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1.
Am J Med Genet A ; 194(4): e63481, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37984424

ABSTRACT

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.


Subject(s)
Hearing Loss, Sensorineural , Ichthyosiform Erythroderma, Congenital , Ichthyosis , Lipid Metabolism, Inborn Errors , Muscular Diseases , Female , Humans , Middle Aged , Ichthyosiform Erythroderma, Congenital/complications , Ichthyosiform Erythroderma, Congenital/diagnosis , Ichthyosiform Erythroderma, Congenital/genetics , Lipid Metabolism, Inborn Errors/genetics , Muscular Diseases/genetics , Ichthyosis/complications , Ichthyosis/diagnosis , Ichthyosis/genetics , Liver Cirrhosis , Hearing Loss, Sensorineural/complications , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics
2.
Biomedicines ; 10(3)2022 Mar 21.
Article in English | MEDLINE | ID: mdl-35327530

ABSTRACT

Background: Recently, increased tissue levels of AIF-1 have been shown in experimental colitis, supporting its role in intestinal inflammation. Therefore, we studied the levels of AIF-1 in Crohn's disease (CD). Methods: This study included 33 patients with CD (14 men and 19 women) who participated in the PREDICROHN project, a prospective multicenter study of the Spanish Group of Inflammatory bowel disease (GETECCU). Results: This article demonstrates declines with respect to baseline levels of serum AIF-1 in Crohn's disease (CD) patients after 14 weeks of treatment with anti-TNFs. Furthermore, in patients with active CD (HB ≥ 5), serum AIF-1 levels were significantly higher than those in patients without activity (HB ≤ 4). The study of serum AIF-1 in the same cohort, revealed an area under the ROC curve (AUC) value of AUC = 0.66 (p = 0.014), while for the CRP (C-reactive protein), (AUC) value of 0.69 (p = 0.0066), indicating a similar ability to classify CD patients by their severity. However, the combination of data on serum levels of AIF-1 and CRP improves the predictive ability of these analyses for classifying CD patients as active (HB ≥ 5) or inactive (HB ≤ 4). When we used the odds ratio (OR) formula, we observed that patients with CRP > 5 mg/L or AIF-1 > 200 pg/mL or both conditions were 13 times more likely to show HB ≥ 5 (active CD) than were those with both markers below these thresholds. Conclusion: The development of an algorithm that includes serum levels of AIF-1 and CRP could be useful for assessing Crohn's disease severity.

3.
Biomed Pharmacother ; 144: 112239, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34601192

ABSTRACT

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and ß-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology.


Subject(s)
Body Weight/drug effects , Colitis/prevention & control , Colon/drug effects , Insulin-Like Growth Factor I/pharmacology , Intestinal Mucosa/drug effects , Adalimumab/therapeutic use , Adult , Animals , Biomarkers/blood , Colitis/metabolism , Colitis/pathology , Colitis, Ulcerative/blood , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/drug therapy , Colon/metabolism , Colon/pathology , Crohn Disease/blood , Crohn Disease/diagnosis , Crohn Disease/drug therapy , Disease Models, Animal , Female , Humans , Insulin Receptor Substrate Proteins/metabolism , Insulin-Like Growth Factor I/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Proto-Oncogene Proteins c-akt/metabolism , Rats, Wistar , Signal Transduction , Spain , Time Factors , Treatment Outcome , Tumor Necrosis Factor Inhibitors/therapeutic use
4.
Pharmaceuticals (Basel) ; 14(9)2021 Aug 25.
Article in English | MEDLINE | ID: mdl-34577545

ABSTRACT

Actinomycin D (ActD) is an FDA-approved NCI oncology drug that specifically targets and downregulates stem cell transcription factors, which leads to a depletion of stem cells within the tumor bulk. Recently, our research group demonstrated the importance of IRS-4 in the development of liver cancer. In this study, we evaluated the protective effects of IRS-4 against ActD. For this study, three hepatocellular carcinoma cell lines (HepG2, Huh7, and Chang cells) were used to study the mechanism of actinomycin D. Most assays were carried out in the Hep G2 cell line, due to the high expression of stem cell biomarkers. We found that ActD caused HepG2 cell necroptosis characterized by DNA fragmentation, decreased mitochondrial membrane potential, cytochrome c depletion, and decreased the levels of reduced glutathione. However, we did not observe a clear increase in apoptosis markers such as annexin V presence, caspase 3 activation, or PARP fragmentation. ActD produced an activation of MAP kinases (ERK, p38, and JNK) and AKT. ActD-induced activation of AKT and MAP kinases produced an activation of the Rb-E2F cascade together with a blockage of cell cycle transitions, due to c-jun depletion. ActD led to the inhibition of pCdK1 and pH3 along with DNA fragmentation resulting in cell cycle arrest and the subsequent activation of p53-dependent cell death in the HepG2 cell line. Only JNK and AKT inhibitors were protective against the effects of ActD. N-Acetyl-L-cysteine also had a protective effect as it restored GSH levels. A likely mechanism for this is IRS-4 stimulating GCL-GSH and inhibiting the Brk-CHK1-p53 pathway. The assessment of the IRS-4 in cancer biopsies could be of interest to carry out a personalized treatment with ActD.

5.
J Int Med Res ; 49(9): 3000605211041275, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34590920

ABSTRACT

OBJECTIVES: Chronic venous disease (CVeD) is a multifactorial and debilitating condition that has a high prevalence in Western countries and an important associated socioeconomic burden. Varicose veins (VVs) are the most common manifestations of CVeD. Pathologically, many morphological and functional changes have been described in VVs, which most notably affect venous wall integrity. Previous studies have found several molecular alterations that negatively affect normal cell signaling pathways. Insulin receptor substrate (IRS)-4 is a central adaptor protein that is closely related to insulin/insulin-like growth factor-1 signaling upstream, phosphatidylinositol 3-kinase/Akt or mitogen-activated protein kinases downstream, and other proteins. These molecular pathways have been implicated in CVeD pathogenesis. Thus, the aim of our study was to identify the role of IRS-4 in VV tissue. METHODS: We conducted a histopathological study to analyze IRS-4 protein expression in CVeD patients compared with healthy controls. RESULTS: Our results demonstrate a significant increase in IRS-4 expression in VV tissue. CONCLUSIONS: IRS-4 may be implicated in CVeD development and progression. Therefore, IRS-4 could be a potential diagnostic or therapeutic target for patients with this condition.


Subject(s)
Phosphoproteins , Saphenous Vein , Adaptor Proteins, Signal Transducing , Humans , Insulin Receptor Substrate Proteins , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/metabolism , Signal Transduction
6.
J Perinatol ; 41(10): 2499-2504, 2021 10.
Article in English | MEDLINE | ID: mdl-34362994

ABSTRACT

OBJECTIVE: To evaluate the impact of changes to neonatal early-onset sepsis (EOS) guidelines on in-hospital breastfeeding. STUDY DESIGN: Asymptomatic neonates admitted to the Neonatal Intensive Care Unit (NICU) for sepsis evaluations over a 2-year period were identified. A retrospective chart review was conducted as part of a larger quality initiative on antibiotic stewardship. RESULT: In Epoch 1, Epoch 2, and Epoch 3, there were 268 babies, 138 babies and 138 babies admitted to the NICU based on sepsis protocol, respectively. When comparing Epoch 1 to Epoch 3, there was a 14% increase in total breast milk consumption rates (p < 0.0001) and a 15% increase in exclusive breastfeeding at discharge (p < 0.002). CONCLUSION: By implementing new EOS protocols, we have decreased NICU length of stay. We suggest that the decrease in mother-infant separation time leads to an improvement in breastfeeding.


Subject(s)
Neonatal Sepsis , Sepsis , Breast Feeding , Female , Humans , Infant , Infant, Newborn , Intensive Care Units, Neonatal , Neonatal Sepsis/drug therapy , Neonatal Sepsis/epidemiology , Retrospective Studies , Sepsis/diagnosis , Sepsis/drug therapy , Sepsis/epidemiology
7.
Cancers (Basel) ; 13(11)2021 May 23.
Article in English | MEDLINE | ID: mdl-34071030

ABSTRACT

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry to examine IRS-4 expression in biopsies of tumoral tissue from a cohort of 31 patient suffering of hepatocellular carcinoma (HCC). We simultaneously analyzed the expression of the cancer biomarkers PCNA, Ki-67, and pH3 in the same tissue samples. The in vitro analysis was conducted by studying the behavior of HepG2 cells following IRS-4 overexpression/silencing. IRS-4 was expressed mainly in the nuclei of tumoral cells from HCC patients. In contrast, in healthy cells involved in portal triads, canaliculi, and parenchymal tissue, IRS-4 was observed in the cytosol and the membrane. Nuclear IRS-4 in the tumoral region was found in 69.9 ± 3.2%, whereas in the surrounding healthy hepatocytes, nuclear IRS-4 was rarely observed. The percentage of tumoral cells that exhibited nuclear PCNA and Ki-67 were 52.1 ± 7%, 6.1 ± 1.1% and 1.3 ± 0.2%, respectively. Furthermore, we observed a significant positive linear correlation between nuclear IRS-4 and PCNA (r = 0.989; p < 0.001). However, when we correlated the nuclear expression of IRS-4 and Ki-67, we observed a significant positive curvilinear correlation (r = 0.758; p < 0.010). This allowed us to define two populations, (IRS-4 + Ki-67 ≤ 69%) and (IRS-4 + Ki-67 > 70%). The population with lower levels of IRS-4 and Ki-67 had a higher risk of suffering from multifocal liver cancer (OR = 16.66; CI = 1.68-164.8 (95%); p < 0.05). Immunoblot analyses showed that IRS-4 in normal human liver biopsies was lower than in HepG2, Huh7, and Chang cells. Treatment of HepG2 with IGF-1 and EGF induced IRS-4 translocation to the nucleus. Regulation of IRS-4 levels via HepG2 transfection experiments revealed the protein's role in proliferation, cell migration, and cell-collagen adhesion. Nuclear IRS-4 is increased in the tumoral region of HCC. IRS-4 and Ki-67 levels are significantly correlated with the presence of multifocal HCC. Moreover, upregulation of IRS-4 in HepG2 cells induced proliferation by a ß-catenin/Rb/cyclin D mechanism, whereas downregulation of IRS-4 caused a loss in cellular polarity and in its adherence to collagen as well as a gain in migratory and invasive capacities, probably via an integrin α2 and focal adhesion cascade (FAK) mechanism.

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