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1.
Nutrients ; 13(10)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34684501

RESUMO

This study was conducted to investigate the therapeutic effect of hydro-alcoholic extract of Spirulina platensis (SP), golden kiwifruit (Actinidia chinensis) flesh (KF), and golden kiwifruit peel (KP) individually or in combination (SFP) on indomethacin-induced gastric ulcer in rats. Negative control rats (GI) were orally administered distilled water in parallel with other treatments. The positive control rat group (GII) was administered 30 mg kg-1 indomethacin to induce gastric ulcers. The KF and KF extracts were used individually or together with SP in treating indomethacin-induced gastric ulcerated rat groups. Gastric ulcerated rat's groups GIII, GIV, GV, GVI, and GVII were orally administered at 30 mg kg-1 rat body weight as total phenolic content (TPC) equivalent from SP, KF, KP, SPF extracts, and Lansoprazole (30 mg kg-1, as reference drug) daily up to 14 days, respectively. The relevant biochemical parameters, antioxidant biomarkers, and histopathological examination were examined. Remarkably, treating rats with SP, KF, KP, and SFP extracts markedly reduced gastric juice and stomach volume expansion induced by indomethacin. The SP significantly retrieved the pH of gastric juice to a regular rate compared to GI. The ulcer index (UI) was significantly attenuated by SP, KF, KP, and SFP administration. The protection index percentage (PI %) was 80.79, 54.51, 66.08, 75.74, and 74.86% in GIII, GIV, GV, GVI, and GVII, respectively. The gastric mucin content was significantly better attenuated by 95.7 in GIII compared to its content in GI. Lansoprazole increased mucin content by 80.3%, which was considerably lower than SP and SFP. SP, KF, KP, SFP, and Lansoprazole improved the reform of gastric mucosal-increased secreted mucus by 95.6, 61.3, 64.8, 103.1, and 80.2% in GIII, GIV, GV, GVI, and GVII, respectively. Interestingly, SFP efficiently increased vit. B12 level by 46.0% compared to other treatments. While Lansoprazole administrating did not significantly attenuate vit. B12 level. The SP and SFP improved iron and Hemoglobin (HB) levels depending on treatment. SP, KF, KP, and SFP significantly decreased the malondialdehyde (MDA) and increased reduced glutathione (GSH) as well as superoxide dismutase (SOD) levels in blood and stomach tissues. The most potent effect was observed with SP, and SFP was even better than Lansoprazole. Histopathologically, treating rats with SP extract showed a marked reduction of gastric damage and severity changes induced by indomethacin. KP was much better than KF in lessening gastric histopathological damages caused by indomethacin. SFP significantly alleviates gastric histopathological alterations. The lansoprazole-treated group (GVII) greatly relieved the gastric histopathological changes and recorded mild focal necrosis and desquamation of the mucosa in addition to mild oedema in the serosal layer. In conclusion, the presented results proved the antiulcer potential of SP and A. chinensis extracts against an indomethacin-induced gastric ulcer in rats, which may be due to their antioxidant and anti-inflammation efficiency. Thus, these data suggested that SP, KF, KP, and SFP extracts as natural and safe alternatives have a gastroprotective potential against indomethacin-induced gastric ulceration. The antioxidative and anti-inflammatory properties are probable mechanisms.


Assuntos
Actinidia , Antiulcerosos/farmacologia , Extratos Vegetais/farmacologia , Spirulina , Úlcera Gástrica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Frutas/química , Mucosa Gástrica/efeitos dos fármacos , Indometacina , Fitoterapia , Epiderme Vegetal/química , Ratos , Úlcera Gástrica/induzido quimicamente
2.
Nutrients ; 13(9)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34579045

RESUMO

Gastric ulcer disease induced by the consumption of NSAIDs is a major public health problem. The therapy used for its treatment causes adverse effects in the patient. Propolis is a natural product that has been used for the treatments of different diseases around the world. Nevertheless, there is little information about the activity of propolis in gastric ulcers caused by treatment with NSAIDs. Therefore, this review evaluates and compares the gastroprotective potential of propolis and its function against NSAID-induced gastric ulcers, for which a systematic search was carried out in the PubMed and ScienceDirect databases. The main criteria were articles that report the gastroprotective activity of propolis against the damage produced by NSAIDs in the gastric mucosa. Gastroprotection was related to the antioxidant, antisecretory, and cytoprotective effects, as well as the phenolic compounds present in the chemical composition of propolis. However, most of the studies used different doses of NSAIDs and propolis and evaluated different parameters. Propolis has proven to be a good alternative for the treatment of gastric ulcer disease. However, future studies should be carried out to identify the compounds responsible for these effects and to determine their potential use in people.


Assuntos
Antiulcerosos/farmacologia , Antioxidantes/farmacologia , Apiterapia , Própole/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Mucosa Gástrica/efeitos dos fármacos , Humanos , Úlcera Gástrica/induzido quimicamente , Resultado do Tratamento
3.
Biomolecules ; 11(8)2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34439913

RESUMO

Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine the anti-ulcer activity of 4α,24-dimethyl-5α-cholest-8ß,18-dihydroxy,22E-en-3ß-ol (ST-1) isolated from samples of a Nephthea species. This in vivo study was supported by in silico molecular docking and protein-protein interaction techniques. Oral administration of ST-1 reduced rat stomach ulcers with a concurrent increase in gastric mucosa. Molecular docking calculations against the H+/K+-ATPase transporter showed a higher binding affinity of ST-1, with a docking score value of -9.9 kcal/mol and a pKi value of 59.7 nM, compared to ranitidine (a commercial proton pump inhibitor, which gave values of -6.2 kcal/mol and 27.9 µM, respectively). The combined PEA-reactome analysis results revealed promising evidence of ST-1 potency as an anti-ulcer compound through significant modulation of the gene set controlling the PI3K signaling pathway, which subsequently plays a crucial role in signaling regarding epithelialization and tissue regeneration, tissue repairing and tissue remodeling. These results indicate a probable protective role for ST-1 against ethanol-induced gastric ulcers.


Assuntos
Antozoários/metabolismo , Antiulcerosos/farmacologia , Esteróis/química , Animais , Simulação por Computador , Etanol/metabolismo , Feminino , Mucosa Gástrica/efeitos dos fármacos , Glicoproteínas/metabolismo , Inflamação , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Mapeamento de Interação de Proteínas , Ratos , Ratos Wistar , Transdução de Sinais , Úlcera Gástrica/metabolismo , Úlcera/metabolismo
4.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203927

RESUMO

Artemisia ludoviciana subsp. mexicana has been traditionally used for the treatment of digestive ailments such as gastritis, whose main etiological agent is Helicobacter pylori. In a previous screening study, the aqueous extract exhibited a good in vitro anti-H. pylori activity. With the aim of determining the efficacy of this species as a treatment for H. pylori related diseases and finding bioactive compounds, its aqueous extract was subjected to solvent partitioning and the fractions obtained were tested for their in vitro anti-H. pylori effect, as well as for their in vivo gastroprotective and anti-inflammatory activities. The aqueous extract showed a MIC = 250 µg/mL. No acute toxicity was induced in mice. A gastroprotection of 69.8 ± 3.8%, as well as anti-inflammatory effects of 47.6 ± 12.4% and 38.8 ± 10.2% (by oral and topical administration, respectively), were attained. Estafiatin and eupatilin were isolated and exhibited anti-H. pylori activity with MBCs of 15.6 and 31.2 µg/mL, respectively. The finding that A. ludoviciana aqueous extract has significant anti-H. pylori, gastroprotective and anti-inflammatory activities is a relevant contribution to the ethnopharmacological knowledge of this species. This work is the first report about the in vivo gastroprotective activity of A. ludoviciana and the anti-H. pylori activity of eupatilin and estafiatin.


Assuntos
Artemisia/metabolismo , Flavonoides/farmacologia , Helicobacter pylori/efeitos dos fármacos , Animais , Antiulcerosos/farmacologia , Flavonoides/metabolismo , Gastrite/tratamento farmacológico , Masculino , Medicina Tradicional , Camundongos , Camundongos Endogâmicos , Extratos Vegetais/farmacologia , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Úlcera Gástrica/tratamento farmacológico
5.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206628

RESUMO

Black rice is a type of rice in the Oryza sativa L. species. There are numerous reports regarding the pharmacological actions of black rice bran, but scientific evidence on its gastroprotection is limited. This study aimed to evaluate the gastroprotective activities of black rice bran ethanol extract (BRB) from the Thai black rice variety Hom Nil (O. sativa L. indica) as well as its mechanisms of action, acute oral toxicity in rats, and phytochemical screening. Rat models of gastric ulcers induced by acidified ethanol, indomethacin, and restraint water immersion stress were used. After pretreatment with 200, 400, and 800 mg/kg of BRB in test groups, BRB at 800 mg/kg significantly inhibited the formation of gastric ulcers in all gastric ulcer models, and this inhibition seemed to be dose dependent in an indomethacin-induced gastric ulcer model. BRB could not normalize the amount of gastric wall mucus, reduce gastric volume and total acidity, or increase gastric pH. Although BRB could not increase NO levels in gastric tissue, the tissue MDA levels could be normalized with DPPH radical scavenging activity. These results confirm the gastroprotective activities of BRB with a possible mechanism of action via antioxidant activity. The major phytochemical components of BRB comprise carotenoid derivatives with the presence of phenolic compounds. These components may be responsible for the gastroprotective activities of BRB. The 2000 mg/kg dose of oral BRB showed no acute toxicity in rats and confirmed, in part, the safe uses of BRB.


Assuntos
Antiulcerosos , Etanol/química , Indometacina/efeitos adversos , Oryza/química , Fitoterapia , Extratos Vegetais , Úlcera Gástrica , Animais , Antiulcerosos/química , Antiulcerosos/farmacologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Indometacina/farmacologia , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia
6.
Clin Nutr ; 40(5): 2663-2672, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33933732

RESUMO

BACKGROUND & AIMS: Enteral nutrition with polymeric intact protein formula is the preferred medical nutrition strategy in critically ill patients when oral intake is insufficient. Enteral nutrition formulas are often rich in casein protein, which has coagulating properties. Coagulation in the stomach impedes gastric emptying and might result in high gastric residual volumes which are a clinical sign of gastrointestinal intolerance and a major reason to decrease or to discontinue enteral feeding. In this study the impact of protein composition of enteral formula on gastric content volume (GCV) during and after continuous feeding was tested in healthy volunteers in whom gastrointestinal conditions of critically ill patients were mimicked. METHODS: An enteral formula including 4 proteins (P4) with non-coagulating properties was compared to a casein-dominant formula (Cas) with coagulating properties. Esomeprazole and codeine were administered to mimic stress ulcer prophylaxis and induce gastroduodenal motor dysfunction, both being hallmarks of critically ill patients. GCV was measured with magnetic resonance imaging during and after continuous enteral feeding (100 mL/h for 4h) in a randomized single-center cross-over study. Results are provided as mean (SD). Significance level of p < 0.05 was applied. RESULTS: Twenty subjects completed the study (14 women, 6 men, 25.8 (4.6) years old, BMI: 22.5 (1.5) kg/m2). The GCV as change from baseline at T = 240 (primary endpoint) did not differ between study products (P4: 124.3 (83.4) vs. Cas: 137.1 (102.0) mL, 95% CI: -57.4, 27.0, p = 0.457). During feeding and after cessation of feeding, the area under the GCV-curve (AUC0-360 GCV) for P4 and Cas was 44631.1 (15546.1) and 52822.2 (19686.1) mL∗min, respectively (p = 0.061). During feeding the GCV was lower at T = 180 min (175.4 (64.8) vs. 205.2 (75.4) mL, p = 0.038) and after cessation of feeding at T = 300 min (81.3 (71.1) vs. 116.3 (84.3) mL, p = 0.004) and T = 330 min (39.9 (53.9) vs. 73.6 (81.1) mL, p = 0.031). With P4 it took less time to reach half of the GCV at T = 240 min compared to Cas (52.8 (27.6) vs. 65.4 (29.9) min, p = 0.020). CONCLUSIONS: In this study in which healthy volunteers received esomeprazole and codeine to mimic gastrointestinal conditions of critically ill patients, observations of secondary endpoints suggest faster gastric emptying with P4 compared to Cas, and less gastric accumulation, possibly due to the non-coagulating properties of the P4 protein blend. Considering the small effect and the possible clinical relevance of reduced intragastric accumulation of enteral nutrition, the potential impact of protein coagulation should be further investigated in relevant study populations. Registered under Netherlands Trial Register identifier no. NTR6423.


Assuntos
Proteínas na Dieta/administração & dosagem , Nutrição Enteral , Adulto , Aminoácidos/sangue , Analgésicos Opioides/farmacologia , Antiulcerosos/farmacologia , Área Sob a Curva , Caseínas/química , Codeína/farmacologia , Estudos Cross-Over , Proteínas na Dieta/análise , Proteínas na Dieta/farmacocinética , Esomeprazol/farmacologia , Feminino , Meia-Vida , Humanos , Masculino , Soro do Leite/química , Adulto Jovem
7.
Biochem Pharmacol ; 190: 114633, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34058185

RESUMO

Proton pump inhibitors (PPI) are commonly used drugs that may increase the cardiovascular risk by mechanisms not entirely known. We examined whether the PPI omeprazole promotes vascular oxidative stress mediated by xanthine oxidoreductase (XOR) leading to activation of matrix metalloproteinases (MMPs) and vascular remodeling. We studied Wistar rats treated with omeprazole (or vehicle) combined with the XOR inhibitor allopurinol (or vehicle) for four weeks. Systolic blood pressure (SBP) measured by tail-cuff plethysmography was not affected by treatments. Omeprazole treatment increased the aortic cross-sectional area and media/lumen ratio by 25% (P < 0.05). Omeprazole treatment decreased gastric pH and induced vascular remodeling accompanied by impaired endothelium-dependent aortic responses (assessed with isolated aortic ring preparation) to acetylcholine (P < 0.05). Omeprazole increased vascular active MMP-2 expression and activity assessed by gel zymography and in situ zymography, respectively (P < 0.05). Moreover, omeprazole enhanced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay (both P < 0.05). All these biochemical changes caused by omeprazole were associated with increased vascular XOR activity (but not XOR expression assessed by Western blot) and treatment with allopurinol fully prevented them (all P < 0.05). Importantly, treatment with allopurinol prevented the vascular dysfunction and remodeling caused by omeprazole. Our results suggest that the long-term use of omeprazole induces vascular dysfunction and remodeling by promoting XOR-derived reactive oxygen species formation and MMP activation. These findings provide evidence of a new mechanism that may underlie the unfavorable cardiovascular outcomes observed with PPI therapy. Clinical studies are warranted to validate our findings.


Assuntos
Metaloproteinases da Matriz/metabolismo , Omeprazol/farmacologia , Xantina Desidrogenase/metabolismo , Alopurinol/farmacologia , Animais , Antiulcerosos/farmacologia , Aorta/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Masculino , Metaloproteinases da Matriz/genética , Distribuição Aleatória , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Remodelação Vascular , Xantina Desidrogenase/genética
8.
Food Funct ; 12(13): 6001-6013, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34037056

RESUMO

The present study investigated the gastroprotective activity of benzyl isothiocyanates (BITC) on indomethacin (IND)-induced gastric injury in a rat model and explicated the possible involved biochemical, cellular, and molecular mechanisms. The rat model with gastric ulcers was established by a single oral dose of IND (30 mg per kg b.wt). BITC (0.75 and 1.5 mg kg-1) and esomeprazole (20 mg per kg b.wt) were orally administered for 3 weeks to rats before the induction of gastric injury. Compared with the IND group, BITC could diminish both the macroscopic and microscopic pathological morphology of gastric mucosa. BITC significantly preserved the antioxidants (glutathione GSH, superoxide dismutase SOD), nitric oxide (NO), and prostaglandin E2 (PGE2) contents, while decreasing the gastric mucosal malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and myeloperoxidase (MPO) contents. Moreover, BITC remarkably upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemoxygenase-1 (HO-1), and NAD(P)H : quinone oxidoreductase (NQO1). In addition, BITC activates the expression of heat shock protein 70 (HSP-70) and downregulated the expression of nuclear factor-κB (NF-κB) and caspase-3 to promote gastric mucosal cell survival. To the best of our knowledge, this study is the first published report to implicate the suppression of inflammation, oxidative stress, and Nrf2 signaling pathway as a potential mechanism for the gastroprotective activity of BITC.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Úlcera Gástrica/tratamento farmacológico , Animais , Antiulcerosos/farmacologia , Caspase 3/metabolismo , Esomeprazol/farmacologia , Feminino , Heme Oxigenase-1/metabolismo , Humanos , Indometacina/efeitos adversos , Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Masculino , NAD(P)H Desidrogenase (Quinona)/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo
9.
Bioorg Chem ; 111: 104827, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33798845

RESUMO

A new set of derivatives bearing pyrazole-methylenehydrazono-thiazolidinone scaffold 4-23 was designed, synthesized and confirmed by different spectroscopic means and elemental analyses. In-vivo anti-inflammatory and ulcerogenic evaluation was performed for all the newly synthesized derivatives using indomethacin, celecoxib and diclofenac as standard drugs. The compounds 5, 10, 15, 17, 21, 22 appeared to be the most promising candidates producing rapid onset and long duration of anti-inflammatory activity as well as promising GIT safety profile. Furthermore, analgesic evaluation revealed that the compounds 5, 10, 15 and 22 produced potent and long acting analgesia accompanied with significant inhibition of the inflammatory cytokine TNF-α level in comparison with the standard drugs. Molecular docking study of the latter derivatives was also carried out to rationalize their binding affinities and their modes of interactions with the active site of TNF-α.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Pirazóis/farmacologia , Tiazolidinas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazolidinas/química , Fator de Necrose Tumoral alfa/metabolismo
10.
Bioorg Chem ; 111: 104883, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33865053

RESUMO

A novel series of thiazolo-pyrazole hybrids has been prepared and assessed for their in vitro COX-1/COX-2 inhibitory activity. Compound 6c exhibited the most selective COX-2 inhibition profile (SI of 264) not far of Celecoxib (294). In-vivo anti-inflammatory activity revealed that compound 6d exhibited the highest activity (97.30% inhibition of edema) exceeding reference standard Indomethacin (84.62% inhibition of edema). The ulcerogenic liability tested, using gross, microscopic, biochemical analysis and apoptotic genes expression, showed that compound 6b matched the optimal candidate activity (ulcer index = 120, selectivity index of ~ 162 and 77% in-vivo inhibition of edema). Meanwhile, compound 6 m (ulcer index = 0) showcased the highest safety profile. Molecular modeling analysis and drug likeness studies presented appreciated agreement with the biological evaluation.


Assuntos
Anti-Inflamatórios/farmacologia , Antiulcerosos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antiulcerosos/síntese química , Antiulcerosos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Edema/induzido quimicamente , Edema/patologia , Formaldeído , Masculino , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia
11.
Expert Rev Clin Pharmacol ; 14(6): 677-686, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33843400

RESUMO

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs widely used due to their pharmacological potential, demonstrating anti-inflammatory, analgesic, or antipyretic activity. However, prolonged use of these medications can lead to the development of gastric ulcers in patients. This review aimed to find patents for drugs with an anti-inflammatory and gastroprotective character to treat NSAID-induced gastric ulcers. AREAS COVERED: For the treatment of NSAID-induced gastric ulcers, formulations with different action mechanisms were found, including donors of nitric oxide, heterocyclic compounds, and natural products. EXPERT OPINION: Many of the structures found have already been used in clinic settings and others, and according to the results found, they are promising for the treatment of gastric ulcers.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/administração & dosagem , Úlcera Gástrica/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antiulcerosos/farmacologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacologia , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/farmacologia , Humanos , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/farmacologia , Patentes como Assunto , Úlcera Gástrica/induzido quimicamente
12.
Biomed Res Int ; 2021: 6685395, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928161

RESUMO

Introduction: The stem bark of Ficus thonningii is used by Ethiopian traditional healers and the community for the treatment of peptic ulcer disease. Thus, the current study was aimed at evaluating the antiulcer effect of hydro-methanol extract and solvent fractions of F. thonningii. Methods: The stem bark of F. thonningii was collected and shed dried. Then, the stem bark was extracted by 80% hydro-methanol solvents and dried. The part of the dried hydro-methanol extract was further fractionated with n-hexane, chloroform, and distilled water. Dose-dependent pylorus ligation, curative indomethacin-induced, and time-dependent ethanol-induced ulcer models were evaluated for the hydro-methanol extract and solvent fractions. Statistical analysis was done by using the Statistical Package for the Social Sciences (SPSS) version 24. The analyses were carried out using one-way analysis of variance (ANOVA), followed by Tukey's multiple comparison tests. The result was considered significant when p < 0.05. Results: The extract of F. thonningii showed a significant (p < 0.001) reduction in total acidity at all the tested doses (100, 200, and 400 mg/kg). All the tested doses of the hydro-methanol extract significantly reduced the gastric volume as compared to the vehicle (NC) (p < 0.01). The gastric pH was significantly (p < 0.05) increased by 200 and 400 mg/kg. Similarly, 200 mg/kg and 400 mg/kg significantly (p < 0.05) lowered gastric ulceration as compared to the NC. The hydro-methanol extract and aqueous fractions of F. thonningii at 200 mg/kg showed significant (p < 0.05) reduction in the ulcer index on a repeated dose of the hydro-methanol and solvent fractions. Ulcer healing effect on indomethacin-induced ulcer was not significant (p > 0.05) for all tested doses of the hydro-methanol extract. Conclusion: The study demonstrated that the stem bark of F. thonningii has a potential antiulcer activity that might be due to antisecretory or cytoprotective effects.


Assuntos
Antiulcerosos/uso terapêutico , Ficus/química , Metanol/química , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Caules de Planta/química , Úlcera Gástrica/tratamento farmacológico , Água/química , Animais , Antiulcerosos/farmacologia , Fracionamento Químico , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Ligadura , Camundongos , Compostos Fitoquímicos/análise , Extratos Vegetais/farmacologia , Piloro/efeitos dos fármacos , Piloro/patologia , Ratos Wistar , Solventes/química
13.
Biomed Pharmacother ; 138: 111513, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33761454

RESUMO

This study investigated the gastroprotective effects and possible mechanism of Kangfuxin (KFX), an ethanol extract of Periplaneta americana L. (Dictyoptera; Blattidae), on improving healing quality and preventing recurrence of gastric ulcer. The effects of KFX were investigated in patients treated with endoscopic submucosal dissection (ESD), gastric ulcer animal model, and rat gastric mucosal cells and fibroblasts. Moreover, the relationship between KFX and p38/NF-κB pathway were explored both in vivo and in vitro. In patients, KFX exhibited protective effects against gastric ulcers and resulted in a decrease in the CD3 expression. In vivo animal experiments confirmed that KFX accelerated ulcer healing by promoting neovascularization (increased CD34 expression), suppressing inflammation (decreased interleukin-1ß (IL-1ß), myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and IL-8 expression), and enhancing growth factor expression, including the epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF). In vitro experiments demonstrated that treatment with 10% KFX rat serum decreased IL-1ß, IL-1Ra, SIL-1RAP, TNF-α, and ICAM-1 expression in rat gastric mucosal cells or fibroblasts and increased IL-1R expression compared to that in the group treatment with 10% normal rat serum. Furthermore, KFX inhibited the activation of p38/NF-κB pathway both in vivo and in vitro. In conclusion, KFX treatment could effectively improve healing quality and prevent gastric ulcer recurrence, which might be attributed to neovascularization, suppressed inflammation, and enhanced growth factor expression. The p38/NF-κB pathway may be one of important mechanism to mediate the effects of KFX.


Assuntos
Antiulcerosos/uso terapêutico , Materia Medica/uso terapêutico , Úlcera Gástrica/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Antiulcerosos/farmacologia , Células Cultivadas , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Masculino , Materia Medica/farmacologia , Ratos , Recidiva , Úlcera Gástrica/patologia , Resultado do Tratamento , Cicatrização/fisiologia
14.
Bioorg Chem ; 109: 104742, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647742

RESUMO

Throughout this study, we present the victorious synthesis of a novel class of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety through a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with cyanoacetamide, acetylacetone or ethyl acetoacetate, and their corresponding aldehydes. In addition, the chromene moiety was introduced into the pyridine skeleton through the cyclization of the cyanoacetamide 2 with salicylaldehyde, followed by treatment with malononitrile, ethyl cyanoacetate, and cyanoacetamide, in order to improve their biological behaviour. Due to their anti-inflammatory, ulcerogenic, and antipyretic characters, the target molecules have undergone in-vitro and in-vivo examination, that display promising results. Moreover, in order to predict the physicochemical and ADME traits of all synthesized compounds and standard reference drugs, paracetamol and phenylbutazone, the in-silico prediction methodology was provided.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Antipiréticos/farmacologia , Edema/tratamento farmacológico , Febre/tratamento farmacológico , Piridonas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Antipiréticos/síntese química , Antipiréticos/química , Relação Dose-Resposta a Droga , Edema/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos , Úlcera Gástrica/patologia , Relação Estrutura-Atividade
15.
Chem Biol Interact ; 339: 109445, 2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33741339

RESUMO

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin, Tax) was identified as a gastroprotective compound and a gastroadhesive formulation was recently developed to prolong its residence time and release in the stomach. So, the gastric healing effectiveness of Tax and gastro-mucoadhesive microparticles containing Tax (MPTax) against the acetic acid induced-gastric ulcer in rats was investigated in this study. Moreover, the interactions between Tax and H+/K+-ATPase were investigated in silico, and its anti- H. pylori activity was determined in vitro. The oral treatment with MPTax (81.37 mg/kg, containing 12.29% of Tax) twice a day for seven days reduced the ulcer area by 63%, compared to vehicle-treated group (Veh: 91.9 ± 10.3 mm2). Tax (10 mg/kg, p.o) reduced the ulcer by 40% but with a p = 0.07 versus Veh group. Histological analysis confirmed these effects. Tax and MPTax increased the gastric mucin amount, reduced the myeloperoxidase activity, and increased the glutathione reduced content at ulcer site. However, only MPTax decreased the lipoperoxide accumulation at ulcer site. Besides, Tax and MPTax normalize the catalase and glutathione S-transferase activity. Tax showed reversible interaction with H+/K+-ATPase in silico and its anti-H. pylori effects was confirmed (MIC = 625 µg/mL). These results suggest that the antiulcer property of Tax involves the strengthening of the gastric protective factors in parallel to its inhibitory interaction with H+/K+-ATPase and H. pylori. Considering that ulcer healing action displayed by Tax was favored by gastroadhesive microparticles, this approach seems to be promising for its oral delivery to treat acid-peptic diseases.


Assuntos
Adesivos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Bombas de Próton/fisiologia , Quercetina/análogos & derivados , Estômago/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ácido Acético/farmacologia , Animais , Antiulcerosos/farmacologia , Antioxidantes/metabolismo , Catalase/metabolismo , Simulação por Computador , Feminino , Mucinas Gástricas/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Quercetina/fisiologia , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/microbiologia
16.
Life Sci ; 273: 119261, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652036

RESUMO

AIMS: Liver cirrhosis leads to cirrhotic cardiomyopathy (CCM) and chronotropic incompetence (CI). Heat shock protein 70 (Hsp70) regulates cellular apoptosis and autophagy in stress. Teprenone modulates the Hsp70 and protects against cellular injury. Thus, we aimed to evaluate the effect of teprenone on CI in biliary cirrhotic rats. MAIN METHODS: Liver cirrhosis was induced in male Wistar rats through bile duct ligation (BDL). The chronotropic responses and QT interval were studied through electrocardiography (ECG) in sham, cirrhotic, and cirrhotic/teprenone (100 mg/kg) pre-treated groups. Brain natriuretic peptide (BNP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemo-attractant protein-1 (MCP-1), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were investigated in serum. The Hsp70, B-cell lymphoma 2 (Bcl-2), and B-cell lymphoma 2-associated X protein (Bax) expressions were quantified through real-time polymerase chain reaction (Real-time PCR). KEY FINDINGS: The chronotropic responses were decreased significantly in cirrhotic and cirrhotic/teprenone groups. The QT interval and serum BNP, TNF-α, IL-6, ALT, AST, and MCP-1 levels were increased significantly in the cirrhotic and decreased significantly, except BNP, in the cirrhotic/teprenone group. The Hsp70 and Bax expressions increased significantly in cirrhotic and decreased significantly in the cirrhotic/teprenone group while the Bcl-2 decreased significantly in cirrhotic and increased significantly in the cirrhotic/teprenone group. SIGNIFICANCE: Teprenone does not relieve the CI and BNP changes in CCM while other indices are treated. Given that CCM is a multifactorial disease and needs to target other genes and proteins concurrent with Hsp70 to relieve CCM.


Assuntos
Antiulcerosos/farmacologia , Biomarcadores/metabolismo , Cardiomiopatias/tratamento farmacológico , Diterpenos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Cirrose Hepática Biliar/complicações , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Masculino , Ratos , Ratos Wistar
17.
Biomed Pharmacother ; 137: 111345, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33556873

RESUMO

The aim of this work was to evaluate the gastroprotective activity of a Mexican propolis on indomethacin-induced gastric ulcers in a mouse model. The following contents of the ethanolic extract of propolis of Chihuahua (EEPCh) were determined: antioxidant activity (SA50), total phenolic content (TPC), total flavonoid content (TFC), and chemical composition by HPLC-DAD and HPLC-MS, as well as acute toxicity by OECD Guideline 423. Gastric lesions were induced by intragastric indomethacin treatment in male ICR mice. As the positive control, omeprazole was administered, and three doses of EEPCh were evaluated (50, 150 and 300 mg/kg). Gastric mucosal injury, histological changes and mucosal content were evaluated by means of H&E and PAS staining. For homogenized gastric tissues, the following were evaluated: TBARS, MPO, and PGE2 levels; SOD and GPx antioxidant enzymatic activity; and the concentrations of the proinflammatory cytokines, TNF-α, IL-1ß and IL-6. EEPCh had a significant SA50 of 41.55 µg/mL. The TPC of EEPCh was 860 mg GAE/g, and its TFC was 49.58 mg QE/g. Different phenolic compounds were identified in the extract and were not toxic. The EEPCh doses decreased mucosal damage and histological injuries, maintained the mucosal content and reduced the TBARS, MPO and concentrations of proinflammatory cytokines in gastric ulcer tissues. The 150 and 300 mg/kg doses increased the SOD activity and maintained the PGE2 content. Only the 300 mg/kg dose increased the GPx activity. The results of this study suggest that EEPCh displays gastroprotective effects by means of its antioxidant activity and anti-inflammatory effects and promotes ulcer protection through the maintenance of mucosal content and PGE2 levels.


Assuntos
Antiulcerosos/química , Antiulcerosos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Própole/química , Própole/farmacologia , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/uso terapêutico , Antioxidantes/análise , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Feminino , Flavonoides/análise , Flavonoides/química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Mucosa Gástrica/patologia , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Indometacina/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Omeprazol/farmacologia , Fenóis/análise , Fenóis/química , Extratos Vegetais/uso terapêutico , Própole/uso terapêutico , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo
18.
J Cell Biochem ; 122(7): 716-730, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33529434

RESUMO

Amelogenin directly binds to glucose-regulated protein 78 (Grp78). Cell migration activity is expected to increase when human periodontal ligament cells (hPDLCs) overexpressing Grp78 are treated with amelogenin. Geranylgeranylacetone (GGA) is a drug that induces the expression of heat shock protein and is routinely used to treat gastric ulcers. Here, we investigated the changes in the properties and behavior of hPDLCs in response to treatment with GGA and the synergistic effects of amelogenin stimulation in hPDLCs pretreated with GGA for the establishment of a novel periodontal tissue regenerative therapy. We observed that GGA treatment increased Grp78 protein expression in hPDLCs and enhanced cell migration. Microarray analysis demonstrated that increased Grp78 expression triggered the production of angiopoietin-like 4 and amphiregulin, which are involved in the enhancement of angiogenesis and subsequent wound healing via the activation of hypoxia-inducible factor 1α and peroxisome proliferator-activated receptors as well as the phosphorylation of cAMP response element-binding protein and protein kinase A. Moreover, the addition of recombinant murine amelogenin (rM180) further accelerated hPDLC migration and tube formation of human umbilical vein endothelial cells due to the upregulation of interleukin-8 (IL-8), monocyte chemotactic protein 1, and IL-6, which are also known as angiogenesis-inducing factors. These findings suggest that the application of GGA to gingival tissue and alveolar bone damaged by periodontal disease would facilitate the wound healing process by inducing periodontal ligament cells to migrate to the root surface and release cytokines involved in tissue repair. Additionally, supplementation with amelogenin synergistically enhanced the migratory capacity of these cells while actively promoting angiogenesis. Therefore, the combined application of GGA and amelogenin may establish a suitable environment for periodontal wound healing and further drive the development of novel therapeutics for periodontal tissue regeneration.


Assuntos
Amelogenina/farmacologia , Diterpenos/farmacologia , Neovascularização Patológica , Ligamento Periodontal/irrigação sanguínea , Cicatrização , Antiulcerosos/farmacologia , Quimioterapia Combinada , Humanos , Ligamento Periodontal/metabolismo , Ligamento Periodontal/patologia
19.
J Enzyme Inhib Med Chem ; 36(1): 669-684, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33618602

RESUMO

The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC50 values of 0.09-0.14 µM) with significant 15-LOX inhibitory activities (IC50s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Modelos Animais de Doenças , Edema/induzido quimicamente , Feminino , Formaldeído , Humanos , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Modelos Moleculares , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Células THP-1 , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
20.
PLoS One ; 16(1): e0245995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33507971

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) induce small intestinal damage. It has been reported that rebamipide, a mucoprotective drug, exerts a protective effect against NSAID-induced small intestinal damage; however, the underlying mechanism remains unknown. In this study, we investigated the significance of the small intestinal microbiota in the protective effect of rebamipide against indomethacin-induced small intestinal damage in mice. A comprehensive analysis of the 16S rRNA gene sequencing revealed an alteration in the composition of the small intestinal microbiota at the species level, modulated by the administration of rebamipide and omeprazole. The transplantation of the small intestinal microbiota of the mice treated with rebamipide suppressed the indomethacin-induced small intestinal damage. Omeprazole, a proton pump inhibitor, exacerbated the indomethacin-induced small intestinal damage, which was accompanied by the alteration of the small intestinal microbiota. We found that the transplantation of the small intestinal microbiota of the rebamipide-treated mice ameliorated indomethacin-induced small intestinal damage and the omeprazole-induced exacerbation of the damage. These results suggest that rebamipide exerts a protective effect against NSAID-induced small intestinal damage via the modulation of the small intestinal microbiota, and that its ameliorating effect extends also to the exacerbation of NSAID-induced small intestinal damage by proton pump inhibitors.


Assuntos
Alanina/análogos & derivados , Antiulcerosos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Indometacina/farmacologia , Intestino Delgado/efeitos dos fármacos , Inibidores da Bomba de Prótons/farmacologia , Quinolonas/uso terapêutico , Alanina/uso terapêutico , Animais , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos
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