The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs) for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA). Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP)/Transforming growth factor-β (TGFβ), Parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), Fibroblast growth factor (FGF), Insulin like growth factor (IGF) and Hypoxia-inducible factor (HIF). This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC) repair, and improves understanding of the disease stages and cellular responses within an OA articular joint.     

Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1G93A Transgenic Mice

Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1^G93A mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1^G93A mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1^G93A mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1^G93A mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1^G93A mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment.     

Cinnamon and health

Cinnamon has been used as a spice and as traditional herbal medicine for centuries. The available in vitro and animal in vivo evidence suggests that cinnamon has anti-inflammatory, antimicrobial, antioxidant, antitumor, cardiovascular, cholesterol-lowering, and immunomodulatory effects. In vitro studies have demonstrated that cinnamon may act as an insulin mimetic, to potentiate insulin activity or to stimulate cellular glucose metabolism. Furthermore, animal studies have demonstrated strong hypoglycemic properties. However, there are only very few well-controlled clinical studies, a fact that limits the conclusions that can be made about the potential health benefits of cinnamon for free-living humans. The use of cinnamon as an adjunct to the treatment of type 2 diabetes mellitus is the most promising area, but further research is needed before definitive recommendations can be made.     

Contribution of proteomics to the study of the role of cytokeratins in disease and physiopathology

Cytokeratins (CKs), the most abundant group of cytoskeletal intermediate filaments, and proteomics are strongly connected. On the one hand, proteomics has been extremely useful to uncover new features and functions of CKs, on the other, the highly abundant CKs serve as an exceptional tool to test new technological developments in proteomics. As a result, proteomics has contributed to finding valuable associations of CKs with diseases as diverse as cancer, cystic fibrosis, steatohepatitis, viral and bacterial infection, keratoconus, vitreoretinopathy, preeclampsia or the chronic fatigue syndrome, as well as to characterizing their participation in a number of physiopathological processes, including drug resistance, response to toxicants, inflammation, stem cell differentiation, embryo development, and tissue repair. In some cases, like in cystic fibrosis, CKs have been described as potential therapeutic targets. The development of a specific field of proteomics where CKs become the main subject of research aims and hypotheses is suggested.     

Synthesis,in vitro Antileishmanial Efficacy and Hit/Lead Identification of Nitrofurantoin-Triazole Hybrids

Leishmaniasis is a vector-borne neglected parasitic infection affecting thousands of individuals, mostly among populations in low- to moderate-income developing countries. In the absence of protective vaccines, the management of the disease banks solely on chemotherapy. However, the clinical usefulness of current antileishmanial drugs is threatened by their toxicity and the emergence of multidrug-resistant strains of the causative pathogens. This emphasizes the imperative for the development of new and effective antileishmanial agents. In this regard, we synthesized and evaluated in vitro the antileishmanial activity and cytotoxicity profile of a series of nitrofurantoin-triazole hybrids. The nitrofurantoin derivative 1 featuring propargyl moiety was distinctively the most active of all, was nontoxic to human cells and possessed submicromolar cellular activity selectively directed towards the pathogens of the life threatening visceral leishmaniasis. Hence it was identified as potential antileishmanial lead for further investigation into its prospective to act as alternative to therapies.     

Fatigue behavior of thermosetting-polyester-matrix sheet-molding compounds

Two sheet molding compounds, one containing 65 weight percent E-glass fiber and no filler (SMC-65) and the other containing 50 weight percent glass and 15 weight percent CaCO₃ filler were subjected to sinusoidal, load-control, tension-tension fatigue. The macroscopic behavior showed some notch sensitivity for both materials, but particularly for SMC-65. The extent of failure damage over the specimen length decreased with decreasing load amplitude. Different failure mechanisms appear to operate under high- and low-cycle fatigue conditions. Microscopic surface damage studies at stresses near the endurance limit showed several stages in the fatigue failure. For SMC-65, these stages are, sequentially, matrix crack initiation and growth, matrix pulverization, fiber fracture, and fiber pullout. A similar, but less distinct pattern was observed for SMC-50. Acoustic emission was also followed during fatigue cycling near the endurance limit. Distinct amplitude distribution peaks for each failure process were seen. It is suggested that matrix fracture, permanent deformation and Euler buckling are all important in high cycle fatigue failure.