Interruption of the long non-coding RNA HOTAIR signaling axis ameliorates chemotherapy-induced cachexia in bladder cancer.

BACKGROUND: Cisplatin-based chemotherapy is the first line of treatment for bladder cancer. However, cisplatin induces muscle wasting associated with NF-κB and cancer cachexia. HOTAIR, an oncogenic long non-coding RNA (lncRNA), promotes cancer progression in different cancers. Crosstalk between HOTAIR and NF-κB is documented. Prothymosin α (ProT) plays important roles in cancer progression and inflammation. However, the potential link between HOTAIR, ProT, and cisplatin-induced cancer cachexia remains unexplored. Here, we investigated the contribution of HOTAIR in cisplatin-induced cancer cachexia and dissected the potential signaling cascade involving the epidermal growth factor receptor (EGFR), ProT, NF-κB, and HOTAIR. MATERIALS AND METHODS: Expression of ProT and HOTAIR transcripts and their correlations in tumor tissues of bladder cancer patients and bladder cancer cell lines were determined by RT-qPCR. Next, levels of phospho-EGFR, EGFR, phospho-NF-κB, and NF-κB were examined by immunoblot analysis in human bladder cancer cells treated with cisplatin. Expression of HOTAIR in cisplatin-treated cells was also assessed by RT-qPCR. Pharmacological inhibitors and overexpression and knockdown approaches were exploited to decipher the signaling pathway. The murine C2C12 myoblasts were used as an in vitro muscle atrophy model. The syngeneic murine MBT-2 bladder tumor was used to investigate the role of mouse Hotair in cisplatin-induced cancer cachexia. RESULTS: Expression of ProT and HOTAIR was higher in bladder tumors than in normal adjacent tissues. There were positive correlations between ProT and HOTAIR expression in clinical bladder tumors and bladder cancer cell lines. Cisplatin treatment increased EGFR and NF-κB activation and upregulated ProT and HOTAIR expression in bladder cancer cells. ProT overexpression increased, whereas ProT knockdown decreased, HOTAIR expression. Notably, cisplatin-induced HOTAIR upregulation was abrogated by EGFR inhibitors or ProT knockdown. ProT-induced HOTAIR overexpression was diminished by NF-κB inhibitors. HOTAIR overexpression enhanced, whereas its knockdown reduced, cell proliferation, cachexia-associated pro-inflammatory cytokine expression, and muscle atrophy. Cachexia-associated symptoms were ameliorated in mice bearing Hotair-knockdown bladder tumors undergoing cisplatin treatment. CONCLUSIONS: We demonstrate for the first time a critical role for HOTAIR and identify the involvement of the EGFR-ProT-NF-κB-HOTAIR signaling axis in cisplatin-induced cachexia in bladder cancer and likely other cancers. Our findings also provide therapeutic targets for this disease.

The optimal treatment for improving cognitive function in elder people with mild cognitive impairment incorporating Bayesian network meta-analysis and systematic review.

It's widely acknowledged that, as a neurodegenerative aging disease representing an intermediate stage between cognitive intactness and Alzheimer's disease (AD), Mild cognitive impairment (MCI) poses an excessive burden on patients' well-being, family members, health-care providers as well as the whole society. This study focuses on three cognitive interventions proposed by Clare and Woods, which are, Cognitive stimulation (CS), Cognitive training (CT) and Cognitive rehabilitation (CR). Our Network meta-analysis (NMA) aims to compar them with one another to determine the optimal cognitive intervention for elderly adults with MCI in improving their cognitive function. We applied extensive strategies to preliminary literature retrieval to identify relevant randomized controlled trials (RCTs) which scrupulously compared any two of the three cognitive interventions with one another or any one of the three with a control group as the placebo or non-active group in treating elder patients with MCI in accordance with Petersen's criteria. Our NMA of cognitive interventions for patients diagnosed with MCI appraised the relative effectiveness of cognitive interventions across trials simultaneously. Our study attempts to summarize available data to suggest that CS (Mean difference [MD] = 0.95, 95% confidence interval [CI]:0.27, 1.70) and CT (MD = 0.70, [CI]:0.11,1.30) were significantly beneficial to MCI patients for improving their cognition status while CR (MD = 0.59, [CI]:-0.30,1.50) scored lowest. Our study suggested CS was most likely to be the best intervention for improving the cognitive function of MCI patients.

[Changes of lipid levels in mice with hypoxic pulmonary arterial hypertension].

OBJECTIVE: To observe the changes of lipid levels in mice with pulmonary hypertension induced by hypoxia. METHODS: The animal model of hypoxic pulmonary hypertension was established by exposing the mice to isobaric hypoxic chamberfor 3 weeks (23 h/d, regular chow feed). Twenty male C57BL/6 mice were randomlydivided into normoxia group and hypoxia group (n=10). The concentrations of total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) in plasma were detected by Elisa method.The mRNA levels of HMG-CoAreductase (HMGCR), low density lipoprotein receptor (LDLR), scavenger receptor class B1 (SR-B1), and sterol regulatory element-binding factor-2 (SREBF2) in liverwere measured by real-time PCR. RESULTS: ① The right ventricular systolic pressure (RVSP) and the weight ratio of right ventricle (RV) to left ventricle plus septum (LV+S) of hypoxia group were significantly higher than those of normoxia group (P<0.05).② The concentrations of HDL and HDL/LDL in plasma were significantly higher in hypoxia group, compared with normoxia group (P<0.05).③The mRNA levels of LDLR and SR-B1in liver were significantly down-regulated in hypoxia group(P<0.05).④RVSP were significantly negative correlated with HDL/LDL, the gene expression of LDLR and SR-B1 (P<0.05). CONCLUSIONS: Abnormal lipid metabolism participates in the pathological proceeding of pulmonary hypertension induced by hypoxia.