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1.
J Med Chem ; 63(9): 4496-4505, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302130

RESUMO

The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resistance against enzymatic degradation or a significantly increased affinity toward the target receptor but never both. To enhance further the tumor-targeting properties of the minigastrin analogs, we studied conjugates with multiple amide-to-triazole substitutions for additive or synergistic effects. Promising candidates were identified by modification of two or three amide bonds, which yielded both improved stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics in mice bearing receptor-positive tumor xenografts revealed up to 4-fold increased tumor uptake in comparison to the all-amide reference compound [Nle15]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
2.
J Med Chem ; 63(9): 4484-4495, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302139

RESUMO

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg356 residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Conformação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
3.
Asian Pac J Cancer Prev ; 21(2): 331-336, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102507

RESUMO

AIM: Develop a program to identify, treat, and prevent severe atrophic gastritis to reduce gastric cancer incidence and mortality. MATERIALS AND METHODS: In total, 2,847 people aged > 40 years old underwent serological noninvasive screening for atrophic gastritis by identifying postprandial gastrin-17 and pepsinogen-1 in the fasting state. Anti-H pylori IgG was found in 2,134 patients. Seven years later, 2,220 patientswho had undergone serological noninvasive screening were asked to fill out a questionnaire survey (were interviewed). We could not find any information on 627 of 2,847 patients. Next, 75 patients with multifocal atrophic gastritis who underwent gastroscopy and biopsies (the Updated Sydney System (USS)) were selected. To study gastrin-17 production, morpho-functional correlation was studies in 75 patients with multifocal atrophic gastritis. RESULTS: During seven years, no reported case of gastric cancer was done among 2,220 persons who underwent serological screening and treatment. In the same population, 4.3 persons who did not receive screening during the same period, developed gastric cancer and died of it. In this study, we can say that 4.3 lives were saved out of 2,220 tested persons. The cost for screening this number of people amounted to €23,750. A comparison of the prevalence rate of the four stages of multifocal atrophic gastritis based on the data of the histopathology tests and noninvasive serologic screening in accordance with OLGA classification showed a strong correlation (the correlation coefficient is 0.812). This finding suggested that using this classification not only for histopathology tests for atrophic gastritis but also for serologic markers of antral mucosa and corpus ventriculi atrophy: gastrin-17 and pepsinogen-1. CONCLUSION: Complex pathogenetic treatment of atrophic gastritis significantly reduced gastric cancer risk and incidence for such patients.
.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/metabolismo , Mucosa Gástrica/patologia , Gastrite Atrófica/patologia , Programas de Rastreamento/métodos , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Gastrite Atrófica/tratamento farmacológico , Gastrite Atrófica/metabolismo , Gastroscopia , Infecções por Helicobacter/virologia , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Pepsinogênio A/metabolismo , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/metabolismo , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
4.
Compr Physiol ; 10(1): 197-228, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853955

RESUMO

Gastric acid secretion (i) facilitates digestion of protein as well as absorption of micronutrients and certain medications, (ii) kills ingested microorganisms, including Helicobacter pylori, and (iii) prevents bacterial overgrowth and enteric infection. The principal regulators of acid secretion are the gastric peptides gastrin and somatostatin. Gastrin, the major hormonal stimulant for acid secretion, is synthesized in pyloric mucosal G cells as a 101-amino acid precursor (preprogastrin) that is processed to yield biologically active amidated gastrin-17 and gastrin-34. The C-terminal active site of gastrin (Trp-Met-Asp-Phe-NH2 ) binds to gastrin/CCK2 receptors on parietal and, more importantly, histamine-containing enterochromaffin-like (ECL) cells, located in oxyntic mucosa, to induce acid secretion. Histamine diffuses to the neighboring parietal cells where it binds to histamine H2 -receptors coupled to hydrochloric acid secretion. Gastrin is also a trophic hormone that maintains the integrity of gastric mucosa, induces proliferation of parietal and ECL cells, and is thought to play a role in carcinogenesis. Somatostatin, present in D cells of the gastric pyloric and oxyntic mucosa, is the main inhibitor of acid secretion, particularly during the interdigestive period. Somatostatin exerts a tonic paracrine restraint on gastrin secretion from G cells, histamine secretion from ECL cells, and acid secretion from parietal cells. Removal of this restraint, for example by activation of cholinergic neurons during ingestion of food, initiates and maximizes acid secretion. Knowledge regarding the structure and function of gastrin, somatostatin, and their respective receptors is providing novel avenues to better diagnose and manage acid-peptic disorders and certain cancers. Published 2020. Compr Physiol 10:197-228, 2020.


Assuntos
Gastrinas , Somatostatina , Animais , Gastrinas/química , Gastrinas/metabolismo , Humanos , Somatostatina/química , Somatostatina/metabolismo
5.
Int J Mol Sci ; 20(21)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684070

RESUMO

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use.


Assuntos
Desprescrições , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Suspensão de Tratamento , Células Enterocromafins/efeitos dos fármacos , Células Enterocromafins/patologia , Gastrinas/metabolismo , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Fatores de Risco , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
6.
Scand J Gastroenterol ; 54(12): 1448-1451, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31725337

RESUMO

Background: Randomized and controlled trials of glucagon-like peptide-1 (GLP-1) derived drugs have shown that the most frequent adverse symptoms are gastrointestinal. Some of the side effects such as dyspepsia, nausea and upper abdominal pain may well be of gastric origin. Since the antral hormone gastrin regulates gastric secretion of acid and enzymes and contributes to the regulation of gastric motility, we examined the effect of GLP-1 on the secretion of gastrin in normal subjects and diabetes patients.Method: Plasma was sampled from ten healthy subjects and ten patients with diabetes mellitus type 1 with glucose clamped between 6 and 9 mM. GLP-1 or saline were infused for 4 h during and after a meal. Plasma concentrations of gastrin and GLP-1 were measured using specific radioimmunoassays.Results: Basal plasma concentrations of gastrin were similar in controls and patients. After the meal, the gastrin concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of gastrin significantly, most pronounced in the diabetes patients.Conclusions: The results show that GLP-1 infusion suppresses the postprandial secretion of gastrin in normal subjects and even more so in the diabetes patients. The results may therefore shed further light on the upper gastrointestinal side effects of GLP-1-derived drugs in diabetic patients.


Assuntos
Diabetes Mellitus Tipo 1 , Gastrinas , Fármacos Gastrointestinais , Peptídeo 1 Semelhante ao Glucagon , Período Pós-Prandial , Estômago , Adulto , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Gastrinas/sangue , Gastrinas/metabolismo , Fármacos Gastrointestinais/metabolismo , Fármacos Gastrointestinais/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Incretinas/metabolismo , Incretinas/farmacologia , Masculino , Período Pós-Prandial/efeitos dos fármacos , Período Pós-Prandial/fisiologia , Projetos de Pesquisa , Via Secretória/efeitos dos fármacos , Via Secretória/fisiologia , Estômago/efeitos dos fármacos , Estômago/enzimologia , Estômago/fisiopatologia
7.
J Med Food ; 22(12): 1208-1221, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621475

RESUMO

This study determined the ameliorative effects of the novel microorganism, Lactobacillus plantarum CQPC02 (LP-CQPC02), fermented in soybean milk, on loperamide-induced constipation in Kunming mice. High-performance liquid chromatography revealed that LP-CQPC02-fermented soybean milk (LP-CQPC02-FSM) had six types of soybean isoflavones, whereas Lactobacillus bulgaricus-fermented soybean milk (LB-FSM) and unfermented soybean milk (U-FSM) only had five types of soybean isoflavones. LP-CQPC02-FSM also contained more total and active soybean isoflavones than LB-FSM and U-FSM. Results from mouse experiments showed that the defecation factors (quantity, fecal weight and water content, gastrointestinal transit ability, and time to first black stool) in the LP-CQPC02-FSM-treated mice were better than those in the LB-FSM- and U-FSM-treated mice. The serum and small intestinal tissue experiments showed that soybean milk increased the motilin, gastrin, endothelin, acetylcholinesterase, substance P, vasoactive intestinal peptide, and glutathione levels and decreased the somatostatin, myeloperoxidase, nitric oxide, and malondialdehyde levels compared with the constipated mice in the control group. The LP-CQPC02-FSM also showed better effects than those of LB-FSM and U-FSM. Further results showed that LP-CQPC02-FSM upregulated cuprozinc-superoxide dismutase (Cu/Zn-SOD), manganese superoxide dismutase (Mn-SOD), catalase (CAT), c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GDNF), neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), and aquaporin-9 (AQP9) and downregulated the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), inducible nitric oxide synthase (iNOS), and aquaporin-3 (AQP3) in the constipated mice. LP-CQPC02-FSM increased the Bacteroides and Akkermansia abundances and decreased the Firmicutes abundance in the feces of the constipated mice and decreased the Firmicutes/Bacteroides ratio. This study confirmed that LP-CQPC02-FSM partially reversed constipation in mice.


Assuntos
Constipação Intestinal/terapia , Fermentação , Lactobacillus plantarum/metabolismo , Loperamida/efeitos adversos , Leite/metabolismo , Alimentos de Soja , Soja/metabolismo , Acetilcolinesterase/metabolismo , Animais , Aquaporina 3/metabolismo , Aquaporinas , Catalase/metabolismo , Constipação Intestinal/induzido quimicamente , Modelos Animais de Doenças , Endotelinas/metabolismo , Fezes/microbiologia , Feminino , Gastrinas/metabolismo , Trânsito Gastrointestinal , Mucosa Intestinal/metabolismo , Intestinos/patologia , Isoflavonas , Lactobacillus plantarum/isolamento & purificação , Malondialdeído/metabolismo , Camundongos , Motilina/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-kit , Fator de Células-Tronco/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/metabolismo , Canais de Cátion TRPV/metabolismo
8.
World J Gastroenterol ; 25(32): 4673-4681, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31528093

RESUMO

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.


Assuntos
Gastroenterologia/normas , Oncologia/normas , Guias de Prática Clínica como Assunto , Síndrome de Zollinger-Ellison/cirurgia , Duodeno/citologia , Duodeno/patologia , Duodeno/cirurgia , Células Secretoras de Gastrina/patologia , Gastrinas/metabolismo , Gastroenterologia/métodos , Hepatectomia , Humanos , Fígado/citologia , Fígado/patologia , Fígado/cirurgia , Excisão de Linfonodo , Oncologia/métodos , Pâncreas/citologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreaticoduodenectomia , Paratireoidectomia , Estômago/citologia , Estômago/patologia , Estômago/cirurgia , Fatores de Tempo , Síndrome de Zollinger-Ellison/patologia
9.
Pancreas ; 48(7): 894-903, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31268978

RESUMO

OBJECTIVE: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. METHODS: LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. RESULTS: In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. CONCLUSIONS: This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.


Assuntos
Carcinogênese/genética , Carcinoma in Situ/genética , Gastrinas/genética , Mutação , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Carcinogênese/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Gastrinas/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
10.
Int J Mol Sci ; 20(10)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108898

RESUMO

BACKGROUND: Studies on the regulation of gastric and pancreatic secretion began more than 100 years ago. Secretin was the first hormone postulated to exist, initiating the field of endocrinology. Gastrin produced in the antral mucosa was the second postulated hormone, and together with histamine and acetylcholine, represent the three major gastric acid secretagogues known since 1920. For a long time, the mast cell was the only recognized histamine-producing cell in the oxyntic mucosa and, in the mid-1980s, the ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. METHODS: This review is based upon literature research and personal knowledge. RESULTS: The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. CONCLUSIONS: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion.


Assuntos
Celulas Tipo Enterocromafim/metabolismo , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Acetilcolina/metabolismo , Animais , Celulas Tipo Enterocromafim/patologia , Mucosa Gástrica/patologia , Histamina/metabolismo , Humanos , Receptor de Colecistocinina B/metabolismo
11.
Esophagus ; 16(4): 377-381, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31119492

RESUMO

BACKGROUND: To investigate the efficacy of long-term (52 weeks) maintenance therapy by 10-mg vonoprazan administration for proton pump inhibitor-resistant reflux esophagitis continued from the preceding study. METHODS: Sixteen patients with proton pump inhibitor-resistant reflux esophagitis (mean age 70.9 years, eight males) in whom endoscopic healing was achieved by 20-mg vonoprazan administration for 4 weeks and maintenance of remission was maintained by 10-mg vonoprazan administration for 8 weeks were enrolled. Endoscopy was performed at 52 weeks after the initiation of maintenance therapy with 10-mg vonoprazan to evaluate whether there was any recurrence of reflux esophagitis. Changes in the gastric mucosa were investigated at 52 weeks. Symptoms were assessed using the frequency scale for the symptoms of gastroesophageal reflux disease and the fast gastrin level at 8 and 52 weeks following the maintenance therapy. RESULTS: Endoscopic remission was maintained at 52 weeks in 15 (93.8%) of the 16 patients with proton pump inhibitor-resistant reflux esophagitis. One patient relapsed with grade C of reflux esophagitis. There were no significant differences in the symptom score at 8 and 52 weeks, nor the gastrin level at 8 and 52 weeks. There was no change in the stomach on endoscopy at 52 weeks. CONCLUSION: Long-term maintenance therapy by 10-mg vonoprazan administration is very effective for proton pump inhibitor-resistant reflux esophagitis patients in whom endoscopic healing was maintained by 8 weeks maintenance therapy with 10-mg vonoprazan administration.


Assuntos
Esofagite Péptica/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Resistência a Medicamentos , Endoscopia Gastrointestinal , Esofagite Péptica/diagnóstico por imagem , Feminino , Mucosa Gástrica/diagnóstico por imagem , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Recidiva , Sulfonamidas/administração & dosagem , Avaliação de Sintomas , Fatores de Tempo
12.
Am J Physiol Regul Integr Comp Physiol ; 316(5): R628-R639, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892908

RESUMO

We investigated expression of cholecystokinin (CCK) in humans and mice, and the bitter taste receptor TAS2R14 in the human placenta. Because CCK and gastrin activate the CCKBR receptor, we also explored placental gastrin expression. Finally, we investigated calcium signaling by CCK and TAS2R14. By RT-PCR, we found CCK/Cck and GAST/Gast mRNA expression in both normal human and mouse placentas, as well as in human trophoblast cell lines (TCL). Although both Cckar and -br mRNA were expressed in the mouse placenta, only CCKBR mRNA was detected in the human placenta and TCL. mRNA expression for TAS2R14 was also observed in the human placenta and TCL. Using immunohistochemistry, CCK protein was localized to the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) in the human term placenta, and to trophoblast glycogen cells in mouse and human placentas. Gastrin and TAS2R14 proteins were also observed in ST and EVT of the human placenta. Both sulfated and nonsulfated CCK elicited a comparable rise in intracellular calcium in TCL, consistent with CCKBR expression. Three TAS2R14 agonists, flufenamic acid, chlorhexidine, and diphenhydramine, also evoked rises in intracellular calcium in TCL. These results establish CCK, gastrin, and their receptor(s) in both human and mouse placentas, and TAS2R14 in the human placenta. Both CCK and TAS2R14 agonists increased intracellular calcium in human TCL. Although the roles of these ligands and receptors, and their potential cross talk in normal and pathological placentas, are currently unknown, this study opens new avenues for placental research.


Assuntos
Colecistocinina/metabolismo , Gastrinas/metabolismo , Receptor de Colecistocinina B/metabolismo , Receptores da Colecistocinina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Trofoblastos/metabolismo , Animais , Sinalização do Cálcio , Linhagem Celular , Colecistocinina/genética , Colecistocinina/farmacologia , Feminino , Gastrinas/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor de Colecistocinina B/genética , Receptores da Colecistocinina/agonistas , Receptores da Colecistocinina/genética , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos
13.
Esophagus ; 16(2): 201-206, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30600486

RESUMO

BACKGROUND: To evaluate the efficacy of on-demand therapy using 20-mg vonoprazan for non-erosive reflux disease. METHODS: On-demand therapy by taking one 20-mg tablet of vonoprazan only when reflux symptoms occurred was performed for 8 weeks by 30 patients (11 men, mean age: 67.8) with non-erosive reflux disease who responded well to maintenance therapy using proton pump inhibitor and answered "very satisfied" or "satisfied" to an overall satisfaction survey (5-grade scale). The degree of overall satisfaction with the treatment, score of symptoms, and fasting gastrin levels before breakfast was examined before and after on-demand therapy. The number of vonoprazan tablets taken and the frequency (regular, temporary, rare) of its administration were also investigated. RESULTS: All patients completed 8-week on-demand therapy with 20-mg vonoprazan. Comparisons of patient satisfaction levels before and after therapy revealed no significant differences in the number of patients who were very satisfied and satisfied with the therapy. Furthermore, there were no significant differences in score of symptoms or gastrin levels before and after therapy. During 8-week on-demand therapy, patients took 11 tablets (median) (7.0-18.0 tablets: 25-75 percentiles), and 30.0% of patients (n = 9) took vonoprazan on a regular basis (at least 2 tablets a week). CONCLUSION: On-demand therapy with 20-mg vonoprazan exerted equivalent effects to continuous PPI maintenance therapy for patients with non-erosive reflux disease.


Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Esquema de Medicação , Feminino , Gastrinas/metabolismo , Refluxo Gastroesofágico/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Prospectivos , Resultado do Tratamento
14.
Surg Today ; 49(1): 38-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30159780

RESUMO

PURPOSE: Functional outcomes were prospectively compared between two types of reconstruction [double tract (L-DT; n = 15) and jejunal interposition (L-JIP; n = 15)] following laparoscopic half-proximal gastrectomy (LPG), including laparoscopic total gastrectomy (L-TG; n = 30) as a control group, at 1 year after surgery. METHODS: Clinical investigations were performed in each patient, and functional evaluations, involving the swallowing of an alimentary liquid containing acetaminophen (AAP), followed by measurements of the concentrations of AAP and hormones in the sitting (n = 5) and in the supine positions (n = 5), were carried out in each group. RESULTS: The post-/preoperative body weight ratios were significantly higher in the L-DT and L-JIP groups than in the L-TG group. The AAP levels were significantly lower in the LPG group than in the LTG group. The AAP, insulin, and gastrin levels in the L-JIP group were markedly increased in the sitting position compared with the supine position, while those in the L-DT and L-TG groups were stable in both positions. CONCLUSIONS: L-JIP and L-DT are procedures that maintain gradual intestinal absorption and help improve the quality of life. Intestinal absorption and hormonal secretion were relatively unaffected by the posture of the meal intake after L-DT, so L-DT might be the procedure providing the most stable results.


Assuntos
Gastrectomia/métodos , Jejuno/cirurgia , Laparoscopia/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Neoplasias Gástricas/cirurgia , Estômago/cirurgia , Acetaminofen/metabolismo , Idoso , Peso Corporal , Feminino , Gastrinas/metabolismo , Humanos , Insulina/metabolismo , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Postura/fisiologia , Estudos Prospectivos , Qualidade de Vida , Neoplasias Gástricas/metabolismo , Fatores de Tempo
15.
Pancreas ; 48(1): 131-134, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531243

RESUMO

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.


Assuntos
Doenças Autoimunes/diagnóstico , Neoplasias Duodenais/diagnóstico , Gastrinoma/diagnóstico , Gastrite Atrófica/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Neoplasias Gástricas/diagnóstico , Doenças Autoimunes/complicações , Doença Crônica , Neoplasias Duodenais/complicações , Feminino , Gastrinoma/complicações , Gastrinas/metabolismo , Gastrite Atrófica/complicações , Humanos , Hipertensão/etiologia , Pessoa de Meia-Idade , Tumores Neuroendócrinos/complicações , Neoplasias Gástricas/complicações
16.
Obes Surg ; 29(2): 593-600, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353248

RESUMO

BACKGROUND: Sleeve gastrectomy with ileal transposition has been shown to be superior to sleeve gastrectomy alone for promoting weight loss in rat and porcine models. The absence of a mouse model for this procedure has impeded efforts to understand the molecular physiology underlying its efficacy. This study demonstrates the long-term survivability of sleeve gastrectomy with ileal transposition in mice. MATERIALS AND METHODS: In this study of technical feasibility, a sleeve gastrectomy with ileal transposition (SGIT), sleeve gastrectomy (SG), or sham surgery (SH) was performed on 7- to 8-week-old C57Bl/6J mice (n = 8 for each). To evaluate long-term survivability, mice were placed on an obesogenic diet and weighed weekly for 10 weeks. The intestinal identity of the transposed segment was assessed with gene expression analysis of duodenal-, jejunal-, and ileal-specific hormones using quantitative polymerase chain reaction. RESULTS: Overall, SGIT better prevented weight gain than the SG or sham procedures (10-week post-operative weight: SH 45.3 ± 1.0 g, SG 41.25 ± 1.6 g, SGIT 35.4 ± 0.8 g). Gene expression pattern analysis of three markers of intestinal identity (gastrin, cholecystokinin, and peptide YY) suggests that the ileal identity of the transposed segment is maintained 10 weeks after transposition. CONCLUSIONS: We demonstrate for the first time a reproducible mouse model of sleeve gastrectomy with ileal transposition. Future studies utilizing this model will expand our understanding of the molecular pathways through which the hindgut regulates satiety.


Assuntos
Gastrectomia/métodos , Íleo/cirurgia , Animais , Biomarcadores , Glicemia/análise , Colecistocinina/genética , Colecistocinina/metabolismo , Modelos Animais de Doenças , Estudos de Viabilidade , Gastrinas/genética , Gastrinas/metabolismo , Expressão Gênica , Camundongos Endogâmicos C57BL , Peptídeo YY/genética , Peptídeo YY/metabolismo , RNA/metabolismo , Distribuição Aleatória , Perda de Peso
17.
J Clin Endocrinol Metab ; 104(4): 1336-1344, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30566620

RESUMO

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with the radiolabeled somatostatin analogue [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) is widely applied for inoperable metastatic small intestinal and nonfunctioning pancreatic neuroendocrine tumors (pNETs). The aim of this study is to describe the safety and efficacy of the treatment of functioning pNETs. METHODS: Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gbq per cycle. Radiological (Response Evaluation Criteria in Solid Tumors 1.1), symptomatic, and biochemical response were analyzed retrospectively for all patients with a functioning pNET (insulinoma, gastrinoma, VIPoma, and glucagonoma) treated with 177Lu-DOTATATE. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module questionnaire. RESULTS: Thirty-four patients with a metastatic functioning pNET (European Neuroendocrine Tumor Society grade 1 or 2) were included: 14 insulinomas, 5 VIPomas, 7 gastrinomas, and 8 glucagonomas. Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL. CONCLUSION: Treatment with 177Lu-DOTATATE is a safe and effective therapy resulting in radiological, symptomatic and biochemical response in a high percentage of patients with metastatic functioning pNETs. Hormonal crises occur relatively frequent and preventive therapy should be considered before and/or during PRRT.


Assuntos
Complexos de Coordenação/administração & dosagem , Lutécio/administração & dosagem , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Radioisótopos/administração & dosagem , Adulto , Idoso , Complexos de Coordenação/efeitos adversos , Feminino , Gastrinas/sangue , Gastrinas/metabolismo , Glucagon/sangue , Glucagon/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Lutécio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/patologia , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/efeitos da radiação , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Qualidade de Vida , Doses de Radiação , Radioisótopos/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Peptídeo Intestinal Vasoativo/sangue , Peptídeo Intestinal Vasoativo/metabolismo
18.
J Nucl Med ; 60(3): 393-399, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30002107

RESUMO

Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog 177Lu-DOTA-PP-F11N (177Lu-DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) performs better than reference analogs with varying in vivo stability, namely 177Lu-DOTA-MG11 (177Lu-DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) and 177Lu-DOTA-PP-F11 (177Lu-DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), and whether the use of protease inhibitors further improves CCKR2 targeting. First human data on 177Lu-DOTA-PP-F11N are also reported. Methods: In vitro stability of all analogs was assessed against a panel of extra- and intracellular endoproteases, whereas their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon and thiorphan was assessed 4 h after injection in MZ-CRC-1 and A431-CCK2R(+) dual xenografts. Autoradiography of 177Lu-DOTA-PP-F11N (without and with phosphoramidon) and NanoSPECT/CT were performed. SPECT/CT images of 177Lu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. Results: natLu-DOTA-PP-F11N is less of a substrate for neprilysins than the other analogs, whereas intracellular cysteine proteases, such as cathepsin-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors than in A431-CCK2R(+), apparently because of the higher number of binding sites on MZ-CRC-1 cells. 177Lu-DOTA-PP-F11N had the same biodistribution as 177Lu-DOTA-PP-F11; however, uptake in the MZ-CRC-1 tumors was almost double (20.7 ± 1.71 vs. 11.2 ± 2.94 %IA [percentage injected activity]/g, P = 0.0002). Coadministration of phosphoramidon or thiorphan increases 177Lu-DOTA-MG11 uptake significantly in the CCK2R(+) tumors and stomach. Less profound was the effect on 177Lu-DOTA-PP-F11, whereas no influence or even reduction was observed for 177Lu-DOTA-PP-F11N (20.7 ± 1.71 vs. 15.6 ± 3.80 [with phosphoramidon] %IA/g, P < 0.05 in MZ-CRC-1 tumors). The first clinical data show high 177Lu-DOTA-PP-F11N accumulation in tumors, stomach, kidneys, and colon. Conclusion: The performance of 177Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance of 177Lu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight the stomach as a potential dose-limiting organ besides the kidneys.


Assuntos
Gastrinas/química , Gastrinas/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Lutécio , Inibidores de Proteases/farmacologia , Radioisótopos , Receptor de Colecistocinina B/metabolismo , Sequência de Aminoácidos , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Feminino , Gastrinas/farmacocinética , Humanos , Camundongos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Distribuição Tecidual/efeitos dos fármacos
19.
Exp Mol Med ; 50(12): 1-14, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510283

RESUMO

DNA methylation is a regulatory mechanism in epigenetics that is frequently altered during human carcinogenesis. To detect critical methylation events associated with gastric cancer (GC), we compared three DNA methylomes from gastric mucosa (GM), intestinal metaplasia (IM), and gastric tumor (GT) cells that were microscopically dissected from an intestinal-type early gastric cancer (EGC) using methylated DNA binding domain sequencing (MBD-seq) and reduced representation bisulfite sequencing (RRBS) analysis. In this study, we focused on differentially methylated promoters (DMPs) that could be directly associated with gene expression. We detected 2,761 and 677 DMPs between the GT and GM by MBD-seq and RRBS, respectively, and for a total of 3,035 DMPs. Then, 514 (17%) of all DMPs were detected in the IM genome, which is a precancer of GC, supporting that some DMPs might represent an early event in gastric carcinogenesis. A pathway analysis of all DMPs demonstrated that 59 G protein-coupled receptor (GPCR) genes linked to the hypermethylated DMPs were significantly enriched in a neuroactive ligand-receptor interaction pathway. Furthermore, among the 59 GPCRs, six GI hormone receptor genes (NPY1R, PPYR1, PTGDR, PTGER2, PTGER3, and SSTR2) that play an inhibitory role in the secretion of gastrin or gastric acid were selected and validated as potential biomarkers for the diagnosis or prognosis of GC patients in two cohorts. These data suggest that the loss of function of gastrointestinal (GI) hormone receptors by promoter methylation may lead to gastric carcinogenesis because gastrin and gastric acid have been known to play a role in cell differentiation and carcinogenesis in the GI tract.


Assuntos
Mucosa Gástrica/fisiologia , Regiões Promotoras Genéticas/genética , Receptores dos Hormônios Gastrointestinais/genética , Neoplasias Gástricas/genética , Carcinogênese , Diferenciação Celular , Linhagem Celular Tumoral , Metilação de DNA , Ácido Gástrico/metabolismo , Gastrinas/metabolismo , Humanos , Metaplasia , Neurotransmissores/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Sulfitos , Sequenciamento Completo do Genoma
20.
Pak J Pharm Sci ; 31(6 (Supplementary): 2585-2589, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30587465

RESUMO

Neuroendocrine tumors (NET) are the rare tumors which often impose graveyard threat. These tumors are characterized by the over expression of various G-protein coupled receptors including cholecystokinin (CCK) receptors-1 and 2 (A or B). Minigastrin peptides are being investigated for theranostic purposes of CCK-2 receptor positive NET. The minigastrin analogue (APHO70) was modified by engineering enzyme susceptible tetrapeptide sequence into APHO70 peptide to reduce the random degradation by lysosome enzymes which pave the way to random trafficking in patient's body and dipeptide addition at c-terminus. All the four modified minigastrin peptides (MG-CL1-4) were investigated for lysosome cathepsin B (catB) enzyme susceptibility and fate into AR42J cancer cell line. The indium-111 labeled MG-CL1-4 peptides were also studied for target (tumor) and non-target saccumulation by using tumor induced mice. The RP-HPLC analysis result showed nonspecific cleavage of standard 111In-APH070 and 111In-MGCL1 while specific cleavage was noted in case of 111In-MGCL (2-4). The effect of specific and non-specific cleavage on biodistribution in tumor induced nude mice model indicates the promising accumulation of 111In-MGCL2, 111In-MGCL3, and 111In-MGCL4 radiotracers while 111In-MGCL1 showed less accumulation. 111In-MGCL2 and 111In-MGCL3 showed highest target-to-kidney ratio (T/K) i.e. 1.71 and 1.72, respectively whereas standard compound showed T/K 1.13. In conclusion, the two indium-111 labeled analogues i.e. 111In-MGCL2 and 111In-MGCL3 showed promising sensitivity for tumor andcould be tested for further investigation to reach pre-clinical studies.


Assuntos
Catepsina B/metabolismo , Gastrinas/metabolismo , Radioisótopos de Índio/metabolismo , Tumores Neuroendócrinos/metabolismo , Fragmentos de Peptídeos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Nus , Tumores Neuroendócrinos/diagnóstico por imagem
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