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1.
Nat Commun ; 12(1): 5426, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521824

RESUMO

Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.


Assuntos
Ácido Glutâmico/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico , Aminoácidos/química , Aminoácidos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Domínio Catalítico , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ésteres do Colesterol/química , Ésteres do Colesterol/farmacologia , Diosgenina/análogos & derivados , Diosgenina/química , Diosgenina/farmacologia , Dissacarídeos/química , Dissacarídeos/farmacologia , Transferência Ressonante de Energia de Fluorescência , Expressão Gênica , Glucosídeos/química , Glucosídeos/farmacologia , Glicolipídeos/química , Glicolipídeos/farmacologia , Células HEK293 , Humanos , Indanos/química , Indanos/farmacologia , Micelas , Octoxinol/química , Octoxinol/farmacologia , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Imagem Individual de Molécula , Xantenos/química , Xantenos/farmacologia
2.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443591

RESUMO

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Resveratrol/farmacologia , Valsartana/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Combinação de Medicamentos , Interações Medicamentosas , Fibrose , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacos
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445301

RESUMO

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-ß and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.


Assuntos
Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência da Valva Mitral/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Compostos de Bifenilo/farmacologia , Células Cultivadas , Combinação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Valva Mitral/efeitos dos fármacos , Valva Mitral/patologia , Valva Mitral/fisiologia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Neprilisina/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Valsartana/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
4.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360535

RESUMO

The aims of this study were to develop the magnolol-chitosan films and study the positive effect of the combination of magnolol and chitosan. The addition of magnolol made the magnolol-chitosan films exhibit higher density (1.06-1.87 g/cm3), but the relatively lower water vapor permeability (12.06-7.36 × 10-11·g·m-1·s-1·Pa-1) and water content (16.10-10.64%). The dense and smooth surface and cross-section of magnolol-chitosan films were observed by environmental scanning electron microscopy (ESEM) images. The interaction of magnolol and chitosan was observed by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA). After the addition of magnolol, the antioxidant capacity of magnolol-chitosan films was increased from 18.99 to 82.00%, the growth of P. aeruginosa was inhibited and the inhibition percentage of biofilm formation was increased from 30.89 to 86.04%. We further verified that the application of magnolol-chitosan films on chilled pork significantly reduced the increases in pH value, inhibited the growth of microorganisms and extended the shelf life. Results suggest that magnolol had a positive effect on magnolol-chitosan films and could be effectively applied to pork preservation.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Quitosana/química , Conservação de Alimentos/métodos , Lignanas/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Embalagem de Alimentos/métodos , Carne de Porco/análise , Infecções por Pseudomonas/microbiologia , Suínos
5.
Phytomedicine ; 90: 153647, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34362632

RESUMO

BACKGROUND: Honokiol is a pleiotropic compound which been isolated from Magnolia species such as Magnolia grandiflora and Magnolia dealbata. Magnolia species Magnolia grandiflora is used in traditional medicine for the treatment of various diseases. PURPOSE: The objective of this review is to summarize the pharmacological potential and therapeutic insights of honokiol. STUDY DESIGN: Honokiol has been specified as a novel alternative to treat various disorders such as liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties and others. Therefore, this study designed to represent the in-depth therapeutic potential of honokiol. METHODS: Literature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using the keywords 'Honokiol', 'Health Benefits' and 'Therapeutic Insights' as the keywords for primary searches and secondary search terms were used as follows: 'Anticancer', 'Oxidative Stress', 'Neuroprotective', 'Antimicrobial', 'Cardioprotection', 'Hepatoprotective', 'Anti-inflammatory', 'Arthritis', 'Reproductive Disorders'. RESULTS: This promising bioactive compound presented an wide range of therapeutic and biological activities which include liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties, and others. Its pharmacokinetics has been established in experimental animals, while in humans, this is still speculative. Some of its mechanism for exhibiting its pharmacological effects includes apoptosis of diseased cells, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6), amelioration of impaired hepatic enzymes and reversal of morphological alterations, among others. CONCLUSION: All these actions displayed by this novel compound could make it serve as a lead in the formulation of drugs with higher efficacy and negligible side effects utilized in the treatment of several human diseases.


Assuntos
Compostos de Bifenilo , Lignanas , Magnolia , Animais , Compostos de Bifenilo/farmacologia , Humanos , Lignanas/farmacologia , Magnolia/química , Extratos Vegetais/farmacologia
6.
Vet Microbiol ; 260: 109186, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34333402

RESUMO

Replication of peste des petits ruminants virus (PPRV) strongly depends on the cellular environment and resources of host cells including nucleoside pool. Thus, enzymes involved in nucleoside biosynthesis (such as pyrimidine biosynthesis pathway) are regarded as attractive targets for antiviral drug development. Here, we demonstrate that brequinar (BQR) and leflunomide (LFM) which are two specific inhibitors of DHODH enzyme and 6-azauracil (6-AU) which is an ODase enzyme inhibitor robustly inhibit PPRV replication in HEK293T cell line as well as in peripheral blood mononuclear cells isolated from goat. We further demonstrate that these agents exert anti-PPRV activity via the depletion of purimidine nucleotide. Interestingly, these inhibitors can trigger the transcription of antiviral interferon-stimulated genes (ISGs). However, the induction of ISGs is largely independent of the classical JAK-STAT pathway. Combination of BQR with interferons (IFNs) exerts enhanced ISG induction and anti-PPRV activity. Taken together, this study reveals an unconventional novel mechanism of crosstalk between nucleotide biosynthesis pathways and cellular antiviral immunity in inhibiting PPRV replication. In conclusion, targeting pyrimidine biosynthesis represents a potential strategy for developing antiviral strategies against PPRV.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Nucleosídeos/metabolismo , Peste dos Pequenos Ruminantes/virologia , Vírus da Peste dos Pequenos Ruminantes/fisiologia , Animais , Compostos de Bifenilo/farmacologia , Células HEK293 , Humanos , Imunidade Celular , Interferons/farmacologia , Leflunomida/farmacologia , Leucócitos Mononucleares/imunologia , Vírus da Peste dos Pequenos Ruminantes/efeitos dos fármacos , Vírus da Peste dos Pequenos Ruminantes/imunologia , Pirimidinas/metabolismo , Uracila/análogos & derivados , Uracila/farmacologia , Replicação Viral
7.
Phytomedicine ; 91: 153692, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34411834

RESUMO

PURPOSE: Magnolol (MA) exhibits anti-depressant effect by inhibiting inflammation. However, its effect on microglia polarization remains not fully understood. Herein, our study was performed to evaluate the effect of MA on microglia polarization in chronic unpredictable mild stress (CUMS)-induced depression and explore its potential mechanism. STUDY DESIGN: The CUMS procedure was conducted, and the mice were intragastrically treated with MA. BV2 cells were pretreated with MA prior to LPS/ATP challenge. METHODS: The levels of TNF-α, IL-1ß, IL-6 and IL-4, IL-10 in brain and BV2 cells were examined by ELISA. The mRNA expressions of Arg1, Ym1, Fizz1 and Klf4 in brains were measured. ROS content was determined using flow cytometry. Immunofluorescence was employed to evaluate Iba-1 level, Nrf2 nuclear translocation, Iba-1+CD16/32+ and Iba-1+CD206+ cell population. The protein expressions of Nrf2, HO-1, NLRP3, caspase-1 p20 and IL-1ß in brains and BV2 cells were investigated by western blot. Nrf2 siRNA was induced in experiments to explore the role of Nrf2 in MA-mediated microglia polarization. The ubiquitination of Nrf2 was visualized by Co-IP. RESULTS: The treatment with MA notably relieved depressive like behaviors, suppressed pro-inflammatory cytokines, promoted anti-inflammatory cytokines and the transcription of M2 phenotype microglia-specific indicators. MA upregulated the expression of Nrf2, HO-1, downregulated the expression of NLRP3, caspase-1 p20, IL-1ß both in vivo and in vitro. MA also reduced ROS concentration, promoted Nrf2 nucleus translocation and prevented Nrf2 ubiquitination. Nrf2 Knockdown by siRNA abolished the MA-mediated microglia polarization. CONCLUSION: The present research demonstrated that MA attenuated CUMS-stimulated depression by inhibiting M1 polarization and inducing M2 polarization via Nrf2/HO-1/NLRP3 signaling.


Assuntos
Compostos de Bifenilo/farmacologia , Depressão/tratamento farmacológico , Lignanas/farmacologia , Microglia , Transdução de Sinais/efeitos dos fármacos , Animais , Polaridade Celular , Heme Oxigenase-1 , Lipopolissacarídeos , Proteínas de Membrana , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR
8.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204643

RESUMO

Plant-derived protein hydrolysates have potential applications in nutrition. Rice protein hydrolysates (RPHs), an excellent source of proteins, have attracted attention for the development of cosmeceuticals. However, few studies have reported the potential application of RPH in analysis, and this study examined their antioxidant activities and the inhibitory activities of skin aging enzymes. The results indicated that the total phenolic and flavonoid concentrations were 2.06 ± 0.13 mg gallic acid equivalent/g RPHs and 25.96 ± 0.52 µg quercetin equivalent/g RPHs, respectively. RPHs demonstrated dose-dependent activity for scavenging free radicals from 1,1-diphenyl-2-picrylhydrazyl [half-maximal inhibitory concentration (IC50) = 42.58 ± 2.1 mg/g RPHs] and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (IC50 = 2.11 ± 0.88 mg/g RPHs), dose-dependent reduction capacity (6.95 ± 1.40 mg vitamin C equivalent/g RPHs) and oxygen radical absorbance capacity (473 µmol Trolox equivalent/g RPHs). The concentrations of the RPH solution required to achieve 50% inhibition of hyaluronidase and tyrosinase activities were determined to be 8.91 and 107.6 mg/mL, respectively. This study demonstrated that RPHs have antioxidant, antihyaluronidase, and antityrosinase activities for future cosmetic applications.


Assuntos
Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Clareadores/química , Clareadores/metabolismo , Flavonoides/farmacologia , Sequestradores de Radicais Livres/química , Ácido Gálico/farmacologia , Camundongos , Oryza/química , Oryza/enzimologia , Oryza/metabolismo , Oxirredução , Fenóis/farmacologia , Picratos/química , Picratos/farmacologia , Extratos Vegetais/química , Quercetina/farmacologia , Células RAW 264.7 , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Tiazóis/química , Tiazóis/farmacologia
9.
Molecules ; 26(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299577

RESUMO

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound 6a exhibited the best cytotoxic activity against four human cancer cell lines, with IC50 values ranging from 20.43 to 28.27 µM. Wound-healing and transwell assays showed that compound 6a significantly inhibited the migration and invasion of MDA-MB-231 cells. In addition, Western blotting experiments, performed using various concentrations of 6a, demonstrated that it downregulates the expression of HIF-1α, MMP-2, and MMP-9 in a concentration-dependent manner. Overall, these results suggest that substituting a benzyl group having F atoms substituted at the C2 position on MAG is a viable strategy for the structural optimization of MAG derivatives as anticancer agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Lignanas/química , Lignanas/farmacologia , Antineoplásicos/síntese química , Compostos de Bifenilo/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Lignanas/síntese química , Invasividade Neoplásica/prevenção & controle , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
10.
Life Sci ; 280: 119692, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102189

RESUMO

AIMS: This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. MATERIALS AND METHODS: Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. KEY FINDINGS: Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-ß1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SIGNIFICANCE: LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-ß1/Smad2/3/CTGF/Collagen IV pathway.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Síndrome Cardiorrenal/patologia , Linhagem Celular , Combinação de Medicamentos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Ratos , Valsartana/farmacologia
11.
Bioorg Med Chem Lett ; 47: 128202, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34139325

RESUMO

Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.


Assuntos
Aorta/metabolismo , COVID-19/tratamento farmacológico , Catepsina C/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Síndrome do Desconforto Respiratório/tratamento farmacológico , Acetonitrilas/química , Acetonitrilas/farmacologia , Aminoácidos/química , Aminoácidos/farmacologia , Compostos de Bifenilo/farmacologia , COVID-19/complicações , Humanos , Modelos Moleculares , Estrutura Molecular , Síndrome do Desconforto Respiratório/etiologia , Relação Estrutura-Atividade
12.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065600

RESUMO

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Monofosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Curcuma/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
13.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073232

RESUMO

Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds-namely, compounds 11 and 12-were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 ± 0.5 µM for 11 and 2.0 ± 0.7 µM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed long-lasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Compostos de Bifenilo , Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Relação Estrutura-Atividade
14.
Cell Prolif ; 54(7): e13072, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34031939

RESUMO

OBJECTIVES: Induction of deactivation and apoptosis of hepatic stellate cells (HSCs) are principal therapeutic strategies for liver fibrosis. Krüppel-like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown. MATERIALS AND METHODS: KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator-activated receptor γ (PPARγ) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14-overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)-treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ-6438 was utilized to treat TAA-induced rat liver fibrosis. RESULTS: KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPARγ promoter activity. Inhibition of PPARγ blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2-regulated histone H3 lysine 27 trimethylation. Adenovirus-mediated KLF14 overexpression ameliorated TAA-induced rat liver fibrosis in PPARγ-dependent manner. Furthermore, EPZ-6438 dramatically alleviated TAA-induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPARγ downregulation. CONCLUSIONS: KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPARγ axis might be a novel therapeutic strategy for liver fibrosis.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Cirrose Hepática/patologia , PPAR gama/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Cirrose Hepática/metabolismo , Camundongos , Morfolinas/farmacologia , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Regiões Promotoras Genéticas , Piridonas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Tioacetamida/farmacologia
15.
Kidney Blood Press Res ; 46(3): 331-341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34034251

RESUMO

BACKGROUND: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). METHODS: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. RESULTS: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. CONCLUSION: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Tetrazóis/farmacologia , Angiotensina II/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Denervação , Taxa de Filtração Glomerular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Rim/fisiologia , Masculino , Ratos Sprague-Dawley , Sódio/metabolismo , Água/metabolismo
16.
J Med Chem ; 64(11): 7453-7467, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34032427

RESUMO

There has been significant attention concerning the biased agonism of G protein-coupled receptors (GPCRs), and it has resulted in various pharmacological benefits. 5-HT7R belongs to a GPCR, and it is a promising pharmaceutical target for the treatment of neurodevelopmental and neuropsychiatric disorders. Based on our previous research, we synthesized a series of 6-chloro-2'-methoxy biphenyl derivatives 1, 2, and 3 with a variety of amine scaffolds. These compounds were evaluated for their binding affinities to 5-HTR subtypes and their functional selectivity toward the Gs protein and the ß-arrestin signaling pathways of 5-HT7R. Among them, 2-(6-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-N-ethylethan-1-amine, 2b, was found to be a G-protein-biased ligand of 5-HT7R. In an in vivo study with Shank3 transgenic mice, the self-grooming behavior test was performed with 2b, which increased the duration of self-grooming. The experiments further suggested that 5-HT7R is associated with autism spectrum disorders (ASDs) and could be a therapeutic target for the treatment of stereotypy in ASDs.


Assuntos
Compostos de Bifenilo/química , Ligantes , Receptores de Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microssomos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Serotonina/química , Relação Estrutura-Atividade
17.
Am J Physiol Renal Physiol ; 320(6): F1133-F1151, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33870733

RESUMO

Although renin-angiotensin blockade has shown beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug, sacubitril/valsartan (Sac/Val), a combination of the angiotensin II receptor blocker Val and neprilysin inhibitor prodrug Sac, has been shown to be more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study, we tested the effects of Sac/Val in diabetic kidney disease. We administered Sac/Val or Val to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3 mo of treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Val shared a similar improvement but to a lesser degree in some parameters compared with Sac/Val. Sac/Val but not Val decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on antioxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self-DNA-activated cGMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, which was activated in diabetic kidneys and prevented by Sac/Val or Val treatment. The present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease, and its effectiveness could be better than Val alone.NEW & NOTEWORTHY The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Valsartana/farmacologia , Albuminúria/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estresse Oxidativo , Valsartana/administração & dosagem
18.
J Phys Chem Lett ; 12(15): 3724-3732, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33843228

RESUMO

Allosteric drugs have been attracting increasing interest over the past few years. In this context, it is common practice to use high-throughput screening for the discovery of non-natural allosteric drugs. While the discovery stage is supported by a growing amount of biological information and increasing computing power, major challenges still remain in selecting allosteric ligands and predicting their effect on the target protein's function. Indeed, allosteric compounds can act both as inhibitors and activators of biological responses. Computational approaches to the problem have focused on variations on the theme of molecular docking coupled to molecular dynamics with the aim of recovering information on the (long-range) modulation typical of allosteric proteins.


Assuntos
Compostos de Bifenilo/farmacologia , Cumarínicos/farmacologia , Di-Hidropiridinas/farmacologia , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Pironas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Compostos de Bifenilo/química , Cumarínicos/química , Di-Hidropiridinas/química , Humanos , Estrutura Molecular , Pironas/química
19.
Chem Biodivers ; 18(5): e2100079, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33821531

RESUMO

Eight natural biphenyl-type phytoalexins exhibiting antifungal effect were isolated from the leaves of Sorbus pohuashanensis, which invaded by Alternaria tenuissi, and their growth inhibition rate towards A. tenuissi were 50.3 %, 54.0 %, 66.4 %, 58.8 %, 48.5 %, 51.0 %, 33.3 %, and 37.0 %, respectively. In vivo activity assay verified the protective effect of these natural biphenyls on tobacco leaves. The observation of mycelial morphology revealed that these compounds possessed adverse effects on mycelial growth of A. tenuissi. Subsequently, the most potent active compounds, 3',4',5'-trimethoxy[1,1'-biphenyl]-4-ol (3) and 3,4,4',5-tetramethoxy-1,1'-biphenyl (4), were conducted to the further antifungal evaluation and showed significant activity against the other four crop pathogens, Fusarium graminearum, Helminthosporium maydis, Sclerotinia sclerotiorum, and Exserohilum turcicum. Further, the structure-activity relationships and biosynthesis of these compounds were speculated in this work.


Assuntos
Alternaria/efeitos dos fármacos , Antifúngicos/farmacologia , Compostos de Bifenilo/farmacologia , Sorbus/química , Alternaria/crescimento & desenvolvimento , Alternaria/patogenicidade , Antifúngicos/química , Antifúngicos/isolamento & purificação , Ascomicetos/efeitos dos fármacos , Ascomicetos/patogenicidade , Compostos de Bifenilo/química , Compostos de Bifenilo/isolamento & purificação , Bipolaris/efeitos dos fármacos , Bipolaris/patogenicidade , Fusarium/efeitos dos fármacos , Fusarium/patogenicidade , Testes de Sensibilidade Microbiana , Estrutura Molecular , Extratos Vegetais , Folhas de Planta/química
20.
Aging (Albany NY) ; 13(7): 9582-9591, 2021 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839697

RESUMO

Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor ß (TNF-ß) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Valsartana/farmacologia , Citocinas/metabolismo , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Malondialdeído/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
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