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Liver fibrosis, one of the leading causes of morbidity and mortality worldwide, lacks effective therapy. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. Luteolin-7-diglucuronide (L7DG) is the major flavonoid extracted from Perilla frutescens and Verbena officinalis. Their beneficial effects in the treatment of liver diseases were well documented. In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms. We established TGF-ß1-activated mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 as in vitro liver fibrosis models. Co-treatment with L7DG (5, 20, 50 µM) dose-dependently decreased TGF-ß1-induced expression of fibrotic markers collagen 1, α-SMA and fibronectin. In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet, administration of L7DG (40, 150 mg·kg-1·d-1, i.g., for 4 or 8 weeks) dose-dependently attenuated hepatic histopathological injury and collagen accumulation, decreased expression of fibrogenic genes. By conducting target prediction, molecular docking and enzyme activity detection, we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 2.10 µM. Further studies revealed that L7DG inhibited PTP1B activity, up-regulated AMPK phosphorylation and subsequently inhibited HSC activation. This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.
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Aggregation of α-synuclein, a component of Lewy bodies (LBs) or Lewy neurites in Parkinson's disease (PD), is strongly linked with disease development, making it an attractive therapeutic target. Inhibiting aggregation can slow or prevent the neurodegenerative process. However, the bottleneck towards achieving this goal is the lack of such inhibitors. In the current study, we established a high-throughput screening platform to identify candidate compounds for preventing the aggregation of α-synuclein among the natural products in our in-house compound library. We found that a small molecule, 03A10, i.e., (+)-desdimethylpinoresinol, which is present in the fruits of Vernicia fordii (Euphorbiaceae), modulated aggregated α-synuclein, but not monomeric α-synuclein, to prevent further elongation of α-synuclein fibrils. In α-synuclein-overexpressing cell lines, 03A10 (10 µM) efficiently prevented α-synuclein aggregation and markedly ameliorated the cellular toxicity of α-synuclein fibril seeds. In the MPTP/probenecid (MPTP/p) mouse model, oral administration of 03A10 (0.3 mg· kg-1 ·d-1, 1 mg ·kg-1 ·d-1, for 35 days) significantly alleviated behavioral deficits, tyrosine hydroxylase (TH) neuron degeneration and p-α-synuclein aggregation in the substantia nigra (SN). As the Braak hypothesis postulates that the prevailing site of early PD pathology is the gastrointestinal tract, we inoculated α-synuclein preformed fibrils (PFFs) into the mouse colon. We demonstrated that α-synuclein PFF inoculation promoted α-synuclein pathology and neuroinflammation in the gut and brain; oral administration of 03A10 (5 mg· kg-1 ·d-1, for 4 months) significantly attenuated olfactory deficits, α-synuclein accumulation and neuroinflammation in the olfactory bulb and SN. We conclude that 03A10 might be a promising drug candidate for the treatment of PD. 03A10 might be a novel drug candidate for PD treatment, as it inhibits α-synuclein aggregation by modulating aggregated α-synuclein rather than monomeric α-synuclein to prevent further elongation of α-synuclein fibrils and prevent α-synuclein toxicity in vitro, in an MPTP/p mouse model, and PFF-inoculated mice.
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Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Doenças Neuroinflamatórias , Substância Negra/metabolismo , Substância Negra/patologia , Encéfalo/metabolismoRESUMO
Dipeptidyl peptidase-4 (DPP4) plays a crucial role in regulating the bioactivity of glucagon-like peptide-1 (GLP-1) that enhances insulin secretion and pancreatic ß-cell proliferation, making it a therapeutic target for type 2 diabetes. Although the crystal structure of DPP4 has been determined, its structure-function mechanism is largely unknown. Here, we examined the biochemical properties of sporadic human DPP4 mutations distal from its catalytic site, among which V486M ablates DPP4 dimerization and causes loss of enzymatic activity. Unbiased molecular dynamics simulations revealed that the distal V486M mutation induces a local conformational collapse in a ß-propeller loop (residues 234-260, defined as the flap) and disrupts the dimerization of DPP4. The "open/closed" conformational transitions of the flap whereby capping the active site, are involved in the enzymatic activity of DPP4. Further site-directed mutagenesis guided by theoretical predictions verified the importance of the conformational dynamics of the flap for the enzymatic activity of DPP4. Therefore, the current studies that combined theoretical modeling and experimental identification, provide important insights into the biological function of DPP4 and allow for the evaluation of directed DPP4 genetic mutations before initiating clinical applications and drug development.
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Diabetes Mellitus Tipo 2 , Dipeptidil Peptidase 4 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/genética , Peptídeo 1 Semelhante ao Glucagon , Humanos , MutaçãoRESUMO
The root Rhynchosia volubilis was widely used for contraception in folk medicine, although its molecular mechanism on antifertility has not yet been revealed. In human sperm, it was reported that the cation channel of sperm, an indispensable cation channel for the fertilization process, could be regulated by various steroid-like compounds in plants. Interestingly, these nonphysiological ligands would also disturb the activation of the cation channel of sperm induced by progesterone. Therefore, this study aimed to explore whether the compounds in R. volubilis affect the physiological regulation of the cation channel of sperm. The bioguided isolation of the whole herb of R. volubilis has resulted in the novel discovery of five new prenylated isoflavonoids, rhynchones Aâ-âE (1: â-â5: ), a new natural product, 5'-O-methylphaseolinisoflavan (6: ) (1H and 13C NMR data, Supporting Information), together with twelve known compounds (7: â-â18: ). Their structures were established by extensive spectroscopic analyses and drawing a comparison with literature data, while their absolute configurations were determined by electronic circular dichroism calculations. The experiments of intracellular Ca2+ signals and patch clamping recordings showed that rhynchone A (1: ) significantly reduced cation channel of sperm activation by competing with progesterone. In conclusion, our findings indicat that rhynchone A might act as a contraceptive compound by impairing the activation of the cation channel of sperm and thus prevent fertilization.
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Progesterona , Motilidade dos Espermatozoides , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Humanos , Masculino , Progesterona/análise , Progesterona/metabolismo , Progesterona/farmacologia , Sementes , Espermatozoides/química , Espermatozoides/metabolismoRESUMO
The chemical constituents of the flower buds of Buddleja officinalis were investigated in this study. Eight compounds were isolated from the water extract of B. officinalis by column chromatography, and their structures were elucidated on the basis of physicochemical properties and spectral data. These compounds were identified as(Z)-hex-3-en-1-ol-1-O-ß-D-glucopyranosyl-(1â2)-[ß-D-xylcopyranosyl-(1â6)]-ß-D-glucopyranoside(1), ebracteatoside B(2), jasmonic acid-11-O-ß-D-glucopyranoside(3), 6-hydroxyluteolin-7-O-ß-D-glucopyranoside(4), luteolin-7-O-galacturonide(5), vicenin-2(6), decaffeoylverbascoside(7), and 6-O-(E)-feruloyl-D-glucopyranoside(8). Compound 1 is a new 3-hexenol glycoside. Compounds 2, 3, and 6 were isolated from Buddleja genus for the first time, and compounds 4 and 5 were isolated from this plant for the first time.
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Buddleja , Glicosídeos Cardíacos , Glicosídeos , Extratos VegetaisRESUMO
Background: When liver metastasis in patients with breast cancer is diagnosed, treatment is generally palliative and usually consists of systemic therapies only. This study aimed to evaluate the efficacy and safety of hepatic arterial infusion (HAI) combined with systemic chemotherapy in patients with breast carcinoma liver metastases (BCLM). Methods: From January 2012 to December 2019, HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 19 patients with BCLM. All patients received systemic chemotherapy and HAI gemcitabine plus floxuridine (FUDR). Methods: The overall response rate (ORR) of intrahepatic lesions was 73.7%, including 2 patients (10.5%) with complete remission (CR) and 12 patients (63.2%) with partial remission (PR). Additionally, we found that young patients (age < 55 years) had a higher ORR than the older (100% vs 44.4%, P = .011). The median overall survival (mOS) was 13.1 months. Kaplan-Meier survival curves demonstrated that the mOS was not significantly different between patients with < 9 intrahepatic lesions and those with ≥ 9 lesions (13.7 months vs 10.9 months, P = .225). The mOS was 14.3 and 10.6 months for patients without extrahepatic metastases and with extrahepatic metastases, respectively (P = .016). None of the patients had grade 4 toxicity. The grade 3 toxicities included leucopenia, neutropenia and diarrhea. Conclusions: HAI gemcitabine plus FUDR combined with systemic chemotherapy is effective in achieving a high local response and prolonging mOS for patients with BCLM and is associated with a relatively low rate of toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Artéria Hepática , Bombas de Infusão , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Gerenciamento Clínico , Feminino , Artéria Hepática/cirurgia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer in humans worldwide. The identification and characterization of cancer-associated transmembrane proteins are important for understanding the molecular biology of CSCC. The aim of the present study was to evaluate the expression pattern of transmembrane protein 40 (TMEM40) in CSCC and its clinical significance. The underlying mechanisms were also examined. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analysis were used to determine the relative expression of TMEM40 in CSCC cell lines and clinical tissue samples. The effect of TMEM40 gene silencing on cell proliferation was also evaluated using Cell Counting Kit-8 assays. Wound healing assays, flow cytometry and Transwell assays were used to explore the migration, cell cycle distribution/apoptosis and invasion of CSCC cells following TMEM40 silencing, respectively. In the present study, increased TMEM40 expression was observed in CSCC tissue samples, compared with normal skin, and TMEM40 expression was associated with large tumor size in patients with CSCC. In vitro functional assays indicated that TMEM40 was involved in the regulation of A431 and SCL1 cell growth through its effects on the cell cycle and apoptosis. Silencing TMEM40 in A431 and SCL1 cells resulted in cell cycle arrest at the G0/G1 phase and promoted apoptosis. In addition, migration and invasion were significantly inhibited following silencing of TMEM40 expression in CSCC cells. Taken together, the results of the present study indicated that reduced TMEM40 expression could inhibit CSCC development and that TMEM40 may represent a therapeutic target in CSCC.
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Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1-10 µM) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 µM) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G1-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy.
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Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Lisossomos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P-glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine ~ jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Berberina/análogos & derivados , Berberina/metabolismo , Animais , Berberina/sangue , Células CACO-2 , Humanos , Ligação de Hidrogênio , Fígado/química , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação ProteicaRESUMO
Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.
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Descoberta de Drogas , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Naftalenos/farmacologia , Sulfonamidas/farmacologia , Células 3T3-L1 , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Proteínas de Ligação a Ácido Graxo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Two novel nitrogenous diterpenoids, sarinfacetamides A (1) and B (2), featuring an uncommon tricyclo[6.3.1.01,5]dodecane scaffold, and a known related diterpene (3) were isolated from the South China Sea soft coral Sarcophyton infundibuliforme. Their structures, including the absolute configuration of 1, were established by extensive spectroscopic analysis and TDDFT-ECD calculation. Compounds 1 and 3 exhibited interesting promotion effects on the ConA-induced T lymphocyte proliferation. A plausible biosynthetic pathway for 1 and 2 was also proposed.
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Diterpenos/química , Alcanos , Animais , Antozoários , China , Estrutura Molecular , NitrogênioRESUMO
A new prenyleudesmane type diterpene, sinupol (8), and a new capnosane type diterpenoid, sinulacetate (9), were isolated from the Xisha soft coral Sinularia polydactyla along with five known related diterpenes (4-7 and 10). Their structures, including absolute configurations, were determined by extensive spectroscopic analysis, the comparison of their NMR data with those of related compounds, and time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculations. Both new compounds (8 and 9) exhibited promising inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), a potential drug target for the treatment of type II diabetes and obesity.
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Antozoários/química , Diterpenos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Diterpenos/química , Modelos Moleculares , Estrutura MolecularRESUMO
The µ opioid receptor (OR), a member of the class A subfamily of G-protein coupled receptors (GPCRs), is a major target for the treatment of pain. G-protein biased µ-OR agonists promise to be developed as analgesics. Thus, TRV130, the first representative µ-OR ligand with G-protein bias, has entered into phase III clinical trials. To identify the detailed G-protein-biased activation and inactivation mechanisms of the µ-OR, we constructed five µ-OR systems that were in complexes with the G-protein-biased agonists TRV130 and BU72, the antagonists ß-FNA and naltrexone, as well as the free receptor. We performed a series of conventional molecular dynamics simulations and analyses of G-protein-biased activation and inactivation mechanisms of µ-OR. Our results, together with previously reported mutation results, revealed the operating mode of the activation switch composed of residues W6.48 and Y7.43 (Ballesteros/Weinstein numbering), the activity of which was responsible for down- and up-regulation, respectively, of the ß-arrestin signaling, which in turn affected G-protein-biased activation of µ-OR. TRV130 was found to stabilize W6.48 by interacting with Y7.43. In addition, we obtained useful information regarding µ-OR-biased activation, such as strong stabilization of W7.35 through a hydrophobic ring interaction in the TRV130 system. These findings may facilitate understanding of µ-OR biased activation and the design of new biased ligands for GPCRs.
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Proteínas de Ligação ao GTP/metabolismo , Morfinanos/metabolismo , Pirróis/metabolismo , Receptores Opioides mu/metabolismo , Compostos de Espiro/metabolismo , Tiofenos/metabolismo , Animais , Proteínas de Ligação ao GTP/química , Ligantes , Camundongos , Simulação de Dinâmica Molecular , Morfinanos/química , Naltrexona/análogos & derivados , Naltrexona/química , Naltrexona/metabolismo , Ligação Proteica , Conformação Proteica , Pirróis/química , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/química , Compostos de Espiro/química , Tiofenos/química , Ureia/análogos & derivados , Ureia/química , Ureia/metabolismo , Água/químicaRESUMO
In drug design and discovery, binding affinity and selectivity are two basic properties of a drug candidate. Opioid receptors (ORs) are the main targets of strong analgesics. Like some other class A members of G-protein-coupled receptors (GPCRs), ORs exhibit complex selectivity on their ligands. The diversity of binding activity and selectivity among opioids has deeply attracted researchers for a long time. To investigate the subtype selectivity of µ, δ and κ ORs in detail, using the κ-selective antagonist JDTic as a probe, we performed a series of computational simulations, including molecular dynamics and metadynamics, on JDTic-µ/δ/κ-OR complexes. From the simulations, we found that the decisive factor of JDTic selectivity on the µ-subtype was the 2.63 position, which affected the efficacy of JDTic through changing the dynamics of the Q2.60 residue. In addition to the 2.63-position residue, the 7.35 position was the other crucial aspect of JDTic selectivity for the δ-subtype. Based on the results, we suggest a new concept, the "message-address-efficacy" hypothesis, to explain the relationships among the affinity, selectivity and function between ORs and opioids. Thus, all the detailed dynamics of JDTic-bound ORs might be helpful to deeply understand the subtype selectivity and binding mechanisms of other GPCRs.
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Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Receptores Opioides/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Estrutura Molecular , Piperidinas/química , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/químicaRESUMO
Three new diterpenes, xishacorenes A-C, featuring an undescribed bicyclo[3.3.1]nonane nucleus bearing 1-vinyl and 13-[(E)-4-methylpenta-1,3-dien-1-yl] alkyl chains, and a related monocyclic known compound, were isolated from the Xisha soft coral Sinularia polydactyla. The structures of xishacorenes A-C, including their absolute configurations, were elucidated by extensive spectroscopic analysis and TDDFT ECD calculations. The new compounds exhibit an interesting dose-dependent promotion effect on the ConA-induced T lymphocyte proliferation. A plausible biosynthetic pathway of xishacorenes A-C is proposed.
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Antozoários/química , Diterpenos/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Concanavalina A/metabolismo , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The mutation of B-RafV600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-RafV600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 µmol/L, which was lower than that of vemurafenib (0.13 µmol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.
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Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Purinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Oximas/síntese química , Oximas/química , Oximas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Purinas/síntese química , Purinas/química , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , VemurafenibRESUMO
Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg-1·d-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg-1·d-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGFß-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.
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Antioxidantes/farmacologia , Cardiomiopatias/tratamento farmacológico , Cardiotônicos/farmacologia , Glucuronatos/farmacologia , Luteolina/farmacologia , Miocárdio/patologia , Animais , Antioxidantes/uso terapêutico , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Cardiotônicos/uso terapêutico , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrose/induzido quimicamente , Fibrose/patologia , Fibrose/prevenção & controle , Glucuronatos/isolamento & purificação , Glucuronatos/uso terapêutico , Isoproterenol , Lamiaceae/química , Luteolina/isolamento & purificação , Luteolina/uso terapêutico , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Necrose/induzido quimicamente , Necrose/tratamento farmacológico , Necrose/patologiaRESUMO
It has been widely recognized that inflammation, particularly chronic inflammation, can increase the risk of cancer and that the simultaneous treatment of inflammation and cancer may produce excellent therapeutic effects. Berberine, an alkaloid isolated from Rhizoma coptidis, has broad applications, particularly as an antibacterial agent in the clinic with a long history. Over the past decade, many reports have demonstrated that this natural product and its derivatives have high activity against both cancer and inflammation. In this review, we summarize the advances in studing berberine and its derivatives as anti-inflammatory and anti-tumor agents in the digestive system; we also discuss their structure-activity relationship. These data should be useful for the development of this natural product as novel anticancer drugs with anti-inflammation activity.