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1.
Cochrane Database Syst Rev ; 1: CD013133, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33448032

RESUMO

BACKGROUND: Symptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored. OBJECTIVES: To determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding. MAIN RESULTS: We included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision. AUTHORS' CONCLUSIONS: High-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Indometacina/uso terapêutico , Viés , Displasia Broncopulmonar/epidemiologia , Causas de Morte , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/cirurgia , Enterocolite Necrosante/induzido quimicamente , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Incidência , Indometacina/administração & dosagem , Indometacina/efeitos adversos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Ligadura/estatística & dados numéricos , Oxigenoterapia/estatística & dados numéricos , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos
2.
Yakugaku Zasshi ; 140(11): 1343-1350, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132270

RESUMO

Disruption of redox balance due to the overproduction of free radicals and reactive oxygen species (ROS) could cause protein denaturation, lipid peroxidation, and DNA mutation. These lead to an induction of gastrointestinal diseases such as gastric ulcers induced by long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) and ulcerative colitis. Magnetic resonance technique, which is non-invasive and free of radiation exposure, is a promising tool for evaluating redox status in the living body. This study investigated ROS production in rats with gastric ulcers induced by a typical NSAIDs indomethacin using in vivo ESR/spin probe technique. The ESR signal intensity of membrane-permeable nitroxyl probe in the indomethacin group showed enhanced decay compared with the vehicle group, but the enhancement was not observed in the presence of a membrane-permeable ROS scavenger, suggesting the intracellular ROS production. The imaging analysis using Overhauser-enhanced MRI (OMRI) with dual probes labeled with 14N and 15N enabled visualization of ROS production in the glandular stomach of rat with indomethacin-induced gastric ulcers. The intracellular ROS production in the distal and proximal colon in the initiation stage and intra- and extra-cellular ROS production of the advanced stage of colitis induced by dextran sodium sulfate (DSS) using the OMRI/dual-probe technique was observed. Furthermore, nitration of src homology protein tyrosine phosphatase 2 in macrophages might be involved in the activation of Toll-like receptor 4 and NF-κB, inducing infiltration of activated neutrophils into colonic mucosa to produce ROS in DSS-induced colitis mice.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Colite/metabolismo , Sulfato de Dextrana/efeitos adversos , Radicais Livres/metabolismo , Indometacina/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Úlcera Gástrica/metabolismo , Animais , Espectroscopia de Ressonância de Spin Eletrônica , Ratos
4.
Rev. Hosp. Ital. B. Aires (2004) ; 40(1): 34-38, mar. 2020. tab
Artigo em Espanhol | LILACS | ID: biblio-1102292

RESUMO

Las mujeres han sido tratadas por décadas con testosterona intentando aliviar una gran variedad de síntomas con riesgos y beneficios inciertos. En la mayoría de los países, la testosterona se prescribe "off-label", de modo que las mujeres están utilizando compuestos y dosis ideadas para tratamientos en hombres. En este sentido, varias sociedades médicas de distintos continentes adoptaron recientemente por consenso una toma de posición sobre los beneficios y potenciales riesgos de la terapia con testosterona en la mujer, explorar las áreas de incertidumbre e identificar prácticas de prescripción con potencial de causar daño. Las recomendaciones con respecto a los beneficios y riesgos de la terapia con testosterona se basan en los resultados de ensayos clínicos controlados con placebo de al menos 12 semanas de duración. A continuación se comentan las recomendaciones. (AU)


There are currently no clear established indications for testosterone replacement therapy for women. Nonetheless, clinicians have been treating women with testosterone to alleviate a variety of symptoms for decades with uncertainty regarding its benefits and risks. In most countries, testosterone therapy is prescribed off-label, which means that women are using testosterone formulations or compounds approved for men with a modified dose for women. Due to these issues, there was a need for a global Consensus Position Statement on testosterone therapy for women based on the available evidence from placebo randomized controlled trials (RCTs). This Position Statement was developed to inform health care professionals about the benefits and potential risks of testosterone therapy intended for women. The aim of the Consensus was to provide clear guidance as to which women might benefit from testosterone therapy; to identify symptoms, signs, and certain conditions for which the evidence does not support the prescription of testosterone; to explore areas of uncertainty, and to identify any prescribing practices that have the potential to cause harm. (AU)


Assuntos
Humanos , Feminino , Idoso , Testosterona/uso terapêutico , Pós-Menopausa/efeitos dos fármacos , Depressores do Apetite/efeitos adversos , Fenitoína/efeitos adversos , Placebos/administração & dosagem , Psicotrópicos/efeitos adversos , Tamoxifeno/efeitos adversos , Testosterona/administração & dosagem , Testosterona/análise , Testosterona/efeitos adversos , Testosterona/farmacologia , Fármacos Cardiovasculares/efeitos adversos , Indometacina/efeitos adversos , Hormônio Liberador de Gonadotropina/efeitos adversos , Pós-Menopausa/fisiologia , Ensaios Clínicos Controlados como Assunto , Antagonistas Colinérgicos/efeitos adversos , Anticoncepcionais Orais/efeitos adversos , Disfunções Sexuais Psicogênicas/etiologia , Disfunções Sexuais Psicogênicas/terapia , Danazol/efeitos adversos , Consenso , Inibidores da Aromatase/efeitos adversos , Uso Off-Label , Inibidores do Fator Xa/efeitos adversos , Anfetaminas/efeitos adversos , Antagonistas dos Receptores Histamínicos/efeitos adversos , Antagonistas de Androgênios/efeitos adversos , Androgênios/fisiologia , Cetoconazol/efeitos adversos , Entorpecentes/efeitos adversos
5.
Cochrane Database Syst Rev ; 2: CD003481, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32045960

RESUMO

BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-weight, or preterm and low-birth-weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 30 November 2017), Embase (1980 to 30 November 2017), and CINAHL (1982 to 30 November 2017). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 39 studies enrolling 2843 infants. Ibuprofen (IV) versus placebo: IV Ibuprofen (3 doses) reduced the failure to close a PDA compared with placebo (typical relative risk (RR); 0.62 (95% CI 0.44 to 0.86); typical risk difference (RD); -0.18 (95% CI -0.30 to -0.06); NNTB 6 (95% CI 3 to 17); I2 = 65% for RR and I2 = 0% for RD; 2 studies, 206 infants; moderate-quality the evidence). One study reported decreased failure to close a PDA after single or three doses of oral ibuprofen compared with placebo (64 infants; RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4; I2 test not applicable). Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure (typical RR 1.07, 95% CI 0.92 to 1.24; typical RD 0.02, 95% CI -0.02 to 0.06; I2 = 0% for both RR and RD; moderate-quality evidence). A reduction in NEC (necrotising enterocolitis) was noted in the ibuprofen (IV or oral) group (18 studies, 1292 infants; typical RR 0.68, 95% CI 0.49 to 0.94; typical RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; I2 = 0% for both RR and RD; moderate-quality evidence). There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies, 576 infants; typical RR 0.28, 95% CI 0.14 to 0.54; typical RD -0.09, 95% CI -0.14 to -0.05; NNTB 11, 95% CI 7 to 20; I2 = 24% for RR and I2 = 69% for RD; moderate-quality evidence). The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants; MD -8.12 µmol/L, 95% CI -10.81 to -5.43). For this comparison, there was high between-study heterogeneity (I2 = 83%) and low-quality evidence. Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09; I2 = 0% for both RR and RD). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was low-quality evidence for these two outcomes. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants; typical RR 0.38, 95% CI 0.26 to 0.56; typical RD -0.22, 95% CI -0.31 to -0.14; NNTB 5, 95% CI 3 to 7; moderate-quality evidence). There was a decreased risk of failure to close a PDA with high-dose versus standard-dose of IV ibuprofen (3 studies 190 infants; typical RR 0.37, 95% CI 0.22 to 0.61; typical RD - 0.26, 95% CI -0.38 to -0.15; NNTB 4, 95% CI 3 to 7); I2 = 4% for RR and 0% for RD); moderate-quality evidence). Early versus expectant administration of IV ibuprofen, echocardiographically-guided IV ibuprofen treatment versus standard IV ibuprofen treatment, continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, and rectal ibuprofen versus oral ibuprofen were studied in too few trials to allow for precise estimates of any clinical outcomes. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Therefore, of these two drugs, ibuprofen appears to be the drug of choice. The effectiveness of ibuprofen versus paracetamol is assessed in a separate review. Oro-gastric administration of ibuprofen appears as effective as IV administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically-guided versus standard IV ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.


Assuntos
Permeabilidade do Canal Arterial/tratamento farmacológico , Ibuprofeno/uso terapêutico , Recém-Nascido de Baixo Peso , Inibidores de Ciclo-Oxigenase/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Humanos , Ibuprofeno/efeitos adversos , Indometacina/efeitos adversos , Indometacina/uso terapêutico , Recém-Nascido , Recém-Nascido Prematuro , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Food Funct ; 11(1): 662-679, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31895380

RESUMO

Our previous studies have demonstrated that the total triterpenes from the fruits of Chaenomeles speciosa (CSTT) exhibit effective therapeutic effects on gastric ulcer patients and animals. The present aim is to further investigate the mechanisms involved. The results indicated that CSTT could ameliorate IND-induced gastric injury, which was related to promoting IND-damaged GES-1 cell proliferation and migration, improving the IND-damaged rat GBF, ulcer area, inhibition rate and pathologic changes of gastric mucous tissue, increasing the amount of adhered gastric mucus, attenuating the volume and total acidity of the gastric effluents, and augmenting the gastric pH; further studies showed that CSTT obviously downregulated miR-423-5p mRNA, NAG-1 mRNA and protein expression, Bax, Bad, cytosol cytochrome C, Apaf-1, cleaved-caspase-3, and cleaved-caspase-9 protein expression and cytosol cytochrome C concentration, and upregulated TFF1, TFF2 and TFF3 mRNA and protein expression, Bcl-2, Bcl-xl, pro-caspase-3, and pro-caspase-9 protein expression, mitochondrial viability, mitochondrial cytochrome C concentration and Bcl-2/Bax, Bcl-xl/Bad ratios. These findings demonstrated that CSTT protected against IND-induced gastric damage by depressing miR-423-5p expression and modulating the TFF/NAG-1 pathway, which in turn restrained mitochondrion-mediated apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Fator 15 de Diferenciação de Crescimento/metabolismo , MicroRNAs/genética , Rosaceae/química , Úlcera Gástrica/tratamento farmacológico , Fator Trefoil-1/metabolismo , Triterpenos/administração & dosagem , Animais , Frutas/química , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Indometacina/efeitos adversos , Masculino , MicroRNAs/metabolismo , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/genética , Úlcera Gástrica/metabolismo , Úlcera Gástrica/fisiopatologia , Fator Trefoil-1/genética , Triterpenos/química
7.
J Gastroenterol Hepatol ; 35(1): 110-117, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31359491

RESUMO

BACKGROUND AND AIM: Dietary emulsifiers are widely used in processed foods and officially approved as safe for intake. However, recent studies have demonstrated that some emulsifiers alter the colonic microbiota, leading to colonic low-grade inflammation, in mice. The effect of dietary emulsifiers on small-intestinal microbiota, which is important for gut immunity, has not been studied. We aimed to investigate the effect of a representative dietary emulsifier, polysorbate-80 (P80), on the small-intestinal microbiota in normal mice. METHODS: Some mice were pretreated with P80 for 8 weeks with or without indomethacin administration on the last 2 days, and intestinal damage was evaluated histologically. The ileal and colonic microbiota composition was assessed using 16S rRNA polymerase chain reaction. RESULTS: Polysorbate-80 increased the Gammaproteobacteria abundance and decreased the α-diversity in the small intestine. No decrease in α-diversity was observed in the colon. P80 pretreatment exacerbated the indomethacin-induced small-intestinal lesions and significantly increased the interleukin-1ß expression. Culture of ileal content on deoxycholate hydrogen sulfide lactose agar showed that P80 significantly increased the colonies of the sulfide-producing bacteria Proteus spp. (genetically identified as Proteus mirabilis). Antibiotic pretreatment abolished the P80-induced aggravation of indomethacin-induced ileitis. Motility assay in semisolid agar showed that adding 0.02% P80 to the agar significantly increased the diameter of P. mirabilis colonies but not that of Escherichia coli colonies. CONCLUSIONS: Polysorbate-80 enhances the vulnerability of the small intestine to indomethacin-induced injury by inducing ileal dysbiosis. Direct enhancement of the motility of specific flagellated microbiota by P80 might be related to dysbiosis and intestinal injury.


Assuntos
Disbiose , Emulsificantes/efeitos adversos , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/microbiologia , Polissorbatos/efeitos adversos , Animais , Humanos , Camundongos
10.
J Matern Fetal Neonatal Med ; 33(4): 645-650, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29986620

RESUMO

Introduction: Premature birth is a leading cause of neonatal morbidity and mortality. Since gestational age at birth is the most important predictive factor of adverse neonatal outcomes, strategies to postpone premature labor are of major importance. Studies on tocolytic drugs show that COX inhibitors such as indomethacin are superior to others in terms of efficiency in delaying birth, but results concerning neonatal outcomes associated with prenatal exposure to these drugs show controversial results. Indomethacin is also used in the postnatal age for pharmacologic treatment of patent ductus arteriosus (PDA), but no data concerning the effects of antenatal exposure on postnatal ductal patency are available.Methods: In this study, we focused primarily on the association between antenatal indomethacin (AI) and postnatal patency of ductus arteriosus while our secondary aim was to highlight any possible influence of AI exposure on adverse neonatal outcomes. We performed a retrospective analysis of 241 medical records of newborns born before 33 weeks' gestation and exposed to antenatal tocolysis. Obstetrical data and neonatal outcomes of newborns exposed to AI were compared to those of neonates exposed to other tocolytic drugs. Early ductal closure (EDC) was defined when functional echocardiography performed within 24 hours of life showed a closed duct. Occurrence of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), respiratory distress syndrome (RDS), chronic lung disease (CLD), necrotizing enterocolitis (NEC), sepsis, and PDA were compared between the groups and the diagnosis of at least one of III-IV grade IVH, PVL, CLD, sepsis, surgical NEC, or death was defined as a severe outcome.Results: The univariate analysis showed that infants in the AI group were at a higher risk of IVH, CLD, RDS, sepsis, and PDA. The incidence of severe outcomes also appeared to be higher in this group, while no effect of AI on PDA was observed. Since we noticed that infants exposed to AI had a lower gestational age and worse clinical conditions at birth when compared to the controls, we considered this as a confounding factor. To overcome this bias, we performed a multivariate analysis that evidenced no significant role of AI on the occurrence of severe outcomes. On the other hand, a possible association was confirmed for all degrees of IVH (OR: 3.16, 95% CI : [1.41; 7.05]) and sepsis (OR: 2.81, 95% CI: [1.24; 6,28]).Conclusions: The unexpected result shown by the multivariate analysis was the association between AI exposure and EDC (OR: 2.52, 95% CI: [1.02; 6.21]). This result, which has never been evidenced in previous studies, has great clinical importance. It is well known that PDA is more frequent at lower gestational ages, thus reducing the incidence of PDA could lead to an improvement of overall outcomes in extremely preterm newborns.


Assuntos
Canal Arterial/efeitos dos fármacos , Indometacina/efeitos adversos , Tocolíticos/efeitos adversos , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez , Estudos Retrospectivos
12.
Sci Transl Med ; 11(516)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666403

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal-regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Comunicação Parácrina , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/terapia , Cicatrização , Animais , Proliferação de Células/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Endoscopia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Indometacina/efeitos adversos , Inflamação/patologia , Inflamação/terapia , Células-Tronco Mesenquimais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo , Comunicação Parácrina/efeitos dos fármacos , Úlcera Péptica/patologia , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Reepitelização/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Úlcera Gástrica/terapia , Suínos , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Cicatrização/efeitos dos fármacos
13.
Sci Rep ; 9(1): 16796, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727909

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Interleucina-17/genética , Intestino Delgado/microbiologia , RNA Ribossômico 16S/genética , Animais , Bifidobacterium/classificação , Bifidobacterium/efeitos dos fármacos , Bifidobacterium/isolamento & purificação , Dextranos/metabolismo , Modelos Animais de Doenças , Disbiose/sangue , Disbiose/induzido quimicamente , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/imunologia , Lipopolissacarídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Análise de Sequência de DNA , Regulação para Cima
14.
Sci Rep ; 9(1): 17490, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767915

RESUMO

Proton pump inhibitors (PPIs) alter the composition of the intestinal microbiome, exacerbating indomethacin (IND)-induced small intestinal damage. Vonoprazan fumarate inhibits gastric acid secretion using a different mechanism from PPIs. We investigated the effects of both drugs on the intestinal microbiome and IND-induced small intestinal damage. We sought to clarify whether PPI-induced dysbiosis and worsening of the damage were due to a specific drug class effect of PPIs. Rabeprazole administration increased operational taxonomic unit numbers in the small intestines of C57BL/6 J mice, whereas the difference was not significant in the vonoprazan-treated group but exhibited a trend. Permutational multivariate analysis of variance of the unweighted UniFrac distances showed significant differences between vehicle- and vonoprazan- or rabeprazole-treated groups. L. johnsonii was the predominant microbial species, and the population ratio decreased after vonoprazan and rabeprazole administration. The vonoprazan- and rabeprazole-treated groups showed increased IND-induced damage. This high sensitivity to IND-induced damage was evaluated by transplantation with contents from the small intestine of mice treated with either vonoprazan or rabeprazole. Supplementation of L. johnsonii orally in mice treated with rabeprazole and vonoprazan prevented the increase in IND-induced small intestinal damage. In conclusion, both rabeprazole and vonoprazan aggravated NSAID-induced small intestinal injury by reducing the population of L. johnsonii in the small intestine via suppressing gastric acid secretion.


Assuntos
Disbiose/induzido quimicamente , Indometacina/efeitos adversos , Intestino Delgado/lesões , Lactobacillus johnsonii/isolamento & purificação , Inibidores da Bomba de Prótons/efeitos adversos , Animais , Modelos Animais de Doenças , Disbiose/microbiologia , Transplante de Microbiota Fecal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Indometacina/administração & dosagem , Injeções Intraperitoneais , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/microbiologia , Lactobacillus johnsonii/efeitos dos fármacos , Lactobacillus johnsonii/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Pirróis/efeitos adversos , RNA Ribossômico 16S/genética , Rabeprazol/administração & dosagem , Rabeprazol/efeitos adversos , Análise de Sequência de DNA , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
15.
J Pediatr Gastroenterol Nutr ; 69(6): 710-718, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31764439

RESUMO

OBJECTIVES: Alanylglutamine (AG) is a dipeptide that fuels enterocytes and has a coadjuvant role during gut healing. The current study aimed to investigate the potential ulcer-healing effect of AG in indomethacin-induced gastropathy. METHODS: Animals (n = 10 rats/group) were randomly allocated into 5 groups. Gastric ulcerated rats were administered AG, AG + dexamethasone, or pantoprazole after indomethacin exposure. RESULTS: Comparable to pantoprazole, AG inhibited H-KATPase pump, and elevated the pH of gastric juice. Moreover, the dipeptide increased the serum/mucosal contents of glucagon-like peptide-1 (GLP-1), pS473-Akt, and cyclin-D1. On the contrary, AG abated serum tumor necrosis factor-α and gastric mucosal content of pS45-ß catenin, pS9-GSK3ß, pS133-CREB, pS536-NF-κB, H2O2, claudin-1, and caspase-3. The administration of dexamethasone before AG hampered its effect on almost all the measured parameters. CONCLUSIONS: AG confers its antiulcerogenic/antisecretory potentials by repressing the proton pump to increase the gastric juice pH via boosting p-CREB, p-Akt, p-GSK-3ß, and GLP-1. Also, it inhibits apoptosis through suppressing nuclear factor-kappa B/tumor necrosis factor-α/H2O2/claudin-1 cue. This trajectory contributes to loosen the tight junction priming AG-mediated GLP-1/ß-catenin/cyclin-D1 that results in pronounced increase in gastric mucosa proliferation. Therefore, the crosstalk between multiple pathways orchestrates the action of AG against gastric ulceration.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Dipeptídeos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Úlcera Gástrica/patologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Dexametasona/metabolismo , Dexametasona/farmacologia , Dipeptídeos/administração & dosagem , Dipeptídeos/metabolismo , Humanos , Indometacina/efeitos adversos , Indometacina/farmacologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Úlcera Gástrica/tratamento farmacológico , Cicatrização/efeitos dos fármacos
16.
Mol Hum Reprod ; 25(12): 825-837, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633177

RESUMO

Prostaglandin E2 (PGE2) is a hormone with many physiological functions. During pregnancy, it is generally believed that there is a high level of PGE2 at the final stage of pregnancy, which induces the contraction of uterine smooth muscle and promotes the occurrence of childbirth. However, we find that high PGE2 levels are present throughout late pregnancy in mice, not just during childbirth, and that PGE2 deficiency induced by indomethacin during late pregnancy causes damage to the placental labyrinth and eventually leads to abortion. Interestingly, the damage is closely related to inflammation, which involves the role of inflammatory factors produced by the periaortic lymph nodes (PLNs) near the uterus. Further, through RNA sequencing, we reveal that PLNs produce a large amount of interleukin-1ß (IL-1ß) when exposed to PGE2 deficiency, which causes damage to the placental labyrinth, probably via destroying the extracellular matrix. Finally, events leading to abortion following indomethacin administration are effectively prevented by supplementing PGE2 or by PLN removal. These results suggest that high levels of PGE2 during late pregnancy protect fetuses from inflammatory damage related to IL-1ß. This work suggests a new role of PGE2 during late pregnancy and may provide potential therapeutic strategies for pathological pregnancy.


Assuntos
Aborto Espontâneo/sangue , Vilosidades Coriônicas/patologia , Dinoprostona/deficiência , Dinoprostona/metabolismo , Interleucina-1beta/metabolismo , Animais , Proteína C-Reativa , Matriz Extracelular/patologia , Feminino , Humanos , Indometacina/efeitos adversos , Inflamação/patologia , Interleucina-1beta/sangue , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/sangue , Gravidez
17.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600995

RESUMO

Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30-190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.


Assuntos
Alanina/análogos & derivados , Anti-Inflamatórios não Esteroides/efeitos adversos , Hemorragia Gastrointestinal/etiologia , Indometacina/efeitos adversos , Nanopartículas , Quinolonas/administração & dosagem , Alanina/administração & dosagem , Animais , Hemorragia Gastrointestinal/tratamento farmacológico , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Nanopartículas/química , Nanopartículas/ultraestrutura , Óxido Nítrico/metabolismo , Ratos , Difração de Raios X
18.
Am J Physiol Gastrointest Liver Physiol ; 317(6): G862-G871, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545918

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DFN) and indomethacin (INDO) are extensively used worldwide. Their main side effects are injury of the gastrointestinal tract, including erosions, ulcers, and bleeding. Since gastric epithelial cells (GEPCs) are crucial for mucosal defense and are the major target of injury, we examined the extent to which DFN- and INDO-induced GEPC injury can be reversed by nerve growth factor (NGF), 16,16 dimethyl prostaglandin E2 (dmPGE2), and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), the pharmacological activator of the metabolic sensor AMP kinase (AMPK). Cultured normal rat gastric mucosal epithelial (RGM1) cells were treated with PBS (control), NGF, dmPGE2, AICAR, and/or NSAID (DFN or INDO) for 1-4 h. We examined cell injury by confocal microscopy, cell death/survival using calcein AM, mitochondrial membrane potential using MitoTracker, and phosphorylation of AMPK by Western blotting. DFN and INDO treatment of RGM1 cells for 2 h decreased mitochondrial membrane potential and cell viability. NGF posttreatment (initiated 1 or 2 h after DFN or INDO) reversed the dissipation of mitochondrial membrane potential and cell injury caused by DFN and INDO and increased cell viability versus cells treated for 4 h with NSAID alone. Pretreatment with dmPGE2 and AICAR significantly protected these cells from DFN- and INDO-induced injury, whereas dmPGE2 and AICAR posttreatment (initiated 1 h after NSAID treatment) reversed cell injury and significantly increased cell viability and rescued the cells from NSAID-induced mitochondrial membrane potential reduction. DFN and INDO induce extensive mitochondrial injury and GEPC death, which can be significantly reversed by NGF, dmPGE2, and AICAR.NEW & NOTEWORTHY This study demonstrated that mitochondria are key targets of diclofenac- and indomethacin-induced injury of gastric epithelial cells and that diclofenac and indomethacin injury can be prevented and, importantly, also reversed by treatment with nerve growth factor, 16,16 dimethyl prostaglandin E2, and 5-aminoimidazole-4-carboxamide ribonucleotide.


Assuntos
16,16-Dimetilprostaglandina E2/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Diclofenaco/efeitos adversos , Mucosa Gástrica , Indometacina/efeitos adversos , Mitocôndrias , Fator de Crescimento Neural/farmacologia , Ribonucleosídeos/farmacologia , Aminoimidazol Carboxamida/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos
19.
BMC Complement Altern Med ; 19(1): 205, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391093

RESUMO

BACKGROUND: Gastric ulcer is one of the most prevalent diseases worldwide. In Iranian folk medicine, Achillea wilhelmsii (AW) is used as a treatment for gastric ulcer. Previous reports also mentioned Antiulcerogenic properties for this herbal plant. This study investigated the therapeutic effects of Achillea wilhelmsii C. Koch extract on indomethacin-induced gastric lesion in rats, from both proteomic and metabolomic perspectives. METHODS: The rats were divided into 4 groups. Gastric ulceration was induced by a single dose of indomethacin (45 mg/kg) by oral gavage. An amount of 800 mg/kg of AW extract was administered orally. Serum and tissue samples were collected for further investigations. The metabolomic study was performed by 1H-NMR CPMG spectrometry. Proteomic analysis was also executed by using two dimensional gel electrophoresis (2DE) followed by liquid chromatography coupled to tandem mass spectrometry (LC-ESI/MS/MS). Real time PCR was used to confirm some of the genes. RESULTS: The macroscopic and microscopic investigations confirmed the effectiveness of the AW extract. There was a panel of metabolites which showed alteration during gastric lesion development. The levels of some of these metabolite reversed nearly to their control values after the administration of AW extract. There were also changes in the levels of some proteins including Alb, Fabp5, Hspb1, Tagln, Lgals7, Csta and Myl9 which were reversed after AW administration. CONCLUSIONS: Our findings suggested that Achillea wilhelmsii C. Koch extract could be a potential therapy to be used for indomethacin-induced gastric lesion treatment in the future. However, further investigations are needed to confirm the results.


Assuntos
Achillea/química , Antiulcerosos/administração & dosagem , Extratos Vegetais/administração & dosagem , Úlcera Gástrica/tratamento farmacológico , Animais , Antiulcerosos/isolamento & purificação , Humanos , Indometacina/efeitos adversos , Masculino , Metabolômica , Extratos Vegetais/isolamento & purificação , Proteômica , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/genética , Úlcera Gástrica/metabolismo
20.
Int J Biol Macromol ; 141: 68-75, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31446106

RESUMO

Galactomannans are neutral polysaccharides isolated from the endosperm of some Leguminosae seeds. They consist of a (1 → 4) linked ß-mannopyranosyl backbone partially substituted at O-6 with α-d-galactopyranosyl side groups. C. pulcherrima have anti-inflammatory and muco-adhesive proprieties. Acute gastritis is an inflammatory disease triggered by use of non-steroidal anti-inflammatory drugs. We investigated the gastroprotective effect of galactomannan obtained from the seeds of Caesalpinia pulcherrima L. (GM-CP) in acute gastritis model induced by indomethacin. Gastritis was induced with indomethacin (30 mg/kg, P.·O.) in female Swiss mice. Animal groups (n = 7) were pretreated with saline-dissolved GM-CP (3 mg/kg, 10 mg/kg, 30 mg/kg, P.O.) or vehicle 1 h before gastritis induction. Mice were euthanized seven hours after the induction. The stomach and blood samples were collected for analysis. At 10 mg/kg, GP-CP reduced the extension of macroscopic lesion and the loss of superficial cells by alleviating inflammatory symptoms (neutrophil infiltration, migration and adhesion of mesenteric leukocytes, production of TNF-α and thiobarbituric acid reactive species (TBARS) and helping to maintain mucin labeling of the tissue. Thus, the findings of the study suggest that GM-CP exhibits gastroprotective effects.


Assuntos
Caesalpinia/química , Gastrite , Indometacina/efeitos adversos , Mananas/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Sementes/química , Doença Aguda , Animais , Feminino , Gastrite/induzido quimicamente , Gastrite/metabolismo , Gastrite/patologia , Gastrite/prevenção & controle , Indometacina/farmacologia , Mananas/química , Camundongos , Neutrófilos/patologia
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