RESUMEN
Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Animales , Humanos , Inflamación/metabolismo , Interleucina-6/metabolismo , Transducción de SeñalRESUMEN
Defective expression of NAD-dependent protein deacetylase sirtuin 1 (SIRT1) triggers endoplasmic reticulum (ER) stress and epithelial cell apoptosis in inflammatory bowel disease. MicroRNA-132 (miR-132) has been shown to regulate inflammatory processes through down-regulating SIRT1. Catalpol is a potential antioxidant and anti-apoptotic agent in inflammatory disease. This study aimed to investigate the signaling mechanisms underlying catalpol-induced SIRT1 activation and inhibition of ER stress in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. miR-132 expression was measured by quantitative real-time polymerase chain reaction and in situ hybridization, and the regulation of SIRT1 by miR-132 was examined by dual luciferase reporter assay. Protein expression related to ER stress and apoptosis was measured by western blotting. The ER stress marker proteins ATF6, CHOP, and caspase12, and acetylation of heat-shock factor-1 were increased in colitis and these increases were significantly reversed by catalpol, while the colitis-induced reduction in GRP78 was also reversed by catalpol. The inhibition of ER stress by catalpol was significantly inhibited by small interfering RNA targeting SIRT1 or miR-132. Moreover, other colitis symptoms including infiltration of inflammatory cells, cytokine profiles, oxidative responses, and epithelial cell apoptosis were also significantly decreased by catalpol. Mechanistically, the defective expression of SIRT1 in colitis was significantly counteracted by catalpol, while miR-132, which is a negative targeting regulator of SIRT1, was confirmed as the potential target of catalpol. These results support a link between ER stress and the miR-132/SIRT1/heat-shock factor-1 signaling pathway, and the modulation of this pathway by catalpol in colitis.
Asunto(s)
Colitis/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glucósidos Iridoides/farmacología , Glucósidos Iridoides/uso terapéutico , MicroARNs/genética , Sirtuina 1/genética , Animales , Apoptosis/efectos de los fármacos , Células CACO-2 , Línea Celular , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Citocinas/metabolismo , Regulación hacia Abajo , Chaperón BiP del Retículo Endoplásmico , Humanos , Masculino , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Ácido TrinitrobencenosulfónicoRESUMEN
Intestinal anti-inflammatory activities of exopolysaccharide from S. commune were assessed using dextran sulfate sodium (DSS)-induced colitis in mice model. The changes of molecular weight (MW), atomic force microscope morphology, X-ray diffraction, particle size distribution, and viscosity were recorded after sonication treatment. The results indicated that the triple helical structure of exopolysaccharide was dissociated into single helical structure and random coiled structure by ultrasonication via breaking of inter- and intramolecular hydrogen bonds. The medium (936kDa) and high MW (1437kDa) exopolysaccharide had the mixture of triple helix and single helix conformation, while the low MW (197kDa) exopolysaccharide exhibit random coiled conformation. The intestinal anti-inflammatory activity study showed that oral administration of medium and high MW (1437kDa) exopolysaccharide significantly recovered DSS-induced colitis in inflamed tissues and reduced inflammation induced infiltration of macrophages. These results showed that medium (936kDa) and high MW (1437kDa) exopolysaccharide had intestinal anti-inflammatory activity. The intestinal anti-inflammatory activity of exopolysaccharide was related to helical structure and molecular weight.
Asunto(s)
Antiinflamatorios/química , Colitis/tratamiento farmacológico , Intestinos/efectos de los fármacos , Polisacáridos/química , Schizophyllum/química , Animales , Colitis/inducido químicamente , Sulfato de Dextran , Masculino , Ratones , Ratones Endogámicos BALB C , Peso MolecularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditional medicine in treatment of many gastrointestinal disorders. AIM OF THE STUDY: This study aimed to evaluate potential protecting effect of ML and its major constituent, eucalyptol, against acetic acid-induced colitis in rats, a model of human inflammatory bowel disease (IBD). MATERIALS AND METHODS: Rats were divided into ten groups (n=8) given orally for three days (mg/kg/day) the following: normal control, acetic acid-induced colitis (un-treated, positive control), vehicle (DMSO), sulfasalazine (500), ML extract (100, 500, 1000), and eucalyptol (100, 200, 400). After 24h-fasting, two ML of acetic acid (3%) was administered intrarectally. On the fifth day, serum and colonic biochemical markers, and histopathological changes were evaluated. RESULTS: Colitis significantly increased colonic myeloperoxidase activity and malonaldehyde level, and serum tumor necrosis factor-α, interleukin-6, and malonaldehyde levels while significantly decreased colonic and serum glutathione levels. All treatments (except ML 100, ML 1000, and eucalyptol 100) significantly reversed these changes where eucalyptol (400) showed the highest activity in a dose-dependent manner. The colitis-induced histopathological changes were mild in sulfasalazine and eucalyptol 400 groups, moderate in ML 500 and eucalyptol 200 groups, and severe in ML 100, ML 1000, and eucalyptol 100 groups nearly similar to colitis-untreated rats. CONCLUSION: ML (in moderate doses) and eucalyptol (dose-dependently) exerted protective effects against acetic acid-induced colitis in rats possibly through antioxidant and antiinflammatory properties suggesting a potential benefit in treatments of IBD. To our knowledge this is the first report addressing this point.
Asunto(s)
Ácido Acético , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Colitis/prevención & control , Colon/efectos de los fármacos , Ciclohexanoles/farmacología , Fármacos Gastrointestinales/farmacología , Mentha/química , Monoterpenos/farmacología , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Biomarcadores/sangre , Colitis/sangre , Colitis/inducido químicamente , Colitis/patología , Colon/metabolismo , Colon/patología , Ciclohexanoles/aislamiento & purificación , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eucaliptol , Fármacos Gastrointestinales/aislamiento & purificación , Glutatión/sangre , Interleucina-6/sangre , Masculino , Malondialdehído/sangre , Monoterpenos/aislamiento & purificación , Peroxidasa/metabolismo , Fitoterapia , Componentes Aéreos de las Plantas/química , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Ratas Sprague-Dawley , Sulfasalazina/farmacología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Nerol is a natural monoterpene with antinociceptive and anti-inflammatory properties. Its possible beneficial effects in ulcerative colitis and its corresponding mechanism of action have not been determined to date. The aim of this study was to investigate whether nerol prevents the appearance of pathological markers and hyperalgesia in oxazolone-induced colitis, and protects against gastric damage produced by ethanol. The experimental design included groups of oxazolone-treated mice receiving nerol at 10-300 mg/kg, p.o., or a reference drug (sulfasalazine, 100 mg/kg, p.o.) compared to sham and untreated groups. Gastric damage was evaluated in the absolute ethanol-induced ulcer model in rats. Variables measured in animals with oxazolone-induced colitis included weight loss, stool consistency and macroscopic colon damage; mechanical nociception was determined by the use of von Frey filaments, whereas levels of inflammatory cytokines were assessed by enzyme-linked immunosorbent assay. Nerol (30-300 mg/kg, p.o.) prevented or significantly decreased the pathological alterations observed in the oxazolone- induced colitis model. It also showed antinociceptive effects and reduced the increased levels of inflammatory cytokines (IL-13 and TNF-α). Gastric damage was also prevented starting at 10 mg/kg, p.o. In conclusion, our results provide evidence for a beneficial effect of nerol after colitis induction involving tissue protection, antinociception and modulation of the immunological system, suggesting the therapeutic potential of this monoterpene as a novel alternative in controlling ulcerative colitis.
Asunto(s)
Analgésicos/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Oxazolona/efectos adversos , Analgésicos/uso terapéutico , Animales , Biomarcadores/metabolismo , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Citocinas/metabolismo , Citoprotección/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , RatasRESUMEN
AIMS: Geraniol, a natural component of plant essential oils, exhibits potent chemopreventive effects in the colon; however, its possible role/mechanisms in experimental colitis have not been elucidated, which is the aim of this study. MAIN METHODS: To fulfill this goal, rats were treated for 11days with geraniol and/or sulfasalazine using a TNBS-induced colitis model. KEY FINDINGS: Geraniol significantly hindered the colitis-clinical signs (weight loss, colon edema,ulcerative area, colon/spleen mass indices) and opposed the altered oxidative/nitrosative stress. It restored the depleted total antioxidant capacity and lessened the elevated levels of nitric oxide and lipid peroxide. TNBS induced apoptosis and inflammatory cell infiltration, whereas geraniol curtailed these effects by diminishing the levels of caspase-3, intercellular adhesion molecule-1, and myeloperoxidase. The anti-inflammatory effect was documented by inhibiting the colon contents of prostaglandin E2 and interleukin-1ß. In order to delve into the anti-colitic signaling pathways, geraniol inhibited the content/expression of glycogen synthase kinase (GSK)-3ß, ß-catenin, p38 mitogen activated protein kinase (p38MAPK), and nuclear factor kappa B (NFκB), but upregulated that of peroxisome proliferator activated receptor γ (PPARγ). These effects were comparable to those of sulfasalazine, the standard drug, whereas its combination with geraniol mediated effects that surpassed either treatment alone. SIGNIFICANCE: Geraniol in the current study improved experimental colitis partly via its antioxidant, anti-inflammatory, and immunosuppressive potentials, possibly by modulating the Wnt/GSK-3ß/ß-catenin, p38MAPK, NFκB, and PPARγ signaling pathways. The study also revealed that geraniol represents a valuable asset against colitis alone or in combination with the conventional anti-colitic therapies.