Rong Jiang

Chongqing Medical University, Ch’ung-ch’ing-shih, Chongqing Shi, China

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Publications (61)131.52 Total impact

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    ABSTRACT: Sesamin has been described to exert anti-oxidant and anti-inflammatory properties. In present study, we investigated the potential effects and mechanisms of sesamin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in D-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with sesamin dose-dependently improved LPS/D-GalN-induced mortality and liver injury as indicated by reduced serum levels of aminotransferases and alleviated pathological damage as well as hepatocyte apoptosis in mice. Additionally, sesamin markedly attenuated LPS/D-GalN-induced adhesion molecules expression, and decreased neutrophils recruitment. Furthermore, sesamin inhibited LPS-induced tumor necrosis factor-alpha (TNF-α) production, p38 mitogen-activated protein kinases (MAPK) and NF-κB activation, and Toll like receptor (TLR) 4 expression in mice and in RAW264.7 macrophage cells. In summary, these results demonstrate that sesamin protects mice from LPS-induced FHF and the molecular mechanisms may down-regulate the expression of TLR4, block MAPK and NF-κB activation, decrease the production of TNF-α. Copyright © 2015 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 04/2015; 461(2). DOI:10.1016/j.bbrc.2015.03.154 · 2.28 Impact Factor
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    ABSTRACT: The glycolytic inhibitor 2-deoxyglucose (2-DG) is a calorie restriction (CR) mimetic produces CR-like beneficial effects in both acute and chronic pathological processes, but whether 2-DG is also helpful in critical and life-threatening situation is not known. In the present study, the potential benefits of 2-DG in lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced lethal liver injury were investigated. The results indicated that treatment with 2-DG suppressed the elevation of plasma aminotransferases, alleviated the histopathological abnormalities and improved the survival rate of LPS/D-Gal-exposed mice. Treatment with 2-DG also suppressed the production of pro-apoptotic cytokine TNF-α, the phosphorylation of JNK, the activation of caspase cascade and the count of TUNEL-positive apoptotic hepatocytes. These data suggested that the CR mimetic 2-DG could also provide beneficial effects in lethal pathological process such as LPS/D-Gal-induced fulminant liver injury. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 03/2015; 459(3). DOI:10.1016/j.bbrc.2015.02.145 · 2.28 Impact Factor
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    ABSTRACT: PurposeThe purpose of this study was to assess the improved absorption and in vivo kinetic characteristics of a novel water-in-oil nanoemulsion containing evodiamine–phospholipid nanocomplex (NEEPN) when administered orally.MethodsNEEPN was fabricated by loading an evodiamine–phospholipid nanocomplex into a water-in-oil nanoemulsive system. The gastrointestinal absorption of NEEPN was investigated using an in situ perfusion method. The modified in vivo kinetic characteristics of evodiamine (EDA) in NEEPN were also evaluated.ResultsCompared with EDA or conventional nanoemulsions containing EDA instead of evodiamine–phospholipid complex, NEEPN with its favorable in vivo kinetic characteristics clearly enhanced the gastrointestinal absorption and oral bioavailability of EDA; for example, the relative bioavailability of NEEPN to free EDA was calculated to be 630.35%, and the effective permeability of NEEPN in the colon was 8.64-fold that of EDA.ConclusionNEEPN markedly improved the oral bioavailability of EDA, which was probably due to its increased gastrointestinal absorption. NEEPN also increased efficacy and reduced adverse effects for oral delivery of EDA. Such finding demonstrates great clinical significance as an ideal drug delivery system demands high efficacy and no adverse effects.
    International Journal of Nanomedicine 09/2014; 9:4411-4420. DOI:10.2147/IJN.S59812 · 4.20 Impact Factor
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    ABSTRACT: Bone morphogenetic protein 2(BMP2) is known to activate unfolded protein response (UPR) signal molecules in chondrogenesis. Inositol-requiring enzyme-1α (IRE1α),as one of three unfolded protein sensors in UPR signaling pathways, can be activated during ER stress. However, the influence on IRE1α in chondrocyte differentiation has not yet been elucidated. Here we present evidence demonstrating that overexpression of IRE1α inhibits chondrocyte differentiation, as revealed by reduced expression of collagen II (ColII), Sox9, collagen X (ColX), matrix metalloproteinase 13 (MMP-13), Indian hedgehog (IHH), Runx2 and enhanced expression of parathyroid hormone-related peptide (PTHrP). Furthermore, IRE1α-mediated inhibition of chondrogenesis depends on its enzymatic activity, since its point mutant lacking enzymatic activity completely loses this activity. The RNase and Kinase domains of IRE1α C-terminal are necessary for its full enzymatic activity and inhibition of chondrocyte differentiation. Mechanism studies demonstrate that granulin–epithelin precursor(GEP), a growth factor known to stimulate chondrogenesis, induced IRE1α expression in chondrogenesis. The expression of IRE1α is depended on GEP signaling, and IRE1α expression is hardly detectable in GEP−/− embryos. In addition, IRE1α inhibits GEP-mediated chondrocyte differentiation as a negative regulator. Altered expression of IRE1α in chondrocyte hypertrophy was accompanied by altered levels of IHH and PTHrP. Collectively, IRE1α may be a novel regulator of chondrocyte differentiation by 1) inhibition GEP-mediated chondrocyte differentiation as a negative regulator; 2) promoting IHH/PTHrP signaling.
    Cellular Signalling 09/2014; 26(9):1998–2007. DOI:10.1016/j.cellsig.2014.05.008 · 4.47 Impact Factor
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    ABSTRACT: Emodin has been reported to possess anti-inflammatory and anti-oxidant activities. The aim of this study was to explore the effect and mechanism of emodin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in D-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with emodin inhibited the elevation of plasma aminotransferases, alleviated the hepatic histopathological abnormalities and improved the survival rate of LPS/D-GalN-primed mice. Moreover, emodin markedly attenuated the increased serum and hepatic tumor necrosis factor-α (TNF-α) production, and activated hepatic p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signal pathways in LPS/D-GalN-challenged mice. Furthermore, using an in vitro experiment, we found that emodin dose-dependently suppressed TNF-α production, dampened AP-1 and NF-κB activation, and blocked toll-like receptor (TLR) 4/myeloid differentiation factor (MD) 2 complex expression in LPS-elicited RAW264.7 mouse macrophage cells. Taken together, these data suggested that emodin could effectively prevent LPS-induced FHF, which might be mediated by inhibition of TNF-α production, deactivation of MAPKs and NF-κB, and blockade of TLR4/MD2 complex expression.
    International Immunopharmacology 08/2014; DOI:10.1016/j.intimp.2014.08.018 · 2.71 Impact Factor
  • 07/2014; 998-999:265-268. DOI:10.4028/www.scientific.net/AMR.998-999.265
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    ABSTRACT: We previously report that BMP2 mediates mild ER stress-activated ATF6 and directly regulates XBP1S splicing in the course of chondrogenesis. The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). Failure to adapt to ER stress causes the UPR to trigger apoptosis. The transcription factor activating transcription factor 6 (ATF6), a key regulator of the UPR, is known to be important for ER stress-mediated apoptosis and cell growth, but the molecular mechanism underlying these processes remains unexplored. In this study, we demonstrate that ATF6 is differentially expressed during BMP2-stimulated chondrocyte differentiation and exhibits prominent expression in growth plate chondrocytes. ATF6 can enhance the level of IRE1a-spliced XBP1S protein in chondrogenesis. IRE1a and ATF6 can synergistically regulate endogenous XBP1S gene expression in chondrogenesis. Furthermore, overexpression ATF6 inhibited, while ATF6-knockdown enhanced, the cell proliferation in chondrocyte development with G1 phase arresting, S phase reducing and G2-M phase delaying. Besides, Ad-ATF6 can activate, whereas knockdown ATF6 by an siRNA-silencing approach inhibited, ER stress-mediated apoptosis in chondrogenesis induced by BMP2, as assayed by cleaved caspase3, CHOP, p-JNK expression in the course of chondrocyte differentiation. On the other hand, FCM, TUNEL assay and immunohistochemistry analysis also proved this result in vitro and in vivo. It was demonstrated that Ad-ATF6 activation of the ER stress-specific caspase cascade in developing chondrocyte tissue. Collectively, these findings reveal a novel critical role of ATF6 in regulating ER stress-mediated apoptosis in chondrocyte differentiation and the molecular mechanisms involved.
    Histochemie 06/2014; 142(5). DOI:10.1007/s00418-014-1233-y · 2.93 Impact Factor
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    ABSTRACT: Bone morphogenetic protein 2 (BMP2) is known to activate unfolded protein response (UPR) signaling molecules, such as BiP (IgH chain-binding protein), PERK (PKR-like ER-resistant kinase), and IRE1α. Inositol-requiring enzyme-1a (IRE1a), as one of three unfolded protein sensors in UPR signaling pathways, can be activated during ER stress. Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. However, the influence on IRE1a in BMP2-induced osteoblast differentiation has not yet been elucidated. Herein we demonstrate that overexpression of IRE1a inhibits osteoblast differentiation, as revealed by reduced activity of alkaline phosphatase (ALP) and osteocalcin; however, knockdown of IRE1a via the RNAi approach stimulates osteoblastogenesis. Mechanistic studies revealed that the expression of IRE1a during osteoblast was a consequence of JunB transcription factor binding to several AP1 sequence (TGAG/CTCA) in the 5'-flanking regulatory region of the IRE1a gene, followed by transcription. In addition, GEP induces IRE1a expressions and this induction of IRE1a by GEP depends on JunB. Furthermore, IRE1a inhibition of GEP-induced osteoblastogenesis relies on JunB. Besides, GEP is required for IRE1a inhibition of BMP2-induced bone formation. Collectively, these findings demonstrate that IRE1a negatively regulates BMP2-induced osteoblast differentiation and this IRE1a inhibition effect depends on GEP growth factor. Thus, IRE1a, BMP2, GEP growth factor, and JunB transcription factor form a regulatory loop and act in concert in the course of osteoblastogenesis.
    Cell Death & Disease 05/2014; 5:e1239. DOI:10.1038/cddis.2014.194 · 5.18 Impact Factor
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    ABSTRACT: The syntheses of inflammatory mediators are energy-intensive processes and the mitochondria play pivotal roles in supporting these energy-requiring molecular responses. In the present studies, a mitochondrial respiratory complex I inhibitor rotenone was administrated in mice with lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced fulminant liver injury and the prophylactic and therapeutic effects on tissue injury were evaluated. We found that pretreatment with rotenone suppressed the elevation of plasma aminotransferases, alleviated the histopathological abnormalities and improved the survival rate of LPS/D-Gal-challenged mice. Pretreatment with rotenone has no obvious effects on hepatic malondialdehyde (MDA) contents but it significantly inhibited the up-regulation of both hepatic mRNA level and plasma protein level of TNF-α and IL-6. In the rotenone-pretreated group, the elevation of hepatic caspase-3, caspase-8 and caspase-9 activities induced by LPS/D-Gal decreased and rotenone reduced the count of TUNEL-positive apoptotic hepatocytes. In addition, posttreatment with rotenone at 1h after LPS/D-Gal challenge also suppressed the elevation of plasma aminotransferases. These data suggest that mitochondrial complex I inhibition might be a potential approach for the control of inflammation.
    International immunopharmacology 05/2014; DOI:10.1016/j.intimp.2014.04.028 · 2.71 Impact Factor
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    ABSTRACT: We previously reported that transcription factor XBP1S is upregulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. Herein, we found that XBP1S stimulates chondrocyte differentiation from mesenchymal stem cells in vitro and endochondral ossification ex vivo. In addition, XBP1S activates granulin-epithelin precursor (GEP), a growth factor known to stimulate chondrogenesis, then enhances GEP-stimulated chondrogenesis and endochondral bone formation. Collectively, these findings demonstrate that XBP1S positively regulates endochondral bone formation by activating GEP chondrogenic growth factor.
    05/2014; 926-930:1136-1139. DOI:10.4028/www.scientific.net/AMR.926-930.1136
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    ABSTRACT: Human ribonuclease inhibitor (RI), a cytoplasmic protein, is constructed almost entirely of leucine rich repeats. RI could suppress activities of ribonuclease and angiogenin (ANG) through closely combining with them. ANG is a potent inducer of blood vessel growth and has been implicated in the establishment, growth, and metastasis of tumors. ILK /PI3K/AKT signaling pathway also plays important roles in cell growth, cell-cycle progression, tumor angiogenesis, and cell apoptosis. Our previous experiments demonstrated that RI might effectively inhibit some tumor growth and metastasis. Our recent study showed that ILK siRNA inhibited the growth and induced apoptosis in bladder cancer cells as well as increased RI expression, which suggest a correlation between RI and ILK. However, the exact molecular mechanism of RI in anti-tumor and in the cross-talk of ANG and ILK signaling pathway remains largely unknown. Here we demonstrated that up-regulating RI obviously decreased ANG expression and activity. We also discovered that RI overexpression could remarkably inhibit cell proliferation, regulate cell cycle and induce apoptosis. Furthermore, up-regulation of RI inhibited phosphorylation of ILK downstream signaling targets protein kinase B/Akt, glycogen synthase kinase 3-beta (GSK-3β), and reduced β-catenin expression in vivo and vitro. More importantly, RI significant inhibited the tumor growth and angiogenesis of tumor bearing C57BL/6 mice. In conclusion, our findings, for the first time, suggest that angiogenin and ILK signaling pathway plays a pivotal role in mediating the inhibitory effects of RI on melanoma cells growth. This study identifies that RI may be a useful molecular target for melanoma therapy.
    Biochimie 04/2014; DOI:10.1016/j.biochi.2014.04.007 · 3.12 Impact Factor
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    ABSTRACT: Progranulin (PGRN) was reported to be a stress-response factor in response to hypoxia and acidosis. Here we present evidences demonstrating that PGRN is also an endoplasmic reticulum(ER) stress responsive factor: PGRN expression was induced and its activation of Erk1/2 and Akt signaling enhanced in response to ER stress; Normal ER stress response was lost in PGRN deficient cells and PGRN deficient cells became hypersusceptible to ER stress-induced apoptosis; additionally, recombinant PGRN could rescue the defects in ER-stress responses seen in PGRN deficient cells. Mechanistic studies indicated that PGRN/TNFR2 was critical for PGRN mediated regulation of ER stress response: similar to PGRN, the expression TNFR2, but not TNFR1, was also induced in the course of ER stress; in addition, the association between PGRN and TNFR2 was markedly enhanced following ER stress; More importantly, PGRN protection of ER stress induced apoptosis was abolished when TNFR2 signaling was blocked. In addition, the 2nd and 3rd cysteine-rich domains (CRD) in the extracellular portion of TNFR2 (CRD2CRD3), known to directly bind to PGRN, disturbed the interaction of PGRN with TNFR2, and in turn abolished PGRN-mediated activation of Erk1/2 and Akt signaling and protection against apoptosis in response to ER-stress. Collectively, PGRN plays an important role in ER stress and regulates ER stress response through interacting with TNFR2. This study provides new insight into PGRN regulation of stress response and may also present PGRN as a potential molecular target for treating stress-associated disorders.
    Cellular Signalling 04/2014; DOI:10.1016/j.cellsig.2014.03.026 · 4.47 Impact Factor
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    ABSTRACT: Garcinol is a polyisoprenylated benzophenone derivative of Garcinia indica. Recent researches have revealed the antioxidant, anticancer and anti-inflammatory properties of garcinol. In the present study, the pharmacological effects of garcinol in lipopolysaccharide (LPS)-induced hepatic injury in D-galactosamine (D-Gal)-sensitized mice were investigated. We found that treatment with garcinol significantly decreased serum ALT and AST levels in LPS/D-Gal-exposed mice. These were accomplished with improved histological alterations in liver sections and reduced malondialdehyde (MDA) content in liver homogenates. Garcinol significantly reduced the acetylation level of NF-κB, but it had no obvious effects on the elevation of TNF-α or IL-6 in plasma or liver tissue. Garcinol significantly attenuated LPS/D-Gal-induced hepatic apoptosis as evidenced by reduced number of TUNEL-positive cells in liver sections. Our experiments also showed that garcinol markedly suppressed the cleavage of caspase-3 and significantly decreased the activities of caspase-3, -8, and -9 in liver tissues. In addition, garcinol obviously reduced the induction of Bax but did not alter the level of Bcl-2. These results indicated that garcinol might provide protective benefits in LPS/D-Gal-induced liver injury through suppressing apoptosis.
    International immunopharmacology 04/2014; 19(2). DOI:10.1016/j.intimp.2014.02.012 · 2.71 Impact Factor
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    ABSTRACT: The latest findings of our laboratory showed that Angelica sinensis polysaccharide (ASP) showed a definite effect in regulating the aging of hematopoietic stem cells. Leukemia is a type of malignant hematopoietic tumor in hematopoietic stem cells. There have been no relevant reports about ASP's effect in regulating the aging of leukemia cells. In this study, human acute myeloid leukemia (AML) KG1alpha cell lines in logarithmic growth phase were taken as the study object, and were divided into the ASP group, the cytarabine (Ara-C) group, the ASP + Ara-C group and the control group. The groups were respectively treated with different concentration of ASP, Ara-C and ASP + Ara-C for different periods, with the aim to study the effect of ASP combined with Ara-C in regulating the aging of human acute myeloid leukemia KG1alpha cell lines and its relevant mechanism. The results showed that ASP, Ara-C and ASP + Ara-C could obviously inhibit KG1alpha cell proliferation in vitro, block the cells in G0/G1 phase. The cells showed the aging morphological feature. The percentage of positive stained aging cells was dramatically increased, and could significantly up-regulate the expression of aging-related proteins P16 and RB, which were more obvious in the ASP + Ara-C group. In conclusion, the aging mechanism of KG1alpha cell induced by ASP and Ara-C may be related to the regulation of the expression of aging-related proteins, suggesting that the combined administration of ASP and anticancer drugs plays a better role in the treatment of leukemia .
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    ABSTRACT: We previously reported that transcription factor XBP1S binds to RUNX2 and enhances chondrocyte hypertrophy through acting as a cofactor of RUNX2. Herein, we report that XBP1S is a key downstream molecule of BMP2 and is required for BMP2-mediated chondrocyte differentiation. XBP1S is up-regulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. XBP1S stimulates chondrocyte differentiation from mesenchymal stem cells in vitro and endochondral ossification ex vivo. In addition, XBP1S activates granulin-epithelin precursor (GEP), a growth factor known to stimulate chondrogenesis, and endogenous GEP is required, at least in part, for XBP1S-stimulated chondrocyte hypertrophy, mineralization and endochondral bone formation. Furthermore, XBP1S enhances GEP-stimulated chondrogenesis and endochondral bone formation. Collectively, these findings demonstrate that XBP1S, a BMP2-inducible transcription factor, positively regulates endochondral bone formation by activating GEP chondrogenic growth factor.
    Journal of Cellular and Molecular Medicine 03/2014; 18(6). DOI:10.1111/jcmm.12261 · 3.70 Impact Factor
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    ABSTRACT: Neurodegenerative diseases remain a significant unresolved societal burden afflicting millions of people worldwide. Neurons in the brain are highly sensitive to oxidative stress, which can be indued by metal toxicity. In this paper, a chronic aluminum overload-induced model of neurodegeneration was used to investigate whether metal ions (Al, Fe, Mn, Cu and Zn)-related oxidative stress was involved in neurodegenerative mechanism and to identify the protective action of meloxicam against rat hippocampal neuronal injury. The metal ion contents, activity of superoxide dismutase (SOD), and content of malondialdehyde (MDA) were detected. The results showed that the spatial learning and memory (SLM) function was significantly impaired in chronic aluminum overload rats. Considerable karyopycnosis was observed in hippocampal neurons. The SOD activity was weakened and the MDA content increased both significantly. In the hippocampus, Al, Fe, Mn, Cu, and Zn contents increased by 184.1%, 186.1%, 884.2%, 199.4% and 149.2%, respectively. Meloxicam administration (without Al) had no effect compared with the control group, while meloxicam treatment with aluminum exposure significantly protected rats from SLM function impairment and neuron death, and resulted in lower SOD activity, higher MDA content and brain metal ion imbalance. Our findings suggest that the cerebral metal ion imbalance-related oxidative stress is involved in mechanism of cerebral injury and neurodegeneration induced by chronic Al overload in rats, and that meloxicam protects neurons by reducing metal ion imbalance- related oxidative stress.
    Behavioral and Brain Functions 03/2014; 10(1):6. DOI:10.1186/1744-9081-10-6 · 2.00 Impact Factor
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    ABSTRACT: The prognosis for fulminant hepatic failure (FHF) still remains extremely poor with a high mortality and, therefore, better treatments are urgently needed. Syringin, a main active substance isolated from Eleutherococcus senticosus, has been reported to exhibit immunomodulatory and anti-inflammatory properties. In this study, we investigated the effects and underlying mechanisms of syringin on lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced FHF in mice. Mice were administered syringin (10, 30 and 100 mg kg(-1) , respectively) intraperitoneally (i.p) 30 min before LPS/D-GalN then mortality and liver injury were evaluated subsequently. We found that syringin dose-dependently attenuated LPS/D-GalN-induced FHF, as indicated by reduced mortality, inhibited aminotransferase and malondialdehyde (MDA) content, an increased glutathione (GSH) concentration and alleviated pathological liver injury. In addition, syringin inhibited LPS/D-GalN-induced hepatic caspase-3 activation and hepatocellular apoptosis, myeloperoxidase (MPO) activity and intercellular adhesion molecule-1 (ICAM-1) expression, as well as hepatic tissues tumor necrosis factor-alpha (TNF-α) production and NF-κB activation in a dose-dependent manner. These experimental data indicate that syringin might alleviate the FHF induced by LPS/D-GalN through inhibiting NF-κB activation to reduce TNF-α production. Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 03/2014; 34(3). DOI:10.1002/jat.2876 · 3.17 Impact Factor
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    ABSTRACT: Fulminant hepatic failure (FHF) is a serious clinic syndrome with extremely poor prognosis and no effective treatment except for liver transplantation. Synthetic RGDS peptide, an inhibitor of integrins, was proved to suppress integrin signals. In this study, we investigated the protection effects of RGDS peptide on Lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced FHF and the underlying molecular mechanisms. Synthetic RGDS peptide was given intraperitoneally (i.p.) 30 min before LPS /D-GalN injection. Liver function and the extent of liver injury were analyzed biochemically and pathologically respectively. Enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting were used to detect effectors and signaling molecules. Pretreatment with synthetic RGDS peptide significantly improved LPS/D-GalN-induced mortality, and liver injury as determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as well as pathological analysis. In addition, RGDS peptide significantly reduced tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-2 production, and decreased myeloperoxidase (MPO) and NF-κB activity. Furthermore, Western blotting indicated that the levels of phospho-integrin β3, phospho-focal adhension kinase (FAK) and phospho-p38 mitogen-activated protein kinases (MAPK) decreased with RGDS peptide pretreatment. Together, these data suggest that synthetic RGDS peptide protect against LPS/D-GalN-induced FHF by inhibiting inflammatory cells migration and blocking the integrin αVβ3-FAK-p38 MAPK and NF-κB signaling.
    Journal of Gastroenterology and Hepatology 01/2014; 29(6). DOI:10.1111/jgh.12525 · 3.63 Impact Factor
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    ABSTRACT: Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML CD34+CD38? cell proliferation in vitro culture in a dose-dependent manner while sparing normal hematopoietic stem and progenitor cells at physiologically achievable concentrations. Furthermore, ASP exerted cytotoxic effects on AML K562 cells, especially LSC-enriched CD34+CD38? cells. Colony formation assays further showed that ASP significantly suppressed the formation of colonies derived from AML CD34+CD38? cells but not those from normal CD34+CD38? cells. Examination of the underlying mechanisms revealed that ASP induced CD34+CD38? cell senescence, which was strongly associated with a series of characteristic events, including up-regulation of p53, p16, p21, and Rb genes and changes of related cell cycle regulation proteins P16, P21, cyclin E and CDK4, telomere end attrition as well as repression of telomerase activity. On the basis of these findings, we propose that ASP represents a potentially important agent for leukemia stem cell-targeted therapy.
    Asian Pacific journal of cancer prevention: APJCP 11/2013; 14(11):6549-56. DOI:10.7314/APJCP.2013.14.11.6549 · 1.50 Impact Factor
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    ABSTRACT: TGF-β1, SNAI1 and MMP-9 are implicated in tumor invasion and metastasis. The purpose of this study was to examine TGF-β1, SNAI1 and MMP-9 expression in papillary thyroid carcinoma (PTC), and to assess association of TGF-β1, SNAI1 and MMP-9 expression with several clinicopathological indicators of PTC. TGF-β1, SNAI1 and MMP-9 protein expression in 83 PTCs and their matched normal thyroid specimens were analyzed using immunohistochemistry. The mRNA expression levels of TGF-β1, SNAI1 and MMP-9 in 12 fresh PTC specimens with lymph node metastasis (LNM), 12 fresh PTC specimens without LNM and their matched normal thyroid specimens were assessed by real-time RT-PCR. The results showed that the mRNA and protein expression levels of TGF-β1, SNAI1 and MMP-9 were significantly higher in PTCs than in their matched normal thyroid tissues. There were not significant differences in TGF-β1, SNAI1 and MMP-9 protein expression relative to age, gender, tumor size and TNM stage, except for MMP-9 whose protein expression correlated with tumor size. However, high mRNA and protein expression levels of TGF-β1, SNAI1 and MMP-9 were significantly correlated with LNM. Furthermore, TGF-β1, SNAI1 and MMP-9 protein expression were significantly correlated with one another. Concomitant expression of any two or all of the three molecules had stronger correlation with LNM than did each alone. Collectively, the present results indicate that immunohistochemical and real-time RT-PCR evaluation of TGF-β1, SNAI1 and MMP-9 expression in PTC may be useful to predict the risk of LNM in PTC patients.
    Journal of molecular histology 11/2013; DOI:10.1007/s10735-013-9557-9 · 1.98 Impact Factor