Nuclear factor (NF)-κB-mediated neuroinflammation is an important mechanism of intracerebral hemorrhage (ICH)-induced neurotoxicity. Silent information regulator 1 (SIRT1) plays a multi-protective effect in a variety of diseases by deacetylating and inhibiting NF-κB/p65. However, the role of SIRT1 in brain damage following ICH remains unclear. We hypothesized that SIRT1 can protect against ICH-induced brain damage by inhibiting neuroinflammation through deacetylating NF-κB/p65. The ICH model was induced in vivo (with collagenase) and in vitro (with hemoglobin).Resveratrol and Ex527 were administered to activate or inhibit SIRT1, respectively.Western blot, immunohistochemistry, and immunofluorescence assays were performed to detect the expression of SIRT1 and p65. Enzyme-linked immunosorbent assays (ELISAs) were used to explore tumor necrosis factor (TNF)-α and interleukin (IL)-1β release. The neurological score, brain water content, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and brain hemoglobin content were determined to evaluate the neuroprotective effect of SIRT1. SIRT1 expression was decreased, whereas the level of acetylated p65 (Ac-p65) was elevated after ICH in vivo. Moreover, hemoglobin treatment decreased the expression of SIRT1 in vitro. Activation of SIRT1 by resveratrol had a neuroprotective effect, along with decreased levels of Ac-p65, IL-1β, TNF-α, and apoptosis after ICH. The effect of resveratrol was abolished by the SIRT1 inhibitor Ex527. Our results are consistent with the hypothesis that SIRT1 exerts a neuroprotective effect after ICH by deacetylating p65 to inhibit the NF-κB-dependent inflammatory response.
Osteoarthritis (OA) is a common degenerative disease that affects the musculoskeletal structure of the whole joint, which is characterized by progressive destruction of both articular cartilage and subchondral bone. Treatment of the bone pathologies, particularly osteoclast‐mediated subchondral bone loss in the early stages of OA, could prevent subsequent cartilage degeneration and progression of OA. In the present study, the PKC inhibitor, Sotrastaurin, was found to inhibit RANKL‐induced osteoclast formation in vitro in a dose‐ and time‐dependent manner. In particular, SO exerted its anti‐osteoclastic effect predominantly at the early stages of RANKL stimulation, suggesting inhibitory effects on precursor cell fusion. Using mature osteoclasts cultured on bovine bone discs, we showed that SO also exerts anti‐resorptive effects on mature osteoclasts bone resorptive function. Mechanistically, SO attenuates the early activation of the p38, ERK and JNK signalling pathways, leeding to impaired induction of crucial osteoclast transcription factors c‐Jun, c‐Fos and NFATc1. We also showed that SO treatment significantly inhibited the phosphorylation of PKCδ and MARCKS, an upstream regulator of cathepsin K secretion. Finally, in animal studies, SO significantly alleviates the osteochondral pathologies of subchondral bone destruction as well as articular cartilage degeneration following DMM‐induced OA, markedly improving OARSI scores. The reduced subchondral bone loss was associated with marked reductions in TRAP(+) osteoclasts in the subchondral bone tissue. Collectively, our data provide evidence for the protective effects of SO against OA by preventing aberrant subchondral bone and articular cartilage changes. Thus, SO demonstrates potential for further development as an alternative therapeutic option against OA.
Backgound Neurosurgical resection is a standard local treatment for lung cancer brain metastases (BMs). This study aims to investigate whether neurosurgical resection provides survival benefit in lung cancer BMs with poor KPS. Materials and methods This multicenter retrospective study included 386 lung cancer BMs with pretreatment KPS ≤ 70 among a total of 1177 lung cancer BMs treated at three centers from August 2010 to July 2021. Data analysis was performed from July to September 2022. Inverse probability of treatment weighting (IPTW) and propensity scores matching (PSM) based on propensity scoring were used to minimize bias. The main outcome was overall survival (OS) after diagnosis of BMs. Risk factors of OS were estimated using Cox proportional hazards regression models. All Characteristics were included in the multivariate Cox regression. Results 386 patients with pretreatment KPS ≤ 70 were included (age mean [SD], 57.85 [10.36] years; KPS mean [SD], 60.91 [10.11]). Among them, 111 patients received neurosurgical resection, while 275 patients did not. Baseline characteristics were balanced between groups after IPTW or PSM. Neurosurgical resection was associated with significantly better prognosis in unadjusted multivariate COX analysis (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.51–0.91, P = 0.01), and PSM-adjusted multivariate COX analysis (HR: 0.61, 95%CI: 0.39–0.94, P = 0.03), IPTW-adjusted multivariate COX analysis (HR: 0.58, 95%CI: 0.40–0.84, P = 0.004). OS was significantly longer in neurosurgical resection group compared with non-surgical resection group according to unadjusted data (Median OS, surgery vs non-surgery, 14.7 vs 12.5 months, P = 0.01), PSM-adjusted data (median OS, 17.7 vs 12.3 months, P < 0.01) and IPTW-adjusted data (median OS, 17.7 vs 12.5 months, P < 0.01). Conclusions Neurosurgical resection was associated with improved survival in patients with lung cancer BMs with poor KPS, suggesting that poor KPS is not a contraindication for neurosurgical resection in these patients.
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