93 research outputs found
Vitamin E protects against extraskeletal calcification in uremic rats fed high fat diets
Background:
High fat diets are implicated in the pathogenesis of metabolic syndrome, obesity and renal disease.
Previous studies have revealed that high fat diets promote vascular calcification in uremic rats. Moreover, vitamin E
has been shown to prevent uremic calcifications in genetically obese Zucker rats fed standard diet. The objective of
this study was to investigate the influence of vitamin E supplementation on the development of extraskeletal
calcifications in non-obese (wild type) uremic rats fed high fat diets.
Methods:
Wistar rats (
n
= 32) were preconditioned by feeding either a normal (NF) or high fat (HF) diet for
45 days and subsequently were subjected to 5/6 nephrectomy (Nx). Just before performing the first Nx step,
a blood sample (Pre-Nx) was obtained. After Nx rat
s were switched to a diet with 0.9% phosphorus and
supplemented with calcitriol. Also, after Nx, half of the rats from each group (NF and HF) were treated with
vitamin E (VitE) in the diet (30,000 mg/kg) and the ot
her half were maintained on basic VitE requirements
(27 mg/kg). Thus, rats were allotted to four experimental groups: Nx-NF (
n
= 8), Nx-NF-VitE (
n
=8),Nx-HF(
n
=8)and
Nx-HF-VitE (
n
= 8). At the time of sacrifice (day 66), blood and tissue samples were obtained.
Results:
Feeding a HF diet for 45 days did not increase body weight but elicited hyperglycemia, hypertriglyceridemia,
an increase in plasma fibroblast growth factor 23 and a reduction in plasma calcitriol concentrations. After Nx, rats fed
HF diet showed substantial extraskeletal calcification with aortic calcium content that was higher than in rats fed NF
diet. Supplementation with VitE significantly (
p
< 0.05) reduced aortic (from 38.4 ± 8.8 to 16.5 ± 1.4 mg/g), gastric (from
5.6 ± 2.7 to 1.2 ± 0.4 mg/g) and pulmonary (from 1.8 ± 0.3 to 0.3 ± 0.2 mg/g) calcium content in rats on HF diets.
Conclusions:
Uremic rats fed HF diets developed more severe extraosseous calcifications than their normocaloric-fed
counterparts and dietary VitE supplementation protected against uremic calcifications in rats fed HF diets. Thus, eating
energy-rich foods should be discouraged in patients with renal disease and their deleterious effect may be ameliorated
with adequate antioxidant suppl
Chronic Vitamin D Intoxication in Captive Iberian Lynx (Lynx pardinus)
To document the biochemical and pathologic features of vitamin D intoxication in lynx and
to characterize mineral metabolism in healthy lynx, blood samples were obtained from 40
captive lynx that had been receiving excessive (approximately 30 times the recommended
dose) vitamin D3 in the diet, and from 29 healthy free ranging lynx. Tissue samples (kidney,
stomach, lung, heart and aorta) were collected from 13 captive lynx that died as a result of
renal disease and from 3 controls. Vitamin D intoxication resulted in renal failure in most
lynx (n = 28), and widespread extraskeletal calcification was most severe in the kidneys and
less prominent in cardiovascular tissues. Blood minerals and calciotropic hormones in
healthy lynx were similar to values reported in domestic cats except for calcitriol which was
higher in healthy lynx. Changes in mineral metabolism after vitamin D intoxication included
hypercalcemia (12.0 ± 0.3 mg/dL), hyperphosphatemia (6.3 ± 0.4 mg/dL), increased plasma
calcidiol (381.5 ± 28.2 ng/mL) and decreased plasma parathyroid hormone (1.2 ± 0.7 pg/
mL). Hypercalcemia and, particularly, hyperphosphatemia were of lower magnitude that
what has been previously reported in the course of vitamin D intoxication in other species.
However, extraskeletal calcifications were severe. The data suggest that lynx are sensitive
to excessive vitamin D and extreme care should be taken when supplementing this vitamin
in captive lynx diets
Caloric Intake in Renal Patients: Repercussions on Mineral Metabolism
The aim of this paper is to review current knowledge about how calorie intake influences mineral metabolism focussing on four aspects of major interest for the renal patient: (a) phosphate (P) handling, (b) fibroblast growth factor 23 (FGF23) and calcitriol synthesis and secretion, (c) metabolic bone disease, and (d) vascular calcification (VC). Caloric intake has been shown to modulate P balance in experimental models: high caloric intake promotes P retention, while caloric restriction decreases plasma P concentrations. Synthesis and secretion of the phosphaturic hormone FGF23 is directly influenced by energy intake; a direct correlation between caloric intake and FGF23 plasma concentrations has been shown in animals and humans. Moreover, in vitro, energy availability has been demonstrated to regulate FGF23 synthesis through mechanisms in which the molecular target of rapamycin (mTOR) signalling pathway is involved. Plasma calcitriol concentrations are inversely proportional to caloric intake due to modulation by FGF23 of the enzymes implicated in vitamin D metabolism. The effect of caloric intake on bone is controversial. High caloric intake has been reported to increase bone mass, but the associated changes in adipokines and cytokines may as well be deleterious for bone. Low caloric intake tends to reduce bone mass but also may provide indirect (through modulation of inflammation and insulin regulation) beneficial effects on bone. Finally, while VC has been shown to be exacerbated by diets with high caloric content, the opposite has not been demonstrated with low calorie intake. In conclusion, although prospective studies in humans are needed, when planning caloric intake for a renal patient, it is important to take into consideration the associated changes in mineral metabolism
Increased 1,25(OH)2-Vitamin D Concentrations after Energy Restriction Are Associated with Changes in Skeletal Muscle Phenotype
The influence of energy restriction (ER) on muscle is controversial, and the mechanisms are not well understood. To study the effect of ER on skeletal muscle phenotype and the influence of vitamin D, rats (n = 34) were fed a control diet or an ER diet. Muscle mass, muscle somatic index (MSI), fiber-type composition, fiber size, and metabolic activity were studied in tibialis cranialis (TC) and soleus (SOL) muscles. Plasma vitamin D metabolites and renal expression of enzymes involved in vitamin D metabolism were measured. In the ER group, muscle weight was unchanged in TC and decreased by 12% in SOL, but MSI increased in both muscles (p < 0.0001) by 55% and 36%, respectively. Histomorphometric studies showed 14% increase in the percentage of type IIA fibers and 13% reduction in type IIX fibers in TC of ER rats. Decreased size of type I fibers and reduced oxidative activity was identified in SOL of ER rats. An increase in plasma 1,25(OH)2-vitamin D (169.7 ± 6.8 vs. 85.4 ± 11.5 pg/mL, p < 0.0001) with kidney up-regulation of CYP27b1 and down-regulation of CYP24a1 was observed in ER rats. Plasma vitamin D correlated with MSI in both muscles (p < 0.001), with the percentages of type IIA and type IIX fibers in TC and with the oxidative profile in SOL. In conclusion, ER preserves skeletal muscle mass, improves contractile phenotype in phasic muscles (TC), and reduces energy expenditure in antigravity muscles (SOL). These beneficial effects are closely related to the increases in vitamin D secondary to ER
Phosphorus restriction does not prevent the increase in fibroblast growth factor 23 elicited by high fat diet
This
study
was
designed
to evaluate
the
influence
of phosphorus
(P)
restriction
on
the
dele-
terious
effects
of high
fat
diets
on
mineral
metabolism.
Twenty-four
rats
were
allotted
to 3
groups
(n = 8 each)
that
were
fed
different
diets
for
7 months.
Rats
in group
1 were
fed
nor-
mal
fat-normal
P (0.6%)
diet
(NF-NP),
rats
in group
2 were
fed
high
fat-
normal
P diet
(HF-
NP)
and
rats
in group
3 were
fed
high
fat-low
P (0.2%)
diet
(HF-LP).
Blood,
urine
and
tissues
were
collected
at the
end
of the
experiments.
When
compared
with
the
control
group
(NF-
NP),
rats
fed
HF
diets
showed
increases
in body
weight,
and
in plasma
concentrations
of tri-
glycerides
and
leptin,
and
decreased
plasma
calcitriol
concentrations.
In rats
fed
HF-NP
plasma
fibroblast
growth
factor
23
(FGF23)
was
higher
(279.6
±
39.4
pg/ml
vs
160.6
±
25.0
pg/ml,
p = 0.018)
and
renal
klotho
(ratio
klotho/GAPDH)
was
lower
(0.75
±
0.06
vs
1.06
±
0.08,
p
<
0.01)
than
in rats
fed
NF-NP.
Phosphorus
restriction
did
not
normalize
plasma
FGF23
or
renal
klotho;
in fact,
rats
fed
HF-LP,
that
only
ingested
an
average
of 22.9
mg/day
of P,
had
higher
FGF23
(214.7
±
32.4
pg/ml)
concentratio
ns
than
rats
fed
NF-NP
(160.6
±
25.
0 pg/ml),
that
ingested
and
average
of 74.4
mg/day
of P over
a 7 month
period.
In conclusion,
our
results
demonstrate
that
severe
P restriction
over
a prolonged
period
of time
(7 months)
does
not
normalize
the
increase
in circulating
FGF23
induced
by
HF
diets.
These
data
indi-
cate
that
the
deleterious
effects
of high
fat
diet
on
the
FGF23/klotho
axis
are
not
eliminated
by
reduced
P intake
Oral Acid Load Down-Regulates Fibroblast Growth Factor 23
Increased dietary acid load has a negative impact on health, particularly when renal function is compromised. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that is elevated during renal failure. The relationship between metabolic acidosis and FGF23 remains unclear. To investigate the effect of dietary acid load on circulating levels of FGF23, rats with normal renal function and with a graded reduction in renal mass (1/2 Nx and 5/6 Nx) received oral NH4Cl for 1 month. Acid intake resulted in a consistent decrease of plasma FGF23 concentrations in all study groups when compared with their non-acidotic control: 239.3 ± 13.5 vs. 295.0 ± 15.8 pg/mL (intact), 346.4 ± 19.7 vs. 522.6 ± 29.3 pg/mL (1/2 Nx) and 988.0 ± 125.5 vs. 2549.4 ± 469.7 pg/mL (5/6 Nx). Acidosis also decreased plasma PTH in all groups, 96.5 ± 22.3 vs. 107.3 ± 19.1 pg/mL, 113.1 ± 17.3 vs. 185.8 ± 22.2 pg/mL and 504.9 ± 75.7 vs. 1255.4 ± 181.1 pg/mL. FGF23 showed a strong positive correlation with PTH (r = 0.877, p < 0.0001) and further studies demonstrated that acidosis did not influence plasma FGF23 concentrations in parathyroidectomized rats, 190.0 ± 31.6 vs. 215 ± 25.6 pg/mL. In conclusion, plasma concentrations of FGF23 are consistently decreased in rats with metabolic acidosis secondary to increased acid intake, both in animals with intact renal function and with decreased renal function. The in vivo effect of metabolic acidosis on FGF23 appears to be related to the simultaneous decrease in PTH
Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats
Rats with normal renal function (Experiment 1, n = 12) and uninephrectomized (1/2Nx) rats
(Experiment 2, n = 12) were fed diets with normal P (NP) and either normal (NF) or high fat (HF).
Rats with intact renal function (Experiment 3, n = 12) were also fed NF or HF diets with high P (HP).
Additionally, uremic (5/6Nx) rats (n = 16) were fed HP diets with NF or HF. Feeding the HF diets resulted
in significant elevation of plasma FGF23 vs rats fed NF diets: Experiment 1, 593 ± 126 vs 157 ± 28 pg/
ml (p < 0.01); Experiment 2, 538 ± 105 vs 250 ± 18 pg/ml (p < 0.05); Experiment 3, 971 ± 118 vs
534 ± 40 pg/ml (p < 0.01). Rats fed HF diets showed P retention and decreased renal klotho (ratio
klotho/actin) vs rats fed NF diets: Experiment 1, 0.75 ± 0.06 vs 0.97 ± 0.02 (p < 0.01); Experiment 2,
0.69 ± 0.07 vs 1.12 ± 0.08 (p < 0.01); Experiment 3, 0.57 ± 0.19 vs 1.16 ± 0.15 (p < 0.05). Uremic rats
fed HF diet showed more severe vascular calcification (VC) than rats fed NF diet (aortic Ca = 6.3 ± 1.4
vs 1.4 ± 0.1 mg/g tissue, p < 0.001). In conclusion, energy-rich diets increased plasma levels of
FGF23, a known risk factor of cardiovascular morbidity and mortality. Even though FGF23 has major
phosphaturic actions, feeding HF diets resulted in P retention, likely secondary to decreased renal
klotho, and aggravated uremic V
Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type
Effects and mechanisms of mindfulness training and physical exercise on cognition, emotional wellbeing, and brain outcomes in chronic stroke patients: Study protocol of the MindFit project randomized controlled trial
Background: Post-stroke cognitive and emotional complications are frequent in the chronic stages of stroke and have important implications for the functionality and quality of life of those affected and their caregivers. Strategies such as mindfulness meditation, physical exercise (PE), or computerized cognitive training (CCT) may benefit stroke patients by impacting neuroplasticity and brain health. Materials and methods: One hundred and forty-one chronic stroke patients are randomly allocated to receive mindfulness-based stress reduction + CCT (n = 47), multicomponent PE program + CCT (n = 47), or CCT alone (n = 47). Interventions consist of 12-week home-based programs five days per week. Before and after the interventions, we collect data from cognitive, psychological, and physical tests, blood and stool samples, and structural and functional brain scans. Results: The effects of the interventions on cognitive and emotional outcomes will be described in intention-to-treat and per-protocol analyses. We will also explore potential mediators and moderators, such as genetic, molecular, brain, demographic, and clinical factors in our per-protocol sample. Discussion: The MindFit Project is a randomized clinical trial that aims to assess the impact of mindfulness and PE combined with CCT on chronic stroke patients' cognitive and emotional wellbeing. Furthermore, our design takes a multimodal biopsychosocial approach that will generate new knowledge at multiple levels of evidence, from molecular bases to behavioral changes. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT04759950
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