RESUMEN
Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.
Asunto(s)
Antiinflamatorios/administración & dosificación , Carragenina/efectos adversos , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inflamación/tratamiento farmacológico , Fenoles/efectos adversos , Ácido Vanílico/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Anticuerpos Monoclonales/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratones , Modelos Moleculares , Fenoles/síntesis química , Fenoles/química , Fenoles/farmacología , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Activation of 5' adenosine monophosphate-activated protein kinase (AMPK) stimulates production of the gaseous mediators nitric oxide (NO) and carbon monoxide (CO), which are involved in mucosal defense and gastroprotection. As AMPK itself has gastroprotective effects against several gastric ulcer etiologies, in the present study, we aimed to elucidate whether AMPK may also prevent ethanol-induced injury and play a key role in the associated gastroprotection mediated by hydrogen sulfide (H2S), NO, and CO. Mice were pretreated with AICAR (20â¯mg/kg, an AMPK activator) alone or with 50% ethanol. Other groups were pretreated with respective gaseous mediator inhibitors PAG, l-NAME, or ZnPP IX 30â¯min prior to AICAR, or with gaseous mediator donors NaHS, Lawesson's reagent and l-cysteine (H2S), SNP, l-Arginine (NO), Hemin, or CORM-2 (CO) 30â¯min prior to ethanol with or without compound C (10â¯mg/kg, a non-selective AMPK inhibitor). H2S, nitrate/nitrite (NO3-/NO2-), bilirubin levels, GSH and MDA concentration were evaluated in the gastric mucosa. The gastric mucosa was also collected for histopathological analysis and AMPK expression assessment by immunohistochemistry. Pretreatment with AICAR attenuated the ethanol-induced injury and increased H2S and bilirubin levels but not NO3-/NO2- levels in the gastric mucosa. In addition, inhibition of H2S, NO, or CO synthesis exacerbated the ethanol-induced gastric damage and inhibited the gastroprotection by AICAR. Pretreatment with compound C reversed the gastroprotective effect of NaHS, Lawesson's reagent, l-cysteine, SNP, l-Arginine, CORM-2, or Hemin. Compound C also reversed the effect of NaHS on H2S production, SNP on NO3-/NO2- levels, and Hemin on bilirubin levels. Immunohistochemistry revealed that AMPK is present at basal levels mainly in the gastric mucosa cells, and was increased by pretreatment with NaHS, SNP, and CORM-2. In conclusion, our findings indicate that AMPK activation exerts gastroprotection against ethanol-induced gastric damage and mutually interacts with H2S, NO, or CO to facilitate this process.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Monóxido de Carbono/metabolismo , Gasotransmisores/metabolismo , Sulfuro de Hidrógeno/metabolismo , Óxido Nítrico/metabolismo , Gastropatías/prevención & control , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Bilirrubina/metabolismo , Activación Enzimática , Activadores de Enzimas/farmacología , Etanol , Femenino , Mucosa Gástrica/patología , Masculino , Ratones , Ribonucleótidos/farmacología , Gastropatías/inducido químicamenteRESUMEN
Hydrogen sulphide (H2S) is a gasotransmitter that participates in various physiological and pathophysiological processes within the gastrointestinal tract. We studied the effects and possible mechanism of action of H2S in secretory diarrhoea caused by cholera toxin (CT). The possible mechanisms of action of H2S were investigated using an intestinal fluid secretion model in isolated intestinal loops on anaesthetized mice treated with CT. NaHS and Lawesson's reagent and l-cysteine showed antisecretory activity through reduction of intestinal fluid secretion and loss of Cl- induced by CT. Pretreatment with an inhibitor of cystathionine-γ-lyase (CSE), dl-propargylglycine (PAG), reversed the effect of l-cysteine and caused severe intestinal secretion. Co-treatment with PAG and a submaximal dose of CT increased intestinal fluid secretion, thus supporting the role of H2S in the pathophysiology of cholera. CT increased the expression of CSE and the production of H2S. Pretreatment with PAG did not reverse the effect of SQ 22536 (an AC inhibitor), bupivacaine (inhibitor of cAMP production), KT-5720 (a PKA inhibitor), and AICAR (an AMPK activator). The treatment with Forskolin does not reverse the effects of the H2S donors. Co-treatment with either NaHS or Lawesson's reagent and dorsomorphin (an AMPK inhibitor) did not reverse the effect of the H2S donors. H2S has antisecretory activity and is an essential molecule for protection against the intestinal secretion induced by CT. Thus, H2S donor drugs are promising candidates for cholera therapy. However, more studies are needed to elucidate the possible mechanism of action.
Asunto(s)
Toxina del Cólera/antagonistas & inhibidores , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Sulfuro de Hidrógeno/farmacología , Transducción de Señal , Proteínas Quinasas Activadas por AMP/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Toxina del Cólera/farmacología , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Femenino , Masculino , RatonesRESUMEN
Hydrogen sulfide (H2S) is a signaling molecule in the gastrointestinal tract. H2S production can derive from d-cysteine via various pathways, thus pointing to a new therapeutic approach: delivery of H2S to specific tissues. This study was designed to evaluate the concentration and effects of H2S (generated by d-amino acid oxidase [DAO] from d-cysteine) in the gastric mucosa and the protective effects against ethanol-induced lesions in mice. Mice were treated with l-cysteine or d-cysteine (100 mg/kg per os). Other groups received oral l-propargylglycine (cystathionine γ-lyase inhibitor, 100 mg/kg) or indole-2-carboxylate (DAO inhibitor), and 30 min later, received d- or l-cysteine. After 30 min, 50% ethanol (2.5 mL/kg, per os) was administered. After 1 h, the mice were euthanized and their stomachs excised and analyzed. Pretreatment with either l-cysteine or d-cysteine significantly reduced ethanol-induced lesions. Pretreatment of d-cysteine- or l-cysteine-treated groups with indole-2-carboxylate reversed the gastroprotective effects of d-cysteine but not l-cysteine. Histological analysis revealed that pretreatment with d-cysteine decreased hemorrhagic damage, edema, and the loss of the epithelium, whereas the administration of indole-2-carboxylate reversed these effects. d-Cysteine also reduced malondialdehyde levels but maintained the levels of reduced glutathione. Furthermore, pretreatment with d-cysteine increased the synthesis of H2S. Thus, an H2S-generating pathway (involving d-cysteine and DAO) is present in the gastric mucosa and protects this tissue from ethanol-induced damage by decreasing direct oxidative damage.
Asunto(s)
Antioxidantes/farmacología , Cisteína/farmacología , D-Aminoácido Oxidasa/metabolismo , Mucosa Gástrica , Sulfuro de Hidrógeno/metabolismo , Animales , Etanol/efectos adversos , Femenino , Mucosa Gástrica/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Glutatión/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Gastropatías/inducido químicamente , Gastropatías/metabolismoRESUMEN
BACKGROUND: It has been reported that simvastatin, a statin commonly prescribed for its anti-inflammatory and antioxidant effects, has gastroprotective effects in indomethacin and ethanol-induced gastric ulcers. However, the effects of simvastatin on alendronate-induced gastric mucosal injury remain unexplored. AIM: This study investigated the use of simvastatin for the treatment of alendronate-induced gastric ulcers in rats. METHODS: Female rats were pretreated with vehicle or simvastatin (20 and 60 mg/kg p.o.). After 1 h, the rats received alendronate (50 mg/kg p.o.). Simvastatin was administered once daily for 7 days, and from the fourth day of simvastatin treatment, alendronate was administered once daily for 4 days. On the final day of treatment, 4 h after alendronate administration, animals were euthanized, their stomachs were removed, and gastric damage was measured. Samples of the stomach were fixed in 10 % formalin immediately after their removal for subsequent histopathological assessment. Unfixed samples were weighed, frozen at -80 °C until assayed for glutathione (GSH), malondialdehyde (MDA), and cytokine levels and myeloperoxidase (MPO) activity. A third group was used to measure mucus and gastric secretion. RESULTS: Pretreatment with simvastatin prevented alendronate-induced macroscopic gastric damage and reduced the levels of MDA and GSH, TNF-α and IL-1ß, MPO activity, and mucus levels, in the stomach. CONCLUSIONS: This study demonstrates the protective effects of simvastatin against alendronate-induced gastric ulceration. Maintenance of mucosal integrity, inhibition of neutrophil activity, and reduced oxidative stress associated with decreased gastric acidity may explain the gastroprotective effects of simvastatin.
Asunto(s)
Alendronato/toxicidad , Mucosa Gástrica/efectos de los fármacos , Simvastatina/farmacología , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & control , Animales , Conservadores de la Densidad Ósea/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Malondialdehído/metabolismo , Peroxidasa/genética , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Simvastatina/administración & dosificación , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Long-term use nonsteroidal anti-inflammatory drug is associated with gastrointestinal (GI) lesion formation. The aim of this study was to investigate the protective activity of cashew gum (CG), a complex heteropolysaccharide extracted from Anacardium occidentale on naproxen (NAP)-induced GI damage. Male Wistar rats were pretreated with vehicle or CG (1, 3, 10, and 30 mg/kg, p.o.) twice daily for 2 days; after 1 h, NAP (80 mg/kg, p.o.) was administered. The rats were euthanized on the 2nd day of treatment, 4 h after NAP administration. Stomach lesions were measured using digital calipers. The medial small intestine was used for the evaluation of macroscopic lesion scores. Samples of the stomach and the intestine were used for histological evaluation, and assays for glutathione (GSH), malonyldialdehyde (MDA), and myeloperoxidase (MPO). Additional rats were used to measure gastric mucus and secretion. Pretreatment with CG reduced the macroscopic and microscopic damage induced by NAP. CG significantly attenuated NAP-induced alterations in MPO, GSH, and MDA levels. Furthermore, CG returned adherent mucus levels to normal values. These results suggest that CG has a protective effect against GI damage via mechanisms that involve the inhibition of inflammation and increasing the amount of adherent mucus in mucosa.
Asunto(s)
Anacardium , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/prevención & control , Naproxeno/efectos adversos , Gomas de Plantas/uso terapéutico , Polisacáridos/uso terapéutico , Animales , Enfermedades Gastrointestinales/patología , Masculino , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Gomas de Plantas/aislamiento & purificación , Polisacáridos/aislamiento & purificación , Ratas , Ratas WistarRESUMEN
AIMS: To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE). MATERIALS AND METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction. KEY FINDINGS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as ß2 integrin, PI3K, and PAD2 due to its intermolecular coupling. SIGNIFICANCE: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
Asunto(s)
COVID-19 , Movimiento Celular , Diminazeno , Trampas Extracelulares , Inflamación , Leucocitos , SARS-CoV-2 , Diminazeno/farmacología , Diminazeno/análogos & derivados , Animales , Ratones , Humanos , Movimiento Celular/efectos de los fármacos , Trampas Extracelulares/metabolismo , Trampas Extracelulares/efectos de los fármacos , Leucocitos/metabolismo , Leucocitos/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , COVID-19/metabolismo , Masculino , Tratamiento Farmacológico de COVID-19 , Adhesión Celular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Glicoproteína de la Espiga del CoronavirusRESUMEN
OBJECTIVE: This study aimed to evaluate the role of pepsin inhibitors in the inflammatory response and their effects on laryngeal mucosal integrity during gastroesophageal reflux (GERD) under in vivo conditions. METHODS: A surgical model of GERD was used, in which mice were treated with pepstatin (0.3 mg/kg) or darunavir (8.6 mg/kg) for 3 days. On the third day after the experimental protocol, the laryngeal samples were collected to assess the severity of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and paracellular epithelial permeability to fluorescein). RESULTS: The surgical GERD model was reproduced. It showed features of inflammation and loss of barrier function in the laryngeal mucosa. Pepstatin and darunavir administration suppressed laryngeal inflammation and preserved laryngeal mucosal integrity. CONCLUSION: Pepsin inhibition by the administration of pepstatin and darunavir improved inflammation and protected the laryngeal mucosa in a mouse experimental model of GERD. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3080-3085, 2024.
Asunto(s)
Modelos Animales de Enfermedad , Reflujo Gastroesofágico , Pepsina A , Animales , Ratones , Reflujo Gastroesofágico/tratamiento farmacológico , Pepstatinas/farmacología , Mucosa Laríngea/efectos de los fármacos , Mucosa Laríngea/patología , Masculino , Inflamación/tratamiento farmacológico , Inflamación/prevención & controlRESUMEN
Biotechnological advancements require the physicochemical alteration of molecules to enhance their biological efficacy for the effective treatment of gastric ulcers. The study aimed to produce a polyelectrolytic compound from red angico gum (AG) by carboxymethylation, evaluate its physicochemical characteristics and investigate gastric protection against ethanol-induced ulcers. AG and carboxymethylated angico gum (CAG) were characterized by Fourier transform infrared spectroscopy, determination of the degree of substitution and gel permeation chromatography (GPC) and 13C NMR techniques. The results demonstrated that the modification of the polymer was satisfactory, presenting conformational changes e improving the interaction with the gastric mucosa. AG and CAG reduced macroscopic and microscopic damage such as edema, hemorrhage and cell loss caused by exposure of the mucosa to alcohol. Both demonstrated antioxidant activity in vitro, and in vivo, pretreatment with gums led to the restoration of superoxide dismutase and glutathione levels compared to the injured group. Concurrently, the levels of malondialdehyde and nitrite decreased. Atomic force microscopy showed that CAG presented better conformational properties of affinity and protection with the gastric mucosa compared to AG in the acidic pH. Based on our findings, it is suggested that this compound holds promise as a prospective product for future biotechnological applications.
Asunto(s)
Colubrina , Fabaceae , Úlcera Gástrica , Estudios Prospectivos , Estómago , Antioxidantes/efectos adversos , Mucosa Gástrica , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Extractos Vegetales/químicaRESUMEN
Diminazene aceturate (DIZE), an antiparasitic, is an ACE2 activator, and studies show that activators of this enzyme may be beneficial for COVID-19, disease caused by SARS-CoV-2. Thus, the objective was to evaluate the in silico and in vitro affinity of diminazene aceturate against molecular targets of SARS-CoV-2. 3D structures from DIZE and the proteases from SARS-CoV-2, obtained through the Protein Data Bank and Drug Database (Drubank), and processed in computer programs like AutodockTools, LigPlot, Pymol for molecular docking and visualization and GROMACS was used to perform molecular dynamics. The results demonstrate that DIZE could interact with all tested targets, and the best binding energies were obtained from the interaction of Protein S (closed conformation -7.87 kcal/mol) and Mpro (-6.23 kcal/mol), indicating that it can act both by preventing entry and viral replication. The results of molecular dynamics demonstrate that DIZE was able to promote a change in stability at the cleavage sites between S1 and S2, which could prevent binding to ACE2 and fusion with the membrane. In addition, in vitro tests confirm the in silico results showing that DIZE could inhibit the binding between the spike receptor-binding domain protein and ACE2, which could promote a reduction in the virus infection. However, tests in other experimental models with in vivo approaches are needed.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Antiparasitarios , Antivirales/química , Antivirales/farmacología , Diminazeno/análogos & derivados , Humanos , Simulación del Acoplamiento Molecular , Péptido Hidrolasas , Peptidil-Dipeptidasa A/química , Proteína SRESUMEN
AIMS: Investigate the involvement of Hydrogen sulfide (H2S) in inflammatory parameters and intestinal morphology caused by cholera toxin (CT) in mice. MAIN METHODS: Mice were subjected to the procedure of inducing diarrhea by CT in the isolated intestinal loop model. The intestinal loops were inoculated with H2S donor molecules (NaHS and GYY 4137) or saline and CT. To study the role of EP2 and EP4 prostaglandin E2 (PGE2) receptors in the H2S antisecretory effect, PAG (DL-propargylglycine - inhibitor of cystathionine-γ-lyase (CSE)), PF-04418948 (EP2 antagonist) and ONO-AE3-208 (EP4 antagonist) were used. The intestinal loops were evaluated for intestinal secretion, relation of the depth of villi and intestinal crypts, and real-time PCR for the mRNA of the CXCL2, IL-6, NOS-2, IL-17, NF-κB1, NF-κBIA, SLC6A4 and IFN-γ genes. KEY FINDINGS: H2S restored the villus/crypt depth ratio caused by CT. NaHS and GYY 4137 increased the expression of NF-κB1 and for the NF-κBIA gene, only GYY 4137 increased the expression of this gene. The increased expression of NF-κB inhibitors, NF-κB1 and NF-κBIA by H2S indicates a possible decrease in NF-κB activity. The pretreatment with PAG reversed the protective effect of PF-04418948 and ONO-AE3-208, indicating that H2S probably decreases PGE2 because in the presence of antagonists of this pathway, PAG promotes intestinal secretion. SIGNIFICANCE: Our results point to a protective activity of H2S against CT for promoting a protection of villus and crypt intestine morphology and also that its mechanism occurs at least in part due to decreasing the activity of NF-κB and PGE2.
Asunto(s)
Diarrea/inducido químicamente , Diarrea/metabolismo , Dinoprostona/metabolismo , Sulfuro de Hidrógeno/farmacología , Mucosa Intestinal/patología , FN-kappa B/metabolismo , Animales , Toxina del Cólera , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones , Morfolinas/farmacología , Compuestos Organotiofosforados/farmacología , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19) is an infectious disease with fast spreading all over the world caused by the SARS-CoV-2 virus which can culminate in a severe acute respiratory syndrome by the injury caused in the lungs. However, other organs can be also damaged. SARS-CoV-2 enter into the host cells using the angiotensin-converting enzyme 2 (ACE2) as receptor, like its ancestor SARS-CoV. ACE2 is then downregulated in lung tissues with augmented serum levels of ACE2 in SARS-CoV-2 patients. Interestingly, ACE2+ organs reveal the symptomatic repercussions, which are signals of the infection such as dry cough, shortness of breath, heart failure, liver and kidney damage, anosmia or hyposmia, and diarrhea. ACE2 exerts a chief role in the renin-angiotensin system (RAS) by converting angiotensin II to angiotensin-(1-7) that activates Mas receptor, inhibits ACE1, and modulates bradykinin (BK) receptor sensitivity, especially the BK type 2 receptor (BKB2R). ACE2 also hydrolizes des-Arg9-bradykinin (DABK), an active BK metabolite, agonist at BK type 1 receptors (BKB1R), which is upregulated by inflammation. In this opinion article, we conjecture a dialogue by the figure of Sérgio Ferreira which brought together basic science of classical pharmacology and clinical repercussions in COVID-19, then we propose that in the course of SARS-CoV-2 infection: i) downregulation of ACE2 impairs the angiotensin II and DABK inactivation; ii) BK and its metabolite DABK seems to be in elevated levels in tissues by interferences in kallikrein/kinin system; iii) BK1 receptor contributes to the outbreak and maintenance of the inflammatory response; iv) kallikrein/kinin system crosstalks to RAS and coagulation system, linking inflammation to thrombosis and organ injury. We hypothesize that targeting the kallikrein/kinin system and BKB1R pathway may be beneficial in SARS-CoV-2 infection, especially on early stages. This route of inference should be experimentally verified by SARS-CoV-2 infected mice.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/fisiopatología , Sistema Calicreína-Quinina/fisiología , Modelos Biológicos , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/fisiopatología , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Infecciones por Coronavirus/etiología , Humanos , Sistema Calicreína-Quinina/efectos de los fármacos , Ratones , Pandemias , Peptidil-Dipeptidasa A/fisiología , Neumonía Viral/etiología , Receptores Virales/fisiología , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , SARS-CoV-2 , Investigación Biomédica Traslacional , Internalización del Virus/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
OBJECTIVES/HYPOTHESIS: The objectives of this study were to evaluate laryngeal inflammation and mucosal integrity in a murine model of reflux disease and to assess the protective effects of topical agents including alginate, hyaluronic acid, and cashew gum. STUDY DESIGN: Animal study. METHODS: A surgical murine model of reflux disease was evaluated at 3 or 7 days postsurgery, and laryngeal samples were collected to measure inflammation (wet weight and myeloperoxidase [MPO]) and mucosal integrity (transepithelial resistance [TER] and mucosal permeability to fluorescein). Additional groups of animals were administered one of several topical agents (alginate, hyaluronic acid, or cashew gum) daily, and laryngeal inflammation and mucosal integrity were evaluated at 3 days postsurgery. RESULTS: At 3 days, and not 7 days postsurgery, we observed increased laryngeal wet weight and MPO, decreased laryngeal TER, and increased laryngeal mucosa permeability. Alginate partially decreased laryngeal inflammation (wet weight and not MPO) and dramatically improved laryngeal mucosal integrity. Conversely, hyaluronic acid eliminated the inflammation; however, it had no effect on laryngeal mucosal integrity impairment. Cashew gum eliminated laryngeal inflammation as well as the impairment in laryngeal mucosal integrity. CONCLUSIONS: This study shows that a surgical model of reflux disease induced laryngeal inflammation and impairment in laryngeal barrier function. These observed alterations were partially attenuated by alginate and hyaluronic acid and completely reversed by cashew gum. LEVEL OF EVIDENCE: NA Laryngoscope, 2020.
Asunto(s)
Alginatos/administración & dosificación , Reflujo Gastroesofágico/complicaciones , Ácido Hialurónico/administración & dosificación , Mucosa Laríngea/efectos de los fármacos , Mucosa Laríngea/patología , Laringitis/etiología , Laringitis/prevención & control , Gomas de Plantas/administración & dosificación , Anacardium , Animales , Modelos Animales de Enfermedad , Masculino , RatonesRESUMEN
Anadenanthera colubrina var. cebil (Griseb.) Altschul (Fabaceae family), commonly known as the red angico tree, is a medicinal plant found throughout Brazil's semi-arid area. In this study, a chemical analysis was performed to investigate the antidiarrheal activity and safety profile of red angico gum (RAG), a biopolymer extracted from the trunk exudate of A. colubrina. Upon FT-IR spectroscopy, RAG showed bands in the regions of 1608 cm-1, 1368 cm-1, and 1029 cm-1, which relate to the vibration of O-H water molecules, deformation vibration of C-O bands, and vibration of the polysaccharide C-O band, respectively, all of which are relevant to glycosidic bonds. The peak molar mass of RAG was 1.89 × 105 g/mol, with the zeta potential indicating electronegativity. RAG demonstrated high yield and solubility with a low degree of impurity. Pre-treatment with RAG reduced the total diarrheal stool and enteropooling. RAG also enhanced Na+/K+-ATPase activity and reduced gastrointestinal transit, and thereby inhibited intestinal smooth muscle contractions. Enzyme-Linked Immunosorbent Assay (ELISA) demonstrated that RAG can interact with GM1 receptors and can also reduce E. coli-induced diarrhea in vivo. Moreover, RAG did not induce any signs of toxicity in mice. These results suggest that RAG is a possible candidate for the treatment of diarrheal diseases.
RESUMEN
This study aimed to investigate a standardized biopolymer, cashew gum (CG), in human oesophageal mucosa and mice with experimentally-induced non-erosive reflux disease (NERD). Human oesophageal biopsies from NERD patients were collected to evaluate the mucosal protection of CG through transepithelial electrical resistance (TER), mucosal permeability, and mucoadhesiveness tests. A surgical model of NERD in mice was induced, and barrier functions followed by suggestive oesophageal inflammatory hallmarks were evaluated. Pre-coating of CG was effective in human oesophageal mucosa by attenuating drop of TER and mucosal permeability. Labelled-CG adheres to human oesophageal mucosa for up to 1â¯h. In animal studies, CG improved parameters of barrier function (TER and mucosal permeability) in distal oesophagus mucosa. CG also promoted sequential support by reducing inflammatory hallmarks of oesophageal damage. CG confers topical oesophageal mucosal protection due to its mucoadhesiveness and anti-inflammatory profile. Long-duration mucoprotective products can be further explored as ï¬rst-line/adjuvant NERD therapy.
Asunto(s)
Anacardium/metabolismo , Biopolímeros/farmacología , Biopolímeros/farmacocinética , Mucosa Esofágica , Reflujo Gastroesofágico/tratamiento farmacológico , Adulto , Anciano , Animales , Impedancia Eléctrica , Mucosa Esofágica/efectos de los fármacos , Mucosa Esofágica/metabolismo , Femenino , Humanos , Ratones , Persona de Mediana Edad , Permeabilidad/efectos de los fármacos , Sustancias Protectoras/farmacología , Adulto JovenRESUMEN
OBJECTIVES/HYPOTHESIS: Evaluate the effect of in vitro exposure of mice laryngeal mucosa to solutions that simulated human gastric juice and to assess the topical protective effect of cashew gum on mice laryngeal mucosal integrity in vitro. STUDY DESIGN: Animal study. METHODS: Murine (Swiss) laryngeal samples were mounted in Ussing chambers. The luminal side of biopsies was exposed to solutions of different acidity with or without pepsin and/or taurodeoxycholic acid (TDC). Transepithelial electrical resistance (TER) was continuously recorded. The topical protective effect of cashew gum solution was evaluated by precoating the biopsies before the exposure with a solution at pH 5 containing 5 mM TDC. Changes in TER and mucosal permeability to fluorescein were measured. RESULTS: Exposure of laryngeal mucosa to acidic solutions containing pepsin and TDC provoked a pH-dependent drop in TER with the maximal effect at pH 1, but still present at pH 5 (weakly acidic). The exposure of the laryngeal mucosa to a solution of pH 5 with TDC, but not with pepsin, produced a dose-dependent decrease in TER. Precoating the mucosa with cashew gum prevented the reduction of TER and increased transepithelial permeability by exposure to a solution at pH5 containing TDC. CONCLUSIONS: Weakly acidic solutions containing bile acids can produce impairment of laryngeal epithelial barrier, which may be protected by topical treatment with cashew gum. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1157-1162, 2018.
Asunto(s)
Anacardium , Mucosa Laríngea/efectos de los fármacos , Extractos Vegetales/farmacología , Administración Tópica , Animales , Masculino , Ratones , Pepsina A/farmacología , Extractos Vegetales/administración & dosificación , Ácido Taurodesoxicólico/farmacologíaRESUMEN
OBJECTIVE: This study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats. METHODS: Initially, rats were pretreated with 0.5% carboxymethylcellulose (vehicle) or EPI (3, 10 and 30mg/kg, p.o. or i.p., groups 3-5, respectively) twice daily, for 2days. After 1h, NAP (80mg/kg, p.o.) was given. The control group received only vehicle (group 1) or vehicle+naproxen (group 2). Rats were euthanized on 2nd day, 4h after NAP treatment. Stomachs lesions were measured. Samples were collected for histological evaluation and glutathione (GSH), malonyldialdehyde (MDA), myeloperoxidase (MPO), and cytokines levels. Moreover, gastric mucosal blood flow (GMBF) was evaluated. RESULTS: EPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4±0.3U/mg of gastric tissue) and inhibited changes in MDA (70.4±8.3mg/g of gastric tissue) and GSH (246.2±26.4mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group. CONCLUSION: Our data show that EPI protects against NAP-induced gastric and intestinal damage by reducing pro-inflammatory cytokines, reducing oxidative stress, and increasing GMBF.
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4-Butirolactona/análogos & derivados , Alcaloides/uso terapéutico , Enfermedades Gastrointestinales/prevención & control , Imidazoles/uso terapéutico , Naproxeno/toxicidad , Pilocarpus , Extractos Vegetales/farmacología , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , 4-Butirolactona/uso terapéutico , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Animales , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/patología , Imidazoles/aislamiento & purificación , Imidazoles/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Sustancias Protectoras/aislamiento & purificación , Sustancias Protectoras/farmacología , Ratas , Ratas WistarRESUMEN
Inflammation is a protective reaction of the microcirculation. However, sustained inflammation can lead to undesired effects. Thuja occidentalis Linn has many pharmacological properties but has no anti-inflammatory activity described. Thus, this study aims evaluating the anti-inflammatory activity of the aqueous extract (AE) and the polysaccharide fraction (PLS) of T. occidentalis L. in mice. The results of our evaluations in various experimental models indicated that AE and PLS (3, 10, and 30mg/kg, i.p.) reduced (pË0.05) paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin (5-HT), bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, it inhibited neutrophils recruitment; decreased MPO activity, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, vascular permeability, nitrite concentration, and MDA concentration; and maintained the GSH levels in the peritoneal exudate. The AE and PLS reduced neutrophil infiltration and cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) immunostaining in paw tissue. Treatment with the AE and PLS (300mg/kg) did not induce gastric toxicity. In conclusion, these results show that the AE and PLS reduced the inflammatory response by inhibiting vascular and cellular events, inhibiting pro-inflammatory cytokine production, and reducing oxidative stress. Furthermore, they did not induce gastric toxicity at high doses.
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Antiinflamatorios/farmacología , Polisacáridos/farmacología , Thuja/química , Agua/química , Animales , Antiinflamatorios/uso terapéutico , Permeabilidad Capilar/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/metabolismo , Glutatión/metabolismo , Interleucina-6/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Óxido Nítrico/biosíntesis , Cavidad Peritoneal , Peritonitis/tratamiento farmacológico , Peroxidasa/metabolismo , Polisacáridos/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Bergenin, a compound derived from gallic acid, is a secondary metabolite of the plant Peltophorum dubium (Spreng.) Taub. OBJECTIVE: In this study, we aimed to characterize the ability of bergenin to eliminate the radicals in non-biological systems. METHODS: We evaluated bergenin's ability to protect erythrocytes from oxidative damage in a biological system. We have elucidated bergenin structure using nuclear magnetic resonance, X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry. We then evaluated its antioxidant capacity in vitro against DPPHâ¢, ABTSâ¢+, hydroxyl radicals, and nitric oxide, and determined its ability to transfer electrons owing to its reduction potential and ability to chelate iron. We also evaluated its protective capacity against oxidative damage produced by AAPH in erythrocytes, its hemolytic properties, its ability to inhibit hemolysis, and its ability to maintain intracellular reduced glutathione homeostasis. RESULTS: Bergenin concentrations between 0.1 and 3mM significantly (p < 0.05) and dose dependently decreased formation of ABTSâ¢+, DPPHâ¢, nitrite ions, OHâ¢, reduced formation ferricyanide, ferrozine-Fe2+complex, inhibited AAPH-induced oxidative hemolysis of erythrocytes, raised GSH levels in the presence of AAPH, inhibited AAPH-induced lipid peroxidation in erythrocytes. CONCLUSION: Bergenin may represent a novel alternative antioxidant, with potential applications in various industries, including drugs, cosmetics, and foods.
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Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Benzopiranos/aislamiento & purificación , Benzopiranos/farmacología , Eritrocitos/efectos de los fármacos , Fabaceae/química , Animales , Antioxidantes/química , Benzopiranos/química , Benzotiazoles/química , Compuestos de Bifenilo/química , Transporte de Electrón/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Glutatión/metabolismo , Hemólisis/efectos de los fármacos , Homeostasis/efectos de los fármacos , Radical Hidroxilo/química , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Hierro/química , Peroxidación de Lípido/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Nitritos/química , Picratos/química , Ratas , Ratas Wistar , Ácidos Sulfónicos/químicaRESUMEN
The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1-7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1-7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent.