Publications by authors named "Guihua Lu"

34 Publications

Design, synthesis and biological evaluation of anilide (dicarboxylic acid) shikonin esters as antitumor agents through targeting PI3K/Akt/mTOR signaling pathway.

Bioorg Chem 2021 Mar 29;111:104872. Epub 2021 Mar 29.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address:

Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC = 4.52 ± 0.28 μM; SK: IC = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure-activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.
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http://dx.doi.org/10.1016/j.bioorg.2021.104872DOI Listing
March 2021

Value of pre-transplant consolidation chemotherapy in adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation without minimal residual disease in first complete remission.

Leuk Lymphoma 2021 04 11;62(4):952-959. Epub 2020 Nov 11.

Department of Hematology, Institute of Hematology, Changhai Hospital Affiliated to Navy Military Medical University, Shanghai, China.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended for adults acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) negative during their first complete remission (CR1). However, the role of pre-transplant consolidation chemotherapy remains unclear. We evaluated 78 CR1/MRD-negative patients, the consolidation and non-consolidation groups had similar 5-year OS (74.8% [95% CI: 62.2-87.3%] vs. 74.2% [95% CI: 53.2-95.1%],  = .894), RFS (72.2% [95% CI: 59.6-84.7%] vs. 73.1% [95% CI: 54.2-91.9%],  = .942), CIR (9.4% [95% CI: 9.1-9.7%] vs. 18.9% [95% CI: 17.3-20.4%],  = .376), and NRM (18.4% [95% CI: 17.7-19.0%] vs. 8.0% [95% CI: 7.3-8.6%],  = .375). Multivariable analysis confirmed that high cytogenetic risk independently predicted poor OS and RFS, although pre-transplant consolidation chemotherapy did not predict the prognosis. Based on these findings, we recommend performing transplantation immediately for adult ALL patients after they have achieved CR1/MRD-negative status when there are readily available donors.
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http://dx.doi.org/10.1080/10428194.2020.1845340DOI Listing
April 2021

Impact of a G2-EPSPS & GAT Dual Transgenic Glyphosate-Resistant Soybean Line on the Soil Microbial Community under Field Conditions Affected by Glyphosate Application.

Microbes Environ 2020 ;35(4)

Institute for Plant Molecular Biology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University.

In the past thirty years, the biosafety of the aboveground part of crops, including horizontal gene transferal through pollen dispersal and hybridization, has been the focus of research; however, microbial communities in the underground part are attracting increasing attention. In the present study, the soybean root-associated bacterial communities of the G2-EPSPS plus GAT transgenic soybean line Z106, its recipient variety ZH10, and Z106 treated with glyphosate (Z106J) were compared at the seedling, flowering, and seed filling stages by high-throughput sequencing of the V4 hypervariable regions of 16S rRNA gene amplicons using Illumina MiSeq. The results obtained showed no significant differences in the alpha/beta diversities of root-associated bacterial communities at the three stages among ZH10, Z106, and Z106J under field growth conditions; however, the relative abundance of four main nitrogen-fixing bacterial genera significantly differed among ZH10, Z106, and Z106J. Ternary plot results indicated that in the root compartment, the proportional contributions of rhizobial nitrogen-fixing Ensifer fredii and Bradyrhizobium elkanii, which exhibit an extremely broad nodulation host range, markedly differed among the three treatments at the three stages. Thus, the present results indicate that transgenic G2-EPSPS and GAT soybean may induce different changes in functional bacterial species in soil, such as E. fredii and B. elkanii, from ZH10, which were compensated for/enriched at the flowering and seed filling stages, respectively, to some extent through as of yet unknown mechanisms by transgenic soybean treated with glyphosate.
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http://dx.doi.org/10.1264/jsme2.ME20056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734404PMC
January 2020

Knockouts of a late flowering gene via CRISPR-Cas9 confer early maturity in rice at multiple field locations.

Plant Mol Biol 2020 Sep 4;104(1-2):137-150. Epub 2020 Jul 4.

Corteva™ Agriscience, Johnston, IA, USA.

Key Message: OsGhd7 gene was discovered by screening our rice activation tagging population. CRISPR-Cas9 created knockouts of OsGhd7 conferred early flowering and early maturity in rice varieties across multiple geographical locations in China. Our research shows that OsGhd7 is a good target for breeding early maturity rice varieties, and an excellent example of the advantages of applying the CRISPR-Cas9 technology for trait improvement. Flowering time (heading date) is an important trait for crop cultivation and yield. In this study, we discovered a late flowering gene OsGhd7 by screening our rice activation tagging population, and demonstrated that overexpression of OsGhd7 delayed flowering time in rice, and the delay in flowering time depended on the transgene expression level. OsGhd7 is a functional allele of the Ghd7 gene family; knockouts of OsGhd7 generated by CRISPR-Cas9 significantly accelerated flowering time and the earliness of the flowering time depended on field location. The homozygous OsGhd7 knockout lines showed approximately 8, 10, and 20 days earlier flowering than controls at three different locations in China (Changsha City, Sanya City, and Beijing City, respectively) that varied from 18.25° N to 39.90° N. Furthermore, knockouts of OsGhd7 also showed an early flowering phenotype in different rice varieties, indicating OsGhd7 can be used as a common target gene for using the CRISPR technology to modulate rice flowering time. The importance of OsGhd7 and CRISPR technology for breeding early maturity rice varieties are discussed.
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http://dx.doi.org/10.1007/s11103-020-01031-wDOI Listing
September 2020

, a Novel QTL for the Fertility Restoration of Maize CMS-C Identified by QTL-seq.

G3 (Bethesda) 2020 07 7;10(7):2457-2464. Epub 2020 Jul 7.

Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China and

C-type cytoplasmic male sterility (CMS-C), one of the three major CMS types in maize, has a promising application prospect in hybrid seed production. However, the complex genetic mechanism underlying the fertility restoration of CMS-C remains poorly understood. The maize inbred line A619 is one of the rare strong restorer lines carrying the restorer gene , but different fertility segregation ratios are found in several F populations derived from crosses between isocytoplasmic allonucleus CMS-C lines and A619. In the present study, the segregation ratios of fertile to sterile plants in the (CHuangzaosi × A619) F and BCF populations (36.77:1 and 2.36:1, respectively) did not follow a typical monogenic model of inheritance, which suggested that some F and BCF plants displayed restored fertility even without To determine the hidden locus affecting fertility restoration, next-generation sequencing-based QTL-seq was performed with two specific extreme bulks consisting of 30 fertile and 30 sterile individuals from the F population. A major QTL related to fertility restoration, designated , was detected on the long arm of chromosome 8 in A619. Subsequently, was further validated and narrowed down to a 17.93-Mb genomic interval by insertion and deletion (InDel) and simple sequence repeat (SSR) marker-based traditional QTL mapping, explaining 12.59% (LOD = 25.06) of the phenotypic variation. Thus, using genetic analyses and molecular markers, we revealed another fertility restoration system acting in parallel with in A619 that could rescue the male sterility of CHuangzaosi. This study not only expands the original fertility restoration system but also provides valuable insights into the complex genetic mechanisms underlying the fertility restoration of CMS-C.
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http://dx.doi.org/10.1534/g3.120.401192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341123PMC
July 2020

A cytokinin-activation enzyme-like gene improves grain yield under various field conditions in rice.

Plant Mol Biol 2020 Mar 23;102(4-5):373-388. Epub 2019 Dec 23.

Corteva Agriscience, Johnston, IA, USA.

Key Message: CRISPR-edited variants at the 3'-end of OsLOGL5's coding sequence (CDS), significantly increased rice grain yield under well-watered, drought, normal nitrogen, and low nitrogen field conditions at multiple geographical locations. Cytokinins impact numerous aspects of plant growth and development. This study reports that constitutive ectopic overexpression of a rice cytokinin-activation enzyme-like gene, OsLOGL5, significantly reduced primary root growth, tiller number, and yield. Conversely, mutations at the 3'-end of OsLOGL5 CDS resulted in normal rice plant morphology but with increased grain yield under well-watered, drought, normal nitrogen, and low nitrogen field conditions at multiple geographical locations. Six gene edited variants (Edit A to F) were created and tested in the field. Edit-B and Edit-F plants increased, but Edit-D and Edit-E plants decreased, the panicle number per plant. All OsLOGL5-edited plants significantly increased seed setting rate, total grain numbers, full-filled grain numbers per panicle, and thousand seed weight under drought conditions, suggesting that OsLOGL5 is likely involved in the regulation of both seed development and grain filling processes. Our results indicate that the C-terminal end of OsLOGL5 protein plays an important role in regulating rice yield improvement under different abiotic stress conditions, and OsLOGL5 is important for rice yield enhancement and stability.
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http://dx.doi.org/10.1007/s11103-019-00952-5DOI Listing
March 2020

CD51 distinguishes a subpopulation of bone marrow mesenchymal stem cells with distinct migratory potential: a novel cell-based strategy to treat acute myocardial infarction in mice.

Stem Cell Res Ther 2019 11 20;10(1):331. Epub 2019 Nov 20.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.

Background: Experimental and clinical trials have demonstrated the efficiency of bone marrow-derived mesenchymal stromal/stem cells (bMSCs) in the treatment of myocardial infarction. However, after intravenous injection, the ineffective migration of engrafted bMSCs to the hearts remains an obstacle, which has an undesirable impact on the efficiency of cell-based therapy. Therefore, we attempted to identify a marker that could distinguish a subpopulation of bMSCs with a promising migratory capacity.

Methods: Here, CD51-negative and CD51-positive cells were isolated by flow cytometry from Ter119CD45CD31bMSCs and cultured in specifically modified medium. The proliferation ability of the cells was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) staining or continuously monitored during culture, and the differentiation potential was assessed by culturing the cells in the appropriate conditioned media. Wound healing assays, transwell assays and quantitative polymerase chain reaction (qPCR) were used to measure the migratory ability. The mice were subjected to a sham operation or myocardial infarction (MI) by permanently occluding the coronary artery, and green fluorescent protein (GFP)-labelled cells were transplanted into the mice via intravenous infusion immediately after MI. Heart function was measured by echocardiography; infarct myocardium tissues were detected by triphenyl tetrazolium chloride (TTC) staining. Additionally, immunofluorescence staining was used to verify the characteristics of CD51bMSCs and inflammatory responses in vivo. Statistical comparisons were performed using a two-tailed Student's t test.

Results: In this study, the isolated CD51bMSCs and CD51bMSCs, especially the CD51 cells, presented a favourable proliferative capacity and could differentiate into adipocytes, osteocytes and chondrocytes in vitro. After the cells were transplanted into the MI mice by intravenous injection, the therapeutic efficiency of CD51bMSCs in improving left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) was better than that of CD51bMSCs. Compared with CD51bMSCs, CD51bMSCs preferentially migrated to and were retained in the infarcted hearts at 48 h and 8 days after intravenous injection. Accordingly, the migratory capacity of CD51bMSCs exceeded that of CD51bMSCs in vitro, and the former cells expressed higher levels of chemokine receptors or ligands. Interestingly, the retained CD51bMSCs retained in the myocardium possessed proliferative potential but only differentiated into endothelial cells, smooth muscle cells, fibroblasts or cardiomyocytes. Transplantation of CD51bMSCs partially attenuated the inflammatory response in the hearts after MI, while the potential for inflammatory suppression was low in CD51bMSC-treated mice.

Conclusions: These findings indicated that the CD51-distinguished subpopulation of bMSCs facilitated proliferation and migration both in vitro and in vivo, which provided a novel cell-based strategy to treat acute MI in mice by intravenous injection.
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http://dx.doi.org/10.1186/s13287-019-1439-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865070PMC
November 2019

Spironolactone suppresses aldosterone-induced Kv1.5 expression by attenuating mineralocorticoid receptor-Nox1/2/4-mediated ROS generation in neonatal rat atrial myocytes.

Biochem Biophys Res Commun 2019 12 9;520(2):379-384. Epub 2019 Oct 9.

Department of Cardiology, Heart Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address:

Our previous investigation indicated that angiotensin II (Ang II) enhances the expression of Kv1.5, a promising target for the treatment of atrial fibrillation (AF), by activating reactive oxygen species (ROS)-dependent phosphorylation of Smad 2/3 (forming P-Smad 2/3) and ERK 1/2 (forming P-ERK 1/2). A recent study indicated that aldosterone (Aldo) upregulates atrial Kv1.5 protein in a rat AF model, but the mechanism remains unknown. The present study aimed to clarify the mechanism underlying Aldo-induced Kv1.5 expression and to test whether spironolactone may modulate atrial Kv1.5. Our Western blot analysis indicated that the Aldo/mineralocorticoid receptor (MR) interacts with Ang II/ATR in upregulating Kv1.5 expression in cultured neonatal atrial myocytes (NRAMs). Blockade of MR with spironolactone and of ATR with losartan significantly suppressed Kv1.5 expression induction by combined Aldo and Ang II treatment. Aldo increased the protein expression of Nox1, Nox2 and Nox4, but this effect was abolished by spironolactone pretreatment. The Aldo-induced upregulation of Kv1.5 was also reversed by the Src protein tyrosine kinase family inhibitor PP2, the Nox2 inhibitor gp91ds-tat and the Nox1/Nox4 inhibitor GKT137831 but not by the Rac GTPase inhibitor NSC23766. Flow cytometry showed that the Aldo-induced ROS production was inhibited by spironolactone, PP2, gp91ds-tat and GKT137831. Spironolactone suppressed the Aldo-induced protein expression phosphorylated Src (P-Src), P-Smad 2/3 and P-ERK 1/2. In conclusion, we have demonstrated that spironolactone suppresses Aldo-induced Kv1.5 expression by attenuating MR-Nox1/2/4-mediated ROS generation in NRAMs.
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http://dx.doi.org/10.1016/j.bbrc.2019.10.039DOI Listing
December 2019

Inhibition of perivascular mast cell activation is involved in the atheroprotective effect of rosiglitazone in apolipoprotein E-deficient mice.

Biochem Biophys Res Commun 2019 11 5;519(2):261-266. Epub 2019 Sep 5.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address:

Activation of perivascular mast cells (MCs) and subsequent release of their abundant inflammatory mediators have been well documented to induce excessive inflammation and subsequent rupture of atherosclerotic plaques. Previous studies have suggested that rosiglitazone affects the stability of plaques, although the precise mechanism of action is not clearly understood. In this study, we evaluated the effects of rosiglitazone on MCs in vivo and in vitro. Apolipoprotein E-deficient (ApoE) mice were fed a high-fat diet (HFD), with or without rosiglitazone supplemented in the drinking water (1.5 mg/kg/day). Compared with the HFD group, rosiglitazone did not affect blood glucose levels, but it attenuated serum levels of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), ameliorated plaque lipid accumulation and the expression of matrix metalloproteinases-2 and -9, increased the collagen content of plaques, and inhibited perivascular MC degranulation and chymase expression. The in vitro experiments showed that rosiglitazone treatment repressed the expression of TNFα and IL-6 induced by antigen-challenged RBL-2H3 cells in a peroxisome proliferator-activated receptor γ (PPARγ)-independent manner, which was related to the repression of protein kinase C (PKC)-β1 activation. Combined, these results suggest that the plaque-stabilizing effect of rosiglitazone is attributable to its ability to inhibit the activation of perivascular MCs.
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http://dx.doi.org/10.1016/j.bbrc.2019.08.146DOI Listing
November 2019

Detection of Acute Myocardial Infarction in a Pig Model Using the SAN-Atrial-AVN-His (SAAH) Electrocardiogram (ECG), Model PHS-A10, an Automated and Integrated Signals Recognition System.

Med Sci Monit 2018 Mar 4;24:1303-1309. Epub 2018 Mar 4.

Division of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, China (mainland).

BACKGROUND The aim of this study was to compare the use of the standard 12-lead electrocardiogram (ECG) with the SAN-Atrial-AVN-His (SAAH) ECG (Model PHS-A10), a new automated and integrated signals recognition system that detects micro-waveforms within the P, QRS, and T-wave, in a pig model of acute myocardial infarction (MI). MATERIAL AND METHODS Six medium-sized domestic Chinese pigs underwent general anesthesia, and an angioplasty balloon was placed and dilated for 120 minutes in the first diagonal coronary artery arising from the left anterior descending (LAD) coronary artery. A standard ECG and a SAAH ECG (Model PHS-A10) were used to evaluate: 1) the number of wavelets in ST-T segment in lead V5; 2) the duration of the repolarization initial (Ri), or duration of the wavelets starting from the J-point to the endpoint of the wavelets in the ST interval; 3) the duration of the repolarization terminal (Rt), of the wavelets, starting from the endpoint of the wavelets in the ST interval to the cross-point of the T-wave and baseline; 4) the ratio Ri: Rt. RESULTS Following coronary artery occlusion, duration of Ri and Ri/Rt increased, and Rt decreased, which was detected by the SAAH ECG (Model PHS-A10) within 12 seconds, compared with standard ECG that detected ST segment depression at 24 seconds following coronary artery occlusion. CONCLUSIONS The findings from this preliminary study in a pig model of acute MI support the need for clinical studies to evaluate the SAAH ECG (Model PHS-A10) for the early detection of acute MI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846368PMC
http://dx.doi.org/10.12659/msm.905961DOI Listing
March 2018

Prewire channel stent: a novel stent for bifurcation lesions in a pig model.

EuroIntervention 2018 02 2;13(15):e1816-e1822. Epub 2018 Feb 2.

Division of Cardiology, First Affiliated Hospital to Hainan Medical College, Haikou, China.

Aims: Avoiding side branch occlusion is challenging when treating bifurcation lesions. A newly designed stent system called the prewire channel stent (PWCS) with a side channel positioned between the metallic mesh material and the balloon is introduced. We aimed to compare the time taken to position the PWCS against that for a conventional stent.

Methods And Results: The PWCS and a conventional stent were used in a pig model. The time taken from the starting point with the stent outside the body to reaching the bifurcation of the vessel ready for further procedures such as balloon dilatation through the stent mesh opening and double kissing balloon technique, etc., was compared in the conventional stent and PWCS groups. The time taken in the PWCS stent group included the time from sending the stent from outside the body to the desired position of the bifurcation of the vessels of the heart, releasing the stent and pulling back the balloon (SB time). The time taken in the conventional stent included the time from sending the stent from outside the body to the desired position of the bifurcation of the vessels of the heart, releasing the stent, pulling back the balloon (SB time), and wire exchange (WE time). The SB times for the PWCS and the conventional stent groups were not different (28.5±3.8 vs. 25.25±0.75 seconds, n=4). The PWCS group did not have "wire exchange," and had no WE time, which was 28.5±5.7 seconds in the conventional stent group. The total time spent in the PWCS group was 28.5±3.8 seconds, which was shorter than the 53.75±6.2 seconds (n=4, p<0.05) in the conventional stent group.

Conclusions: The PWCS makes "wire exchange" in the side branch (SB) unnecessary and it can be as easily manipulated as a conventional stent.
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http://dx.doi.org/10.4244/EIJ-D-17-00513DOI Listing
February 2018

Climate and drought risk regionalisation in China based on probabilistic aridity and drought index.

Sci Total Environ 2018 Jan 1;612:513-521. Epub 2017 Sep 1.

College of Hydrology and Water Resources, Hohai University, No.1 Xikang Road, Nanjing 210098, China.

The general approach to drought regionalisation regards the multi-year average values of drought indexes as regionalisation indicators, without taking long-term variability into account. This type of regionalisation is known as static regionalisation, or mean regionalisation, and does not consider possible variations over multiple years. In order to analyse the probability of climate aridity and drought, in this study, we firstly introduce the novel concept of a probabilistic aridity index for climate regionalisation and a drought index for drought risk regionalisation, as well as a methodology for estimating the frequency of the probabilistic aridity and drought index. Details of the approach used in the regionalisation of aridity and drought risk, and its associated characteristics, are then discussed. Finally, the value of our approach is demonstrated in China. The result shows that climate and drought risk regionalisation is able to provide enriched aridity and drought probability information compared with general climate and drought regionalisation, and can thus provide enhanced technical support for the rational allocation of water resources and the prevention and mitigation of drought disasters.
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http://dx.doi.org/10.1016/j.scitotenv.2017.08.078DOI Listing
January 2018

Antiviral activity of a synthesized shikonin ester against influenza A (H1N1) virus and insights into its mechanism.

Biomed Pharmacother 2017 Sep 5;93:636-645. Epub 2017 Jul 5.

State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address:

This study aimed to examine the antiviral effects of shikonin ester ((R)-1-(5, 8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl3-(1H- indol-3-yl) propanoate (PMM-034) against influenza A (H1N1) virus. We investigated PMM-034 anti-H1N1 activity and its effect on caspase 3 gene expression during cellular apoptosis after influenza virus infection in vitro. Neuraminidase (NA) inhibition was assessed in comparison with oseltamivir in the influenza virus standard strains A/PR/8/34 to understand the viral mechanism. MDCK and A549 cells were used to investigate influenza viral infection and the structure-activity relationship between PMM-034 and NA was evaluated by pharmacophore-based docking modeling. The production of viral protein was tested by western blot. A/PR/8/34 induced cell inhibition but this was reduced by PMM-034 to 16μg/mL and this showed a selective index of 10mM. PMM-034 inhibited NA in a dose dependent manner, similar to oseltamivir inhibition. A sharp decrease in viral nucleocapsid protein mRNA was observed in infected cells after treatment with PMM-034. Apoptosis of infected A459 cells was inhibited by PMM-034 with decreased caspase 3 levels. ARG 118, ARG 152, ARG 371 and GLU 227 in the binding pocket of NA bound to PMM-034 in the docking model. Taken together, these results suggest PMM-034 shikonin ester blocked H1N1 infection and might be a potential anti-H1N1 drug.
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http://dx.doi.org/10.1016/j.biopha.2017.06.076DOI Listing
September 2017

Selenium modulates MMP2 expression through the TGFβ1/Smad signalling pathway in human umbilical vein endothelial cells and rabbits following lipid disturbance.

J Trace Elem Med Biol 2017 Jul 23;42:59-67. Epub 2017 Apr 23.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Background: A high-fat diet is a major risk factor for coronary heart diseases. Matrix metalloprotease (MMP) expression is changed in many cardiovascular diseases. Selenium, which is an important trace element in animals, has a close relationship with cardiovascular diseases. The TGFβ1/Smad signalling pathway is ubiquitous in diverse tissues and cells, and it is also associated with the occurrence and development of cardiovascular diseases. Therefore, in this study, we aimed to determine selenium's effect on lipid metabolism, atherosclerotic plaque formation, and MMP2 expression, as well as the underlying functional mechanism.

Methods And Results: In vivo tests: 24 male New Zealand white rabbits were randomly divided into 4 groups: regular diet, high-fat diet, high-fat diet+selenium and regular diet+selenium groups. The high-fat diet induced the lipid disturbances of rabbits at week 12. Selenium supplementation lowered total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels (p<0.01). Selenium supplementation also suppressed MMP2 over-expression in thoracic aortas. In vitro tests: Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of selenium or ox-LDL. Ox-LDL promoted MMP2 expression by increasing TGFβ1, pSmad2, pSmad3 and Smad3 expression (p<0.01). Selenium attenuated MMP2 over-expression by regulating the TGFβ1/Smad signalling pathway.

Conclusions: Selenium suppressed high-fat diet-induced MMP2 over-expression in vivo by improving lipid metabolism. In vitro, selenium attenuated MMP2 over-expression through the TGFβ1/Smad signalling pathway.
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http://dx.doi.org/10.1016/j.jtemb.2017.04.006DOI Listing
July 2017

Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.

Cardiovasc Ther 2017 Apr;35(2)

Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.

Aims: Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects.

Methods: Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II.

Results: After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts.

Conclusions: Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.
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http://dx.doi.org/10.1111/1755-5922.12246DOI Listing
April 2017

HS inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation.

Biochem Biophys Res Commun 2017 01 21;483(1):534-540. Epub 2016 Dec 21.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Our previous study demonstrated that angiotensin II (Ang II) upregulates the expression of Kv1.5, a promising target for atrial fibrillation (AF) therapy, by activating ROS-dependent P-Smad2/3 and P-ERK 1/2. A recent study showed that hydrogen sulfide (HS) may modulate the effects of angiotensin II (Ang II) by inhibiting the NADPH oxidase 4 (Nox4)-ROS signaling in the heart. The present study aimed to determine whether HS is involved in the regulation of atrial Kv1.5 via ROS-related mechanisms in AF. Cultured neonatal rat atrial myocytes and a beagle model of AF were used for this study. In the neonatal rat atrial myocytes, quantitative PCR and enzyme immunoassays revealed that the mRNA expression levels of angiotensinogen, angiotensin-converting enzyme, and Ang II type I receptor (ATR) and the Ang II supernatant concentration were significantly increased by hydrogen peroxide (HO) incubation, and these HO-induced alterations were reversed by diphenyleneiodonium, apocynin and HS supplementation. Flow cytometry and Western blotting revealed that blockade of HS biosynthesis using dl-propargylglycine increased ROS production and the expression of Ang II and Kv1.5. Sodium hydrosulfide (an exogenous HS donor) and Nox4 siRNA inhibited Ang II-induced ROS production and Ang II-induced expression of Kv1.5, P-Smad2/3, P-ERK 1/2. Sodium hydrosulfide suppressed the Ang II-induced upregulation of Nox4. In our beagle AF model, 24 h of rapid atrial pacing (RAP) increased the atrial Ang II concentration, ROS production and the protein expression of Nox4, Kv1.5, P-Smad2/3 and P-ERK 1/2. These RAP-induced changes were inhibited by HS supplementation and losartan (an ATR blocker) pretreatment. In conclusion, our study indicates that HS downregulates Ang II-induced atrial Kv1.5 expression by attenuating Nox4-related ROS-triggered P-Smad2/3 and P-ERK 1/2 activation during AF. HS supplementation would be beneficial for AF treatment via the suppression of atrial Kv1.5 expression.
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http://dx.doi.org/10.1016/j.bbrc.2016.12.110DOI Listing
January 2017

Spatio-temporal analysis of drought in a typical plain region based on the soil moisture anomaly percentage index.

Sci Total Environ 2017 Jan 31;576:752-765. Epub 2016 Oct 31.

Institute of Water Problems, College of Hydrology and Water Resources, Hohai University, Nanjing 210098, China.

Drought strongly affects the agricultural economy, most severely in plain regions, with prosperous agricultural development, which suffer huge economic losses. An effective index is required to describe the process of drought initiation, development, and alleviation, and soil moisture is a vital variable with respect to agricultural drought as a comprehensive variable. In this study, Jiangsu province was selected as a typical plain region, the VIC (Variable Infiltration Capacity) model was used to simulate soil moisture at a resolution of 0.125°×0.125°, and the soil moisture anomaly percentage index (SMAPI) was established for drought identification and investigation of drought spatio-temporal characteristics between 1956 and 2011. The results show that the VIC model built in our study is feasible, and the simulated 3-layer daily soil moisture database can be used in drought studies as an alternative to measured soil moisture. The droughts in the northern part of the province are more severe than those in the southern part, and Xuzhou is the most frequently affected city. There are no strong trends of drought duration in 13 cities of Jiangsu province. Among the 13 cities, drought intensity decreases as drought duration increases for the same drought area, and drought intensity decreases with drought area for the same drought duration. The methods used here in our study to build the VIC model for plain regions that lack closed basin hydrologic data may be helpful for further studies of VIC, and the regional analysis of drought can provide a powerful reference for regional drought prevention and resistance in Jiangsu province.
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http://dx.doi.org/10.1016/j.scitotenv.2016.10.116DOI Listing
January 2017

C-Reactive Protein and Inflammatory Cytokines during Percutaneous Coronary Intervention.

J Vasc Res 2016 4;53(1-2):39-48. Epub 2016 Aug 4.

Division of Cardiology, Xiangtan Central Hospital, Xiangtan, PR China.

Background: C-reactive protein (CRP) is significantly associated with cardiovascular diseases; however, whether CRP plays a causal role in coronary artery disease has yet to be determined. In addition, the relationship between CRP, atherosclerosis, and inflammation remains controversial.

Methods And Results: Serum interleukin (IL)-6, IL-1β, and CRP levels were determined in 160 patients at time points around percutaneous coronary intervention (PCI) with drug-eluting stent implantation. The levels were found to be at peak at 24 h post-PCI and gradually declined to the level before PCI at day 30 post-PCI. These inflammation markers around PCI have no statistical difference in the different postdilation pressures (≤14, 14-18, and ≥18 atm) and stent number (1 and ≥2 stents) groups. Treatment of cultured human vascular smooth muscle cells (VSMCs) with a combination of IL-6 and IL-1β at concentrations associated with PCI did not result in any significant change in the CRP mRNA levels. The IL-6-augmented CRP expression in human internal mammary arteries (IMAs) stretched with a mechanical strength of 3 g was blocked by the nuclear factor-κB (NF-κB) peptide inhibitor SN50 and not by the inactive SN50 analog SN50M. IL-6 treatment increased NF-κB activity in human IMAs stretched with 3 g, and this effect was further blocked by stretch-activated channel (SAC) inhibitors (streptomycin or GdCl3) and SN50.

Conclusions: The current study provides evidence that increased serum IL-6, IL-1β, and CRP levels around PCI are not different between different postdilation pressure and stent number groups. The combination of IL-6 and IL-1β at concentrations associated with PCI cannot induce CRP expression in human VSMCs, but they can augment mechanical strain-induced CRP synthesis via the SAC-NF-κB pathway in human IMAs.
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http://dx.doi.org/10.1159/000447558DOI Listing
May 2017

Effect of Valsartan on Sarcoplasmic Reticulum Ca2+-ATPase Pump of the Left Ventricular Myocardium in Rats with Heart Failure with Preserved Ejection Fraction.

Biomed Hub 2016 May-Aug;1(2):1-9. Epub 2016 Jul 30.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Objectives: The aim was to investigate the effects of valsartan on the sarcoplasmic reticulum Ca-ATPase pump (SERCA) and L-type Ca channel current (ICaL) of the left ventricular myocardium in rats with heart failure with preserved ejection fraction.

Methods: The 30-week-old male spontaneously hypertensive rats (SHRs) are randomly divided into the non-Valsartan and Valsartan groups, and the 30-week-old male Wistar-Kyoto rats served as control rats. The expression of SERCA is measured by Western blot. The ICaL is measured by whole-cell patch clamp. The left ventricular end-diastolic pressure and left ventricular relaxation time constant quantity are measured at the same time.

Results: The left ventricular end-diastolic pressure is much higher in SHRs compared with that in control rats (p < 0.01). The left ventricular relaxation time constant quantity is markedly extended in SHRs compared with control rats (p < 0.01). Valsartan cannot increase the expression of SERCA nor decrease the density of ICaL compared with the non-Valsartan group (p > 0.05).

Conclusions: Valsartan has no effect on SERCA and ICaL of the left ventricular myocardium in rats with heart failure with preserved ejection fraction.
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http://dx.doi.org/10.1159/000448132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945928PMC
July 2016

Transgenic studies reveal the positive role of LeEIL-1 in regulating shikonin biosynthesis in Lithospermum erythrorhizon hairy roots.

BMC Plant Biol 2016 05 26;16(1):121. Epub 2016 May 26.

State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210046, People's Republic of China.

Background: The phytohormone ethylene (ET) is a key signaling molecule for inducing the biosynthesis of shikonin and its derivatives, which are secondary metabolites in Lithospermum erythrorhizon. Although ETHYLENE INSENSITIVE3 (EIN3)/EIN3-like proteins (EILs) are crucial transcription factors in ET signal transduction pathway, the possible function of EIN3/EIL1 in shikonin biosynthesis remains unknown. In this study, by targeting LeEIL-1 (L. erythrorhizon EIN3-like protein gene 1) at the expression level, we revealed the positive regulatory effect of LeEIL-1 on shikonin formation.

Results: The mRNA level of LeEIL-1 was significantly up-regulated and down-regulated in the LeEIL-1-overexpressing hairy root lines and LeEIL-1-RNAi hairy root lines, respectively. Specifically, LeEIL-1 overexpression resulted in increased transcript levels of the downstream gene of ET signal transduction pathway (LeERF-1) and a subset of genes for shikonin formation, excretion and/or transportation (LePAL, LeC4H-2, Le4CL-1, HMGR, LePGT-1, LeDI-2, and LePS-2), which was consistent with the enhanced shikonin contents in the LeEIL-1-overexpressing hairy root lines. Conversely, LeEIL-1-RNAi dramatically repressed the expression of the above genes and significantly reduced shikonin production.

Conclusions: The results revealed that LeEIL-1 is a positive regulator of the biosynthesis of shikonin and its derivatives in L. erythrorhizon hairy roots. Our findings gave new insights into the molecular regulatory mechanism of ET in shikonin biosynthesis. LeEIL-1 could be a crucial target gene for the genetic engineering of shikonin biosynthesis.
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http://dx.doi.org/10.1186/s12870-016-0812-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880835PMC
May 2016

Downregulation of VEGF and upregulation of TL1A expression induce HUVEC apoptosis in response to high glucose stimuli.

Mol Med Rep 2016 Apr 22;13(4):3265-72. Epub 2016 Feb 22.

Department of Cardiology, First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.

High glucose‑induced endothelial cell apoptosis is considered to be the initiator of diabetes‑associated vascular complications. Experiments in vivo and in vitro have demonstrated that high glucose levels contribute to the apoptosis of endothelial cells by mediating cellular dysfunction and metabolic disorder via the production of various cytokines. As the most important endogenous vascular regulators, the balance between pro‑proliferative effector vascular endothelial growth factor (VEGF) and anti‑proliferative effector tumor necrosis factor‑like cytokine 1A (TL1A) is important in the modulation of endothelial cell survival and proliferation, and neovascularization. The present study aimed to explore whether the imbalance between VEGF and TL1A affected the apoptosis of human umbilical vein endothelial cells (HUVECs) exposed to high glucose conditions and then further investigated the potential mechanism. The results showed that the downregulation of VEGF in combination with the upregulation of TL1A in response to high glucose levels led to enhanced HUVEC apoptosis. Further experiments revealed that silencing high glucose‑induced TL1A expression using TL1A small interfering (si)RNA or the overexpression of VEGF by transfection with VEGF DNA resulted in a reduced HUVEC apoptosis rate compared with the controls. The effects occurred by attenuating and activating the phosphoinositide 3‑kinase/Akt/endothelial nitric oxide synthase pathway, respectively. In addition, VEGF and TL1A inhibited each other in hyperglycemia. In conclusion, these findings provide theoretical support for the further investigation of novel therapeutic strategies designed to maintain the balance between VEGF and TL1A and, thus, to prevent the onset and progression of endothelial cell apoptosis in response to high glucose stimuli.
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http://dx.doi.org/10.3892/mmr.2016.4924DOI Listing
April 2016

Transgenic analysis reveals LeACS-1 as a positive regulator of ethylene-induced shikonin biosynthesis in Lithospermum erythrorhizon hairy roots.

Plant Mol Biol 2016 Mar 18;90(4-5):345-58. Epub 2016 Jan 18.

State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China.

The phytohormone ethylene (ET) is a crucial signaling molecule that induces the biosynthesis of shikonin and its derivatives in Lithospermum erythrorhizon shoot cultures. However, the molecular mechanism and the positive regulators involved in this physiological process are largely unknown. In this study, the function of LeACS-1, a key gene encoding the 1-aminocyclopropane-1-carboxylic acid synthase for ET biosynthesis in L. erythrorhizon hairy roots, was characterized by using overexpression and RNA interference (RNAi) strategies. The results showed that overexpression of LeACS-1 significantly increased endogenous ET concentration and shikonin production, consistent with the up-regulated genes involved in ET biosynthesis and transduction, as well as the genes related to shikonin biosynthesis. Conversely, RNAi of LeACS-1 effectively decreased endogenous ET concentration and shikonin production and down-regulated the expression level of above genes. Correlation analysis showed a significant positive linear relationship between ET concentration and shikonin production. All these results suggest that LeACS-1 acts as a positive regulator of ethylene-induced shikonin biosynthesis in L. erythrorhizon hairy roots. Our work not only gives new insights into the understanding of the relationship between ET and shikonin biosynthesis, but also provides an efficient genetic engineering target gene for secondary metabolite production in non-model plant L. erythrorhizon.
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http://dx.doi.org/10.1007/s11103-015-0421-zDOI Listing
March 2016

Effects of thrombin and thrombin receptor activation on cardiac function after acute myocardial infarction.

Am J Transl Res 2015 15;7(4):654-69. Epub 2015 Apr 15.

Division of Cardiology, Xiangtan Central Hospital Xiangtan, China.

Thrombin and thrombin receptor activation impact cardiomyocyte contraction and ventricular remodeling. However, there is some controversy regarding their effects in cardiac function, especially in cardiac dysfunction after acute myocardial infarction (AMI). A rat AMI model was created by left coronary artery ligation (LCA). Cardiac functional parameters, including the maximum left ventricular (LV) systolic pressure (LVSPmax), LV end-diastolic pressure (LVEDP), and the rise and fall rates in LV pressure (dp/dt max and dp/dt min, respectively), were measured. Hirudin decreased cardiac function within 120 minutes after AMI, whereas treatment with thrombin receptor-activating peptide (TRAP) reversed this hirudin-induced decrease in cardiac function. The mRNA and protein expression levels of inositol 1,4,5-trisphosphate receptor (IP3R) subtypes in infarct area tissues were analyzed by reverse transcription-polymerase chain reaction and immunoreaction. Hirudin decreased the expression levels of IP3R-1, -2, and -3 in the infarct area for up to 40 minutes after AMI, whereas TRAP treatment reversed these hirudin-induced effects. Treatment with the IP3R antagonist 2-aminoethoxydiphenyl borate (2.5 mg/kg) eliminated the effect of TRAP on the hirudin-induced decrease in cardiac function after AMI. Finally, TRAP increased the maximum binding capacity of the three IP3R subtypes, but only enhanced the affinity of IP3R-2. Thrombin and thrombin receptor activation improved cardiac function after AMI by an IP3R-mediated pathway, probably through the IP3R-2 subtype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455342PMC
June 2015

Zinc Regulates Lipid Metabolism and MMPs Expression in Lipid Disturbance Rabbits.

Biol Trace Elem Res 2015 Dec 20;168(2):411-20. Epub 2015 May 20.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.

Lipid disturbance induced by high-fat diet is a worldwide problem, and it can induce inflammation and oxidative stress in vivo. Zinc is considered as an antioxidant, anti-inflammatory agent. Since matrix metalloprotease 2 (MMP2) and matrix metalloprotease 9 (MMP9)'s expressions are changed under many pathological conditions, we would like to know how zinc affects lipid metabolism and MMP2, MMP9's expressions in the lipid disturbance rabbits. Twenty-four male New Zealand white rabbits were randomly divided into four groups. Each group had six rabbits, and they were fed with regular diet, high-fat diet, high-fat diet+zinc, and regular diet+zinc separately for 12 weeks. High-fat diet induced lipid disturbance significantly which raised the level of aspartate aminotransferase (p<0.01) and alanine transaminase (p<0.05) in the high-fat diet group, but zinc supplement reversed this phenomenon (p<0.05). Zinc did not reduce total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p>0.05), but it lowered triglyceride (TG) and raised high-density lipoprotein cholesterol (HDL-C) (p<0.01). Zinc also reduced high-sensitivity C-reactive protein (hs-CRP) (p<0.01) and interleukin-6 (IL-6)'s expressions (p<0.05). Zinc reduced the epicardial adipose tissue and alleviated the hepatic steatosis. Zinc suppressed MMP2 and MMP9's expressions in vivo, but it did not alleviate the aorta fatty streak's severity in the lipid disturbance rabbits. Zinc protected the liver, reduced TG, hs-CRP, and IL-6 and raised HDL-C in the lipid disturbance rabbits. Zinc suppressed MMP2 and MMP9's expressions in vivo, but it did not alleviate the severity of aorta fatty streak induced by the high-fat diet.
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http://dx.doi.org/10.1007/s12011-015-0367-7DOI Listing
December 2015

The secretion patterns and roles of cardiac and circulating arginine vasopressin during the development of heart failure.

Neuropeptides 2015 Jun 18;51:63-73. Epub 2015 Mar 18.

Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Electronic address:

Objective: The aim of this study is to investigate local cardiac and circulating AVP secretion during heart failure and to determine whether AVP mediates ventricular remodeling.

Methods: We assessed cardiac function and AVP levels of post-myocardial infarction (MI) heart-failure rats 3 weeks (n = 10), 4 weeks (n = 10), 6 weeks (n = 10), 9 weeks (n = 15) after the proximal left anterior descending coronary artery (LAD) ligation. Ten sham-operated rats were used as the control group. In vitro, cardiac microvascular endothelial cells (CMECs) were initiated from isolated Wistar rat hearts and subjected to Ang II to induce AVP expression and secretion. Besides, the effects of AVP stimulation on CMECs and cardiac fibroblasts (CFs) were studied using methylthiazol tetrazolium assay, Western blotting and real-time PCR.

Results: With cardiac dysfunction, plasma and local cardiac AVP, aldosterone levels increased over time, peaking at 9 weeks post-MI. AVP levels were negatively correlated with serum Na(+) and LVEF but positively correlated with LVEDD and myocardial hydroxyproline. In CMECs treated with Ang II, AVP mRNA and protein expression increased. In addition, AVP promoted CFs proliferation and up-regulated the expression of endothelin-1 and connective tissue growth factor.

Conclusion: CMECs are the cellular sources of elevated local heart AVP stimulated with Ang II/AT1. An intrinsic cardiac AVP system exists. Local cardiac and circulating AVP secretion were enhanced by deteriorating cardiac function. AVP may promote ventricular remodeling. Thus, AVP could be an important mediator of myocardial fibrosis in late-stage heart failure.
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http://dx.doi.org/10.1016/j.npep.2015.03.003DOI Listing
June 2015

Angiotensin II upregulates Kv1.5 expression through ROS-dependent transforming growth factor-beta1 and extracellular signal-regulated kinase 1/2 signalings in neonatal rat atrial myocytes.

Biochem Biophys Res Commun 2014 11 24;454(3):410-6. Epub 2014 Oct 24.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Kv1.5 potassium channel represents a promising target for atrial fibrillation (AF) therapy. During AF, the renin-angiotensin system is markedly activated. Recent evidence indicates that angiotensin II (Ang II) can upregulate Kv1.5 channel, but the mechanism remains unknown. In this study, we report that Ang II-mediated transforming growth factor-beta1 (TGF-β1)/Smad2/3 and extracellular signal-regulated kinase (ERK) 1/2 signalings are involved in atrial Kv1.5 expression. In neonatal rat atrial myocytes, quantitative PCR and Western blotting revealed that Ang II upregulated TGF-β1, synapse-associated protein 97 (SAP97) and Kv1.5 expression in a time- and concentration-dependent manner. The Ang II-induced upregulation of Kv1.5, SAP97 and phosphorylated Smad2/3 (P-Smad2/3) were reversed by the Ang II type 1 (AT1) receptor antagonist losartan, an anti-TGF-β1 antibody and the ERK 1/2 inhibitor PD98059 but not by the AT2 receptor antagonist PD123319. mRNA knockdown of either Smad2 or Smad3 blocked Ang II-induced expression of Kv1.5 and SAP97. These data suggest that AT1 receptor/TGF-β1/P-Smad2/3 and ERK 1/2 signalings are involved in Ang II-induced Kv1.5 and SAP97 expression. Flow cytometry and Western blotting revealed that losartan and the anti-TGF-β1 antibody diminished Ang II-induced reactive oxygen species (ROS) generation and that the antioxidants diphenyleneiodonium and N-acetyl cysteine inhibited Ang II-induced expression of P-Smad2/3, phosphorylated ERK (P-ERK) 1/2, Kv1.5, SAP97, suggesting that ROS participate in Kv1.5 and SAP97 regulation by modulating Ang II-induced P-Smad2/3 and P-ERK 1/2 expression. In conclusion, we demonstrate that ROS-dependent Ang II/AT1 receptor/TGF-β1/P-Smad2/3 and Ang II/ERK 1/2 signalings are involved in atrial Kv1.5 and SAP97 expression. Antioxidants would be beneficial for AF treatment through inhibiting atrial Kv1.5 expression.
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http://dx.doi.org/10.1016/j.bbrc.2014.10.088DOI Listing
November 2014

Application of T-DNA activation tagging to identify glutamate receptor-like genes that enhance drought tolerance in plants.

Plant Cell Rep 2014 Apr 29;33(4):617-31. Epub 2014 Mar 29.

Beijing Kaituo DNA Biotech Research Center, Co., Ltd., Beijing, 102206, China,

Key Message: A high-quality rice activation tagging population has been developed and screened for drought-tolerant lines using various water stress assays. One drought-tolerant line activated two rice glutamate receptor-like genes. Transgenic overexpression of the rice glutamate receptor-like genes conferred drought tolerance to rice and Arabidopsis. Rice (Oryza sativa) is a multi-billion dollar crop grown in more than one hundred countries, as well as a useful functional genetic tool for trait discovery. We have developed a population of more than 200,000 activation-tagged rice lines for use in forward genetic screens to identify genes that improve drought tolerance and other traits that improve yield and agronomic productivity. The population has an expected coverage of more than 90 % of rice genes. About 80 % of the lines have a single T-DNA insertion locus and this molecular feature simplifies gene identification. One of the lines identified in our screens, AH01486, exhibits improved drought tolerance. The AH01486 T-DNA locus is located in a region with two glutamate receptor-like genes. Constitutive overexpression of either glutamate receptor-like gene significantly enhances the drought tolerance of rice and Arabidopsis, thus revealing a novel function of this important gene family in plant biology.
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http://dx.doi.org/10.1007/s00299-014-1586-7DOI Listing
April 2014

Changes in cell autophagy and apoptosis during age-related left ventricular remodeling in mice and their potential mechanisms.

Biochem Biophys Res Commun 2013 Jan 29;430(2):822-6. Epub 2012 Nov 29.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China.

Cardiac structures and functions change with advanced age, but the underlying mechanisms are not well understood. Autophagy and apoptosis play important roles in the process of cardiac remodeling. This study was designed to explore changes in cell autophagy and apoptosis during age-related left ventricular remodeling and to determine whether the mitogen-activated protein kinase (MAPK) pathway is an underlying mechanism. Eight 5-month-old (adult group) and eight 24-month-old male C57bl/6 mice (aged group) were studied. The heart mass index, left ventricular mass index and hydroxyproline content of both groups were compared. Western Blotting was used to quantitate the protein expression of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, caspase-3, B-cell leukemia-2 (Bcl-2) and MAPKs in the left ventricles of adult and aged mice. Our results showed that the heart mass index, left ventricular mass index and hydroxyproline content in the left ventricles of the aged mice were increased significantly compared with the adult mice, indicating that left ventricular remodeling occurs with aging. The expression of LC3 and Beclin-1 in the left ventricles of aged mice were decreased significantly compared to adult mice. Meanwhile, the level of myocardial caspase-3 in adult mice remained the same in aged mice, and the level of myocardial Bcl-2 increased significantly in aged mice. There were no differences in the expression level of myocardial extracellular signal-regulated kinase 1/2 (ERK1/2), activated/phospho-ERK1/2, c-Jun N-terminal kinase 1/2 (JNK1/2) and p38 between aged and adult mice. However, the expression of myocardial activated/phospho-JNK1/2 increased significantly in aged mice, while activated/phospho-p38 decreased significantly. These findings indicate that autophagy decreases without a concurrent change in apoptosis during age-related left ventricular remodeling in mice. The MAPK pathway may be involved in the regulation of age-related left ventricular remodeling by modulating autophagy.
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http://dx.doi.org/10.1016/j.bbrc.2012.11.062DOI Listing
January 2013

Sorghum insect problems and management.

J Integr Plant Biol 2011 Mar;53(3):178-92

Beijing Kaituo DNA Biotech Research Center, Beijing 100085, China.

Sorghum (Sorghum bicolor) has high levels of starch, sugar, and fiber and is one of the most important energy crops in the world. Insect damage is one of the challenges that impacts sorghum biomass production. There are at least 150 insect species that can infest sorghum varieties worldwide. These insects can complete several generations within a growing season, they target various parts of sorghum plants at developmental stages, and they cause significant biomass losses. Genetic research has revealed the existence of resistant genetics in sorghum and insect tolerant sorghum varieties have been identified. Various control methods have been developed, yet more effective management is needed for increasing sorghum biomass production. Although there are no transgenic sorghum products on the market yet, biotechnology has been recognized as an important tool for controlling insect pests and increasing sorghum production.
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http://dx.doi.org/10.1111/j.1744-7909.2010.01019.xDOI Listing
March 2011

A protein phosphorylation/dephosphorylation network regulates a plant potassium channel.

Proc Natl Acad Sci U S A 2007 Oct 26;104(40):15959-64. Epub 2007 Sep 26.

Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA.

Potassium (K(+)) is an essential nutrient for plant growth and development. Plants often adapt to low K(+) conditions by increasing their K(+) uptake capability. Recent studies have led to the identification of a calcium signaling pathway that enables plants to act in this capacity. Calcium is linked to two calcineurin B-like calcium sensors (CBLs) and a target kinase (CBL-interacting protein kinase 23 or CIPK23) that, in turn, appears to phosphorylate and activate the potassium channel, Arabidopsis K(+) transporter 1 (AKT1), responsible for K(+) uptake in roots. Here, we report evidence that this regulatory mechanism is more elaborate than earlier envisaged. The recently described pathway is part of an extensive network whereby several CBLs interact with multiple CIPKs in the activation of the potassium channel, AKT1. The physical interactions among the CBL, CIPK, and AKT1 components provide a mechanism for specifying the members of the CBL and CIPK families functional in AKT1 regulation. The interaction between the CIPKs and AKT1 was found to involve the kinase domain of the CIPK component and the ankyrin repeat domain of the channel. Furthermore, we identified a 2C-type protein phosphatase that physically interacts and inactivates the AKT1 channel. These findings provide evidence that the calcium-sensitive CBL and CIPK families together with 2C-type protein phosphatases form a protein phoshporylation/dephosphorylation network that regulates the AKT1 channel for K(+) transport in plants.
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http://dx.doi.org/10.1073/pnas.0707912104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000415PMC
October 2007