Arterial tortuosity syndrome (ATS) is an autosomal recessive\ud disorder characterized by tortuosity, elongation, stenosis and\ud aneurysm formation in the major arteries owing to disruption\ud of elastic fibers in the medial layer of the arterial wall1.\ud Previously, we used homozygosity mapping to map a candidate\ud locus in a 4.1-Mb region on chromosome 20q13.1 (ref. 2).\ud Here, we narrowed the candidate region to 1.2 Mb containing\ud seven genes. Mutations in one of these genes, SLC2A10,\ud encoding the facilitative glucose transporter GLUT10, were\ud identified in six ATS families. GLUT10 deficiency is associated\ud with upregulation of the TGFb pathway in the arterial wall, a\ud finding also observed in Loeys-Dietz syndrome, in which aortic\ud aneurysms associate with arterial tortuosity3. The identification\ud of a glucose transporter gene responsible for altered arterial\ud morphogenesis is notable in light of the previously suggested\ud link between GLUT10 and type 2 diabetes4,5. Our data\ud could provide new insight on the mechanisms causing\ud microangiopathic changes associated with diabetes and\ud suggest that therapeutic compounds intervening with\ud TGFb signaling represent a new treatment strategy

BackgroundNeuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.MethodsThe potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ1–42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide.Results3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.ConclusionsOur data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

Urokinase‐type plasminogen activator (uPA) and c‐met play a major role in cancer invasion and metastasis. Evidence has suggested that uPA and c‐met overexpression may be coordinated in human hepatocellular carcinoma (HCC). In the present study, to understand whether the expression of these genes might be coregulated by specific microRNAs (miRs) in human cells, we predicted that Homo sapiens microRNA‐23b could recognize two sites in the 3′‐UTR of uPA and four sites in the c‐met 3′‐UTR by the algorithm pictar. The miR‐23b expression analysis in human tumor and normal cells revealed an inverse trend with uPA and c‐met expression, indicating that uPA and c‐met negative regulation might depend on miR‐23b expression. Transfection of miR‐23b molecules in HCC cells (SKHep1C3) led to inhibition of protein expression of the target genes and caused a decrease in cell migration and proliferation capabilities. Furthermore, anti‐miR‐23b transfection in human normal AB2 dermal fibroblasts upregulated the expression of endogenous uPA and c‐met. Cotransfection experiments in HCC cells of the miR‐23b with pGL4.71 Renilla luciferase reporter gene constructs, containing the putative uPA and c‐met 3′‐UTR target sites, and with the pGL3 firefly luciferase‐expressing vector showed a decrease in the relative luciferase activity. This would indicate that miR‐23b can recognize target sites in the 3′‐UTR of uPA and of c‐met mRNAs and translationally repress the expression of uPA and c‐met in HCC cells. The evidence obtained shows that overexpression of miR‐23b leads to uPA and c‐met downregulation and to decreased migration and proliferation abilities of HCC cells.

In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis. In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the LPS-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases.

Dermal fibroblasts derived from types I and IV EhlersDanlos syndrome (EDS) patients, carrying mutations in. Functionblocking antibodies to COLLV, COLLIII, or ␣ 2 ␤ 1 integrin induce in control fibroblasts an EDS-like phenotype. These results show that in human fibroblasts ␣ 2 ␤ 1 integrin organization and function are controlled by its ligand, and that the ␣ 2 ␤ 1 -COLL interaction, in turn, regulates FN integrin receptor recruitment: high ␣ 2 ␤ 1 integrin levels induce ␣ 5 ␤ 1 integrin organization, while low ␣ 2 ␤ 1 integrin levels lead to ␣ v ␤ 3 integrin organization. The extracellular matrix (ECM)1 is a complex structure formed by distinct molecular networks that interact with specific cell receptors, triggering numerous responses that play essential roles in cell behavior regulation (1). The ECM provides a substrate for cell migration during embryonic development and wound healing, regulating tissue architecture and morphogenesis (2), and is also signaling variations in the cell microenvironment affecting cell proliferation, differentiation, and death (3-7).Collagens (COLLs) and fibronectin (FN) are major ECM protein components (1, 8 -10). COLLs, the most abundant proteins of connective tissues, are formed by three polypeptide chains, synthesized as propeptide (pro-␣ chains), coiled into triple helices, and encoded by the same or different genes (11). Types I, III, V, and XI COLLs are organized in fibrillar structures and are therefore referred to as fibrillar COLLs. In particular, COLLIII is an ␣ 1 (III) 3 homotrimer encoded by the COL3A1 gene and is mainly distributed in skin, tendon, aorta, and cornea (12), whereas COLLV is a quantitatively minor fibrillar COLL with a broad tissue distribution that regulates COLLI fibrillogenesis (13). COLLV molecules may contain ␣1(V), ␣2(V) and ␣3(V) or ␣1(V) 2 ␣2(V) chains (13).Mutations in COLLs are related to a variety of hereditary connective tissue disorders one of which is Ehlers-Danlos syndrome (EDS), a group of heterogeneous diseases (at least 11 types) caused by alterations in different COLL genes, COL1A1, COL1A2, COL3A1, COL5A1,, and to mutations in lysyl hydroxylase (18) and N-proteinase genes (19), altering the post-translational modification of COLLs. In particular, mutations in COL5A1 and COL5A2 genes have been reported in EDSI patients showing classical signs of the syndrome, i.e. widespread scarring and bruising, skin hyperextensibility, and joint laxity (15-16). Mutations in COL3A1 genes have been disclosed in EDSIV patients showing as common features vascular rupture (vascular type), colonic perforation, thin, translucent skin, and severe bruising (15)(16)(17)(18)(19)(20).FN is a dimeric glycoprotein that triggers cell adhesion, migration, cell cycle progression, and differentiation (4,7,21). FN deposition in vivo represents the initial event during fibrillogenesis of connective tissue matrices occurring during embryogenesis and wound healing (3,22,23). Human skin fibroblasts adhere in vitro through the organization of an ECM mainly composed of FN an...