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1.
Eur J Med Chem ; 238: 114469, 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35605360

RESUMO

As one of the most important features of myocardial ischemia reperfusion (MI/R) injury, the overproduction of reactive oxygen species (ROS) overwhelms the intrinsic antioxidant and impairs the function of mitochondria and, finally, leads to cardiomyocyte death. To improve the damage of cardiomyocyte caused by oxidative stress, a series of α-carboline derivatives were designed and synthesized in this study. The biological studies revealed that most of the α-carbolines exhibited obvious protective activities against H2O2-induced cardiomyocyte injury. Among them, compound 14b significantly increased the cell viability in H2O2-induced oxidative stress in H9c2 cardiomyoblasts with a concentration-dependent manner, which was more potent than polydatin. Pretreatment of 14b obviously inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, enhanced the capacity of endogenous antioxidant defenses, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduced the formation of the toxic product of lipid peroxidation (malondialdehyde, MDA). In addition, 14b effectively reduced the overproduction of ROS and restored the mitochondrial membrane potential ΔΨm, better than that of polydatin. Flow cytometry analysis demonstrated that 14b markedly reduced both necrosis and apoptosis in H9c2 cells after the exposure to H2O2. Further Western blot analysis revealed that 14b obviously decreased the ratio of Bax/Bcl-2 and reduced the expression of cytochrome c. Overall, these results revealed the potential of α-carboline 14b as a promising cardioprotective agent against H2O2-induced oxidative injury.

2.
Front Microbiol ; 13: 822148, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35369527

RESUMO

Staphylococcus haemolyticus (S. haemolyticus) is the second most commonly isolated coagulase-negative staphylococcus (CoNS) in patients with hospital-acquired infections. It can produce phenol-soluble modulin (PSM) toxins and form biofilms. Compared with the wealth of information on Staphylococcus aureus and Staphylococcus epidermidis, very little is known about S. haemolyticus. There is an urgent need to find an effective preparation to combat the harm caused by S. haemolyticus infection. Chinese herbs have been utilized to cure inflammation and infectious diseases and have a long history of anticancer function in China. Here, we modified fusaric acid characterized from the metabolites of Gibberella intermedia, an endophyte previously isolated from Polygonum capitatum. This study shows that fusaric acid analogs (qy17 and qy20) have strong antibacterial activity against S. haemolyticus. In addition, crystal violet analyses and scanning electron microscopy observations demonstrated that qy17 inhibited biofilm formation and disrupted mature biofilms of S. haemolyticus in a dose-dependent manner. Additionally, it reduced the number of live bacteria inside the biofilm. Furthermore, the antibiofilm function of qy17 was achieved by downregulating transcription factors (sigB), transpeptidase genes (srtA), and bacterial surface proteins (ebp, fbp) and upregulating biofilm-related genes and the density-sensing system (agrB). To further elucidate the bacteriostatic mechanism, transcriptomic analysis was carried out. The following antibacterial mechanisms were uncovered: (i) the inhibition of heat shock (clpB, groES, groL, grpE, dnaK, dnaJ)-, oxidative stress (aphC)- and biotin response (bioB)-related gene expression, which resulted in S. haemolyticus being unable to compensate for various stress conditions, thereby affecting bacterial growth; and (ii) a reduction in the expression of PSM-beta (PSMß1, PSMß2, PSMß3) toxin- and Clp protease (clpP, clpX)-related genes. These findings could have major implications for the treatment of diseases caused by S. haemolyticus infections. Our research reveals for the first time that fusaric acid derivatives inhibit the expression of biofilm formation-related effector and virulence genes of S. haemolyticus. These findings provide new potential drug candidates for hospital-acquired infections caused by S. haemolyticus.

3.
Nat Prod Res ; : 1-10, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34852682

RESUMO

Two fusidane-type active compounds (6 and 7) and five new ones (1-5), along with other nine known compounds (8-16) were isolated from the metabolites of Schizophyllum commune MST7-3. Their structures were elucidated on the basis of spectroscopic analysis. The absolute configurations of compounds 2 and 3 were established by Mosher's method and optical rotation. Compounds 6 and 7 showed significant antibacterial activities against Stenotrophomonas maltophilia with MIC values of 4 µg/mL and 16 µg/mL, respectively.

4.
Phytomedicine ; 93: 153765, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34610527

RESUMO

BACKGROUND: Hyperuricemia (HUA) is an important risk factor for gout, renal dysfunction and cardiovascular diseases. The whole plant of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, namely Persicaria capitata herba, is a well-known ethnic herb with potent therapeutic effects on urinary tract infections and urinary calculus, yet previous reports have only focused on its effect on urinary tract infections. PURPOSE: To evaluate the therapeutic potential of P. capitata herba against gout by investigating its antihyperuricemia and antigouty arthritis effects and possible mechanisms. METHODS: The ethanol extract (EP) and water extract (WP) of P. capitata herba were prepared by extracting dried and ground whole plants of P. capitata with 75% ethanol and water, respectively, followed by removal of solvents and characterization by UHPLC-Q-TOF/MS. The antihyperuricemia and antigouty arthritis effects of the two extracts were evaluated in a potassium oxonate- and hypoxanthine-induced hyperuricemia mouse model and a monosodium urate crystal (MSUC)-induced acute gouty arthritis mouse model, respectively. The mechanisms were investigated by testing their effects on the expression of correlated proteins (by Western blot) and mRNAs (by RT-PCR). RESULTS: UHPLC-HRMS fingerprinting and two chemical markers (i.e., quercetin and quercitrin) determination were used for the characterization of the WP and EP extracts. Both WP and EP extracts showed pronounced antihyperuricemia activities, with a remarkable decline in serum uric acid and a marked increase in urine uric acid in hyperuricemic mice. Unlike the clinical xanthine oxidase (XOD) inhibitor allopurinol, WP and EP did not show any distinct renal toxicities. The underlying antihyperuricemia mechanism involves the inhibition of the activity and expression of XOD and the downregulation of the mRNA and protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1). The extracts of P. capitata herba also demonstrated remarkable anti-inflammatory activity in MSUC-induced acute gouty arthritis mice. The mechanism might involve inhibitory effects on the expression of proinflammatory factors. CONCLUSIONS: The extracts of P. capitata herba possessed pronounced antihyperuricemia and antigouty arthritis effects and were, therefore, promising natural medicines for hyperuricemia-related disorders and gouty arthritis. The use of P. capitata herba for the treatment of urinary calculus may be, at least to some degree, related to its potential as an antihyperuricemia and antigouty arthritis drug.


Assuntos
Artrite Gotosa , Hiperuricemia , Animais , Artrite Gotosa/tratamento farmacológico , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Camundongos , Ácido Oxônico , Extratos Vegetais/farmacologia , Ácido Úrico , Xantina Oxidase
5.
Molecules ; 26(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34443633

RESUMO

Pseudostellaria heterophylla is used in China not only as a functional food but also as an herb to tonify the spleen, enhance immunity, and treat palpitation. Our previous investigation showed that a fraction enriched in glycosides obtained from the roots of P. heterophylla possessed pronounced protective effects on H9c2 cells against CoCl2-induced hypoxic injury. However, the active compounds responsible for the observed effects were still unknown. In the current investigation, pseudosterins A-C (1-3), three new alkaloids with a 1-ethyl-3-formyl-ß-carboline skeleton, together with polydatin, have been isolated from the active fraction. Their structures were elucidated on the basis of spectroscopic analysis and quantum chemical calculations. The four compounds showed cardioprotective effects against sodium hydrosulfite-induced hypoxia-reoxygenation injury in H9c2 cells, with the three alkaloids being more potent. This is also the first report of alkaloids with a ß-carboline skeleton isolated from P. heterophylla as cardioprotective agents.


Assuntos
Alcaloides/farmacologia , Carbolinas/farmacologia , Cardiotônicos/farmacologia , Caryophyllaceae/química , Extratos Vegetais/farmacologia , Alcaloides/química , Animais , Carbolinas/química , Cardiotônicos/química , Linhagem Celular , China , Glicosídeos/química , Glicosídeos/farmacologia , Hipóxia/tratamento farmacológico , Extratos Vegetais/química , Raízes de Plantas/química , Ratos
6.
Eur J Med Chem ; 222: 113573, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091209

RESUMO

A series of 2,4-diamino pyrimidine (DAPY) derivatives were designed, synthesized, and evaluated as inhibitors of focal adhesion kinase (FAK) with antitumor and anti-angiogenesis activities. Most compounds effectively suppressed the enzymatic activities of FAK, and the IC50s of 11b and 12f were 2.75 and 1.87 nM, respectively. 11b and 12f exhibited strong antiproliferative effects against seven human cancer cells, with IC50 values against two FAK-overexpressing pancreatic cancer cells (PANC-1 and BxPC-3) of 0.98 µM, 0.55 µM, and 0.11 µM, 0.15 µM, respectively. Moreover, 11b and 12f obviously suppressed the colony formation, migration, and invasion of PANC-1 cells in a dose-dependent manner. Meanwhile, these two compounds could induce the apoptosis of PANC-1 cells and arrest the cell cycle in G2/M phase according to the flow cytometry assay. Western blot revealed that 11b and 12f effectively inhibited the FAK/PI3K/Akt signal pathway and significantly decreased the expression of cyclin D1 and Bcl-2. In addition, compounds 11b and 12f potently inhibited the antiproliferative of HUVECs and obviously altered the cell morphology. 11b and 12f also significantly inhibited the migration, tube formation of HUVECs and severely impaired the angiogenesis in the zebrafish model. Overall, these results revealed the potential of compounds 11b and 12f as promising candidates for further preclinical studies.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinase 1 de Adesão Focal/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 1 de Adesão Focal/metabolismo , Humanos , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
7.
Fitoterapia ; 153: 104966, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34144143

RESUMO

Euphorboside A (1), an unusual meroterpenoid glycoside featuring the incorporation of an acylphloroglucinol moiety into a humulene skeleton to form a 6/6/11 ring system, was isolated from the roots of Euphorbia kansuensis. Its structure was elucidated by extensive spectroscopic analysis, chemical methods, and ECD calculations. Compound 1 was screened for the cytotoxicity against nine cancer cell lines, and 1 showed marked inhibitory activities against human colon cancer RKO and human breast cancer MDA-MB-231 cell lines with IC50 values of 3.70 and 4.15 µM, respectively.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Euphorbia/química , Glicosídeos/farmacologia , Sesquiterpenos Monocíclicos/química , Floroglucinol/química , Terpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , China , Glicosídeos/isolamento & purificação , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Terpenos/isolamento & purificação
8.
J Med Chem ; 64(13): 9166-9181, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34132541

RESUMO

Timely myocardial reperfusion salvages ischemic myocardium from infarction, whereas reperfusion itself induces cardiomyocyte death, which is called myocardial ischemia/reperfusion (MI/R) injury. Herein, ß-carboline derivative 17c was designed and synthesized with obvious myocardial protective activity for the first time. Pretreatment of 17c effectively protected the cardiomyocyte H9c2 cells from H2O2-induced lactate dehydrogenase leakage and restored the endogenous antioxidants, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Besides, 17c effectively protected the mitochondria through decreasing the reactive oxygen species overproduction and enhancing the mitochondrial membrane potential. As a result, 17c significantly reduced the necrosis of cardiomyocytes in H2O2-induced oxidative stress, which was more potent than polydatin. In MI/R injury rats, 17c pretreatment obviously increased the levels of SOD and GSH-Px and inhibited the apoptosis of cardiomyocytes. Through this way, the size of myocardial infarction was significantly reduced after MI/R injury in vivo, better than that of polydatin, suggesting that 17c is a promising cardioprotectant for the prevention of MI/R injury.


Assuntos
Carbolinas/farmacologia , Descoberta de Drogas , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Masculino , Estrutura Molecular , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Superóxido Dismutase/metabolismo
9.
Nat Prod Res ; 35(9): 1445-1451, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-31460795

RESUMO

Two new dihydroisocoumarins (1 and 2), together with six known compounds (3-8), were isolated from the fungus Penicillium sp. XR046 collected from the Xinren coal area of Guizhou province in China. Their structures were elucidated on the basis of spectroscopic analysis. The absolute configurations of C-3 in 1 and 2 were established by comparison of their CD data with those of known compounds. Compounds 1-6 showed anti-microbial activities with MIC values in the range of 50∼100 µg/mL against Candida albicans, Staphylococcus epidermidis, Bacillus subtilis, and Escherichia coli.


Assuntos
Anti-Infecciosos/farmacologia , Carvão Mineral/microbiologia , Isocumarinas/farmacologia , Penicillium/química , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , China , Fungos/efeitos dos fármacos , Isocumarinas/química , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética
10.
Biomed Pharmacother ; 130: 110537, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32717630

RESUMO

Rhizoma Bletillae, the tubes of Bletilla striata, has been traditionally used in China as a hemostatic agent. In preliminary studies, the major active fraction responsible for its hemostatic effect have been confirmed to be Rhizoma Bletillae polysaccharide (RBp), but the hemostatic mechanism of action of RBp is still unknown.The main aim of this study was to clarify its mechanism of hemostatic effect. RBp was prepared by 80 % ethanol precipitation of the water extract of Rhizoma Bletillae followed by the Sevag method to remove proteins. The average molecular weight (Mw) of the crude RBp maintained at a range of 30.06-200 KDa. The hemostatic effects of RBp were evaluated by testing its effect on the platelet aggregation of rat platelet-rich plasma (PRP). PRP was dealt with different concentrations of RBp and platelet aggregation was measured by the turbidimetric method. The hemostatic mechanism of RBp was investigated by examining its effect on platelet shape, platelet secretion, and activation of related receptors (P2Y1, P2Y12 and TXA2) by electron microscopy and the turbidimetric method. RBp significantly enhanced the platelet aggregations at concentrations of 50-200 mg/L in a concentration-dependent manner. The inhibitory rate of platelet aggregation was significantly increased by apyrase and Ro31-8220 in a concentration-dependent manner, while RBp-induced platelet aggregation was completely inhibited by P2Y1, P2Y12 and the PKC receptor antagonists. However, the aggregation was not sensitive to TXA2. RBp, the active ingredients of Rhizoma Bletillae responsible for its hemostatic effect, could significantly accelerate the platelet aggregation and shape change. The hemostatic mechanism may involve activation of the P2Y1, P2Y12, and PKC receptors in the adenosine diphosphate (ADP) receptor signaling pathway.


Assuntos
Hemostáticos/farmacologia , Plasma Rico em Plaquetas/efeitos dos fármacos , Polissacarídeos/farmacologia , Receptores Purinérgicos P2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Técnicas In Vitro , Peso Molecular , Extratos Vegetais/farmacologia , Tubérculos/química , Agregação Plaquetária/efeitos dos fármacos , Proteína Quinase C/efeitos dos fármacos , Ratos , Receptores Purinérgicos P2Y1/efeitos dos fármacos , Receptores Purinérgicos P2Y12/efeitos dos fármacos
11.
Bioorg Chem ; 101: 104025, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32599368

RESUMO

Metastatic progression of cancer is a complex and clinically daunting process, with migration, invasion and angiogenesis being the key features. Tetrandrine (TET) is a typical dibenzylisoquinoline alkaloid with promising anti-tumor activity. In our previous work, a number of TET derivatives were designed and synthesized with obvious anti-proliferation activities against cancer cells, however, the anti-metastatic effects of these compounds were not evaluated. In the current investigation, five TET derivatives (8, 18, 32, 71, and 72) with pronounced anti-proliferative activities (IC50 values of 1.00, 1.91, 3.43, 3.78, and 1.93 µM, respectively) against human umbilical vein endothelial cells (HUVECs) were screened out. Scratch assays showed that these compounds significantly suppressed the migration of HUVECs and induced their apoptosis. Among them, derivatives 8 and 72 obviously inhibited the proliferation, colony formation and invasion of HCT-15 cells. Tube formation assays revealed that 4 µM of 8 or 72 remarkably inhibited the tube forming capacity of HUVECs. Moreover, 8 and 72 surpressed the formation of filopodia in HUVECs and severely impaired their motility. Both compounds effectively inhibited the angiogenesis in the zebrafish model with low toxicities in vivo. These results indicated that TET derivatives 8 and 72 are promising anti-metastatic inhibitors.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Benzilisoquinolinas/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Benzilisoquinolinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Humanos , Invasividade Neoplásica , Neoplasias/genética
12.
Phytochemistry ; 177: 112449, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32599373

RESUMO

Twelve previously undescribed mexicanolide-type limonoids, including two pairs of isomers, together with seven known analogues were isolated from the twigs and leaves of Cipadessa baccifera. Their structures were determined by extensive spectroscopic methods and electronic circular dichroism (ECD) calculations. Structural variations mainly occurred at the attachment of C-3 and the carbon residues linked to C-17. 21-deoxo-23-oxofebrifugin A and 3-O-detigloyl-3-O-isobutyryl-21-deoxo-23-oxofebrifugin A are two rare naturally occurring mexicanolide-type limonoids bearing an α,ß-unsaturated-γ-lactone motif at C-17. Moreover, cipaferen R is the first degraded tetranortriterpenoid derivative featuring an unique acetyl group at C-17. Some isolated compounds were evaluated for nematicidal, antifungal, cytotoxic (against five human cancer cell lines), and acetylcholinesterase inhibitory activities. No nematicidal and antifungal activities were observed, yet 3-O-detigloyl-3-O-isobutyrylfebrifugin A, febrifugin A, febrifugin, and khaysin T exhibited moderate cytotoxic activity against the tested cells with IC50 values ranging from 18.56 ± 0.27 to 38.00 ± 0.85 µM, and 3-O-detigloyl-3-O-isobutyrylfebrifugin A, granatumin E, khaysin T, and 2'S-cipadesin A showed moderate inhibitory activities against acetylcholinesterase (AChE) at 50 µM.


Assuntos
Limoninas , Meliaceae , Humanos , Estrutura Molecular , Folhas de Planta
13.
Bioorg Med Chem Lett ; 29(24): 126638, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31685340

RESUMO

Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (1) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 1 derivatives (2-18) were designed, synthesized and tested in vitro for their antiviral activities. The biological results showed that compound 5 and 16 inhibited the virus replication efficiently with EC50 values of 9.81 and 4.62 µM. Meanwhile, low cytotoxicities on H9 cells were observed for the generated compounds by the MTT assay. The structure-activity relationship of compound 1 was preliminarily clarified, which gave rise to the development of more potent Vif inhibitors.


Assuntos
Benzamidas/síntese química , HIV-1/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Benzamidas/química , Relação Estrutura-Atividade
14.
J Sep Sci ; 41(10): 2130-2138, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29430840

RESUMO

Shenxiong glucose injection, a pharmaceutical preparation containing a water extract of the roots of Salvia miltiorrhizae and ligustrazine hydrochloride, is widely used in clinical to treat cardiovascular diseases in China. The chemical components of the water extract have been reported and the cardioprotective effects of the injection have been evaluated. However, the chemical constituents of the injection and their correlations with its pharmacological effects have not been established. In this study, 13 chemical constituents of the injection have been identified or characterized by ultra-high performance liquid chromatography with diode array detection and electrospray ionization quadrupole time-of-flight tandem mass spectrometry. Besides, the potentially active compounds of this preparation that directly act on cardiac cells have been screened by cell extraction and ultra high performance liquid chromatography targeted multiple reaction monitoring. As a result, eight potentially active compounds, danshensu (1), ligustrazine hydrochloride (4), salvianolic acid I/H (7), lithospermic acid (8), salvianolic acid D (9), rosmarinic acid (10), salvianolic acid B (12), and salvianolic acid C (13), were obtained and structurally characterized from the 11 target compounds used for screening. The liquid chromatography with quadrupole time-of-flight mass spectrometry and liquid chromatography with multiple reaction monitoring tandem mass spectrometry combination method has demonstrated its potency for the screening, detection, and structural identification of bioactive compounds in a complex matrix.


Assuntos
Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/análise , Espectrometria de Massas em Tandem , Animais , Linhagem Celular , Concentração de Íons de Hidrogênio , Luz , Raízes de Plantas/química , Pirazinas/química , Ratos , Salvia miltiorrhiza/química , Espectrometria de Massas por Ionização por Electrospray , Água/química
15.
Eur J Med Chem ; 145: 691-716, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29353722

RESUMO

Liver diseases are one of the leading causes of death in the world. In spite of tremendous advances in modern drug research, effective and safe hepatoprotective agents are still in urgent demand. Natural products are undoubtedly valuable sources for drug leads. A number of natural triterpenoids were reported to possess pronounced hepatoprotective effects, and triterpenoids have become one of the most important classes of natural products for hepatoprotective agents. However, the significance of natural triterpenoids has been underestimated in the hepatoprotective drug discovery, with only very limited triterpenoids being covered in the reviews of hepatoprotective natural products. In this paper, ca 350 natural triterpenoids with reported hepatoprotective effects in ca 120 references between 1975 and 2016 will be reviewed, and the structure-activity relationships of certain types of natural triterpenoids, if available, will be discussed. Patents are not included.


Assuntos
Produtos Biológicos/farmacologia , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Triterpenos/farmacologia , Animais , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Humanos , Fígado/patologia , Estrutura Molecular , Substâncias Protetoras/química , Relação Estrutura-Atividade , Triterpenos/química
16.
Front Pharmacol ; 8: 769, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163158

RESUMO

Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C0) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (Cmax) of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P-glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P-gp expression and altering the activities of CES and UGT.

17.
Bioorg Med Chem Lett ; 27(16): 3636-3642, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28729056

RESUMO

Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10µM. Structure activity relationship on auriculatone and its analogs showed that absence of the C17 carboxyl group of auriculatone was essential to achieve good hepatoprotective activity, and that the C3-OH, C16 carbonyl and C12-C13 olefinic group were critical for retaining the exceptional activity of auriculatone. Any modifications in the current investigation were all detrimental to the hepatoprotective activity. Docking and drug-metabolizing activity studies demonstrated that CYP3A4 was likely the main target of auriculatone, and that auriculatone elicited the hepatoprotective effect possibly through inhibiting CYP3A4's metabolism of APAP to the toxic metabolite NAPQI. The work may pave the way for the use of auriculatone in the treatment of APAP-induced liver injury.


Assuntos
Acetaminofen/toxicidade , Fígado/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Substâncias Protetoras/farmacologia , Acetilcisteína/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Glutationa/metabolismo , Humanos , Fígado/metabolismo , Simulação de Acoplamento Molecular , Ácido Oleanólico/farmacologia , Substâncias Protetoras/química , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
18.
Molecules ; 22(3)2017 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-28245598

RESUMO

The principal active constituents of Polygonum capitatum are phenolic acids and flavonoids, such as gallic acid, quercitrin, and quercetin. The aim of this study was to develop and validate a method to determine the three constituents and the corresponding conjugated metabolites of Polygonum capitatum in vivo and to conduct pharmacokinetic studies on the herb, a well-known Miao medicinal plant in China. Gallic acid, quercitrin, and quercetin were analysed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). Protein precipitation in plasma samples was performed using methanol. For the determination of total forms of analytes, an additional process of hydrolysis was conducted using ß-glucuronidase and sulphatase. The analytes were separated on a BEH C18 column (50 mm × 2.1 mm; i.d., 1.7 µm) and quantified by multiple reaction monitoring (MRM) mode. The linear regression showed high linearity over a 729-fold dynamic range for the three analytes. The relative standard deviations of intra- and inter-day measurements were less than 9.5%, and the method was accurate to within -11.1% to 12.5%. The extraction recoveries for gallic acid, quercitrin, and quercetin were 94.3%-98.8%, 88.9%-98.8%, and 95.7%-98.5%, respectively. All samples were stable under short- and long-term storage conditions. The validated method was successfully applied to a comparative pharmacokinetic study of gallic acid, quercitrin, and quercetin in their free and total forms in rat plasma. The study revealed significantly higher exposure of the constituents in total forms for gallic acid and quercetin, while quercitrin was detected mainly in its corresponding free form in vivo. The established method was rapid and sensitive for the simultaneous quantification of free and total forms of multiple constituents of Polygonum capitatum extract in plasma.


Assuntos
Ácido Gálico/sangue , Polygonum/química , Quercetina/análogos & derivados , Quercetina/sangue , Animais , Cromatografia Líquida de Alta Pressão , Ácido Gálico/química , Ácido Gálico/farmacocinética , Masculino , Extratos Vegetais/química , Plantas Medicinais/química , Plasma/química , Quercetina/química , Quercetina/farmacocinética , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
19.
Eur J Med Chem ; 131: 222-236, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28329729

RESUMO

Triterpenoids are structurally diverse organic compounds that exist widely as natural products. Triterpenoids and their derivatives possess a wide range of biological effects including hepatoprotective, hypoglycemic, immunomodulatory, anti-inflammatory, anti-oxidant, and antitumor activities. In particular, the lupane-, oleanane-, and ursane-type triterpenes have been reported to exhibit pharmacological effects without prominent toxicity even at higher concentrations. Whereas, the poor drug-like properties (e.g., low solubility and selectivity, poor bioavailability, and short half-life) severely limit their applications. This review summarized the advances in prodrug strategies for improving the drug-like properties of different types of triterpenoids, and the information indicated in the review will surely stimulate further efforts toward the development of these compounds for potential clinical uses.


Assuntos
Pró-Fármacos/química , Terpenos/química , Animais , Humanos , Estrutura Molecular , Pró-Fármacos/síntese química , Terpenos/síntese química
20.
Nat Prod Commun ; 12(4): 525-526, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30520588

RESUMO

A new flavonoid diglycoside named buxusoside (1), together with its aglycone chrysosplenol-D (2), as well as 4', 5-dihydroxy-3,6,7-trimethoxyflavone (3) and 3',4',5-tiihydroxy-3,6,7-trimethoxyflavone (4), were isolated from the 70% EtOH extract of the air-dried plant of Buxus sinica. Its structure was elucidated mainly by iD and 2D NMR spectra.


Assuntos
Buxus/química , Dissacarídeos/química , Flavonoides/química , Extratos Vegetais/química , Dissacarídeos/isolamento & purificação , Flavonoides/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/isolamento & purificação
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