Inhibition of the gastric H,K-ATPase by potassium competitive acid blockers

The gastric H,K-ATPase is a membrane protein found in the parietal cells of the stomach, where it couples H+ extrusion to the uptake of K+ , leading to the acidification of gastric juice (1). Acid-related diseases are an important public health issue where the mainstay of treatment has been the suppression of H,K-ATPase activity. As K+ plays a vital role in this catalytic cycle, for the dephosphorylation of the H,K-ATPase and the subsequent conformational changes, acid secretion can be inhibited by agents that are competitive with respect to K+ binding. This argument led in the past decades to the development of a new class of acid suppressants, known as potassium competitive acid blockers (P-CABs). Since a systematic investigation of enzyme-inhibition mechanisms has become a fruitful way to design and test new drugs, the effects of P-CABs-type inhibitors have been extensively studied analyzing how the apparent Michaelis and Menten parameters are affected (2). Working with the non-compartmentalized enzyme preparation, we analyzed the interactions between K+ , the H,K-ATPase, and two different inhibitors under steady state conditions. Our results from ATPase activity as a function of K+ concentration was described by a rational function where the maximal exponent on [K+] is 2. Data show that K+ , as a product, can inhibit the reaction steps that involve its release, which implies that ATPase activity would not obey the Michaelis-Menten equation. This can lead to mistakes when analysing the results according to variations in Vmax and KM . Here we propose a minimal model to describe the binding of K+ to different enzyme conformations and the inhibition by P-CABs compounds allowing a more realistic evaluation of their effects.Fil: Cerf, Nicole Talia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Faraj, Santiago Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Valsecchi, Wanda M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Rossi, Rolando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Montes, Monica Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaXLIX Reunión Anual de la Sociedad Argentina de BiofísicaArgentinaSociedad Argentina de Biofísic

The Effect of Dietary Patterns on Clinical Pregnancy and Live Birth Outcomes in Men and Women Receiving Assisted Reproductive Technologies: A Systematic Review and Meta-Analysis

The nutritional status of reproductive-aged couples can have a significant impact on fertility status, but the effect of dietary patterns on pregnancy outcomes in people using assisted reproductive technologies (ARTs) is currently unknown. This review aimed to synthesize the published research investigating the relation between preconception dietary patterns and clinical pregnancy or live birth in men and women of reproductive age undergoing ART. Six electronic databases were systematically searched for original research published between January 1978 and June 2021. Original research reporting on the effect of predefined dietary patterns on either clinical pregnancy and/or live birth rates following in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in men and women aged 18–49 y was eligible for inclusion. Studies were assessed for risk of bias according to the Cochrane guidelines. Included studies underwent qualitative and quantitative synthesis using random-effects model meta-analyses. Thirteen studies (12 cohort studies, 1 randomized controlled trial) reporting on 3638 participants (93% female) were included in the review. All studies had a moderate–high risk of bias. In individual studies, maternal adherence to 4 dietary patterns [Mediterranean diet (RR: 1.22; 95% CI: 1.05, 1.43), novel profertility diet (OR: 1.43; 95% CI: 1.19, 1.72), Iranian traditional medicine diet (OR: 3.9; 95% CI: 1.2, 12.8), Dutch national dietary recommendations diet (OR: 1.65; 95% CI: 1.08, 2.52)] was associated with increased likelihood of achieving a clinical pregnancy, while 2 dietary patterns [novel profertility diet (OR: 1.53; 95% CI: 1.26, 1.85), Mediterranean diet (RR: 1.25; 95% CI: 1.07, 1.45)] were associated with increased probability of live birth. Meta-analyses showed an association between adherence to the Mediterranean dietary pattern and live birth across 2 studies (OR: 1.98; 95% CI: 1.17, 3.35; I2 = 29%, n = 355), but no association with clinical pregnancy. As the relation between dietary patterns and ART outcomes is currently inconsistent, higher-quality nutrition research is required to further explore this emerging field of interest (PROSPERO registration: CRD42020188194)

Alimentation et excès de poids en Polynésie française. Socio-anthropologie de l’obésité Prévalence, distribution sociale, représentations du corps Modèles et pratiques alimentaires.

Rapport de recherch

Bioinformatic Study of Possible Acute Regulation of Acid Secretion in the Stomach

The gastric H+,K+-ATPase is an integral membrane protein which uses the energy of ATP hydrolysis to pump H+ ions from the parietal cells of the gastric mucosa into the stomach in exchange for K+ ions. It is responsible for the acidic environment of the stomach, which is essential for digestion. Acid secretion is regulated by the recruitment of the H+,K+-ATPase from intracellular stores into the plasma membrane on the ingestion of food. The similar amino acid sequences of the lysine-rich N-termini α-subunits of the H+,K+- and Na+,K+-ATPases, suggests similar acute regulation mechanisms, specifically, an electrostatic switch mechanism involving an interaction of the N-terminal tail with the surface of the surrounding membrane and a modulation of the interaction via regulatory phosphorylation by protein kinases. From a consideration of sequence alignment of the H+,K+-ATPase and an analysis of its coevolution with protein kinase C and kinases of the Src family, the evidence points towards a phosphorylation of tyrosine-7 of the N-terminus by either Lck or Yes in all vertebrates except cartilaginous fish. The results obtained will guide and focus future experimental research.Fil: Lee, Yan Hay Grace. University Of Sidney. Faculty Of Science; AustraliaFil: Cerf, Nicole Talia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Shalaby, Nicholas. University Of Sidney. Faculty Of Science; AustraliaFil: Montes, Monica Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Clarke, Ronald J.. University Of Sidney. Faculty Of Science; Australi

The interaction of Na+, K+, and phosphate with the gastric H,K-ATPase. Kinetics of E1–E2 conformational changes assessed by eosin fluorescence measurements

H,K-ATPase and Na,K-ATPase show the highest degree of sequence similarity among all other members of the P-type ATPases family. To explore their common features in terms of ligand binding, we evaluated conformational transitions due to the binding of Na+, K+, and Pi in the H,K-ATPase, and compared the results with those obtained for the Na,K-ATPase. This work shows that eosin fluorescence time courses provide a reasonably precise method to study the kinetics of the E1−E2 conformational changes in the H,K-ATPase. We found that, although Na+ shifts the equilibrium toward the E1 conformation and seems to compete with H+ in ATPase activity assays, it was neither possible to isolate a Na+-occluded state, nor to reveal an influx of Na+ related to H,K-ATPase activity. The high rate of the E2K→E1 transition found for the H,K-ATPase, which is not compatible with the presence of a K+-occluded form, agrees with the negligible level of occluded Rb+ (used as a K+ congener) found in the absence of added ligands. The use of vanadate and fluorinated metals to induce E2P-like states increased the level of occluded Rb+ and suggests that?during dephosphorylation?the probability of K+ to remain occluded increases from the E2P-ground to the E2P-product state. From kinetic experiments we found an unexpected increase in the values of kobs for E2P formation with [Pi]; consequently, to obey the Albers-Post model, the binding of Pi to the E2 state cannot be a rapid-equilibrium reaction.Fil: Faraj, Santiago Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Valsecchi, Wanda Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Cerf, Nicole Talia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Fedosova, N. U.. Aarhus University. Department of Bioscience; DinamarcaFil: Rossi, Rolando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Montes, Monica Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy.

Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes.Among seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.This case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals