RESUMO
Tubulointerstitial fibrosis is a common pathological change in end-stage renal disease. However, limited treatment methods are developed, and unexplained potential mechanisms of renal diseases are urgent problems to be solved. In the present research, we first elucidated the role of podocarpusflavone (POD), a biflavone compound, in unilateral ureteral obstruction (UUO) in rodent model which is characterized by inflammation and fibrosis. The changes in histology and immunohistochemistry were observed that POD exerted renoprotective effects by retarding the infiltration of macrophage and aberrant deposition of É-SMA, Col1a1, and fibronectin. Consistent with in vivo assay, POD treatment also ameliorated the process of fibrosis in TGF-ß1-stimulated renal tubular epithelial cells and inflammation in LPS-induced RAW264.7 cells in vitro. In terms of mechanism, our results showed that treatment with POD inhibited the aggravated activation of Fyn in the UUO group, and weakened the level of phosphorylation of Stat3 which indicated that POD may alleviate the process of fibrosis by the Fyn/Stat3 signaling pathway. Furthermore, the gain of function assay by lentivirus-mediated exogenous forced expression of Fyn abrogated the therapeutic effect of the POD on renal fibrosis and inflammation. Collectively, it can be concluded that POD exerted a protective effect on renal fibrosis by mediating Fyn/Stat3 signaling pathway.
Assuntos
Nefropatias , Obstrução Ureteral , Camundongos , Fibrose , Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Proteínas Proto-Oncogênicas c-fyn/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Células RAW 264.7/efeitos dos fármacos , Células RAW 264.7/metabolismo , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , AnimaisRESUMO
As a traditional Chinese medicine, Rhododendron molle G. Don has a long history of treating rheumatoid arthritis. In this study, RAW 264.7 cells induced by lipopolysaccharide (LPS) were established as cell inflammatory model to evaluate the anti-inflammatory activity of chloroform extract from R. molle leaves (CERL), ethyl acetate extract from R. molle leaves (EERL) and butanol extract from R. molle leaves (BERL) and analyze the potential anti-inflammatory components of R. molle. Potential anti-inflammatory components analysis of CERL were performed by HPLC and UHPLC-Q-TOF-MS. Prediction of potential anti-inflammatory components by molecular docking experiments. Compared with negative control group, 25â µg/mL CERL could reduce the release level of NO by 62 %, and the mRNA expression levels of COX-2, IL-6, IL-1ß and TNF-α were reduced by 69.74 %, 86.25 %, 77.94 % and 56.80 %, respectively. Western-Blot showed similar results. CERL, EERL and BERL exerted their inhibitory activity in dose-dependent manner. All results showed that the higher the concentration, the better the anti-inflammatory activity. CERL showed the best inhibitory activity, the second was EERL, and then was BERL. 21 terpenoids and 4 flavonoids were identified in CERL by UHPLC-Q-TOF-MS. Molecular docking results showed that triterpenoids in CERL had better interaction with target proteins (TNF-α, IL-1ß). It indicated that triterpenoids may be potential anti-inflammatory components of R. molle leaves. This study explored the anti-inflammatory activities of CERL, EERL, BERL, which laid a foundation for further promoting the clinical application of R. molle.
Assuntos
Extratos Vegetais , Rhododendron , Animais , Camundongos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Células RAW 264.7/efeitos dos fármacos , Rhododendron/química , Fator de Necrose Tumoral alfaRESUMO
Abrus mollis Hance (Leguminosae) has a variety of biological activities, including anti-inflammatory, antioxidant, antibacterial, antiviral, and antitumor activities. However, the specific substances responsible for the anti-inflammatory effects are unknown. Abrusamide H (BJBS) is a truxillic acid derivative obtained from the leaves of Abrus mollis Hance and has potential anti-inflammatory effects. In this study, we aimed to estimate the potential effect and mechanism of BJBS in inflammation by establishing lipopolysaccharide (LPS)-stimulated RAW264.7 cells inâ vitro and an injured zebrafish tail fin inâ vivo. The RAW264.7 cells were treated with different concentrations of BJBS after LPS stimulation. The production of nitric oxide (NO) was detected by Griess reaction, and reactive oxygen species (ROS) were detected by an ROS assay kit. The levels of proinflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interleukin 18 (IL-18) were measured by ELISA. Results showed that BJBS at all concentrations inhibited the proliferation of RAW264.7 macrophages after LPS stimulation by cell counting kit-8 and the production of NO and ROS. In the BJBS treatment group, the levels of IL-6, TNF-α, IL-1ß, and IL-18 decreased in a concentration-dependent manner. The results inâ vivo showed that no significant difference in the survival of zebrafish between the BJBS and blank groups and BJBS inhibited the migration and aggregation of zebrafish neutrophils in a dose-dependent manner in inflammation induced by tail transection-induced inflammation. In conclusion, BJBS inhibited the production of NO and ROS, decreased the levels of secreted IL-6, TNF-α, IL-1ß, and IL-18, and reduced the migration and aggregation of zebrafish neutrophils.
Assuntos
Anti-Inflamatórios , Peixe-Zebra , Animais , Camundongos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Citocinas , Fabaceae/química , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Interleucina-18/efeitos adversos , Interleucina-6 , Lipopolissacarídeos/farmacologia , Óxido Nítrico , Células RAW 264.7/efeitos dos fármacos , Células RAW 264.7/metabolismo , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa , Peixe-Zebra/metabolismoRESUMO
Two new germacranolides, carpelipine C (1) and carpelipine D (2), together with four known ones (3-6), were isolated from Carpesium lipskyi Winkl. flowers, a folk Tibetan herbal medicine with antipyretic-analgesic and anti-inflammatory effects. The chemical structures of new structure were illuminated by diversified spectroscopic and X-ray crystallographic analyses. Compounds 1 and 3 dramatically suppressed the synthesis of NO and decreased pre-inflammatory protein expression of iNOS and COX-2 in LPS-induced RAW264.7 cells. Furthermore, it was revealed that NF-κB/MAPK signaling pathway were involved in the anti-inflammatory process of 1 and 3, and their effects on reducing oxidative stress by activating Nrf2/HO-1 pathway were also measured. This article indicated that the traditional use of C. lipskyi to treat inflammatory diseases has a certain rationality.
Assuntos
Asteraceae , Sesquiterpenos de Germacrano , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Asteraceae/química , Flores/química , Flores/metabolismo , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/farmacologia , Células RAW 264.7/efeitos dos fármacos , Células RAW 264.7/metabolismo , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/farmacologiaRESUMO
Increasing knowledge of probiotics has shown that co-cultures of probiotics can achieve better fermentation and beneficial effects, and adding LAB to fermented milk fat products can increase the production of polyunsaturated fatty acids. In this study, the fatty acid profiles of milk fermented by L. reuteri DMSZ 8533, L. plantarum A3, and L. acidophilus CICC 6074 were investigated, and the strain difference on the polyunsaturated fatty acid profiles is also confirmed. The results found that L. plantarum A3 fermented milk with a mixed fermentation starter ratio of 1 : 1 : 2 could promote the hydrolysis of lipase to produce more polyunsaturated fatty acids. Furthermore, the milk fat complex hydrolyzed lipids can inhibit the expression of inflammatory factors TNF-α and IL-6 and promote the secretion of IL-10 through the MAPK-dependent NF-κB pathway. Furthermore, the anti-inflammation potential of the fatty acid profiles in the fermented milk products was also revealed in an LPS-induced RAW264.7 cell model. It is hoped that this study can shed light on the anti-inflammatory properties of fermented milk by the release of polyunsaturated fatty acids and the possibility to develop functional fermented milk with intestinal inflammation prevention properties.
Assuntos
Anti-Inflamatórios/farmacologia , Produtos Fermentados do Leite/análise , Ácidos Graxos/farmacologia , Leite , Animais , Anti-Inflamatórios/análise , Ácidos Graxos/análise , Fermentação , Lipopolissacarídeos , Camundongos , Células RAW 264.7/efeitos dos fármacosRESUMO
Bovine milk-derived extracellular vesicles (EVs) have been proved to have positive effects on innate immunity and intestinal health. However, the effect of different processing treatments on the biological function of EVs in dairy products remains unclear. Thus, we explored the immunomodulatory function of EVs from different dairy products (pasteurized milk, UHT milk, freeze-dried powder and organic milk powder) by constructing the RAW264.7 cell model, the most commonly used in vitro model to study immune responses and screen for anti-inflammatory active substances. The results showed that EVs from different dairy products had similar bidirectional immunomodulatory effects to EVs from raw milk, which not only promoted the normal macrophage proliferation and increased NO and cytokine (IL-1ß, IL-6 and TNF-α) levels, but also inhibited the lipopolysaccharide (LPS)-induced TLR4/NF-κB pathway and inflammatory cytokines. In particular, EVs from different dairy products also could regulate the expression of immune-related miR-155, miR-223 and miR-181a, which were involved in the anti-infection response. Although the immunomodulatory effects of EVs in the pasteurized milk and freeze-dried powder groups were lower than that of the raw milk group, they were superior to the UHT milk group and significantly higher than the organic milk powder group. Therefore, we hypothesize that pasteurization and freeze-drying treatments might have less effect on the physiological activity of EVs, making the potential health benefits of the corresponding products superior to those of other dairy products.
Assuntos
Vesículas Extracelulares , Manipulação de Alimentos , Fatores Imunológicos/farmacologia , Leite , Animais , Fatores Imunológicos/análise , Imunomodulação/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismoRESUMO
Four new streptoglycerides E-H (1-4), with a rare 6/5/5/-membered ring system, were isolated from a marine-derived actinomycete Streptomyces specialis. The structures of 1-4 were elucidated by detailed analysis of HRESIMS, 1D and 2D NMR data and ECD spectra as well as comparison of their spectroscopic data with those reported in literature. Compounds 1-4 showed significant anti-inflammatory activity by inhibiting lipopolysaccharide (LPS)-induced nitric oxide (NO) production in Raw 264.7 cells with IC50 values ranging from 3.5 to 10.9 µM. Especially, 2 suppressed mRNA expression levels of iNOS and IL-6 without cytotoxicity.
Assuntos
Anti-Inflamatórios/farmacologia , Policetídeos/farmacologia , Streptomyces , Animais , Anti-Inflamatórios/química , Organismos Aquáticos , Sedimentos Geológicos , Concentração Inibidora 50 , Interleucina-6/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Policetídeos/química , Células RAW 264.7/efeitos dos fármacosRESUMO
Fruit juice is one of the most popular drinks, which requires strict processing conditions to ensure its quality, especially to prevent enzymatic browning and turbidity loss. In this work, a new strategy for the preparation of composite nanofibers for juice clarification and anti-browning control was proposed. The strategy used microfluidic spinning to combine Fucoxanthin (Fx), hydroxypropyl-γ-cyclodextrin (HP-γ-CD) and polyvinyl pyrrolidone (PVP) to prepare Fx/HP-γ-CD-PVP (PCF) nanofibers, which not only reflected the excellent antioxidant properties of cyclodextrin-wrapped Fx, but also achieved a more optimized juice clarification agent dosage. Molecular docking technique was used to prove that the stable inclusion complex of Fx and HP-γ-CD could be formed by hydrogen bonding when the molar ratio of Fx to HP-γ-CD was 1 : 2, and the binding energy was as low as -10.23 kcal mol-1. SEM, XRD, FT-IR and TGA were used to characterize the structure of the composite nanofibers, which showed that the thermal stability and water solubility of the embedded Fx were improved. Further studies showed that the apple juice with PCF nanofibers containing inclusion complexes of Fx and HP-γ-CD at a molar ratio of 1 : 2 (PCF 1 : 2) could significantly improve the DPPH and ABTS radical scavenging activity, and could significantly protect the cell membrane integrity of RAW264.7 cells against H2O2 oxidative damage. Finally, the effects of PCF nanofibers on the quality of fresh juice were studied, including clarification experiment and sensory evaluation. The results showed that the dosage of PVP in PCF 1 : 2 was only about 4% of the conventional dosage, and the browning index of fresh juice was significantly reduced with the best clarification. The available data provided in this study would provide a promising safety strategy for the food processing of fresh juice and the extension of its storage life.
Assuntos
Antioxidantes/química , Manipulação de Alimentos , Sucos de Frutas e Vegetais , Xantofilas/química , Animais , Camundongos , Microfluídica , Nanofibras , Células RAW 264.7/efeitos dos fármacosRESUMO
Six new secoiridoids, syrretosides E-J (1-6) and four known secoiridoids (7-10), were isolated from the stem barks of Syringa reticulata. Their structures were established by the 1D and 2D NMR spectra, HR-ESI-MS, and comparison with the literature. The cytotoxicity of the isolated monomeric compounds against RAW264.7 cells was investigated by the CCK8 assay, and the results showed that the individual compounds were not cytotoxic to RAW264.7. The anti-inflammatory activity of these compounds was evaluated using the LPS-induced RAW264.7 inflammatory cell model and the results showed that compounds 3-7 and 9 showed varying degrees of anti-inflammatory activity.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Glicosídeos Iridoides/isolamento & purificação , Syringa/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , China , Glicosídeos Iridoides/química , Glicosídeos Iridoides/toxicidade , Espectroscopia de Ressonância Magnética , Camundongos , Casca de Planta/química , Células RAW 264.7/efeitos dos fármacos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
In this study, Chinese yam polysaccharide (CYP) was isolated from yam by hydroextraction and alcoholic precipitation. Subsequently, the chlorosulfate-pyridine (CSA-Pyr) method was used to obtain the sulfated Chinese yam polysaccharide derivative (S-CYP) to evaluate its immunomodulatory activity in RAW 264.7 cells and to investigate its mechanism of action. The results revealed that the sulfated modification altered the physicochemical properties of CYP but had no impact on the main chain structure. S-CYP demonstrated excellent immunomodulatory activity by increasing the viability of RAW 264.7 macrophage cells and stimulating the production of reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. Moreover, signal transduction experiments showed that S-CYP induced the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways through toll-like receptor 4 (TLR4), dramatically increasing p-ERK, p-JNK and p-p38 proteins. Meanwhile, immunofluorescence results showed that S-CYP could significantly promote the entry of NF-κB p65 into the nucleus, which is essential for triggering the NF-κB pathway. Furthermore, blocking antibody experiments revealed that specific inhibitors of TLR4, MAPKs, and NF-κB suppressed the generation of TNF-α and IL-6 in RAW 264.7 cells. These findings suggested that both CYP and S-CYP could be used as immunomodulatory agents and may have potential application prospects in the food and pharmaceutical industries.
Assuntos
Dioscorea , Medicamentos de Ervas Chinesas/farmacologia , Fatores Imunológicos/farmacologia , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Medicamentos de Ervas Chinesas/química , Alimento Funcional , Fatores Imunológicos/química , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Polissacarídeos/química , Células RAW 264.7/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismoRESUMO
Microbe-based cancer immunotherapy has recently emerged as a hot topic for cancer treatment. However, serious limitations remain including infection associated side-effect and unsatisfactory outcomes in clinic trials. Here, we fabricate different sizes of nano-formulations derived from yeast cell wall (YCW NPs) by differential centrifugation. The induction of anticancer immunity of our formulations appears to inversely correlate with their size due to the ability to accumulate in tumor-draining lymph node (TDLN). Moreover, we use a percolation model to explain their distribution behavior toward TDLN. The abundance and functional orientation of each effector component are significantly improved not only in the microenvironment in tumor but also in the TDLN following small size YCW NPs treatment. In combination with programmed death-ligand 1 (PD-L1) blockade, we demonstrate anticancer efficiency in melanoma-challenged mice. We delineate potential strategy to target immunosuppressive microenvironment by microbe-based nanoparticles and highlight the role of size effect in microbe-based immune therapeutics.
Assuntos
Imunoterapia/métodos , Linfonodos/efeitos dos fármacos , Melanoma Experimental/terapia , Nanopartículas/administração & dosagem , Saccharomyces cerevisiae/química , Neoplasias Cutâneas/terapia , Aloenxertos , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Parede Celular/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Injeções Intralesionais , Linfonodos/imunologia , Linfonodos/patologia , Ativação de Macrófagos/efeitos dos fármacos , Melanoma Experimental/genética , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Tamanho da Partícula , Células RAW 264.7/efeitos dos fármacos , Células RAW 264.7/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Quinase Syk/antagonistas & inibidores , Quinase Syk/genética , Quinase Syk/imunologia , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Sepsis-induced acute kidney injury (AKI) and acute lung injury (ALI) have high morbidity and mortality, with no effective clinically available drugs. Anti-inflammation is effective strategy in the therapy of AKI and ALI. NF-κB is a target for the development of antiinflammatory agents. The purpose of the study is to evaluate the effect of 270, self-developed NF-κB inhibitor, in LPS-induced AKI and ALI. LPS-induced macrophages were used to examine the anti-inflammation activity of 270 in vitro. Sepsis-induced AKI and ALI mice models were established by intraperitoneal injection of LPS (10 mg/kg) for 24 h. Oral administration 270 for 14 days before LPS stimulation. Plasma, kidney and lung tissues were collected and used for histopathology, biochemical assay, ELISA, RT-PCR, and western blot analyses. In vitro, we showed that 270 suppressed the inflammation response in LPS-induced RAW 264.7 macrophages and bone marrow derived macrophages. In vivo, we found that 270 ameliorated LPS-induced AKI and ALI, as evidenced by improving various pathological changes, reducing the expression of pro-inflammation genes, blocking the activation of NF-κB and JNK pathways, attenuating the elevated myeloperoxidase (MPO) activity and malondialdehyde (MDA) content, ameliorating the activated ER stress, reversing the inhibition effect on autophagy in kidney and lung tissues, and alleviating the enhanced plasma level of creatinine (Crea), blood urea nitrogen (BUN) and pro-inflammation cytokines. Our investigations provides evidence that NF-κB inhibitor 270 is a potential drug that against LPS-induced AKI and ALI in the future.
Assuntos
Injúria Renal Aguda/prevenção & controle , Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7/efeitos dos fármacosRESUMO
Manipulating the structures, physicochemical properties, and monosaccharide compositions of exopolysaccharides (EPS) isolated from microorganisms has been reported to enhance their biological activities. Hence, the aim of this work was to examine the effects of genistein addition during fermentation on the amount, physicochemical properties, and immunomodulatory activity of EPS secreted by M. purpureus. Results showed that genistein addition significantly increased M. purpureus biomass and EPS yield to 2.42 g L-1 and 6.08 g L-1, respectively, and affected the physicochemical properties and structures of EPS. Furthermore, EPS produced by genistein-treated M. purpureus (G-EMP) improved the immunomodulatory activity of RAW264.7 macrophages by increasing the secretion of nitric oxide and cytokines. Moreover, phospho-Jun N-terminal kinase (p-JNK), phospho-extracellular regulated protein kinase (p-ERK), phospho-p38 (p-p38) mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) phospho-p65 (p65) proteins were remarkably upregulated by G-EMP stimulation, blocking Toll-like receptor 4 (TLR4) that dramatically reduced the pinocytic and phagocytic capacities. Overall, these findings provide potential rationales for the application of genistein in improving the EPS yield of M. purpureus.
Assuntos
Genisteína/farmacologia , Fatores Imunológicos/farmacologia , Monascus , Polissacarídeos/biossíntese , Animais , Camundongos , Células RAW 264.7/efeitos dos fármacosRESUMO
Acute lung injury (ALI) is a continuum of pulmonary changes caused by various lung insults. Previously, we synthesized a series of nordihydroguaiaretic acid analogs; of these, compound 3a exhibited excellent antioxidant capacity in a murine model of middle cerebral artery occlusion. However, it remains unclear whether compound 3a can modulate lipopolysaccharide (LPS)-induced ALI. ALI was induced via tracheal LPS administration, and the pathological changes were assessed. The level of inflammation was verified by immunofluorescence and immunohistochemical analyses. Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling assays and Western blotting. Changes in the levels of mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) pathway proteins were assessed by immunofluorescence assays and Western blotting. In vitro, RAW 264.7 cells were treated with compound 3a prior to LPS challenge, and the intracellular level of inflammation was assessed by quantitative PCR (qPCR). Relevant proteins were detected via immunofluorescence assays and Western blotting. Mice developed extensive lung inflammation by 24 h after LPS challenge. Histological examination revealed signs typical of ALI. Preadministration of compound 3a markedly ameliorated the histopathological changes and reduced fluid exudation into the alveolar space. Compound 3a also greatly reduced the levels of inflammation and apoptosis both in vivo and in vitro. Moreover, compound 3a markedly reduced phosphorylation of MAPK/NF-κB pathway-related proteins and p65 translocation, consistent with the in vitro observations. In summary, administration of compound 3a prior to LPS suppressed ALI via inhibition of the MAPK/NF-κB pathway.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Masoprocol/farmacologia , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Masoprocol/química , Masoprocol/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Células RAW 264.7/efeitos dos fármacosRESUMO
Penicillium is a rich source of bioactive compounds. Among all Penicillium species, Penicillium oxalicum has been reported to produce various types of secondary metabolites, including alkaloids, phenolics, and tetrahydroxanthone dimeric compounds, exhibiting many pharmacological effects, such as antiviral, antibacterial, and cytotoxic activities. Three secondary metabolites were isolated from a fermented culture of the sponge-associated fungal strain P. oxalicum CLC-MF05: oxaline (1), isorhodoptilometrin (2), and 5-hydroxy-7-(2'-hydroxypropyl)-2-methyl-chromone (3). Their chemical structures were identified by 1D and 2D NMR and high-resolution mass spectroscopic analyses and compared with previously reported data. All three compounds inhibited NO and PGE2 overproduction and iNOS and COX-2 overexpression in both LPS-stimulated BV2 and rat primary microglia. These metabolites also repressed mRNA expression of TNF-α, IL-1ß, IL-6, and IL-12. Further, mechanistic studies revealed that the inhibitory actions of compounds 1-3 were regulated by the inactivation of the NF-κB and MAPK signaling pathways. Furthermore, inactivation of the TLR4/MyD88 pathway contributed to the anti-neuroinflammatory activity of these compounds. These results suggest that compounds 1-3 represent potential anti-inflammatory candidates for the treatment of neurodegenerative diseases; however, further investigation is needed.
Assuntos
Anti-Inflamatórios/farmacologia , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Penicillium , Poríferos , Animais , Anti-Inflamatórios/química , Organismos Aquáticos , Lipopolissacarídeos , Camundongos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/química , Células RAW 264.7/efeitos dos fármacos , RatosRESUMO
Atlantic cod (Gadus morhua) is one of the most important fishes in the world with high nutritional value and economic value. However, the impact and underlying mechanism of the G. morhua peptides (GMPs) on osteoclastogenesis and bone mineral density (BMD) regulation remain unclear. The purpose of this study was to investigate the effects of GMPs on osteoclast formation and anti-osteoporosis activity in vitro and in vivo. The results showed that GMPs significantly reduced receptor activator of nuclear factor (RANKL) induced tartrate-resistant acid phosphatase (TRAP) activity, and decreased the expression of osteoclast regulatory factors c-Fos and NFATc1 by inhibiting the activation of MAPK and NF-κB pathways, and thereby inhibiting osteoclast formation and bone resorption. In vivo, GMP protects mice against ovariectomy-induced bone loss by regulating the balance of major factors released in bone formation and resorption. Taken together, GMP could be a potential candidate or dietary supplement for the prevention of osteoporosis.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Alimento Funcional , Gadus morhua , Peptídeos/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoporose/induzido quimicamente , Osteoporose/prevenção & controle , Ovariectomia , Peptídeos/farmacologia , Ligante RANK , Células RAW 264.7/efeitos dos fármacosRESUMO
Adiponectin, an adipose tissue-derived hormone, exhibits a modulatory effect on cell death/survival and possesses potent anti-inflammatory properties. However, the underlying molecular mechanisms remain elusive. Sestrin2, a stress-inducible metabolic protein, has shown cytoprotective and inflammation-modulatory effects under stressful conditions. In this study, we examined the role of sestrin2 signaling in the modulation of cell survival and inflammatory responses by globular adiponectin (gAcrp) in macrophages. We observed that gAcrp induced a significant increase in sestrin2 expression in both RAW 264.7 murine macrophages and primary murine macrophages. Notably, gAcrp treatment markedly increased expression of hypoxia inducible factor-1 α (HIF-1α) and gene silencing of HIF-1α blocked sestrin2 induction by gAcrp. In addition, pretreatment with a pharmacological inhibitor of ERK or PI3K abrogated both sestrin2 and HIF-1α expression by gAcrp, indicating that ERK/PI3K-mediated HIF-1α signaling pathway plays a critical role in sestrin2 induction by gAcrp. Furthermore, sestrin2 induction is implicated in autophagy activation, and knockdown of sestrin2 prevented enhanced cell viability by gAcrp. Moreover, gene silencing of sestrin2 caused restoration of gAcrp-induced expression of anti-inflammatory genes in a gene-selective manner. Taken together, these results indicate that sestrin2 induction critically contributes to cell survival and anti-inflammatory responses by gAcrp in macrophages.
Assuntos
Adiponectina/farmacologia , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Peroxidases/metabolismo , Células RAW 264.7/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Western Blotting , Inativação Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Células RAW 264.7/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Brown algae of the Family Dictyotaceae produce an array of structurally diverse terpenoids, whose biomedical potential in the anti-inflammatory area has been scarcely explored. Herein, the chemical study of the alga Rugulopteryx okamurae has led to the isolation of ten new diterpenoids: rugukadiol A (1), rugukamurals A-C (2-4), and ruguloptones A-F (6-10). The structures of the new compounds were established by spectroscopic means. Compound 1 exhibits an unprecedented diterpenoid skeleton featuring a bridged tricyclic undecane system. Compounds 2-10 belong to the secospatane class of diterpenoids and differ by the oxygenated functions that they contain. In anti-inflammatory assays, the new diterpenoid 1 and the secospatanes 5 and 10 significantly inhibited the production of the inflammatory mediator NO in LPS-stimulated microglial cells Bv.2 and macrophage cells RAW 264.7. Moreover, compounds 1 and 5 were found to strongly inhibit the expression of Nos2 and the pro-inflammatory cytokine Il1b in both immune cell lines.
Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Phaeophyceae , Animais , Anti-Inflamatórios/química , Organismos Aquáticos , Diterpenos/química , Camundongos , Células RAW 264.7/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
One strain-many compounds (OSMAC) manipulation of the sponge-derived fungus Pestalotiopsis heterocornis XWS03F09 resulted in the production of new secondary metabolites. The chemical study of the fermentation, cultivated on 3% artificial sea salt in the rice media, led to the isolation of twelve compounds, including eight new polyketide derivatives, heterocornols Q-X (1-8), one new ceramide (9), and three known analogues (10-12). The structures and absolute configurations of the new compounds were elucidated by spectroscopic data and calculated ECD analysis. Heterocornols Q (1) and R (2) are novel 6/5/7/5 tetracyclic polyketide derivatives featuring dihydroisobenzofuran and benzo-fused dioxabicyclo [4.2.1] nonane system, which might be derived from the acetyl-CoA by epoxidation, polyene cyclization, and rearrangement to form the core skeleton. Compound 12 showed moderate or weak antimicrobial activities against with MIC values ranging from 25 to 100 µg/mL. Heterocornols T and X (7 and 8) could inhibit the production of LPS-induced NO significantly, comparable to dexamethasone. Further Western blotting analysis showed 7 and 8 markedly suppressed the iNOS protein expression in LPS-induced RAW 264.7 cells in a dose-dependent manner. The result showed that 7 and 8 might serve as potential leads for development of anti-inflammatory activity.
Assuntos
Anti-Inflamatórios/farmacologia , Pestalotiopsis , Policetídeos/farmacologia , Poríferos , Animais , Anti-Inflamatórios/química , Organismos Aquáticos , Relação Dose-Resposta a Droga , Camundongos , Policetídeos/química , Células RAW 264.7/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Inflammation is a double-edged sword, as it can have both protective effects and harmful consequences, which, combined with oxidative stress (OS), can lead to the development of deathly chronic inflammatory conditions. Over the years, research has evidenced the potential of marine sponges as a source of effective anti-inflammatory therapeutic agents. Within this framework, the purpose of this study was to evaluate the antioxidant and the anti-inflammatory potential of the marine sponge Cliona celata. For this purpose, their organic extracts (C1-C5) and fractions were evaluated concerning their radical scavenging activity through 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and anti-inflammatory activity through a (lipopolysaccharides (LPS)-induced inflammation on RAW 264.7 cells) model. Compounds present in the two most active fractions (F5 and F13) of C4 were tentatively identified by gas chromatography coupled to mass spectrometry (GC-MS). Even though samples displayed low antioxidant activity, they presented a high anti-inflammatory capacity in the studied cellular inflammatory model when compared to the anti-inflammatory standard, dexamethasone. GC-MS analysis led to the identification of n-hexadecanoic acid, cis-9-hexadecenal, and 13-octadecenal in fraction F5, while two major compounds, octadecanoic acid and cholesterol, were identified in fraction F13. The developed studies demonstrated the high anti-inflammatory activity of the marine sponge C. celata extracts and fractions, highlighting its potential for further therapeutic applications.