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1.
Life Sci ; 253: 117683, 2020 Jul 15.
Article in English | MEDLINE | ID: mdl-32315727

ABSTRACT

OBJECTIVE: To explore the potential mechanism of KMUP-1 in the vascular calcification of chronic renal failure (CRF) through mediating NO/cGMP/PKG pathway, and provide novel insights into the CRF treatment. METHODS: CRF rats were treated by KMUP-1 with/without L-NNA (a NOS inhibitor) and then performed by ELISA, alizarin red staining, Von Kossa staining, Masson's trichrome, Sirius red staining and CD3 immunohistochemical staining. Simultaneously, vascular smooth muscle cells (VSMCs) were collected from rats to confirm the effect of KMUP-1 on vascular calcification in vitro via NO/cGMP/PKG pathway. Besides, protein and mRNA expressions were determined via Western blotting and qRT-PCR, respectively. RESULTS: CRF rats were elevated in 24-h urine protein, blood urea nitrogen (BUN), serum creatinine, Cys-C levels and inflammatory cytokines. Besides, CRF rats also showed increased calcium content and ALP level with up-regulated mRNA of osteogenic differentiation-related markers. Furthermore, the up-regulated expressions of eNOS and PKG, as well as down-regulated levels of NOx and cGMP were also found in CRF rats. However, renal failure and vascular calcification of CRF were improved significantly by KMUP-1 treatment via activation of NO/cGMP/PKG pathway. Moreover, KMUP-1 treatment attenuated calcified VSMCs, accompanied by the decreases in the calcified nodules, level of calcium and activity of ALP. In addition, either L-NNA treatment for CRF rats or the calcified VSMCs could antagonize the improving effect of KMUP-1. CONCLUSION: KMUP-1 can improve the renal function and vascular calcification in CRF rats at least in part by activating NO/cGMP/PKG pathway.


Subject(s)
Kidney Failure, Chronic/drug therapy , Myocytes, Smooth Muscle/drug effects , Piperidines/pharmacology , Vascular Calcification/drug therapy , Xanthines/pharmacology , Animals , Calcium/metabolism , Cyclic GMP/metabolism , Cyclic GMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Kidney Failure, Chronic/physiopathology , Male , Myocytes, Smooth Muscle/pathology , Nitric Oxide/metabolism , Osteogenesis/drug effects , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Vascular Calcification/pathology
2.
Lab Invest ; 94(8): 839-50, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24862968

ABSTRACT

Peritoneal fibrosis is a complication of patients with long-term continuous ambulatory peritoneal dialysis (CAPD). Reports have indicated that angiotensin (Ang) II may correlate with the development of peritoneal fibrosis. However, it is unknown whether aldosterone also has a role in the development of peritoneal inflammation and fibrosis. The aim of the present study was to clarify the role of aldosterone in peritoneal inflammation and fibrosis. A rat model of peritoneal inflammation and fibrosis was established by daily intraperitoneal injection of dialysates and lipopolysaccharide in a 4-day interval over a period of 7 days. The animals were randomly assigned to five groups as follows: control (C); peritoneal dialysis (PD); peritoneal dialysis-spironolactone (PD-S); peritoneal dialysis-cilazapril (PD-C); and peritoneal dialysis-spironolactone-cilazapril (PD-SC). After 30 days, the TGF-ß1 concentration in dialysates from all treatment groups was determined by ELISA. The histopathology of the parietal peritoneum was examined, and the expression of MCP-1, c-Jun, fibronectin (FN) and TGF-ß1 in the abdominal membrane was determined by immunohistochemistry. Mineralocorticoid receptor (MR), 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) and CYP11B2 (aldosterone synthase) were analyzed by real time-PCR. Collagen deposition was significantly higher in PD compared with the other groups. The expression of MR, 11ß-HSD2 and CYP11B2 was significantly higher in PD compared with the other groups. Spironolactone and/or cilazapril treatment partially ablated the increase in monocyte chemoattractant protein (MCP)-1, p-c-Jun, transforming growth factor (TGF)-ß1, FN, MR, 11ß-HSD2 and CYP11B2. Furthermore, treatment with spironolactone and/or cilazapril also reduced the infiltration of CD-4- and ED-1-positive cells in rat peritoneal tissues after peritoneal fibrosis. Exogenous aldosterone may have a key role in the development of peritoneal inflammation and fibrosis. Spironolactone decreased peritoneal inflammation and fibrosis, which was associated with reduced secretion from peritoneal macrophages, inactivation of the c-Jun N-terminal kinase (JNK) pathway and subsequent downregulation of the expression of TGF-ß1.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Disease Models, Animal , Mineralocorticoid Receptor Antagonists/therapeutic use , Peritoneal Fibrosis/prevention & control , Peritoneum/drug effects , Peritonitis/prevention & control , Spironolactone/therapeutic use , Aldosterone/chemistry , Aldosterone/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Cilazapril/therapeutic use , Dialysis Solutions/chemistry , Drug Therapy, Combination , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/pathology , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Male , Peritoneal Dialysis, Continuous Ambulatory/adverse effects , Peritoneal Fibrosis/etiology , Peritoneal Fibrosis/immunology , Peritoneal Fibrosis/pathology , Peritoneum/immunology , Peritoneum/metabolism , Peritoneum/pathology , Peritonitis/etiology , Peritonitis/immunology , Peritonitis/pathology , Random Allocation , Rats , Rats, Wistar , Receptors, Mineralocorticoid/chemistry , Receptors, Mineralocorticoid/metabolism , Transforming Growth Factor beta1/analysis , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/metabolism
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 20(4): 965-70, 2012 Aug.
Article in Chinese | MEDLINE | ID: mdl-22931665

ABSTRACT

This study was aimed to investigate the prophylactic effect of Toll like receptor (TLR)5 agonist flagellin on acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its possible mechanism. The animal model with allo-HSCT aGVHD was established by using purebred mice (male mouse C57BL/6 as donor, female mouse BALB/c as recipient) with complete-unidentical major histocompatibility antigen. The recipient mice were randomly divided into 3 groups: group 1 in which mice were injected with high purity (95%) flagellin before and after allo-HSCT respectively, group 2 in which mice received allo-HSCT without injection of flagellin, group 3 in which mice were radiated alone. The aGVHD features of mice in group 1 and 2 were observed and compared. The results showed that the typical symptoms of aGVHD appeared in transplanted mice. The death peak of mice in group 2 appeared at day 4-5 after transplantation. The aGVHD symptoms were obviously alleviated and the mean survival time was prolonged significantly in mice group 1 as compared with mice in group 2 (P < 0.05). The comparison of WBC count in peripheral blood of mice in 3 groups before transplantation showed no significant difference (P > 0.05), while WBC count of mice in group 1 and 2 showed the significant difference at days 14 and 21 after transplantation (P < 0.05). The pathological appearances of aGVHD in mice of group 1 were obviously reduced as compared with mice in group 2. The flow cytometric detection of Treg cell/CD4(+) T cell levels at different time before and after transplantation demonstrated that the Treg cell level in mice of group 1 at weeks 2-4 after transplantation significantly increased as compared with mice in group 2 (P < 0.05). It is concluded that flagellin can effectively prevent the aGVHD occurrence after allo-HSCT, reduce the symptoms and pathological changes of aGVHD, obviously prolong mean survival time of mice in group 1. The mechanism of flagellin effect may be associated to increase of Treg cell level in mice after allo-HSCT.


Subject(s)
Flagellin/therapeutic use , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Animals , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes, Regulatory , Toll-Like Receptor 6/agonists , Transplantation, Homologous
4.
Cancer Biol Med ; 9(4): 261-5, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23691487

ABSTRACT

OBJECTIVE: The present study aims to find a convenient, rapid, and stable method to establish bladder tumor in mice. METHODS: Female Balb/C-nu-nu nude mice (or female T739 mice) were narcotized by sodium pentobarbital at a dosage of 60 mg/kg. The stylet of the 24# venous retention needles was bent in a 5° to 7° angle at a distance of 15 mm from the needlepoint to form a circle with 2.61 mm to 3.66 mm radius when the stylet is rotated. The pipe casing was lubricated with liquid paraffin, and inserted into the bladder cavity. The drift angle stylet was inserted into the pipe casing slowly, rotated for five times, and then pulled out. A cell suspension (0.1 mL) of approximately 1×10(6) T24 cells (or BTT cells) was then injected immediately. RESULTS: A total of 60 T739 mice and 60 Balb/C-nu-nu nude mice were inoculated with BTT cells and T24 cells, respectively. The bladder tumor incidence and the average survival time of the tumor-bearing mice were 100% and (26.69±9.24) d and 100% and (34.59±9.8) d for the T739 mice and Balb/C-nu-nu nude mice, respectively. CONCLUSIONS: Using the drift angle stylet to injure the mucous membrane of the urinary bladder can establish a stable bladder transplantable tumor model in mice.

5.
Zhonghua Nan Ke Xue ; 15(2): 153-7, 2009 Feb.
Article in Chinese | MEDLINE | ID: mdl-19323377

ABSTRACT

OBJECTIVE: To study the different features of hyperplasia in castrated and uncastrated mice after testosterone (T) treatment. METHODS: Forty-eight BALB/c mice were randomly divided into 6 groups of 8 in each: castrated (A), uncastrated (B) , castrated + low T (C), uncastrated + low T (D), castrated + high T (E), uncastrated + high T (F). Groups C and D were treated with testosterone solution at the dose of 12.5 mg/(kg d) and Groups E and F at 125 mg/(kg d) for 20 consecutive days, while Groups A and B received saline only. All the mice were sacrificed on the 21st day, their ventral and dorsal prostate glands weighed and their pathological features studied. RESULTS: Atrophic prostates were observed in Group A, but normal in Group B; prostatic hyperplasia was found in both Group C and D, but more obvious in the latter (P <0.05); and a slightly higher degree of hyperplasia was noted in Groups E and F than in C and D. There was an increase in serum T and vascular endothelial growth factor (VEGF) concentration and a decrease in serum estrogen (E2) concentration in the testosterone treated groups. CONCLUSION: Both castrated and uncastrated mice develop prostate hyperplasia after short-term testosterone treatment, although in different degrees and with different features, which may help further the studies on the association of castration and androgen with prostate diseases.


Subject(s)
Prostate/pathology , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/pathology , Testosterone/therapeutic use , Animals , Hyperplasia , Male , Mice , Mice, Inbred BALB C , Orchiectomy
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