Publications by authors named "Shuying He"

28 Publications

  • Page 1 of 1

A novel histone deacetylase inhibitor LT-548-133-1 induces apoptosis by inhibiting HDAC and interfering with microtubule assembly in MCF-7 cells.

Invest New Drugs 2021 Mar 31. Epub 2021 Mar 31.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.

Many studies have indicated that histone deacetylase inhibitors (HDACis) have a significant antitumor effect in cancer. Here we report a compound named LT-548-133-1 that not only acts as an HDAC inhibitor but also interferes with microtubule assembly to inhibit MCF-7 cell proliferation and induce apoptosis. Consistent with Chidamide, LT-548-133-1 inhibited HDAC activity and increased histone H3 acetylation. But the difference is that it significantly induced cell cycle G2/M arrest while Chidamide caused G0/G1 arrest in MCF-7 cells. By Western blotting, we found the accumulation of CyclinB1 and phosphorylated histone H3 in LT-548-133-1 treated cells. Immunofluorescence based microtubule-repolymerization experiments and immunofluorescence staining of cell microtubules and nuclei showed that LT-548-133-1inhibited microtubule-repolymerization and induced mitotic abnormalities. The decreased expression of Bcl-2 and the increased expression of Bax, p53, p21, and cleaved-Caspase3 indicated the occurrence of apoptosis. Flow cytometry results also showed an increase in the proportion of apoptotic cells after administration of LT-548-133-1 or Chidamide. Therefore, we demonstrated that LT-548-133-1 could act as an HDAC inhibitor while inhibiting microtubule-repolymerization, causing mitosis to be arrested in G2/M. These two effects ultimately lead to proliferation inhibition and apoptosis of MCF-7 cells.
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http://dx.doi.org/10.1007/s10637-021-01102-9DOI Listing
March 2021

Review: Inhibitory potential of low molecular weight Heparin in cell adhesion; emphasis on tumor metastasis.

Eur J Pharmacol 2021 Feb 1;892:173778. Epub 2020 Dec 1.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. Electronic address:

Low molecular weight heparin is a Heparin derivative, produced from commercial-grade Heparin through Chemical or enzymatic depolymerization. LMWH has remained a favored regimen for anticoagulation in cancer patients. Evidence from several studies has suggested that LMWHs possess antitumor and antimetastatic activity aside from their anticoagulant activity. Cancer metastasis is the foremost reason for cancer-related motility rate. Studies have pointed out that adhesion molecules play a decisive role in enhancing recurrent, invasive, and distant metastasis. Therefore, it is hypothesized that Cell adhesion molecules can be determined as a potential therapeutic target group, as antibodies or small-molecule inhibitors could easily access their extracellular domains. Furthermore, data from several investigations have reported LWMH potential effects as antimetastatic agents through influencing cell adhesion molecules. This review's objective is to emphasize the evidence available for the effects of the LMWHs in cell adhesion to inhibit tumor metastasis.
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http://dx.doi.org/10.1016/j.ejphar.2020.173778DOI Listing
February 2021

Parathyroid hormone-related protein activates HSCs via hedgehog signalling during liver fibrosis development.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):1984-1994

a Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou , China.

Recently, we showed that parathyroid hormone-like hormone (PTHLH), a cytokine-like polyprotein, is critical for extracellular matrix (ECM) deposition through the activation of hepatic stellate cells (HSCs). Here, we show that N-terminal PTHLH is secreted into the supernatant of injured hepatocytes, its expression is positively correlated with liver fibrosis severity based on mice liver biopsies, and it is primarily expressed in the cytoplasm of hepatocytes along the fibrous septa of fibrotic livers. PTHLH overexpression in mice was achieved through adeno-associated virus-mediated gene delivery (AAV9-PTHLH), and liver fibrosis was induced with carbon tetrachloride (CCl). We observed that AAV9-PTHLH induced spontaneous development of liver fibrosis and increased sensitivity to CCl. PTHLH increased Hedgehog (Hh) pathway activation in a PTH1R-dependent manner, and the effect of PTHLH was primarily mediated by protein kinase C (PKC) . PTHLH-mediated PTH1R-PKC pathway activation is a key event in the profibrotic Hh-dependent activation of HSCs.
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http://dx.doi.org/10.1080/21691401.2019.1615931DOI Listing
December 2019

A Molecular Targeted Immunotherapeutic Strategy for Ulcerative Colitis via Dual-targeting Nanoparticles Delivering miR-146b to Intestinal Macrophages.

J Crohns Colitis 2019 Mar;13(4):482-494

Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.

Background And Aims: Macrophages are a promising therapeutic target for intestinal mucosal repair. MiR-146b appears to control macrophage activation and cell proliferation.

Methods: By loading miR-146b mimic on mannose-modified trimethyl chitosan [MTC]-conjugated nanoparticles [NPs] [MTC-miR146b], a molecular targeted immunotherapeutic approach was developed to selectively target intestinal macrophages for mucosal regeneration and tumourigenesis in mouse models.

Results: We first confirmed that miR-146b expression was significantly enhanced during mucosal regeneration in a murine colitis model. Moreover, after mucosal damage, MTC-miR146b mimic-treated wild-type mice had dramatically restored body weight and mucosal barrier function compared with MTC-NC treated mice. Strikingly, MTC-miR146b mimic oral administration protected miR-146b-deficient mice from dextran sodium sulphate [DSS] injury and the colitis-associated cancer process. Mechanistically, miR-146b strongly inhibited M1 macrophage activation by suppressing the Toll-like receptor 4 [TLR4] signalling pathway, resulting in the repression of the induction of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. More importantly, miR-146b overexpression in bone marrow-derived macrophages [BMDMs] in M1 differentiation conditions induced a phenotype similar to M2 macrophages and improved the proliferation of co-cultured colonic epithelial cells via STAT3-dependent IL-10 production.

Conclusions: MTC-miR146b should be regarded as an effective candidate for oral delivery and could improve the efficacy of immunotherapies for ulcerative colitis and colitis-associated cancer.
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http://dx.doi.org/10.1093/ecco-jcc/jjy181DOI Listing
March 2019

Low-Molecular-Weight Heparins: Reduced Size Particulate Systems for Improved Therapeutic Outcomes.

Molecules 2018 Jul 18;23(7). Epub 2018 Jul 18.

School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.

A wide range of diseases have been treated using low-molecular-weight heparins (LMWHs), the drug of choice for anticoagulation. Owing to their better pharmacokinetic features compared to those of unfractionated heparin (uFH), several systems incorporating LMWHs have been investigated to deliver and improve their therapeutic outcomes, especially through development of their micro- and nano-particles. This review article describes current perspectives on the fabrication, characterization, and application of LMWHs-loaded micro- and nano-particles to achieve ameliorated bioavailability. The valuable applications of LMWH will continue to encourage researchers to identify efficient delivery systems that have specific release characteristics and ameliorated bioavailability, overcoming the challenges presented by biological obstructions and the physicochemical properties of LMWHs.
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http://dx.doi.org/10.3390/molecules23071757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100363PMC
July 2018

Parathyroid Hormone-Like Hormone Induces Epithelial-to-Mesenchymal Transition of Intestinal Epithelial Cells by Activating the Runt-Related Transcription Factor 2.

Am J Pathol 2018 06 22;188(6):1374-1388. Epub 2018 Mar 22.

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address:

Epithelial-to-mesenchymal transition (EMT) is a key contributor to fibroblast activation in fibrosis of multiple organs, including the intestine. Parathyroid hormone-like hormone (PTHLH) is an important factor in renal fibrosis and regulates several processes, including EMT. Herein, we investigated the role of PTHLH-induced EMT in intestinal fibrosis associated with Crohn disease. The expression levels of the EMT-related proteins, PTHLH, and parathyroid hormone receptor 1 (PTH1R) in intestinal tissues were determined by immunohistochemistry, and our results revealed that PTHLH and PTH1R were significantly elevated and associated with EMT marker expression. Moreover, neutralizing PTH1R and antagonizing PTHLH bioactivity prevented transforming growth factor-β1-induced EMT. PTH1R can propagate the protein kinase A (PKA) signal and activate downstream nuclear transcription factors, including runt-related transcription factor 2 (Runx2). In addition, lentiviral vector-PTHLH-treated mice were highly sensitive to 2,4,6-trinitrobenzene sulfonic acid, and analysis of the PTHLH-PTH1R axis revealed the involvement of PKA-Runx2 in PTHLH-induced EMT. Our results indicate that PTHLH triggered EMT in intestinal epithelial cells through the PKA-Runx2 pathway, which might serve as a therapeutic target for intestinal fibrosis in Crohn disease.
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http://dx.doi.org/10.1016/j.ajpath.2018.03.003DOI Listing
June 2018

Targeted delivery of microRNA 146b mimic to hepatocytes by lactosylated PDMAEMA nanoparticles for the treatment of NAFLD.

Artif Cells Nanomed Biotechnol 2018 21;46(sup2):217-228. Epub 2018 Mar 21.

c Department of Gastroenterology , First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , Guangzhou , China.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and precision therapeutic will be a benefit for the NAFLD regression. In this study, we observed low microRNA 146 b (miR-146 b) expression in NAFLD mice model induced by methionine-choline-deficient diet (MCD) compared with control group. Furthermore, miR-146b mice induced MCD exhibited severe liver steatosis and hepatitis. A bio-distribution study showed that novel Lactosylated PDMAEMA nanoparticles effectively targeted hepatocytes Lac-PDMAEMA. We coupled miR-146b mimic with Lac-PDMAEMA and then were administrated to NAFLD mice model, which could obviously alleviate the hepatic steatosis. Lac-PDMAEMA effectively delivered miR-146b mimic to hepatocytes with a ∼8-fold upregulation of miR-146b mimic targeting MyD88 and IRAK1, and in turn suppressed the expression of PPARγ. Meanwhile, TNF-α and IL-6 mRNA levels were decreased after administration of Lac-PDMAEMA/miR-146b mimic. So, we made a conclusion that targeted delivering miR-146b mimic to the hepatocytes by, coupling Lac-PDMAEMA nanoparticles could effectively alleviate the hepatic steatosis in NAFLD mice, which maybe bring a new and effective way to intervene and therapy the NAFLD.
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http://dx.doi.org/10.1080/21691401.2018.1453830DOI Listing
June 2019

The rs1024611 in the CCL2 gene and risk of gynecological cancer in Asians: a meta-analysis.

World J Surg Oncol 2018 Feb 20;16(1):34. Epub 2018 Feb 20.

1st Department, Gynecology Oncology, Shaanxi Provincial Tumor Hospital, No. 309, Yantaxi Road, Xi'an, 710061, China.

Background: The -2518A/G (rs1024611) polymorphism of the CCL2 (C-C motif chemokine ligand 2), also known as MCP-1 (monocyte chemotactic protein-1) gene, has been reported to be associated with increased gynecological cancer risk, but the results are conflicting.

Methods: In this analysis, 1089 cases and 1553 controls from six publications were used to investigate the association between CCL2-2518A/G (rs1024611) polymorphism and the risk of gynecological cancer with a meta-analytic approach. Studies published on EBSCO, EMBASE, Web of Science, PubMed, SpringerLink, ScienceDirect, Weipu, and CNKI databases were identified (last update was on November 3, 2015). Six articles focused on the association between CCL2-2518A/G (rs1024611) polymorphism, and gynecological cancer risk was selected and data were extracted. The cancer type included endometrial cancer (n = 1), breast cancer (n = 2), ovarian cancer (n = 2), and cervical cancer (n = 1). All statistical analyses were performed using the STATA version 12.0 software.

Results: The meta-analysis showed that CCL2-2518A/G (rs1024611) polymorphism is associated with risk of gynecological cancer (GG vs AG + AA, OR = 1.55, 95%CI = 1.07-2.24, P < 0.05; AA vs GG, OR = 0.59 95%CI = 0.38-0.92, P < 0.05). Notably, the subgroup analysis demonstrated that the genotype AA is associated with a reduced gynecological cancer risk in Asians, but an increased risk when compared to AG in Europeans.

Conclusions: Our data demonstrated the CCL2-2518A/G (rs1024611) polymorphism is significantly associated with risk of gynecological cancer, and the association differs by ethnicity.
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http://dx.doi.org/10.1186/s12957-018-1335-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819160PMC
February 2018

How to relieve breathing difficulties in high-temperature conditions for heart disease patients.

Eur J Prev Cardiol 2018 06 15;25(9):976. Epub 2018 Feb 15.

1 Biomedical Center, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

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http://dx.doi.org/10.1177/2047487318759833DOI Listing
June 2018

How can heart disease patients prevent complications from viral infections?

Eur J Prev Cardiol 2018 05 31;25(7):758. Epub 2018 Jan 31.

1 Biomedical Center, School of Life Sciences, Sun Yat-sen University, China.

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http://dx.doi.org/10.1177/2047487318756693DOI Listing
May 2018

Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling.

J Transl Med 2017 Nov 25;15(1):238. Epub 2017 Nov 25.

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Baiyun District, Guangzhou, Guangdong, China.

Background And Aims: Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development.

Methods: The CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Luciferase reporter, chromatin immunoprecipitation (ChIP) and DNA pull-down assays were used to verify the transcription regulation of activating transcription factor-2 (ATF2).

Results: PTHLH was significantly upregulated in ICC compared with adjacent and normal tissues. Upregulation of PTHLH indicated a poor pathological differentiation and intrahepatic metastasis. Functional study demonstrated that PTHLH silencing markedly suppressed ICC cells growth, while specific overexpression of PTHLH has the opposite effect. Mechanistically, secreted PTHLH could promote ICC cell growth by activating extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and subsequently upregulated ATF2 and cyclinD1 expression. Further study found that the promoter activity of PTHLH were negatively regulated by ATF2, indicating that a negative feedback loop exists.

Conclusions: Our findings demonstrated that the ICC-secreted PTHLH plays a characteristic growth-promoting role through activating the canonical ERK/JNK-ATF2-cyclinD1 signaling pathways in ICC development. We identified a negative feedback loop formed by ATF2 and PTHLH. In this study, we explored the therapeutic implication for ICC patients.
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http://dx.doi.org/10.1186/s12967-017-1342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702246PMC
November 2017

Advanced Oxidation Protein Products Induce Epithelial-Mesenchymal Transition of Intestinal Epithelial Cells via a PKC δ-Mediated, Redox-Dependent Signaling Pathway.

Antioxid Redox Signal 2017 07 30;27(1):37-56. Epub 2016 Sep 30.

1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .

Aims: Epithelial-mesenchymal transition (EMT) has been considered a fundamental mechanism in complications of Crohn's disease (CD), especially intestinal fibrosis. However, the mechanism underlying EMT regulation in intestinal fibrosis remains unclear. This study aimed to investigate the role of advanced oxidation protein products (AOPPs) in the occurrence of intestinal EMT.

Results: AOPPs accumulated in CD tissues and were associated with EMT marker expression in fibrotic lesions from CD patients. Challenge with AOPPs induced intestinal epithelial cell (IEC) phenotype transdifferentiation, fibroblast-like phenotype acquisition, and production of extracellular matrix, both in vitro and in vivo. The effect of AOPPs was mainly mediated by a protein kinase C (PKC) δ-mediated redox-dependent pathway, including phosphorylation of PKC δ, recruitment of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, production of reactive oxygen species, and NF-κB p65 activation. Inhibition of AOPP-redox signaling activation effectively blocked AOPP-induced EMT in vitro. Studies performed in normal rats showed that chronic administration of AOPPs triggered the occurrence of EMT in rat intestinal epithelia, accompanied by disruption of intestinal integrity, and by promotion of collagen deposition. These effects could be reversed by inhibition of NADPH oxidase. Innovation and Conclusion: This is the first study to demonstrate that AOPPs triggered the occurrence of EMT in IECs in vitro and in vivo through PKC δ-mediated redox-dependent signaling. Our study identifies the role of AOPPs and, in turn, EMT in intestinal fibrosis and provides novel potential targets for the treatment of intestinal fibrotic diseases. Antioxid. Redox Signal. 27, 37-56.
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http://dx.doi.org/10.1089/ars.2015.6611DOI Listing
July 2017

Improved 1, 2, 4-butanetriol production from an engineered Escherichia coli by co-expression of different chaperone proteins.

World J Microbiol Biotechnol 2016 Sep 18;32(9):149. Epub 2016 Jul 18.

The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122, China.

1, 2, 4-Butanetriol (BT) is a high-value non-natural chemical and has important applications in polymers, medical production and military industry. In the constructed BT biosynthesis pathway from xylose in Escherichia coli, the xylose dehydrogenase (Xdh) and the benzoylformate decarboxylase (MdlC) are heterologous enzymes and the activity of MdlC is the key limiting factor for BT production. In this study, six chaperone protein systems were introduced into the engineered E. coli harboring the recombinant BT pathway. The chaperone GroES-GroEL was beneficial to Xdh activity but had a negative effect on MdlC activity and BT titer. The plasmid pTf16 containing the tig gene (trigger factor) was beneficial to Xdh and MdlC activities and improved the BT titer from 0.42 to 0.56 g/l from 20 g/l xylose. However, co-expression of trigger factor and GroES-GroEL simultaneously reduced the activity of MdlC and had no effect on the BT production. The plasmid pKJE7 harboring dnaK-dnaJ-grpE showed significant negative effects on these enzyme activities and cell growth, leading to completely restrained the BT production. Similarly, co-expression of DnaKJ-GrpPE and GroES-GroEL simultaneously reduced Xdh and MdlC activities and decreased the BT titer by 45.2 %. The BT production of the engineered E. coli harboring pTf16 was further improved to the highest level at 1.01 g/l under pH control (pH 7). This work showed the potential application of chaperone proteins in microorganism engineering to get high production of target compounds as an effective and valuable tool.
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http://dx.doi.org/10.1007/s11274-016-2085-5DOI Listing
September 2016

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation.

Development 2016 06;143(11):1937-47

Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h(flox) mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27(Kip1) (Cdkn1b) and p57(Kip2) (Cdkn1c) gene expression. The abnormal Snf2h(-/-) fiber cells also retain their nuclei. RNA profiling of Snf2h(-/) (-) and Brg1(-/-) eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIβ, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation.
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http://dx.doi.org/10.1242/dev.135285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920164PMC
June 2016

Effect of CPU-XT-008, a combretastatin A-4 analogue, on the proliferation, apoptosis and expression of vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells.

Oncol Lett 2016 Jan 5;11(1):491-499. Epub 2015 Nov 5.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, P.R. China.

The present study investigated the effect of the combretastatin A-4 analogue CPU-XT-008 on the proliferation, apoptosis and expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) in human umbilical vein endothelial cells (HUVECs). The proliferation capacity of HUVECs was analyzed with a cell viability assay, while their apoptosis and migration abilities were evaluated via flow cytometry and monolayer denudation assay, respectively. The mRNA and protein expression levels of VEGF and FGF-2 in these cells were determined by reverse transcription-polymerase chain reaction, and cell-based ELISA, western blotting and immunocytochemistry, respectively. The results demonstrated that CPU-XT-008 inhibited proliferation and migration, and induced apoptosis in HUVECs in a dose-dependent manner. In addition, CPU-XT-008 downregulated the mRNA and protein expression levels of VEGF and FGF-2 in these cells. These findings suggest that CPU-XT-008 exerts anti-angiogenic effects in HUVECs, which may explain the inhibition of cell proliferation and migration, induction of apoptosis, and reduction in the mRNA and protein expression levels of VEGF and FGF-2 observed in the present study.
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http://dx.doi.org/10.3892/ol.2015.3867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727199PMC
January 2016

Lysine Methyltransferase SETD7 (SET7/9) Regulates ROS Signaling through mitochondria and NFE2L2/ARE pathway.

Sci Rep 2015 Oct 5;5:14368. Epub 2015 Oct 5.

Inflammation and Immunology Research Unit, Pfizer Research, Cambridge, MA 02139.

Reactive oxygen species (ROS) homeostasis requires stringent regulation. ROS imbalance, especially ROS accumulation, has profound implications in various disease pathogenesis. Lysine methylation of histone and non-histone proteins has been implicated in various cellular responses. The main objective of this study is to investigate the role of SET domain containing lysine methyltransferase SETD7 (SET7/9) in the regulation of ROS-mediated signaling. Here we report that inhibition of SETD7 with siRNA or a SETD7 small molecule inhibitor in both macrophages and a human bronchial epithelial cell line (Beas-2B) were able to counter NF-ĸB-induced oxidative stress and pro-inflammatory cytokine production. Meanwhile, inhibition of SETD7 elevates mitochondria antioxidant functions via negative regulation of PPARGC1A and NFE2L2. Using a co-expression system and purified proteins, we detected direct interaction between SETD7 and NFE2L2. These results indicate that lysine methylation by SETD7 is important for the fine-tuning of ROS signaling through its regulation on pro-inflammatory responses, mitochondrial function and the NFE2L2/ARE pathway. Up-regulation of multiple antioxidant genes and improved ROS clearance by inhibition of SETD7 suggests the potential benefit of targeting SETD7 in treating ROS-associated diseases.
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http://dx.doi.org/10.1038/srep14368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593030PMC
October 2015

Advanced oxidation protein products decrease the expression of calcium transport channels in small intestinal epithelium via the p44/42 MAPK signaling pathway.

Eur J Cell Biol 2015 May 6;94(5):190-203. Epub 2015 Mar 6.

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. Electronic address:

Advanced oxidation protein products (AOPPs), novel protein markers of oxidative damage, accumulate in the plasma of patients with inflammatory bowel disease (IBD). Osteoporosis, which is closely related to the regulation of intestinal calcium transport channels (CTCs), is a prevalent extraintestinal complication of IBD and is associated with oxidative stress. However, the underlying mechanisms are unknown. The present study aimed to verify whether AOPPs inhibit CTCs in the small intestinal epithelium and to identify the underlying mechanisms that may contribute to IBD-associated osteoporosis. Normal Sprague-Dawley rats were treated with AOPP-modified rat serum albumin. The calcium ion level in serum was not significantly altered, while the duodenal expression of CTCs (e.g. transient receptor potential vanilloid [TRPV6], calbindin-D9k [CaBP-D9k], plasma membrane Ca(2+)-ATPase 1 [PMCA1], and Na(+)/Ca(2+) exchanger 1 [NCX1]) were decreased. In contrast, the levels of the related hormones that regulate calcium absorption including parathyroid hormone (PTH), 25-(OH)D₃, and 1,25-(OH)₂D₃ were increased, although the trend toward an increase in PTH levels was not significant. In order to further investigate the effects of AOPP exposure, we also evaluated the expression of CTCs (including the voltage-dependent L-type calcium channel [CaV1.3], TRPV6, CaBP-D9k, PMCA1, and NCX1) in cultured human colorectal adenocarcinoma cells (Caco-2). The expression levels of total CTC protein and mRNA, except for CaV1.3, were significantly down-regulated in a concentration- and time-dependent manner. Moreover, phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) was observed in vivo and in vitro. The p44/42 inhibitor U0126 reversed the down-regulation of CTCs induced by AOPPs in the Caco-2 monolayer. Our results indicate that AOPPs down-regulate the expression of CTCs through p44/42 MAPK signaling mechanisms in the small intestinal epithelium. These data provide new insights regarding the molecular basis of AOPP-induced reductions in intestinal CTCs, and are relevant to understanding the mechanisms of IBD-associated osteoporosis. Further studies are needed to explore these mechanisms in greater detail.
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http://dx.doi.org/10.1016/j.ejcb.2015.02.002DOI Listing
May 2015

Effect of heparin-derived oligosaccharide on bFGFR1 and bFGFR2 in vascular smooth muscle cells.

Vasc Endovascular Surg 2014 May 27;48(4):289-96. Epub 2014 Jan 27.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.

Our purpose is to investigate the inhibitory effect and mechanisms of heparin-derived oligosaccharide (HDO) on proliferation of vascular smooth muscle cells (VSMCs) induced by basic fibroblast growth factor (bFGF). Proliferation of VSMCs was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; cell cycle distribution was analyzed by flow cytometry; bFGF receptor 1 and receptor 2 (bFGFR1 and bFGFR2) messenger RNA (mRNA) expression levels were determined by reverse transcription-polymerase chain reaction; and its protein expression levels were detected by Western blotting and immunocytochemical methods. Results showed that HDO inhibited VSMC proliferation in a dose-dependent manner; HDO inhibited cells in G1 phase entering the S phase; HDO inhibited bFGFR1 and bFGFR2 mRNA expression levels. In addition, bFGFR1 and bFGFR2 protein expression levels were significantly inhibited by HDO dose dependently. These results imply that HDO can inhibit VSMC proliferation. The proliferation of bFGF-induced VSMCs by HDO is associated with the inhibition of bFGFR1 and bFGFR2 expression levels. This altered molecular signature may explain one mechanism of HDO-mediated inhibition of VSMC proliferation.
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http://dx.doi.org/10.1177/1538574413520518DOI Listing
May 2014

Effects of high nutrient intake on the growth performance, intestinal morphology and immune function of neonatal intra-uterine growth-retarded pigs.

Br J Nutr 2013 Nov 19;110(10):1819-27. Epub 2013 Apr 19.

Institute of Animal Nutrition, Sichuan Agricultural University, No. 211, Huimin Road, Wenjiang District, Chengdu, Sichuan 611130, People's Republic of China.

Intra-uterine growth-retarded (IUGR) neonates have shown an impairment of postnatal intestinal development and function. We hypothesised that the immune function of IUGR neonates might be affected by increased nutrient intake (NI) during the suckling period. Therefore, we investigated the effects of high NI (HNI) on the growth performance, intestinal morphology and immunological response of IUGR and normal-birth weight (NBW) piglets. A total of twelve pairs of IUGR and NBW piglets (7 d old) were randomly assigned to two different nutrient-level formula milk groups. After 21 d of rearing, growth performance, the composition of peripheral leucocytes, serum cytokines and intestinal innate immune-related genes involved in the Toll-like receptor (TLR)-4–myeloid differentiation factor 88–NF-κB pathway were determined. The results indicated that IUGR decreased the average daily DM intake (ADMI) and the average daily growth (ADG). However, the ADMI and ADG were increased by HNI, irrespective of body weight. Likewise, serum cytokines (TNF-α and IL-1β) and ileal gene expressions (TLR-4, TLR-9, TRAF-6 and IL-1β) were lower in IUGR piglets, whereas HNI significantly increased blood lymphocyte percentage and serum IL-10 concentrations, but decreased neutrophil percentage, serum IL-1β concentrations and ileal gene expressions (NF-kB and IL-1β). Furthermore, IUGR piglets with HNI exhibited lower serum concentrations of TNF-α and IL-1β than NBW piglets, and these alterations in the immune traits of IUGR piglets receiving HNI were accompanied by decreasing ileal gene expressions of TLR-4, TLR-9, NF-κB and IL-1β that are related to innate immunity. In conclusion, the present findings suggest that increased NI during the suckling period impaired the immune function of neonatal piglets with IUGR.
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http://dx.doi.org/10.1017/S0007114513001232DOI Listing
November 2013

Effect of heparin-derived oligosaccharide on vascular smooth muscle cell proliferation and the signal transduction mechanisms involved.

Cardiovasc Drugs Ther 2012 Dec;26(6):479-88

School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.

Purpose: In this study, the effect of heparin-derived oligosaccharide (HDO) on vascular endothelial growth factor (VEGF) induced vascular smooth muscle cell (VSMC) proliferation and the signal transduction mechanisms involved were investigated.

Methods: MTT assays were used to measure VSMC proliferation, flow cytometry to analyze cell cycle distribution, RT-PCR for detection of gene transcript levels, and cell-based ELISA, Western blotting and immunocytochemical methods to detect the expression of PKC-α, ERK 1/2, p-ERK 1/2, Akt, p-Akt, p-PDK1 and p-GSK-3β.

Results: HDO at concentrations of 0.01, 0.1 and 1 μmol·L(-1) dose-dependently inhibited VEGF-induced VSMC proliferation with inhibition indices of 6.8 %, 13.1 % and 28.9 %, respectively. Similar concentrations of HDO dose-dependently decreased the percentage of VEGF-induced cells in S phase to 3.6 %, 3.4 %, and 5.4 %, while increasing that of cells arrested in the G0/G1 phase to 80 %, 82 % and 83.6 %. HDO at 0.01, 0.1 or 1 μmol·L(-1) inhibited VEGF-induced PKC-α mRNA expression, with inhibition indices of 9.2 %, 16.1 % and 54.0 %. HDO at 0.1 or 1 μmol·L(-1) inhibited VEGF-induced proto-oncogene mRNA expression, with inhibition indices of 5.2 % and 6.6 % for c-jun, 8.8 % and 11.6 % for c-myc, and 6.5 % and 11.9 % for c-fos, respectively. Additionally, treatment with 0.01, 0.1 or 1 μmol·L(-1) HDO, inhibited VEGF-induced expression of some proliferation related proteins with inhibition indices of 33.2 %, 56.3 % and 77.0 % for PKC-α, 33.7 %, 38.7 % and 53.2 % for p-Akt, 3.5 %, 24.2 % and 49.3 % for p-ERK 1/2, 39.2 %, 71.8 % and 80.7 % for p-PDK 1 and 41.4 %, 89.4 % and 92.4 % for p-GSK-3β, respectively. The results showed that HDO inhibited PKC-α, c-jun, c-fos and c-myc mRNA transcription, and also down-regulated phosphorylation levels of ERK 1/2 and Akt.

Conclusion: Our study demonstrates that HDO inhibits transcription of proliferation-related proto-oncogenes and arrests G1/S transition through inhibition of the PKC, MAPK and Akt/PI3K pathways in association with inhibition of VSMC proliferation. This altered molecular signature may explain one mechanism of HDO-mediated inhibition of VSMC proliferation.
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http://dx.doi.org/10.1007/s10557-012-6419-8DOI Listing
December 2012

Spatial expression patterns of autophagy genes in the eye lens and induction of autophagy in lens cells.

Mol Vis 2012 30;18:1773-86. Epub 2012 Jun 30.

Department of Biomedical Science, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431, USA.

Purpose: Mutation of the autophagy gene FYVE (named after the four cysteine-rich proteins: Fab 1 [yeast orthologue of PIKfyve], YOTB, Vac 1 [vesicle transport protein], and EEA1) and coiled coil containing 1 (fyco1) causes human cataract suggesting a role for autophagy in lens function. Here, we analyzed the range and spatial expression patterns of lens autophagy genes and we evaluated whether autophagy could be induced in lens cells exposed to stress.

Methods: Autophagy gene expression levels and their spatial distribution patterns were evaluated between microdissected human lens epithelium and fibers at the mRNA and protein levels by microarray data analysis, real-time PCR and western blot analysis. Selected autophagy protein spatial expression patterns were also examined in newborn mouse lenses by immunohistochemistry. The autophagosomal content of cultured human lens epithelial cells was determined by counting the number of microtubule-associated protein 1 light chain 3B (LC3B)-positive puncta in cells cultured in the presence or absence of serum.

Results: A total of 42 autophagy genes were detected as being expressed by human lens epithelium and fibers. The autophagosomal markers LC3B and FYCO1 were detected throughout the newborn mouse lens. Consistently, the autophagy active form of LC3B (LC3B II) was detected in microdissected human lens fibers. An increased number of LC3B-positive puncta was detected in cultured lens cells upon serum starvation suggesting induction of autophagy in lens cells under stress conditions.

Conclusions: The data provide evidence that autophagy is an important component for the function of lens epithelial and fiber cells. The data are consistent with the notion that disruption of lens autophagy through mutation or inactivation of specific autophagy proteins could lead to loss of lens resistance to stress and/or loss of lens differentiation resulting in cataract formation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398491PMC
November 2012

Effect of heparin-derived oligosaccharide on vascular smooth muscle cell proliferation.

Vasc Endovascular Surg 2012 Jul 17;46(5):393-400. Epub 2012 May 17.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.

In this study, the effect of heparin-derived oligosaccharide on bovine vascular smooth muscle cell (VSMC) proliferation and signal transduction mechanism was investigated. Extracellular-signal-regulated kinase (ERK) 1/2 has been implicated in the regulation of various cellular functions including proliferation, and we sought to define a functional role for ERK 1/2 in an established proliferation model in order to find a possible mechanism for inhibition of VSMC proliferation by heparin-derived oligosaccharide. The VSMC proliferation model was developed by platelet-derived growth factor (PDGF), and the level of ERK 1/2 protein and messenger RNA was determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunocytochemical methods. Flow cytometry analysis indicated that heparin-derived oligosaccharide blocked PDGF-induced cell cycle progression by arresting cells in the G0/G1 phase. The results imply that heparin-derived oligosaccharide inhibits VSMC proliferation by moderating the gene and the phosphorylation levels of ERK 1/2, eventually blocking G1/S transition, may be one of the mechanisms for inhibition of VSMC proliferation by heparin-derived oligosaccharide.
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http://dx.doi.org/10.1177/1538574412442595DOI Listing
July 2012

Focus on molecules: Brg1: a range of functions during eye development.

Exp Eye Res 2012 Oct 24;103:117-8. Epub 2011 Sep 24.

Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue Bronx, NY 10461, USA.

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http://dx.doi.org/10.1016/j.exer.2011.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288191PMC
October 2012

Analysis of optic coherence tomography for congenital macular retinoschisis.

Eye Sci 2011 Jun;26(2):80-4

Aier Eye Hospital, Guangzhou 510080, China.

Purpose: To investigate the pathological characteristics of congenital macular retinoschisis by optic coherence tomography (OCT).

Methods: The data of 7 cases (14 eyes) with congenital macular retinoschisis were collected. Electroretinogram (ERG), fundus fluorecein angiography (FFA) and OCT examination were performed, respectively.

Results: The OCT images showed schisis cavity in all eyes. Schisis was confined to the fovea and parafovea in 2 eyes (1 patient). Schisis was involved in entire macular area in 12 eyes (6 patients). Inner nuclear layer (INL) schisis was seen in all eyes. Schisis was located at both INL and outer nuclear layer (ONL)/outer plexiform layer (OPL) in 2 of the 14 eyes. Besides the schisis cavity, small cysts within ganglion cell layer were found in 3 eyes. The small cysts were confined to parafoveal area. The OCT images of both eyes in one patient were similar but not exactly the same or symmetrical.

Conclusion: Morphology, extension and schisis location in congenital macular retinoschisis have respective diversity.
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http://dx.doi.org/10.3969/j.issn.1000-4432.2011.02.016DOI Listing
June 2011

[Macular morphology and function in patients with diabetic retinopathy without apparent visual loss].

Yan Ke Xue Bao 2010 Aug;25(1):41-3

Guangzhou Aier Eye Hospital,Guangzhou,510080,China.

Purpose: To investigate the macular morphology and function in patients with diabetic retinopathy(DR) without apparent visual loss.

Methods: Multifocal electroretinograms(mfERG) and optical coherence tomography(OCT) examination were performed in the DR patients on phase 0, 1 to 2, 3 to 4 as well as the normal control non-diabetes subjects.

Results: Macular edema was detected in DR phase 1 and 2 (3 eyes,10%) and DR phase 3 and 4 group (6 eyes,23.1%). In comparison with the normal control and DR phase 0 group,the thickness of retinal neuroepithelium increased in DR phase 3 and 4 group(P>0.05). The amplitude and the average density of P1 wave and N1 wave decreased in all DR groups in comparison with normal controls although the latency of P1 wave and N1 wave was not statistically significant (P>0.05).However,comparing with the DR phase 1 and 2 group,the latency of P1 wave and N1 waves were longer whereas the amplitude and the average density decreased in DR phase 3 and 4 group.

Conclusion: In the patients with DR but without apparent visual loss,abnormalities of the macular morphology and function already develop. The changes of function appear to develop earlier than that of morphology.
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http://dx.doi.org/10.3969/g.issn.1000-4432.2010.01.011DOI Listing
August 2010

Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation.

Epigenetics Chromatin 2010 Nov 30;3(1):21. Epub 2010 Nov 30.

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Background: Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2β) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs.

Results: To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific αA-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase IIβ, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase IIβ, for lens fiber cell denucleation and indirectly for retinal development.

Conclusions: These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase IIβ as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.
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http://dx.doi.org/10.1186/1756-8935-3-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003251PMC
November 2010

The effect of organic loading on bacterial community composition of membrane biofilms in a submerged polyvinyl chloride membrane bioreactor.

Bioresour Technol 2010 Sep 7;101(17):6601-9. Epub 2010 Apr 7.

State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.

The effect of organic loading on bacterial community composition of membrane biofilms was investigated using a submerged polyvinyl chloride membrane bioreactor. The low and high loadings were set at 0.33 and 0.52 gCOD/(gVSSd), respectively. The results showed that membrane fouling occurred earlier and faster under the high loading conditions. Denaturing gradient gel electrophoresis (DGGE) analysis revealed that the similarity of bacterial community in the membrane biofilms between the two loadings was 0.67, higher than that in the mixed liquors (0.52-0.55), which indicated that some specific bacteria were selected preferentially on the membranes. Clone library analysis of the membrane biofilms indicated that Betaproteobacteria and Bacteroidetes under the high loading were 54.72% and 19.81%, respectively. Microarray results further confirmed that the two bacteria were the dominant microorganisms in the high loading biofilm. The severe membrane fouling may be aroused mainly by the enrichment of the two bacteria under the high loading.
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http://dx.doi.org/10.1016/j.biortech.2010.03.082DOI Listing
September 2010

Increased expression ratio of Bcl-2/Bax is associated with crocin-mediated apoptosis in bovine aortic endothelial cells.

Basic Clin Pharmacol Toxicol 2007 Jan;100(1):31-5

Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, and The 81st Hospital of People's Liberation Army, Nanjing, China.

Crocin, extracted and purified from Gardenia jasminoids Ellis in our laboratory, has been reported to have antioxidative, hypolipidaemic and anti-atherosclerorotic effects. However, the underlying molecular mechanisms by which crocin acts as a cytoprotective agent remain to be elucidated. In the present study, we examined the mechanisms of crocin, the digentiobiosyl ester of crocetin, on bovine aortic endothelial cell apoptosis induced by hydrogen peroxide (H2O2). The cells were obtained from the thoracic aorta of newborn calves, and apoptosis was induced by 200 microM H2O2. Before addition of H2O2, the cells were pretreated with different concentrations of crocin for 6 hr. After incubation of the cells with H2O2, a comparative reverse transcriptase-polymerase chain reaction-based repeated amplification protocol assay was used to determine the ratio of bcl-2/bax mRNA expression, and cells loaded with fluo-3/AM were subjected to laser scanning confocal microscopy for detection of intracellular calcium ([Ca2+]i) levels. Treatment of the cells with H2O2 alone decreased the ratio of bcl-2/bax expression to almost twice of those of untreated cells (from 0.33+/-0.05 to 0.16+/-0.02). In the presence of 1 and 10 microM crocin, the ratios were enhanced when compared with H2O2 alone respectively (from 0.16+/-0.02 to 0.58+/-0.04, 1.18+/-0.13). The treatment of cells with crocin alone had little effect on the value of this ratio. In the presence or absence of extracellular Ca2+, H2O2 could induce intracellular calcium elevation not only in the elevation presence of extracellular Ca2+ (Hanks), but also without extracellular calcium present (D-Hanks). But the extent of [Ca2+]i under conditions lacking extracellular calcium is less. Crocin concentration dependently inhibited the [Ca2+]i elevation induced by H2O2 under these two conditions. Our data suggest that crocin may exert anti-atherosclerotic effects by increasing the expression ratio of bcl-2/bax, as a result, inhibiting the bovine aortic endothelial cell apoptosis that plays an important role in the initiation and progression of atherosclerosis.
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http://dx.doi.org/10.1111/j.1742-7843.2007.00001.xDOI Listing
January 2007