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ABSTRACT: SCOPE: Hydroxytyrosol (HT), a main phenolic compound in olive oil, has been proved to be a potent antioxidant and has beneficial effects on health. However, the effect of HT on oxidative liver damage, as seen in ischemia/reperfusion (I/R) injury, is unknown. Here, we examined whether HT could protect liver against I/R injury. METHODS AND RESULTS: By using a mouse model, we found that HT administration protects against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and less parenchymal necrosis and apoptosis. Serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein 2, as well as reactive oxygen species (ROS) content in liver tissues, were all decreased by HT, the latter correlated with the reduction of hepatic malondialdehyde (an index of oxidative stress) content and increased activities and expressions of liver antioxidant enzymes superoxide dismutase and catalase. The protective effect was also seen in isolated hepatocytes anoxia/reoxygenation assay. CONCLUSION: HT exerts protective effects against hepatic I/R injury in mice, which might be associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties. HT may be an effective hepatoprotective agent and a promising candidate for the treatment of liver I/R injury.
Molecular Nutrition & Food Research 05/2013; · 4.30 Impact Factor
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Huayang Pan,
Yong Ma,
Dawei Wang,
Jizhou Wang,
Hongchi Jiang,
Shangha Pan,
Baolei Zhao,
Yaohua Wu,
Dongsheng Xu, Xueying Sun,
Lianxin Liu,
Zhilin Xu
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ABSTRACT: The spleen is a crucial lymphoid organ. It is involved in the recruitment of various immunocytes to their correct locations using specific chemokines, but little is known concerning the role of type-I interferon (IFN) in the regulation of chemokines. In this study, we first used protein microarrays to assess the expression of keratinocyte-derived chemokine (KC) and lipopolysaccharide-induced CXC chemokine (LIX) in murine spleens. Both expressions were smoothly enhanced by IFN-α pretreatment after LPS injection. Then, we focused on the IFN-α regulation of KC, LIX, and their target cells, neutrophils, using an IFN-α neutralizing antibody and fludarabine (specific signal transducers and activators of transcription 1 - STAT1 inhibitor). Next, LPS was found to attenuate the production of KC and LIX in spleen. Even the elevated production of chemokines caused by exogenous IFN-α was found to be attenuated by fludarabine pretreatment. We later determined that the marginal zone and red pulp are the main sites of KC and LIX production. Last, we determined that the number of neutrophils was slightly increased by IFN-α treatment and diminished by IFN-α neutralization or fludarabine treatment. Further, the elevated neutrophils due to exogenous IFN-α were partially reversed by fludarabine pretreatment. In this way, these results indicate that IFN-α facilitates KC and LIX expression in mouse spleens after an LPS challenge. This effect was found to be mainly dependent upon the activation of STAT1, it may be involved in the recruitment of neutrophils to the spleen for the clearance of pathogens.
Molecular Immunology 05/2013; 56(1-2):12-22. · 2.90 Impact Factor
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ABSTRACT: Here we describe an entirely new class of cell-penetrating peptide (CPP) represented by the short peptide Xentry (LCLRPVG) derived from an N-terminal region of the X-protein of the hepatitis B virus. Xentry permeates adherent cells using syndecan-4 as a portal for entry, and is uniquely restricted from entering syndecan-deficient, non-adherent cells, such as resting blood cells. Intravenous injection of Xentry alone or conjugated to β-galactosidase led to its delivery to most tissues in mice, except circulating blood cells. There was a predilection for uptake by epithelia. Anti-B-raf antibodies and siRNAs linked to Xentry were capable of killing B-raf-dependent melanoma cells. Xentry represents a new class of CPP with properties that are potentially advantageous for life science and therapeutic applications.
Scientific Reports 04/2013; 3:1661.
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ABSTRACT: The interleukin-6 (IL-6)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway mediates cell proliferation and migration. S-phase kinase-associated protein-2 (Skp2) catalyzes the ubiquitylation of p27 and p21. Here we investigated that the cross-talk of the two pathways regulates motility and invasion of gastric cancer SGC7901 and MGC803 cells. Both cell lines endogenously secret IL-6, and blockage of IL-6 or JAK2 inhibited the activation of JAK2 and STAT3. Depletion of STAT3 downregulated Skp2 expression, and thereby increased the expression of p27 and p21. Depletion of STAT3 inhibited the ability of cells to migrate and invade, and impaired cellular cytoskeleton mainly microtubules; while depletion of p27 partially restored the impaired ability to migrate, and reversed the impaired microfilaments, further inhibited the ability to invade, but had little effect on microtubules and cellular adhering ability, of STAT3-depleted cells. STAT3 depletion inhibited the activity of RhoA and the interaction with stathmin, downregulated expression of pFAK (phosphorylated focal adhesion kinase), acetylated-tubulin, RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and Sp1, upregulated E-cadherin, and reduced activities of MMP (matrix metalloproteinase)-2 and -9. Depletion of p27 increased RhoA (Ras homolog family member A) activity, upregulated RECK, and downregulated E-cadherin and Sp1. The results indicate that the interaction between STAT3 and Skp2/p27/p21 pathway plays an important role in mediating the motility, migration and invasion of gastric cancer cells, and inhibition of STAT3 may be a useful therapeutic approach for metastasis of gastric cancer, but cautions need to be taken for its effects on Skp2/p27/p21 pathway.
Cellular signalling 01/2013; · 4.09 Impact Factor
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Peng Xiu,
Xuesong Dong,
Xiaofeng Dong,
Zongzhen Xu,
Huaqiang Zhu,
Feng Liu,
Zheng Wei,
Bo Zhai,
Jagat R Kanwar,
Hongchi Jiang,
Jie Li, Xueying Sun
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ABSTRACT: Secretory clusterin (sCLU) is expressed in numerous cancers and associated with the resistance to chemotherapy. However, the role of sCLU in the resistance of hepatocellular carcinoma (HCC) to oxaliplatin (OXA), a recently used third-generation platinum agent, remains unclear. The stable transfectants that are depleted of or overexpress sCLU, and OXA-resistant cells were generated using human HCC cells. Overexpression of sCLU abrogated OXA-induced inhibition of cell growth and cell apoptosis, but depletion of sCLU synergized with OXA to inhibit cell growth and enhance cell apoptosis, by regulating proteins involved in mitochondrial apoptosis pathways, such as Bcl-2, Bax, Bcl-xL and caspase-9, and affecting phosphorylation of Akt and GSK-3β. Overexpression of sCLU in either OXA-resistant cells or stable transfectants that overexpress sCLU significantly increased phosphorylated Akt. However, specific inhibition of Akt enhanced sensitivity of sCLU-overexpressing cells to OXA, but had no effect on sCLU expression, suggesting that the regulatory effects between sCLU and pAkt may be in a one-way manner in HCC cells. The expression levels of sCLU affected the therapeutic efficacy of OXA to treat HCC tumors established in immunodeficiency mice. The results have demonstrated that sCLU contributes to OXA resistance by activating Akt pathway, indicating that sCLU may be a novel molecular target for overcoming OXA resistance in HCC.
Cancer Science 12/2012; · 3.33 Impact Factor
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ABSTRACT: BACKGROUND: Tamoxifen is used in hormone therapy for estrogen-receptor (ER)-positive breast cancer, but also has chemopreventative effects against ER-negative breast cancers. This study sought to investigate whether oral iron-saturated bovine lactoferrin (Fe-Lf), a natural product which enhances chemotherapy, could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers. METHODS: In a model of breast cancer prevention, female Balb/c mice treated with tamoxifen (5 mg/Kg) were fed an Fe-Lf supplemented diet (5 g/Kg diet) or the base diet. At week 2, 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad. In a model of breast cancer treatment, tamoxifen treatment was not started until two weeks following tumour cell injection. Tumour growth, metastasis, body weight, and levels of interleukin 18 (IL-18) and interferon gamma (IFN-gamma) were analyzed. RESULTS: Tamoxifen weakly (IC50 ~ 8 muM) inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro. In the tumor prevention study, a Fe-Lf diet in combination with tamoxifen caused a 4 day delay in tumor formation, and significantly inhibited tumor growth and metastasis to the liver and lung by 48, 58, and 66% (all P < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-gamma, and intestinal cells expressing IL-18 and IFN-gamma. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors. CONCLUSIONS: The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors.
BMC Cancer 12/2012; 12(1):591. · 3.01 Impact Factor
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Zheng Wei,
Xian Jiang,
Fengjun Liu,
Haiquan Qiao,
Baoguo Zhou,
Bo Zhai,
Lianfeng Zhang,
Xuwen Zhang,
Likun Han,
Hongchi Jiang,
Geoffrey W Krissansen, Xueying Sun
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ABSTRACT: S-phase kinase-associated protein-2 (Skp2) is overexpressed in human cancers and associated with poor prognosis. Skp2 acts as an oncogenic protein by enhancing cancer cell growth and tumor metastasis. The present study has demonstrated that small hairpin RNA (shRNA)-mediated downregulation of Skp2 markedly inhibits the viability, proliferation, colony formation, migration, invasion, and apoptosis of human gastric cancer MGC803 cells, which express a high level of Skp2. In contrast, Skp2 shRNA had only a slight effect on the above properties of BGC823 cells, which express a low level of Skp2. In accord, knockdown of Skp2 suppressed the ability of MGC803 cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors, by inhibiting cell proliferation and enhancing cell apoptosis. In contrast, overexpression of Skp2 promoted tumorigenesis of BGC823 cells in mice. Skp2 depletion induced cell cycle arrest in the G(1)/S phase by upregulating p27, p21, and p57 and downregulating cyclin E and cyclin-dependent kinase 2. Skp2 depletion also increased caspase-3 activity, impeded the ability of cells to form filopoidia and locomote, upregulated RECK (reversion-inducing cysteine-rich protein with kazal motifs), and downregulated matrix metalloproteinase (MMP)-2 and MMP-9 activity and expression. The results suggest that downregulating Skp2 warrants investigation as a promising strategy to treat gastric cancers that express high levels of Skp2.
Tumor Biology 12/2012; · 1.94 Impact Factor
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Dawei Wang,
Yong Ma,
Zhengtian Li,
Kai Kang, Xueying Sun,
Shangha Pan,
Jizhou Wang,
Huayang Pan,
Lianxin Liu,
Desen Liang,
Hongchi Jiang
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ABSTRACT: Hydrogen sulphide (H 2S) exerts a protective effect in hepatic ischemia-reperfusion (I/R) injury. However, the exact mechanism of H 2S action remains largely unknown. This study was designed to investigate the role of the PtdIns3K-AKT1 pathways and autophagy in the protective effect of H 2S against hepatic I/R injury. Primary cultured mouse hepatocytes and livers with or without NaHS (a donor of H 2S) preconditioning were exposed to anoxia/reoxygenation (A/R) and I/R, respectively. In certain groups, they were also pretreated with LY294002 (AKT1-specific inhibitor), 3-methyladenine (3MA, autophagy inhibitor) or rapamycin (autophagy enhancer), alone or simultaneously. Cell viability, expression of P-AKT1, T-AKT1, LC3 and BECN1 were examined. The severity of liver injury was measured by the levels of serum aminotransferase and inflammatory cytokine, apoptosis and histological examination. GFP-LC3 redistribution and transmission electron microscopy were used to test the activity of autophagy. H 2S preconditioning activated PtdIns3K-AKT1 signaling in hepatocytes. LY294002 could abolish the AKT1 activation and attenuate the protective effect of H 2S on hepatocytes A/R and hepatic I/R injuries. H 2S suppressed hepatic autophagy in vitro and in vivo. Further reducing autophagy by 3MA also diminished the protective effect of H 2S, while rapamycin could reverse the autophagy inhibitory effect and enhance the protective effect of H 2S against hepatocytes A/R and hepatic I/R injuries, consequently. Taken together, H 2S protects against hepatocytic A/R and hepatic I/R injuries, at least in part, through AKT1 activation but not autophagy. An autophagy agonist could be applied to potentiate this hepatoprotective effect by reversing the autophagy inhibition of H 2S.
Autophagy 06/2012; 8(6):954-62. · 7.45 Impact Factor
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ABSTRACT: Pluronic F127 (PF-127) shows thermoreversible property, which is of the utmost interest in optimizing drug formulation and delivery. However, its hitherto unresolved drawback of a low phase transition temperature (T (tr)) has limited its application in injectable drug delivery systems. We have recently synthesized a new type of PF-127 copolymers with higher T (tr) using a simple oxidative method. Here, we have investigated the drug-releasing feature of oxidized PF-127 and oxidized PF-127-containing silver nanoparticles (SNPs), carrying arsenic trioxide (ATO), in a subcutaneous model of rats. Injectable hydrogels prepared with oxidized PF-127s were less viscous and easier to inject, at the same concentration, than their precursor. Addition of SNPs further elevated T (tr), resulting in even lower viscosity of the injectable hydrogel prepared from SNP-containing oxidized PF-127. The oxidized PF-127 copolymers did not differ significantly in ATO-releasing ability, compared with parental PF-127, but the addition of SNPs altered the ATO-releasing feature of oxidized PF-127 to some extent. ATO-carrying oxidized PF-127s had similar toxicity, but the addition of SNPs enhanced the hepatotoxicity of ATO, as evidenced by elevated serum levels of alanine aminotransferase and aspartate aminotransferase and histological alterations, compared to parental PF-127. The results presented herein warrant further investigation of the modified PF-127 copolymers to deliver ATO or other drugs in the form of injectable hydrogels.
AAPS PharmSciTech 02/2012; 13(2):441-7. · 1.43 Impact Factor
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Dongsheng Fei,
Xianglin Meng,
Mingran Zhao,
Kai Kang,
Gang Tan,
Shangha Pan,
Yunpeng Luo,
Wen Liu,
Chuanchuan Nan,
Hongchi Jiang,
Geoffrey W Krissansen,
Mingyan Zhao, Xueying Sun
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ABSTRACT: Heme oxygenase-1 (HO-1) displays anti-inflammatory and cytoprotective activities in sepsis. Here, we investigated the effects of HO-1 on thrombus formation and the protein C system in a septic C57BL/6 mouse model induced by cecal ligation and perforation (CLP). Septic mice were either preinjected with the vehicle, pretreated with hemin (an HO-1 inducer) or zinc protoporphyrin IX (ZnPP, an HO-1 inhibitor), or given a combination of hemin + ZnPP. CLP increased significantly the hepatic expression of HO-1; increased thrombosis in livers, kidneys, and lungs; shortened the prothrombin time (PT) and activated partial thromboplastin time (APTT); elevated the levels of tumor necrosis factor-1α (TNF-1α), interleukin-6 (IL-6), and thrombomodulin (TM); reduced the levels of protein C (PC) and activated protein C (aPC); and downregulated hepatic expression of PC and TM. The preadministration of hemin to septic mice increased the expression and activity of HO-1; inhibited thrombosis in the preceding 3 organs; prolonged PT and APTT; inhibited the production of TNF-α and IL-6; upregulated the expression of PC and TM in livers; elevated the plasma levels of PC and aPC; and reduced the plasma levels of TM. In contrast, ZnPP showed opposite effects to hemin and reversed the effects of hemin by inhibiting the activity of HO-1. The administration of tricarbonyl dichloro ruthenium (II) dimer (CORM-2), which is a CO-releasing molecule, had a similar effect to hemin on thrombosis and the protein C system. The data indicate that the enhanced induction of HO-1 inhibits thrombus formation and affects the protein C system in sepsis.
Translational research : the journal of laboratory and clinical medicine. 02/2012; 159(2):99-109.
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ABSTRACT: Hydrogen sulfide (H(2)S) displays an anti-apoptotic activity against myocardial ischemia reperfusion (MIR). Apoptosis repressor with caspase recruitment domain (ARC) is constitutively expressed in the heart and inhibits cell apoptosis when it is phosphorylated. Here, we investigated whether H(2)S could inhibit apoptosis by affecting ARC phosphorylation using cultured rat cardiomyocytes and a rat model of MIR. Primary cardiomyocytes were prepared from hearts of newborn rats and were pre-incubated with NaHS, a donor of H(2)S, for 60 min. Cardiomyocytes were subjected to hypoxia for 4 h, followed by reoxygenation for 2 h. The hypoxia and subsequent reoxygenation (H/R) significantly induced cell apoptosis, increased expression levels of Fas and FasL proteins, enhanced release of cytochrome c from mitochondria, and elevated caspase-3 activity, while H/R reduced ARC phosphorylation and increased the activity of calcineurin that dephosphorylates ARC. Pre-incubation with NaHS significantly attenuated the above effects through promoting ARC phosphorylation by reducing calcineurin activity and by increasing the activity of protein kinase casein kinase II (CK2) that phosphorylates ARC. In fact, TBB, a specific inhibitor of CK2, abolished the effects of NaHS. In rats undergoing MIR, NaHS significantly reduced the myocardial infarct size, cell apoptosis, calcineurin activity, and the expression levels of Fas, FasL and cleaved caspase-3 proteins, while NaHS increased ARC phosphorylation. In contrast, DL-propargylglycine, an inhibitor of cystathionine γ-lyase, the main enzyme for H(2)S production in hearts, showed opposite effects to NaHS. The results indicate that H(2)S inhibits apoptosis of cardiomyocytes induced by MIR through enhancing ARC phosphorylation.
The Tohoku Journal of Experimental Medicine 01/2012; 226(4):275-85. · 1.24 Impact Factor
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ABSTRACT: The hypoxic microenvironment inside solid tumors, including hepatocellular carcinoma (HCC), is a major cause of tumor resistance to chemotherapy. The recently identified hypoxia-inducible factor (HIF)-2 executes the hypoxia response. Its expression feature and transcriptional targets indicate a possible dominance of HIF-2 in regulating genes in HCC. The aim of the present study was to determine whether transfection of siRNA targeting HIF-2α could enhance the efficacy of doxorubicin, the most commonly used drug in the treatment of HCC. Transfection of HIF-2 siRNA into human HCC cells downregulated the expression of HIF-2α, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-α, and cyclin D1, but had little effect on the expression of HIF-1α, fms-related tyrosine kinase-1 (Flt-1), the glucose transporter (GLUT)-1, and lactate dehydrogenase A (LDHA). Doxorubicin itself only downregulated VEGF expression. Furthermore, HIF-2 siRNA inhibited proliferation, induced cell cycle arrest at the G(0)/G(1) phase, and acted synergistically with doxorubicin to inhibit the growth of human HCC cells in vitro. Transfection of HIF-2 siRNA also downregulated tumoral expression of HIF-2α, VEGF, TGF-α, and cyclin D1 in vivo, and acted synergistically with doxorubicin to suppress the growth of HepG2 tumors established in immunodeficient mice by inhibiting cell proliferation, tumor angiogenesis and microvessel perfusion. The results of the present study suggest that targeting HIF-2α with siRNA warrants investigation as a potential strategy to enhance the efficacy of doxorubicin in the treatment of HCC.
Cancer Science 12/2011; 103(3):528-34. · 3.33 Impact Factor
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ABSTRACT: The incidence of neurological diseases of unknown etiology is increasing, including well-studied diseases such as Alzhiemer's, Parkinson's, and multiple sclerosis. The blood-brain barrier provides protection for the brain but also hinders the treatment and diagnosis of these neurological diseases, because the drugs must cross the blood-brain barrier to reach the lesions. Thus, attention has turned to developing novel and effective delivery systems that are capable of carrying drug and that provide good bioavailability in the brain. Nanoneurotechnology, particularly application of nanoparticles in drug delivery, has provided promising answers to some of these issues in recent years. Here we review the recent advances in the understanding of several common forms of neurological diseases and particularly the applications of nanoparticles to treat and diagnose them. In addition, we discuss the integration of bioinformatics and modern genomic approaches in the development of nanoparticles. FROM THE CLINICAL EDITOR: In this review paper, applications of nanotechnology-based diagnostic methods and therapeutic modalities are discussed addressing a variety of neurological disorders, with special attention to blood-brain barrier delivery methods. These novel nanomedicine approaches are expected to revolutionize several aspects of clinical neurology.
Nanomedicine: nanotechnology, biology, and medicine 08/2011; 8(4):399-414. · 5.44 Impact Factor
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ABSTRACT: Hepatic ischemia/reperfusion (HIR) injury is an unavoidable consequence of major liver surgery, during which endotoxemia often takes place. This study aimed to investigate whether matrine has a protective effect against HIR-induced liver injury aggravated by endotoxin.
Wistar rats were subjected to 30 min of HIR followed by lipopolysaccharide (LPS) (0.5 mg/kg) administration. At the indicated time points, six rats from each group (24 rats) were randomly euthanized to collect blood samples and livers.
Preadministration of matrine protected livers from injury induced by HIR+LPS as the histological score, myeloperoxidase activity and malondialdehyde contents, expression of macrophage-inflammatory protein-2, DNA-binding activity of nuclear factor κB, and serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, and nitric oxide were significantly reduced, and serum levels of interleukin-6 were further increased. HIR+LPS markedly induced cell apoptosis and necrosis, and upregulated the expression of cleaved caspase-3, Fas, and FasL. Matrine significantly reduced cell necrosis, but had a nonsignificant inhibitory effect on cell apoptosis and expression of cleaved caspase-3 and FasL CONCLUSIONS: Matrine attenuates endotoxin-induced acute liver injury after HIR mainly by its anti-inflammatory and antioxidative activities, and has little inhibitory effect on cell apoptosis.
Surgery Today 08/2011; 41(8):1075-84. · 1.22 Impact Factor
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ABSTRACT: Milk fat is a natural product containing essential nutrients as well as fatty acids and other food factors with reported anti-cancer potential. Here bovine milk fat was tested for its ability to inhibit the growth of breast and colon cancers and their metastasis to the lung and liver; either alone or in combination with the chemotherapeutic agent paclitaxel. A diet containing 5% typical anhydrous milk fat (representing ~70% of the total dietary fat component) fed to Balb/c mice delayed the appearance of subcutaneous 4T1 breast and CT26 colon cancer tumours and inhibited their metastasis to the lung and liver, when compared to the control diet containing soybean oil as the only fat component. It augmented the inhibitory effects of paclitaxel on tumour growth and metastasis, and reduced the microvessel density of tumours. It displayed no apparent organ toxicity, but instead was beneficial for well-being of tumour-bearing mice by maintaining gastrocnemius muscle and epididymal adipose tissue that were otherwise depleted by cachexia. The milk fat diet ameliorated gut damage caused by paclitaxel in non-tumour-bearing mice, as evidenced by retention of jejunal morphology, villi length and intestinal γ-glutamyl transpeptidase activity, and inhibition of crypt apoptosis. It prevented loss of red and white blood cells due to both cancer-mediated immunosuppression and the cytotoxic effects of chemotherapy. The present study warrants the use of milk fat as an adjuvant to inhibit tumour metastasis during cancer chemotherapy, and to spare patients from the debilitating side-effects of cytotoxic drugs.
Clinical and Experimental Metastasis 07/2011; 28(7):675-88. · 3.52 Impact Factor
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ABSTRACT: Hydrogen sulfide (H(2)S) displays anti-inflammatory and cytoprotective activities to attenuate myocardial ischemia-reperfusion (MIR)-induced injury, but its role in MIR in diabetics is not known. This study was undertaken to investigate whether H(2)S plays a protective role in MIR in diabetic rats.
Diabetes was induced by streptozocin in Wistar rats, which were subjected to myocardial ischemia by blocking the left circumflex artery for 30 min, followed by 2h reperfusion. dl-propargylglycine (PAG) and sodium hydrosulfide (NaHS) were administered to the rats to investigate their effects on severity of MIR-induced injury.
Diabetic rats had smaller myocardial infarct sizes and higher serum levels of H(2)S (both P < 0.05) than non-diabetics when they underwent MIR. MIR significantly increased the serum level of H(2)S (49.5 ± 7.1 μM), H(2)S-synthesizing activity (7.4 ± 1.6 nmol/mg) and the myocardial infarct size (44.0 ± 7.2%), compared with sham-operated diabetic rats (21.7 ± 2.1 μM, 0.15 ± 0.4 nmol/mg and 1.2 ± 0.4%, respectively). Administration of NaHS increased the H(2)S level (65.8 ± 6.9 μM) and had little effect on H(2)S production activity (6.5 ± 2.2 nmol/mg), while PAG reduced both the H(2)S level (29.2 ± 5.0 μM) and H(2)S-synthesizing activity (2.2 ± 1.8 nmol/mg). NaHS significantly reduced the myocardial infarct size (31.2 ± 4.7%), inhibited the production of lipid peroxidation, MPO activity, and cell apoptosis, and downregulated expression of caspase-3, Fas, FasL, and TNF-α, which had been elevated by MIR, while PAG further increased the myocardial infarct size (58.3 ± 5.9%), and displayed opposite effects.
The study indicates that H(2)S may play a protective role in MIR-induced myocardial injury in diabetics by its anti-apoptotic, anti-oxidative and anti-inflammatory activities.
International journal of cardiology 02/2011; 152(2):177-83. · 7.08 Impact Factor
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ABSTRACT: B7-H4 is one of the most recently identified members of B7 superfamily of costimulatory molecules serving as an inhibitory modulator of T-cell response. B7-H4 is broadly expressed in human peripheral tissues and inducibly expressed in immune cells. The expression of B7-H4 has been observed in various types of human cancer tissues, and its soluble form has been detected in blood samples from cancer patients. However, its precise physiological role is still elusive, as its receptor has not been identified and the expression levels are not consistent. This paper summarizes the pertinent data on the inhibitory role of B7-H4 in antitumor immunity and its association with cancer progression and survival in human patients. The paper also discusses the clinical significance of investigating B7-H4 as potential markers for cancer diagnosis and prognosis, and as therapeutic targets.
Clinical and Developmental Immunology 01/2011; 2011:695834. · 1.84 Impact Factor
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Gang Tan,
Shangha Pan,
Jie Li,
Xuesong Dong,
Kai Kang,
Mingyan Zhao,
Xian Jiang,
Jagat R Kanwar,
Haiquan Qiao,
Hongchi Jiang, Xueying Sun
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ABSTRACT: Hydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension.
Sodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine γ-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters.
Exogenous H(2)S attenuates CCl(4)-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2)S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.
PLoS ONE 01/2011; 6(10):e25943. · 4.09 Impact Factor
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ABSTRACT: Heme oxygenase (HO)-1 protects transplanted organs from ischemia reperfusion injury and immune rejection. This study sought to investigate whether persistent overexpression of HO-1 in donor livers could improve the survival by expanding T regulatory cells in a rat model of orthotopic liver transplantation.
Livers of Dark Agouti rats were intraportally perfused with an AAV expression vector encoding rat HO-1 (AAV-HO-1), and then transplanted into Lewis rats. The survival, HO-1 activity, Banff rejection activity index, serum levels of IL-2 and TNF-α, infiltration of CD4(+), CD8(+), and T(reg) (CD4(+)CD25(+)Foxp3(+)) cells into donor livers, and expression of Foxp3, TGF-β, and IL-10 were examined. A mixed lymphocyte reaction (MLR) was performed.
Intraportal delivery of AAV-HO-1 resulted in persistent expression of HO-1 and increased activity of HO-1 in transplanted livers, leading to prolonged survival of recipients. Overexpression of HO-1 reduced the Banff rejection activity index, and production of IL-2 and TNF-α, inhibited infiltration of CD4(+) and CD8(+) cells, and increased infiltration of T(reg) cells, into donor livers. The spleens of recipients expressed higher levels of Foxp3, TGF-β, and IL-10 than those of control rats, and the transplanted livers expressed higher levels of Foxp3 and TGF-β. Splenocytes from the tolerant recipients had higher percentages of T(reg) cells, and responded poorly to the allogeneic donor splenocytes.
Persistent expression of HO-1 in donor livers by intraportal delivery of AAV-HO-1 improves the survival by expanding T(reg) cells. HO-1-based therapies, as described herein, promise new strategies to prevent the rejection of liver transplants.
Journal of Surgical Research 12/2010; 166(2):e187-94. · 2.25 Impact Factor
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ABSTRACT: Hypoxia-inducible factors (HIFs) and nuclear factor-κB (NF-κB) regulate genes involved in carcinogenesis and progression of cancers including hepatocellular carcinoma (HCC). The von Hippel-Lindau (VHL) protein (pVHL) targets HIFα subunits for destruction and participates in modulating the activity of NF-κB. The present study aimed to investigate whether the overexpression of pVHL synergizes with doxorubicin in the treatment of HCC.
Overexpression of pVHL was induced by infecting mouse HCC Hepa1-6 and H22 cells, or injecting subcutaneous Hepa1-6 tumors in C57BL/c mice, with adenoviral vectors encoding mouse VHL gene. Cell proliferation, apoptosis, tumoral angiogenesis, and gene expression and DNA-binding activity of NF-κB were examined. The therapeutic effects of pVHL were also evaluated in orthotopic Hepa1-6 tumors by intraportal delivery of Ad-VHL.
Ad-VHL enhanced the anti-tumor activity of doxorubicin by inhibiting cell proliferation, and causing cell cycle arrest and apoptosis. The Ad-VHL infection downregulated HIF-1α and HIF-2α expression, and inhibited NF-κB activity and the expression of genes involved in apoptosis, proliferation, angiogenesis, invasion, and metastasis. Injection of Ad-VHL into HCC tumors augmented doxorubicin-induced suppression of tumor growth by inhibiting cell proliferation and tumor angiogenesis, and by inducing cell apoptosis. Effects on the expression of HIFαs, activity of NF-κB, and their downstream genes were in accordance with the in vitro findings. Intraportal injection of Ad-VHL enhanced the efficacy of doxorubicin to suppress the growth of orthotopic liver tumors.
By targeting HIF and NF-κB, overexpression of pVHL enhances the efficacy of doxorubicin, and warrants consideration as a potential therapeutic strategy for treating HCC.
Journal of Hepatology 12/2010; 55(2):359-68. · 9.26 Impact Factor
