Piperine attenuates the inflammation, oxidative stress, and pyroptosis to facilitate recovery from spinal cord injury via autophagy enhancement.

Spinal cord injury (SCI) is a serious injury that can lead to irreversible motor dysfunction. Due to its complicated pathogenic mechanism, there are no effective drug treatments. Piperine, a natural active alkaloid extracted from black pepper, has been reported to influence neurogenesis and exert a neuroprotective effect in traumatic brain injury. The aim of this study was to investigate the therapeutic effect of piperine in an SCI model. SCI was induced in mice by clamping the spinal cord with a vascular clip for 1 min. Before SCI and every 2 days post-SCI, evaluations using the Basso mouse scale and inclined plane tests were performed. On day 28 after SCI, footprint analyses, and HE/Masson staining of tissues were performed. On a postoperative Day 3, the spinal cord was harvested to assess the levels of pyroptosis, reactive oxygen species (ROS), inflammation, and autophagy. Piperine enhanced functional recovery after SCI. Additionally, piperine reduced inflammation, oxidative stress, pyroptosis, and activated autophagy. However, the effects of piperine on functional recovery after SCI were reversed by autophagy inhibition. The study demonstrated that piperine facilitated functional recovery after SCI by inhibiting inflammatory, oxidative stress, and pyroptosis, mediated by the activation of autophagy.

Catalpol as a Component of Rehmannia glutinosa Protects Spinal Cord Injury by Inhibiting Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis.

Disturbance of the internal environment in the spinal cord after spinal cord injury (SCI) is an important cause of the massive death of neurons in the injury area and one of the major problems that lead to the difficult recovery of motor function in patients. Rehmannia glutinosa, a famous traditional Chinese medicine, is commonly used in neurodegenerative diseases, whereas an iridoid glycoside extract of catalpol (CAT), with antioxidant, antiapoptotic, and neuroprotective pharmacological effects. However, the neuroprotective and anti-apoptosis mechanism of CAT in SCI remains unclear. In our study, we found that CAT has a restorative effect on the lower limb motor function of rats with SCI by establishing a rat model of SCI and treating CAT gavage for 30 days. Our study further found that CAT has the effect of inhibiting apoptosis and protecting neurons, and the action pathway may reduce endoplasmic reticulum (ER) stress by inhibiting CHOP and GRP78 expression and then reduce apoptosis and protect neurons through the Caspase3/Bax/Bcl-2 pathway. In conclusion, we demonstrated that CAT can treat SCI by inhibiting ER stress-mediated neuronal apoptosis and has the potential to be a clinical drug for the treatment of SCI.

Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway.

Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. We used a mouse model of SCI, and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, pyroptosis, and AMPK-related signaling pathways were also examined. Our results showed that BA significantly improved functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS level and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induced mitophagy to eliminate the accumulation of ROS and inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Those results showed that BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

Comparison of fracture risk using different supplemental doses of vitamin D, calcium or their combination: a network meta-analysis of randomised controlled trials.

OBJECTIVE: Inconsistent findings in regard to association between different concentrations of vitamin D, calcium or their combination and the risk of fracture have been reported during the past decade in community-dwelling older people. This study was designed to compare the fracture risk using different concentrations of vitamin D, calcium or their combination. DESIGN: A systematic review and network meta-analysis. DATA SOURCES: Randomised controlled trials in PubMed, Cochrane library and Embase databases were systematically searched from the inception dates to 31 December 2017. OUTCOMES: Total fracture was defined as the primary outcome. Secondary outcomes were hip fracture and vertebral fracture. Due to the consistency of the original studies, a consistency model was adopted. RESULTS: A total of 25 randomised controlled trials involving 43 510 participants fulfilled the inclusion criteria. There was no evidence that the risk of total fracture was reduced using different concentrations of vitamin D, calcium or their combination compared with placebo or no treatment. No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of hip or vertebral fractures. CONCLUSIONS: The use of supplements that included calcium, vitamin D or both was not found to be better than placebo or no treatment in terms of risk of fractures among community-dwelling older adults. It means the routine use of these supplements in community-dwelling older people should be treated more carefully. PROSPERO REGISTRATION NUMBER: CRD42017079624.

Cryptotanshinone protects against IL-1ß-induced inflammation in human osteoarthritis chondrocytes and ameliorates the progression of osteoarthritis in mice.

Osteoarthritis (OA) is a common degenerative disease characterized by progressive erosion of articular cartilage, subchondral bone sclerosis and synovitis. Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge, has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of CTS on human OA chondrocytes and mice OA models. Human OA chondrocytes were pretreated with CTS (5, 10 and 20µM) for 2h and subsequently stimulated with IL-1ß for 24h. Production of NO, PGE2, IL-6, TNF-α was evaluated by the Griess reaction and ELISA. The protein expression of COX-2, iNOs, MMP-3, MMP13, COX-2, ADAMTS-5, JNK, p-JNK, ERK, p-ERK, p38, p-p38, p-IKKα/ß, p65, p-p65, IκB-α, and p-IκB-α was tested by Western blot. In vivo, the severity of OA was determined by histological analysis. We found that CTS significantly inhibited the IL-1ß-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-3, MMP-13, and ADAMTS-5. Furthermore, CTS in dramatically suppressed IL-1ß-stimulated NF-κB and MAPK activation. Immunofluorescence staining demonstrated that CTS could suppress IL-1ß-induced phosphorylation of p65 nuclear translocation. In vivo, treatment of CTS prevented the destruction of cartilage and the thickening of subchondral bone in mice OA models. These results indicate that the therapeutic effect of CTS on OA is accomplished through the inhibition of both NF-κB and MAPK signaling pathways. Our findings provide the evidence to develop CTS as a potential therapeutic agent f or patients with OA.