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1.
ACS Chem Neurosci ; 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33884870

RESUMO

The development of multifunctional molecules that are able to simultaneously interact with several pathological components has been considered as a solution to treat the complex pathologies of neurodegenerative diseases. Herein, a series of aminomethylindole derivatives were synthesized, and evaluation of their application for antineuroinflammation and promoting neurite outgrowth was disclosed. Our initial screening showed that most of the compounds potently inhibited lipopolysaccharide (LPS)-stimulated production of NO in microglial cells and potentiated the action of NGF to promote neurite outgrowth of PC12 cells. Interestingly, with outstanding NO/TNF-α production inhibition and neurite outgrowth-promoting activities, compounds 8c and 8g were capable of rescuing cells after injury by H2O2. Their antineuroinflammatory effects were associated with the downregulation of the LPS-induced expression of the inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Western blotting and immunofluorescence assay results indicated that the mechanism of their antineuroinflammatory actions involved suppression of the MAPK/NF-κB signal pathways. Further studies revealed that another important reason for the high comprehensive antineuroinflammatory activity was the anti-COX-2 capabilities of the compounds. All these results suggest that the potential biochemical multifunctional profiles of the aminomethylindole derivatives provide a new sight for the treatment of neurodegenerative diseases.

2.
Br J Pharmacol ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33687738

RESUMO

BACKGROUND AND PURPOSE: Pancreatic cancer is an exceptionally fatal disease. However, therapeutic drugs for pancreatic cancer have presented a serious shortage over the past few decades. Signal transducer and activator of transcription-3 (STAT3) is persistently activated in many human cancers where it promotes tumour development and progression. Natural products serve as an inexhaustible source of anticancer drugs. Here, we identified the natural product trienomycin A (TA), an ansamycin antibiotic, as a potential inhibitor of the STAT3 pathway with potent activity against pancreatic cancer. EXPERIMENTAL APPROACH: Effects of trienomycin A on transcriptional activity of STAT3 were assessed by the STAT3-luciferase (STAT3-luc) reporter system. In vitro and in vivo inhibitory activity of TA against pancreatic cancer made use of molecular docking, surface plasmon resonance (SPR) assay, MTS assay, colony formation assay, transwell migration/invasion assay, flow cytometric analysis, immunofluorescence staining, quantitative real-time polymerase chain reaction (PCR), western blotting, tumour xenograft model, haematoxylin and eosin (H&E) staining and immunohistochemistry. KEY RESULTS: Trienomycin A directly bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, thus inhibiting the STAT3 pathway. Trienomycin A also inhibited colony formation, proliferation, migration and invasion of pancreatic cancer cell lines. Trienomycin A also markedly blocked pancreatic tumour growth in vivo. More importantly, trienomycin A did not show obvious toxicity at the effective dose in mice. CONCLUSIONS AND IMPLICATIONS: Trienomycin A exerted anti-neoplastic activity by suppressing STAT3 activation in pancreatic cancer. This natural product could be a novel therapeutic candidate for pancreatic cancer.

3.
Phytochemistry ; 184: 112647, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33434790

RESUMO

Chaga mushroom, Inonotus obliquus, was used as food and nutrient food and traditional herbs in Russia, China and Japan, with anti-inflammatory and anticancer activities. Chemical investigations of the fruiting bodies of Chaga were carried to uncover the bioactive metabolites. As a result, seven undescribed lanostane-type triterpenoids, namely inonotusols H-N, were isolated, and all lanostanoids remarkably inhibited NO production in lipopolysaccharide-stimulated BV-2 microglial cells. Of these, inonotusols I and L presented the most potent inhibitory effects on inducible nitric oxide synthase (iNOS) and NO production without any significant cytotoxicity. Molecular docking studies confirmed the capacity of inonotusols I and L to interact with iNOS protein. Structure-activity relationships were also discussed. These results indicated that the potential anti-inflammatory effects of inonotusols I and L in microglial BV-2 cells may be imparted through suppression of iNOS. These results may support the use of I. obliquus for food and medicinal application.


Assuntos
Agaricales , China , Japão , Lanosterol/análogos & derivados , Simulação de Acoplamento Molecular
4.
Nat Prod Res ; : 1-5, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33459059

RESUMO

1,2,3,4,6-Penta-O-galloyl-ß-D-glucopyranose (ß-PGG) is a compound commonly available in vegetables and fruits. It exhibited potential inhibition of α-glucosidase and hypoglycemic effect in vivo. This study explored its dynamics properties inhibiting α-glucosidase by Lineweaver - Burk plots, spectral analysis, docking analysis, and molecular dynamics simulations. ß-PGG showed a mix-type inhibition when it was interacting with α-glucosidase. The fluorescence quenching indicated that the PGG-glucosidase complex formed in a spontaneous exothermic process and was driven by enthalpy. The synchronous fluorescence and ECD spectra indicate that ß-PGG induced and changed the enzyme conformation in the complex formation. Docking results revealed multiple hydrogen bonds between the phenols and the amino acid residues. Further dynamic simulations indicated that the residues Asp345, Phe153, Arg435, Glu300, Pro305, and Phe296 played a more critical role in the interactions between ß-PGG and α-glucosidase.

5.
J Agric Food Chem ; 69(2): 668-675, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33398984

RESUMO

A chemical study on the fruiting bodies of cultivated edible mushroom Inonotus hispidus resulted in 14 metabolites including three new hispolon congeners, named inonophenols A-B and one new lanostane triterpenoid, named inonoterpene A. These structures were identified by NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) data analysis. All metabolites were assessed for neurotrophic, anti-inflammatory, and antioxidative activities. Among them, inonophenols B and C were the most active in promoting PC-12 cell neurite outgrowth at a concentration of 10 µM. The phenolic derivatives reduced NO generation by lipopolysaccharide (LPS)-induced BV-2 microglial cells by suppressing the expression of toll-like receptor-4 (TLR-4) and the nuclear factor-kappa-B (NF-κB) signaling pathway as well as the inflammatory mediators including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, the phenolics showed antioxidant effects in DPPH scavenging assay with the IC50 values of 9.82-21.43 µM. These findings showed that I. hispidus may be a new source of neurotrophic and protective agents against neurodegenerative disorders.


Assuntos
/química , Fenóis/química , Extratos Vegetais/química , Esteroides/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Espectrometria de Massas , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Neuritos/efeitos dos fármacos , Neuritos/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células PC12 , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Células RAW 264.7 , Ratos , Esteroides/farmacologia
6.
Phytochemistry ; 183: 112642, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33421888

RESUMO

Fifteen eremophilane sesquiterpenoids, including nine undescribed congeners, septeremophilane A-H, and chaetopenoid G, together with four conjugated unsaturated polyketide fatty acids, including an undescribed derivative, were isolated from cultures of the fungus Septoria rudbeckiae, a plant pathogenic fungus isolated from the halophyte Karelinia caspia. Septeremophilane A represents an unprecedented tetranor-eremophilane sesquiterpenoid with an α,ß-unsaturated δ-lactone unit bearing a hemiacetal group, while septeremophilane B-H possesses a trinor-eremophilane skeleton. Their structures and absolute configurations were established based on spectroscopic data (NMR and HRESIMS), quantum chemical calculations and electronic circular dichroism (ECD) experiments. All metabolites were tested for nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, while dendryphiellin D, septeremophilane D, and septeremophilane E were found to display significant inhibition, with IC50 values of 11.9 ± 1.0, 8.5 ± 0.1, and 6.0 ± 0.2 µM, respectively.


Assuntos
Ascomicetos , Sesquiterpenos , Lipopolissacarídeos/farmacologia , Sesquiterpenos Policíclicos , Sesquiterpenos/farmacologia
7.
Microbiol Res ; 244: 126652, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33310352

RESUMO

Actinobacteria that inhabit lichen symbionts are considered a promising yet previously underexplored source of novel compounds. Here, for the first time, we conducted a comprehensive investigation with regard to strain isolation and identification of lichen-associated actinobacteria from Tibet Plateau, antimicrobial activity screening, biosynthetic genes detection, bioactive metabolites identification and activity prediction. A large number of culturable actinomycetes were isolated from lichens around Qinghai Lake, in Qinghai-Tibet Plateau. Twenty-seven strains with distinct morphological characteristics were preliminarily studied. 16S rRNA gene identification showed that 13 strains were new species. The PCR-screening of specific biosynthetic genes indicated that these 27 isolates had abundant intrinsic biosynthetic potential. The antimicrobial activity experiment screened out some potential biological control antagonistic bacteria. The metabolites of 13 strains of Streptomyces with antibacterial activity were analyzed by LC-HRMS, and further 18 compounds were identified by NMR and / or LC-HRMS. The identified compounds were mainly pyrrolidine and indole derivatives, as well as anthracyclines. Seven compounds were identified with less biological activity, then predicted and evaluated their biological activity. The predicted results showed that compound 2 had excellent inhibitory activity on HIV-1 reverse transcriptase. Overall, the results indicate actinobacteria isolated from unexploited plateau lichen are promising sources of biological active metabolite, which could provide important bioactive compounds as potential antibiotic drugs.

8.
Nat Prod Res ; : 1-9, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33356581

RESUMO

Plants of the genus Hypericum contain various types of secondary metabolites that exhibited extensive biological activities. In the ongoing efforts to discover natural neuroinflammatory inhibitors with the potential to develop into therapeutic agents for neurodegenerative diseases, two new benzophenone glycosides, hyperewalones A and B (1 and 2), along with eight known compounds (3-10), were isolated from the aerial parts of Hypericum przewalskii. Their structures were elucidated by comprehensive analysis of IR, HRESIMS, 1D and 2D NMR spectra, and chemical derivatization. The anti-neuroinflammatory activity of compounds 1-10 was evaluated by determining their ability to inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Compounds 2, 4, 6-8 exhibited significant anti-neuroinflammatory activity with IC50 values of 0.61-4.90 µM. These findings suggest that the benzophenone, ionone, and flavonoid glycosides isolated from H. przewalskii are promising anti-neuroinflammatory compounds worthy of further investigations.

9.
J Nat Med ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084986

RESUMO

Four new pyrrole alkaloids, named amokoens A-D (1-4), together with three known compounds (5-7) were isolated from the rhizomes of Amomum koenigii. Their structures and absolute configurations were established by spectroscopic data, including 1D and 2D NMR, and the optical rotation calculations. All the isolates were evaluated for their effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 macrophages. Compounds 1-7 inhibited NO production ranging from 27.1 to 82.4% at a concentration of 100 µM, and compounds 5 and 6 showed efficacious inhibitory activities with IC50 values of 42.2 and 69.3 µM, respectively.

10.
Oxid Med Cell Longev ; 2020: 5780703, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32952851

RESUMO

Aberrant microglial activation drives neuroinflammation and neurodegeneration in Alzheimer's disease (AD). The present study is aimed at investigating whether the herbal formula Qi-Fu-Yin (QFY) could inhibit the inflammatory activation of cultured BV-2 microglia. A network pharmacology approach was employed to predict the active compounds of QFY, protein targets, and affected pathways. The representative pathways and molecular functions of the targets were analyzed by Gene Ontology (GO) and pathway enrichment. A total of 145 active compounds were selected from seven herbal ingredients of QFY. Targets (e.g., MAPT, APP, ACHE, iNOS, and COX-2) were predicted for the selected active compounds based on the relevance to AD and inflammation. As a validation, fractions were sequentially prepared by aqueous extraction, ethanolic precipitation, and HPLC separation, and assayed for downregulating two key proinflammatory biomarkers iNOS and COX-2 in lipopolysaccharide- (LPS-) challenged BV-2 cells by the Western blotting technique. Moreover, the compounds of QFY in 90% ethanol downregulated iNOS in BV-2 cells but showed no activity against COX-2 induction. Among the herbal ingredients of QFY, Angelicae Sinensis Radix and Ginseng Radix et Rhizoma contributed to the selective inhibition of iNOS induction. Furthermore, chemical analysis identified ginsenosides, especially Rg3, as antineuroinflammatory compounds. The herbal formula QFY may ameliorate neuroinflammation via downregulating iNOS in microglia.

11.
Chem Commun (Camb) ; 56(70): 10195-10198, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32748900

RESUMO

Ganorbifate A featuring an unprecedented 6/6/6/5/5 pentacyclic system, and ganorbifate B with an unusual 6/4/6/5/8/5 ring system were isolated from the fruiting body of Ganoderma orbiforme. Their structures were established using extensive spectroscopic analysis, including DFT calculations of NMR data and ECD spectra.

12.
Microbiol Resour Announc ; 9(31)2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732231

RESUMO

Here, we describe the genome of Streptomyces morookaense DSM 40503, an 8-azaguanine-producing strain. The genome is the basis for future study and presents an underexplored taxonomy and biosynthetic potential, which expands our understanding of the diversity of microorganisms that produce nitrogen heterocyclic compounds.

13.
Molecules ; 25(13)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32630339

RESUMO

Mosquito-transmitted Plasmodium parasites cause millions of people worldwide to suffer malaria every year. Drug-resistant Plasmodium parasites and insecticide-resistant mosquitoes make malaria hard to control. Thus, the next generation of antimalarial drugs that inhibit malaria infection and transmission are needed. We screened our Global Fungal Extract Library (GFEL) and obtained a candidate that completely inhibited Plasmodium falciparum transmission to Anopheles gambiae. The candidate fungal strain was determined as Aspergillus aculeatus. The bioactive compound was purified and identified as asperaculane B. The concentration of 50% inhibition on P. falciparum transmission (IC50) is 7.89 µM. Notably, asperaculane B also inhibited the development of asexual P. falciparum with IC50 of 3 µM, and it is nontoxic to human cells. Therefore, asperaculane B is a new dual-functional antimalarial lead that has the potential to treat malaria and block malaria transmission.

14.
Mar Drugs ; 18(6)2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32545418

RESUMO

We describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs (23 new members in all), structurally related to cyathane diterpenoid scaffold, and their anti-neuroinflammatory and neurite outgrowth-stimulating (neurotrophic) activity. Compounds 9a, 9h, 9o, and 9q exhibited moderate nerve growth factor (NGF)-mediated neurite-outgrowth promoting effects in PC-12 cells at the concentration of 20 µm. Compounds 9b, 9c, 9o, 9q, and 9t showed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, of which 9c and 9q were the most potent inhibitors, with IC50 values of 5.85 and 6.31 µm, respectively. Two derivatives 9q and 9o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers. Cytotoxicity experiments, H2O2-induced oxidative injury assay, and ELISA reaction speculated that compounds may inhibit the TNF-α pathway to achieve anti-inflammatory effects on nerve cells. Moreover, molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives (like 9c, 9q) with the active site of iNOS protein. The structure-activity relationships (SARs) were also discussed. These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.

15.
Pharmacol Res ; 159: 104953, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32485283

RESUMO

The presence of a fused 5/6/7 tricyclic core characterizes the group of cyathane diterpene natural products, that include more than 170 compounds, isolated from fungi such as Cyathus africanus and Hericium erinaceus. These compounds have a common biosynthetic precursor (cyatha-3,12-diene) and can be produced bio- or hemi-synthetically, or via total syntheses. Cyathane diterpenes display a range of pharmacological properties, including anti-inflammatory (possibly through binding to the iNOS protein) and neuroprotective effects. Many cyathanes like cyahookerin C, cyathin Q and cyafranines B and G can stimulate neurite outgrowth in cells, whereas conversely a few molecules (such as scabronine M) inhibit NGF-stimulated neurite outgrowth. The main anticancer cyathanes are erinacine A and cyathins Q and R, with a capacity to trigger cancer cell death dependent on the production of reactive oxygen species (ROS). These compounds, active both in vitro and in vivo, activate different signaling pathways in tumor cells to induce apoptosis (and autophagy) and to upregulate the expression of several proteins implicated in the organization and functioning of the actin cytoskeleton. An analysis of the functional analogy between erinacine A and other natural products known to interfere with the actin network in a ROS-dependent manner (notably cucurbitacin B) further supports the idea that erinacine A functions as a perturbator of the cytoskeleton organization. Collectively, we provide an overview of the molecular diversity of cyathane diterpenes and the main mechanisms of action of the lead compounds, with the objective to encourage further research with these fungal products. The anticancer potential of erinacine A deserves further attention but it will be necessary to better characterize the implicated targets and signaling pathways.

16.
Biochem Biophys Res Commun ; 527(4): 854-860, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32430174

RESUMO

In contrast to the well-characterized second messenger adenosine 3',5'-cyclic monophosphate (3',5'-cAMP), the biological roles of its isomer 2',3'-cAMP remain largely unknown, especially in bacteria. Recent work reported that RNase I-dependent elevation of 2',3'-cNMP levels in Escherichia coli correlated with reduced biofilm production, and separate studies demonstrated E. coli ribonuclease activation in response to aminoglycoside antibiotics. Here we report that E. coli produced 2',3'-cAMP in response to kanamycin at sub-inhibitory levels. Surprisingly, other aminoglycosides like streptomycin or gentamicin did not generate levels of 2',3'-cAMP detectable by 31P NMR. Interestingly, because 2',3'-cAMP is also produced in E. coli strains expressing a plasmid-encoded kanamycin resistance gene but not by other ribosome-targeting antibiotics, this kanamycin-specific production may not reflect disrupted protein synthesis. Overall, this finding provides a link between aminoglycoside-induced ribonuclease activity and 2',3'-cAMP production in E. coli.

17.
J Nat Prod ; 83(5): 1592-1597, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32342692

RESUMO

Phaeosphaeria fuckelii, an endophytic fungus associated with the herbal medicine Phlomis umbrosa, produced four new thiodiketopiperazine alkaloids, phaeosphaones A-D (1-4), featuring an unusual ß-(oxy)thiotryptophan motif, along with four known analogues, phaeosphaone E (5), chetoseminudin B (6), polanrazine B (7), and leptosin D (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. Compounds 4, 6, and 8 were found to display mushroom tyrosinase inhibitory activity with IC50 values of 33.2 ± 0.2, 31.7 ± 0.2, and 28.4 ± 0.2 µM, respectively, more potent than that of the positive control, kojic acid (IC50 = 40.4 ± 0.1 µM). A molecular-docking study disclosed the π-π stacking interaction between the indole moiety of 8 and the His243 residue of tyrosinase.

18.
J Agric Food Chem ; 68(16): 4624-4631, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32216259

RESUMO

Microbial transformations of two tetracyclic beyerane-type diterpenes, ent-16ß-oxobeyeran-19-oic acid (1) and its chemical reduction product, ent-16ß-hydroxybeyeran-19-oic acid (2), by the filamentous fungus Cunninghamella echinulata ATCC 8688a yielded eight metabolites (3-10). Incubation of the substrate 2 with C. echinulata afforded three new hydroxylated ones (3-5) along with two known ones (6-7), while incubation of 1 gave three known ones (8-10). The new compounds were characterized by 1D and 2D NMR as well as HRESIMS analysis, and the stereostructures of 3 and 4 were confirmed by X-ray crystallography. The bioreactions were involved not only in stereoselective incorporation of hydroxyl groups at inert positions C-7, -9, -12, and -14 of the two beyerane diterpenes but also in glucosidation at C-19 of 2. This is the first report on the biotransformation of the diterpenes by using C. echinulata. All compounds were assayed for their α-glucosidase inhibitory, neurotrophic, anti-inflammatory, and phytotoxic activity, and only in neurotrophic assay compounds, 2 and 9 were found to display nerve growth factor-mediated neurite-outgrowth promoting effects in PC12 cells; the others were inactive.

19.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 55-61, 2020 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-32131940

RESUMO

Objective To investigate the clinical values of nutritional status and chest CT phenotypes in the assessment of chronic obstructive pulmonary disease(COPD). Methods A total of 256 patients with stable COPD were enrolled from Peking Union Medical College Hospital and Civil Aviation General Hospital from June 2017 to June 2018.Demographic data,height,weight,smoking history,and number of exacerbations were collected.Pulmonary function tests and COPD assessment test(CAT)questionnaire-based survey were performed.The correlations of Goddard score with pulmonary function,CAT score,and number of exacerbations were analyzed.The clinical features of COPD patients with different body mass index(BMI)grades and CT phenotype were analyzed. Results The forced expiratory volume in one second as percentage of predicted value(FEV1%pred)was significantly higher in normal body mass group(t=-2.701,P=0.0080),overweight group(t=-3.506,P=0.001),and obese group(t=-4.323,P=0.000)than in low body mass group and was significantly higher in obese group than in normal body mass group(t=-3.096,P=0.002).The forced vital capacity as percentage of predicted value(FVC%pred)of normal body mass group(t=-3.081,P=0.002)and overweight group(t=-2.766,P=0.006)were significantly higher than that of low body mass group.The forced expiratory volume in one second(FEV1)/forced vital capacity(FVC)was significantly higher in overweight group than in normal body mass group(t=-3.702,P=0.001)and significantly higher in obese group than in low body mass group(t=-4.742,P=0.000),normal body mass group(t=-5.785,P=0.000),and overweight group(t=-2.984,P=0.003).In addition,the carbon monoxide diffusing capacity as percentage of predicted value(DLco%pred)was significantly higher in overweight group than in underweight(t=-3.042,P=0.003)and normal body mass groups(t=-3.128,P=0.002)and significantly higher in obese group than in underweight group(t=-4.742,P=0.000)and normal body mass group(t=-5.785,P=0.000).The Goddard scores of overweight(Z=4.535,P=0.000)and obese groups(Z=5.422,P=0.000)were significantly lower than that of normal body mass group.Partial correlation analysis showed that Goddard score was negatively correlated with FEV1/FVC(r =-0.230,P = 0.022)and DLco%pred(r =-0.531,P = 0.000)and positively correlated with CAT score(r = 0.244,P = 0.021).BMI of phenotype E(t=3.467,P=0.001)and M(t=3.031,P=0.003),FEV1/FVC of phenotype E(t=2.484,P=0.015)and M(t=2.969,P=0.004)as well as DLco%pred of phenotype E(t=4.928,P=0.000)and M(t=2.489,P=0.0163)were significantly lower than those of phenotype A.Patients with phenotype M had worse FEV1%pred,FVC%pred,residual volume/total lung capacity and number of acute exacerbations than patients with phenotypes A and E,but the differences were not statistically significant(all P >0.05). Conclusions The nutritional status is closely related to lung function,severity of emphysema,and number of exacerbations in COPD patients.Chest CT phenotype is clinically valuable in the assessment of COPD.


Assuntos
Índice de Massa Corporal , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Obesidade/patologia , Sobrepeso/patologia , Radiografia Torácica , Testes de Função Respiratória
20.
Int J Mol Sci ; 21(5)2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155790

RESUMO

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 µM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.


Assuntos
Microtúbulos/efeitos dos fármacos , Estilbenos/química , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Proliferação de Células , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Moduladores de Tubulina/química
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