Potential anti-neuroinflammatory NF-кB inhibitors based on 3,4-dihydronaphthalen-1(2H)-one derivatives.

Nuclear factor kappa B (NF-кB) inhibition represents a new therapeutic strategy for the treatment of neuroinflammatory diseases. In this study, a series of 3,4-dihydronaphthalen-1(2H)-one (DHN; 6a-n, 7a-c) derivatives were synthesised and characterised by NMR and HRMS. We assessed the toxicity and anti-neuroinflammatory properties of these compounds and found that 6m showed the greatest anti-neuroinflammatory properties, with relatively low toxicity. Specifically, 6m significantly reduced reactive oxygen species production, down-regulated the expression of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 and prevented lipopolysaccharide-stimulated BV2 microglia cells polarisation towards an M1 phenotype. Furthermore, 6m significantly decreased IκBα and NF-кB p65 phosphorylation, thus inhibiting the NF-кB signalling pathway. This suggests that 6m may be explored as a functional anti-neuroinflammatory agent for the treatment of inflammatory diseases in the central nervous system, such as multiple sclerosis, traumatic brain injury, stroke and spinal cord injury.

The change of break modulus drives human fibroblast differentiation in 3D collagen gels.

Extracellular matrix is one of the key environmental factors influencing cell survival and provides signals for cell morphological change, migration, proliferation and differentiation. However, the mechanism through which denatured collagen modulates the biological properties of fibroblasts, is unclear. We investigated the regulation of human fibroblast differentiation in vitro grown in collagen gels with different properties. The break modulus of collagen with denatured collagen and half-load normal collagen was reduced compared with that of normal collagen gel. Fibroblasts cultured in denatured collagen gels showed increased expression of matrix metalloproteinase9 ( MMP-9), tissue inhibitor of metalloproteinase 2 (TIMP2), α-smooth muscle actin (α-SMA), osteoblast cadherin, phosphorylated Myosin phosphatase target subunit1 (p-MYPT1), connective tissue growth factor, type I collagen, type III collagen, α-smooth muscle actin messenger RNA, RhoA, rho-associated protein kinase, and transforming growth factor ß receptors 1 and 2 compared with that in cells cultured in normal collagen gel. But there was no significant difference regarding expression level between denatured collagen gel and half-load normal collagen gel .These findings suggest that the change in break modulus caused by decreasing normal collagen concentration may be the key factor inducing fibroblast differentiation.