Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.223
Filtrar
1.
Ann Biol Clin (Paris) ; 78(4): 417-424, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32753366

RESUMO

We present the case of a four-year-old girl, who was hospitalized in intensive care unit for a coma resulting from metabolic acidosis with increased anion gap. The patient was treated for short bowel syndrome, following necrotising enterocolitis, which occurred 51 days after birth. In our initial evaluation of the patient's metabolic acidosis, we were unable to identify the cause of the increased anion gap. Urinary organic acids chromatography identified a large peak of lactate (quantified at 15 mmol/mol of creatiniuria), as well as its metabolites. The discrepancy between normal blood lactate concentration assayed by enzymatic assay, and the large amount of lactate found by gas-chromatography/mass spectrometry (GC/MS) in urine highlights the limit of the stereospecificity of enzymatic assays. Indeed, most lactates assay use enzymatic assays that are specific for L-lactate, whereas organic acids chromatography, whose column is mostly achiral, can detect both stereoisomers, D- and L-lactate. Organic acids in urine analysis, in addition to the clinical context, suggested a diagnosis of D-lactic acidosis. Following a review of the physiopathology and treatment of short bowel syndrome, we will discuss the mechanism and diagnosis of the D-lactic acidosis in our patient. This case highlights the need to perform an organic acid profile in urine in the presence of any unexplained increased anion gap to determine its cause.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Acidose Láctica/diagnóstico , Acidose/diagnóstico , Coma/diagnóstico , Síndrome do Intestino Curto/diagnóstico , Acidose/etiologia , Acidose/metabolismo , Acidose Láctica/etiologia , Acidose Láctica/metabolismo , Acidose Láctica/urina , Análise Química do Sangue/métodos , Pré-Escolar , Coma/sangue , Coma/etiologia , Coma/urina , Diagnóstico Diferencial , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Ácido Láctico/sangue , Ácido Láctico/urina , Síndrome do Intestino Curto/complicações , Síndrome do Intestino Curto/metabolismo , Urinálise
2.
PLoS One ; 15(5): e0233851, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470084

RESUMO

Brain interstitial pH (pHbrain) alterations play an important role in the mechanisms of neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia. The newborn pig is an established large animal model to study HIE, however, only limited information on pHbrain alterations is available in this species and it is restricted to experimental perinatal asphyxia (PA) and the immediate reventilation. Therefore, we sought to determine pHbrain over the first 24h of HIE development in piglets. Anaesthetized, ventilated newborn pigs (n = 16) were instrumented to control major physiological parameters. pHbrain was determined in the parietal cortex using a pH-selective microelectrode. PA was induced by ventilation with a gas mixture containing 6%O2-20%CO2 for 20 min, followed by reventilation with air for 24h, then the brains were processed for histopathology assessment. The core temperature was maintained unchanged during PA (38.4±0.1 vs 38.3±0.1°C, at baseline versus the end of PA, respectively; mean±SEM). In the arterial blood, PA resulted in severe hypoxia (PaO2: 65±4 vs 23±1*mmHg, *p<0.05) as well as acidosis (pHa: 7.53±0.03 vs 6.79±0.02*) that is consistent with the observed hypercapnia (PaCO2: 37±3 vs 160±6*mmHg) and lactacidemia (1.6±0.3 vs 10.3±0.7*mmol/L). Meanwhile, pHbrain decreased progressively from 7.21±0.03 to 5.94±0.11*. Reventilation restored pHa, blood gases and metabolites within 4 hours except for PaCO2 that remained slightly elevated. pHbrain returned to 7.0 in 29.4±5.5 min and then recovered to its baseline level without showing secondary alterations during the 24 h observation period. Neuropathological assessment also confirmed neuronal injury. In conclusion, in spite of the severe acidosis and alterations in blood gases during experimental PA, pHbrain recovered rapidly and notably, there was no post-asphyxia hypocapnia that is commonly observed in many HIE babies. Thus, the neuronal injury in our piglet model is not associated with abnormal pHbrain or low PaCO2 over the first 24 h after PA.


Assuntos
Encéfalo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Acidose/sangue , Acidose/complicações , Acidose/metabolismo , Acidose/fisiopatologia , Animais , Animais Recém-Nascidos , Asfixia Neonatal/sangue , Asfixia Neonatal/metabolismo , Asfixia Neonatal/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Hemodinâmica , Concentração de Íons de Hidrogênio , Hipercapnia/sangue , Hipercapnia/complicações , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Hipóxia-Isquemia Encefálica/sangue , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Neurônios/patologia , Oxigênio/metabolismo , Suínos
3.
Arch Razi Inst ; 75(1): 109-121, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32292009

RESUMO

The transition from normal forage to a highly fermentable diet to achieve rapid weight gain in the cattle industry can induce ruminal acidosis. The molecular host mechanisms that occur in acidosis are largely unknown. Therefore, the histology and transcriptome profiling of rumen epithelium was investigated in normal and acidosis animals to understand the molecular mechanisms involved in the disease. The rumen epithelial transcriptome from acidosis (n=3) and control (n=3) Holstein steers was obtained using RNA-sequencing. The mean values of clean reads were 70,975,460&plusmn;984,046 and 71,142,189&plusmn;834,526 in normal and acidosis samples, respectively. In total, 1,074 differentially expressed genes were identified in the two groups (P&lt;0.05), of which 624 and 450 genes were up- and down-regulated in the acidosis samples, respectively. Functional analysis indicated that the majority of the up-regulated genes had a function in filament organization, positive regulation of epithelial and muscle fiber concentration, biomineral tissue development, negative regulation of fat cell differential, regulation of ion transmembrane transport, regulation of cell adhesion and butyrate, as well as short-chain fatty acid absorption that was metabolized as an energy source. Functional analysis of the down-regulated genes revealed effects in immune response, positive regulation of T-cell migration, regulation of metabolic processes, and localization. Furthermore, the results showed a differential expression of genes involved in the Map Kinase and Toll-like receptor signaling pathways. The IL1B, CXCL5, IL36A, and IL36B were significantly down-regulated in acidosis rumen tissue samples. The results suggest that rapid shifts to rich fermentable carbohydrates diets cause an increase in the concentration of ruminal volatile fatty acids, tissue damage, and significant changes in transcriptome profiles of rumen epithelial.


Assuntos
Acidose/veterinária , Doenças dos Bovinos/metabolismo , Rúmen/fisiopatologia , Gastropatias/veterinária , Transcriptoma , Acidose/metabolismo , Animais , Bovinos , Epitélio/fisiopatologia , Perfilação da Expressão Gênica/veterinária , Masculino , Análise de Sequência de RNA/veterinária , Gastropatias/metabolismo
4.
J Dairy Sci ; 103(5): 4702-4716, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32171513

RESUMO

We investigated changes in rumen fermentation, the fluid bacterial community, and predicted functional pathway profiles in Holstein cows with and those without subacute ruminal acidosis (SARA) during the periparturient period. Eighteen multiparous Holstein cows categorized in the SARA (n = 9) or non-SARA (n = 9) groups depending on whether they developed SARA during the 2 wk after parturition. Reticulo-ruminal pH was measured continuously throughout the study. Rumen fluid and blood samples were collected 3 wk before and 2 and 6 wk after parturition, with an additional blood sample collected during the 0 and 4 wk after parturition. The 7-d mean reticulo-ruminal pH was significantly decreased in both groups postpartum compared with prepartum, with a greater and longer lasting change in the SARA group. The postpartum total volatile fatty acid concentration was significantly higher in the non-SARA than in SARA cows. Rumen bacterial richness and diversity were not affected by the periparturient period, but the non-SARA group had a significantly higher Simpson diversity index postpartum. No significant change was observed in the composition of major bacterial phyla or genera during the periparturient period. Among 17 operational taxonomic units (OTU) shared by all cows, the relative abundances of OTU36 (genus Pseudobutyrivibrio) in the SARA group and OTU4 (genus Prevotella) in the non-SARA group decreased significantly during the postpartum period compared with prepartum. In contrast, non-SARA cows had more diverse core bacterial OTU community including 23 additional OTU than those with SARA including 3 additional OTU (40 vs. 20 OTU). The OTU36 was significantly correlated with the proportion of iso-valeric acid (r = -0.353), and OTU4 was significantly correlated with the 7-d mean reticulo-ruminal pH (r = 0.432) and the proportions of acetic acid (r = 0.353) and propionic acid (r = -0.380). Prepartum, OTU2 (genus Prevotella) was the only OTU that differed significantly between the 2 groups. Changes in predicted functional pathway were primarily identified during the postpartum period, with 2 pathways upregulated at 3 wk prepartum and 24 upregulated and 34 downregulated at 6 wk postpartum in the SARA group. Our results suggest that SARA incidence is not strictly related to changes in rumen fermentation or fluid bacterial community structure, but the predicted functional pathways of bacterial communities showed late responses to a postpartum decrease in reticulo-ruminal pH. Therefore, postpartum predicted functional pathway analysis may indicate the underlying mechanisms causing SARA in Holstein cows during the periparturient period.


Assuntos
Acidose/veterinária , Bactérias/isolamento & purificação , Doenças dos Bovinos/microbiologia , Ácidos Graxos Voláteis/análise , Microbioma Gastrointestinal , Acidose/metabolismo , Acidose/microbiologia , Animais , Bactérias/genética , Bovinos , Doenças dos Bovinos/metabolismo , Dieta/veterinária , Feminino , Fermentação , Concentração de Íons de Hidrogênio , Parto , Gravidez , Prevotella/genética , Prevotella/isolamento & purificação , Rúmen/metabolismo , Rúmen/microbiologia
5.
Animal ; 14(S1): s176-s186, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32024561

RESUMO

Rumen sensors provide specific information to help understand rumen functioning in relation to health disorders and to assist in decision-making for farm management. This review focuses on the use of rumen sensors to measure ruminal pH and discusses variation in pH in both time and location, pH-associated disorders and data analysis methods to summarize and interpret rumen pH data. Discussion on the use of rumen sensors to measure redox potential as an indication of the fermentation processes is also included. Acids may accumulate and reduce ruminal pH if acid removal from the rumen and rumen buffering cannot keep pace with their production. The complexity of the factors involved, combined with the interactions between the rumen and the host that ultimately determine ruminal pH, results in large variation among animals in their pH response to dietary or other changes. Although ruminal pH and pH dynamics only partially explain the typical symptoms of acidosis, it remains a main indicator and may assist to optimize rumen function. Rumen pH sensors allow continuous monitoring of pH and of diurnal variation in pH in individual animals. Substantial drift of non-retrievable rumen pH sensors, and the difficulty to calibrate these sensors, limits their application. Significant within-day variation in ruminal pH is frequently observed, and large distinct differences in pH between locations in the rumen occur. The magnitude of pH differences between locations appears to be diet dependent. Universal application of fixed conversion factors to correct for absolute pH differences between locations should be avoided. Rumen sensors provide high-resolution kinetics of pH and a vast amount of data. Commonly reported pH characteristics include mean and minimum pH, but these do not properly reflect severity of pH depression. The area under the pH × time curve integrates both duration and extent of pH depression. The use of this characteristic, as well as summarizing parameters obtained from fitting equations to cumulative pH data, is recommended to identify pH variation in relation to acidosis. Some rumen sensors can also measure the redox potential. This measurement helps to understand rumen functioning, as the redox potential of rumen fluid directly reflects the microbial intracellular redox balance status and impacts fermentative activity of rumen microorganisms. Taken together, proper assessment and interpretation of data generated by rumen sensors requires consideration of their limitations under various conditions.


Assuntos
Acidose/veterinária , Doenças dos Bovinos/metabolismo , Bovinos/metabolismo , Acidose/metabolismo , Acidose/fisiopatologia , Animais , Doenças dos Bovinos/fisiopatologia , Dieta/veterinária , Feminino , Fermentação , Concentração de Íons de Hidrogênio , Oxirredução , Rúmen/metabolismo
6.
Adv Exp Med Biol ; 1232: 277-282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893421

RESUMO

Acidification of the cellular microenvironment is found in different pathological states such as inflammation, ischemia and in solid tumors. It can affect cell function and phenotype, and by this aggravate the pathological process. Epithelial cells are a relevant functional part in several normal organs as well as in tumors and will thus be challenged by the acidic extracellular pH (acidosis). Therefore, the impact of acidosis on the expression of different inflammatory mediators (MCP-1, IL-6, osteopontin, iNOS, TNF-α, and COX-2), as well as the role of different signaling pathways regulating the expression, was studied in epithelial normal rat kidney cells (NRK-52E). Acidosis led to an increase in TNF-α expression but a down-regulation of MCP-1, iNOS and COX-2. Expression of IL-6 was only slightly modulated, while osteopontin was not regulated at all. Since acidosis activates ERK1/2 and p38 signaling in NRK-52E cells, the impact of MAP kinase signaling pathways on the expression of the inflammatory markers was analyzed. At normal pH, blocking ERK1/2 or p38 decreased the level of MCP-1, iNOS and partly TNF-α. However, the effect of acidosis on the expression of inflammatory mediators was not affected by inhibition of the MAP kinase pathways. In conclusion, our results show that an acidic microenvironment affects the transcriptional program of epithelial cells. Low pH mostly reduced the expression of pathological relevant genes and might thus repress inflammatory processes induced by epithelial cells.


Assuntos
Acidose , Células Epiteliais , Regulação da Expressão Gênica , Mediadores da Inflamação , Proteínas Quinases p38 Ativadas por Mitógeno , Acidose/metabolismo , Animais , Linhagem Celular , Quimiocina CCL2/genética , Ciclo-Oxigenase 2/genética , Células Epiteliais/metabolismo , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Óxido Nítrico Sintase Tipo II/genética , Ratos , Fator de Necrose Tumoral alfa/genética
7.
Nat Commun ; 11(1): 454, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974393

RESUMO

Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-ß2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-ß2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-ß2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-ß2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Gotículas Lipídicas/metabolismo , Fator de Crescimento Transformador beta2/genética , Acetilcoenzima A/metabolismo , Acidose/metabolismo , Acidose/patologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Gotículas Lipídicas/efeitos dos fármacos , Camundongos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cell Mol Life Sci ; 77(6): 965-976, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31563996

RESUMO

Crystallins were firstly found as structural proteins of the eye lens. To this family belong proteins, such as ζ-crystallin, expressed ubiquitously, and endowed with enzyme activity. ζ-crystallin is a moonlighting protein endowed with two main different functions: (1) mRNA binding with stabilizing activity; (2) NADPH:quinone oxidoreductase. ζ-crystallin has been clearly demonstrated to stabilize mRNAs encoding proteins involved in renal glutamine catabolism during metabolic acidosis resulting in ammoniagenesis and bicarbonate ion production that concur to compensate such condition. ζ-crystallin binds also mRNAs encoding for antiapoptotic proteins, such as Bcl-2 in leukemia cells. On the other hand, the physiological role of its enzymatic activity is still elusive. Gathering research evidences and data mined from public databases, we provide a framework where all the known ζ-crystallin properties are called into question, making it a hypothetical pivotal player in cancer, allowing cells to hijack or subjugate the acidity response mechanism to increase their ability to resist oxidative stress and apoptosis, while fueling their glutamine addicted metabolism.


Assuntos
Neoplasias/metabolismo , zeta-Cristalinas/metabolismo , Acidose/metabolismo , Amônia/metabolismo , Animais , Apoptose , Glutamina/metabolismo , Humanos , Estresse Oxidativo , Ligação Proteica , RNA Mensageiro/metabolismo
9.
Am J Physiol Renal Physiol ; 318(2): F468-F474, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841391

RESUMO

Acute pyelonephritis is frequently associated with metabolic acidosis. We previously reported that metabolic acidosis stimulates expression of hypoxia-inducible factor (HIF)-1α-induced target genes such as stromal derived factor-1 and cathelicidin, an antimicrobial peptide. Since the collecting duct (CD) plays a pivotal role in regulating acid-base homeostasis and is the first nephron segment encountered by an ascending microbial infection, we examined the contribution of HIF-1α to innate immune responses elicited by acid loading of an M-1 immortalized mouse CD cell line. Acid loading of confluent M-1 cells was achieved by culture in pH 6.8 medium supplemented with 5-(N-ethyl-N-isopropyl)-amiloride to block Na+/H+ exchange activity for 24 h. Acid loading induced antimicrobial peptide [cathelicidin and ß-defensin (Defb2 and Defb26)] mRNA expression and M-1 cell resistance to uropathogenic Escherichia coli infection to an extent similar to that obtained by inhibition of HIF prolyl hydroxylases, which promote HIF-1α protein degradation. The effect of acid loading on M-1 cell resistance to uropathogenic E. coli infection was reduced by inhibition of HIF-1α (PX-478), and, in combination with prolyl hydroxylase inhibitors, acidosis did not confer additional resistance. Thus, metabolic stress of acidosis triggers HIF-1α-dependent innate immune responses in CD (M-1) cells. Whether pharmacological stabilization of HIF prevents or ameliorates pyelonephritis in vivo warrants further investigation.


Assuntos
Acidose/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Infecções por Escherichia coli/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Túbulos Renais Coletores/metabolismo , Infecções Urinárias/prevenção & controle , Escherichia coli Uropatogênica/patogenicidade , Acidose/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Linhagem Celular , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Interações Hospedeiro-Patógeno , Imunidade Inata , Túbulos Renais Coletores/imunologia , Túbulos Renais Coletores/microbiologia , Camundongos , Prolil Hidroxilases/metabolismo , Estabilidade Proteica , Transdução de Sinais , Regulação para Cima , Infecções Urinárias/imunologia , Infecções Urinárias/metabolismo , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/imunologia , beta-Defensinas/metabolismo
10.
Am J Physiol Renal Physiol ; 318(2): F402-F421, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841393

RESUMO

Hypokalemia increases ammonia excretion and decreases K+ excretion. The present study examined the role of the proximal tubule protein NBCe1-A in these responses. We studied mice with Na+-bicarbonate cotransporter electrogenic, isoform 1, splice variant A (NBCe1-A) deletion [knockout (KO) mice] and their wild-type (WT) littermates were provided either K+ control or K+-free diet. We also used tissue sections to determine the effect of extracellular ammonia on NaCl cotransporter (NCC) phosphorylation. The K+-free diet significantly increased proximal tubule NBCe1-A and ammonia excretion in WT mice, and NBCe1-A deletion blunted the ammonia excretion response. NBCe1-A deletion inhibited the ammoniagenic/ammonia recycling enzyme response in the cortical proximal tubule (PT), where NBCe1-A is present in WT mice. In the outer medulla, where NBCe1-A is not present, the PT ammonia metabolism response was accentuated by NBCe1-A deletion. KO mice developed more severe hypokalemia and had greater urinary K+ excretion during the K+-free diet than did WT mice. This was associated with blunting of the hypokalemia-induced change in NCC phosphorylation. NBCe1-A KO mice have systemic metabolic acidosis, but experimentally induced metabolic acidosis did not alter NCC phosphorylation. Although KO mice have impaired ammonia metabolism, experiments in tissue sections showed that lack of ammonia does impair NCC phosphorylation. Finally, urinary aldosterone was greater in KO mice than in WT mice, but neither expression of epithelial Na+ channel α-, ß-, and γ-subunits nor of H+-K+-ATPase α1- or α2-subunits correlated with changes in urinary K+. We conclude that NBCe1-A is critical for the effect of diet-induced hypokalemia to increase cortical proximal tubule ammonia generation and for the expected decrease in urinary K+ excretion.


Assuntos
Amônia/urina , Hipopotassemia/metabolismo , Túbulos Renais Proximais/metabolismo , Potássio na Dieta/sangue , Eliminação Renal , Simportadores de Sódio-Bicarbonato/metabolismo , Acidose/genética , Acidose/metabolismo , Acidose/fisiopatologia , Aldosterona/urina , Animais , Biomarcadores/sangue , Biomarcadores/urina , Modelos Animais de Doenças , Canais Epiteliais de Sódio/metabolismo , Glutamato-Amônia Ligase/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/genética , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Hipopotassemia/genética , Hipopotassemia/fisiopatologia , Túbulos Renais Proximais/fisiopatologia , Camundongos Knockout , Fosforilação , Simportadores de Sódio-Bicarbonato/deficiência , Simportadores de Sódio-Bicarbonato/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo
11.
Neoplasia ; 21(11): 1085-1090, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31734629

RESUMO

Differentiating pancreatitis from pancreatic cancer would improve diagnostic specificity, and prognosticating pancreatitis that progresses to pancreatic cancer would also improve diagnoses of pancreas pathology. The high glycolytic metabolism of pancreatic cancer can cause tumor acidosis, and different levels of pancreatitis may also have different levels of acidosis, so that extracellular acidosis may be a diagnostic biomarker for these pathologies. AcidoCEST MRI can noninvasively measure extracellular pH (pHe) in the pancreas and pancreatic tissue. We used acidoCEST MRI to measure pHe in a KC model treated with caerulein, which causes pancreatitis followed by development of pancreatic cancer. We also evaluated the KC model treated with PBS, and wild-type mice treated with caerulein or PBS as controls. The caerulein-treated KC cohort had lower pHe of 6.85-6.92 before and during the first 48 h after initiating treatment, relative to a pHe of 6.92 to 7.05 pHe units for the other cohorts. The pHe of the caerulein-treated KC cohort decreased to 6.79 units at 5 weeks when pancreatic tumors were detected with anatomical MRI, and sustained a pHe of 6.75 units at the 8-week time point. Histopathology was used to evaluate and validate the presence of tumors and inflammation in each cohort. These results showed that acidoCEST MRI can differentiate pancreatic cancer from pancreatitis in this mouse model, but does not appear to differentiate pancreatitis that progresses to pancreatic cancer vs. pancreatitis that does not progress to cancer.


Assuntos
Acidose/metabolismo , Imagem por Ressonância Magnética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Pancreatite/diagnóstico , Pancreatite/metabolismo , Animais , Biomarcadores , Meios de Contraste/administração & dosagem , Meios de Contraste/química , Diagnóstico Diferencial , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Feminino , Imuno-Histoquímica , Ácido Iotalâmico/administração & dosagem , Ácido Iotalâmico/química , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos
12.
Microb Pathog ; 137: 103781, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593757

RESUMO

Sub-acute ruminal acidosis (SARA) [1] is one of the most common problems of dairy animals causing great economical loss due to decreased milk production. Here we determined the antioxidant effect of sodium butyrate (NaB) [2] in experimentally induced SARA and its effects on mammary epithelial tissues of goat. Goats (n = 12) were equally divided into two groups: high-concentrate (HC) as control group fed with HC diet (concentrate: forage = 6:4) whereas HC + NaB as treatment group fed HC diet with NaB at 1% by weight for 24 weeks. Mammary epithelial tissue samples were analyzed for the expression of genes and proteins responsible for oxidative stress as well as biochemical markers of antioxidant activity in the form of Reactive Oxygen Species (ROS). The total antioxidant capacity (T-AOC) of antioxidant enzymes was also calculated. Butyrate induced antioxidant effect by increasing mRNA and protein abundance of antioxidants in mammary gland of HC + NaB group compared to HC group. Likewise, the total antioxidant capacity (T-AOC) was significantly increased and Malondialdehyde (MDA) concentration was decreased in HC + NaB group compared to HC group. It is concluded that oxidative stress in mammary gland of goats induced by high concentrate diet was alleviated by NaB supplementation.


Assuntos
Acidose/metabolismo , Acidose/veterinária , Ácido Butírico/administração & dosagem , Doenças das Cabras/tratamento farmacológico , Glândulas Mamárias Animais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acidose/tratamento farmacológico , Acidose/fisiopatologia , Animais , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Feminino , Doenças das Cabras/genética , Doenças das Cabras/metabolismo , Doenças das Cabras/fisiopatologia , Cabras , Lactação/efeitos dos fármacos , Malondialdeído/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/química , Leite/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
14.
Nefrología (Madrid) ; 39(4): 343-354, jul.-ago. 2019. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-189755

RESUMO

En la actualidad se ha evidenciado el rol de la composición dietética en el equilibrio ácido-base, al proveer precursores ácidos y álcalis. De manera general, los alimentos altos en proteína, como la carne, los quesos, huevo, entre otros, incrementan la producción de ácidos en el organismo, mientras que las frutas y los vegetales incrementan los álcalis. La capacidad que tiene un alimento para producir precursores ácidos o bases se denomina carga ácida potencial renal (PRAL). Dietas con PRAL elevados ocasionan un estado de acidosis metabólica de bajo grado, el cual se ha asociado con el desarrollo de alteraciones metabólicas como resistencia a la insulina, diabetes, hipertensión, enfermedad renal crónica, alteraciones óseas y baja musculatura, entre otras complicaciones. El objetivo del presente trabajo es realizar una revisión de la evidencia disponible a la fecha que evalúa la asociación entre el PRAL de la dieta con la incidencia de enfermedades crónicas y alteraciones metabólicas, mencionando los mecanismos involucrados en su desarrollo


Diet composition has long been known to influence acid-base balance by providing acid or base precursors. In general, foods rich in protein, such as meat, cheese, eggs, and others, increase the production of acid in the body, whereas fruit and vegetables increase alkalis. The capacity of acid or base production of any food is called potential renal acid load (PRAL). Diets high in PRAL induce a low-grade metabolic acidosis state, which is associated with the development of metabolic alterations such as insulin resistance, diabetes, hypertension, chronic kidney disease, bone disorders, low muscle mass and other complications. The aim of this paper is to review the available evidence which evaluates the association of the PRAL of the diet with the incidence of chronic diseases and metabolic disorders, as well as related mechanisms involved in their development


Assuntos
Humanos , Equilíbrio Ácido-Base , Rim/metabolismo , Dieta/efeitos adversos , Acidose/metabolismo
15.
Semin Nephrol ; 39(4): 394-405, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31300094

RESUMO

Ammonia metabolism has a critical role in acid-base homeostasis and in other cellular functions. Kidneys have a central role in bicarbonate generation, which occurs through the process of net acid excretion; ammonia metabolism is the quantitatively greatest component of net acid excretion, both under basal conditions and in response to acid-base disturbances. Several recent studies have advanced our understanding substantially of the molecular mechanisms and regulation of ammonia metabolism. First, the previous paradigm that ammonia transport could be explained by passive NH3 diffusion and NH4+ trapping has been advanced by the recognition that specific transport of NH3 and of NH4+ by specific membrane proteins is critical to ammonia transport. Second, significant advances have been made in the understanding of the regulation of ammonia metabolism. Novel studies have shown that hyperkalemia directly inhibits ammonia metabolism, thereby leading to the metabolic acidosis present in type IV renal tubular acidosis. Other studies have shown that the proximal tubule protein NBCe1, specifically the A variant NBCe1-A, has a major role in regulating renal ammonia metabolism. Third, there are important sex differences in ammonia metabolism that involve structural and functional differences in the kidney. This review addresses these important aspects of ammonia metabolism and transport.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Amônia/metabolismo , Rim/metabolismo , Acidose/metabolismo , Animais , Transporte Biológico , Homeostase/fisiologia , Humanos , Hiperpotassemia/metabolismo
16.
Animal ; 13(S1): s75-s81, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31280745

RESUMO

The increasing lactational performance of dairy cows over the last few decades is closely related to higher nutritional requirements. The decrease in dry matter intake during the peripartal period results in a considerable mobilisation of body tissues (mainly fat reserves and muscle mass) to compensate for the prevailing lack of energy and nutrients. Despite the activation of adaptive mechanisms to mobilise nutrients from body tissues for maintenance and milk production, the increased metabolic load is still a risk factor for animal health. The prevalence of production diseases, particularly subclinical ketosis is high in the early lactation period. Increased ß-hydroxybutyrate (BHB) concentrations further depress gluconeogenesis, feed intake and the immune system. Despite a variety of adaptation responses to nutrient and energy deficit that exists among dairy cows, an early and non-invasive detection of developing metabolic disorders in milk samples would be useful. The frequent and regular milking process of dairy cows creates the ability to obtain samples at any stage of lactation. Routine identification of biomarkers accurately characterising the physiological status of an animal is crucial for decisive strategies. The present overview recapitulates established markers measured in milk that are associated with metabolic health of dairy cows. Specifically, measurements of milk fat, protein, lactose and urea concentrations are evaluated. Changes in the ratio of milk fat to protein may indicate an increased risk for rumen acidosis and ketosis. The costly determination of individual fatty acids in milk creates barriers for grouping of fatty acids into saturated, mono- and polyunsaturated fatty acids. Novel approaches include the potential of mid-IR (MIR) based predictions of BHB and acetone in milk, although the latter are not directly measured, but only estimated via indirect associations of concomitantly altered milk composition during (sub)clinical ketosis. Although MIR-based ketone body concentrations in milk are not suitable to monitor the metabolic status of the individual cow, they provide an estimate of the overall herd or specific groups of animals earlier in a particular stage of lactation. Management decisions can be made earlier and animal health status improved by adjusting diet composition.


Assuntos
Acidose/veterinária , Doenças dos Bovinos/metabolismo , Cetose/veterinária , Lactação/fisiologia , Doenças Metabólicas/veterinária , Leite/química , Ácido 3-Hidroxibutírico/análise , Acidose/metabolismo , Animais , Biomarcadores/análise , Bovinos , Dieta/veterinária , Ácidos Graxos/análise , Feminino , Cetose/metabolismo , Doenças Metabólicas/metabolismo , Leite/metabolismo , Necessidades Nutricionais , Rúmen/fisiopatologia
17.
Am J Physiol Cell Physiol ; 317(4): C714-C718, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339771

RESUMO

Intracellular acidosis is a putative agent of skeletal muscle fatigue, in part, because it depresses the calcium (Ca2+) sensitivity of the myofilaments. However, the molecular mechanism behind this depression in Ca2+ sensitivity is unknown, providing a significant challenge to a complete understanding of the fatigue process. To elucidate this mechanism, we directly determined the effect of acidosis on the ability of a single myosin molecule to bind to a regulated actin filament in a laser trap assay. Decreasing pH from 7.4 to 6.5 significantly (P < 0.05) reduced the frequency of single actomyosin-binding events at submaximal (pCa 8-pCa 6) but not at maximal Ca2+ concentration (pCa 5-pCa 4). To delineate whether this was due to a direct effect on myosin versus an indirect effect on the regulatory proteins troponin (Tn) and tropomyosin (Tm), binding frequency was also quantified in the absence of Tn and Tm. This revealed that acidosis did not significantly alter the frequency of actomyosin binding events in the absence of regulatory proteins (1.4 ± 0.15 vs. 1.4 ± 0.15 events/s for pH 7.4 and 6.5, respectively). Acidosis also did not significantly affect the size of myosin's powerstroke or the duration of binding events in the presence of regulatory proteins, at every [Ca2+]. These data suggest acidosis impedes activation of the thin filament by competitively inhibiting Ca2+ binding to TnC. This slows the rate at which myosin initially attaches to actin; therefore, less cross bridges will be bound and generating force at any given submaximal [Ca2+]. These data provide a molecular explanation for the acidosis-induced decrease in force observed at the submaximal Ca2+ concentrations that might contribute to the loss of force during muscle fatigue.


Assuntos
Acidose/metabolismo , Citoesqueleto de Actina/metabolismo , Actomiosina/metabolismo , Cálcio/metabolismo , Animais , Galinhas , Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , Miofibrilas/metabolismo , Miosinas/metabolismo , Sarcômeros/metabolismo
18.
Lancet ; 394(10196): 396-406, 2019 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-31248662

RESUMO

BACKGROUND: Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. METHODS: We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate 12-20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. FINDINGS: Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0·001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life-Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12·1 points (SE 3·3; p<0·0001). Time to do the repeat chair stand test improved by 4·3 s (1·2) on veverimer versus 1·4 s (1·2) on placebo (p<0·0001). INTERPRETATION: In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. FUNDING: Tricida.


Assuntos
Acidose/tratamento farmacológico , Polímeros/administração & dosagem , Insuficiência Renal Crônica/complicações , Acidose/etiologia , Acidose/metabolismo , Administração Oral , Idoso , Bicarbonatos/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polímeros/efeitos adversos , Insuficiência Renal Crônica/metabolismo , Resultado do Tratamento
19.
Am J Physiol Regul Integr Comp Physiol ; 317(2): R312-R318, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141417

RESUMO

Chronic kidney disease (CKD) patients experience augmented blood pressure (BP) reactivity during exercise that is associated with an increased risk of cardiovascular mortality. Exaggerated exercise pressor responses in CKD are in part mediated by augmented sympathetic nerve activation due to heightened muscle mechanoreflex. One mechanism that may lead to sensitization of the muscle mechanoreflex in CKD is metabolic acidosis. We hypothesized that CKD patients with low serum [bicarbonate] would exhibit exaggerated increases in arterial BP, greater reductions in muscle interstitial pH, and fatigue earlier during exercise compared with CKD patients with normal serum bicarbonate concentration ([bicarbonate]). Eighteen CKD participants with normal serum [bicarbonate] (≥24 mmol/l, normal-bicarb) and 9 CKD participants with mild metabolic acidosis ([bicarbonate] range 20-22 mmol/l, low-bicarb) performed rhythmic handgrip (RHG) exercise to volitional fatigue at 40% of maximal voluntary contraction. BP, heart rate, and muscle interstitial pH using near infrared spectroscopy were measured continuously. While mean arterial pressure (MAP) increased with exercise in both groups (P ≤ 0.002), CKD with low-bicarb had an exaggerated MAP response compared with CKD with normal-bicarb (+5.9 ± 1.3 mmHg/30 s vs. +2.6 ± 0.5 mmHg/30 s, P = 0.01). The low-bicarb group reached exhaustion earlier than the normal-bicarb group (179 ± 21 vs. 279 ± 19 s, P = 0.003). There were no differences in the change in muscle interstitial pH during exercise between groups (P = 0.31). CKD patients with metabolic acidosis have augmented exercise-induced increases in BP and poorer exercise tolerance. There was no difference in change in muscle interstitial pH between groups, however, suggesting that augmented exercise BP responses in metabolic acidosis are not due to impaired muscle-buffering capacity.


Assuntos
Acidose/metabolismo , Exercício Físico/fisiologia , Força da Mão/fisiologia , Insuficiência Renal Crônica/fisiopatologia , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/fisiopatologia , Músculo Esquelético/metabolismo , Sistema Nervoso Simpático/fisiopatologia
20.
Cancer Metastasis Rev ; 38(1-2): 103-112, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31069574

RESUMO

The glycolytic phenotype of the Warburg effect is associated with acidification of the tumor microenvironment. In this review, we describe how acidification of the tumor microenvironment may increase the invasive and degradative phenotype of cancer cells. As a template of an extracellular acidic microenvironment that is linked to proteolysis, we use the resorptive pit formed between osteoclasts and bone. We describe similar changes that have been observed in cancer cells in response to an acidic microenvironment and that are associated with proteolysis and invasive and metastatic phenotypes. This includes consideration of changes observed in the intracellular trafficking of vesicles, i.e., lysosomes and exosomes, and in specialized regions of the membrane, i.e., invadopodia and caveolae. Cancer-associated cells are known to affect what is generally referred to as tumor proteolysis but little direct evidence for this being regulated by acidosis; we describe potential links that should be verified.


Assuntos
Acidose/metabolismo , Acidose/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/fisiologia , Animais , Humanos , Proteólise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA