ABSTRACT
Inflammation and neuronal apoptosis aggravate the secondary damage after spinal cord injury (SCI). Rehmannioside A (Rea) is a bioactive herbal extract isolated from Rehmanniae radix with low toxicity and neuroprotection effects. Rea treatment inhibited the release of pro-inflammatory mediators from microglial cells, and promoted M2 polarization in vitro, which in turn protected the co-cultured neurons from apoptosis via suppression of the NF-κB and MAPK signalling pathways. Furthermore, daily intraperitoneal injections of 80 mg/kg Rea into a rat model of SCI significantly improved the behavioural and histological indices, promoted M2 microglial polarization, alleviated neuronal apoptosis, and increased motor function recovery. Therefore, Rea is a promising therapeutic option for SCI and should be clinically explored.
Subject(s)
Apoptosis/drug effects , MAP Kinase Signaling System/drug effects , Microglia/drug effects , Microglia/metabolism , Neurons/metabolism , Neuroprotective Agents/pharmacology , Spinal Cord Injuries/metabolism , Animals , Biomarkers , Cells, Cultured , Disease Models, Animal , Female , Inflammation Mediators/metabolism , Microglia/immunology , Models, Biological , Motor Activity , NF-kappa B/metabolism , Plant Extracts/chemistry , Plant Extracts/pharmacology , Rats , Rehmannia/chemistry , Signal Transduction , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/etiology , Spinal Cord Injuries/rehabilitationABSTRACT
The metabolicosteopathy known as postmenopausal osteoporosisiscaused by disruption of the balance between bone resorption and osteogenesis, processes that are mediated by osteoclasts and osteoblasts, respectively. The current therapeutic approaches to treating osteoporosis have several limitations. In this study, we demonstrated that the natural chemical compound isoalantolactone (IAL) could inhibit osteoclastogenesis, without affecting osteogenesis. This is the first study reporting a role of IAL in suppressing the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in a dose-dependent manner, and downregulating the expression of osteoclast-related marker genes. Furthermore, IAL abrogated the phosphorylation of c-Jun N-terminal kinase (JNK)/p38, NF-κB, and phosphatidylinositol 3-kinase (PI3K)-AKT, and also diminished the expression of osteoclastogenesis-related proteins. In conclusion, our results indicated that IAL has promise for the treatment of osteoporosis and other metabolicbone diseases.
Subject(s)
Bone Resorption/drug therapy , Osteoclasts/drug effects , Osteogenesis/drug effects , Sesquiterpenes/therapeutic use , Actins/metabolism , Animals , Cathepsin K/genetics , Cathepsin K/metabolism , Cells, Cultured , Female , Macrophages/drug effects , Macrophages/metabolism , Mice, Inbred C57BL , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Osteoclasts/metabolism , Ovariectomy , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-fos/metabolism , RANK Ligand , Sesquiterpenes/pharmacology , Signal Transduction/drug effectsABSTRACT
Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.