Background: Non-alcoholic fatty liver disease is the most common cause of liver-related morbidity and mortality in the world. However, no effective pharmacological treatment for this condition has been found. Purpose: This study evaluated the effect of a nutraceutical containing bioactive components from Bergamot citrus and wild cardoon as a treatment for individuals with fatty liver disease. The primary outcome measure was the change in liver fat content. Methods: A total of 102 patients with liver steatosis were enrolled in a double-blind placebo controlled clinical trial. The intervention group received a nutraceutical containing a Bergamot polyphenol fraction and Cynara Cardunculus extract, 300 mg/day for 12 weeks. The control group received a placebo daily. Liver fat content, by transient elastography, serum transaminases, lipids and glucose were measured at the baseline and the end of the study. Results: We found a greater liver fat content reduction in the participants taking the nutraceutical rather than placebo (−48.2 ± 39 vs. −26.9 ± 43 dB/m, p = 0.02); The percentage CAP score reduction was statistically significant in those with android obesity, overweight/obesity as well as in women. However, after adjustment for weight change, the percentage CAP score reduction was statistically significant only in those over 50 years (44 vs. 78% in placebo and nutraceutical, respectively, p = 0.007). Conclusions: This specific nutraceutical containing bioactive components from Bergamot and wild cardoon reduced the liver fat content during 12 weeks in individuals with liver steatosis over 50 years. If confirmed, this nutraceutical could become the cornerstone treatment of patients affected by liver steatosis. Clinical Trial Registration: www.isrctn.com, identifier ISRCTN12833814.
The v-Ki-Ras oncoprotein dedifferentiates thyroid cells and inhibits nuclear accumulation of the catalytic subunit of cAMP-dependent protein kinase. After activation of v-Ras or protein kinase C, the regulatory subunit of type II protein kinase A, RII, translocates from the membranes to the cytosol. RII mRNA and protein were eventually depleted. These effects were mimicked by expressing AKAP45, a truncated version of the RII anchor protein, AKAP75. Because AKAP45 lacks membrane targeting domains, it induces the translocation of PKAII to the cytoplasm. Expression of AKAP45 markedly decreased thyroglobulin mRNA levels and inhibited accumulation of C-PKA in the nucleus. Our results suggest that: 1) The localization of PKAII influences cAMP signaling to the nucleus; 2) Ras alters the localization and the expression of PKAII; 3) Translocation of PKAII to the cytoplasm reduces nuclear C-PKA accumulation, resulting in decreased expression of cAMP-dependent genes, including RII, TSH receptor, and thyroglobulin. The loss of RII permanently downregulates thyroid-specific gene expression.Ras is a small GTP binding protein that serves as a central molecular switch. Ras links activated receptor tyrosine kinases with downstream signaling systems that include Ser/Thr and dual specificity protein kinases (1, 2). Constitutive expression of activated Ras bypasses the transient, ligand-regulated activation of transmembrane receptor tyrosine kinases and tonically stimulates signaling molecules that in turn affect cell growth, proliferation, and differentiation. Depending on the cell type, Ras activation elicits differentiation (PC12 neuroendocrine cells or 3T3-LI adipocytes) (3, 4) or deregulated growth and dedifferentiation (5, 6). Signaling proteins that couple Ras to receptor tyrosine kinases have been identified and characterized (for review see Ref. 7). Moreover, the formation of the complex between Ras-GTP and Raf-1 is essential for the subsequent activation of the downstream mitogen-activated protein kinase cascade (8). Recent work has demonstrated that Ras recruits Raf to the plasma membrane (9), where another tyrosine kinase-generated signal activates the membranebound Raf (10). cAMP blocks mitogenic signaling in fibroblasts by reducing the affinity of Raf-1 for Ras (11). The reduction in binding affinity is correlated with the phosphorylation of a consensus PKA substrate site in the N-terminal regulatory domain of Raf-1 (11, 12). These findings indicate an antagonistic relationship between the Ras and cAMP signals (13).Signals carried by cyclic AMP are received, amplified, and transmitted by PKA. 1 In eukaryotic cells the multiple isoforms of the regulatory (R) and catalytic (C-PKA) subunits assemble to generate several distinct PKA holoenzymes. The characteristics of the PKA holoenzyme are largely determined by the structure and properties of their R subunits; the C-PKA subunits exhibit similar kinetic features and substrate specificities (14). The specific regulatory roles of PKA isoenzymes remain to be determined (...
Present data demonstrate that the increase in LVM prevalent in human essential hypertension is directly associated with serum GH levels and inversely related to circulating IGF-1.
Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.
We analysed the allelic and genotypic frequencies of three restriction fragment length polymorphisms in the region of chromosome 11 encoding apolipoprotein AI and CIII genes in a free-living population from South Italy (Calabria). These markers are located at -2500 and -78 bp from the transcription start site of apolipoprotein AI gene (XmnI and MspI, respectively), and in the 3' untranslated region of apolipoprotein CIII gene (SstI). XmnI and SstI label rare alleles (X2 and S2 indicate the presence of the site), whereas the absence of the MspI site (because of a G to A transition) marks the rare allele, M2. Pairwise linkage disequilibrium analysis was determined. Two significant non-random associations were found: a positive disequilibrium between ApoA1/XmnI and ApoA1/MspI markers (P < 0.0001), and a negative disequilibrium between ApoA1/XmnI and ApoC3/SstI markers (P < 0.05). Statistical analysis showed a significant difference in the S2-M2 haplotype frequency between the group of subjects with serum cholesterol levels in the highest decile (P < 0.005) and the group with serum cholesterol levels below the highest decile. The allelic frequency for each locus showed no significant difference between the two groups for all other metabolic parameters, included total cholesterol serum levels. These haplotypes are a more precise measure of genetic variations in the apolipoprotein cluster and their use should allow the mapping of mutations responsible for high serum cholesterol levels.
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