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1.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 972-980, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701228

RESUMO

OBJECTIVE: To investigate the effects of acid-sensing ion channels (ASICs) on electrophysiological epileptic activities of mouse hippocampal pyramidal neurons in the extracellular acidotic condition. METHODS: We investigated effects of extracellular acidosis on epileptic activities induced by elevated extracellular K + concentration or the application of an antagonist of GABAA receptors in perfusate of mouse hippocampal slices under field potential recordings. We also tested the effects of extracellular acidosis on neuronal excitability under field potential recording and evaluated the changes in epileptic activities of the neurons in response to pharmacological inhibition of ASICs using a specific inhibitor of ASICs. RESULTS: Extracellular acidosis significantly suppressed epileptic activities of the hippocampal neurons by converting ictal-like epileptic activities to non-ictal-like epileptic activities in both high [K +]o and disinhibition models, and also suppressed the intrinsic excitability of the neurons. ASICs inhibitor did not antagonize the inhibitory effect of extracellular acidosis on ictal epileptic activities and intrinsic neuronal excitability, but exacerbated non-ictal epileptic activities of the neurons in extracellular acidotic condition in both high [K+]o and disinhibition models. CONCLUSIONS: ASICs can differentially modulate ictal-like and non-ictallike epileptic activities via its direct actions on excitatory neurons.


Assuntos
Canais Iônicos Sensíveis a Ácido , Acidose , Epilepsia , Células Piramidais , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Epilepsia/fisiopatologia , Concentração de Íons de Hidrogênio , Camundongos , Células Piramidais/patologia , Células Piramidais/fisiologia
2.
Medicine (Baltimore) ; 99(18): e19964, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358368

RESUMO

RATIONALE: Holocarboxylase synthetase (HCLS) deficiency, especially the late-onset type, is a rare disease. Affected patients can present with irreversible metabolic acidosis and may be misdiagnosed with a glucose metabolic disorder. Prompt and correct diagnosis and treatment can reduce mortality to a great extent. PATIENT CONCERNS: We report 2 Chinese patients who were diagnosed with late-onset HCLS deficiency. The age of onset of the 2 patients was approximately 8 months. The 2 patients had skin lesions, severe profound metabolic acidosis, dyspnea, and hyperglycemia. DIAGNOSES: The results of urinary and blood organic acid analysis with gas chromatography/mass spectrometry revealed multiple carboxylase deficiency. Maple syrup urine disease and diabetic ketoacidosis could not be excluded. This finding is different from those of hypoglycemic complications reported in previous reports. Human genetic analysis eventually provided a definite diagnosis. INTERVENTIONS: Prompt oral treatment with biotin dramatically corrected the metabolic imbalances of the 2 patients, and continued oral biotin therapy was essential to the improvement of their prognoses. OUTCOMES: Their metabolic disorders were corrected within 48 hours. During long-term follow-up, the patients achieved developmental milestones. LESSONS: Late-onset HCLS deficiency may present with obvious hyperglycemia. Human genetic analysis eventually provided a definite diagnosis. Prompt treatment with biotin is vital to correct metabolic imbalances, and continued therapy is essential to the improving long-term prognoses. Their mutations were p.R508W and c.1088T > A, and these mutations might represent hot-spot genes in Chinese populations with HCLS deficiency. The variants c.1484T > G(p.L495*) and c.835G > T(p.E279x) are likely pathogenic, and more studies are needed to confirm these results.


Assuntos
Deficiência de Holocarboxilase Sintetase/diagnóstico , Deficiência de Holocarboxilase Sintetase/fisiopatologia , Acidose/etiologia , Biotina/uso terapêutico , China , Dispneia/etiologia , Feminino , Deficiência de Holocarboxilase Sintetase/complicações , Deficiência de Holocarboxilase Sintetase/tratamento farmacológico , Humanos , Hiperglicemia/etiologia , Lactente , Masculino
3.
PLoS One ; 15(4): e0230708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271786

RESUMO

Neonatal calf diarrhea (NCD) is a major problem to calf health worldwide, in terms of both morbidity and mortality. A five-point ordinal scale clinical assessment scoring (CAS) chart was utilized to assess calves suffering from NCD-related clinical abnormalities (acidosis and dehydration) on commercial farms. The objective of this research was to determine the predictive capability of this CAS chart against gold standard blood gas parameters, designed to assist farmers in the accurate assessment of the clinical consequences of NCD. A total of 443 diarrheic and non-diarrheic calves were enrolled in the study. The CAS chart rated a calf's health from no clinical signs to varying degrees of clinical severity on a 0 (clinically normal) to 4 (grave) scale, based on clinical indicators including calf demeanour, ear position, mobility, suckle reflex, desire-to-feed, and enophthalmos. Blood gas analysis was conducted for individual calves, consisting of pH, base excess, Na+, K+, Ca2+, Cl-, glucose, total hemoglobin, bicarbonate, anion gap, and strong ion difference. Statistical evaluation was performed by comparison of the CAS score with blood gas profiles using ordinal logistic regression and a non-parametric estimation of the Receiver Operating Characteristics (ROC). The ROC analysis indicated that the CAS chart had acceptable specificity (>95%) with low sensitivity (<60%) in differentiating clinically normal from acidotic/dehydrated cases. Assessment of individual severity classes indicated that the chart can predict and differentiate both clinically normal and advanced cases from the other severity classes (peak estimations >80%) but had reduced accuracy in differentiating mild and moderate cases (peak estimations >50%). The chart, as presented, provides a simple tool to differentiate clinically normal from calves suffering the consequences of diarrhea, but fails to accurately differentiate severity for NCD related acidosis and dehydration. Further efforts are required to enhance the sensitivity and differential diagnostic value of this type of chart.


Assuntos
Animais Recém-Nascidos , Doenças dos Bovinos/diagnóstico , Técnicas e Procedimentos Diagnósticos/veterinária , Diarreia/diagnóstico , Design de Software , Acidose/sangue , Acidose/diagnóstico , Acidose/veterinária , Animais , Gasometria/normas , Gasometria/veterinária , Bovinos , Doenças dos Bovinos/sangue , Doenças dos Bovinos/patologia , Desidratação/sangue , Desidratação/diagnóstico , Desidratação/veterinária , Técnicas e Procedimentos Diagnósticos/normas , Diarreia/sangue , Diarreia/patologia , Diarreia/veterinária , Feminino , Masculino , Valor Preditivo dos Testes , Prognóstico , Projetos de Pesquisa , Índice de Gravidade de Doença
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.
Am J Physiol Renal Physiol ; 318(3): F720-F731, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036699

RESUMO

Impaired insulin-induced suppression of renal gluconeogenesis could be a risk for hyperglycemia. Diabetes is associated with elevated renal gluconeogenesis; however, its regulation in early insulin resistance is unclear in humans. A noninvasive marker of renal gluconeogenesis would be helpful. Here, we show that human urine exosomes (uE) contain three gluconeogenic enzymes: phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Their protein levels were positively associated with whole body insulin sensitivity. PEPCK protein in uE exhibited a meal-induced suppression. However, subjects with lower insulin sensitivity had blunted meal-induced suppression. Also, uE from subjects with prediabetes and diabetic rats had higher PEPCK relative to nondiabetic controls. Moreover, uE-PEPCK was higher in drug-naïve subjects with diabetes relative to drug-treated subjects with diabetes. To determine whether increased renal gluconeogenesis is associated with hyperglycemia or PEPCK expression in uE, acidosis was induced in rats by 0.28 M NH4Cl with 0.5% sucrose in drinking water. Control rats were maintained on 0.5% sucrose. At the seventh day posttreatment, gluconeogenic enzyme activity in the kidneys, but not in the liver, was higher in acidotic rats. These rats had elevated PEPCK in their uE and a significant rise in blood glucose relative to controls. The induction of gluconeogenesis in human proximal tubule cells increased PEPCK expression in both human proximal tubules and human proximal tubule-secreted exosomes in the media. Overall, gluconeogenic enzymes are detectable in human uE. Elevated PEPCK and its blunted meal-induced suppression in human urine exosomes are associated with diabetes and early insulin resistance.


Assuntos
Diabetes Mellitus Tipo 2 , Gluconeogênese/fisiologia , Resistência à Insulina , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/urina , Acidose/induzido quimicamente , Adulto , Idoso , Animais , Diabetes Mellitus Experimental , Exossomos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Ratos , Ratos Sprague-Dawley
7.
Vet Res Commun ; 44(1): 19-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32043213

RESUMO

Sub-acute ruminal acidosis is a type of metabolic disorder in which affected cattle show a considerable depression of rumen pH. This leads to a dramatic decline in productivity and consequent loss of income for many dairy farms. The objective of the present study is to identify and characterize novel long non-coding RNAs (lncRNAs) in Holstein cattle affected by sub-acute ruminal acidosis. Two replicates from six animals were sequenced that bioinformatically analyzed. Results showed 6679 novel lncRNAs among which 12 intergenic lncRNAs showed differential expression (p value ≤0.05). GO and KEGG analysis revealed that calcium signaling and G protein couple-receptor pathways may be involved in regulating metabolic processes during sub-acute ruminal acidosis. Furthermore, other biological processes including transmembrane transport, adult behavior, neuroactive ligand-receptor interaction, GABAergic synapse, cholinergic synapse were significantly enriched. The present data suggest that these differentially expressed lncRNAs may play regulatory roles in modulating biological processes associated with sub-acute ruminal acidosis in cattle rumen.


Assuntos
Acidose/veterinária , Doenças dos Bovinos/genética , RNA Longo não Codificante/genética , Rúmen/fisiopatologia , Gastropatias/veterinária , Acidose/genética , Acidose/fisiopatologia , Animais , Bovinos/genética , Bovinos/metabolismo , Doenças dos Bovinos/fisiopatologia , Masculino , RNA Longo não Codificante/metabolismo , Gastropatias/genética , Gastropatias/fisiopatologia
8.
Crit Care Resusc ; 22(1): 80-82, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32102646

RESUMO

BACKGROUND: Due to the lack of double-blind randomised controlled trials, the true effect of intravenous sodium bicarbonate therapy in ICU patients with metabolic acidosis remains unclear. METHODS: We diluted 100 mL 8.4% sodium bicarbonate in 150 mL 5% dextrose (D5W) within a 250 mL polyolefin bag after removing 100 mL. We asked ICU clinicians to inspect a 250 mL bag containing sodium bicarbonate or a 250 mL bag where 100 mL of D5W had been removed and then returned. The bags were attached to intravenous giving sets. We asked participants to identify the contents of the bags. RESULTS: Among 60 participants (39 nursing staff [65%], 20 medical staff [33.3%] and one pharmacist), 36 (60%) answered correctly. The Cohen κ for agreement between test bag content and participants' answers was 0.20 (95% CI, -0.05 to 0.45; P = 0.12), implying the answers were correct by chance. In the group of 28 participants who indicated they used a clue to help them decide their answer, 15 (53.6%) answered correctly, whereas in the remainder (n = 32), 21 (65.6%) answered correctly (P = 0.49). CONCLUSION: When 100 mL of 8.4% sodium bicarbonate were diluted in 150 mL of D5W within a 250 mL polyolefin bag, clinicians were unable to correctly identify the contents of the bags. Our findings imply that sodium bicarbonate therapy can be successfully blinded.


Assuntos
Acidose/tratamento farmacológico , Glucose/uso terapêutico , Bicarbonato de Sódio/uso terapêutico , Administração Intravenosa , Método Duplo-Cego , Eletrólitos , Glucose/administração & dosagem , Humanos , Injeções Intravenosas , Sódio/sangue , Bicarbonato de Sódio/administração & dosagem , Resultado do Tratamento
9.
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
10.
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
11.
Nat Commun ; 11(1): 475, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980622

RESUMO

We reported previously that acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1) to its C terminus (CT), independent of its ion-conducting function. Here we show that the N-terminus (NT) of ASIC1a interacts with its CT to form an auto-inhibition that prevents RIPK1 recruitment/activation under resting conditions. The interaction involves glutamate residues at distal NT and is disrupted by acidosis. Expression of mutant ASIC1a bearing truncation or glutamate-to-alanine substitutions at distal NT causes constitutive cell death. The NT-CT interaction is further disrupted by N-ethylmaleimide-sensitive fusion ATPase (NSF), which associates with ASIC1a-NT under acidosis, facilitating RIPK1 interaction with ASIC1a-CT. Importantly, a membrane-penetrating synthetic peptide representing the distal 20 ASIC1a NT residues, NT1-20, reduced neuronal damage in both in vitro model of acidotoxicity and in vivo mouse model of ischemic stroke, demonstrating the therapeutic potential of targeting the auto-inhibition of ASIC1a for neuroprotection against acidotoxicity.


Assuntos
Canais Iônicos Sensíveis a Ácido/química , Canais Iônicos Sensíveis a Ácido/fisiologia , Necroptose/fisiologia , Neurônios/fisiologia , Canais Iônicos Sensíveis a Ácido/genética , Acidose/patologia , Acidose/fisiopatologia , Substituição de Aminoácidos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Modelos Neurológicos , Proteínas Sensíveis a N-Etilmaleimida/farmacologia , Proteínas Sensíveis a N-Etilmaleimida/fisiologia , Neurônios/citologia , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/fisiologia , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia , Transdução de Sinais , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
12.
Sci Rep ; 10(1): 1438, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996710

RESUMO

Proton-sensing ovarian cancer G-protein coupled receptor (OGR1) plays an important role in pH homeostasis. Acidosis occurs at sites of intestinal inflammation and can induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), an evolutionary mechanism that enables cells to cope with stressful conditions. ER stress activates autophagy, and both play important roles in gut homeostasis and contribute to the pathogenesis of inflammatory bowel disease (IBD). Using a human intestinal epithelial cell model, we investigated whether our previously observed protective effects of OGR1 deficiency in experimental colitis are associated with a differential regulation of ER stress, the UPR and autophagy. Caco-2 cells stably overexpressing OGR1 were subjected to an acidic pH shift. pH-dependent OGR1-mediated signalling led to a significant upregulation in the ER stress markers, binding immunoglobulin protein (BiP) and phospho-inositol required 1α (IRE1α), which was reversed by a novel OGR1 inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor. Proton-activated OGR1-mediated signalling failed to induce apoptosis, but triggered accumulation of total microtubule-associated protein 1 A/1B-light chain 3, suggesting blockage of late stage autophagy. Our results show novel functions for OGR1 in the regulation of ER stress through the IRE1α-JNK signalling pathway, as well as blockage of autophagosomal degradation. OGR1 inhibition might represent a novel therapeutic approach in IBD.


Assuntos
Endorribonucleases/metabolismo , Células Epiteliais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/metabolismo , Microtúbulos/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Acidose , Autofagia , Células CACO-2 , Estresse do Retículo Endoplasmático/genética , Feminino , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Sistema de Sinalização das MAP Quinases , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Resposta a Proteínas não Dobradas
13.
Nat Biomed Eng ; 4(3): 314-324, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31235828

RESUMO

Owing to the diversity of cancer types and the spatiotemporal heterogeneity of tumour signals, high-resolution imaging of occult malignancy is challenging. 18F-fluorodeoxyglucose positron emission tomography allows for near-universal cancer detection, yet in many clinical scenarios it is hampered by false positives. Here, we report a method for the amplification of imaging contrast in tumours via the temporal integration of the imaging signals triggered by tumour acidosis. This method exploits the catastrophic disassembly, at the acidic pH of the tumour milieu, of pH-sensitive positron-emitting neutral copolymer micelles into polycationic polymers, which are then internalized and retained by the cancer cells. Positron emission tomography imaging of the 64Cu-labelled polymers detected small occult tumours (10-20 mm3) in the brain, head, neck and breast of mice at much higher contrast than 18F-fluorodeoxyglucose, 11C-methionine and pH-insensitive 64Cu-labelled nanoparticles. We also show that the pH-sensitive probes reduce false positive detection rates in a mouse model of non-cancerous lipopolysaccharide-induced inflammation. This macromolecular strategy for integrating tumour acidosis should enable improved cancer detection, surveillance and staging.


Assuntos
Acidose/diagnóstico por imagem , Cobre/química , Neoplasias/diagnóstico por imagem , Polímeros/química , Tomografia por Emissão de Pósitrons/métodos , Coloração e Rotulagem/métodos , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/química , Nanotecnologia/métodos , Neoplasias/patologia
14.
J Urol ; 203(3): 585-590, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31596652

RESUMO

PURPOSE: Ileal neobladder construction is a common choice for orthotopic urinary diversion following radical cystectomy. We investigated risk factors for metabolic acidosis during the early recovery period. MATERIALS AND METHODS: This study relied on retrospectively collected data on 345 patients who underwent inpatient rehabilitation after radical cystectomy and ileal neobladder construction for bladder cancer between January 2014 and March 2017. Acid-base status, use of sodium bicarbonate to correct metabolic acidosis and continence status were evaluated at the beginning and end of 3 weeks of inpatient rehabilitation. Multivariate logistic regression analysis was performed to identify risk factors associated with the development of metabolic acidosis. RESULTS: At the start of rehabilitation a median of 29 days after surgery (IQR 23-37) 200 patients (58.0%) had metabolic acidosis. During the inpatient rehabilitation period the need for oral sodium bicarbonate replacement due to acidosis increased significantly from 45.2% to 86.7% of patients (p <0.001) while urine loss measured by a 24-hour pad test decreased significantly from a median of 387 (IQR 98-918) to 88 gm (IQR 5-388, p <0.001). The median base excess was within the normal range (-1.2 mmol/l, IQR -2.4 - 0.0) at the end of inpatient rehabilitation. Decreased urinary leakage was identified as an independent risk factor for metabolic acidosis.Conclusions:The risk of metabolic acidosis after neobladder construction correlated with continuously improved continence in the early recovery period. Therefore, during this period the acid-base status should be assessed more frequently to identify metabolic acidosis.


Assuntos
Acidose/epidemiologia , Íleo/cirurgia , Complicações Pós-Operatórias/epidemiologia , Neoplasias da Bexiga Urinária/cirurgia , Coletores de Urina , Cistectomia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
15.
J Dairy Sci ; 103(2): 1931-1943, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837780

RESUMO

This study aimed to examine the role of thiamine in the local inflammation of ruminal epithelium caused by high-concentrate diets. Eighteen mid-lactating (148 ± 3 d in milk; milk yield = 0.71 ± 0.0300 kg/d) Saanen goats (body weight = 36.5 ± 1.99 kg; body condition score = 2.73 ± 0.16, where 0 = emaciated and 5 = obese) in parity 1 or 2 were selected. The goats were randomly divided into 3 groups (n = 6/group): (1) control diet (concentrate:forage 30:70), (2) high-concentrate diet (HC; concentrate:forage 70:30), and (3) high-concentrate diet with 200 mg of thiamine/kg of dry matter intake (THC; concentrate:forage 70:30). Goats remained on experimental diets for 8 wk. On the last day of 8 wk, ruminal and blood samples were collected to determine ruminal parameters, endotoxin lipopolysaccharide, and blood inflammatory cytokines. Goats were slaughtered to collect ruminal tissue to determine gene and protein expression of toll-like receptor 4 (TLR4) signaling pathways. Thiamine supplementation increased ruminal pH (6.03 vs. 5.42) compared with the HC group. Propionate (21.08 vs. 31.61 mM), butyrate (12.08 vs. 19.39 mM), lactate (0.52 vs. 0.71 mM), and free lipopolysaccharide (42.16 vs. 55.87 × 103 endotoxin units/mL) concentrations in ruminal fluid were lower in THC goats compared with HC goats. Similar to plasma interleukin 1ß (IL-1ß) concentration (209.31 vs. 257.23 pg/mL), blood CD8+ percentage (27.57 vs. 34.07%) also decreased in response to thiamine. Compared with HC goats, THC goats had lower ruminal epithelium activity of the enzymes myeloperoxidase and matrix metalloproteinase (MMP) 2 and 9. In contrast to HC, THC had downregulated mRNA expression of nuclear factor-κB (NFKB), TLR4, IL1B, MMP2, and MMP9 in ruminal epithelium. Thiamine supplementation led to lower relative protein expression of IL-1ß, NF-κB unit p65, and phosphorylated NF-κB unit p65 in ruminal epithelium. Taken together, these results suggest that thiamine supplementation mitigates HC-induced local inflammation and ruminal epithelial disruption.


Assuntos
Acidose/veterinária , Suplementos Nutricionais/análise , Inflamação/veterinária , Leite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiamina/farmacologia , Acidose/tratamento farmacológico , Acidose/patologia , Animais , Citocinas/análise , Dieta/veterinária , Epitélio/metabolismo , Epitélio/patologia , Feminino , Cabras , Concentração de Íons de Hidrogênio , Inflamação/tratamento farmacológico , Lactação , Lipopolissacarídeos/análise , Distribuição Aleatória , Rúmen/metabolismo , Rúmen/patologia
16.
Anesth Analg ; 130(4): 1063-1076, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31609256

RESUMO

BACKGROUND: Coagulopathy and hemostatic abnormalities remain a challenge in patients following trauma and major surgery. Coagulopathy in this setting has a multifactorial nature due to tissue injury, hemodilution, hypothermia, and acidosis, the severity of which may vary. In this study, we combined computational kinetic modeling and in vitro experimentation to investigate the effects of multifactorial coagulopathy on thrombin, the central enzyme in the coagulation system. METHODS: We measured thrombin generation in platelet-poor plasma from 10 healthy volunteers using the calibrated automated thrombogram assay (CAT). We considered 3 temperature levels (31°C, 34°C, and 37°C), 3 pH levels (6.9, 7.1, and 7.4), and 3 degrees of dilution with normal saline (no dilution, 3-fold dilution, and 5-fold dilution). We measured thrombin-generation time courses for all possible combinations of these conditions. For each combination, we analyzed 2 scenarios: without and with (15 nM) supplementation of thrombomodulin, a key natural regulator of thrombin generation. For each measured thrombin time course, we recorded 5 quantitative parameters and analyzed them using multivariable regression. Moreover, for multiple combinations of coagulopathic conditions, we performed routine coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). We compared the experimental results with simulations using a newly developed version of our computational kinetic model of blood coagulation. RESULTS: Regression analysis allowed us to identify trends in our data (P < 10). In both model simulations and experiments, dilution progressively reduced the peak of thrombin generation. However, we did not experimentally detect the model-predicted delay in the onset of thrombin generation. In accord with the model predictions, hypothermia delayed the onset of thrombin generation; it also increased the thrombin peak time (up to 1.30-fold). Moreover, as predicted by the kinetic model, the experiments showed that hypothermia increased the area under the thrombin curve (up to 1.97-fold); it also increased the height of the thrombin peak (up to 1.48-fold). Progressive acidosis reduced the velocity index by up to 24%; acidosis-induced changes in other thrombin generation parameters were much smaller or none. Acidosis increased PT by 14% but did not influence aPTT. In contrast, dilution markedly prolonged both PT and aPTT. In our experiments, thrombomodulin affected thrombin-generation parameters mainly in undiluted plasma. CONCLUSIONS: Dilution with normal saline reduced the amount of generated thrombin, whereas hypothermia increased it and delayed the time of thrombin accumulation. In contrast, acidosis in vitro had little effect on thrombin generation.


Assuntos
Acidose/sangue , Transtornos da Coagulação Sanguínea/prevenção & controle , Hemodiluição/métodos , Hipotermia Induzida , Trombina/biossíntese , Adulto , Idoso , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Temperatura Corporal , Feminino , Voluntários Saudáveis , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Adulto Jovem
17.
Am J Obstet Gynecol ; 222(1): 98-99, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545940
19.
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
20.
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