The present study is undertaken to assess the alleviating effects of antimicrobial peptide cecropin A on inflammatory bowel disease (IBD) in C57BL/6 mice and changes in the gut microbiota, compared to an antibiotic gentamicin. Different doses of cecropin A were intraperitoneally injected into C57BL/6 mice for 5 days to determine the safe doses. The injection doses at ≤ 15 mg/kg showed no negative impact on the liver, heart, spleen, and kidney. The severe and moderate IBD mice model was successfully established via supplementation of 4 or 2.5% dextran sulfate sodium (DSS) in drinking water for 5 days. The severe IBD model was used to ensure the optimal therapeutic dose of cecropin A. Survival rate, body weight and disease activity index (DAI) scores were measured. Administration of 15 mg/kg, not 5 mg/kg cecropin A, for 5 days increased survival rate and decreased body weight loss of mice. The moderate IBD model was applied to investigate the mechanisms for cecropin A to alleviate inflammation in comparison to gentamicin. The mice were treated with 15 mg/kg cecropin A or 5 mg/kg gentamicin for 3 days. The levels of cytokines and related proteins in the colon were detected by ELISA and Western blotting. The microbiota in cecum contents were analyzed using 16S rRNA gene sequencing. The results showed that cecropin A and gentamicin relieved body weight loss, DAI, and gut mucosa disruption, while decreasing tumor necrosis factor-α (TNF-α), interlukin-1β (IL-1β), and interlukin-6 (IL-6) induced by DSS. In addition, cecropin A and gentamicin showed different effects on the gut microbiota structure. Both cecropin A and gentamicin decreased DSS-induced enrichment of Bacteroidaceae and Enterobacteriaceae . However, cecropin A showed a selective enrichment of Lactobacillus in contrast to gentamicin, which demonstrated a selective effect on Desulfovibrionaceae and Ruminococcaceae . Cecropin A alleviates IBD through decreasing harmful gut microflora and specifically enhancing beneficial gut microflora. The mechanism of this effect is different from gentamicin.
Silencing of hypoxia-inducible factor-1␣ gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol 306: F1236 -F1242, 2014. First published March 12, 2014 doi:10.1152/ajprenal.00673.2013.-Overactivation of hypoxia-inducible factor (HIF)-1␣ is implicated as a pathogenic factor in chronic kidney diseases (CKD). However, controversy exists regarding the roles of HIF-1␣ in CKD. Additionally, although hypoxia and HIF-1␣ activation are observed in various CKD and HIF-1␣ has been shown to stimulate fibrogenic factors, there is no direct evidence whether HIF-1␣ is an injurious or protective factor in chronic renal hypoxic injury. The present study determined whether knocking down the HIF-1␣ gene can attenuate or exaggerate kidney damage using a chronic renal ischemic model. Chronic renal ischemia was induced by unilaterally clamping the left renal artery for 3 wk in Sprague-Dawley rats. HIF-1␣ short hairpin (sh) RNA or control vectors were transfected into the left kidneys. Experimental groups were shamϩcontrol vector, clipϩcontrol vector, and clipϩHIF-1␣ shRNA. Enalapril was used to normalize blood pressure 1 wk after clamping the renal artery. HIF-1␣ protein levels were remarkably increased in clipped kidneys, and this increase was blocked by shRNA. Morphological examination showed that HIF-1␣ shRNA significantly attenuated injury in clipped kidneys: glomerular injury indices were 0.71 Ϯ 0.04, 2.50 Ϯ 0.12, and 1.34 Ϯ 0.11, and the percentage of globally damaged glomeruli was 0.02, 34.3 Ϯ 5.0, and 6.3 Ϯ 1.6 in sham, clip, and clipϩshRNA groups, respectively. The protein levels of collagen and ␣-smooth muscle actin also dramatically increased in clipped kidneys, but this effect was blocked by HIF-1␣ shRNA. In conclusion, long-term overactivation of HIF-1␣ is a pathogenic factor in chronic renal injury associated with ischemia/hypoxia. collagen; ␣-smooth muscle actin; renal fibrosis; chronic kidney diseases REDUCED RENAL TISSUE OXYGEN levels have been demonstrated in a large variety of chronic kidney diseases (CKD) in both human patients and in experimental animal models. Hypoxia in CKD results from a combination of structural and functional changes (12, 36). As a result, hypoxia-inducible factor (HIF)-1␣ has been reported to be consistently upregulated in almost all types of CKD (7, 16, 17, 36 -38). However, it is unclear whether upregulation of HIF-1␣ is beneficial or deleterious in progressive CKD. HIF-1␣ is a transcription factor and has been shown to stimulate collagen accumulation (7,15,43,44) and promote the epithelial-to-mesenchymal transition (EMT) (11,35), an important mechanism involved in the progression of CKD (3,33,57,67). Therefore, although upregulation of HIF-1␣ is protective in acute kidney injury (9, 18, 37, 53), ample evidence indicates that long-term overactivation of HIF-1␣ may be a pathogenic factor in CKD (10,16,21,24,36,45).Previous studies have shown that genetic ablation of renal epithelial HIF-1␣ inhibits the development of renal tubulointerstitia...
ABSTRACT:Nutlin-3a is an MDM2 inhibitor that is under investigation in preclinical models for a variety of pediatric malignancies, including retinoblastoma, rhabdomyosarcoma, neuroblastoma, and leukemia. We used physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of nutlin-3a in the mouse. Plasma protein binding and blood partitioning were assessed by in vitro studies. After intravenous (10 and 20 mg/kg) and oral (50, 100, and 200 mg/kg) dosing, tissue concentrations of nutlin-3a were determined in plasma, liver, spleen, intestine, muscle, lung, adipose, bone marrow, adrenal gland, brain, retina, and vitreous fluid. The PBPK model was simultaneously fit to all pharmacokinetic data using NONMEM. Nutlin-3a exhibited nonlinear binding to murine plasma proteins, with the unbound fraction ranging from 0.7 to 11.8%. Nutlin-3a disposition was characterized by rapid absorption with peak plasma concentrations at approximately 2 h and biphasic elimination consistent with a saturable clearance process. The final PBPK model successfully described the plasma and tissue disposition of nutlin-3a. Simulations suggested high bioavailability, rapid attainment of steady state, and little accumulation when administered once or twice daily at dosages up to 400 mg/kg. The final model was used to perform simulations of unbound tissue concentrations to determine which dosing regimens are appropriate for preclinical models of several pediatric malignancies.
Serum β-CTX and P1NP levels were negatively correlated with BMD. β-CTX was significantly higher in postmenopausal women with sustained fracture or vertebral fracture. Vitamin D deficiency was highly prevalent in postmenopausal women in Beijing.
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