Objective To explore the effects of C/EBPα knockout in podocyte on diabetic nephropathy and its mechanisms.Methods C/EBPαloxp/loxp mice were crossed with podocin-cre mice to obtain F1 hybrids and then propagated until homozygous mice (C/EBPαf/f) were obtained.Diabetic nephropathy (DN) models were established by low-dose streptozotocin (STZ,100 mg/kg) administration after 25 weeks of normal diet or 45％ high-fat diet treatment,and biochemical indicators of blood and urea were measured.The morphological characteristics and the proteins regulating oxidative stress and mitochondrial function were detected.Results The type 2 DN models were successfully constructed based on transgenic mice.The kidneys of 8-month-old C/EBPαf/f mice did not show obvious morphological changes,but after constructing DN models,they showed obvious renal impairment,inflammation and oxidative stress.Compared with wild-type DN mice,the protein levels of nephrin and E-cadherin in DN C/EBPαf/f mice with DN were significantly decreased (P ＜ 0.01);fibronectin and Nrf2 protein levels were all increased (all P ＜ 0.05).Keap1,phospho-AMPK and mitochondrial function related genes Pgc-1α protein levels were all decreased (all P ＜ 0.05).Conclusion Podocyte C/EBPα knockout exacerbates diabetic nephropathy by promoting fibrosis and inhibiting Pgc-1α-mediated mitochondrial antioxidant function.

OBJECTIVE： To systematically evaluate the efficacy and safety of Tapentadol immediate-release preparation （Tap IR） for relieving severe acute pain after brachiocephalic arteritis， and to provide evidence-based reference for rational drug use. METHODS： Retrieved from PubMed， Medline， Cochrane library， CNKI， VIP， Wanfang database and American clinical trial database， randomized controlled trials （RCTs） about Tap IR （trial group） versus Oxycodone immediate-release preparation or placebo for relieving severe acute pain after brachiocephalic arteritis were collected. After literature screening， data extraction and literature quality evaluation with modified Jadad scale， Meta-analysis was conducted by using RevMan 5.3 software. RESULTS： A total of 6 RCTs were included， involving 2 378 patients. Results of Meta-analysis showed that 48 h total pain relief value （TOTPAR48） of trial group was significantly higher than control group [MD＝35.60，95％CI（27.31， 43.88）， P＜0.000 01]. Results of sub-group analysis showed that TOTPAR48 of trial group using Tap IR 50 mg [MD＝28.68， 95％CI （18.18， 39.17），P＜0.00 001]， 75 mg [MD＝39.97， 95％CI （34.21， 45.73）， P＜0.000 01] and 100 mg[MD＝38.50， 95％CI（1.46， 75.54），P＝0.04] were significantly higher than control group； TOTPAR48 of patients who received Tap IR 75 mg were significantly higher than patients who received Tap IR 50 mg [MD＝9.04，95％ CI（4.31， 13.77），P＝0.000 2]. There was no statistical significance in the utilization rate of rescue medicine （URM） between 2 groups [RR＝1.23，95％ CI（0.84， 1.80），P＝0.29]. Subgroup analysis showed that URM in patients who received Tap IR 75 mg was significantly lower than those receiving Tap IR 50 mg [RR＝0.62，95％CI（0.41， 0.94），P＝0.02]. The total difference of 48 h pain intensity （SPID48） in trial group was significantly lower than control group [MD＝－18.96，95％CI（－37.28，－0.64），P＝0.04]. Subgroup analysis showed that SPID48 in patients who received Tap IR 75 mg was significantly higher than those receiving Tap IR 50 mg [MD＝21.66，95％CI（8.93， 34.39），P＝0.000 9]. There was no statistical significance in the total change of pain impression （PGIC） between 2 groups [RR＝0.95，95％CI（0.88， 1.03），P＝0.23]. Subgroup analysis showed that PGIC in patients who received Tap IR 75 mg was significantly higher than those receiving Tap IR 50 mg [RR＝1.07，95％CI（1.01， 1.13），P＝0.02] but significantly lower than those receiving Tap IR 100 mg [RR＝0.86，95％CI（0.77， 0.97），P＝0.01]. The incidence of nausea， vomiting， constipation， dizziness and headache in trial group were significantly lower than control group （P＜0.05）. CONCLUSIONS： Tap IR shows good therapeutic efficacy and safety for severe acute pain after brachiocephalic arteritis， and the efficacy of Tap IR might be better when the dose of Tap IR is 75 mg.

BACKGROUND: Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood. METHODS: The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al . RESULTS: In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients. CONCLUSION Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.
Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism* ; Culture Media, Conditioned/pharmacology* ; Cachexia/pathology* ; Gastrointestinal Neoplasms ; Somatomedins/metabolism* ; Insulins/metabolism* ; Lipids