Maria Salvado

Grape seed procyanidins improve atherosclerotic risk index and induce liver CYP7A1 and SHP expression in healthy rats

Moderate consumption of red wine reduces risk of death from cardiovascular disease. The polyphenols in red wine are ultimately responsible for this effect, exerting antiatherogenic actions through their antioxidant capacities and modulating intracellular signaling pathways and transcriptional activities. Lipoprotein metabolism is crucial in atherogenesis, and liver is the principal organ controlling lipoprotein homeostasis. This study was intended to identify the primary effects of procyanidins, the most abundant polyphenols in red wine, on both plasma lipoprotein profile and the expression of genes controlling lipoprotein homeostasis in the liver. We show that procyanidins lowered plasma triglyceride, free fatty acids, apolipoprotein B (apoB), LDL‐cholesterol and nonHDL:nonLDL‐cholesterol levels and slightly increased HDL‐cholesterol. Liver mRNA levels of small heterodimer partner (SHP), cholesterol 7α‐hydroxylase (CYP7A1), and cholesterol biosynthetic enzymes increased, whereas those of apoAII, apoCI, and apoCIII decreased. Lipoprotein lipase (LPL) mRNA levels increased in muscle and decreased in adipose tissue. In conclusion, procyanidins improve the atherosclerotic risk index in the postprandial state, inducing in the liver the overexpression of CYP7A1 (suggesting an increase of cholesterol elimination via bile acids) and SHP, a nuclear receptor emerging as a key regulator of lipid homeostasis at the transcriptional level. These results could explain, at least in part, the beneficial long‐term effects associated with moderate red wine consumption.

Grape seed procyanidin extract reduces the endotoxic effects induced by lipopolysaccharide in rats

Acute inflammation is a response to injury, infection, tissue damage, or shock. Bacterial lipopolysaccharide (LPS) is an endotoxin implicated in triggering sepsis and septic shock, and LPS promotes the inflammatory response, resulting in the secretion of proinflammatory and anti-inflammatory cytokines such as the interleukins (IL-6, IL-1β, and IL-10) and tumor necrosis factor-α by the immune cells. Furthermore, nitric oxide and reactive oxygen species levels increase rapidly, which is partially due to the activation of inducible nitric oxide synthase in several tissues in response to inflammatory stimuli. Previous studies have shown that procyanidins, polyphenols present in foods such as apples, grapes, cocoa, and berries, have several beneficial properties against inflammation and oxidative stress using several in vitro and in vivo models. In this study, the anti-inflammatory and antioxidant effects of two physiological doses and two pharmaceutical doses of grape seed procyanidin extract (GSPE) were analyzed using a rat model of septic shock by the intraperitoneal injection of LPS derived from Escherichia coli. The high nutritional (75mg/kg/day) and the high pharmacological doses (200mg/kg/day) of GSPE showed anti-inflammatory effects by decreasing the proinflammatory marker NOx in the plasma, red blood cells, spleen, and liver. Moreover, the high pharmacological dose also downregulated the genes Il-6 and iNos; and the high nutritional dose decreased the glutathione ratio (GSSG/total glutathione), further illustrating the antioxidant capability of GSPE. In conclusion, several doses of GSPE can alleviate acute inflammation triggered by LPS in rats at the systemic and local levels when administered for as few as 15 days before the injection of endotoxin.

miRNAs, polyphenols, and chronic disease

MicroRNAs (miRNAs) are small noncoding RNAs, approximately 18-25 nucleotides in length, that modulate gene expression at the posttranscriptional level. Thousands of miRNAs have been described, and it is thought that they regulate some aspects of more than 60% of all human cell transcripts. Several polyphenols have been shown to modulate miRNAs related to metabolic homeostasis and chronic diseases. Polyphenolic modulation of miRNAs is very attractive as a strategy to target numerous cell processes and potentially reduce the risk of chronic disease. Evidence is building that polyphenols can target specific miRNAs, such as miR-122, but more studies are necessary to discover and validate additional miRNA targets.

CX3CR1 Is a Modifying Gene of Survival and Progression in Amyotrophic Lateral Sclerosis

The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27±4.90) than patients with 249V/V genotype (67.65±7.42; diff −25.49 months 95%CI [−42.79,−8.18]; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff = −29.78 months; 95%CI [−49.42,−10.14]; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I–280M haplotype (diff = −27.02 months; 95%CI [−49.57, −4.48]; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the diseases symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.

Grape seed proanthocyanidin extract improves the hepatic glutathione metabolism in obese Zucker rats

SCOPE Increased oxidative stress may play an important role in metabolic syndrome and related manifestations, including obesity, atherosclerosis, hypertension, and insulin resistance. Its relation to obesity is due to increased reactive oxygen species and/or decreased glutathione (GSH) antioxidant metabolism. Consequently, the activation of glutathione metabolism appears to be a central defense response to prevent oxidative stress. In this sense, dietary supplements with natural antioxidant molecules, including proanthocyanidins, may present a useful strategy of controlling and reducing complications of obesity, including hepatic steatosis. MATERIALS AND RESULTS We assessed the grape seed proanthocyanidin extract (GSPE) effect on oxidative alterations related to genetically obese rats (Zucker rats) and, more specifically, to hepatic GSH metabolism. We demonstrate that the administration of GSPE reduced the oxidized glutathione accumulation increasing the total GSH/oxidized glutathione hepatic ratio and consequently decreasing the activation of antioxidant enzymes, including glutathione peroxidase, glutathione reductase, and glutathione S-transferase, and increasing the total antioxidant capacity of the cell. CONCLUSION In Zucker rats, the obesity-induced oxidative stress related to liver glutathione alteration was mitigated by GSPE administration.

Identification of PPARgamma Partial Agonists of Natural Origin (II): In Silico Prediction in Natural Extracts with Known Antidiabetic Activity

Background Natural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action. Methodology/Principal Findings From an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally), we have predicted as potential peroxisome proliferators-activated receptor gamma (PPARγ) partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPARγ partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus) to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPARγ partial agonists show chemical similarity with a group of 211 known PPARγ partial agonists obtained from the literature. Conclusions/Significance Our results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPARγ partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused towards the prevention/treatment of type 2 Diabetes Mellitus.

Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient

We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication.

Study of the prevalence of familial autoimmune myasthenia gravis in a Spanish cohort

BACKGROUND Myasthenia gravis (MG) is an autoimmune disease caused by a failure of neuromuscular transmission. Familial clustering has been reported despiteMG usually manifesting as a sporadic condition presumed not to be inherited. Our study investigated the prevalence of FAMG in a Spanish cohort, characterizing their phenotype,antibody titres and thymus findings. MATERIAL/METHODS We investigated the presence of familial cases in 462 MG patients, characterizing by age and MGFA class at debut, quantitative MG score, antibody titres, MGFA post-intervention status and thymus pathology. RESULTS Sixteen cases from8 unrelated pedigrees were identified. The prevalence of FAMG caseswas 3.46%.Mean age at onset was 57.8 ± 17.4 years (range=23–82). Distribution at debut was: 6 ocular, 4 IIa, 4IIb, 1 IIIa and 1 IIIb. Thymoma was identified in two of the 7 thymectomized individuals. CONCLUSIONS The prevalence of FAMG in Spain is similar to other populations. Post-intervention status did not differ from sporadic autoimmune MG. As in other neuromuscular disorders, phenotype and inheritance heterogeneity are present in FAMG. In addition to the interfamilial heterogeneity observed, members of the same family affected with FAMG may even present different ages of onset, severity and thymus involvement. Further studies are necessary to clarify the role of genetic risk factors in this form of autoimmune MG.

PFN1 mutations are also rare in the Catalan population with amyotrophic lateral sclerosis

Evidence of genetic heterogeneity in ALS has been found, with at least 31 genes being identified to date as causing ALS, and other genes being suggested as risk factors for susceptibility to the disease and for phenotype modifications. In recent years, new molecular genetic methodologies, especially GWAS and exome sequencing, have contributed to the identification of new ALS genes. Some of these genes (SOD1, TARDBP, FUS, and C9orf72) have homogenous frequencies in different populations. However, a few genes are rare in populations other than those in which they were first identified. Here we investigate the frequency of the PFN1 gene in a Catalan ALS population. A mutational analysis of the PFN1 gene was carried out on a Catalan cohort of 42 ALS families (FALS) and 423 sporadic ALS patients (SALS). The screening included 600 healthy controls. No PFN1 mutations were identified in either the FALS or SALS group. We also found no mutations in the control group. Our results are consistent with those described in other populations with very low frequencies, suggesting that PFN1 is a very rare cause of ALS worldwide. Together with the absence of a distinctive phenotype associated with ALS18, these results mean that this gene should be a second or third line for inclusion in screening in patients requesting genetic counseling.

SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.