RESUMEN
Yu et al's study in the World Journal of Gastroenterology (2023) introduced a novel regimen of Vonoprazan-amoxicillin dual therapy combined with Saccharomyces boulardii (S. boulardii) for the rescue therapy against Helicobacter pylori (H. pylori), a pathogen responsible for peptic ulcers and gastric cancer. Vonoprazan is a potassium-competitive acid blocker renowned for its rapid and long-lasting acid suppression, which is minimally affected by mealtime. Compared to proton pump inhibitors, which bind irreversibly to cysteine residues in the H+/K+-ATPase pump, Vonoprazan competes with the K+ ions, prevents the ions from binding to the pump and blocks acid secretion. Concerns with increasing antibiotic resistance, effects on the gut microbiota, patient compliance, and side effects have led to the advent of a dual regimen for H. pylori. Previous studies suggested that S. boulardii plays a role in stabilizing the gut barrier which improves H. pylori eradication rate. With an acceptable safety profile, the dual-adjunct regimen was effective regardless of prior treatment failure and antibiotic resistance profile, thereby strengthening the applicability in clinical settings. Nonetheless, S. boulardii comes in various formulations and dosages, warranting further exploration into the optimal dosage for supplementation in rescue therapy. Additionally, larger, randomized, double-blinded controlled trials are warranted to confirm these promising results.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Pirroles , Saccharomyces boulardii , Sulfonamidas , Humanos , Amoxicilina/uso terapéutico , Antibacterianos/efectos adversos , Infecciones por Helicobacter/tratamiento farmacológico , Claritromicina/uso terapéutico , Quimioterapia Combinada , Inhibidores de la Bomba de Protones/efectos adversos , ATPasa Intercambiadora de Hidrógeno-Potásio , Iones/farmacología , Iones/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Hymenocardia acida (HA) is one of the numerous medicinal plants in Nigeria with ethnomedicinal history of usage in the treatment of ulcer. The study aimed at isolating antiulcer principle(s) from the stem bark of HA as well as the mechanism of action determination. METHODS: Antiulcer screenings of the crude extract, aqueous fraction, and bulked VLC fractions were performed using in vivo and in vitro models. Docking was carried out by using PyRx. RESULTS: Crude extract (HA; 1 mg/mL) and the aqueous fraction of H. acida (HAA; 1 mg/mL) showed an acid neutralizing capacity (MEq) of 0.3948 and 0.4035, respectively which is significantly different from 0.431 MEq showed by negative control (distilled water) at p<0.05. BVLC 3 (1 mg/mL) showed a significant value of 0.4049 MEq. However, HA showed a dose-dependent decrease in activity across doses examined, with 100 mg/kg showing an ulcer index of 10.00±2.89 (61.50%) and cimetidine (positive control; 100 mg/kg), also showed the highest ulcer index of 3.67±0.88 (85.9%), which is significantly different from ulcer index of 26.00±6.35 (0.00%) p<0.05 observed in the negative control (5% dimethylsulphoxide). The highest ulcer index of 8.00±1.32 (65.10%) was noted in BVLC 3. Bioactive BVLC 3, resulted in an isolated compound (BF3B2A). The compound was suggested to be lupeol, with a docking score of -7.7. It showed a van der Waal interaction with some key amino acid residues in the vonoprazan binding site. CONCLUSION: The experimental studies justify the ethnomedicinal claim of usage among locals.
Asunto(s)
Antiulcerosos , Úlcera Gástrica , Triterpenos , Ratas , Animales , Extractos Vegetales/uso terapéutico , Fitoterapia , Úlcera/tratamiento farmacológico , Antiulcerosos/farmacología , Triterpenos/farmacología , Triterpenos/análisis , Triterpenos/uso terapéutico , Ratas Wistar , ATPasa Intercambiadora de Hidrógeno-Potásio/análisis , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/uso terapéutico , Corteza de la Planta/química , Úlcera Gástrica/tratamiento farmacológicoRESUMEN
Calanthe fimbriata Franch. is a Tujia ethnic herb, which has traditionally been used to treat gastric ulcers, chronic hepatitis, etc. We explored the chemical constitutes, gastroprotective effects, and the active fraction of C. fimbriata, as well as elucidating the underlying mechanisms. Firstly, four in vitro antioxidant tests were applied to determine the oxidation resistance of C. fimbriata methanol extract and its fractions. The gastroprotective effects were evaluated in ethanol-induced gastric ulcer rats, gastric histopathology was visualized by H&E staining, and the acidity of gastric juice was measured by titrating with NaOH solution. The contents of malondialdehyde, catalase, superoxide dismutase, gastrin, and the activity of H+K+-ATPase were estimated using commercial kits. EtOAc fraction of C. fimbriata methanol extract (CfEF) exhibited significant gastroprotective effects by ameliorating stomach pathological changes and elevating the pH value of gastric juice. It also manifested remarkable antioxidant activities in vitro and in vivo. Using various chromatographic methods and spectroscopic techniques, 22 compounds were isolated and characterized from CfEF, in which alkaloids were the predominant components. All of these substances were derived from C. fimbriata for the first time. The results indicated that CfEF is a promising source of gastroprotective agents. The antioxidant activity of this herb, as well as prevention of gastrin secretion and inhibition of H+K+ -ATPase, was found to be the underlying mechanism of action.
Asunto(s)
Antiulcerosos , Orchidaceae , Úlcera Gástrica , Animales , Antiulcerosos/uso terapéutico , Antioxidantes/uso terapéutico , Mucosa Gástrica , Gastrinas/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Metanol/química , Extractos Vegetales/uso terapéutico , Ratas , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/prevención & controlRESUMEN
Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). Biovia Discovery Studio visualizer (DSV) was utilized for virtual screening. A tissue antioxidant investigation, H+/K+-ATPase test, and anti-H. pylori activities were carried out. ELISA, immunohistochemistry, and PCR methods were employed for the proteome analysis. An ethanol-induced stomach ulcer model was used to examine the anti-ulcer potential in rats. The binding affinities for MBO ranged from -5.4 to -8.2 Kcal/mol. In vitro findings revealed inhibitory activity against H. pylori and the H+/K+-ATPase pump. It also enhanced levels of glutathione, catalase, and glutathione-S-transferase and reduced lipid peroxidation levels in gastric tissues of rats. In vivo results showed the gastro-protective effect of MBO (30 mg/kg) in ulcerative rat stomachs. The proteomic study revealed decreased expression of inflammatory markers (cyclooxygenase-2, p-NFkB, and TNF-α). In RT-PCR analysis, the expression levels of H+/K+-ATPase were reduced. Furthermore, ADMET (absorption, distribution, metabolism, excretion and toxicity) studies revealed that MBO has high GIT solubility and has a safer profile for cardiac toxicity. This study suggests that MBO displayed anti-ulcer potential, which may have been mediated through the inhibition of the H+/K+-ATPase pump, as well as antioxidant and anti-inflammatory pathways. It has the potential to be a lead molecule in the treatment of peptic ulcers with fewer adverse effects.
Asunto(s)
Antiulcerosos , Helicobacter pylori , Úlcera Gástrica , Animales , Antiulcerosos/química , Antioxidantes/metabolismo , Etanol/metabolismo , Mucosa Gástrica , Glutatión/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Isoxazoles/farmacología , Estrés Oxidativo , Extractos Vegetales/química , Proteómica , Ratas , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/prevención & controlRESUMEN
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.
Asunto(s)
Adhesivos/farmacología , Helicobacter pylori/efectos de los fármacos , Bombas de Protones/fisiología , Quercetina/análogos & derivados , Estómago/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Ácido Acético/farmacología , Animales , Antiulcerosos/farmacología , Antioxidantes/metabolismo , Catalasa/metabolismo , Simulación por Computador , Femenino , Mucinas Gástricas/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Fitoterapia/métodos , Extractos Vegetales/farmacología , Quercetina/fisiología , Ratas , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/microbiologíaRESUMEN
Blumea lacera (Burm.f.) DC. is described as a valuable medicinal plant in various popular systems of medicine. The aim of the experiment reports the in vivo antiulcer activity of methanol extract of Blumea lacera (MEBLL) and in silico studies of bioactive constituents of MEBLL. In this study, fasted Long-Evans rat treated with 80 % ethanol (0.5â¯mL) to induce gastric ulcer, were pretreated orally with MEBLL at different doses (250 and 500â¯mg/kg, p.o., b.w) and omeprazole (20â¯mg/kg, p.o.) and distilled water were used as a reference drug and normal control respectively. In silico activity against gastric H+-K+ATPase enzyme was also studied. The findings demonstrated that the treatment with MEBLL attenuated markedly ulcer and protected the integrity of the gastric mucosa by preventing the mucosal ulceration altered biochemical parameters of gastric juice such total carbohydrate, total protein and pepsin activity. Additionally, the experimental groups significantly (pâ¯<â¯0.001) inhibited gastric lesions and malondealdehyde (MDA) levels and upregulated antioxidant enzymes level. Furthermore, nine compounds were documented as bioactive, displayed good binding affinities to against gastric H+-K+ATPase enzyme while these compounds illustrated inhibitory effect. From these studies, it is established MEBLL has ulcer healing property as unveiled by in vivo and in silico studies.
Asunto(s)
Antiulcerosos/farmacología , Antioxidantes/farmacología , Asteraceae , Mucosa Gástrica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Inhibidores de la Bomba de Protones/farmacología , Úlcera Gástrica/prevención & control , Animales , Antiulcerosos/aislamiento & purificación , Antiulcerosos/farmacocinética , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacocinética , Asteraceae/química , Modelos Animales de Enfermedad , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacocinética , Hojas de la Planta , Inhibidores de la Bomba de Protones/aislamiento & purificación , Inhibidores de la Bomba de Protones/farmacocinética , Ratas Long-Evans , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologíaRESUMEN
Boldine is the main alkaloid of Peumus boldus Molina, widely used in the traditional medicine for the treatment of digestive disorders. It is a compound with excellent antioxidant and anti-inflammatory properties already described. Despite the widespread use of P. boldus for digestive disorders treatment, the gastroprotective effect of Boldine remains unknown. Considering the need for new approaches to treat gastric ulcers with fewer side effects than current therapy, this study aimed to investigate the gastroprotective effect of Boldine in mice, as well as the mechanisms underlying this effect. The gastroprotective effect of Boldine was evaluated on gastric ulcer induced by 60% ethanol/0.3 M HCl or indomethacin (100 mg/kg) in mice. Histological analysis and the mucin-like glycoprotein content were evaluated in ethanol-ulcerated tissue, as well as, oxidative stress and inflammatory parameters. The mechanisms involved in the effect of Boldine were evaluated by pretreating mice with NEM (a sulfhydryl group chelator, 10 mg/kg, i.p.), l-NAME (a non-selective nitric oxide synthase inhibitor, 70 mg/kg, i.p.), yohimbine (an alpha-adrenergic receptor antagonist, 2 mg/kg, i.p.) and indomethacin (a cyclooxygenase inhibitor, 10 mg/kg, i.p.). In addition, the in vitro effect of Boldine on H+/K+-ATPase activity was determined. Boldine was able to protect gastric mucosa against the damage induced by ethanol/HCl and indomethacin, as evidenced by reduced lesion area and histological analysis. Moreover, the alkaloid reduced oxidative stress and inflammatory mediators in ethanol-ulcerated tissue, beyond has increased mucin-like glycoprotein amount. Finally, Boldine effect is dependent on non-protein sulfhydryl groups and prostanoids but does not involve the inhibition of H+/K + -ATPase activity, being a promising natural resource for gastric ulcer treatment.
Asunto(s)
Antiulcerosos/farmacología , Aporfinas/farmacología , Mucosa Gástrica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Úlcera Gástrica/prevención & control , Animales , Etanol , Femenino , Mucosa Gástrica/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Indometacina , Inflamación/inducido químicamente , Inflamación/prevención & control , Peroxidación de Lípido/efectos de los fármacos , Ratones , Prostaglandinas/metabolismo , Conejos , Úlcera Gástrica/inducido químicamente , Compuestos de Sulfhidrilo/metabolismoRESUMEN
BACKGROUND: H+/K+ ATPase a protein present in the gastric parietal cells is a better target for the prevention and treatment of gastric ulcer. Plant flavonoids have been reported to elicit anti-ulcer activity by inhibiting the proton pump as well as by antioxidant defense mechanism. METHODS: Chloroform fraction of hydro-alcoholic extract of passion fruit was screened for proton pump inhibitory assay using goat parietal cell. In-silico computational docking studies were carried out using Glide program in order to validate the inhibitory action of selected constituents. RESULTS: The flavonoid rich fruit possess a promising radical scavenging activity against DPPH. 10.41µg/mL is sufficient to inhibit 50% of ATPase enzyme activity. A synergistic activity was also achieved by the fruit with sub-effective doses of lansoprazole. Fenton's oxidation induced by H2O2 was also blunted by the fruit extract. CONCLUSION: The in-vitro and in-silico findings indicated that, passion fruit can be a good dietary supplement for the prevention and management of ulcer.
Asunto(s)
ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Simulación del Acoplamiento Molecular , Passiflora/química , Extractos Vegetales/farmacología , Inhibidores de la Bomba de Protones/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Flavonoides/análisis , Flavonoides/farmacología , Frutas , Cabras , Oxidación-Reducción , EstómagoRESUMEN
BACKGROUND: Altered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4-17, 2014; Kim and Bae, Curr Opin Hematol 25:52-59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism. METHODS: Firstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a-/- mouse model (Spicer etal., J Biol Chem 275:21555-21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4a-/-mice. RESULTS: In this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a-/- mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05). CONCLUSIONS: Conclusively, WPL could ameliorate GPLs in Atp4a-/- mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.
Asunto(s)
Medicamentos Herbarios Chinos/administración & dosificación , Mucosa Gástrica/efectos de los fármacos , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Lesiones Precancerosas/tratamiento farmacológico , Animales , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismoRESUMEN
BACKGROUND: Trachyspermum ammi (L.) Sprague is used for treating gastrointestinal disorders. Several studies indicated gastric antiulcer activity of T. ammi extract, yet the effect of its essential oil has not been studied on. OBJECTIVES: The present study evaluates chemical composition of T. ammi essential oil and anti-peptic ulcer effect of the essential oil as well as its three major components in ethanol induced-gastric ulcers in rats. METHODS: Primarily chemical composition of the essential oil was analyzed by gas chromatography-mass spectrometry (GC/MS). Rats received the essential oil (500, 250, 125, 62.5, 31.25 mg/kg), thymol (30, 100 mg/kg), para-cymene (100, 150 mg/kg) and gamma-terpinene (100, 150 mg/kg) using gavage tube along with ethanol 80%. Finally, dissected stomachs were assessed both macroscopically and microscopically to evaluate anti-ulcerative effect of the essential oil and the pure compounds. Moreover, molecular docking was utilized to explore the interactive behavior of the main components with active site residues of H+/K+ ATPase. RESULTS: Analysis of the essential oil indicated that para-cymene (37.18%), gamma-terpinene (35.36%) and thymol (20.51%) are the main components. Administration of different doses of the essential oil noticeably diminished the number of peptic ulcers in a dose-dependent manner. Among the main components, thymol was more potent than para-cymene and gamma-terpinene. Administration of the essential oil (500 mg/kg) and thymol (100 mg/kg) observed maximum inhibition percentage (98.58% and 79.37%, respectively). Molecular docking study provides the evidence of thymol ability to inhibit H+/K+ ATPase. CONCLUSIONS: The findings revealed that T. ammi essential oil can be applied to treat gastric ulcer as a natural agent. Graphical abstract.
Asunto(s)
Ammi/química , Etanol/efectos adversos , Aceites Volátiles/administración & dosificación , Úlcera Péptica/tratamiento farmacológico , Animales , Monoterpenos Ciclohexánicos/administración & dosificación , Monoterpenos Ciclohexánicos/aislamiento & purificación , Monoterpenos Ciclohexánicos/farmacología , Cimenos/administración & dosificación , Cimenos/aislamiento & purificación , Cimenos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Cromatografía de Gases y Espectrometría de Masas , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Simulación del Acoplamiento Molecular , Aceites Volátiles/química , Aceites Volátiles/farmacología , Úlcera Péptica/inducido químicamente , Úlcera Péptica/metabolismo , Aceites de Plantas/administración & dosificación , Aceites de Plantas/química , Aceites de Plantas/farmacología , Ratas , Timol/administración & dosificación , Timol/aislamiento & purificación , Timol/farmacologíaRESUMEN
The aim of this study was to elucidate the gastroprotective activity and possible mechanism of involvement of araloside A (ARA) against ethanol- and aspirin-induced gastric ulcer in mice. The experimental mice were randomly divided into control, model, omeprazole (20 mg/kg, orally) and ARA (10, 20 and 40 mg/kg, orally). Gastric ulcer in mice was induced by intragastric administration of 80% ethanol (10 mL/kg) containing 15 mg/mL aspirin 4 h after drug administration on day 7. The results indicated that ARA could significantly raise gastric juice volume and acidity; ameliorate gastric mucosal blood flow, gastric binding mucus volume, ulcer index and ulcer inhibition rate; suppress H+/K+-ATPase activity, which was confirmed by computer-aided docking simulations; inhibit the release of mitochondrial cytochrome c into the cytoplasm; inhibit caspase-9 and caspase-3 activities and down-regulate mRNA expression levels; down-regulate the mRNA and protein expressions of apoptosis protease-activating factor-1 and protein expression of cleaved poly(ADP ribose) polymerase-1; and up-regulate Bcl-2 mRNA and protein expressions and down-regulate Bax mRNA and protein expressions, thus elevating the Bcl-2/Bax ratio in a dose-dependent manner. Histopathological observations further provided supportive evidence for the aforementioned results. The results demonstrated that ARA exerted beneficial gastroprotective effects on alcohol- and aspirin-induced gastric ulcer in mice, which was related to suppressing H+/K+-ATPase activity as well as pro-apoptotic protein expression, and promoting anti-apoptotic protein expression, thus alleviating gastric mucosal injury and cell death.
Asunto(s)
Antiulcerosos/uso terapéutico , Mucosa Gástrica/efectos de los fármacos , ATPasa Intercambiadora de Hidrógeno-Potásio/efectos de los fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/uso terapéutico , Úlcera Gástrica/prevención & control , Animales , Antiulcerosos/aislamiento & purificación , Antiulcerosos/farmacología , Factor Apoptótico 1 Activador de Proteasas/metabolismo , Aralia/química , Aspirina/efectos adversos , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Citocromos c/metabolismo , Evaluación Preclínica de Medicamentos , Etanol/efectos adversos , Jugo Gástrico/efectos de los fármacos , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Masculino , Ratones , Mitocondrias/metabolismo , Simulación del Acoplamiento Molecular , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Distribución Aleatoria , Flujo Sanguíneo Regional/efectos de los fármacos , Saponinas/aislamiento & purificación , Saponinas/farmacología , Úlcera Gástrica/inducido químicamenteRESUMEN
Four hundred structurally diverse drug-like compounds comprising the Medicines for Malaria Venture's 'Pathogen Box' were screened for their effect on a range of physiological parameters in asexual blood-stage malaria (Plasmodium falciparum) parasites. Eleven of these compounds were found to perturb parasite Na+, pH and volume in a manner consistent with inhibition of the putative Na+ efflux P-type ATPase PfATP4. All eleven compounds fell within the subset of 125 compounds included in the Pathogen Box on the basis of their having been identified as potent inhibitors of the growth of asexual blood-stage P. falciparum parasites. All eleven compounds inhibited the Na+-dependent ATPase activity of parasite membranes and showed reduced efficacy against parasites carrying mutations in PfATP4. This study increases the number of chemically diverse structures known to show a 'PfATP4-associated' phenotype, and adds to emerging evidence that a high proportion (7-9%) of the structurally diverse antimalarial compounds identified in whole cell phenotypic screens share the same mechanism of action, exerting their antimalarial effect via an interaction with PfATP4.
Asunto(s)
Antimaláricos/farmacología , Evaluación Preclínica de Medicamentos , ATPasa Intercambiadora de Hidrógeno-Potásio , Homeostasis/efectos de los fármacos , Metabolismo/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Inhibidores de la Bomba de Protones/farmacología , Antimaláricos/aislamiento & purificación , Cationes/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Inhibidores de la Bomba de Protones/aislamiento & purificación , Sodio/metabolismoRESUMEN
Myricetin (3,3',4',5,5',7-hexahydroxyflavone), a major flavonoid in berries and red wine, has been recently used as a health food supplement based on its antioxidant and antitumor properties. We report here that myricetin preferentially exerts inhibitory effects on gastric H+, K+-ATPase. Myricetin inhibited H+, K+-ATPase with a sub-micromolar IC50 value in an enzyme assay using freeze-dried tubulovesicles prepared from hog stomach. Na+, K+-ATPase and Ca2+-ATPase were also inhibited by myricetin in a dose-dependent manner, but the IC50 values for these enzymes were approximately an order of magnitude higher compared to the H+, K+-ATPase. In structure-inhibitory functional analysis of sixteen myricetin derivatives, several phenolic hydroxy groups attached to the flavonoid backbone were highlighted as essential modifications for the inhibition of P2-type ATPases. Furthermore, oral administration of myricetin significantly attenuated histamine-induced gastric acid secretion in an in vivo mouse assessment. Therefore, myricetin derivatives seem to be useful seed compounds for developing new drugs and supplements to alleviate gastric acid secretion.
Asunto(s)
Productos Biológicos/farmacología , Flavonoides/farmacología , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Estómago/enzimología , Animales , Productos Biológicos/química , Calcio/metabolismo , Flavonoides/química , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Inhibidores de la Bomba de Protones/química , Bombas de Protones/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
Acid suppressant SCH28080 and its derivatives reversibly reduce acid secretion activity of the H+,K+-ATPase in a K+ competitive manner. The results on homologation of the SCH28080 by varying the linker chain length suggested the improvement in efficacy. However, the pharmacokinetic studies reveal that the hydrophobic nature of the CH2 linker units may not help it to function as a better acid suppressant. We have exploited the role of linker unit to enhance the efficacy of such reversible acid suppressant drug molecules using hetero linker, i.e., disulfide and peroxy linkers. The logarithm of partition coefficient defined for a drug molecule relates to the partition coefficient, which allows the optimum solubility characteristics to reach the active site. The logarithm of partition coefficient calculated for the designed inhibitors suggests that inhibitors would possibly reach the active site in sufficient concentration like in the case of SCH28080. The steered molecular dynamics studies have revealed that the Inhibitor-1 with disulfide linker unit is more stable at the active site due to greater noncovalent interactions compared to the SCH28080. Centre of mass distance analysis suggests that the Cysteine-813 amino acid residue selectively plays an important role in the inhibition of H+,K+-ATPase for Inhibitor-1. Furthermore, the quantum chemical calculations with M11L/6-31+G(d,p) level of theory have been performed to account the noncovalent interactions responsible for the stabilization of inhibitor molecules in the active site gorge of the gastric proton pump at different time scale. The hydrogen bonding and hydrophobic interaction studies corroborate the center of mass distance analysis as well. Well-tempered metadynamics free energy surface and center of mass separation analysis for the Inhibitor-1 is in good agreement with the steered molecular dynamics results. The torsional angle of the linker units seems to be crucial for better efficacy of drug molecules. The torsional angle of linker units of SCH28080 (COCH2C) and of Inhibitor 1 (CSSC) prefers to lie within â¼60°-90° for a longer time during the simulations, whereas, the peroxy linker (COOC) of Inhibitor 2 prefers to adopt â¼120-160°. Therefore, it appears that the smaller torsion angle of linker units can achieve better interactions with the active site residues of H+,K+-ATPase to inhibit the acid secretion activity. The reversible drug molecules with disulfide linker unit would be a promising candidate as proton pump antagonist to H+,K+-ATPase.
Asunto(s)
ATPasa Intercambiadora de Hidrógeno-Potásio/química , Imidazoles/química , Inhibidores de la Bomba de Protones/química , Secuencia de Aminoácidos , Sitios de Unión/efectos de los fármacos , Dominio Catalítico/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Imidazoles/uso terapéutico , Simulación de Dinámica Molecular , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
Asunto(s)
ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Piperidinas/química , Potasio/metabolismo , Inhibidores de la Bomba de Protones/síntesis química , Compuestos de Espiro/química , Administración Intravenosa , Animales , Área Bajo la Curva , Sitios de Unión , Evaluación Preclínica de Medicamentos , Ácido Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/química , Semivida , Histamina/toxicidad , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Naftalenos/química , Piperidinas/síntesis química , Piperidinas/farmacocinética , Potasio/química , Inhibidores de la Bomba de Protones/química , Inhibidores de la Bomba de Protones/farmacocinética , Curva ROC , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
The natural alkaloid sanguinarine has remarkable therapeutic properties and has been used for centuries as a folk remedy. This compound exhibits interesting anticancer properties and is currently receiving attention as a potential chemotherapeutic agent. Nevertheless, limited information exists regarding its safety for developing organisms. Planarians are an animal model known for their extraordinary stem cell-based regenerative capabilities and are increasingly used for toxicological and pharmacological studies. Here, we report that sanguinarine, at micromolar concentrations, perturbs the regeneration process in the planarian Dugesia japonica. We show that sanguinarine exposure causes defects during anterior regeneration and visual system recovery, as well as anomalous remodelling of pre-existing structures. Investigating the effects of sanguinarine on stem cells, we found that sanguinarine perturbs the transcriptional profile of early and late stem cell progeny markers. Our results indicate that sanguinarine exposure alters cell dynamics and induces apoptosis without affecting cell proliferation. Finally, sanguinarine exposure influences the expression level of H +, K+-ATPase α subunit, a gene of the P-type-ATPase pump family which plays a crucial role during anterior regeneration in planaria. On the whole, our data reveal that sanguinarine perturbs multiple mechanisms which regulate regeneration dynamics and contribute to a better understanding of the safety profile of this alkaloid in developing organisms.
Asunto(s)
Apoptosis/efectos de los fármacos , Benzofenantridinas/farmacología , Isoquinolinas/farmacología , Planarias/efectos de los fármacos , Regeneración/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Planarias/genética , Planarias/metabolismo , Regeneración/fisiología , Células Madre/efectos de los fármacos , Células Madre/fisiologíaRESUMEN
BACKGROUND: We previously described the gastroprotective effect of 2-phenylquinoline (2-PQ), the main alkaloid isolated from the bark of Galipea longiflora (Rutaceae). However, despite the significant and promising results, the pharmacological mechanisms of the gastroprotection induced by 2-PQ have not been investigated. PURPOSE: To evaluate the mechanisms underlying the gastroprotective effects of 2-PQ. STUDY DESIGN: We used an in vivo mouse ulcer model and in vitro methodologies involving Hâº/Kâº-ATPase and L929 murine fibroblasts. METHODS: The gastroprotective activity of 2-PQ (10-100 mg/kg, orally, p.o) was assessed against gastric ulcer induced by 60% ethanol/0.03 M hydrochloric acid (HCl) in mice or that induced by indomethacin (80 mg/kg, p.o) in rats. The cytotoxicity was assessed in L929 murine fibroblasts. Ulcerated tissues were analyzed histologically, histochemically, and biochemically. The antisecretory activity of 2-PQ was evaluated in vivo and in vitro. RESULTS: 2-PQ showed no cytotoxicity, reduced the lesion area induced by ethanol/HCl (log half-maximal effective dose, ED50 = 1.507), and the histological evaluation supported these results. Furthermore, 2-PQ reduced indomethacin-induced gastric ulceration. The gastroprotection was accompanied by normalization of superoxide dismutase (SOD) and glutathione-S-transferase (GST) activity, an intense increase in reduced glutathione (GSH) levels, and reduction in lipid peroxide (LPO) and tumor necrosis factor (TNF)-α levels in the gastric mucosa. The antisecretory properties of 2-PQ were confirmed by the decreased volume and total acidity of the gastric juice, and it reduced histamine- or pentagastrin-stimulated gastric acid secretion. However, 2-PQ did not change the in vitro Hâº/Kâº-ATPase activity or the content of gastric-adhered mucous in mice. In addition, pretreatment with N-ethylmaleimide, NG-nitro-l-arginine methyl esters, yohimbine, or indomethacin reversed the gastroprotective effect of 2-PQ, suggesting nitric oxide, nonprotein sulfhydryl compounds, α-2-receptors, and prostaglandin were involved. CONCLUSION: 2-PQ provides gastroprotection by reducing oxidative damage and inhibiting acid secretion mediated by histaminergic and gastrinergic regulatory pathways.
Asunto(s)
Alcaloides/farmacología , Antiulcerosos/farmacología , Mucosa Gástrica/efectos de los fármacos , Extractos Vegetales/farmacología , Quinolinas/farmacología , Rutaceae/química , Úlcera Gástrica/metabolismo , Alcaloides/aislamiento & purificación , Alcaloides/uso terapéutico , Animales , Antiulcerosos/aislamiento & purificación , Antiulcerosos/uso terapéutico , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Etanol/efectos adversos , Ácido Gástrico/metabolismo , Jugo Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Glutatión/metabolismo , Glutatión Transferasa/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Ácido Clorhídrico , Indometacina , Masculino , Ratones , Corteza de la Planta/química , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Quinolinas/aislamiento & purificación , Quinolinas/uso terapéutico , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/patología , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
ETHNO-PHARMACOLOGICAL RELEVANCE: Pattanga is botanically equated as Caesalpinia sappan Linn. (Family: Caesalpiniaceae) and is used in Ayurveda system of medicine since ages. According to Ayurveda, useful part is Heartwood, which is bitter, astringent and acrid and is useful in vitiated conditions of vata and pitta, burning sensation, wounds, ulcers, leprosy, skin diseases, menorrhagia, leucorrhea, and diabetes. It is used as a major ingredient in Ayurvedic formulations and preparations like Patrangasava, Chandanadya Thalia, and Karpuradyarka. AIM OF THE STUDY: The present study is planned to evaluate the gastroprotective activity of the selected Ayurvedic drug using three different in vivo gastric ulcer models, so as to provide scientific evidence for the Ayurvedic claims. MATERIALS AND METHODS: For this study, Wistar albino rats fasted overnight were selected. The hydroalcoholic extract of Caesalpinia sappan heartwood at the dose level 250 and 500mg/kg body weight was selected and administered orally before necrotizing agents. Antioxidant and antiulcer parameters were evaluated and the stomach samples were subjected for histopathological studies. In addition, PGE2 estimation and protein expressions of COX-1, COX-2 and iNOS were analyzed by Western blot. The plant extract was subjected to LCMS/MS analysis. In addition, Cytoprotective effect in isolated gastric mucosal cells, TUNEL Assay, Acid neutralizing capacity assay, H+/K+ ATPase inhibitory assay were performed. RESULTS: The ulcer protection was found to be 92%, 86% and 64% against ethanol, NSAID and pylorus ligation induced ulcer respectively. The hydro-alcoholic extract of C. sappan heartwood exhibited cytoprotective effect with 76.82% reduction against indomethacin-induced cytotoxicity at the concentration of 25µg/ml. C. sappan showed 63.91% inhibition in H+/K+ ATPase inhibitory assay at the concentration 500µg/ml. CONCLUSIONS: Our results depict that Caesalpinia sappan heartwood possesses gastroprotective activity, possibly mediated through cytoprotection and antioxidant mechanisms. The data obtained in the present study provides scientific support for the traditional use of Caesalpinia sappan in the management of peptic ulcer.
Asunto(s)
Caesalpinia/química , Mucosa Gástrica/efectos de los fármacos , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/química , Antiulcerosos/farmacología , Antioxidantes/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Etanol/química , Femenino , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Indometacina/farmacología , Proteínas de la Membrana/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fitoterapia/métodos , Extractos Vegetales/química , Sustancias Protectoras/química , Ratas , Ratas Wistar , Úlcera Gástrica/metabolismoRESUMEN
How the immune system maintains peripheral tolerance under inflammatory conditions is poorly understood. Here we assessed the fate of gastritogenic T cells following inflammatory activation in vivo. Self-reactive T cells (A23 T cells) specific for the gastric H+ /K+ ATPase α subunit (HKα) were transferred into immunosufficient recipient mice and immunised at a site distant to the stomach with adjuvant containing the cognate HKα peptide antigen. Activation of A23 T cells by immunisation did not impact on either immune tolerance or protection from gastric autoimmunity in wild-type BALB/c mice. However, increased presentation of endogenously derived HKα epitopes by dendritic cells (DCs) in the gastric lymph node of IE-H+ /K+ ß transgenic mice (IEß) reduces A23 T-cell tolerance to gastric antigens after inflammatory activation, with subsequent development of gastritis. While HKα-specific A23 T cells from immunised wild-type mice were poorly responsive to in vitro antigen specific activation, A23 T cells from immunised IEß transgenic mice were readily re-activated, indicating loss of T-cell anergy. These findings show that DCs of gastric lymph nodes can maintain tolerance of pathogenic T cells following inflammatory stimulation and that the density of endogenous antigen presented to self-reactive T cells is critical in the balance between tolerance and autoimmunity.
Asunto(s)
Presentación de Antígeno , Autoantígenos/inmunología , Autoinmunidad , Susceptibilidad a Enfermedades , Gastritis/inmunología , Animales , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Anergia Clonal/genética , Anergia Clonal/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Gastritis/metabolismo , Gastritis/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Inmunofenotipificación , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Fenotipo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Delonix regia, commonly called Flame Tree or Flamboyant (locally, Gul Mohor) is a common tree traditionally used to treat various diseases like gastric problems, body pain, rheumatic pains of joints and wound healing. Here, we carried out biological profiling of Delonix regia as antiulcer agent. Antiulcer activity of the ethanol extract from stem bark was evaluated on pylorus ligation and indomethacin induced ulcer in Wistar albino rats. Ethanol extract from stem bark of D.regia was administered at the doses 100, 200 and 400 mg/kg/day, p.o. for 7 days. Ulcer index, gastric pH, volume, free acidity, total acidity, total carbohydrate (TC), protein (P), mucin content (TC/P) and gastric mucus were evaluated in pylorus ligation model, while ulcer index, malondialdehyde, GSH, PGE2, and gastric mucus were estimated in the indomethacin induced ulcer model. Ex vivo assay for the activity of H+/K+-ATPase was also done. The results showed significant inhibition on H+/K+-ATPase in a dose dependent manner and comparableto their respective positive control group of rats demonstrating that ethanol extract of stem bark of Delonix regia possesses significant antiulcer properties.