Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34.230
Filtrar
1.
Nat Metab ; 5(1): 61-79, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36593272

RESUMO

Enhanced glycolysis and accumulation of lactate is a common feature in various types of cancer. Intracellular lactate drives a recently described type of posttranslational modification, lysine lactylation (Kla), on core histones. However, the impact of lactylation on biological processes of tumour cells remains largely unknown. Here we show a global lactylome profiling on a prospectively collected hepatitis B virus-related hepatocellular carcinoma (HCC) cohort. Integrative lactylome and proteome analysis of the tumours and adjacent livers identifies 9,275 Kla sites, with 9,256 sites on non-histone proteins, indicating that Kla is a prevalent modification beyond histone proteins and transcriptional regulation. Notably, Kla preferentially affects enzymes involved in metabolic pathways, including the tricarboxylic acid cycle, and carbohydrate, amino acid, fatty acid and nucleotide metabolism. We further verify that lactylation at K28 inhibits the function of adenylate kinase 2, facilitating the proliferation and metastasis of HCC cells. Our study therefore reveals that Kla plays an important role in regulating cellular metabolism and may contribute to HCC progression.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Histonas/metabolismo , Lactatos
2.
Trials ; 24(1): 3, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597167

RESUMO

BACKGROUND: Critically ill patients must be monitored constantly in intensive care units (ICUs). Among many laboratory variables, nutritional status indicators are a key role in the prognosis of diseases. We investigated the effects of L-carnitine adjunctive therapy on monitoring variables in critical illness. METHOD: A prospective, double-blind, randomized controlled trial was implemented in a medical ICU. Participants were 54 patients, aged > 18 years, with multiple conditions, randomly assigned to receive 3 g L-carnitine per day or placebo, along with enteral feeding, for 1 week. Primary outcomes included monitoring variables related to nutritional status. RESULT: Of 54 patients randomly assigned, 51 completed the trial. Serum albumin (Alb) (P-value: 0.001), total protein (P-value: 0.003), and calcium (Ca) (0.044) significantly increased in the intervention vs. control group. Alanine transaminase (ALT) (0.022), lactate (<0.001), creatinine (Cr) (0.005), and international normalized ratio (INR) (0.049) decreased meaningfully in the intervention vs. control group. CONCLUSION: L-Carnitine supplementation in critically ill patients can improve several parameters including INR, Cr, ALT, lactate, Ca, Alb, and total protein. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT 20151108024938N2. This trial was approved by the Research Ethics Committee of Mashhad University of Medical Sciences (registration code: IR.MUMS.fm.REC.1396.671) (available at https://en.irct.ir/trial/30748 , May 2018).


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Carnitina/efeitos adversos , Estado Terminal , Irã (Geográfico) , Estudos Prospectivos , Unidades de Terapia Intensiva , Lactatos
3.
Medicine (Baltimore) ; 102(4): e32743, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36705345

RESUMO

RATIONALE: Methylene blue (MB) has been used to increase blood pressure in septic shock, acting on the activity of guanylate cyclase and nitric oxide synthase. PATIENCE CONCERNS: The aim of this study is to demonstrate the benefit of MB in early phase of septic shock.Diagnoses: We report 6 cases of patients with septic shock with up to 72 hours of evolution. INTERVENTIONS: We used MB after fluid replacement, use of norepinephrine and vasopressin. Patients received a loading dose of MB and maintenance for 48 hours. OUTCOMES: All patients presented a reduction in the dose of vasopressors and lactate levels soon after the administration of the loading dose of MB, an effect that was maintained with the maintenance dose for 48 hours. Interleukin 6 and interleukin 8 were elevated at the beginning of the septic condition, with a progressive and marked reduction after the beginning of MB infusion, demonstrating a role of MB in reducing the inflammatory activity. LESSONS: This case series suggests that MB used early in the treatment of septic shock may be useful in reducing vasopressor dose and lactate levels. Further studies are still required to further validate these findings.


Assuntos
Azul de Metileno , Choque Séptico , Humanos , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Hemodinâmica , Pressão Sanguínea/fisiologia , Vasoconstritores/uso terapêutico , Norepinefrina/uso terapêutico , Lactatos
4.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674540

RESUMO

This study addresses a joint nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy approach to provide a platform for dynamic assessment of kidney viability and metabolism. On porcine kidney models, ROS production, oxidative damage kinetics, and metabolic changes occurring both during the period between organ retrieval and implantation and after kidney graft were examined. The 1H-NMR metabolic profile-valine, alanine, acetate, trimetylamine-N-oxide, glutathione, lactate, and the EPR oxidative stress-resulting from ischemia/reperfusion injury after preservation (8 h) by static cold storage (SCS) and ex vivo machine perfusion (HMP) methods were monitored. The functional recovery after transplantation (14 days) was evaluated by serum creatinine (SCr), oxidative stress (ROS), and damage (thiobarbituric-acid-reactive substances and protein carbonyl enzymatic) assessments. At 8 h of preservation storage, a significantly (p < 0.0001) higher ROS production was measured in the SCS vs. HMP group. Significantly higher concentration data (p < 0.05-0.0001) in HMP vs. SCS for all the monitored metabolites were found as well. The HMP group showed a better function recovery. The comparison of the areas under the SCr curves (AUC) returned a significantly smaller (-12.5 %) AUC in the HMP vs. SCS. EPR-ROS concentration (µmol·g-1) from bioptic kidney tissue samples were significantly lower in HMP vs. SCS. The same result was found for the NMR monitored metabolites: lactate: -59.76%, alanine: -43.17%; valine: -58.56%; and TMAO: -77.96%. No changes were observed in either group under light microscopy. In conclusion, a better and more rapid normalization of oxidative stress and functional recovery after transplantation were observed by HMP utilization.


Assuntos
Transplante de Rim , Animais , Suínos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Preservação de Órgãos/métodos , Espécies Reativas de Oxigênio/metabolismo , Perfusão/métodos , Rim/metabolismo , Estresse Oxidativo , Lactatos/metabolismo , Metaboloma , Alanina/metabolismo
5.
Ren Fail ; 45(1): 2167661, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36692196

RESUMO

BACKGROUND: This retrospective study aimed to determine the incidence, risk factors, and outcomes of acute kidney injury (AKI) in neonates following the arterial switch operation (ASO) for transposition of great arteries (TGA). METHODS: Retrospective review of medical data of children who underwent ASO in 2019-2020 in the Ukrainian Children's Cardiac Center. RESULTS: 76 consecutive neonatal patients were included, 48 developed AKI after ASO (51.7%), and 24 - had severe AKI (25.8%). Severe AKI development was associated with longer cross-clamp time: 82 (61-127) versus 73.5 (53-136) in the non-severe AKI group (p = 0.02). 76 min of cross-clamp time were defined as a threshold value for increased severe AKI risk, OR 4.4 (95% CI: 1.5 - 13, p = 0.01). Higher lactate levels during cardiopulmonary bypass (CPB) increased severe AKI development risk, OR 1.5 (95% CI: 1.0 - 2.0, p = 0.03). Children with severe AKI had prolonged mechanical ventilation, longer time to negative fluid balance, and higher postoperative day 3 (POD3) Inotropic Score (IS). Only one patient required peritoneal dialysis. CONCLUSIONS: In our study, 51.7% of patients developed AKI after ASO, 25.8%-severe AKI. Prolonged cross-clamp time and higher lactate levels during cardiopulmonary bypass increased the risk for severe AKI development. The development of AKI was associated with prolonged mechanical ventilation, longer time to negative fluid balance, higher POD 3 Inotropic Score.


Assuntos
Injúria Renal Aguda , Transposição das Grandes Artérias , Recém-Nascido , Criança , Humanos , Estudos Retrospectivos , Transposição das Grandes Artérias/efeitos adversos , Incidência , Complicações Pós-Operatórias/etiologia , Injúria Renal Aguda/etiologia , Ponte Cardiopulmonar/efeitos adversos , Fatores de Risco , Lactatos
6.
Vet Rec ; 192(2): 63, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36661166
7.
Pediatr Surg Int ; 39(1): 75, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36617603

RESUMO

PURPOSE: This study aimed to examine the diagnostic value of IL-6, thiol-disulfide homeostasis, complete blood count and inflammatory biomarkers in the prediction of acute appendicitis in children. METHODS: The study was designed as a prospective and controlled study in children-the study was conducted at a tertiary referential university hospital between May 2020 and April 2021. Patients were divided between study groups and one control group (CG): 1: confirmed acute appendicitis group (AAP); 2: perforated appendicitis group (PAP); and 3: non-specified abdominal pain (NAP). The age and gender of the patients were determined. The following listed laboratory parameters were compared between groups: TOS: total oxidative status, TAS: total antioxidant status, OSI: oxidative stress index, TT: total thiol, NT (µmol/L): native thiol, DIS: disulfide, IL-6: interleukin 6, TNF-a: tumor necrosis factor-alpha, WBC: white blood cell, NEU: neutrophil, NEU%: neutrophil percentage, LY: lymphocyte, LY%: lymphocyte percentage, PLT: platelet, MPV: mean platelet volume NLR: neutrophil lymphocyte ratio, CRP: C-reactive protein, LCR: lymphocyte CRP ratio, and serum lactate. RESULTS: The TOS level of the PAP group was found to be significantly higher than that in the AAP, NAP and control groups (p = 0.006, < 0.001 and p < 0.001). TAS, TT, and NT levels in the PAP group were significantly lower than those in the AAP, NAP and control groups. OSI was significantly higher in the PAP group than in the other groups. The TT and NT levels of the NAP group were both similar to those of the control group. Serum DIS level was similar between the AAP and PAP groups, AAP and NAP groups, and NAP and control groups. Serum IL-6 and TNF-α levels were found to be significantly higher in the PAP group compared to those in all groups. The WBC, NEU, and NEU% values were found to be significantly higher in the PAP group than those in the NAP and control groups, while LY and LY% values were found to be significantly lower. PAP and AAP groups were found to be similar in terms of WBC, NEU, LYM, NEU%, and LYM% values. PLT and MPV values and serum lactate values did not show a significant difference between the groups. NLR was similar in the AAP and PAP groups. A significant increase in CRP versus a decrease in LCR was detected in the PAP group compared to that in the AAP group. Multivariate analysis demonstrated that only IL-6 has significant estimated accuracy rates as 80% for the control group, 78.8% for AAP, 96.9% for PAP, and 81.6% for NAP. CONCLUSION: Rather than AAP, PAP caused significantly higher oxidative stress (increased TOS and OSI), and lower antioxidation capacity (decreased TT and NT). IL-6 levels can provide a significant stratification. Nevertheless, simply detecting WBC or CRP is not enough to distinguish the specific pathology in acute appendicitis and related conditions.


Assuntos
Apendicite , Interleucina-6 , Humanos , Criança , Apendicite/diagnóstico , Dissulfetos , Compostos de Sulfidrila , Estudos Prospectivos , Biomarcadores , Antioxidantes , Homeostase , Lactatos
8.
J Coll Physicians Surg Pak ; 33(1): 5-9, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36597226

RESUMO

OBJECTIVE: To compare intravenous lidocaine infusion adjunct to NSAID and Acetaminophen with regular analgesics for postoperative mean pain score and mean ambulation time after laparoscopic cholecystectomy. STUDY DESIGN: Randomised controlled trial. PLACE AND DURATION OF STUDY: Department of General Surgery, Islamabad Medical Complex, (IMC), from March 2020 to December 2021. METHODOLOGY: Sixty (n=60) adult patients, both males and females between the ages of 18-60 years planned for laparoscopic cholecystectomy, were selected and randomly allocated to two groups of treatment (Lidocaine and Ringer Lactate). The control group did not receive any other placebo other than Ringer Lactate infusion. Both groups received Intramuscular Diclofenac 12 hourly and intravenous acetaminophen infusion 8 hourly. Postoperative pain 2, 6, 12 and 24 hours (h) and mean ambulation time were compared in both groups. RESULTS: Mean VAS (Visual Analogue Scale) of group 1 versus group 2 at 2 h, 6 h, 12 h and 24 h were 3.47 ± 0.82 vs. 6.27 ± 0.52 (p=<0.001), 2.7 ± 0.75 vs. 4.8 ± 0.8 (p<0.001), 2.0 ± 0.49 vs. 3.93 ± 0.94 (p<0.001), 0.73 ± 0.82 vs. 2.2 ± 0.61 (p<0.001). Time for spontaneous ambulation after surgery was 5.57 ± 1.55 hours for Group 1 versus 7.3 ± 1.9 hours for Group 2 (p<0.001). CONCLUSION: Pain scores at all-time intervals were lower, and ambulation time was shorter in patients who received intravenous infusion of lidocaine as compared to patients who received only regular analgesics for laparoscopic cholecystectomy. KEY WORDS: Ambulation time, Laparoscopic cholecystectomy, Postoperative pain.


Assuntos
Anestésicos Locais , Colecistectomia Laparoscópica , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Acetaminofen/uso terapêutico , Analgésicos/uso terapêutico , Analgésicos Opioides , Colecistectomia , Colecistectomia Laparoscópica/efeitos adversos , Método Duplo-Cego , Infusões Intravenosas , Lactatos , Lidocaína , Dor Pós-Operatória/tratamento farmacológico
9.
J Am Coll Surg ; 236(1): 241-252, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36519920

RESUMO

BACKGROUND: Partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) is a potential method to mitigate the ischemia observed in full REBOA (fREBOA). However, the effect of pREBOA on cerebral perfusion in the setting of raised intracranial pressure (rICP) is unknown. The aim was to evaluate the effects of no REBOA (nREBOA) vs pREBOA vs fREBOA on cerebral perfusion in a swine model of rICP and hemorrhagic shock. STUDY DESIGN: Anesthetized swine (n = 18) underwent instrumentation. Controlled hemorrhage was performed over 30 minutes. rICP was achieved using an intracranial Fogarty catheter inflated to achieve an ICP of 20 mmHg. Animals underwent intervention for 30 minutes, followed by resuscitation. The primary outcome was cerebral perfusion measured by ICP (millimeters of mercury), cerebral perfusion pressure (CPP; millimeters of mercury), and cerebral blood flow (CBF; milliliters per minute per 100 g) derived from CT perfusion. The secondary outcomes included hemodynamics and lactate (millimoles per liter). RESULTS: The peak ICP of pREBOA animals (22.7 ± 2.5) was significantly lower than nREBOA and fREBOA. pREBOA CPP was significantly higher compared with nREBOA and fREBOA during resuscitation. The pREBOA CBF was greater during intervention and resuscitation compared with nREBOA (p < 0.001). Systolic blood pressure was similar between pREBOA and fREBOA, and coronary perfusion was significantly greater in pREBOA. fREBOA had significantly higher lactate during the intervention (9.3 ± 1.3) and resuscitation (8.9 ± 3.5) compared with nREBOA and pREBOA. CONCLUSION: pREBOA produced greater cerebral perfusion, as demonstrated by more favorable CPP, CBF, and ICP values. fREBOA was associated with metabolic derangement and diminished pressure during resuscitation. pREBOA is superior to fREBOA in a swine model and should be considered over fREBOA for aortic occlusion.


Assuntos
Oclusão com Balão , Procedimentos Endovasculares , Hipertensão Intracraniana , Mercúrio , Choque Hemorrágico , Suínos , Animais , Choque Hemorrágico/terapia , Pressão Intracraniana , Modelos Animais de Doenças , Oclusão com Balão/métodos , Ressuscitação/métodos , Aorta , Lactatos , Procedimentos Endovasculares/métodos
10.
J Steroid Biochem Mol Biol ; 225: 106197, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36183994

RESUMO

Activated dendritic cells (DCs) undergo significant metabolic reprogramming, which is characterized by an increase in aerobic glycolysis and a concurrent progressive loss of oxidative phosphorylation. The modulation of metabolic reprogramming is believed to be closely related to the function of DCs. Vitamin D has been reported to inhibit the maturation of DCs. DC dysfunction has been reported in diabetic patients, and hyperglycemia is associated with impaired glycolytic metabolism in immune cells. Therefore, vitamin D and diabetes may affect intracellular metabolism, thereby regulating the activity of DCs. We investigated the effect of in vitro treatment of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on metabolic reprogramming and maturation of bone marrow-derived dendritic cells (BMDCs) from diabetic mouse. Six-week-old male C57BLKS/J-m+/m+ mice (CON) and C57BLKS/J-db/db mice (db/db) were fed with a 10% kcal fat diet for seven weeks. BMDCs were generated by culturing bone marrow cells from the mice with rmGM-CSF (20 ng/mL) in the absence or presence of 10 nM 1,25(OH)2D3. The maturation of BMDCs was induced via lipopolysaccharide (LPS, 50 ng/mL) stimulation for 24 h. LPS stimulation induced iNOS protein expression and decreased the mitochondrial respiration, while increased lactate production and the expression of glycolytic pathway-related genes (Glut1 and Pfkfb3) in BMDCs from both CON and db/db groups. In LPS-stimulated mature BMDCs, 1,25(OH)2D3 treatment decreased the expression of surface markers related to immunostimulatory functions (MHC class II, CD80, CD86, and CD40) and production of IL-12p70 in both CON and db/db groups. While the mRNA level of the gene related to glucose uptake (Glut1) was increased in both groups, lactate production was decreased by 1,25(OH)2D3 treatment. mTORC1 activity was suppressed following 1,25(OH)2D3 treatment. Collectively, our findings confirmed that metabolic reprogramming occurred in BMDCs following LPS stimulation. In vitro 1,25(OH)2D3 treatment induced tolerogenic phenotypes by reducing the expression of surface markers, as well as cytokine production. However, no significant difference was observed regarding the effects of 1,25(OH)2D3 treatment on metabolic conversion and maturation of BMDCs between the control and diabetic mice. Additionally, the decreased aerobic glycolysis induced by the 1,25(OH)2D3 treatment appeared to be associated with the diminished maturation of BMDCs, and mTORC1 appears to play a key role in the 1,25(OH)2D3-mediated regulation of glycolysis.


Assuntos
Células Dendríticas , Diabetes Mellitus Experimental , Camundongos , Masculino , Animais , Lipopolissacarídeos/farmacologia , Calcitriol/farmacologia , Calcitriol/metabolismo , Medula Óssea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Células da Medula Óssea , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Lactatos/metabolismo , Lactatos/farmacologia , Diferenciação Celular
11.
Semin Cancer Biol ; 88: 32-45, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36496155

RESUMO

Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.


Assuntos
Imunoterapia , Neoplasias , Humanos , Neoplasias/metabolismo , Lactatos , Microambiente Tumoral
12.
Neuroscience ; 510: 49-59, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36529295

RESUMO

Exercise has been reported to elicit a transient suppression of appetite. Plasma lactate, which is produced by exercising muscle, is believed to have a critical effect on exercise-induced appetite suppression. However, the underlying mechanisms and signaling steps of central lactate metabolism remain unexplored. After central oxamate administration, C57BL/6J male mice performed 10 high-intensity interval running at 90% Vmax for 4 minutes each, which separated by 2 minutes at 12 m/min. Food intake and the expression of hypothalamic appetite-regulating neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were investigated following exercise training. Janus kinase 2 (Jak2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway was also determined by Western blot. In addition, hypoxia-inducible factor-1α (HIF-1α) was investigated to explore the effect of central lactate metabolism following exercise. We found that central oxamate administration reversed exercise-induced suppression of food intake, and as well as changes in the expression of POMC and NPY. Moreover, acute exercise led to an increase in the phosphorylation of Jak2 and STAT3 in the hypothalamus, while central lactate inhibition significantly blunted this effect. In addition, HIF-1α expression increased obviously after exercise, while it was attenuated by central oxamate administration. Collectively, our data reveal that central lactate metabolism mediates exercise-induced suppression of appetite and changes in neuropeptides, possibly through enhanced Jak2-STAT3 signaling.


Assuntos
Apetite , Neuropeptídeos , Camundongos , Animais , Masculino , Pró-Opiomelanocortina/metabolismo , Camundongos Endogâmicos C57BL , Hipotálamo/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeo Y/metabolismo , Lactatos/metabolismo , Lactatos/farmacologia
13.
J Dairy Sci ; 106(2): 1002-1012, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36543642

RESUMO

The objective of this study was to determine the effects of including exogenous amylolytic or fibrolytic enzymes in a diet for high-producing dairy cows on in vitro ruminal fermentation. Eight dual-flow continuous-culture fermentors were used in a replicated 4 × 4 Latin square. The treatments were control (CON), a xylanase and glucanase mixture (T1), an α-amylase mixture (T2), or a xylanase, glucanase, and α-amylase mixture (T3). Treatments were included at a rate of 0.008% of diet dry matter (DM) for T1 and T2 and at 0.02% for T3. All treatments replaced the equivalent amount of soybean meal in the diet compared with CON. All diets were balanced to have the same nutrient composition [30.2% neutral detergent fiber (NDF), 16.1% crude protein (CP), and 30% starch; DM basis], and fermentors were fed 106 g/d divided into 2 feedings. At each feeding, T2 was pipetted into the respective fermentor and an equivalent amount of deionized water was added to each fermentor to eliminate potential variation. Experimental periods were 10 d (7 d for adaptation and 3 d for sample collection). Composite samples of daily effluent were collected and analyzed for volatile fatty acids (VFA), NH3-N, and lactate concentrations, degradability of DM, organic matter, NDF, CP, and starch, and flow and metabolism of N. Samples of fermentor contents were collected from each fermentor at 0, 1, 2, 4, 6, and 8 h after feeding to determine kinetics of pH, NH3-N, lactate, and VFA concentrations over time. All data were analyzed using PROC GLIMMIX of SAS (SAS Institute Inc.), and the repeated variable of time was included for kinetics measurements. Treatment did not affect mean pH, degradability, N flow and metabolism, or the concentrations of VFA, NH3-N, or lactate in the effluent samples. Treatment did not affect pH, acetate:propionate ratio, or the concentrations of lactate, NH3-N, total VFA, acetate, propionate, butyrate, isobutyrate, valerate, or caproate. However, the concentration of total VFA tended to change at each time point depending upon the treatment, and T2 tended to have a greater proportion of 2-methylbutyrate and isovalerate than CON, T1, or T3. As 2-methylbutyrate and isovalerate are branched-chain VFA that are synthesized from branched-chain amino acids, T2 may have an increased fermentation of branched-chain amino acids or decreased uptake by fibrolytic microorganisms. Although we did not observe changes in N metabolism due to the enzymes, there could be changes in microbial populations that utilize branched-chain VFA. Overall, the tested enzymes did not improve in vitro ruminal fermentation in the diet of high-producing dairy cows.


Assuntos
Lactação , Propionatos , Animais , Bovinos , Feminino , alfa-Amilases/metabolismo , Ração Animal/análise , Dieta/veterinária , Digestão , Ácidos Graxos Voláteis/metabolismo , Fermentação , Lactatos/metabolismo , Propionatos/metabolismo , Rúmen/metabolismo , Amido/metabolismo
14.
Crit Care ; 26(1): 372, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36457089

RESUMO

Although guidelines provide excellent expert guidance for managing patients with septic shock, they leave room for personalization according to patients' condition. Hemodynamic monitoring depends on the evolution phase: salvage, optimization, stabilization, and de-escalation. Initially during the salvage phase, monitoring to identify shock etiology and severity should include arterial pressure and lactate measurements together with clinical examination, particularly skin mottling and capillary refill time. Low diastolic blood pressure may trigger vasopressor initiation. At this stage, echocardiography may be useful to identify significant cardiac dysfunction. During the optimization phase, echocardiographic monitoring should be pursued and completed by the assessment of tissue perfusion through central or mixed-venous oxygen saturation, lactate, and carbon dioxide veno-arterial gradient. Transpulmonary thermodilution and the pulmonary artery catheter should be considered in the most severe patients. Fluid therapy also depends on shock phases. While administered liberally during the resuscitation phase, fluid responsiveness should be assessed during the optimization phase. During stabilization, fluid infusion should be minimized. In the de-escalation phase, safe fluid withdrawal could be achieved by ensuring tissue perfusion is preserved. Norepinephrine is recommended as first-line vasopressor therapy, while vasopressin may be preferred in some patients. Essential questions remain regarding optimal vasopressor selection, combination therapy, and the most effective and safest escalation. Serum renin and the angiotensin I/II ratio may identify patients who benefit most from angiotensin II. The optimal therapeutic strategy for shock requiring high-dose vasopressors is scant. In all cases, vasopressor therapy should be individualized, based on clinical evaluation and blood flow measurements to avoid excessive vasoconstriction. Inotropes should be considered in patients with decreased cardiac contractility associated with impaired tissue perfusion. Based on pharmacologic properties, we suggest as the first test a limited dose of dobutamine, to add enoximone or milrinone in the second line and substitute or add levosimendan if inefficient. Regarding adjunctive therapies, while hydrocortisone is nowadays advised in patients receiving high doses of vasopressors, patients responding to corticosteroids may be identified in the future by the analysis of selected cytokines or specific transcriptomic endotypes. To conclude, although some general rules apply for shock management, a personalized approach should be considered for hemodynamic monitoring and support.


Assuntos
Monitorização Hemodinâmica , Choque Séptico , Humanos , Angiotensina II , Hemodinâmica , Lactatos , Choque Séptico/terapia , Vasoconstritores/uso terapêutico , Medicina de Precisão
15.
Front Immunol ; 13: 1051514, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466921

RESUMO

Metabolic adaptations shape immune cell function. In the acute response, a metabolic switch towards glycolysis is necessary for mounting a proinflammatory response. During the clinical course of sepsis, both suppression and activation of immune responses take place simultaneously. Leukocytes from septic patients present inhibition of cytokine production while other functions such as phagocytosis and production of reactive oxygen species (ROS) are preserved, similarly to the in vitro endotoxin tolerance model, where a first stimulation with lipopolysaccharide (LPS) affects the response to a second stimulus. Here, we sought to investigate how cellular metabolism is related to the modulation of immune responses in sepsis and endotoxin tolerance. Proteomic analysis in peripheral blood mononuclear cells (PBMCs) from septic patients obtained at intensive care unit admission showed an upregulation of proteins related to glycolysis, the pentose phosphate pathway (PPP), production of ROS and nitric oxide, and downregulation of proteins in the tricarboxylic acid cycle and oxidative phosphorylation compared to healthy volunteers. Using the endotoxin-tolerance model in PBMCs from healthy subjects, we observed increased lactate production in control cells upon LPS stimulation, while endotoxin-tolerant cells presented inhibited tumor necrosis factor-α and lactate production along with preserved phagocytic capacity. Inhibition of glycolysis and PPP led to impairment of phagocytosis and cytokine production both in control and in endotoxin-tolerant cells. These data indicate that glucose metabolism supports leukocyte functions even in a condition of endotoxin tolerance.


Assuntos
Endotoxinas , Sepse , Humanos , Proteoma , Leucócitos Mononucleares , Lipopolissacarídeos/farmacologia , Proteômica , Espécies Reativas de Oxigênio , Leucócitos , Via de Pentose Fosfato , Lactatos , Glucose , Citocinas
16.
Dis Markers ; 2022: 5926049, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569219

RESUMO

Background: There were controversies over the relationship between Anion gap (AG) and mortality in critically ill patients. Therefore, a large multicenter cohort study was conducted to evaluate the association of AG and mortality in large-scale intensive care units (ICUs) patients. Methods: This retrospective cohort study included adult ICU patients enrolled from eICU Collaborative Research Database. According to initial serum AG upon ICU admission, patients were divided into three groups: AG < 8 mmol/L, 8 ≤ AG ≤ 16 mmol/L, and AG > 16 mmol/L. Logistic regression models were built to investigate the association between serum AG and ICU and hospital mortalities. Serum AG was added into Acute Physiology and Chronic Health Evaluation (APACHE) IV score and the model discrimination was assessed by the area under the curve (AUC) of receiver operating characteristic curves. The relationship between serum AG and mortalities in patients with different acid-base status and serum lactate were also evaluated. An external validation was performed with the Critical care database comprising patients with infection at Zigong Fourth People's Hospital. Results: A total of 8520 patients entered the final cohort. There are 42 patients with serum AG < 8 mmol/L, 3238 patients with 8 ≤ AG ≤ 16 mmol/L, and 5240 patients with AG > 16 mmol/L. Serum AG > 16 mmol/L is related with increased ICU mortality (odds ratio [OR], 1.530; 95% confidence interval [CI], 1.305-1.794) and hospital mortality (OR, 1.618; 95% CI, 1.415-1.849), compared with 8 ≤ AG ≤ 16 mmol/L. Adding Serum AG to APACHE IV score could statistically improve the prediction of ICU (0.770 [0.761-0.779] to 0.774 [0.765-0.783], P = 0.001) and hospital mortalities (0.756 [0.747-0.765] to 0.761 [0.751-0.770], P = 0.012). The associations between serum AG and mortalities remain robust in patients with different acid-base statuses and serum lactate. The findings are validated in the external cohort. Conclusions: Initial serum AG > 16 mmol/L after ICU admission is associated with increased mortality in critically ill patients.


Assuntos
Equilíbrio Ácido-Base , Estado Terminal , Adulto , Humanos , Estudos de Coortes , Estudos Retrospectivos , Unidades de Terapia Intensiva , Prognóstico , Mortalidade Hospitalar , Lactatos
18.
Cell Rep ; 41(13): 111894, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36577374

RESUMO

Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.


Assuntos
NAD , Pró-Opiomelanocortina , Camundongos , Animais , Pró-Opiomelanocortina/metabolismo , NAD/metabolismo , Glucose/metabolismo , Neurônios/metabolismo , Lactatos/metabolismo , Hipotálamo/metabolismo , Proteína Desacopladora 2/metabolismo
19.
J Sports Sci Med ; 21(4): 545-554, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36523893

RESUMO

High intensity functional training (HIFT) provides a potential option to meet public exercise recommendations for both cardiorespiratory and strength outcomes in a time efficient manner. To better understand the potential for HIFT as an exercise approach, energy expenditure (EE) and relative intensity need quantifying. In thirteen sedentary men and women with metabolic syndrome (MetS), we used both indirect calorimetry and blood lactate levels to calculate EE of a single session of HIFT. The HIFT session included four, 6-minute sets of consecutive functional exercises. Examples of the exercises involved were squats, deadlifts, suspension rows, suspension chest press, and planks. Intensity is described relative to individual ventilatory thresholds. The total group EE was 270.3 ± 77.3 kcal with approximately 5% attributed anaerobic energy production. VO2 ranged between 88.8 ± 12.3% and 99 ± 12% of the second ventilatory threshold (VT2), indicating a vigorous effort. After each work interval, peak blood lactate ranged between 7.9 ± 1.9 and 9.3 ± 2.9 mmol, and rate of perceived exertion between 6.9 ± 1.0 and 8.7 ± 0.8 arbitrary units from 1-10. These were achieved in approximately 46 minutes of exercise per participant. In conclusion, HIFT elicits the energy expenditure and effort requisite to result in the adaptive responses to produce the known suite of benefits of exercise for individuals with MetS.


Assuntos
Treinamento Intervalado de Alta Intensidade , Masculino , Humanos , Feminino , Metabolismo Energético/fisiologia , Calorimetria Indireta , Exercício Físico/fisiologia , Lactatos
20.
Sci Rep ; 12(1): 21640, 2022 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-36517529

RESUMO

Although probiotics are often indiscriminately prescribed, they are not equal and their effects on the host may profoundly differ. In vitro determination of the attributes of probiotics should be a primary concern and be performed even before clinical studies are designed. In fact, knowledge on the biological properties a microbe possesses is crucial for selecting the most suitable bacteriotherapy for each individual. Herein, nine strains (Bacillus clausii NR, OC, SIN, T, Bacillus coagulans ATCC 7050, Bifidobacterium breve DSM 16604, Limosilactobacillus reuteri DSM 17938, Lacticaseibacillus rhamnosus ATCC 53103, and Saccharomyces boulardii CNCM I-745) declared to be contained in six commercial formulations were tested for their ability to tolerate simulated intestinal conditions, adhere to mucins, and produce ß-galactosidase, antioxidant enzymes, riboflavin, and D-lactate. With the exception of B. breve, all microbes survived in simulated intestinal fluid. L. rhamnosus was unable to adhere to mucins and differences in mucin adhesion were evidenced for L. reuteri and S. boulardii depending on oxygen levels. All microorganisms produced antioxidant enzymes, but only B. clausii, B. coagulans, B. breve, and L. reuteri synthesize ß-galactosidase. Riboflavin secretion was observed for Bacillus species and L. rhamnosus, while D-lactate production was restricted to L. reuteri and L. rhamnosus. Our findings indicate that the analyzed strains possess different in vitro biological properties, thus highlighting the usefulness of in vitro tests as prelude for clinical research.


Assuntos
Probióticos , Antioxidantes , beta-Galactosidase , Mucinas , Lactatos , Riboflavina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...