BACKGROUND & AIMS: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.
- Klíčová slova
- Fibroscan, Lung Emphysema, SERPINA1,
- MeSH
- alfa-1-antitrypsin * genetika MeSH
- aspartátaminotransferasy krev MeSH
- deficit alfa1-antitrypsinu * genetika mortalita komplikace diagnóza MeSH
- dospělí MeSH
- elastografie MeSH
- genotyp MeSH
- homozygot MeSH
- jaterní cirhóza * genetika mortalita diagnóza etiologie krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- mutace MeSH
- progrese nemoci MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Názvy látek
- alfa-1-antitrypsin * MeSH
- aspartátaminotransferasy MeSH
- SERPINA1 protein, human MeSH Prohlížeč
Primary hyperoxaluria type I (PH1) is caused by deficient alanine:glyoxylate aminotransferase (AGT) activity. PH1-causing mutations in AGT lead to protein mistargeting and aggregation. Here, we use hydrogen-deuterium exchange (HDX) to characterize the wild-type (WT), the LM (a polymorphism frequent in PH1 patients) and the LM G170R (the most common mutation in PH1) variants of AGT. We provide the first experimental analysis of AGT structural dynamics, showing that stability is heterogeneous in the native state and providing a blueprint for frustrated regions with potentially functional relevance. The LM and LM G170R variants only show local destabilization. Enzymatic transamination of the pyridoxal 5-phosphate cofactor bound to AGT hardly affects stability. Our study, thus, supports that AGT misfolding is not caused by dramatic effects on structural dynamics.
- Klíčová slova
- disease-causing variants, functional sites, primary hyperoxaluria, protein dynamics, protein stability,
- MeSH
- lidé MeSH
- mutace MeSH
- polymorfismus genetický MeSH
- primární hyperoxalurie * genetika metabolismus MeSH
- transaminasy * chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Alanine-glyoxylate transaminase MeSH Prohlížeč
- glyoxylate aminotransferase MeSH Prohlížeč
- transaminasy * MeSH
BACKGROUND: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed. OBJECTIVE: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib. DESIGN, SETTING, AND PARTICIPANTS: Patients enrolled in KEYNOTE-426 were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s). RESULTS AND LIMITATIONS: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred. CONCLUSIONS: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment. PATIENT SUMMARY: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.
- Klíčová slova
- Advanced renal cell carcinoma, Aminotransferase elevations, Axitinib, PD-1 checkpoint inhibitor, Pembrolizumab, Vascular endothelial growth factor receptor inhibitor,
- MeSH
- alanintransaminasa terapeutické užití MeSH
- axitinib terapeutické užití MeSH
- humanizované monoklonální protilátky MeSH
- karcinom z renálních buněk * farmakoterapie patologie MeSH
- lidé MeSH
- nádory ledvin * farmakoterapie patologie MeSH
- sunitinib škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alanintransaminasa MeSH
- axitinib MeSH
- humanizované monoklonální protilátky MeSH
- pembrolizumab MeSH Prohlížeč
- sunitinib MeSH
BACKGROUND AND AIMS: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. APPROACH AND RESULTS: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). CONCLUSIONS: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.
- MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- časové faktory MeSH
- dítě MeSH
- gama-glutamyltransferasa krev MeSH
- glukokortikoidy terapeutické užití MeSH
- idiopatické střevní záněty epidemiologie MeSH
- internacionalita MeSH
- léková rezistence MeSH
- lidé MeSH
- mladiství MeSH
- portální hypertenze epidemiologie patofyziologie MeSH
- přežívání štěpu MeSH
- progrese nemoci MeSH
- recidiva MeSH
- registrace MeSH
- rejekce štěpu farmakoterapie epidemiologie patologie MeSH
- rizikové faktory MeSH
- sklerozující cholangitida krev epidemiologie chirurgie MeSH
- transplantace jater * MeSH
- věkové faktory MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- alanintransaminasa MeSH
- aspartátaminotransferasy MeSH
- gama-glutamyltransferasa MeSH
- glukokortikoidy MeSH
BACKGROUND: Predictive markers can help tailor treatment to the individual in metastatic renal cell carcinoma (mRCC). De Ritis ratio (DRR) is associated with oncologic outcomes in various solid tumors. OBJECTIVE: To assess the value of DRR in prognosticating survival in mRCC patients treated with tyrosine-kinase inhibitors (TKI). METHODS: Overall, 220 mRCC patients treated with TKI first-line therapy were analyzed. An optimal cut-off point for DRR was determined with Youden's J. We used multiple strata for DRR, performed descriptive, Kaplan-Meier and multivariable Cox-regression analyses to assess associations of DRR with progression-free (PFS) and overall survival (OS). RESULTS: Patients above the optimal cut-off point for DRR of ≥ 1.58 had fewer liver metastases (p = 0.01). There was no difference in PFS (p > 0.05) between DRR groups. DRR above the median of 1.08 (HR 1.42; p = 0.03), DRR ≥ 1.1(HR 1.44; p = 0.02), ≥ 1.8 (HR 1.56; p = 0.03), ≥ 1.9 (HR 1.59; p = 0.02) and ≥ 2.0 (HR 1.63; p = 0.047) were associated with worse OS. These associations did not remain after multivariable adjustment. In the intermediate MSKCC group, DRR was associated with inferior OS at cut-offs ≥ 1.0 (HR 1.78; p = 0.02), ≥ 1.1 (HR 1.81; p = 0.01) and above median (HR 1.88; p = 0.007) in multivariable analyses. In patients with clear-cell histology, DRR above median (HR 1.54; p = 0.029) and DRR ≥ 1.1 (HR 1.53; p = 0.029) were associated with OS in multivariable analyses. CONCLUSION: There was no independent association between DRR and survival of mRCC patients treated with TKI in the entire cohort. However, OS of patients with intermediate risk and clear-cell histology were affected by DRR. DRR could be used for tailored decision-making in these subgroups.
- Klíčová slova
- De ritis ratio, Metastatic renal cell carcinoma, Prognostic marker, Tumor markers, Tyrosine-kinase inhibitors,
- MeSH
- alanintransaminasa analýza krev MeSH
- analýza přežití MeSH
- aspartátaminotransferasy analýza krev MeSH
- cytoredukční chirurgie metody MeSH
- indazoly * aplikace a dávkování škodlivé účinky MeSH
- inhibitory proteinkinas aplikace a dávkování škodlivé účinky MeSH
- karcinom z renálních buněk * krev farmakoterapie patologie chirurgie MeSH
- Karnofského skóre MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory ledvin * krev farmakoterapie patologie chirurgie MeSH
- nefrektomie metody MeSH
- prediktivní hodnota testů MeSH
- prognóza MeSH
- pyrimidiny * aplikace a dávkování škodlivé účinky MeSH
- sorafenib aplikace a dávkování škodlivé účinky MeSH
- staging nádorů MeSH
- stupeň nádoru MeSH
- sulfonamidy * aplikace a dávkování škodlivé účinky MeSH
- sunitinib * aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alanintransaminasa MeSH
- aspartátaminotransferasy MeSH
- indazoly * MeSH
- inhibitory proteinkinas MeSH
- pazopanib MeSH Prohlížeč
- pyrimidiny * MeSH
- sorafenib MeSH
- sulfonamidy * MeSH
- sunitinib * MeSH
PURPOSE: The De Ritis ratio (aspartate aminotransferase/alanine aminotransferase, DRR) has been linked to oncological outcomes in several cancers. We aimed to assess the association of DRR with recurrence-free survival (RFS) and progression-free survival (PFS) in patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: We conducted a retrospective analysis of 1117 patients diagnosed with NMIBC originating from an established multicenter database. To define the optimal pretreatment DRR cut-off value, we determined a value of 1.2 as having a maximum Youden index value. The overall population was therefore divided into two De Ritis ratio groups using this cut-off (lower, < 1.2 vs. higher, ≥ 1.2). Univariable and multivariable Cox regression analyses were used to investigate the association of DRR with RFS and PFS. The discrimination of the model was evaluated with the Harrel's concordance index (C-index). RESULTS: Overall, 405 (36%) patients had a DRR ≥ 1.2. On univariable Cox regression analysis, DRR was significantly associated with RFS (HR: 1.23, 95% CI 1.02-1.47, p = 0.03), but not with PFS (HR: 0.96, 95% CI 0.65-1.44, p = 0.9). On multivariable Cox regression analysis, which adjusted for the effect of established clinicopathologic features, DRR ≥ 1.2 remained significantly associated with worse RFS (HR:1.21, 95% CI 1.00-1.46, p = 0.04). The addition of DRR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index = 0.683 vs. C-index = 0.681). On DCA the inclusion of DRR did not improve the net-benefit of the prognostic model. CONCLUSION: Despite the statistically significant association of the DRR with RFS in patients with NMIBC, it does not seem to add any prognostic or clinical benefit beyond that of currently available clinical factors.
- Klíčová slova
- Bladder cancer, De Ritis ratio, NMIBC, PFS, RFS,
- MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- doba přežití bez progrese choroby MeSH
- invazivní růst nádoru MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru epidemiologie MeSH
- nádory močového měchýře krev patologie chirurgie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alanintransaminasa MeSH
- aspartátaminotransferasy MeSH
Cadmium (Cd) is a heavy metal that occurs in all areas of the environment, including the food chain. In the body, it causes oxidative stress by producing free radicals that are harmful to the cells. Grape seed extract (GSE) contains a wide range of biologically active components that help to neutralize the adverse effects of free radicals. In this study, the effects of GSE prepared form semi-resistant grapevine cultivar Cerason, which is rich in phenolics, on biochemical markers of brown rats exposed to the effects of cadmium were monitored. GSE increased the plasma antioxidant activity and, in the kidneys and the liver, Cd content was significantly lowered by GSE co-administration. Accordingly, the increase in creatinine content and alanine aminotransferase activity and the decrease of catalase and superoxide dismutase activities caused by cadmium were slowed down by GSE co-administration. The results of this work reveal that grape seed extract offers a protective effect against the intake of heavy metals into the organism.
- Klíčová slova
- antioxidants, biochemical markers, cadmium, grape seed extract, protective effect, rattus norvegicus,
- MeSH
- alanintransaminasa krev MeSH
- antioxidancia analýza MeSH
- aspartátaminotransferasy krev MeSH
- biologické markery metabolismus MeSH
- extrakt ze semen vinné révy farmakologie MeSH
- fytonutrienty analýza MeSH
- játra účinky léků enzymologie metabolismus MeSH
- kadmium krev MeSH
- katalasa metabolismus MeSH
- kreatinin krev MeSH
- krysa rodu Rattus MeSH
- ledviny účinky léků metabolismus MeSH
- metalothionein metabolismus MeSH
- močovina krev MeSH
- potkani Wistar MeSH
- semena rostlinná chemie MeSH
- superoxiddismutasa metabolismus MeSH
- zdraví * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alanintransaminasa MeSH
- antioxidancia MeSH
- aspartátaminotransferasy MeSH
- biologické markery MeSH
- extrakt ze semen vinné révy MeSH
- fytonutrienty MeSH
- kadmium MeSH
- katalasa MeSH
- kreatinin MeSH
- metalothionein MeSH
- močovina MeSH
- superoxiddismutasa MeSH
Selenium deficiency is a common nutritional disorder in dairy cattle globally. However, selenium supplementation can lead to selenium toxicity. This study evaluated a novel, low-toxicity selenium supplement, selenitetriglycerides, to determine its efficacy and safety in dairy cows. The study was conducted on 12 Holstein Friesian cows divided in two equal groups (control group without supplementation of selenium and experimental group with supplementation of selenitetriglycerides). Experimental cows (n=6) were orally administered 300 mg/cow/day of selenitetriglycerides for 14 days (days 1-14) and then monitored for a further 14 days (days 15-28). Blood from both groups of cows was sampled for determination of selenium concentrations, activity of aspartate aminotransferase, creatine kinase, lactate dehydrogenase, gamma- -glutamyl transferase, concentrations of triglycerides, cholesterol, non-esterified fatty acids, glucose, total protein, urea, creatinine and hematological parameters. Serum selenium concentrations in the experimental group increased significantly on day 2 (from 64.92±6.89 μg/L to 127.95±13.75 μg/L), peaked on day 7 (266.22±14.21 μg/L) and remained significantly above the initial baseline values (day 1) for 28 days. Serum selenium concentrations in the control group did not change significantly during the 28 day period (65.22 μg/L on 1st day and 64,35 μg/L on 28th day) and were significantly lower than those in the experimental group from day 2 to day 28. The results of clinical examinations, analyses of hematological parameters, and liver and kidney function tests showed that selenitetriglycerides had no adverse effect on the health or on the metabolic or haematological statuses of the cows. These findings indicate that selenitetriglycerides are safe and effective selenium supplements for cattle.
- Klíčová slova
- biochemical parameters, cattle, haematology, selenitetriglycerides, selenium,
- MeSH
- aspartátaminotransferasy krev metabolismus MeSH
- cholesterol krev MeSH
- gama-glutamyltransferasa krev metabolismus MeSH
- játra účinky léků MeSH
- kreatinin krev MeSH
- kreatinkinasa krev metabolismus MeSH
- krevní glukóza MeSH
- krevní proteiny MeSH
- kyseliny mastné neesterifikované krev MeSH
- L-laktátdehydrogenasa krev metabolismus MeSH
- ledviny účinky léků MeSH
- močovina krev MeSH
- potravní doplňky MeSH
- selen krev MeSH
- skot krev metabolismus MeSH
- sloučeniny selenu chemie farmakologie MeSH
- triglyceridy krev chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- skot krev metabolismus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie veterinární MeSH
- Názvy látek
- aspartátaminotransferasy MeSH
- cholesterol MeSH
- gama-glutamyltransferasa MeSH
- kreatinin MeSH
- kreatinkinasa MeSH
- krevní glukóza MeSH
- krevní proteiny MeSH
- kyseliny mastné neesterifikované MeSH
- L-laktátdehydrogenasa MeSH
- močovina MeSH
- selen MeSH
- sloučeniny selenu MeSH
- triglyceridy MeSH
PURPOSE: Identifying which patients are likely to benefit from cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is important. We tested the association between preoperative serum De Ritis ratio (DRR, Aspartate Aminotransferase/Alanine Aminotransferase) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN. MATERIAL AND METHODS: mRCC patients treated with CN at different institutions were included. After assessing for the optimal pretreatment DRR cut-off value, we found 1.2 to have the maximum Youden index value. The overall population was therefore divided into 2 DRR groups using this cut-off (low, <1.2 vs. high, ≥1.2). Univariable and multivariable Cox regression analyses tested the association between DRR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel's concordance index (C-index). The clinical value of the DRR was evaluated with decision curve analysis. RESULTS: Among 613 mRCC patients, 239 (39%) patients had a DRR ≥1.2. Median follow-up was 31 (IQR 16-58) months. On univariable analysis, high DRR was significantly associated with OS (hazard ratios [HR]: 1.22, 95% confidence interval [CI]: 1.01-1.46, P = 0.04) and CSS (HR: 1.23, 95% CI: 1.02-1.47, P = 0.03). On multivariable analysis, which adjusted for the effect of established clinicopathologic features, high DRR remained significantly associated with both OS (HR: 1.26, 95% CI: 1.04-1.52, P = 0.02) and CSS (HR: 1.26, 95% CI: 1.05-1.53, P = 0.01). The addition of DRR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index = 0.633 vs. C-index = 0.629). On decision curve analysis, the inclusion of DRR did not improve the net-benefit beyond that obtained by established subgroup analyses stratified by IMDC risk groups, type of systemic therapy, body mass index and sarcomatoid features, did not reveal any prognostic value to DRR. CONCLUSION: Despite the statistically significant association between DRR and OS as well as CSS in mRCC patients treated with CN, DRR does not seem to add any further prognostic value beyond that obtained by currently available features.
- Klíčová slova
- CSS, Cytoreductive nephrectomy, De Ritis ratio, OS, mRCC,
- MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- cytoredukční chirurgie * MeSH
- karcinom z renálních buněk krev mortalita sekundární chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- nádory ledvin krev mortalita patologie chirurgie MeSH
- nefrektomie metody MeSH
- předoperační období MeSH
- retrospektivní studie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alanintransaminasa MeSH
- aspartátaminotransferasy MeSH
Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis with inflammation and fibrosis. Membrane endoglin (Eng) expression is shown to participate in fibrosis, and plasma concentrations of soluble endoglin (sEng) are increased in patients with hypercholesterolemia and type 2 diabetes mellitus. We hypothesize that NASH increases both hepatic Eng expression and sEng in blood and that high levels of sEng modulate cholesterol and bile acid (BA) metabolism and affect NASH progression. Three-month-old transgenic male mice overexpressing human sEng and their wild type littermates are fed for six months with either a high-saturated fat, high-fructose high-cholesterol (FFC) diet or a chow diet. Evaluation of NASH, Liquid chromatography-mass spectrometry (LC/MS) analysis of BA, hepatic expression of Eng, inflammation, fibrosis markers, enzymes and transporters involved in hepatic cholesterol and BA metabolism are assessed using Real-Time Quantitative Reverse Transcription Polymerase Chain reaction (qRT-PCR) and Western blot. The FFC diet significantly increases mouse sEng levels and increases hepatic expression of Eng. High levels of human sEng results in increased hepatic deposition of cholesterol due to reduced conversion into BA, as well as redirects the metabolism of triglycerides (TAG) to its accumulation in the liver, via reduced TAG elimination by β-oxidation combined with reduced hepatic efflux. We propose that sEng might be a biomarker of NASH development, and the presence of high levels of sEng might support NASH aggravation by impairing the essential defensive mechanism protecting NASH liver against excessive TAG and cholesterol accumulation, suggesting the importance of high sEng levels in patients prone to develop NASH.
- Klíčová slova
- FFC diet, NASH, bile acids, bile production, cholesterol, endoglin,
- MeSH
- alkalická fosfatasa metabolismus MeSH
- aspartátaminotransferasy metabolismus MeSH
- biologické markery krev metabolismus MeSH
- biologické modely MeSH
- cholesterol krev metabolismus MeSH
- dieta s vysokým obsahem tuků MeSH
- endoglin krev metabolismus MeSH
- fruktosa MeSH
- jaterní cirhóza krev komplikace patologie MeSH
- játra metabolismus patologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nealkoholová steatóza jater krev komplikace metabolismus MeSH
- oxidační stres MeSH
- rozpustnost MeSH
- triglyceridy metabolismus MeSH
- zánět patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkalická fosfatasa MeSH
- aspartátaminotransferasy MeSH
- biologické markery MeSH
- cholesterol MeSH
- endoglin MeSH
- fruktosa MeSH
- triglyceridy MeSH
