Macrophages represent primary players of the innate immune system. Macrophage activation triggers several signaling pathways and is tightly associated with metabolic changes, which drive different immune subsets. Recent studies unveil the role of various metabolic enzymes in macrophage activation.
View Article and Find Full Text PDFProtein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation.
View Article and Find Full Text PDFRecombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years.
View Article and Find Full Text PDFLysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown.
View Article and Find Full Text PDFTo maintain cellular homeostasis, the endoplasmic reticulum (ER) necessitates a continuous removal of ER fragments via a selective, receptor-mediated, form of autophagy known as ER-phagy. In this issue of The EMBO Journal, Jiang et al (2020) shed light on how the best characterized autophagy receptor FAM134B mediates ER membrane fragmentation, the earliest event during ER-phagy. They propose a dynamic model for FAM134B protein oligomerization and ER membrane scission, which are driven by CAMK2B-mediated phosphorylation of the receptor and are altered in sensory neuropathy.
View Article and Find Full Text PDFProtein misfolding occurring in the endoplasmic reticulum (ER) might eventually lead to aggregation and cellular distress, and is a primary pathogenic mechanism in multiple human disorders. Mammals have developed evolutionary-conserved quality control mechanisms at the level of the ER. The best characterized is the ER-associated degradation (ERAD) pathway, through which misfolded proteins translocate from the ER to the cytosol and are subsequently proteasomally degraded.
View Article and Find Full Text PDFAutophagy is a cytosolic quality control process that recognizes substrates through receptor-mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown.
View Article and Find Full Text PDFThe lysosome is a catabolic organelle devoted to the degradation of cellular components, such as protein complexes and whole or portion of organelles that reach the lysosomes through (macro)autophagy. The lysosomes also function as signaling organelles by controlling the activity of key metabolic kinases, such as the mechanistic target of Rapamycin complex 1 (mTORC1). Lysosome dysfunction has dramatic consequences on cellular homeostasis and causes lysosomal storage disorders (LSDs).
View Article and Find Full Text PDFResponse to recombinant human growth hormone (r-hGH) in the first year of therapy has been associated with single-nucleotide polymorphisms (SNPs) in children with GH deficiency (GHD). Associated SNPs were screened for regulatory function using a combination of in silico techniques. Four SNPs in regulatory sequences were selected for the analysis of in vitro transcriptional activity (TA).
View Article and Find Full Text PDFBackground: The effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis.
Methods: Prepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets.
The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown.
View Article and Find Full Text PDFBRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse.
View Article and Find Full Text PDFEnzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI).
View Article and Find Full Text PDFJuvenile idiopathic arthritis (JIA) is a clinically diverse and genetically complex autoimmune disease. Currently, there is very limited understanding of the potential underlying mechanisms that result in the range of phenotypes which constitute JIA.The elucidation of the functional relevance of genetic associations with phenotypic traits is a fundamental problem that hampers the translation of genetic observations to plausible medical interventions.
View Article and Find Full Text PDFBackground: Cardiovascular (CV) risk factors have been identified in adults with untreated growth hormone deficiency (GHD). Existing evidence suggests that the development of the atheromatous plaque begins early in childhood. Previous reports have shown that GHD children are prone to increased CV risks including impaired cardiac function, dyslipidemia and abnormalities in body composition.
View Article and Find Full Text PDFBackground: Controversial data exist on the possibility that inhaled corticosteroids (ICs) affect growth in children with mild-to-moderate asthma. We assessed whether ICs affect growth and final height (FH) in asthmatic children compared to controls.
Methods: A retrospective study was conducted on 113 asthmatic children compared with 66 control children.
Lamellar ichthyosis is a rare congenital disorder characterized by collodion membrane at birth and facial anomalies (eclabium and ectropion). The major underlying genetic defect is in TGM1, with mutations of this gene found in 50% of patients. An early diagnosis is fundamental in view of establishing a specific treatment due to the severity of the disease.
View Article and Find Full Text PDFObjective: To measure cerebral regional oxygen saturation (CrSO2), renal regional oxygenation saturation (RrSO2) and mesenteric tissue regional oxygen saturation (MrSO2) during immediate transition and continuously for the first 9 hours of age. Fractional tissue oxygen extraction of the brain (CtFOE), kidneys (RtFOE), splanchnic tissue (MtFOE) were also assessed.
Study Design: Prospective, observational study of 61 term infants, delivered by elective caesarean section.
The advances in high-throughput genomic technologies have improved the understanding of disease pathophysiology and have allowed a better characterization of drug response and toxicity based on individual genetic make up. Pharmacogenomics is being recognized as a valid approach used to identify patients who are more likely to respond to medication, or those in whom there is a high probability of developing severe adverse drug reactions. An increasing number of pharmacogenomic studies are being published, most include only adults.
View Article and Find Full Text PDFChildhood obesity is a growing and alarming problem, associated with several short-term and long-term metabolic and cardiovascular complications. In addition, it has also been suggested that excess adiposity during childhood influences growth and pubertal development. Several studies have shown that during pre-pubertal years, obese patients present higher growth velocity and that this pre-pubertal advantage tends to gradually decrease during puberty, leading to similar final heights between obese and non-obese children.
View Article and Find Full Text PDFAlthough a relationship between obesity and hyperthyrotropinemia has been hypothesized in obese children, the underlying pathogenesis is not completely known. In the current cross-sectional study, we evaluated the thyroid function in a group of 80 obese pre-pubertal children compared to 41 healthy normal weight peers, exploring the possible association between hyperthyrotropinemia and oxidative stress. In all children, thyrotropin (TSH), free T4 (fT4), free T3 (fT3) and anti-thyroid antibodies were evaluated.
View Article and Find Full Text PDFUnlabelled: Hypophosphatasia is characterized by deficiency of serum alkaline phosphatase with defective bone and teeth mineralization. We report on an 11-month-old boy who developed a complex clinical picture characterized by bulging anterior fontanelle, growth failure, nephrocalcinosis and impaired bone mineralization during high-dose calcium and vitamin D supplementation. This therapy had been started 5 months earlier for a presumed diagnosis of nutritional rickets established on the grounds of isolated widened anterior fontanelle.
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