RESUMEN
A phytochemical investigation was conducted on Euphorbia helioscopia, resulting in the isolation of thirteen compounds, including nine undescribed diterpenoids, Euphzycopias A - I (1-9), of which the skeletons of compounds 1-4 were found in E. helioscopia L. Compounds 1-3 had 5/7/6 cyclic systems, while compound 4 had a 4/11 polycyclic system with a 4,7-cyclic ether between C-4 and C-7. The anti-inflammasome test using the isolated compounds (1-6, 8-13) showed that the diterpenes from E. helioscopia L. had a strong inhibitory effect on NLRP3 inflammasomes with IC50 values of 3.34-14.92 µM.
Asunto(s)
Diterpenos/farmacología , Euphorbia/química , Inflamasomas/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Humanos , Inflamasomas/química , Inflamasomas/aislamiento & purificación , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Rotación Óptica , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Espectrofotometría InfrarrojaRESUMEN
Ulcerative colitis (UC) is an inflammatory bowel disease that affects the colon and rectum. Although galectin-3 (Gal-3) has been reported to play a proinflammatory role in UC, it is unknown whether pectic polysaccharide, a Gal-3 inhibitor in tumor metastasis, can alleviate UC by inhibiting Gal-3. The aim of this study was to investigate the anti-inflammatory effects and underlying mechanisms of SCLP, a pectic polysaccharide purified from Smilax china L. in our previous work, on dextran sulfate sodium-induced UC in BALB/c mice. The results showed that SCLP could significantly improve symptoms, alleviate histopathological damage and reduce the secretion of inflammatory mediators in mice with UC. Analysis of the anti-colitis mechanisms indicated that SCLP could inhibit the Gal-3/NLRP3 inflammasome/IL-1ß pathway by suppressing the expression of Gal-3 and the interaction of Gal-3 and NLRP3. Our results suggested that SCLP could be a promising candidate for prevention and treatment of UC.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Inflamasomas/antagonistas & inhibidores , Pectinas/farmacología , Polisacáridos/farmacología , Smilax/química , Animales , Antiinflamatorios no Esteroideos/química , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Sulfato de Dextran , Galectina 3/antagonistas & inhibidores , Galectina 3/metabolismo , Inflamasomas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Pectinas/química , Polisacáridos/químicaRESUMEN
Erianin (Eri) is the extract of Dendrobium chrysotoxum Lindl. The NLRP3 inflammasome is a multiprotein complex that plays key roles in a wide variety of chronic inflammation-driven human diseases. Nevertheless, little is known about the protection of Eri against NLRP3 inflammasome-related diseases. In this study, we demonstrated that Eri inhibited NLRP3 inflammasome activation in vitro and in vivo. Mechanistically, Eri directly interacted with NLRP3, leading to inhibition of NLRP3 inflammasome assembly. Eri associated with the Walker A motif in the NACHT domain and suppressed NLRP3 ATPase activity. In mouse models, Eri had therapeutic effects on peritonitis, gouty arthritis and type 2 diabetes, via NLRP3. More importantly, Eri was active ex vivo for synovial fluid cells and monocytes from patients with IAV infection and gout. Eri may serve as a potential novel therapeutic compound against NLRP3-driven diseases.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Gotosa/tratamiento farmacológico , Bibencilos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inflamasomas/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Peritonitis/tratamiento farmacológico , Fenol/farmacología , Animales , Artritis Gotosa/genética , Artritis Gotosa/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Perros , Células HEK293 , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Células de Riñón Canino Madin Darby , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Peritonitis/genética , Peritonitis/metabolismo , Dominios y Motivos de Interacción de Proteínas , Células THP-1RESUMEN
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is an extreme form of non-alcoholic fatty liver disease. The present study concentrated on the role of Capillin, a polyacetylene compound isolated from Artemisia capillaris Thunb., in NASH development. MATERIALS AND METHODS: Palmitic acid (PA) was treated with FL83B hepatocytes, and high-fat diet was given to mouse to construct the NASH model in vivo. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were carried out to measure the viability and apoptosis of FL83B hepatocytes. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to measure the mRNA expressions of infiltration markers (Cd11c, Ccr2, and Ly6c), fibrosis genes (Tgfß1, Col1a1, and Timp1), and alpha-smooth muscle actin (α-SMA). Western blot, immunofluorescence, and Enzyme-linked immunosorbent assay (ELISA) were implemented to examine the proteins of Caspase-3, Bcl2, Nrf2, HO-1, NLRP3, ASC, and Caspase-1, the ROS level, and oxidative stress markers (MDA, GSH-ST, SOD, and GSH-Px), and the lipid peroxidation level, respectively. Moreover, HE staining was manipulated to observe the histopathological changes in liver tissue. RESULTS: Capillin hampered PA-mediated hepatocytes apoptosis and enhanced cell viability. Furthermore, Capillin suppressed PA-mediated oxidative stress in hepatocytes, promoted Nrf2/HO-1 expression, and repressed NLRP3-ASC-Caspase1 inflammasome. The in vivo studies indicated that Capillin vigorously improves liver fat accumulation, oxidative stress, and liver injury in NASH mice. Mechanistically, Capillin repressed NLRP3-ASC-Caspase1 inflammasome and up-regulated the Nrf2-HO-1 pathway in the liver. CONCLUSION: Capillin ameliorates hepatocyte injury by dampening oxidative stress and repressing NLRP3 inflammasome in NASH mice.
Asunto(s)
Diinos/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Animales , Dieta Alta en Grasa/efectos adversos , Diinos/farmacología , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés Oxidativo/fisiología , Extractos Vegetales/farmacologíaRESUMEN
Luohuazizhu suppository is a Traditional Chinese Medicine used in clinic to treat cervicitis, which is prepared from Callicarpa nudiflora Hook. et Arn (C. nudiflora), an herbal Chinese medicine named Luohuazizhu. This study aimed to figure out the active constituents of C. nudiflora and the potential mechanism for its anti-cervicitis effect. The ethanol extract in C. nudiflora (CNE) and the different fractions of CNE extracted by petroleum ether (CNE-p), dichloromethane (CNE-d), and n-butanol (CNE-b) were tested in vivo for their anti-cervicitis effects. Then the isolated compounds from the CNE-p were tested in vitro for their anti-inflammatory activities. The results displayed that CNE-p, CNE-d, and CNE-b exhibited adequate anti-cervicitis effects, with CNE-p showing the highest efficacy. Further experiment demonstrated that CNE-p could significantly inhibit the expression of NLRP3 in vitro. Six diterpenoids obtained from the CNE-p showed the ability to regulate inflammatory factor levels in vitro. Among these compounds, compounds 1 (callicarpic acid A) and 2 (syn-3,4-seco-12S-hydroxy-15,16-epoxy-4(18),8(17),3(16),14(15)-labdatetraen-3-oic acid) were the most effective agents, and they also inhibited the expression level of NLRP3 in vitro. The results confirmed that C. nudiflora has significant anti-cervicitis effects and the diterpenoids were most likely to be its active components. These data provide scientific support for the clinic usage of Luohuazizhu suppository and the development of new agents in treating cervicitis.
Asunto(s)
Callicarpa/química , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Fitoquímicos/farmacología , Cervicitis Uterina/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Femenino , Humanos , Medicina Tradicional China , Ratones , Simulación del Acoplamiento Molecular , Proteína con Dominio Pirina 3 de la Familia NLR/química , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/farmacología , Plantas Medicinales/química , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Cervicitis Uterina/metabolismo , Cervicitis Uterina/patologíaRESUMEN
The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.
Asunto(s)
Berberina/farmacología , Inflamasomas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Humanos , Inflamasomas/química , Inflamación/metabolismo , Enfermedades Metabólicas/tratamiento farmacológico , Modelos Biológicos , Proteína con Dominio Pirina 3 de la Familia NLR/química , Neoplasias/tratamiento farmacológico , Neoplasias/etiología , Neoplasias/metabolismo , Fitoquímicos/farmacología , Fitoterapia , Transducción de Señal/efectos de los fármacosRESUMEN
Previous studies reported that Agrimonia pilosa (AP) Ledeb possessed diverse biological activities, including anti-inflammatory, antioxidant, and anti-tumor activities. However, the effect of AP on ulcerative colitis (UC) remains unclear. In this study, we investigated the therapeutic effect and mechanisms of AP on dextran sodium sulfate (DSS)-induced colitis. The potential constituents of AP were investigated by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A total of 13 compounds were recognized by UPLC-Q-TOF/MS chromatogram. Furthermore, a network pharmacology approach revealed that there are 297 candidate targets of UC and 549 common targets for the 13 active ingredients of AP. GO enrichment and KEGG pathway analysis indicated that AP might have a protective effect on UC through the nuclear factor κB (NF-κB) and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathways. Subsequent experimental validation in a DSS-induced colitis model revealed that AP alleviated the severity of DSS-induced colitis, reduced the production of proinflammatory factors, and protected against the loss of intestinal integrity. Moreover, AP inhibited the phosphorylation of NF-κB p65 and the activation of the NLRP3 inflammasome. In conclusion, AP ameliorated DSS-induced colitis through suppressing the activation of the NLRP3 inflammasome and NF-κB signaling pathways.
Asunto(s)
Agrimonia/química , Colitis Ulcerosa/prevención & control , Extractos Vegetales/farmacología , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Farmacología en Red , Extractos Vegetales/uso terapéutico , Transducción de Señal/efectos de los fármacos , Proteínas de Uniones Estrechas/metabolismoRESUMEN
5-Fluorouracil (5-FU)-based chemotherapy is the first-line recommended regimen in colorectal cancer (CRC), but resistance limits its clinical application. Andrographolide sulfonate, a traditional Chinese medicine, is mainly used to treat infectious diseases. In the present study, we reported that andrographolide sulfonate could significantly inhibit the growth of transplanted CT26 colon cancer in mice and improve survival when combined with 5-FU. Furthermore, TUNEL assay and immunohistochemistry analysis of proliferating cell nuclear antigen, Ki-67 and p-STAT3 confirmed that co-treatment could inhibit tumor proliferation and promote apoptosis. In tumor tissues of groups that received 5-FU and andrographolide sulfonate, CD4+ and CD8+ T cell infiltration was increased, and the expression of IFN-γ and Granzyme B detected by immunohistochemistry and qPCR was upregulated, reflecting improved antitumor immunity. Finally, we verified that 5-FU significantly activated the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) and that andrographolide sulfonate reversed this process to sensitize cells to 5-FU. In summary, andrographolide sulfonate synergistically enhanced antitumor effects and improved antitumor immunity by inhibiting 5-FU-induced NLRP3 activation in MDSCs. These findings provide a novel strategy to address 5-FU resistance in the treatment of CRC.
Asunto(s)
Antiinflamatorios/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Diterpenos/administración & dosificación , Fluorouracilo/administración & dosificación , Células Supresoras de Origen Mieloide/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Sinergismo Farmacológico , Femenino , Ratones , Ratones Endogámicos BALB C , Células Supresoras de Origen Mieloide/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
PURPOSE: Berberine (BBR) is an active component of Phellodendri Cortex (PC), which is a traditional Chinese medicine that has been prescribed clinically for hyperuricemia (HUA) for hundreds of years. Many studies reported the anti-inflammatory and nephroprotective properties of BBR and PC; however, the therapeutic effects of BBR on HUA have not been explored. This study aims to investigate the efficacy and mechanism of BBR for treating HUA. METHODS: The mechanism of BBR in the treatment of HUA were predicted by network pharmacology. A mouse model of HUA established by potassium oxonate and hypoxanthine was used to verify the prediction. The levels of serum uric acid (UA), urea nitrogen (BUN) and creatinine (CRE) were determined by biochemical test kits. Hematoxylin and eosin staining of kidney tissues was used to observe the kidney damage. ELISA kits were applied to detect the levels of interleukin (IL)-1ß and IL-18 in serum and kidney tissues. Quantitative real-time PCR and Western blotting were adopted to analyze the expression of NLRP3, ASC, Caspase1, IL-1ß and URAT1. The expressions of URAT1 in the kidney tubules were visualized by immunohistochemical staining. Molecular docking was used to assess the interaction between URAT1 and BBR. RESULTS: The network pharmacology screened out 82 genes and several inflammation-related signaling pathways related to the anti-hyperuricemia effect of BBR. In the in vivo experiment, BBR substantially decreased the level of UA, BUN and CRE, and alleviated the kidney damage in mice with HUA. BBR reduced IL-1ß and IL-18, and downregulated expressions of NLRP3, ASC, Caspase1 and IL-1ß. BBR also inhibited expression of URAT1 and exhibited strong affinity with this target in silico docking. CONCLUSION: BBR exerts anti-HUA and nephroprotective effects via inhibiting activation of NLRP3 inflammasome and correcting the aberrant expression of URAT1 in kidney. BBR might be a novel therapeutic agent for treating HUA.
Asunto(s)
Berberina/uso terapéutico , Hiperuricemia/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Farmacología en Red , Animales , Berberina/farmacología , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Transportadores de Anión Orgánico/análisis , Transportadores de Anión Orgánico/antagonistas & inhibidores , Ácido Úrico/sangreRESUMEN
Inhibition of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome has recently emerged as a promising therapeutic target for several inflammatory diseases. After priming and activation by inflammation triggers, NLRP3 forms a complex with apoptosis-associated speck-like protein containing a CARD domain (ASC) followed by formation of the active inflammasome. Identification of inhibitors of NLRP3 activation requires a well-validated primary high-throughput assay followed by the deployment of a screening cascade of assays enabling studies of structure-activity relationship, compound selectivity and efficacy in disease models. We optimized a NLRP3-dependent fluorescent tagged ASC speck formation assay in murine immortalized bone marrow-derived macrophages and utilized it to screen a compound library of 81,000 small molecules. Our high-content screening assay yielded robust assay metrics and identified a number of inhibitors of NLRP3-dependent ASC speck formation, including compounds targeting HSP90, JAK and IKK-ß. Additional assays to investigate inflammasome priming or activation, NLRP3 downstream effectors such as caspase-1, IL-1ß and pyroptosis form the basis of a screening cascade to identify NLRP3 inflammasome inhibitors in drug discovery programs.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Inflamasomas/efectos de los fármacos , Macrófagos/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Proteínas Adaptadoras de Señalización CARD/metabolismo , Caspasa 1/biosíntesis , Células Cultivadas , Dimetilsulfóxido/farmacología , Descubrimiento de Drogas , Furanos/farmacología , Genes Reporteros , Indenos/farmacología , Interleucina-1beta/biosíntesis , Lipopolisacáridos/farmacología , Ratones , Nigericina/farmacología , Fenotipo , Piroptosis/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequeñas , Sulfonamidas/farmacologíaRESUMEN
The present study was conducted to evaluate the effect of Forsythiae Fructus aqueous extract (FAE) against cisplatin-induced emesis and to explore the antiemetic mechanism of FAE by focusing on NLRP3 inflammasome activation in a rat pica model. Our results showed that FAE significantly ameliorated cisplatin-induced acute and delayed pica in rats. Moreover, FAE improved the gastrointestinal histopathological injury and reduced the levels of serum ROS, IL-1ß, and IL-18 in cisplatin-treated rats. In addition, the expressions of NLRP3, ASC, caspase-1, and IL-1ß and the colocalization of the NLRP3 with ASC or caspase-1 in rat gastric antrum and ileum were also suppressed by FAE. Taken together, our findings indicate that FAE has a therapeutic effect against CINV, which may be related to its inhibition of the activation of NLRP3 inflammasome.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Forsythia/química , Inflamasomas/efectos de los fármacos , Caolín/análisis , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Pica/inducido químicamente , Extractos Vegetales/farmacología , Animales , Antineoplásicos/aislamiento & purificación , Cisplatino/aislamiento & purificación , Extractos Vegetales/química , RatasRESUMEN
Lagotis brachystachya Maxim is a herb widely used in traditional Tibetan medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and in vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which was consistent with the finding in the kidneys of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3). Congruently, western blot analysis showed that the components inhibited TLR4/myeloid differentiation primary response 88 (MyD88)/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by inhibiting inflammatory signaling pathways.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Hiperuricemia/metabolismo , Riñón/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptor Toll-Like 4/metabolismo , Ácido Úrico/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/uso terapéutico , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Hiperuricemia/tratamiento farmacológico , Riñón/efectos de los fármacos , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Plantas Medicinales , Estructura Secundaria de Proteína , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Receptor Toll-Like 4/antagonistas & inhibidores , Ácido Úrico/toxicidadRESUMEN
Non-alcoholic steatohepatitis (NASH), an extreme progressive subtype of metabolic associated fatty liver disease, is well characterized by hepatic steatosis, injury and inflammation. It causes irreversible hepatic damage and there are no approved interventions for it. ß-PAE, a representatively pharmacological active substance isolated from Pogostemon cablin, has been indicated to alleviate hepatic steatosis and injury through modulating lipid metabolism in rats with simple steatosis. However, its protection against NASH remains unclear. Here, this study explored the potential effect of ß-PAE against high-fat diet-induced NASH in rats. The results displayed that ß-PAE significantly reduced the gains of body weight and epididymal adipose tissue, liver index and attenuated liver histological damages in NASH rats. It also markedly alleviated hepatic inflammation by inhibiting NLRP3 inflammasome activation. In NASH, the active NLRP3 inflammasome is caused by hepatic lipid abnormal accumulation-induced oxidative stress. Excessive oxidative stress results in hepatic histanoxia, which exacerbates lipid metabolism disorders by elevating CD36 to suppress AMPK signalling pathways. Moreover, the lipid accumulation led by lipid metabolism dysfunction intensifies oxidative stress. A vicious circle is formed among oxidative stress, histanoxia and lipid accumulation, eventually, but ß-PAE effectively interrupted it. Interestingly, soluble CD36 (sCD36) was tightly associated not only with hepatic steatosis and injury but also with inflammation. Collectively, ß-PAE exerted a positive effect against NASH by interrupting the vicious circle among oxidative stress, histanoxia and lipid accumulation, and sCD36 may be a promising non-invasive tool for NASH diagnosis.
Asunto(s)
Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Sesquiterpenos de Guayano/farmacología , Animales , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/inmunología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/inmunología , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Ratas , Sesquiterpenos de Guayano/uso terapéuticoRESUMEN
Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure-activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.
Asunto(s)
Abietanos/farmacología , Furanos/farmacología , Gota/tratamiento farmacológico , Inflamasomas/antagonistas & inhibidores , Fenantrenos/farmacología , Quinonas/farmacología , Choque Séptico/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/metabolismo , Abietanos/uso terapéutico , Animales , Autofagia/efectos de los fármacos , Autofagia/inmunología , Modelos Animales de Enfermedad , Femenino , Furanos/uso terapéutico , Gota/inducido químicamente , Gota/inmunología , Gota/patología , Humanos , Inflamasomas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fenantrenos/uso terapéutico , Quinonas/uso terapéutico , Ratas , Especies Reactivas de Oxígeno/metabolismo , Choque Séptico/inmunología , Choque Séptico/patología , Ácido Úrico/administración & dosificación , Ácido Úrico/toxicidadRESUMEN
The NLRP3 inflammasome holds a crucial role in innate immune responses. Pathogen- and danger-associated molecular patterns may initiate inflammasome activation and following inflammatory cytokine release. The inflammasome formation and its-associated activity are involved in various pathological conditions such as cardiovascular, central nervous system, metabolic, renal, inflammatory and autoimmune diseases. Although the mechanism behind NLRP3-mediated disorders have not been entirely illuminated, many phytochemicals and medicinal plants have been described to prevent inflammatory disorders. In the present review, we mainly introduced phytochemicals inhibiting NLRP3 inflammasome in addition to NLRP3-mediated diseases. For this purpose, we performed a systematic literature search by screening PubMed, Scopus, and Google Scholar databases. By compiling the data of phytochemical inhibitors targeting NLRP3 inflammasome activation, a complex balance between inflammasome activation or inhibition with NLRP3 as central player was pointed out in NLRP3-driven pathological conditions. Phytochemicals represent potential therapeutic leads, enabling the generation of chemical derivatives with improved pharmacological features to treat NLRP3-mediated inflammatory diseases.
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Antiinflamatorios/farmacología , Inflamasomas/antagonistas & inhibidores , Mediadores de Inflamación/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Fitoquímicos/farmacología , Animales , Humanos , Inflamasomas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de SeñalRESUMEN
Myocardial injury and cardiovascular dysfunction are serious consequences of sepsis and contribute to high mortality. Currently, the pathogenesis of myocardial injury in sepsis is still unclear, and therapeutic approaches are limited. In this study, we investigated the protective effect of emodin on septic myocardial injury and the underlying mechanism. Lipopolysaccharide (LPS)-induced C57BL/6 mice and cardiomyocytes were used as models of sepsis in vivo and in vitro, respectively. The results showed that emodin alleviated cardiac dysfunction, myocardial injury and improved survival rate in LPS-induced septic mice. Emodin attenuated the levels of inflammatory cytokines and cardiac inflammation induced by LPS. Emodin reduced NOD-like receptor protein 3 (NLRP3) and Gasdermin D (GSDMD) expression in the heart tissue of LPS-induced septic mice. In vitro, emodin alleviated LPS-induced cell injury and inflammation in cardiomyocytes by inhibiting NLRP3 inflammasome activation. In addition, an NLRP3 inhibitor was used to further confirm the function of the NLRP3 inflammasome in LPS-induced myocardial injury. Taken together, our findings suggest that emodin improves LPS-induced myocardial injury and cardiac dysfunction by alleviating the inflammatory response and cardiomyocyte pyroptosis by inhibiting NLRP3 inflammasome activation, which provides a feasible strategy for preventing and treating myocardial injury in sepsis.
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Emodina , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Animales , Emodina/farmacología , Corazón/efectos de los fármacos , Inflamasomas/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Proteínas NLRRESUMEN
Obesity is characterized by a condition of low-grade chronic inflammation that facilitates development of numerous comorbidities and dysregulation of brain homeostasis. It is reported that obesity can lead to behavioral alterations such as cognitive decline and depression-like behaviors both in humans and rodents. Saponins from panax japonicus (SPJ) have been reported to exhibit anti-inflammatory action in mouse model of diet-induced obesity. We evaluated the neuroprotection of SPJ on high fat diet (HFD) induced impaired behaviors such as memory deficit and depressive-like behaviors, and explored the underlying mechanisms. 6-week male Balb/c mice were divided into normal control group (NC, 17% total calories from fat), HFD group (60% total calories from fat), and HFD treated with SPJ groups (orally gavaged with dosages of 15 mg/kg and 45 mg/kg), respectively. After treatment for 16 weeks, behavioral tests were performed to evaluate the cognition and depression-like behaviors of the mice. The underling mechanisms of SPJ on HFD-induced impaired behaviors were investigated through histopathological observation, Western blot analysis and immunofluorescence. Our results showed that HFD-fed mice caused behavioral disorders, neuronal degeneration as well as elevated neuroinflammation, which was partly involved in NLRP3 inflammasome that finally resulted in decreased protein levels of AMPA receptors and down-regulated phosphorylated levels of CaMKII and CREB in cortex and hippocampus. All the above changes in cortex and hippocampus induced by HFD were mitigated by SPJ treatment. SPJ treatment alleviated HFD-induced recognitive impairment and depression-like behaviors of mice, which could be partly due to the capacity of SPJ to mitigate neuroinflammation through inhibition of NLRP3 inflammasome and upregulation of AMPA receptors signaling pathway.
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Conducta Animal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Inflamasomas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Panax/química , Receptores AMPA/biosíntesis , Receptores AMPA/efectos de los fármacos , Saponinas/farmacología , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/biosíntesis , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/biosíntesis , Depresión/inducido químicamente , Depresión/psicología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. PURPOSE: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. STUDY DESIGN: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. METHODS: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. RESULTS: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1ß (IL-1ß) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro. CONCLUSIONS: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.
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Proteínas Portadoras/antagonistas & inhibidores , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Inflamasomas/efectos de los fármacos , Lipopolisacáridos/toxicidad , Luteolina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Tiorredoxinas/antagonistas & inhibidores , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Muerte Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hepatitis/tratamiento farmacológico , Hepatitis/etiología , Hepatitis/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Inflamasomas/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMEN
The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that induces caspase-1 activation and the downstream substrates involved with the processing and secretion of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and tumor necrosis factor-α (TNF- α). The NLRP3 inflammasome is activated by a wide range of danger signals that derive from metabolic dysregulation. Activation of this complex often involves the adaptor ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. It has been shown that nutraceuticals and medicinal plants have antiinflammatory properties and could be used as complementary therapy in the treatment of several chronic diseases that are related to inflammation, for example, cardiovascular diseases and diabetes mellitus. Herb-based medicine has demonstrated protective effects against NLRP3 inflammasome activation. Therefore, this review focuses on the effects of nutraceuticals and bioactive compounds derived from medicinal plants on NLRP3 inflammasome activation and the possible mechanisms of action of these natural products. Thus, herb-based, natural products/compounds can be considered novel, practical, and accessible agents in chronic inflammatory diseases by inhibiting NLRP3 inflammasome activation.
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Productos Biológicos , Inflamasomas/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Plantas Medicinales , Productos Biológicos/farmacología , Caspasa 1 , Citocinas , Fitoquímicos/farmacología , Plantas Medicinales/químicaRESUMEN
Inflammation plays a major role in the pathogenesis of acute lung injury (ALI), but the mechanism remains unclear. Current anti-inflammatory therapy has poor efficacy on ALI. The aim of this study was to investigate the protective mechanism of curcumin against ALI. In in vivo experiments, curcumin significantly alleviated lung inflammation, histopathological injury and MPO activity, serum concentrations of CCL7, IL-6 and TNF-α, and mortality in mice compared to the model group. RAW264.7 cells cultured in the presence of lipopolysaccharide and adenosine triphosphate showed significantly lower viability, higher pyroptotic percentage and inflammation, but supplement of curcumin increased the cell viability, reduced pyroptosis and inflammation. Additionally, the expressions of NF-κB and pyroptosis related proteins were notably increased, while Sirtuin 1 (SIRT1) was decreased in both in vivo and in vitro ALI models. The results suggested that curcumin remarkably inhibited the expression of NF-κB and pyroptosis related proteins and increased the expression of SIRT1. However, EX527, a SIRT1 inhibitor, blocked the protective effect of curcumin against ALI. In conclusion, curcumin has protective effect against ALI. It may inhibit inflammatory process by inhibiting the activation of NLRP3 inflammasome-dependent pyroptosis through the up-regulation of SIRT1.