101 research outputs found
Dietary Mg Supplementation Decreases Oxidative Stress, Inflammation, and Vascular Dysfunction in an Experimental Model of Metabolic Syndrome with Renal Failure
Background: Metabolic syndrome (MetS) and chronic kidney disease (CKD) are commonly
associated with cardiovascular disease (CVD) and in these patients Mg concentration is usually
decreased. This study evaluated whether a dietary Mg supplementation might attenuate vascular
dysfunction through the modulation of oxidative stress and inflammation in concurrent MetS and
CKD. Methods: A rat model of MetS (Zucker strain) with CKD (5/6 nephrectomy, Nx) was used.
Nephrectomized animals were fed a normal 0.1%Mg (MetS+Nx+Mg 0.1%) or a supplemented 0.6%Mg
(MetS+Nx+Mg0.6%) diet; Sham-operated rats with MetS receiving 0.1%Mg were used as controls.
Results: As compared to controls, the MetS+Nx-Mg0.1% group showed a significant increase in
oxidative stress and inflammation biomarkers (lipid peroxidation and aortic interleukin-1b and
-6 expression) and Endothelin-1 levels, a decrease in nitric oxide and a worsening in uremia and MetS
associated pathology as hypertension, and abnormal glucose and lipid profile. Moreover, proteomic
evaluation revealed changes mainly related to lipid metabolism and CVD markers. By contrast, in
the MetS+Nx+Mg0.6% group, these parameters remained largely similar to controls. Conclusion: In
concurrent MetS and CKD, dietary Mg supplementation reduced inflammation and oxidative stress
and improved vascular function.This research was funded by a Spanish government grant from the Programa Nacional
I+D+I 2008–2011 from the MINECO-Instituto de Salud Carlos III (PI20/0660 and PI21/00654) with
co-financing from European Funds (FEDER) and EUTOX and REDinREN from the ISCIII, Consejería
de Salud (grants PI-0071-2021) from the Junta de Andalucía and Grant PY20_00773 from Consejería
de Innovación, Ciencia y Empleo from the Junta de Andalucía. J.M.D.-T. hold a Sara Borrell contract
by the Spanish Ministry of Science, Innovation and Universities, Carlos III Health Institute (ISCIII),
co-funded by European Social Fund (European Social Fund-Investment in your future). Y.A. and
J.R.M.-C. are senior researchers supported by the Nicolás Monardes Programme, Consejería de
Salud-SAS (Junta de Andalucía)
La inhibición de la síntesis de óxido nítrico durante la colestasis inducida experimentalmente reduce la lesión hepatocelular al facilitar la homeostasis de nitrosotioles
Comunicaciones a congreso
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
Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease
Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications
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
Procaine Inhibits Osteo/Odontogenesis through Wnt/β-Catenin Inactivation
Introduction
Periodontitis is a complex pathology characterized by the loss of alveolar bone. The causes
and the mechanisms that promote this bone resorption still remain unknown. The knowledge
of the critical regulators involved in the alteration of alveolar bone homeostasis is of
great importance for developing molecular therapies. Procaine is an anesthetic drug with
demethylant properties, mainly used by dentists in oral surgeries. The inhibitor role of Wnt
signaling of procaine was described in vitro in colon cancer cells.
Methods
In this work we evaluated the role of procaine (1 uM) in osteo/odontogenesis of rat bone
marrow mesenchymal stem cells. Similarly, the mechanisms whereby procaine achieves
these effects were also studied.
Results
Procaine administration led to a drastic decrease of calcium content, alkaline phosphatase
activity, alizarin red staining and an increase in the expression of Matrix Gla Protein. With
respect to osteo/odontogenic markers, procaine decreased early and mature osteo/odontogenic
markers. In parallel, procaine inhibited canonical Wnt/β-catenin pathway, observing a
loss of nuclear β-catenin, a decrease in Lrp5 and Frizzled 3, a significant increase of sclerostin
and Gsk3β and an increase of phosphorylated β-catenin. The combination of osteo/
odontogenic stimuli and Lithium Chloride decreased mRNA expression of Gsk3β, recovered
by Procaine. Furthermore it was proved that Procaine alone dose dependently
increases the expression of Gsk3β and β-catenin phosphorylation. These effects of procaine
were also observed on mature osteoblast. Interestingly, at this concentration of procaine
no demethylant effects were observed.
PLO
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
Nuclear Translocation of b-Catenin during Mesenchymal Stem Cells Differentiation into Hepatocytes Is Associated with a Tumoral Phenotype
Wnt/b-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of
this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated
the role of Wnt/b-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The
differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, b-catenin
nuclear translocation, up-regulation of genes related to the Wnt/b-catenin pathway, such as Lrp5 and Fzd3, as well as the
oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/b-catenin inactivation. Hepatocytes
with nuclear translocation of b-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved
in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal
capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic
analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and
D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans
isomerase A or lactate dehydrogenase b-chain were up-regulated only with the protocol associated with Wnt signaling
activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin b-chain were downregulated
in this protocol. In conclusion, our results suggest that activation of the Wnt/b-catenin pathway during human
mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotyp
Magnesium Inhibits Wnt/β-Catenin Activity and Reverses the Osteogenic Transformation of Vascular Smooth Muscle Cells
Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved
Buenas prácticas de transferencia del conocimiento en la Universidad de Córdoba
La iniciativa consiste en proporcionar la materia prima. El proyecto, que se ha realizado con cerdos y ha tenido una duración de tres años, demuestra que la administración de Cardiotrofina-1 en el transplante hepático incrementa la supervivencia del animal, mejora su función cardiaca, respiratoria y renal, y también consigue reducir el daño hepatocelecuar y el estrés oxidativo y nitrosativo en el injerto
- …