The functional derangement affecting human chondrocytes during osteoarthritis (OA) onset and progression is sustained by the failure of major homeostatic mechanisms. This makes them more susceptible to oxidative stress (OS), which can induce DNA damage responses and exacerbate stress-induced senescence. The knockdown (KD) of IκB kinase α (IKKα), a dispensable protein in healthy articular cartilage physiology, was shown to increase the survival and replication potential of human primary OA chondrocytes.
View Article and Find Full Text PDFNotch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy "maturation arrested state" and resume their natural route of proliferation, hypertrophy, and terminal differentiation.
View Article and Find Full Text PDFIKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media.
View Article and Find Full Text PDFDuring osteoarthritis development, chondrocytes are subjected to a functional derangement. This increases their susceptibility to stressful conditions such as oxidative stress, a characteristic of the aging tissue, which can further provoke extrinsic senescence by DNA damage responses. It was previously observed that IκB kinase α knockdown increases the replicative potential of primary human OA chondrocytes cultured in monolayer and the survival of the same cells undergoing hypertrophic-like differentiation in 3-D.
View Article and Find Full Text PDFOxidative stress (OS) contributes to Osteoarthritis (OA) pathogenesis and its effects are worsened by the impairment of homeostatic mechanisms such as autophagy in OA chondrocytes. Rescue of an efficient autophagic flux could therefore reduce the bulk of damaged molecules, and at the same time improve cell function and viability. As a promising dietary or intra-articular supplement to rescue autophagy in OA chondrocytes, we tested spermidine (SPD), known to induce autophagy and to reduce OS in several other cellular models.
View Article and Find Full Text PDFOsteoarthritis (OA), the most prevalent degenerative joint disease, still lacks a true disease-modifying therapy. The involvement of the NF-κB pathway and its upstream activating kinases in OA pathogenesis has been recognized for many years. The ability of the N-acetyl phenylalanine glucosamine derivative (NAPA) to increase anabolism and reduce catabolism via inhibition of IKKα kinase has been previously observed in vitro and in vivo.
View Article and Find Full Text PDFThe prevalence of Osteoarthritis (OA) is increasing because of the progressive aging and unhealthy lifestyle. These risk factors trigger OA by removing constraints that keep the tightly regulated low turnover of the extracellular matrix (ECM) of articular cartilage, the correct chondrocyte phenotype, and the functionality of major homeostatic mechanisms, such as mitophagy, that allows for the clearance of dysfunctional mitochondria, preventing increased production of reactive oxygen species, oxidative stress, and senescence. After OA onset, the presence of ECM degradation products is perceived as a "danger" signal by the chondrocytes and the synovial macrophages that release alarmins with autocrine/paracrine effects on the same cells.
View Article and Find Full Text PDFPatients with long-standing ulcerative colitis (UC) have an increased colorectal cancer (CRC) risk. In this pilot study we evaluated the effect of Eicosapentaenoic acid as free fatty acid (EPA-FFA) supplementation on mucosal disease activity, colonic differentiation markers and microbiota composition in UC patients. Twenty long-standing UC patients in stable clinical remission and with fecal calprotectin (FC) > 150 µg/g were enrolled (T0) and supplemented with EPA-FFA 2 g/daily for 90 days (T3).
View Article and Find Full Text PDFOsteoarthritis (OA) is a debilitating degenerative disease of the articular cartilage with a multifactorial etiology. Aging, the main risk factor for OA development, is associated with a systemic oxidative and inflammatory phenotype. Autophagy is a central housekeeping system that plays an antiaging role by supporting the clearance of senescence-associated alterations of macromolecules and organelles.
View Article and Find Full Text PDFHepatocellular carcinoma (HCC) ranks fifth in frequency worldwide amongst all human cancers causing one million deaths annually. Despite many promising treatment options, long-term prognosis remains dismal for the majority of patients who develop recurrence or present with advanced disease. Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver.
View Article and Find Full Text PDFIntroduction: Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA), but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3β inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3β inactivation in vitro to assess their contribution to cell senescence and hypertrophy.
Methods: In vivo level of phosphorylated GSK3β was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining.
To successfully target Notch receptors as part of a multidrug anticancer strategy, it will be essential to fully characterize the factors that are modulated by Notch signaling. We recently reported that Notch3 silencing in HCC results in p53 up-regulation in vitro and, therefore, we focused on the mechanisms that associate Notch3 to p53 protein expression. We explored the regulation of p53 by Notch3 signalling in three HCC cell lines HepG2, SNU398 and Hep3B.
View Article and Find Full Text PDFHydroxytyrosol (HT), a phenolic compound mainly derived from olives, has been proposed as a nutraceutical useful in prevention or treatment of degenerative diseases. In the present study we have evaluated the ability of HT to counteract the appearance of osteoarthritis (OA) features in human chondrocytes. Pre-treatment of monolayer cultures of chondrocytes with HT was effective in preventing accumulation of reactive oxidant species (ROS), DNA damage and cell death induced by H2O2 exposure, as well as the increase in the mRNA level of pro-inflammatory, matrix-degrading and hypertrophy marker genes, such as iNOS, COX-2, MMP-13, RUNX-2 and VEGF.
View Article and Find Full Text PDFThe first step in skeleton development is the condensation of mesenchymal precursors followed by any of two different types of ossification, depending on the type of bone segment: in intramembranous ossification, the bone is deposed directly in the mesenchymal anlagen, whereas in endochondral ossification, the bone is deposed onto a template of cartilage that is subsequently substituted by bone. Polyamines and polyamine-related enzymes have been implicated in bone development as global regulators of the transcriptional and translational activity of stem cells and pivotal transcription factors. Therefore, it is tempting to investigate their use as a tool to improve regenerative medicine strategies in orthopedics.
View Article and Find Full Text PDFThe molecular mechanisms underlying spermine osteo-inductive activity on human adipose-derived stem cells (ASCs) grown in 3-dimensional (3D) cultures were investigated. Spermine belongs to the polyamine family, naturally occurring, positively charged polycations that are able to control several cellular processes. Spermine was used at a concentration close to that found in platelet-rich plasma (PRP), an autologous blood product containing growth and differentiation factors, which has recently become popular in in vitro and in vivo bone healing and engineering.
View Article and Find Full Text PDFCDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers, including hepatocellular carcinoma (HCC); however, little is known regarding the role of CDKN1C/P57 and its regulation in HCC. In this study, we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation, CDKN1C/P57 up-regulation, and reduced cell growth. In line with these data, we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector, Hes1.
View Article and Find Full Text PDFWe described the optimization, by molecular modelling, of small pyrazole derivatives, as kinase inhibitors, obtained through a 1,3-dipolar cycloaddition between nitrile imines and functionalized acetylenes. The two compounds, selected as potential agents active against hepatocellular carcinoma (HCC) were then evaluated in vitro for their biological activity on HCC-derived cell lines. The compounds show a promising inhibitory growth efficacy (IC(50) 50-100 μM) in SNU449 cell line, as well as block of cell cycle progression and induction of apoptosis, and can be considered as lead compounds for further SAR developments.
View Article and Find Full Text PDFBackground/aims: The functional roles of endogenous Notch3 and Notch1 for protecting human hepatocellular carcinoma (HCC) lines against doxorubicin-induced death have been investigated. We previously reported aberrant Notch3 and Notch4 up-regulation in HCC and we have extended these observations to include Notch1.
Methods: Notch1 expression was assessed by immunohistochemistry and immunoblotting.
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