Chen G.,Baylor College of Medicine |
Chen G.,Shuguang Hospital |
Lin S.-C.,Baylor College of Medicine |
Chen J.,Baylor College of Medicine |
And 9 more authors.
Journal of the American Society of Nephrology | Year: 2011
Although fibroblasts are responsible for the production and deposition of extracellular matrix in renal fibrosis, their origin is controversial. Circulating fibroblast precursors may contribute to the pathogenesis of renal fibrosis, but the signaling mechanisms underlying the recruitment of bone marrow-derived fibroblast precursors into the kidney in response to injury are incompletely understood. Here, in the unilateral ureteral obstruction model of renal fibrosis, tubular epithelial cells upregulated the chemokine CXCL16 in obstructed kidneys, and circulating fibroblast precursors expressed the CXCL16 receptor, CXCR6. Compared with wild-type mice, CXCL16-knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors in obstructed kidneys. CXCL16-knockout mice also exhibited significantly fewer CD45-, collagen I-, and CXCR6-triple-positive fibroblast precursors in injured kidneys. Furthermore, targeted deletion of CXCL16 inhibited myofibroblast activation, reduced collagen deposition, and suppressed expression of collagen I and fibronectin. In conclusion, CXCL16 contributes to the pathogenesis of renal fibrosis by recruiting bone marrow-derived fibroblast precursors. Copyright © 2011 by the American Society of Nephrology.
Liu C.,Shuguang Hospital |
Liu C.,Shanghai University of Traditional Chinese Medicine |
Tao Q.,Shuguang Hospital |
Sun M.,Shuguang Hospital |
And 7 more authors.
Laboratory Investigation | Year: 2010
Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMN- and CCL4-treated rats. Confocal microscopy analysis showed that CD68-positive KCs, but not α-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN- and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-α (TNF-α) and KC co-localized in the liver in the neighbor of HSCs. The double α-SMA- and collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for α-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models. © 2010 USCAP, Inc All rights reserved.
Zhong Y.,University of Tennessee at Knoxville |
Zhong Y.,Shuguang Hospital |
Krisanapun C.,University of Tennessee at Knoxville |
Krisanapun C.,Srinakharinwirot University |
And 5 more authors.
European Journal of Cancer | Year: 2010
Persuasive epidemiological and experimental evidence suggests that dietary flavonoids have anti-cancer activity. Since conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of most cancer types, including colorectal neoplasia, there is an urgent need to develop alternative approaches for the management of cancer. We sought to develop the best flavonoids for the inhibition of cell growth, and apigenin (flavone) proved to be the most promising compound in colorectal cancer cell growth arrest. Subsequently, we found that pro-apoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21) were induced in the presence of apigenin, and kinase pathways, including PKCδ and ataxia telangiectasia mutated (ATM), play an important role in activating these proteins. The data generated by in vitro experiments were confirmed in an animal study using APC MIN+ mice. Apigenin is able to reduce polyp numbers, accompanied by increasing p53 activation through phosphorylation in animal models. Our data suggest apparent beneficial effects of apigenin on colon cancer. © 2010 Elsevier Ltd. All rights reserved.
Lin X.,China University of Technology |
Lin X.,Shanghai University of Traditional Chinese Medicine |
Wang S.,China University of Technology |
Jiang Y.,Shuguang Hospital |
And 5 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2010
Radix Ophiopogonis polysaccharide (ROP), a natural graminan-type fructan with Mw of ∼5. kDa, had been found to have an excellent anti-myocardial ischemic activity. However, its rapid renal excretion following administration remarkably limits its efficacy and clinical use, which makes necessary the development of an effective delivery system. In this article, the feasibility of PEGylation to solve this problem was examined. A moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG was chosen to PEGylate ROP. Five different mPEG-ROP conjugates (with mPEG of molecular mass 2, 5 or 20. kDa) were prepared, purified, characterized and evaluated in pharmacokinetics and in vitro bioactivity. Results showed that only when the apparent molecular weight of the conjugate approached to a certain value, would its plasma elimination reduce abruptly. In general, the conjugation caused the reduction in the bioactivity of ROP; however, well-preserved bioactivity was observed when the grafting degree of the conjugate was lower. Among the five conjugates studied, the one with an average 1.3 mPEG (20. kDa) residues per single ROP was found to be satisfactory both in plasma retention and in bioactivity. It had a 47.4-fold increased elimination half-life and preserved approximately 74% of the bioactivity of ROP; moreover, the decrease in bioactivity is not significant. These findings demonstrate that PEGylation would be a promising approach for improving the clinical efficacy of ROP by prolonged retention in plasma. © 2010 Elsevier B.V.
Yang J.,Baylor College of Medicine |
Lin S.-C.,Baylor College of Medicine |
Chen G.,Baylor College of Medicine |
Chen G.,Huazhong University of Science and Technology |
And 6 more authors.
Journal of the American Society of Nephrology | Year: 2013
Bone marrow-derived fibroblasts may contribute substantially to the pathogenesis of renal fibrosis through the excessive production and deposition of extracellular matrix. However, the mechanisms underlying the accumulation and activation of these fibroblasts are not understood. Here, we used a mouse model of tubulointerstitial fibrosis to determine whether adiponectin, which is elevated in CKD and is associated with disease progression, regulates monocyte-to-fibroblast transition and fibroblast activation in injured kidneys. In wild-type mice, the expression of adiponectin and the number of bone marrow-derived fibroblasts in the kidney increased after renal obstruction. In contrast, the obstructed kidneys of adiponectin-knockout mice had fewer bone marrow-derived fibroblasts. Adiponectin deficiency also led to a reduction in the number ofmyofibroblasts, the expression of profibrotic chemokines and cytokines, and the number of procollagen-expressing M2 macrophages in injured kidneys. Consistent with these findings, adiponectin-deficiency reduced the expression of collagen I and fibronectin. Similar results were observed in wild-type and adiponectin-knockout mice after ischemia-reperfusion injury. In cultured bone marrow-derived monocytes, adiponectin stimulated the expression of a-smooth muscle actin (SMA) and extracellular matrix proteins and activated AMP-activated protein kinase (AMPK) in a time- and dose-dependent manner. Furthermore, specific activation of AMPK increased the expression of α-SMA and extracellular matrix proteins, while inhibition of AMPK attenuated these responses. Taken together, these findings identify adiponectin as a critical regulator of monocyte-to-fibroblast transition and renal fibrosis, suggesting that inhibition of adiponectin/AMPK signaling may represent a novel therapeutic target for fibrotic kidney disease. Copyright © 2013 by the American Society of Nephrology.
Yu F.,Changzheng Hospital |
Yu F.,No 98 Hospital Of Pla |
Miao J.,Shuguang Hospital |
Liao X.,Changzheng Hospital |
And 3 more authors.
European Spine Journal | Year: 2013
Study design: A retrospective review of prospectively collected data in an academic institution. Objective: To evaluate the safety and efficacy of a new type of titanium mesh cage (TMC) in single-level, anterior cervical corpectomy and fusion (ACCF). Methods: Fifty-eight patients consecutive with cervical spondylotic myelopathy (CSM) from cervical degenerative spondylosis and isolated ossification of the posterior longitudinal ligament were treated with a single-level ACCF using either a new type of TMC (28 patients, group A) or the traditional TMC (30 patients, group B). We evaluated the patients for TMC subsidence, cervical lordosis (C2-C7 Cobb and Cobb of fused segments) and fusion status for a minimum of 30 months postoperatively based on spine radiographs. In addition, neurologic outcomes were evaluated using the Japanese Orthopedic Association (JOA) scores. Neck pain was evaluated using a 10-point visual analog scale (VAS). Results: The loss of height of the fused segments was less for group A than for group B (0.8 ± 0.3 vs. 2.8 ± 0.4 mm) (p < 0.01); also, there was a lower rate of severe subsidence (≥3 mm) in group A (4 %, 1/28) than in group B (17 %, 5/30) (p < 0.01). There were no differences in the C2-C7 Cobb and Cobb of fused segments between the groups preoperatively or at final follow-up (p > 0.05), but the Cobb of fused segments immediately postoperative were significantly less for group B than for group A (p < 0.01). All patients, however, had successful fusion (100 %, each). Both groups had marked improvement in the JOA score after operation (p < 0.01), with no significant differences in the JOA recovery ratio (p > 0.05). The postoperative VAS neck pain scores for group A were significantly less than that for group B (p < 0.05); severe subsidence was correlated with neck pain. Conclusions: The new type of TMC provides comparable clinical results and fusion rates with the traditional TMC for patients undergoing single-level corpectomy. The new design TMC decreases postoperative subsidence (compared to the traditional TMC); the unique design of the new type of TMC matches the vertebral endplate morphology which appears to decrease the severity of subsidence-related neck pain in follow-up. © 2013 Springer-Verlag Berlin Heidelberg.
Yang J.,Baylor College of Medicine |
Yang J.,Huazhong University of Science and Technology |
Chen J.,Baylor College of Medicine |
Yan J.,Baylor College of Medicine |
And 4 more authors.
PLoS ONE | Year: 2012
Our recent studies have shown that bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying the recruitment and activation of bone marrow-derived fibroblast precursors are incompletely understood. We found that interleukin 6 was induced in the kidney in a murine model of renal fibrosis induced by unilateral ureteral obstruction. Therefore, we investigated if interleukin 6 play a role in the recruitment and maturation of bone marrow-derived fibroblast precursors in the kidney during the development of renal fibrosis. Wild-type and interleukin 6 knockout mice were subjected to unilateral obstructive injury for up to two weeks. Interleukin 6 knockout mice accumulated similar number of bone marrow-derived fibroblast precursors and myofibroblasts in the kidney in response to obstructive injury compared to wild-type mice. Furthermore, IL-6 knockout mice expressed comparable α-SMA in the obstructed kidney compared to wild-type mice. Moreover, targeted disruption of Interleukin 6 did not affect gene expression of profibrotic chemokine and cytokines in the obstructed kidney. Finally, there were no significant differences in renal interstitial fibrosis or expression of extracellular matrix proteins between wild-type and interleukin 6 knockout mice following obstructive injury. Our results indicate that interleukin 6 does not play a significant role in the recruitment of bone marrow-derived fibroblast precursors and the development of renal fibrosis. © 2012 Yang et al.
PubMed | Pudong Hospital of Traditional Chinese Medicine, Shuguang Hospital and Shanghai University of Traditional Chinese Medicine
Type: | Journal: Evidence-based complementary and alternative medicine : eCAM | Year: 2016
Aim. To determine one traditional Chinese medicine (TCM) Nao-Xue-Shu oral liquid which protects and improves secondary brain insults (SBI) in hypertensive cerebral hemorrhage (HCH). Methods. 158 patients with HCH were divided into routine clinical medicine plus Nao-Xue-Shu oral liquid (n = 78) as treatment group, and routine clinical medicine (n = 80) only served as the control group. The incidence of SBI and the classification of a favorable prognosis and a bad prognosis using the Glasgow outcome scale (GOS) were assessed to evaluate the clinical effects. The changes of IL-6 and TNF- levels were determined to study the mechanism of the effects for the TCM. Results. The incidence of SBI at the end of week 2 was 8.97% in the treatment group and 23.75% in the control group, and the difference was significant (P < 0.001). The incidence of a favorable prognosis was 48.72% in the treatment group and 32.72% in the control group, and the difference was significant (P < 0.01) at the end of week 2. These findings indicate clear differences for IL-6 and TNF- at the end of week 1 and week 2 compared with before treatment for the treatment group and a marked difference at the end of week 2 between the two groups. It also shows a significant difference between the end of week 2 and before treatment for IL-6 and TNF- for the control group, although the difference was much smaller than the treatment group. Conclusion. Nao-Xue-Shu oral liquid could protect against the occurrence of SBI and improve HCH and SBI patients. It may also decrease the damage and the mass effects of the hematoma by reducing IL-6 and TNF- to obtain the effects, and thus it is a potentially suitable drug for HCH and SBI.
PubMed | Shuguang Hospital and Baylor College of Medicine
Type: Journal Article | Journal: American journal of physiology. Heart and circulatory physiology | Year: 2016
Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration.
PubMed | Astrazeneca and Shuguang Hospital
Type: Clinical Trial, Phase I | Journal: Clinical drug investigation | Year: 2016
Avibactam is a non--lactam -lactamase inhibitor that restores the in vitro activity of -lactams, such as ceftazidime, against bacterial pathogens harboring Ambler class A, C, and some class D -lactamases.This randomized, double-blind, placebo-controlled, phase I study (NCT01920399) evaluated the safety, tolerability, and pharmacokinetics of single and repeated doses of avibactam and ceftazidime in healthy Chinese subjects.Sixteen healthy Chinese males aged 18-45 years were randomized 3:1 to receive 2000 mg ceftazidime and 500 mg avibactam (n = 12) or matched placebo (n = 4) as a 120-min intravenous infusion, once on Days 1 and 9, and every 8 h on Days 2-8.Avibactam and ceftazidime showed time-independent pharmacokinetics. Plasma exposure to avibactam and ceftazidime was similar following single and multiple dosing and accumulation of either agent was negligible. The majority of the avibactam and ceftazidime dose was recovered in urine. Adverse events were reported in three subjects (25.0%) in the ceftazidime-avibactam group and one subject (25.0%) in the placebo group. Two subjects in the ceftazidime-avibactam group had elevations in transaminases and one subject in the placebo group had elevated serum bilirubin levels that were considered causally related to study treatment. All adverse events were of mild intensity.Single and multiple doses of 2000 mg ceftazidime and 500 mg avibactam were well tolerated in healthy Chinese subjects, and the observed pharmacokinetics were comparable to previous studies conducted in Western subjects.