RESUMO
Andrographis paniculata (AP) has been widely used in China for centuries to treat various diseases, and especially to treat inflammation. Diterpenoid lactones are the main anti-inflammatory components of AP. However, systematic chemical composition and biological activities, as well as key pharmacophores, of these diterpenoid lactones from AP have not yet been clearly understood. In this study, 17 diterpenoid lactones, including 2 new compounds, were identified by spectroscopic methods, and most of them attenuated the generation of TNF-α and IL-6 in LPS-induced RAW 274.7 cells examined by ELISA. Pharmacophores of diterpenoid lactones responsible for the anti-inflammatory activities were revealed based on the quantitative structure-activity relationship (QSAR) models. Moreover, new compounds (AP-1 and AP-4) exerted anti-inflammatory activity in LPS microinjection-induced zebrafish, which might be correlated with the inhibition of the translocation of NF-κB p65 from cytoplasm to nucleus. Our study provides guidelines for future structure modification and rational drug design of diterpenoid lactones with anti-inflammatory properties in medical chemistry.
Assuntos
Andrographis/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diterpenos/química , Lactonas/química , Lactonas/farmacologia , Componentes Aéreos da Planta/química , Animais , Anti-Inflamatórios/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Lactonas/isolamento & purificação , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Relação Quantitativa Estrutura-Atividade , Células RAW 264.7 , Análise Espectral , Peixe-ZebraRESUMO
Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.
Assuntos
Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Emodina/análogos & derivados , Inflamação/etiologia , Inflamação/metabolismo , NF-kappa B/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Emodina/farmacologia , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Modelos Biológicos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Transporte Proteico , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismoRESUMO
Liver X receptors (LXRs) are master regulators of various biological processes, including metabolism, inflammation, development, and reproduction. As well-known nuclear oxysterol receptors of the nuclear receptor (NR) family, LXRs have two homologous subtypes, LXRα (NR1H3) and LXRß (NR1H2). Since the mid-1990s, numerous LXR-targeted drugs have been designed to treat diseases such as atherosclerosis, systemic lupus erythematosus, and cancer. These modulators include agonists and antagonists, and the selectivity of them have been development from diverse aspects, including subtype-specific, cell-specific, tissue-specific types. Meanwhile, advanced delivery systems are also exploreed to facilitate the application of LXR drugs in clinical setting. One of the most promising delivery systems involves the use of nanoparticles and is expected to increase the clinical potential of LXR modulators. This review discusses our current understanding of LXR biology and pharmacology, focusing on the development of modulators for LXRα and/or LXRß, and the nanoparticle-based delivery systems for promising LXR modulators with potential for use as drugs.
Assuntos
Aterosclerose , Receptores Nucleares Órfãos , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/metabolismo , Receptores Nucleares Órfãos/uso terapêutico , Aterosclerose/tratamento farmacológicoRESUMO
Pattern-recognition receptors (PRRs) have been shown to promote tumour metastasis via sensing tumour cell-derived small extracellular vesicles (EVs). Nucleotide-binding oligomerisation domain 1 (NOD1), a cytoplasmic PRR, plays a role in colorectal cancer (CRC) by detecting bacterial products. However, the precise mechanisms underlying the effects of NOD1, following identification of CRC cell-derived EVs (CRC-EVs), to potentiate CRC liver metastasis (CRC-LM), remain poorly understood. Here, we demonstrate that CRC-EVs activate NOD1 in macrophages to initiate secretion of inflammatory cytokines and chemokines. NOD1-activated macrophages also promote CRC cell migration, while in a murine model of liver metastasis (LM), NOD1-deficient mice exhibit reduced metastasis following CRC-EV treatment. Furthermore, cell division cycle 42 (CDC42), a small Rho guanosine-5'-triphosphate (GTP)ase, is delivered by CRC-EVs into macrophages where it activates NOD1. In addition, EVs from the plasma of patients with CRC-LM mediate NOD1 activation in human peripheral blood mononuclear cells. Moreover, high NOD1 expression in tumour tissues is associated with poor prognosis of CRC-LM. Our findings suggest that CRC-EVs activate NOD1 to promote tumour metastasis, thus, NOD1 may serve as a potential target in the diagnosis and treatment of CRC-LM.
Assuntos
Neoplasias Colorretais , Vesículas Extracelulares , Neoplasias Hepáticas , Animais , Vesículas Extracelulares/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , Proteína Adaptadora de Sinalização NOD1/metabolismo , Transdução de SinaisRESUMO
Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1/2) receptors are potential immune checkpoints. In this article, a quinazolinone derivative (36b) as a NOD1/2 dual antagonist was identified that significantly sensitizes B16 tumor-bearing mice to paclitaxel treatment by inhibiting both nuclear factor κB (NF-κB) and mitogen-activated protein kinase inflammatory signaling that mediated by NOD1/2.
Assuntos
Proteína Adaptadora de Sinalização NOD1/antagonistas & inibidores , Proteína Adaptadora de Sinalização NOD2/antagonistas & inibidores , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Linhagem Celular , Descoberta de Drogas , Humanos , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Nucleotídeos/metabolismoRESUMO
Nucleotide-binding oligomerization domain-containing proteins 1 and 2 play important roles in immune system activation. Recently, a shift has occurred due to the emerging knowledge that preventing nucleotide-binding oligomerization domains (NODs) signaling could facilitate the treatment of some cancers, which warrants the search for dual antagonists of NOD1 and NOD2. Herein, we undertook the synthesis and identification of a new class of derivatives of dual NOD1/NOD2 antagonists with novel benzofused five-membered sultams. Compound 14k was finally demonstrated to be the most potent molecule that inhibits both NOD1-and NOD2-stimulated NF-κB and MAPK signaling in vitro and in vivo.
Assuntos
Naftalenossulfonatos/química , Naftalenossulfonatos/farmacologia , Proteína Adaptadora de Sinalização NOD1/antagonistas & inibidores , Proteína Adaptadora de Sinalização NOD2/antagonistas & inibidores , Animais , Desenho de Fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Proteína Adaptadora de Sinalização NOD1/química , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/química , Proteína Adaptadora de Sinalização NOD2/metabolismo , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacosRESUMO
SIS3 is a specific inhibitor of Smad3 that inhibits the TGFß1-induced phosphorylation of Smad3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)phenoxy)pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Descoberta de Drogas/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Isoquinolinas/química , Isoquinolinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Resistência a Múltiplos Medicamentos/fisiologia , Humanos , Isoquinolinas/metabolismo , Células K562 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular/métodos , Piridinas/metabolismo , Pirróis/metabolismo , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
PURPOSE: Every year, almost one million individuals are diagnosed with hepatocellular carcinoma (HCC) worldwide and more than 690,000 patients die of it. At present, most therapeutic anti-HCC agents are not effective, which is due to the appearance of chemo-resistance and/or toxic side effects. Therefore, it is imperative to find novel more effective anti-HCC agents. Here, we evaluated the effect of giganteaside D (GD), an oleanolic acid saponin from P. scabiosaefolia, on the growth and apoptosis of HCC cells. METHODS AND RESULTS: Using MTT and clonogenic assays, we found that GD exhibited a significant growth inhibitory effect on the HCC-derived cell lines HepG2 and Bel-7402. In addition, we found that GD induced mitochondria-mediated apoptosis in these HCC-derived cells, as indicated by a decreased mitochondrial potential, activation of Caspase-9 and Caspase-3, cleavage of PARP and release of Cytochrome C from the mitochondria. Besides, we found that GD stimulated the generation of reactive oxygen species (ROS) and that blockage of ROS attenuated the GD-induced mitochondria-mediated apoptosis. Additionally, we found that GD treatment led to a decrease in phosphorylated Erk (p-Erk) and triggered the generation of p-JNK, both components of the mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of Erk or JNK by specific inhibitors or siRNAs augmented or attenuated the cytotoxic and apoptotic effects of GD. CONCLUSIONS: From our results we conclude that GD can induce ROS-mediated apoptosis in HCC-derived cells through the MAPK pathway. This observation may open up avenues to explore the future use of GD as a HCC chemotherapeutic agent.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Apoptose/fisiologia , Western Blotting , Carcinoma Hepatocelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Patrinia/química , Fitoterapia/métodos , Raízes de Plantas/química , RNA Interferente Pequeno , TransfecçãoRESUMO
Liang-Ge-San (LGS) is a classic formula in traditional Chinese medicine, which is widely used to treat acute lung injury (ALI), pharyngitis and amygdalitis in clinic. However, the underlying mechanisms remain poorly defined. In this study, we discovered that LGS exerted potent anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation. We found that LGS significantly depressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophage cells. The degradation and phosphorylation of IκBα and the nuclear translocation of NF-κB p65 were also inhibited. Moreover, LGS activated α7 nicotinic cholinergic receptor (α7nAchR). The blockage of α7nAchR by selective inhibitor methyllycaconitine (MLA) or α7nAchR siRNA attenuated the inhibitory effects of LGS on IκBα, NF-κB p65, IL-6 and TNF-α. Critically, LGS significantly inhibited inflammation in LPS-induced ALI rats through the activation of NF-κB signaling pathway. However, these protective effects could be counteracted by the treatment of MLA. Taken together, we first demonstrated anti-inflammatory effects of LGS both in vitro and in vivo through cholinergic anti-inflammatory pathway. The study provides a rationale for the clinical application of LGS as an anti-inflammatory agent and supports the critical role of cholinergic anti-inflammatory pathway in inflammation.