DSpace Collection:https://hdl.handle.net/10171/189372024-03-29T12:38:53Z2024-03-29T12:38:53ZGhrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLDhttps://hdl.handle.net/10171/689972024-02-12T06:09:10Z2019-01-01T00:00:00ZTitle: Ghrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLD
Abstract: Context: Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death.
Objective: The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated.
Design, settings, and participants: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes.
Results: Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR.
Conclusions: Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.2019-01-01T00:00:00ZEvaluation of the quality of multiple-choice questions according to the students’ academic levelhttps://hdl.handle.net/10171/689622024-02-12T06:08:45Z2022-01-01T00:00:00ZTitle: Evaluation of the quality of multiple-choice questions according to the students’ academic level
Abstract: Background: One of the most important challenges in medical education is the preparation of multiple-choice
questions able to discriminate between students with diferent academic level. Average questions may be very easy
for students with good performance, reducing their discriminant power in this group of students. The aim of this
study was to analyze if the discriminative power of multiple-choice questions is diferent according to the students’
academic performance.
Methods: We retrospectively analyzed the difculty and discrimination indices of 257 multiple-choice questions
used for the end of course examination of pathophysiology and analyzed whether the discrimination indices were
lower in students with good academic performance (group 1) than in students with moderate/poor academic perfor‐
mance (group 2). We also evaluated whether case-based questions maintained their discriminant power better than
factual questions in both groups of students or not. Comparison of the difculty and discrimination indices between
both groups was based on the Wilcoxon test.
Results: Difculty index was signifcantly higher in group 1 (median: 0.78 versus 0.56; P< 0.001) and discrimination
index was signifcantly higher in group 2 (median: 0.21 versus 0.28; P< 0.001). Factual questions had higher discrimi‐
native indices in group 2 than in group 1 (median: 0.28 versus 0.20; P< 0.001), but discriminative indices of case-
based questions did not difer signifcantly between groups (median: 0.30 versus 0.24; P=0.296).
Conclusions: Multiple-choice question exams have lower discriminative power in the group of students with high
scores. The use of clinical vignettes may allow to maintain the discriminative power of multiple-choice questions.2022-01-01T00:00:00ZAssociation of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolismhttps://hdl.handle.net/10171/688022024-02-12T06:06:59Z2016-01-01T00:00:00ZTitle: Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism
Abstract: Objectives: Cystatin C has been shown to be associated
with heart failure with preserved ejection fraction (HFPEF).
In addition, myocardial fibrosis has been involved in
diastolic dysfunction in HFPEF. Therefore, we hypothesized
that increased cystatin C levels may be associated with
altered collagen metabolism, contributing to diastolic
dysfunction in patients with HFPEF.
Methods: One hundred and forty-one elderly hypertensive
patients with HFPEF were included. Cardiac morphology
and function was assessed by echocardiography.
Circulating levels of cystatin C, biomarkers of collagen type
I synthesis (carboxy-terminal propeptide of procollagen
type I) and degradation [matrix metalloproteinase-1 (MMP-
1) and its inhibitor TIMP-1] and osteopontin were analyzed
by ELISA. Twenty elderly sex-matched patients with no
identifiable cardiac disease were used as controls. In-vitro
studies were performed in human cardiac fibroblasts.
Results: Compared with controls, cystatin C was increased
(P < 0.001) in patients with HFPEF, even in those with a
normal estimated glomerular filtration rate (eGFR;
P < 0.05). Cystatin C was directly correlated with the
estimated pulmonary capillary wedge pressure (P < 0.01),
TIMP-1 and osteopontin (P < 0.001) and inversely
correlated with MMP-1:TIMP-1 (P < 0.01), but not with
carboxy-terminal propeptide of procollagen type I or MMP-
1 in all patients with HFPEF. These associations were
independent of eGFR. In vitro, osteopontin (P < 0.01) and
TIMP-1 (P < 0.001) increased in the supernatant of cardiac
fibroblasts exposed to cystatin C.
Conclusion: In patients with HFPEF of hypertensive origin,
cystatin C is increased and associated with diastolic
dysfunction and alterations in collagen metabolism
independently of eGFR. An excess of cystatin C might
contribute to diastolic dysfunction in HFPEF by facilitating
myocardial fibrosis via accumulation of osteopontin and
TIMP-1.2016-01-01T00:00:00ZAssociation of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: A pilot studyhttps://hdl.handle.net/10171/687852024-02-12T06:06:53Z2015-01-01T00:00:00ZTitle: Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with type 2 diabetes mellitus: A pilot study
Abstract: Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide
glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to
investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating
GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of
cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14
nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP-
1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1
decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated
with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP-
1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated
HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial
ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase
activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total
and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and
exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in
HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may
counteract OS, protect from CR, and prevent CVE in patients with T2DM.2015-01-01T00:00:00Z