Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 25(11)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38891948

RESUMO

Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells, including A1AR, A2AAR, A2BAR, and A3AR. In addition to A1AR, A3AR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on A3AR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including Gi or Gq protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several A3AR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating A3ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A3ARs as potential treatments for heart diseases.


Assuntos
Cardiopatias , Receptor A3 de Adenosina , Transdução de Sinais , Humanos , Animais , Transdução de Sinais/efeitos dos fármacos , Receptor A3 de Adenosina/metabolismo , Cardiopatias/metabolismo , Cardiopatias/tratamento farmacológico , Agonistas do Receptor A3 de Adenosina/uso terapêutico , Agonistas do Receptor A3 de Adenosina/farmacologia , Adenosina/metabolismo
2.
J Ethnopharmacol ; 327: 117997, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442805

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yataprasen is a topical Thai herbal remedy for the treatment of musculoskeletal pain and is included in Kumpe Thart Phra Narai, the first Thai textbook of traditional medicine. The herbal preparation is made from a hydroethanolic extract of a mixture of 13 medicinal plants, of which Putranjiva roxburghii Wall. leaves are the major ingredient. AIM OF THE STUDY: In this study, we investigated the underlying mechanism of action for the anti-inflammatory effects of the Yataprasen remedy, its main ingredients, and the phytochemicals isolated from P. roxburghii leaves. MATERIALS AND METHODS: The anti-inflammatory effects of the Yataprasen remedy, along with its main ingredients, including the leaves of Baliospermum solanifolium (Burm.) Suresh, Melia azedarach L., P. roxburghii, Senna siamea (Lam.) Irwin & Barneby, and Tamarindus indica L. were determined by measuring prostaglandin E2 (PGE2) secretion, nitric oxide (NO) production, and the synthesis of inflammatory biomarkers in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells. The active ingredients of the P. roxburghii leaves were separated by chromatography and spectroscopic measurements were used to identify their chemical structures. RESULTS: Ethanol extracts of the Yataprasen remedy and some of its ingredients significantly suppressed LPS-induced PGE2 secretion and NO production in a dose-dependent manner. Treatment of RAW264.7 cells with ethanolic extracts of the Yataprasen remedy (50 µg/mL) significantly inhibited LPS-induced mRNA expression of TNF-α, COX-2, iNOS, and NF-κB. Among the plant ingredient extracts, P. roxburghii leaf extract exhibited the highest inhibitory effects on LPS-induced TNF-α and iNOS expression. Moreover, T. indica leaf extract showed the highest activity on the inhibition of LPS-induced COX-2 and NF-κB expression. Putraflavone, podocarpusflavone A, and amentoflavone were isolated biflavonoids from P. roxburghii leaf extract and showed the inhibitory effects on LPS-induced PGE2 secretion and NO synthesis in RAW264.7 cells. Of the isolated biflavonoids, amentoflavone exhibited the strongest anti-inflammatory activity by inhibiting the expression of TNF-α, COX-2, and iNOS. CONCLUSION: The results support reported the anti-inflammatory effects of the Yataprasen remedy, which are associated with the downregulation of proinflammatory mediators. P. roxburghii, along with its biflavonoids, are the impact components that contribute to the anti-inflammatory effects of the herbal remedy.


Assuntos
Biflavonoides , NF-kappa B , NF-kappa B/metabolismo , Biflavonoides/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Tailândia , Linhagem Celular , Macrófagos , Extratos Vegetais/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Etanol/farmacologia , Óxido Nítrico/metabolismo
3.
Int J Mol Sci ; 24(16)2023 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-37629047

RESUMO

Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and ß-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection fraction (HFrEF). Novel drug classes, including angiotensin receptor blocker/neprilysin inhibitor (ARNI), sodium-glucose co-transporter-2 (SGLT2) inhibitor, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, soluble guanylyl cyclase (sGC) stimulator/activator, and cardiac myosin activator, have recently been introduced for HF intervention based on their proposed novel mechanisms. SGLT2 inhibitors have been shown to be effective not only for HFrEF but also for HF with preserved ejection fraction (HFpEF). In the myocardium, excess cyclic adenosine monophosphate (cAMP) stimulation has detrimental effects on HFrEF, whereas cyclic guanosine monophosphate (cGMP) signaling inhibits cAMP-mediated responses. Thus, molecules participating in cGMP signaling are promising targets of novel drugs for HF. In this review, we summarize molecular pathways of cGMP signaling and clinical trials of emerging drug classes targeting cGMP signaling in the treatment of HF.


Assuntos
Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Coração , Miocárdio , Antagonistas de Receptores de Angiotensina , Bloqueadores dos Canais de Cálcio , AMP Cíclico , GMP Cíclico , Vasodilatadores
4.
Foods ; 12(9)2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37174355

RESUMO

Kombucha is a traditional health beverage produced by fermenting sweetened tea with a symbiotic culture of bacteria and yeasts. Consumption of kombucha beverages has been growing and there is kombucha commercially available worldwide as one of the most famous low-alcohol beverages. Kombucha beverages have been claimed to have beneficial effects on human health because they contain a variety of bioactive compounds that possess various functional properties. At present, several kinds of raw material (e.g., milk, fruit, vegetables, and herbs) have been fermented with kombucha consortium and consumed as kombucha beverages. Although several studies have been written regarding the biological activities of kombucha and raw materials, there is however little information available on the characterization of their components as well as the biological activities of fermented kombucha from many raw material mixtures. Several pharmacological activities were reviewed in the scientific literature, describing their potential implications for human health. In addition, the adverse effects and toxicity of kombucha consumption were also reviewed. In this study, we focused on the main and latest studies of the pharmacological effects of kombucha beverages produced from various kinds of raw materials, including antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, anticancer, antidiabetic, antihypertensive, and antihyperlipidemic effects in in vitro and in vivo studies.

5.
Eur J Pharmacol ; 951: 175780, 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37209939

RESUMO

Angiotensin II receptors are members of G protein-coupled receptor superfamily that manifest biased signals toward G protein- and ß-arrestin-dependent pathways. However, the role of angiotensin II receptor-biased ligands and the mechanisms underlying myofibroblast differentiation in human cardiac fibroblasts have not been fully elucidated. Our results demonstrated that antagonism of angiotensin II type 1 receptor (AT1 receptor) and blockade of Gαq protein suppressed angiotensin II (Ang II)-induced fibroblast proliferation, overexpression of collagen I and α-smooth muscle actin (α-SMA), and stress fibre formation, indicating the AT1 receptor/Gαq axis is necessary for fibrogenic effects of Ang II. Stimulation of AT1 receptors by their Gαq-biased ligand (TRV120055), but not ß-arrestin-biased ligand (TRV120027), substantially exerted fibrogenic effects at a level similar to that of Ang II, suggesting that AT1 receptor induced cardiac fibrosis in a Gαq-dependent and ß-arrestin-independent manner. Valsartan prevented TRV120055-mediated fibroblast activation. TRV120055 mediated the upregulation of transforming growth factor-beta1 (TGF-ß1) through the AT1 receptor/Gαq cascade. In addition, Gαq protein and TGF-ß1 were necessary for ERK1/2 activation induced by Ang II and TRV120055. Collectively, TGF-ß1 and ERK1/2 are downstream effectors of the Gαq-biased ligand of AT1 receptor for the induction of cardiac fibrosis.


Assuntos
Receptor Tipo 1 de Angiotensina , Fator de Crescimento Transformador beta1 , Ratos , Animais , Humanos , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Miofibroblastos/metabolismo , Ligantes , Ratos Sprague-Dawley , Proteínas de Ligação ao GTP/metabolismo , Fibroblastos/metabolismo , Fibrose , Arrestinas/metabolismo
6.
Int J Mol Sci ; 24(8)2023 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-37108136

RESUMO

Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-ß1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-ß1 and ET-1, and their effectors that play an essential role in myofibroblast differentiation, are not fully understood. Therefore, we investigated the ATR networking with TGF-ß1 and ET-1 and identified the signal transduction of these mediators by measuring the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen I using qRT-PCR. Myofibroblast phenotypes were monitored by α-SMA and stress fiber formation with fluorescence microscopy. Our findings suggested that Ang II induced collagen I and α-SMA synthesis and stress fiber formation through the AT1R/Gαq axis in adult human cardiac fibroblasts (HCFs). Following AT1R stimulation, Gαq protein, not Gßγ subunit, was required for upregulation of TGF-ß1 and ET-1. Moreover, dual inhibition of TGF-ß and ET-1 signaling completely inhibited Ang II-induced myofibroblast differentiation. The AT1R/Gαq cascade transduced signals to TGF-ß1, which in turn upregulated ET-1 via the Smad- and ERK1/2-dependent pathways. ET-1 consecutively bound to and activated endothelin receptor type A (ETAR), leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Remarkably, dual blockade of TGF-ß receptor and ETR exhibited the restorative effects to reverse the myofibroblast phenotype induced by Ang II. Collectively, TGF-ß1 and ET-1 are major effectors of AT1R/Gαq cascade, and therefore, negative regulation of TGF-ß and ET-1 signaling represents a targeted therapeutic strategy for the prevention and restoration of cardiac fibrosis.


Assuntos
Miofibroblastos , Fator de Crescimento Transformador beta1 , Adulto , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Miofibroblastos/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Receptores de Endotelina/metabolismo , Diferenciação Celular , Fibroblastos/metabolismo , Colágeno Tipo I/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Actinas/metabolismo
7.
Int J Mol Sci ; 24(5)2023 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-36901906

RESUMO

Endothelin-1 (ET-1) has been implicated in the pathogenesis of cardiac fibrosis. Stimulation of endothelin receptors (ETR) with ET-1 leads to fibroblast activation and myofibroblast differentiation, which is mainly characterized by an overexpression of α-smooth muscle actin (α-SMA) and collagens. Although ET-1 is a potent profibrotic mediator, the signal transductions and subtype specificity of ETR contributing to cell proliferation, as well as α-SMA and collagen I synthesis in human cardiac fibroblasts are not well clarified. This study aimed to evaluate the subtype specificity and signal transduction of ETR on fibroblast activation and myofibroblast differentiation. Treatment with ET-1 induced fibroblast proliferation, and synthesis of myofibroblast markers, α-SMA, and collagen I through the ETAR subtype. Inhibition of Gαq protein, not Gαi or Gßγ, inhibited these effects of ET-1, indicating the essential role of Gαq protein-mediated ETAR signaling. In addition, ERK1/2 was required for ETAR/Gαq axis-induced proliferative capacity and overexpression of these myofibroblast markers. Antagonism of ETR with ETR antagonists (ERAs), ambrisentan and bosentan, inhibited ET-1-induced cell proliferation and synthesis of α-SMA and collagen I. Furthermore, ambrisentan and bosentan promoted the reversal of myofibroblasts after day 3 of treatment, with loss of proliferative ability and a reduction in α-SMA synthesis, confirming the restorative effects of ERAs. This novel work reports on the ETAR/Gαq/ERK signaling pathway for ET-1 actions and blockade of ETR signaling with ERAs, representing a promising therapeutic strategy for prevention and restoration of ET-1-induced cardiac fibrosis.


Assuntos
Sistema de Sinalização das MAP Quinases , Miofibroblastos , Humanos , Miofibroblastos/metabolismo , Endotelina-1/metabolismo , Bosentana/farmacologia , Transdução de Sinais , Fibroblastos/metabolismo , Diferenciação Celular , Proliferação de Células , Colágeno Tipo I/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Colágeno/metabolismo , Fibrose
8.
Eur J Pharmacol ; 937: 175384, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36372276

RESUMO

Stimulation of angiotensin II receptor (ATR) with angiotensin II (Ang II) accelerates cardiac fibroblast activation, resulting in upregulation of cytokines and growth factors. Growth factors were strongly upregulated in animal models of myocardial fibrosis and hypertrophy as well as patients with heart failure. Nevertheless, the signal transduction of ATR for upregulation of growth factors in human cardiac fibroblasts contributing to myocyte hypertrophy have not fully understood. Long-term Ang II treatment of human cardiac fibroblasts provokes the synthesis and secretion of connective tissue growth factor (CTGF), transforming growth factor beta1 (TGF-ß1), and vascular endothelial growth factor (VEGF) through the AT1R subtype. Blockade of Gαq, not Gαi or Gα12/13, protein signaling inhibited AT1R-mediated upregulation of CTGF, TGF-ß1, and VEGF. In addition, AT1R overstimulation induced upregulation of growth factors via the TGF-ß-dependent and ERK1/2-dependent pathways. Growth factors secreted from cardiac fibroblasts are necessary for the induction of hypertrophic markers, atrial natriuretic peptide (ANP) and ß-myosin heavy chain (ß-MHC), resulting in myocyte hypertrophy. Candesartan, irbesartan, and valsartan had greater effects than losartan for blockade of fibrotic and hypertrophic effects of Ang II. Our data support the concept whereby sustained AT1R stimulation contributes to the development of myocardial fibrosis and hypertrophy, and advances understanding of this complex AT1R signaling, including fibroblasts-myocytes communication during pathological conditions.


Assuntos
Cardiomiopatias , Fator de Crescimento Transformador beta , Animais , Humanos , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Cardiomiopatias/metabolismo , Fibroblastos , Fibrose , Hipertrofia/patologia , Células Musculares/metabolismo , Miocárdio/metabolismo , Receptores de Angiotensina , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo
9.
ACS Appl Bio Mater ; 5(5): 2262-2272, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35500214

RESUMO

Previous studies have shown that chemotherapeutic efficacy could be enhanced with targeted drug delivery. Various DNA origami nanostructures have been investigated as drug carriers. Here, we compared drug delivery functionalities of three similar DNA origami nanostructures, Disc, Donut, and Sphere, that differ in structural dimension. Our results demonstrated that Donut was the most stable and exhibited the highest Dox-loading capacity. MUC1 aptamer modification in our nanostructures increased cellular uptake in MUC1-high MCF-7. Among the three nanostructures, unmodified Donut exerted the highest Dox cytotoxicity in MCF-7, and MUC1 aptamer modification did not further improve its effect, implicating that Dox delivery by Donut was efficient. However, all Dox-loaded nanostructures showed comparable cytotoxicity in MDA-MB-231 due to the innate sensitivity of this cell line to Dox. Our results successfully demonstrated that functional properties of DNA origami nanocarriers could be tuned by structural design, and three-dimensional Donut appeared to be the most efficient nanocarrier.


Assuntos
Neoplasias da Mama , Nanoestruturas , Neoplasias da Mama/tratamento farmacológico , DNA/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Feminino , Humanos , Nanoestruturas/química
10.
Cancer Sci ; 111(9): 3164-3173, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32589345

RESUMO

Structural DNA nanotechnology enables DNA to be used as nanomaterials for novel nanostructure construction with unprecedented functionalities. Artificial DNA nanostructures can be designed and generated with precisely controlled features, resulting in its utility in bionanotechnological and biomedical applications. A tetrahedral DNA nanostructure (TDN), the most popular DNA nanostructure, with high stability and simple synthesis procedure, is a promising candidate as nanocarriers in drug delivery and bioimaging platforms, particularly in precision medicine as well as diagnosis for cancer therapy. Recent evidence collectively indicated that TDN successfully enhanced cancer therapeutic efficiency both in vitro and in vivo. Here, we summarize the development of TDN and highlight various aspects of TDN applications in cancer therapy based on previous reports, including anticancer drug loading, photodynamic therapy, therapeutic oligonucleotides, bioimaging platforms, and other molecules and discuss a perspective in opportunities and challenges for future TDN-based nanomedicine.


Assuntos
DNA/química , Sistemas de Liberação de Medicamentos , Imagem Molecular , Nanoestruturas , Neoplasias/diagnóstico , Neoplasias/terapia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Portadores de Fármacos , Desenho de Fármacos , Humanos , Imagem Molecular/métodos , Terapia de Alvo Molecular , Nanomedicina/métodos , Nanotecnologia/métodos , Neoplasias/genética , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...