Publications by authors named "Shu-Wen Liu"

75 Publications

Danshensu alleviates pseudo-typed SARS-CoV-2 induced mouse acute lung inflammation.

Acta Pharmacol Sin 2021 Jul 15. Epub 2021 Jul 15.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce acute inflammatory response like acute lung inflammation (ALI) or acute respiratory distress syndrome, leading to severe progression and mortality. Therapeutics for treatment of SARS-CoV-2-triggered respiratory inflammation are urgent to be discovered. Our previous study shows that Salvianolic acid C potently inhibits SARS-CoV-2 infection. In this study, we investigated the antiviral effects of a Salvia miltiorrhiza compound, Danshensu, in vitro and in vivo, including the mechanism of S protein-mediated virus attachment and entry into target cells. In authentic and pseudo-typed virus assays in vitro, Danshensu displayed a potent antiviral activity against SARS-CoV-2 with EC of 0.97 μM, and potently inhibited the entry of SARS-CoV-2 S protein-pseudo-typed virus (SARS-CoV-2 S) into ACE2-overexpressed HEK-293T cells (IC = 0.31 μM) and Vero-E6 cell (IC = 4.97 μM). Mice received SARS-CoV-2 S via trachea to induce ALI, while the VSV-G treated mice served as controls. The mice were administered Danshensu (25, 50, 100 mg/kg, i.v., once) or Danshensu (25, 50, 100 mg·kg·d, oral administration, for 7 days) before SARS-CoV-2 S infection. We showed that SARS-CoV-2 S infection induced severe inflammatory cell infiltration, severely damaged lung tissue structure, highly expressed levels of inflammatory cytokines, and activated TLR4 and hyperphosphorylation of the NF-κB p65; the high expression of angiotensinogen (AGT) and low expression of ACE2 at the mRNA level in the lung tissue were also observed. Both oral and intravenous pretreatment with Danshensu dose-dependently alleviated the pathological alterations in mice infected with SARS-CoV-2 S. This study not only establishes a mouse model of pseudo-typed SARS-CoV-2 (SARS-CoV-2 S) induced ALI, but also demonstrates that Danshensu is a potential treatment for COVID-19 patients to inhibit the lung inflammatory response.
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http://dx.doi.org/10.1038/s41401-021-00714-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280584PMC
July 2021

GLA missense and promoter variants co-segregating in a Chinese family with Fabry disease.

Ann Transl Med 2020 Jul;8(14):865

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China.

Background: Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder due to mutations in the GLA gene leading to deficiency of lysosomal α-galactosidase A (α-Gal A) and has a wide range of clinical presentations. Over 900 GLA gene mutations are currently known and of those most are thought not to be clinically significant, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician.

Methods: Whole-exome sequencing (WES) was performed to detect the mutation in family members with Fabry disease. The function of g.1170C>T mutation was confirmed by dual luciferase system.

Results: A total of 1,375 variants were found in a Chinese family with FD. A missense variants c.1025C>T (p.Arg342Gln) which have been previously reported in association with FD and g.1170C>T single-nucleotide polymorphism (SNP) in the GLA gene were found in five patients. The g.1170C>T SNP affects transcription of GLA gene, presumably the transcription start site. Female patients only have hypohidrosis and neuropathic pain, while male patients have severe symptoms with simultaneous renal impairment.

Conclusions: Two simultaneous variants in cis of the GLA gene, c.1025C>T (p.Arg342Gln) and g.1170C>T, were verified in Chinese individuals, and the corresponding clinical symptoms were described. The disease severity in male patients is worse than in female patients. These results may be helpful for genetic counseling, diagnosis and prognosis of patients with FD.
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http://dx.doi.org/10.21037/atm-19-4510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396806PMC
July 2020

Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19.

Acta Pharmacol Sin 2020 Sep 3;41(9):1141-1149. Epub 2020 Aug 3.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.
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http://dx.doi.org/10.1038/s41401-020-0485-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396720PMC
September 2020

[1,2,4]Triazolo[1,5-a]pyrimidine derivative (Mol-5) is a new NS5-RdRp inhibitor of DENV2 proliferation and DENV2-induced inflammation.

Acta Pharmacol Sin 2020 May 15;41(5):706-718. Epub 2019 Nov 15.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

Dengue fever is an acute infectious disease caused by dengue virus (DENV) and transmitted by Aedes mosquitoes. There is no effective vaccine or antiviral drug available to date to prevent or treat dengue disease. Recently, RNA-dependent RNA polymerase (RdRp), a class of polymerases involved in the synthesis of complementary RNA strands using single-stranded RNA, has been proposed as a promising drug target. Hence, we screened new molecules against DENV RdRp using our previously constructed virtual screening method. Mol-5, [1,2,4]triazolo[1,5-a]pyrimidine derivative, was screened out from an antiviral compound library (~8000 molecules). Using biophysical methods, we confirmed the direct interactions between mol-5 and purified DENV RdRp protein. In luciferase assay, mol-5 inhibited NS5-RdRp activity with an IC value of 1.28 ± 0.2 μM. In the cell-based cytopathic effect (CPE) assay, mol-5 inhibited DENV2 infectivity with an EC value of 4.5 ± 0.08 μM. Mol-5 also potently inhibited DENV2 RNA replication as observed in immunofluorescence assay and qRT-PCR. Both the viral structural (E) and non-structural (NS1) proteins of DENV2 were dose-dependently decreased by treatment with mol-5 (2.5-10 μM). Mol-5 treatment suppressed DENV2-induced inflammation in host cells, but had no direct effect on host defense (JAK/STAT-signaling pathway). These results demonstrate that mol-5 could be a novel RdRp inhibitor amenable for further research and development.
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http://dx.doi.org/10.1038/s41401-019-0316-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471397PMC
May 2020

Predictive Capabilities of Three Widely Used Pathology Classification Systems and a Simplified Classification (Beijing Classification) in Primary IgA Nephropathy.

Kidney Blood Press Res 2019 28;44(5):928-941. Epub 2019 Aug 28.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.

Background/aims: Several pathological classification systems were commonly used in clinical practice to predict the prognosis of IgA nephropathy (IgAN). However, how prognostic value differs between these systems is unclear. The aim of this study was to compare the Lee grade, the Oxford classification, and the Haas classification and to find a simplified classification.

Methods: We retrospectively analyzed IgAN cases diagnosed between January 2002 and December 2007. The endpoints were progression to end-stage renal disease (ESRD) or a ≥50% decline in estimated glomerular filtration rate (eGFR). The predictive capabilities were evaluated by comparing the ability of discrimination (continuous net reclassification) and calibration (Akaike information criterion [AIC]).

Results: A total of 412 IgAN patients were included in the study. The average follow-up period was 80.62 ± 23.63 months. A total of 44 (10.68%) patients progressed to ESRD, and 70 (16.99%) patients showed a ≥50% decline in eGFR. All multivariate Cox regression models had limited power for high AIC values. The prognostic values of the Lee grade and the Oxford classification were higher than those of models containing only established baseline clinical indicators for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.50, 95% CI 0.21-0.74; Oxford classification 0.48, 95% CI 0.28-0.71). The prognostic value of the Haas classification was lower than that of the other pathological classification systems for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.53, 95% CI 0.23-0.92; Oxford classification 0.59, 95% CI 0.10-0.74). The prognostic value of hierarchical classification (Beijing classification) using M and T lesion was similar to the Oxford classification.

Conclusions: Both the Lee grade and the Oxford classification showed incremental prognostic values beyond established baseline clinical indicators. The Haas classification was slightly inferior to the Lee grade and the Oxford classification. The hierarchical classification (Beijing classification) using less pathological parameters does not lose predictive efficiency.
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http://dx.doi.org/10.1159/000500459DOI Listing
March 2020

Artesunate attenuates LPS-induced osteoclastogenesis by suppressing TLR4/TRAF6 and PLCγ1-Ca-NFATc1 signaling pathway.

Acta Pharmacol Sin 2020 Feb 20;41(2):229-236. Epub 2019 Aug 20.

Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with elevated inflammation, which disturbs the bone homeostasis and results in osteolysis. Lipopolysaccharide (LPS), as a bacteria product, plays an important role in this process. Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL. In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo, and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL. In preosteoclastic RAW264.7 cells, we found that artesunate (1.56-12.5 μM) dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression (Fra-2, TRAP, Cathepsin K, β3-integrin, DC-STAMP, and Atp6v0d2). We showed that artesunate (3.125-12.5 µM) inhibited LPS-stimulated nuclear factor of activated T cells c1 (NFATc1) but not NF-κB transcriptional activity; artesunate (6.25, 12.5 μM) significantly inhibited LPS-stimulated NFATc1 protein expression. Furthermore, artesunate treatment markedly suppressed LPS-induced Ca influx, and decreased the expression of PP2B-Aα (calcineurin) and pPLCγ1 in the cells. In addition, artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis. Administration of artesunate (10 mg/kg, ip) for 8 days effectively inhibited serum TNF-α levels and ameliorated LPS (5 mg/kg, ip)-induced inflammatory bone loss in vivo. Taken together, artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca-NFATc1 signaling pathway. Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.
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http://dx.doi.org/10.1038/s41401-019-0289-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468527PMC
February 2020

The anti-parasitic drug suramin potently inhibits formation of seminal amyloid fibrils and their interaction with HIV-1.

J Biol Chem 2019 09 25;294(37):13740-13754. Epub 2019 Jul 25.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China

Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs. Previously, we reported that the polysulfonic compound ADS-J1 is a potential candidate microbicide that not only inhibits HIV-1 entry, but also seminal fibrils. However, the carcinogenic azo moieties in ADS-J1 preclude its clinical application. Here, we screened several ADS-J1-like analogs and found that the antiparasitic drug suramin most potently inhibited seminal amyloid fibrils. Using various biochemical methods, including Congo red staining, CD analysis, transmission EM, viral infection assays, surface plasmon resonance imaging, and molecular dynamics simulations, we investigated suramin's inhibitory effects and its putative mechanism of action. We found that by forming a multivalent interaction, suramin binds to proteolytic peptides and mature fibrils, thereby inhibiting seminal fibril formation and blocking fibril-mediated enhancement of viral infection. Of note, suramin exhibited potent anti-HIV activities, and combining suramin with several antiretroviral drugs produced synergistic effects against HIV-1 in semen. Suramin also displayed a good safety profile for vaginal application. Moreover, suramin inhibited the semen-derived enhancer of viral infection (SEVI)/semen-mediated enhancement of HIV-1 transcytosis through genital epithelial cells and the subsequent infection of target cells. Collectively, suramin has great potential for further development as a combination microbicide to reduce the spread of the AIDS pandemic by targeting both viral and host factors involved in HIV-1 sexual transmission.
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http://dx.doi.org/10.1074/jbc.RA118.006797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746445PMC
September 2019

The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation.

Acta Pharmacol Sin 2019 Jan 22;40(1):98-110. Epub 2018 May 22.

Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, State Key Laboratory of Organ Failure Research, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol. In the current study, we examined the impact of apabetalone on HIV-1 latency. We showed that apabetalone (10-50 μmol/L) dose-dependently reactivated latent HIV-1 in 4 types of HIV-1 latency cells in vitro and in primary human CD4 T cells ex vivo. In ACH2 cells, we further demonstrated that apabetalone activated latent HIV-1 through Tat-dependent P-TEFB pathway, i.e., dissociating bromodomain 4 (BDR4) from the HIV-1 promoter and recruiting Tat for stimulating HIV-1 elongation. Furthermore, we showed that apabetalone (10-30 μmol/L) caused dose-dependent cell cycle arrest at the G/G phase in ACH2 cells, and thereby induced the preferential apoptosis of HIV-1 latent cells to promote the death of reactivated reservoir cells. Notably, cardiovascular diseases and low HDL cholesterol are known as the major side effects of cART, which should be prevented by apabetalone. In conclusion, apabetalone should be an ideal bifunctional latency-reversing agent for advancing HIV-1 eradication and reducing the side effects of BET inhibitors.
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http://dx.doi.org/10.1038/s41401-018-0027-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318340PMC
January 2019

Amentoflavone is a potent broad-spectrum inhibitor of human UDP-glucuronosyltransferases.

Chem Biol Interact 2018 Mar 19;284:48-55. Epub 2018 Feb 19.

Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

Amentoflavone (AMF), an abundant natural biflavonoid found in many medicinal plants, displays various beneficial effects including anti-inflammatory, anti-oxidative and anti-cancer. Despite the extensive studies on pharmacological activities, the toxicity or undesirable effects of AMF are rarely reported. In this study, the inhibitory effects of AMF on human UDP-glucuronosyltransferases (UGTs) were carefully investigated. AMF displayed strong inhibition towards most of human UGTs including UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4 and 2B17, with the IC values ranging from 0.12 μM to 16.81 μM. Inhibition constants (K) of AMF against various human UGTs varied from 0.29 μM to 11.51 μM. Further investigation demonstrated that AMF was a noncompetitive inhibitor of UGT1A1 mediated NCHN-O-glucuronidation but functioned as a competitive inhibitor of UGT1A1 mediated 4-MU-O-glucuronidation. In addition, AMF was a competitive inhibitor of UGT1A4 mediated TFP-N-glucuronidation in both UGT1A4 and human liver microsomes, while functioned as a competitive inhibitor of UGT1A9 mediated propofol or 4-MU-O-glucuronidation. These findings demonstrated that AMF was a strong and broad-spectrum natural inhibitor of most human UGTs, which might bring potential risks of herb-drug interactions (HDIs) via UGT inhibition. Additionally, this study provided novel insights into the underlying mechanism of AMF-associated toxicity from the perspective of UGT inhibition.
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http://dx.doi.org/10.1016/j.cbi.2018.02.009DOI Listing
March 2018

Zwitterionic Manganese and Gadolinium Metal-Organic Frameworks as Efficient Contrast Agents for in Vivo Magnetic Resonance Imaging.

ACS Appl Mater Interfaces 2017 Nov 16;9(47):41378-41386. Epub 2017 Nov 16.

Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.

Two water-stable three-dimensional Mn- and Gd-based metal-organic frameworks (MOFs), {[Mn(Cmdcp)(HO)]·HO} (1) and {[Gd(Cmdcp)(HO)](NO)·3HO} (2, HCmdcpBr = N-(4-carboxy benzyl)-(3,5-dicarboxyl)pyridinium bromide), have been prepared and analyzed. In vitro magnetic resonance imaging indicated that MOFs 1 and 2 possess relaxivity r values of 17.50 and 13.46 mM·S, respectively, which are superior to that of the control Gd-DTPA (r = 4.87 mM·S, DTPA = diethylene triamine pentaacetate). MOFs 1 and 2 also possessed good biocompatibility and low cytotoxicity against a model cell line. In vivo magnetic resonance images of treated Kunming mice indicated that kidneys showed remarkably positive signal enhancement after 15 min with intravenous administration of MOF 1 and the hyperintensity of both kidneys persisted for about 240 min with no obvious tissue damage. MOF 1 is therefore promising in vivo probes for imaging intravascular diseases and renal dysfunction.
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http://dx.doi.org/10.1021/acsami.7b09608DOI Listing
November 2017

[Lactic acid inhibits the formation of semen-derived amyloid fibrils].

Nan Fang Yi Ke Da Xue Xue Bao 2017 Jul;37(7):907-913

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.E-mail:

Objective: To investigate the inhibitory effect of lactic acid on semen-derived amyloid (SEVI) fibril formation.

Methods: PAP248-286 (2 mg/mL) was incubated with 4.0, 2.0, 1.0, 0.5, 0.25, and 0.125 mg/mL of lactic acid. After incubation for different times, aliquots were drawn from each sample for Thioflavin T (ThT) and Congo red staining to monitor semen-derived amyloid fibril formation. The β sheet structure formation of PAP248-286 was measured by circular dichroism spectrum, and the morphology of amyloid fibrils incubated with or without lactic acid was observed with transmission electron microscopy (TEM). The enhancing effect of amyloid fibril incubated with lactic acid at different time points was determined using virus infection assay. PAP248-286 (2 mg/mL) was incubated with dilutions of vaginal secretion from healthy women, and amyloid fibril formation was detected with ThT and Congo red staining.

Results: Lactic acid inhibited SEVI fibril formation in a dose-dependent manner in vitro. Lactic acid at 0.5 mg/mL completely inhibited 2 mg/mL SEVI fibril formation within 48 h. After incubation for 48 h, lactic acid at 1 mg/mL inhibited the formation of β-sheet structure of SEVI (2 mg/mL) and completely inhibited 2 mg/mL PAP248-286 aggregation as observed with TEM. In the presence of lactic acid, PAP248-286 lost the ability to enhance virus infection. Vaginal secretion inhibited SEVI fibril formation in a dose-dependent manner, and virtually no SEVI fibril occurred after incubation of 2 mg/mL PAP248-286 with 67% vaginal secretion.

Conclusion: Lactic acid inhibits SEVI fibril formation in vitro.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765509PMC
July 2017

ABT-263 induces G/G-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro.

Acta Pharmacol Sin 2017 Dec 10;38(12):1632-1641. Epub 2017 Jul 10.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 μmol/L) dose-dependently induced G/G-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G/G-phase arrest. Knockdown of p21 attenuated ABT-263-induced G/G-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.
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http://dx.doi.org/10.1038/aps.2017.78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719159PMC
December 2017

Urinary sediment miRNAs reflect tubulointerstitial damage and therapeutic response in IgA nephropathy.

BMC Nephrol 2017 Feb 15;18(1):63. Epub 2017 Feb 15.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, China.

Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN.

Methods: Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed.

Results: 1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group (p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group (p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN (p = 0.001, OR = 1.042).

Conclusions: The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression.
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http://dx.doi.org/10.1186/s12882-017-0482-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312444PMC
February 2017

Efficacy and safety of calcineurin inhibitor treatment for IgA nephropathy: a meta-analysis.

BMC Nephrol 2017 Feb 13;18(1):61. Epub 2017 Feb 13.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, People's Republic of China.

Background: IgA nephropathy is the most common progressive glomerular disease to end stage renal failure worldwide. Calcineurin inhibitors (CNIs) is a selective immunosuppressant widely used in organ transplantation. The efficacy and safety of calcineurin inhibitors for the treatment of IgA nephropathy remain uncertain.

Methods: We performed a systematic literature search using the PubMed, Embase, Science Citation Index, Ovid evidence-based medicine, Chinese Biomedical Literature (CBM) and Chinese science and technology periodicals (CNKI, VIP, and Wan Fang) for randomized, controlled trials of CNIs therapy of IgA nephropathy. Complete remission rate (CR) was defined as proteinuria less than 0.5 or 0.3 g/d. Partial remission rate (PR) was defined as proteinuria reduced to at least half of the baseline measurement and an absolute value of >0.5 or 0.3 g/d.

Results: Seven relevant trials were conducted with 374 patients enrolled. CNIs plus medium/low-dose steroid had a higher CR (RR = 2.51 [95% CI,1.25 to 5.04], P = 0.02) compared to therapy with steroid alone or placebo, but were not significant on PR (RR = 0.87 [95% CI,0.32 to 2.38]; P = 0.78). Also, significant alterations were observed in proteinuria (weighted mean difference, -0.46 g/d,[95% CI:-0.55 to -0.24], P < 0.01) with no differences were found in serum creatinine (SCr) (weighted mean difference, 0.57,95% CI:-4.05 to 5.19; P = 0.78) and estimated glomerular filtration rate (eGFR) (weighted mean difference, 1.13,95% CI:-4.05 to 6.32; P = 0.34) level between the two groups. CNI therapy was associated with an increased risk for adverse events (RR = 2.21,95% CI:1.52 to 3.21, P < 0.01), such as gastrointestinal and neurological symptoms or hirsutism.

Conclusions: CNIs might provide renal protection in patients with IgAN, but at an increased risk of adverse events. Reliably defining the efficacy and safety of CNIs in IgAN requires a high-quality trial with a large sample size.
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http://dx.doi.org/10.1186/s12882-017-0467-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307812PMC
February 2017

Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition.

J Biol Chem 2016 Dec 31;291(50):26177-26187. Epub 2016 Oct 31.

From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China,

The persistence of HIV in resting memory CD4 T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication.
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http://dx.doi.org/10.1074/jbc.M116.743906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207085PMC
December 2016

Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy: A Randomized Controlled Trial.

Chin Med J (Engl) 2016 Aug;129(16):1894-903

Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China.

Background: The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN.

Methods: It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry.

Results: The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18-0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44-96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54-12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (-6.72 [95% CI-9.46 to -3.98] ml·min-1·1.73 m-2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed.

Conclusions: Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients.

Trial Registration: chictr.org.cn, ChiCTR-TRC-10000776; http://www.chictr.org.cn/showproj.aspx?proj=8760.
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http://dx.doi.org/10.4103/0366-6999.187848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989418PMC
August 2016

Heat Shock Factor 1 Mediates Latent HIV Reactivation.

Sci Rep 2016 05 18;6:26294. Epub 2016 May 18.

Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

HSF1, a conserved heat shock factor, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. To our knowledge, it is not known whether HSF1 regulates viral transcription, particularly HIV-1 and its latent form. Here we reveal that HSF1 extensively participates in HIV transcription and is critical for HIV latent reactivation. Mode of action studies demonstrated that HSF1 binds to the HIV 5'-LTR to reactivate viral transcription and recruits a family of closely related multi-subunit complexes, including p300 and p-TEFb. And HSF1 recruits p300 for self-acetylation is also a committed step. The knockout of HSF1 impaired HIV transcription, whereas the conditional over-expression of HSF1 improved that. These findings demonstrate that HSF1 positively regulates the transcription of latent HIV, suggesting that it might be an important target for different therapeutic strategies aimed at a cure for HIV/AIDS.
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http://dx.doi.org/10.1038/srep26294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870680PMC
May 2016

[Small molecular agents against MERS-CoV infection].

Yao Xue Xue Bao 2015 Dec;50(12):1520-6

Middle East respiratory syndrome coronavirus (MERS-CoV) has caused outbreaks of SARS-like disease with 35% case-fatality rate, mainly in the Middle East. A more severe outbreak of MERS occurred recently in the Republic of Korea, where 186 people contracted the infections, causing great concern worldwide. So far, there has been no clinically available drug for the treatment of MERS-CoV infection. The potential drugs against MERS-CoV mainly consist of monoclonal antibodies, peptides and small molecular agents. Small molecular agents have an advantage of easier synthesis, lower cost in production and relatively higher stability. There is better chance for those candidates to gain a quick development. This article reviews the progress of developing small molecular MERS-CoV agents.
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December 2015

[Development of peptidic MERS-CoV entry inhibitors].

Yao Xue Xue Bao 2015 Dec;50(12):1513-9

In 2012, a new SARS-like coronavirus emerged in the Middle East, namely the Middle East respiratory syndrome coronavirus (MERS-CoV). It has caused outbreaks with high mortality. During infection of target cell, MERS-CoV S protein S1 subunit binds to the cellular receptor (DPP4), and its S2 subunit HR1 and HR2 regions intact with each other to form a stable six-helix bundle to mediate the fusion between virus and target cell membranes. Hence, blocking the process of six-helix bundle formation can effectively inhibit MERS-CoV entry into the target cells. This review focuses on the recent advance in the development of peptidic entry inhibitors targeting the MERS-CoV S2 subunit.
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December 2015

[Synergistic anti-tumor effect of obatoclax and MG-132 in esophageal cancer cell line CaES-17].

Nan Fang Yi Ke Da Xue Xue Bao 2016 Apr;36(4):506-13

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. E-mail:

Objective: To explore whether MG-132 could enhance the anti-tumor activity of obatoclax against esophageal cancer cell line CaES-17.

Methods: MTT assay was used to determine the cytotoxicity of obatoclax and MG-132 in CaES-17 cells. The IC(50) of obatoclax and MG-132 were used to determine the molar ratio (1:2.4) of the two drugs for combined treatment of the cells. The concentrations of obatoclax and MG-132 ranged from 1/8 IC(50) to 4 IC(50) after serial dilution, and their combination index (CI) was calculated using CompuSyn software. The expression of ubiquitin and the cleavage of PARP, caspase-9, phospho-histone H3 and phospho-aurora A/B/C in the exposed cells were examined with Western blotting; the cell apoptosis was measured by flow cytometry with Annexin V staining, and the percentage of cells in each cell cycle phase was also determined by flow cytometry.

Results: The CI of obatoclax and MG-132 was 0.296 for a 50% inhibition of Caes-17 cells and was 0.104 for a 95% inhibition. The cells treated with obatoclax or MG-132 alone showed increased expression of ubiquitin and cleavage of PARP and caspase-9. Compared with the cells treated with obatoclax or MG-132 alone, the cells with a combined treatment exhibited significantly increased expression of ubiquitin, cleavage of PARP and caspase-9, and expression of phospho-Histone H3 (P<0.05). The combined treatment of the cells also resulted in significantly increased expression of phospho-Aurora A/B/C compared with obatoclax treatment alone. The cells with the combined treatment showed significantly higher percentages of apoptotic cells and cells in sub-G(1) and G(2)/M phases compared with the cells treated with either of the drugs (P<0.05).

Conclusion: Obatoclax combined with MG-132 shows a significant synergistic anti-tumor effect against esophageal cancer CaES-17 cells by inducing apoptosis and cell cycle arrest.
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April 2016

Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases.

Toxicol Appl Pharmacol 2016 06 16;301:42-9. Epub 2016 Apr 16.

Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China. Electronic address:

Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68μM and 30.82μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.
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http://dx.doi.org/10.1016/j.taap.2016.04.009DOI Listing
June 2016

Platforms Formed from a Three-Dimensional Cu-Based Zwitterionic Metal-Organic Framework and Probe ss-DNA: Selective Fluorescent Biosensors for Human Immunodeficiency Virus 1 ds-DNA and Sudan Virus RNA Sequences.

Anal Chem 2015 Dec 30;87(24):12206-14. Epub 2015 Nov 30.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, P. R. China.

We herein report a water-stable three-dimensional Cu-based metal-organic framework (MOF) 1 supported by a tritopic quaternized carboxylate and 4,4'-dipyridyl sulfide as an ancillary ligand. This MOF exhibits unique pore shapes with aromatic rings, positively charged pyridinium and unsaturated Cu(II) cation centers, free carboxylates, tessellating H2O, and coordinating SO4(2-) on the pore surface. Compound 1 can interact with two carboxyfluorescein (FAM)-labeled single-stranded DNA sequences (probe ss-DNA, delineated as P-DNA) through electrostatic, π-stacking, and/or hydrogen-bonding interactions to form two [email protected] systems, and thus quench the fluorescence of FAM via a photoinduced electron-transfer process. These [email protected] systems can be used as effective fluorescent sensors for human immunodeficiency virus 1 double-stranded DNA and Sudan virus RNA sequences, respectively, with detection limits of 196 and 73 pM, respectively.
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http://dx.doi.org/10.1021/acs.analchem.5b03084DOI Listing
December 2015

Aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing NF-κB and NFATc1 activation and DC-STAMP expression.

Acta Pharmacol Sin 2016 Feb 23;37(2):255-63. Epub 2015 Nov 23.

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

Aim: Aconiti Lateralis Radix Preparata is a traditional Chinese medicine used to treat chronic arthritis and is highly effective against rheumatoid arthritis. However, the effects of aconine, a derivative of aconitum alkaloids, on osteoclasts, which can absorb bone, remain unknown. Here, we investigated the effects of aconine on osteoclast differentiation and bone resorption in vitro.

Methods: The viability of mouse leukemic monocyte/macrophage cell line RAW264.7 was measured using CCK-8 assays. Osteoclast differentiation was induced by incubation of RAW264.7 cells in the presence of RANKL, and assessed with TRAP staining assay. Bone resorption was examined with bone resorption pits assay. The expression of relevant genes and proteins was analyzed using RT-PCR and Western blots. The activation of NF-κB and nuclear factor of activated T-cells (NFAT) was examined using stable NF-κB and NFATc1 luciferase reporter gene systems, RT-PCR and Western blot analysis.

Results: Aconine (0.125, 0.25 μmol/L) did not affect the viability of RAW264.7 cells, but dose-dependently inhibited RANKL-induced osteoclast formation and bone resorptive activity. Furthermore, aconine dose-dependently inhibited the RANKL-induced activation of NF-κB and NFATc1 in RAW264.7 cells, and subsequently reduced the expression of osteoclast-specific genes (c-Src, β3-Integrin, cathepsin K and MMP-9) and the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which played an important role in cell-cell fusion.

Conclusion: These findings suggest that aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing the activation of NF-κB and NFATc1 and the expression of the cell-cell fusion molecule DC-STAMP.
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http://dx.doi.org/10.1038/aps.2015.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753374PMC
February 2016

The Chinese version of the Child and Adolescent Scale of Environment (CASE-C): validity and reliability for children with disabilities in Taiwan.

Res Dev Disabil 2015 Mar 26;38:64-74. Epub 2014 Dec 26.

Graduate Institute of Early Intervention, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address:

Measurement of children's participation and environmental factors is a key component of the assessment in the new Disability Evaluation System (DES) in Taiwan. The Child and Adolescent Scale of Environment (CASE) was translated into Traditional Chinese (CASE-C) and used for assessing environmental factors affecting the participation of children and youth with disabilities in the DES. The aim of this study was to validate the CASE-C. Participants were 614 children and youth aged 6.0-17.9 years with disabilities, with the largest condition group comprised of children with intellectual disability (61%). Internal structure, internal consistency, test-retest reliability, convergent validity, and discriminant (known group) validity were examined using exploratory factor analyses, Cronbach's α coefficient, intra-class correlation coefficients (ICC), correlation analyses, and univariate ANOVAs. A three-factor structure (Family/Community Resources, Assistance/Attitude Supports, and Physical Design Access) of the CASE-C was produced with 38% variance explained. The CASE-C had adequate internal consistency (Cronbach's α=.74-.86) and test-retest reliability (ICCs=.73-.90). Children and youth with disabilities who had higher levels of severity of impairment encountered more environmental barriers and those experiencing more environmental problems also had greater restrictions in participation. The CASE-C scores were found to distinguish children on the basis of disability condition and impairment severity, but not on the basis of age or sex. The CASE-C is valid for assessing environmental problems experienced by children and youth with disabilities in Taiwan.
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http://dx.doi.org/10.1016/j.ridd.2014.12.019DOI Listing
March 2015

Development of a SCAR (sequence-characterised amplified region) marker for acid resistance-related gene in Lactobacillus plantarum.

Extremophiles 2015 Mar 17;19(2):355-61. Epub 2014 Dec 17.

College of Enology, Northwest A&F University, Yangling, Shaanxi, 712100, China,

A sequence characterised amplified region marker was developed to determine an acid resistance-related gene in Lactobacillus plantarum. A random amplified polymorphic DNA marker named S116-680 was reported to be closely related to the acid resistance of the strains. The DNA band corresponding to this marker was cloned and sequenced with the induction of specific designed PCR primers. The results of PCR test helped to amplify a clear specific band of 680 bp in the tested acid-resistant strains. S116-680 marker would be useful to explore the acid-resistant mechanism of L. plantarum and to screen desirable malolactic fermentation strains.
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http://dx.doi.org/10.1007/s00792-014-0721-2DOI Listing
March 2015

Effects of Biejia Ruangan Tablet-containing serum on matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in cultured renal interstitial fibroblasts.

Chin J Integr Med 2015 Feb 16;21(2):152-6. Epub 2014 Dec 16.

Department of Nephrology, the PLA General Hospital, Beijing, 100853, China,

Objective: To investigate the effects of Biejia Ruangan Tablet ([symbol in text], BRT)-containing serum on the expression of matrix metalloproteinase (MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) in cultured renal interstitial fibroblasts.

Methods: Different BRT-containing sera were prepared by gastric gavages to rats with the high-dose (7 g/kg), mid-dose (3.5 g/kg), and low-dose (1.75 g/kg) BRT respectively. The expression of extracellular matrix in NRK-49F cells was induced by treatment with human transforming growth factor-β1 (recombined human TGF-β1), and BRT-containing serum. Western blotting and Northern blotting were used to measure type I and III procollagen, MMP-9, and TIMP-1.

Results: The high dose BRT-containing serum could decrease the type I and III procollagen gene expression which boosted by TGF-β1, at the same time cut down TIMP-1 protein and gene expression which increased by TGF-β1 (P <0.05). Treatment of cells with recombined human TGF-β1 had no significant effect on MMP-9 expression and BRT-containing serum also had no effect on MMP-9 expression.

Conclusions: High dose BRT has anti-fibrosis effects in NRK-49F cells, as indicated by its inhibition of type I and III procollagen and TIMP-1 expression.
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http://dx.doi.org/10.1007/s11655-014-1784-0DOI Listing
February 2015

Synthesis and anticancer activities of 3-arylflavone-8-acetic acid derivatives.

Eur J Med Chem 2015 Jan 18;90:251-7. Epub 2014 Nov 18.

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address:

This paper describes the synthesis and the antiproliferative activities of compounds 9a-r, 3-aryl analogs of flavone-8-acetic acid that bear diverse substituents on the benzene rings at the 2- and 3-positions of the flavone nucleus. Their direct and indirect cytotoxicities were evaluated against HT-29 human colon adenocarcinoma cell lines, A549 lung adenocarcinoma cell lines and Human Peripheral Blood Mononuclear Cells (HPBMCs). The results indicate that most of the compounds bearing electron-withdrawing substituents (9b-m) exhibited moderate direct cytotoxicities. And compounds 9e and 9i showed comparable indirect cytotoxicities with 5, 6-dimethylxanthenone-4-acetic acid (DMXAA), and low direct cytotoxicities toward HPBMCs. Interestingly, the compounds 9n-r bearing methoxy groups at the 2- or 3-position of the flavone nucleus exhibited higher indirect cytotoxicities against A549 cell lines than DMXAA, and lower cytotoxicities against HPBMCs. In addition, compounds 9p-r were found to be able to induce tumor necrosis factor α (TNF-α) production in HPBMCs.
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http://dx.doi.org/10.1016/j.ejmech.2014.11.030DOI Listing
January 2015

Bioactive metabolites produced by the endophytic fungus Phomopsis sp. YM355364.

Nat Prod Commun 2014 May;9(5):669-70

A new compound, 16-acetoxycytosporone B (1), along with four known ones, dankasterone A (2), dankasterone B (3), 3beta,5alpha,9alpha-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (4), and cyclonerodiol oxide (5), were isolated from Phomopsis sp. YM355364, an endophytic fungus of Aconitum carmichaeli. Their structures were characterized by spectral analysis. Compound 2 exhibited significant inhibitory activity against influenza A/Thailand/Kan353/2004(H5N1) pseudovirus with all IC50 value of 3.56 microM. Compounds 1, 2, and 4 showed either moderate or weak antifungal activities against four pathogenic fungi.
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May 2014

Validation of a differential diagnostic model of diabetic nephropathy and non-diabetic renal diseases and the establishment of a new diagnostic model.

J Diabetes 2014 Nov 25;6(6):519-26. Epub 2014 Apr 25.

Department of Nephrology, Chinese PLA General Hospital (301 Hospital), Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases (2011DAV00088), National Clinical Research Center of Kidney Diseases (2013BAI09B05), Beijing, China.

Background: The aims of the present study were to validate the differential diagnostic model of diabetic nephropathy (DN) and non-diabetic renal diseases (NDRD) established in 2003 and to establish a new diagnostic model suitable for the current clinical characteristics of DN.

Methods: We examined 200 patients with Type 2 diabetes who underwent kidney biopsy from 2004 to 2012. The 2003 differential diagnostic model based on the data collected from 1993 to 2003 was evaluated by the diagnostic test and changes in the clinical differentiation parameters of DN and NDRD were analyzed. Logistic regression, receiver operating characteristics (ROC) curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analysis were applied.

Results: The 2003 diagnostic model showed an accuracy of 77.5%. A significantly elevated incidence of hematuria, longer history of diabetes, and reduced level of glycated hemoglobin (HbA1c) were observed in the DN group from 2004 to 2012 compared with DN group from 1993 to 2003. Histories of diabetes mellitus (Dm), systolic blood pressure (Bp), HbA1c (Gh), hematuria (Hu), diabetic retinopathy (Dr), and hemoglobin (Hb) are independently related to DN. Thus, a new diagnostic model was constructed as follows: PDN  = exp (0.846 + 0.022 Dm + 0.033Bp + 2.050 Gh-2.664 Hu-0.078 Hb + 2.942Dr)/[1 + exp (0.846 + 0.022 Dm + 0.033 Bp + 2.050 Gh-2.664 Hu-0.078 Hb + 2.942 Dr)].Validation tests determined that the accuracy of the new model were 90.9%.

Conclusions: Changes in people with DN, clinical characteristics have reduced the diagnostic efficacy of the 2003 diagnostic model. The newly established model can provide a better, more current differentiation between DN and NDRD.
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http://dx.doi.org/10.1111/1753-0407.12150DOI Listing
November 2014

Synthesis, selective cytotoxicities and probable mechanism of action of 7-methoxy-3-arylflavone-8-acetic acids.

Bioorg Med Chem 2014 Mar 31;22(5):1539-47. Epub 2014 Jan 31.

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address:

Thirteen new analogues of flavone-8-acetic acid, that is, compounds 10a-m bearing a methoxy group at the 7-position and diverse subsitiuents on the benzene ring at the 2- and 3-positions of flavone nucleus, were synthesized and evaluated for their direct antiproliferative effects on two human tumor cell lines and for their indirect antiproliferative activities in the transwell co-culture system. The results indicated that most of compounds 10a-m showed moderate direct cytotoxicities. Among them, compound 10i exhibited higher direct cytotoxicity and selectivity for both cell lines over BJ human foreskin fibroblast cells than 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Interestingly, compared with DMXAA, compound 10e showed comparable indirect cytotoxicity and higher selectivity. In addition, compound 10e was found to be able to induce tumor necrosis factor α (TNF-α) production in human peripheral blood mononuclear cells.
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http://dx.doi.org/10.1016/j.bmc.2014.01.042DOI Listing
March 2014
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