RESUMO
Neonatal immune activation (NIA) through exposure to lipopolysaccharide (LPS) induces adult behavioral changes in rodents that resemble symptoms of developmental disorders, such as autism spectrum disorder. The neonatal timing of LPS exposure appears to play a crucial role in determining the nature and extent of long-term changes. This study aims to explore whether a 3-day LPS-NIA triggers sex- and age-related changes in gut function, potentially linking LPS-NIA to gastrointestinal dysfunction. Male and female Swiss mice received intraperitoneal injections of LPS or saline on postnatal days (PN) 3, 5, and 7. At PN35 (juvenile) and PN70 (adult), gut inflammation and oxidative stress were evaluated in addition to assessments of working memory, depressive-like symptoms, sociability, and repetitive behavior. Gut examination showed elevated C-X-C motif chemokine receptor 3 (CXCR3) in LPS-NIA mice, while MyD88 and Zonulin expressions were significantly higher only in adult LPS-NIA females. Interleukin (IL)-23 expression increased in juvenile and adult male and juvenile female LPS-NIA mice. Oxidative changes included decreased duodenal reduced glutathione (GSH) in juvenile females and ileal GSH in adult females exposed to LPS-NIA. Regarding behavioral alterations, adult LPS-NIA females exhibited depressive-like behavior. Working memory deficits were observed across all LPS-NIA groups. Only juvenile LPS-NIA females increased grooming, while rearing was higher in adult LPS-NIA mice of both sexes. The findings imply that LPS-NIA impacts intestinal barrier function and causes gut inflammatory alterations that are sex- and age-specific. These findings pave the way for exploring potential mechanisms that could contribute to LPS-induced gastrointestinal disturbances among individuals with ASD.
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Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1ß; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.
Assuntos
Euterpe , Fluoruracila , Mucosite , Fator 88 de Diferenciação Mieloide , Extratos Vegetais , Polifenóis , Sementes , Transdução de Sinais , Serina-Treonina Quinases TOR , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Mucosite/prevenção & controle , Mucosite/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sementes/química , Polifenóis/farmacologia , Masculino , Euterpe/química , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fator de Transcrição RelA/metabolismo , Antioxidantes/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismoRESUMO
Plant polysaccharides have biological activities in the brain and those obtained from Genipa americana leaves present antioxidant and anticonvulsant effects in the mice model of pentylenetetrazole (PTZ)-induced acute seizures. This study aimed to evaluate the polysaccharide-rich extract of Genipa americana leaves (PRE-Ga) in the models of acute seizures and chronic epilepsy (kindling) induced by PTZ. In the acute seizure model, male Swiss mice (25-35 g) received PRE-Ga (1 or 9 mg/kg; intraperitoneal- IP), alone or associated with diazepam (0.01 mg/kg), 30 min before induction of seizures with PTZ (70 mg/kg; IP). In the chronic epilepsy model, seizures were induced by PTZ (40 mg/kg) 30 min after treatment and in alternated days up to 30 days and evaluated by video. Brain areas (prefrontal cortex, hippocampus, striatum) were assessed for inflammatory and oxidative stress markers. Diazepam associated to PRE-Ga (9 mg/kg; i.p.) increased the latency of seizures in acute (222.4 ± 47.57 vs. saline: 62.00 ± 4.709 s) and chronic models (6.267 ± 0.502 vs. saline: 4.067 ± 0.407 s). In hippocampus, PRE-Ga (9 mg/kg) inhibited TNF-α (105.9 ± 5.38 vs. PTZ: 133.5 ± 7.62 pmol/g) and malondialdehyde (MDA) (473.6 ± 60.51) in the chronic model. PTZ increased glial fibrillar acid proteins (GFAP) and Iba-1 in hippocampus, which was reversed by PRE-Ga (GFAP: 1.9 ± 0.23 vs PTZ: 3.1 ± 1.3 and Iba-1: 2.2 ± 0.8 vs PTZ: 3.2 ± 1.4). PRE-Ga presents neuroprotector effect in the mice model of epilepsy induced by pentylenetetrazole reducing seizures, gliosis, inflammatory cytokines and oxidative stress.
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Epilepsia , Pentilenotetrazol , Animais , Camundongos , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/prevenção & controle , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Estresse Oxidativo , Diazepam/farmacologia , Diazepam/uso terapêutico , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
OBJECTIVE: This study aimed to evaluate the in vivo protective effect of the angico gum biopolymer in reducing the inflammatory response and preserving the integrity of the laryngeal and esophageal mucosa. STUDY DESIGN: Animal study. METHODS: A murine surgical model of gastroesophageal reflux disease was accomplished and subsequently treated with angico gum or omeprazole. On days 3 and 7 post surgery, samples of the larynx and esophagus, respectively, were collected to measure the level of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and mucosal permeability to fluorescein). RESULTS: Angico gum and omeprazole decreased laryngeal inflammation (wet weight and myeloperoxidase activity) and dramatically improved the integrity of the laryngeal mucosa. It also reduced inflammation (decreased wet weight and myeloperoxidase activity) of the esophagus and preserved the barrier function (inferred by assessing the integrity of the mucosa). CONCLUSION: This study demonstrates the protective effect of angico gum in an experimental gastroesophageal reflux disease model. Angico gum attenuates inflammation and impairment of the mucosal barrier function not only in the larynx but also in the esophagus. LEVEL OF EVIDENCE: NA Laryngoscope, 133:162-168, 2023.
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Mucosa Esofágica , Refluxo Gastroesofágico , Camundongos , Animais , Refluxo Gastroesofágico/tratamento farmacológico , Impedância Elétrica , Mucosa , Modelos Animais de DoençasRESUMO
Lectins isolated from Canavalia ensiformis (ConA) and Canavalia brasiliensis (ConBr) are promising molecules to prevent cell death. Acute pancreatitis, characterized by acinar cell necrosis and inflammation, presents significant morbidity and mortality. This study has investigated the effects of ConA and ConBr in experimental acute pancreatitis and pancreatic acinar cell death induced by bile acid. Pancreatitis was induced by retrograde pancreatic ductal injection of 3% sodium taurocholate (Na-TC) in male Swiss mice. ConA or ConBr (0.1, 1 or 10 mg/kg) were intravenously applied to mice 1 h and 12 h after induction. After 24 h, the severity of pancreatitis was evaluated by serum amylase and lipase, histopathological changes and myeloperoxidase assay. Pancreatic acinar cells were incubated with ConA (200 µg/ml) or ConBr (200 µg/ml) and taurolithocholic acid 3-sulfate (TLCS; 500 µM). Necrosis and changes in mitochondrial membrane potential (ΔÑ°m) were detected by fluorescence confocal microscopy. Treatment (post-insult) with ConA and ConBr decreased pancreatic damage caused by retrograde injection of Na-TC in mice, reducing pancreatic neutrophil infiltration, edema and necrosis. In addition, ConA and ConBr decreased pancreatic acinar cell necrosis and depolarization of ΔÑ°m caused by TLCS. The inhibition of necrosis was prevented by the lectin domain blockade. In conclusion, ConA and ConBr markedly inhibited in vitro and in vivo damage, effects partly dependent on the interaction with mannose residues on acinar cells. These data support the potential application of these proteins for treatment of acute pancreatitis.
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Canavalia , Pancreatite , Doença Aguda , Animais , Anti-Inflamatórios , Canavalia/química , Lectinas/farmacologia , Masculino , Camundongos , Necrose/tratamento farmacológico , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Lectinas de Plantas/química , Sementes/químicaRESUMO
Significance: Carbon monoxide (CO) is an endogenous gaseous mediator that plays an important role in maintaining gastrointestinal (GI) tract homeostasis, acting in mucosal defense, and providing negative modulation of pathophysiological markers of clinical conditions. Recent Advances: Preclinical studies using animal models and/or cell culture show that CO can modulate the inflammatory response and oxidative stress in GI mucosal injuries and pathological conditions, reducing proinflammatory cytokines and reactive oxygen species, while increasing antioxidant defense mechanisms. Critical Issues: CO has potent anti-inflammatory and antioxidant effects. The defense mechanisms of the GI tract are subject to aggression by different chemical agents (e.g., drugs and ethanol) as well as complex and multifactorial diseases, with inflammation and oxidative stress as strong triggers for the deleterious effects. Thus, it is possible that CO acts on a variety of molecules involved in the inflammatory and oxidative signaling cascades, as well as reinforcing several defense mechanisms that maintain GI homeostasis. Future Directions: CO-based therapies are promising tools for the treatment of GI disorders, such as gastric and intestinal injuries, inflammatory bowel disease, and pancreatitis. Therefore, it is necessary to develop safe and selective CO-releasing agents and/or donor drugs to facilitate effective treatments and methods for analysis of CO levels that are simple and inexpensive. Antioxid. Redox Signal. 37, 98-114.
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Gasotransmissores , Gastroenteropatias , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Monóxido de Carbono/farmacologia , Gastroenteropatias/tratamento farmacológico , Estresse OxidativoRESUMO
AIM: The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. MATERIAL AND METHODS: After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-ß) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. RESULTS: Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. CONCLUSION: The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.
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Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia , Colite Ulcerativa/tratamento farmacológico , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/metabolismo , Animais , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/metabolismo , Colo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Glutationa/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Agonistas Muscarínicos/farmacologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor Muscarínico M1 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Euterpe oleracea Mart., commonly known as açaí, has been demonstrated to exhibit significantly antioxidant and inflammatory activities in experimental models. These effects of the hydroalcoholic extract from the açaí seed (ASE) were investigated in TNBS-induced (2,4,6-trinitrobenzenesulfonic acid) acute colitis model in rats. Wistar rats (180-220 g) were orally pretreated with saline (0.3 mL), ASE (10, 30 and 100 mg/kg) and dexamethasone (control group, 1 mg/kg) once daily for 3 days starting before TNBS instillation. On day 3 after TNBS, the animals were euthanized, the portion of distal colon was collected and washed with 0.9% saline for macroscopy and histological evaluation, glutathione (GSH) and malonyldialdehyde (MDA) levels, myeloperoxidase (MPO) and catalase (CAT) activity, nitrate and nitrite (NO3/NO2) concentration, pro-inflammatory cytokines levels and intestinal barrier integrity. We also evaluated Toll-like Receptor 4/cyclooxygenase-2/nuclear factor kappa B expression as a possible mechanism related to the ASE effects. Treatment with ASE 100 mg/kg decreased significantly macroscopic and microscopic damage induced by TNBS. In addition, MPO activity, TNF-α (tumor necrosis factor-alpha) and IL-1ß (interleukin 1) levels were reduced in rats with colitis. ASE 100 mg/kg restored GSH and MDA levels, CAT activity, NO3/NO2 concentration and improved the intestinal barrier integrity in the TNBS group. ASE 100 mg/kg significantly reduced TNBS-induced expression of the TLR4, COX-2 and NF-κB p65. ASE 100 mg/kg improved macroscopy and histological parameters, inflammation, intestinal barrier integrity and nitric and oxidative stress through the TLR-4/COX-2/NF-κB pathway.
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Colite/tratamento farmacológico , Euterpe/química , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Colite/fisiopatologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inflamação/fisiopatologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Receptor 4 Toll-Like/metabolismo , Ácido TrinitrobenzenossulfônicoRESUMO
Polysaccharide from marine alga Gracilaria caudata has potential health benefits, such as anti-inflammatory, gastroprotective and antidiarrheal effects. Here, we investigated the effect of a sulfated polysaccharide from G. caudata (SP-GC) on hypernociception and inflammatory response in arthritis models. The animals received SP-GC (3, 10 or 30 mg/kg) 1 h before tibio-tarsal injection of zymosan. Hypernociception, histopathology, edema, vascular permeability, myeloperoxidase (MPO) activity, cell influx, interleukin (IL)-1ß and nitric oxide (NO) levels were evaluated in acute phase. In another protocol, animals received SP-GC (30 mg/kg) 2 h post-complete Freund's adjuvant (CFA). Hypernociception, edema and arthritis index were determined in acute, sub-chronic and chronic phases. Rota-rod test measured the motor performance. SP-GC significantly reduced, in a dose-dependent manner, the zymosan-induced hypernociception with maximal effect at 30 mg/kg. The microscopic inflammation, joint edema, MPO activity, cell influx, IL-1ß and NO levels were also reduced by SP-GC. In the CFA-induced arthritis, SP-GC inhibits the hypernociception, edema and arthritic index in acute, sub-chronic and chronic phases. SP-GC did not alter the motor performance of animals. In conclusion, SP-GC exerts protective effect in models of arthritis due to the modulation of cell influx, IL-1ß and NO levels, culminating in the reduction of hypernociception and edema.
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Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Gracilaria/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Sulfatos/química , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Artrite Experimental/patologia , Biomarcadores , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/etiologia , Adjuvante de Freund , Imuno-Histoquímica , Masculino , Camundongos , Roedores , Zimosan/efeitos adversosRESUMO
Gabapentin is an anticonvulsant drug that is also used for post-herpetic neuralgia and neuropathic pain. Recently, gabapentin showed anti-inflammatory effect. Nuclear factor kappa B (NFκB) is a regulator of the inflammatory process, and Peroxisome Proliferator-activated Receptor gamma (PPAR-gamma) is an important receptor involved in NFκB regulation. The aim of the present work was to study the potential role of PPAR-gamma receptor in gabapentin-mediated anti-inflammatory effects in a colitis experimental model. We induced colitis in rats using trinitrobenzenosulfonic acid and treated them with gabapentin and bisphenol A dicyldidyl ether (PPAR-gamma inhibitor). Macroscopic lesion scores, wet weight, histopathological analysis, mast cell count, myeloperoxidase, malondialdehyde acid, glutathione, nitrate/nitrite, and interleukin levels in the intestinal mucosa were determined. In addition, western blots were performed to determine the expression of Cyclooxygenase-2 (COX-2) and NFκB; Nitric Oxide Inducible Synthase (iNOS) and Interleukin 1 beta (IL-1ß) levels were also determined. Gabapentin was able to decrease all inflammatory parameters macroscopic and microscopic in addition to reducing markers of oxidative stress and cytokines such as IL-1ß and Tumor Necrosis Factor alpha (TNF-α) as well as enzymes inducible nitric oxide synthase and cyclooxygenase 2 and inflammatory genic regulator (NFκB). These effect attributed to gabapentin was observed to be lost in the presence of the specific inhibitor of PPAR-gamma. Gabapentin inhibits bowel inflammation by regulating mast cell signaling. Furthermore, it activates the PPAR-gamma receptor, which in turn inhibits the activation of NFκB, and consequently results in reduced activation of inflammatory genes involved in inflammatory bowel diseases.
Assuntos
Colite/tratamento farmacológico , Gabapentina/uso terapêutico , PPAR gama/efeitos dos fármacos , Animais , Compostos Benzidrílicos/uso terapêutico , Colite/induzido quimicamente , Colite/patologia , Citocinas/metabolismo , Glutationa/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Malondialdeído/metabolismo , Mastócitos/efeitos dos fármacos , NF-kappa B/metabolismo , PPAR gama/antagonistas & inibidores , Peroxidase/metabolismo , Fenóis/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Ácido TrinitrobenzenossulfônicoRESUMO
This study aimed to evaluate the in vitro protective effect of topical treatment with a native sulfated polysaccharide of G. caudata (SP-Gc), hydrolyzed (H-SP-Gc), or desulfated (D-SP-Gc) polysaccharide of Gracilaria caudata in esophageal biopsies obtained from GERD patients. Biopsies were obtained from nonerosive reflux disease (NERD) patients and from erosive esophagitis patients. Then, the biopsies were mounted in an Ussing chamber to measure the basal transepithelial electrical resistance (TEER). The effect of mucosal exposure to an acid solution on TEER was analyzed with or without different concentrations (1, 0.3 or 1%) of SP-Gc, H-SP-Gc, or D-SP-Gc, precoated on the mucosa. Basal esophageal mucosal electrical resistance was significantly lower in erosive esophagitis than from NERD. Mucosal samples precoated with native SP-Gc (1%) significantly prevented TEER drop induced by an acidic solution in NERD, but this effect was not observed in erosive esophagitis. Topical application of D-SP-Gc showed no difference compared to native SP-Gc. However, when treated with chemically-modified SP-Gc, the protective effect observed with native SP-Gc was lost. The present study indicated that SP-Gc protects the human esophageal mucosal barrier in NERD patients. This effect is dependent on the structure but is independent of the presence of sulfate.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Gracilaria/química , Mucosa/efeitos dos fármacos , Polissacarídeos/química , Polissacarídeos/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Adulto , Idoso , Biópsia , Esôfago , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/metabolismo , Refluxo Gastroesofágico/patologia , Humanos , Hidrólise , Masculino , Pessoa de Meia-Idade , Análise Espectral , Adulto JovemRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: There are many reports of pharmacological activities of extracts and fractions of different vegetable-derived products in the scientific literature and in folk medicine. Ethnopharmacological use of these products by various communities continues to be extensively explored, and they account for more than half of all medications used worldwide. Polysaccharides (PLS) extracted from plants such as Morinda Citrifolia Linn present therapeutic potential in treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). AIM OF THE STUDY: To evaluate the anti-inflammatory action of Noni-PLS against the intestinal damage in UC induced by acetic acid in mice. MATERIALS AND METHODS: In acetic acid-induced colitis, the mice were treated intraperitoneally (ip) with Noni-PLS (0.1, 0.3, and 3.0â¯mg/kg) or subcutaneously (sc) with dexamethasone (2.0â¯mg/kg) 30â¯min before euthanasia to determine the best dose of Noni-PLS with an anti-inflammatory effect in the course of UC. The colonic tissue samples were collected for macroscopic, wet weight, microscopic and biochemical (myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), nitrate/nitrite (NO3/NO2), cytokines, cyclooxygenase (COX-2) and inducible nitric oxide (iNOS)) analyses. RESULTS: Treatment with Noni-PLS reduced the intestinal damage induced by acetic acid as it reduced macroscopic and microscopic scores and the wet weight of the colon. In addition, MPO activity and levels of GSH, MDA, NO3/NO2, pro-inflammatory cytokines, and COX-2 expression reduced. CONCLUSIONS: This study suggests that Noni-PLS exhibits anti-inflammatory action against intestinal damage by reducing inflammatory cell infiltration, oxidative stress, pro-inflammatory action of cytokines, COX-2 and iNOS expression in the inflamed colon. Noni-PLS shows therapeutic potential against inflammatory disorders like UC.
Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Morinda , Polissacarídeos/uso terapêutico , Ácido Acético , Animais , Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Frutas , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Peroxidase/metabolismo , Polissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The gastroprotective effects of N-acylarylhydrazone derivatives on ethanol-induced gastric lesions in mice were investigated with respect to the NO/cGMP/KATP pathway. To investigate our hypothesis, the mice were intraperitoneally pretreated with glibenclamide, L-NAME, or ODQ 30â¯min before treatment with DMSO, LASSBio-294 (1, 2, and 4â¯mg/kg, p.o.), LASSBio-897 (0.5, 1, and 2â¯mg/kg, p.o.), or omeprazole. After 1â¯h, the mice received absolute ethanol (4â¯ml/kg) by gavage to induce gastric mucosal lesions, and the microscopic and macroscopic parameters were evaluated. GSH (non-protein sulfhydryl groups) and MDA (malondialdehyde) concentrations, hemoglobin levels, nitric oxide production, myeloperoxidase (MPO) activity, and TNF-α and IL-1ß levels were also analyzed in the stomach after absolute ethanol administration. Pretreatment with LASSBio-294 or LASSBio-897 significantly reduced the microscopic and macroscopic lesion area. The compounds restored the GSH, MDA, and hemoglobin levels and reduced MPO activity. Moreover, the compounds significantly reduced nitrate and nitrite concentrations in the stomach samples after ethanol administration. Molecular docking studies revealed that LASSBio-294 and LASSBio-897 interact with active sites of the eNOS (endothelial nitric oxide synthase) enzymes through hydrogen bonds. LASSBio-294 and LASSBio-897 also reduced TNF-α and IL-1ß levels. It was observed that a NO synthase inhibitor, an ATP-sensitive potassium channel blocker, and a guanylate cyclase inhibitor significantly reversed the gastroprotective effects of these compounds. Thus, the gastroprotective effect of LASSBio-294 and LASSBio-897 against gastric lesions is mediated through the NO/cGMP cascade, followed by blocking of the KATP channels.
Assuntos
GMP Cíclico/fisiologia , Mucosa Gástrica/efeitos dos fármacos , Hidrazonas/farmacologia , Canais KATP/fisiologia , Óxido Nítrico/fisiologia , Tiofenos/farmacologia , Animais , Etanol/toxicidade , Mucosa Gástrica/patologia , Glutationa/metabolismo , Canais KATP/antagonistas & inibidores , Masculino , Camundongos , Simulação de Acoplamento Molecular , Peroxidase/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Galactomannans are neutral polysaccharides isolated from the endosperm of some Leguminosae seeds. They consist of a (1â¯ââ¯4) linked ß-mannopyranosyl backbone partially substituted at O-6 with α-d-galactopyranosyl side groups. C. pulcherrima have anti-inflammatory and muco-adhesive proprieties. Acute gastritis is an inflammatory disease triggered by use of non-steroidal anti-inflammatory drugs. We investigated the gastroprotective effect of galactomannan obtained from the seeds of Caesalpinia pulcherrima L. (GM-CP) in acute gastritis model induced by indomethacin. Gastritis was induced with indomethacin (30â¯mg/kg, P.·O.) in female Swiss mice. Animal groups (nâ¯=â¯7) were pretreated with saline-dissolved GM-CP (3â¯mg/kg, 10â¯mg/kg, 30â¯mg/kg, P.O.) or vehicle 1â¯h before gastritis induction. Mice were euthanized seven hours after the induction. The stomach and blood samples were collected for analysis. At 10â¯mg/kg, GP-CP reduced the extension of macroscopic lesion and the loss of superficial cells by alleviating inflammatory symptoms (neutrophil infiltration, migration and adhesion of mesenteric leukocytes, production of TNF-α and thiobarbituric acid reactive species (TBARS) and helping to maintain mucin labeling of the tissue. Thus, the findings of the study suggest that GM-CP exhibits gastroprotective effects.
Assuntos
Caesalpinia/química , Gastrite , Indometacina/efeitos adversos , Mananas/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Sementes/química , Doença Aguda , Animais , Feminino , Galactose/análogos & derivados , Gastrite/induzido quimicamente , Gastrite/metabolismo , Gastrite/patologia , Gastrite/prevenção & controle , Indometacina/farmacologia , Mananas/química , Camundongos , Neutrófilos/patologiaRESUMO
BACKGROUND: This study aimed to investigate and characterize the anti-inflammatory and anti-hypernociceptive effects of the total polysaccharides of X. americana (TPL-Xa) bark in a mouse model of acute pancreatitis-induced by caerulein and the potential involvement of cannabinoid receptors. METHODS: TPL-Xa was characterized by1H and 13C NMR spectroscopy. Animals received TPL-Xa (10 mg/kg, i.v.) 30 min before and after caerulein (50 µg/kg, 10×, i.p.) administration. To evaluate the involvement of cannabinoid receptors, AM281 (3 mg/kg, s.c.) and AM630 (1 mg/kg, s.c.) were administered 30 min before TPL-Xa. Plasma levels of amylase and lipase, pancreatic myeloperoxidase (MPO), histology, visceral hypernociception and motor coordination were evaluated 11 and 24 h after acute pancreatitis (AP) induction. RESULTS: TPL-Xa, containing a heteropolysaccharide composed of glucose, galactose, arabinose, rhamnose, fucose and galacturonic acid, reduced amylase and lipase levels, MPO activity, acinar cell necrosis, edema and neutrophil infiltration. TPL-Xa increased the threshold of visceral hypernociception, an effect reversed by AM630, an antagonist of cannabinoid receptor type 2 (CB2). In addition, TPL-Xa did not alter the animals' motor coordination. CONCLUSIONS: TPL-Xa contains heteropolysaccharides that inhibit inflammation and hypernociception in the experimental model of caerulein-induced AP, by a mechanism involving type CB2 receptors.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Ceruletídeo , Dor Nociceptiva/prevenção & controle , Olacaceae , Pâncreas/efeitos dos fármacos , Pancreatite/prevenção & controle , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Receptor CB2 de Canabinoide/agonistas , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Agonistas de Receptores de Canabinoides/isolamento & purificação , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Modelos Animais de Doenças , Enzimas/sangue , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/metabolismo , Olacaceae/química , Limiar da Dor/efeitos dos fármacos , Pâncreas/enzimologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Polissacarídeos/isolamento & purificação , Espectroscopia de Prótons por Ressonância Magnética , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Barks of Ximenia americana are used by the population to treat gastrointestinal inflammatory disorders. Indomethacin is a non-selective non-steroidal anti-inflammatory drug that induces marked gastrointestinal damage. AIMS OF THE STUDIES: To evaluate the gastroprotective activity of total polysaccharides contained in the extract (TPL-Xa) or tea (Tea-Xa) of Ximenia americana barks in the mice gastric damage induced by indomethacin. MATERIALS AND METHODS: TPL-Xa was obtained by a combination of NaOH extraction and ethanol precipitation. Tea-Xa was prepared in distilled water boiled during 5â¯min. Animals received p.o. 0.9% NaCl (saline - control group), TPL-Xa (1-90â¯mg/kg) or Tea-Xa 1â¯h before gastritis induction by indomethacin (20â¯mg/kg). Mice were sacrificed 7â¯h after gastritis induction and analyzed for the following parameters: stomach lesions measurement; histological evaluation; myeloperoxidase (MPO) activity; nitrate/nitrite and cytokine levels; leukocyte adhesion and rolling by intravital microscopy. RESULTS: TPL-Xa reduced macroscopic and microscopic damage, MPO activity (59%), leukocyte rolling (86%) and adhesion (84%), nitrite/nitrate ratio (100%) and IL-8 (69%), but increased IL-4 (50%). Tea-Xa (12.8 yield; 39.3% carbohydrate, including 25.8% uronic acid; 4% protein) reduced macroscopic damage (62%) and MPO activity (50%). CONCLUSION: TPL and Tea of Ximenia americana barks ameliorate the gastric injury induced by indomethacin in mice, an effect that was dependent on the reduction of neutrophil infiltration.
Assuntos
Bebidas , Gastrite/tratamento farmacológico , Olacaceae , Extratos Vegetais , Polissacarídeos , Substâncias Protetoras , Animais , Anti-Inflamatórios não Esteroides , Adesão Celular/efeitos dos fármacos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Gastrite/imunologia , Gastrite/metabolismo , Indometacina , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Nitratos/metabolismo , Nitritos/metabolismo , Peroxidase/metabolismo , Fitoterapia , Casca de Planta , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêuticoRESUMO
AIM: The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H2S) donors and possible interactions between these two systems in modulating gastric function. METHODS: Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1 h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson's reagent (H2S donor), PAG + SNP, L-NAME, L-NAME + NaHS, or L-NAME + Lawesson's reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated. RESULTS: SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson's reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and L-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and L-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and L-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or L-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus. CONCLUSION: NO and H2S interact in gastric physiological functions, and this "cross-talk" is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.
Assuntos
Cistationina gama-Liase/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Nitroprussiato/farmacologia , Estômago/efeitos dos fármacos , Sulfetos/farmacologia , Alcinos/farmacologia , Animais , Depressores do Sistema Nervoso Central/farmacologia , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Etanol/farmacologia , Imunofluorescência , Ácido Gástrico/metabolismo , Fundo Gástrico/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Fluxometria por Laser-Doppler , Masculino , Malondialdeído/metabolismo , Camundongos , Muco/efeitos dos fármacos , Muco/metabolismo , Contração Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Piloro/efeitos dos fármacos , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional , Estômago/irrigação sanguíneaRESUMO
BACKGROUND/AIMS: Cisplatin is a chemotherapeutic agent. The use of remote ischemic preconditioning (RIPC) was proposed after the observation that ischemic preconditioning of a cardiac vascular area could protect another completely distinctly. METHODS: This is an experimental study. Male Wistar rats were anesthetized, and they underwent a hearing evaluation via measurement of the brainstem auditory evoked potential (BSAEP). Then, cisplatin was administered intraperitoneally (IP) at a dose of 8 mg/kg/day for 4 consecutive days to group 1, whereas saline solution was administered IP to group 2. In groups 3 and 4, ischemia of the right hind paw was performed for 10 min, followed by reperfusion for 30 min, after which cisplatin or saline was administered IP to group 3 or group 4, respectively. Afterwards, all animals were evaluated via the BSAEP. The right cochlea was dissected for immunohistochemistry. RESULTS: RIPC lowered the increase in BSAEP of the animals treated with cisplatin (p = 0.0146). Weight loss decreased in the animals subjected to RIPC (p < 0.005). In group 3, RIPC reversed immunostaining for tumor necrosis factor-α and inducible nitric oxide synthase in the stria vascularis injured by cisplatin (p < 0.05). CONCLUSION: RIPC protects against systemic toxicity and ototoxicity induced by cisplatin in rats.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Precondicionamento Isquêmico/métodos , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Cóclea/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Audição/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos WistarRESUMO
OBJECTIVE:: To evaluate the effects of passive inhalation of cigarette smoke on the respiratory system of guinea pigs. METHODS:: Male guinea pigs were divided into two groups: control and passive smoking, the latter being exposed to the smoke of ten cigarettes for 20 min in the morning, afternoon and evening (30 cigarettes/day) for five days. After that period, inflammatory parameters were studied by quantifying mesenteric mast cell degranulation, as well as oxidative stress, in BAL fluid. In addition, we determined MIP, MEP, and mucociliary transport (in vivo), as well as tracheal contractility response (in vitro). RESULTS:: In comparison with the control group, the passive smoking group showed a significant increase in mast cell degranulation (19.75 ± 3.77% vs. 42.53 ± 0.42%; p < 0.001) and in the levels of reduced glutathione (293.9 ± 19.21 vs. 723.7 ± 67.43 nM/g of tissue; p < 0.05); as well as a significant reduction in mucociliary clearance (p < 0.05), which caused significant changes in pulmonary function (in MIP and MEP; p < 0.05 for both) and airway hyperreactivity. CONCLUSIONS:: Passive inhalation of cigarette smoke caused significant increases in mast cell degranulation and oxidative stress. This inflammatory process seems to influence the decrease in mucociliary transport and to cause changes in pulmonary function, leading to tracheal hyperreactivity. OBJETIVO:: Avaliar os efeitos da inalação passiva da fumaça de cigarro no sistema respiratório de cobaias. MÉTODOS:: Foram utilizadas cobaias machos, divididas em dois grupos: controle e tabagismo passivo, esse último exposto à fumaça de dez cigarros por 20 min pela manhã, tarde e noite (30 cigarros/dia) por 5 dias. Após esse período, parâmetros inflamatórios foram estudados através da contagem de degranulação de mastócitos no mesentério e de estresse oxidativo a partir do LBA. Adicionalmente, foram verificadas PImáx, PEmáx, transporte mucociliar (in vivo) e contratilidade traqueal (in vitro). RESULTADOS:: Na comparação com o grupo controle, o grupo tabagismo passivo apresentou um aumento significativo na degranulação de mastócitos (19,75 ± 3,77% vs. 42,53 ± 0,42%; p < 0,001), nos níveis de glutationa reduzida (293,9 ± 19,21 vs. 723,7 ± 67,43 nM/g de tecido; p < 0,05) e uma redução significativa no transporte mucociliar (p < 0,05), provocando alterações significativas na função pulmonar, tanto na PImáx como na PEmáx (p < 0,05 para ambas), e hiper-reatividade nas vias aéreas. CONCLUSÕES:: A inalação passiva da fumaça de cigarro ocasionou aumentos significativos na degranulação de mastócitos e no estresse oxidativo. Esse processo inflamatório parece ter influenciado a diminuição do transporte mucociliar e causado alterações na função pulmonar, proporcionando um quadro de hiper-reatividade traqueal.
Assuntos
Degranulação Celular , Inflamação/etiologia , Exposição por Inalação/efeitos adversos , Mastócitos/fisiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Estudos de Avaliação como Assunto , Cobaias , Estudos Longitudinais , Masculino , Modelos Animais , Depuração Mucociliar/fisiologia , Contração Muscular/fisiologia , Estresse Oxidativo/fisiologiaRESUMO
Mimosa tenuiflora (Mimosaceae) or "jurema-preta" is well distributed in the northeast Brazil, being popularly used to treat skin lesions, burns and inflammation. The healing effect of the alcoholic extract prepared with its barks corroborates the popular use. This study aimed to evaluate the inflammatory response of polysaccharides extracted from M. tenuiflora barks (EP-Mt) by methanol/NaOH and ethanol precipitation. Inflammatory activity was assessed in rat models of acute inflammation (paw edema and peritonitis), by the following parameters: edema, vascular permeability, leukocyte migration, myeloperoxidase activity and pharmacological modulation of nitric oxide and prostaglandins. EP-Mt presented 3.8% yield, 41% carbohydrate and 0.34% protein. EP-Mt (0.01, 0.1, 1.0 mg kg-1) injected by subcutaneous route elicited paw edema that lasted from 30-420 min, with maximal effect at 1 mg kg-1 (40x vs. saline), and was inhibited by L-NAME (52%) and dexamethasone (26%). EP-Mt (1 mg kg-1, via intraperitoneal) stimulated leukocytes migration (2.2x), mainly neutrophils (6.5x) and MPO activity (96%). The leukocyte migration elicited by EP-Mt was inhibited by dexamethasone (39%) and L-NAME (38%). EP-Mt containing high carbohydrate content induces acute inflammation via nitric oxide, which open perspectives of application in pathological conditions of immunosuppression.
Mimosa tenuiflora (Mimosaceae) ou "jurema-preta", amplamente distribuída no nordeste brasileiro, é utilizada popularmente no tratamento de lesões de pele, queimaduras e inflamação. O efeito cicatrizante do extrato alcoólico de suas cascas corrobora o uso popular. Avaliou-se o efeito inflamatório dos polissacarídeos da casca de M. tenuiflora (EP-Mt), obtidos por extração com metanol/NaOH e precipitação com etanol. O efeito inflamatório foi avaliado em modelos agudos em ratos (edema de pata, peritonite) por meio dos seguintes parâmetros: edema, permeabilidade vascular, migração leucocitária, atividade da mieloperoxidase e modulação farmacológica de prostaglandinas e óxido nítrico. EP-Mt apresentou 3,8% de rendimento, 41% de carboidratos totais e 0,34% de proteína. EP-Mt (0,01, 0,1, 1,0 mg kg -1), administrado por via subcutânea, induziu edema de pata com duração de 30 a 420 min e efeito máximo na dose de 1 mg kg-1 (40x vs. salina), o qual foi inibido por L-NAME (52%) e dexametasona (26%). EP-Mt (1 mg kg-1, via intraperitoneal) estimulou a migração de leucócitos (2,2x vs. salina), principalmente de neutrófilos (6,5x), com aumento da atividade da mieloperoxidase (96%). A migração de leucócitos foi inibida por dexametasona (39%) e L-NAME (38%). EP-Mt contendo elevado teor de carboidratos induz inflamação aguda via óxido nítrico com perspectivas de aplicação em condições patológicas de imunossupressão.