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Mas-related G-protein-coupled receptor subtype C (MrgC) has been shown to play an important role in the development of bone cancer pain. Ubiquitination is reported to participate in pain. However, whether MrgC ubiquitination plays a role in bone cancer pain remains unclear. To answer this question, we designed and performed this study. Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer pain. MrgC agonist bovine adrenal medulla 8–22 (BAM 8–22) or MrgC antagonist anti-MrgC antibody were injected intrathecally on day 14 after bone cancer pain was successfully induced. The pain behaviors, the MrgC ubiquitination levels and intracellular calcium concentration in spinal neurons were measured before and after injection, respectively. With comparison to normal and sham group, mice in tumor group exhibited serious bone cancer pain on day 14, and the level of MrgC ubiquitination and intracellular calcium concentration in spinal neurons was significantly higher. Intrathecal injection of BAM 8–22 significantly alleviated bone cancer pain, increased the MrgC ubiquitination level and decreased intracellular calcium concentration in spinal neurons; however, these effects were reversed by administration of anti-MrgC antibody. Our study reveals that MrgC ubiquitination participates in the production and maintenance of bone cancer pain in mice, possibly through the regulation of intracellular calcium concentration in mice spinal neurons. [ABSTRACT FROM AUTHOR]

Notch signalling pathway plays an essential role in the development of cochlea, which inhibits the proliferation of hair cells. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea, which presents strong antioxidant activation and has been applied for anti-cancer and anti-inflammatory. In this study, we treated the cochlear explant cultures with EGCG and found that EGCG can protect cochlear hair cells from ototoxic drug gentamicin. We demonstrated that EGCG could down-regulate the expression of Notch signalling pathway target genes, such as Hes1, Hes5, Hey1 and Hey5. However, the Notch pathway ligands such as Delta1, Jag1 and Jag2 were not affected by EGCG. To further illustrate the mechanism of recover cochlear hair cells, we demonstrated that EGCG inhibited the activity of γ-secrectase to suppress Notch signalling pathway and promoted the proliferation and regeneration of hair cells in the damaged cochlea. Our results suggest for the first time the role of EGCG as an inhibitor of the Notch signalling pathway, and support its potential value in hearing-impaired recovery in clinical therapy. [ABSTRACT FROM AUTHOR]

Acute inflammation plays an important role in brain damage following cerebral ischemia and reperfusion (I/R) injury. The present study employed a rat model of middle cerebral artery occlusion to explore the neuroprotective effects of tanshinone IIA (TSN), which is widely used in China for treating cerebrovascular and cardiovascular diseases. Rats were divided into a sham-operated group and I/R transiently occluded then reperfused groups. Some of the I/R animals were treated daily for 7 or 15 days with two different doses of TSN. After 15 days, triphenyl tetrazolium chloride staining revealed less unstained area indicating fewer lesions in the TSN-treated I/R group relative to the untreated corresponding I/R group. TSN treatment dramatically reduced infarct sizes and reduced content of high mobility group box 1 protein following I/R. Nuclear translocation of NFκB was also attenuated in I/R animals subsequently receiving TSN. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining revealed more apoptosis in the I/R model group and this was reduced in the I/R animals treated with TSN for 15 days. Thus, TSN mitigates the severity of damage effected by I/R. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) results in neuronal apoptosis, autophagic cell death and necroptosis. Necroptosis is a newly discovered caspases-independent programmed necrosis pathway which can be triggered by activation of death receptor. Previous works identified that necrostatin-1 (NEC-1), a specific necroptosis inhibitor, could reduce tissue damage and functional impairment through inhibiting of necroptosis process following TBI. However, the role of NEC-1 on apoptosis and autophagy after TBI is still not very clear. In this study, the amount of TBI-induced neural cell deaths were counted by PI labeling method as previously described. The expression of autophagic pathway associated proteins (Beclin-1, LC3-II, and P62) and apoptotic pathway associated proteins (Bcl-2 and caspase-3) were also respectively assessed by immunoblotting. The data showed that mice pretreated with NEC-1 reduced the amount of PI-positive cells from 12 to 48 h after TBI. Immunoblotting results showed that NEC-1 suppressed TBI-induced Beclin-1 and LC3-II activation which maintained p62 at high level. NEC-1 pretreatment also reversed TBI-induced Bcl-2 expression and caspase-3 activation, as well as the ratio of Beclin-1/Bcl-2. Both 3-MA and NEC-1 suppressed TBI-induced caspase-3 activation and LC3-II formation, Z-VAD only inhibited caspase-3 activation but increased LC3-II expression at 24 h post-TBI. All these results revealed that multiple cell death pathways participated in the development of TBI, and NEC-1 inhibited apoptosis and autophagy simultaneously. These coactions may further explain how can NEC-1 reduce TBI-induced tissue damage and functional deficits and reflect the interrelationship among necrosis, apoptosis and autophagy. [ABSTRACT FROM AUTHOR]