO cells. Furthermore, activated L1 promoted CHO cells migration and survival as shown by transwell assay and MTT assay. Inhibitors of sialylation and fucosylation blocked L1-induced cell migration and survival, while decreasing FUT9 and ST6Gal1 expressions via the PI3K-dependent and Erk-dependent signaling pathways. Conclusion : L1 modulated cell migration and survival by regulation of cell surface sialylation and fucosylation via the PI3K-dependent and Erk-dependent signaling pathways.


Assuntos
Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Molécula L1 de Adesão de Célula Nervosa/fisiologia , Animais , Células CHO , Membrana Celular/metabolismo , Cricetulus , Fucosiltransferases/metabolismo , Glicosilação , Fosfatidilinositol 3-Quinases/metabolismo , Sialiltransferases/metabolismo
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