Publications by authors named "Yuanyuan Qian"

56 Publications

Downregulated ARID1A by miR-185 Is Associated With Poor Prognosis and Adverse Outcomes in Colon Adenocarcinoma.

Front Oncol 2021 2;11:679334. Epub 2021 Aug 2.

Department of Clinical Biochemistry, College of Laboratory Diagnostic Medicine, Dalian Medical University, Dalian, China.

AT-rich interaction domain 1A (ARID1A) is a tumor suppressor gene that mutates in several cancer types, including breast cancer, ovarian cancer, and colorectal cancer (CRC). In colon adenocarcinoma (COAD), the low expression of ARID1A was reported but the molecular reason is unclear. We noticed that ARID1A low expression was associated with increased levels of miR-185 in the COAD. Therefore, this study aims to explore ncRNA-dependent mechanism that regulates ARID1A expression in COAD regarding miR-185. The expression of ARID1A was tested in COAD cell line under the effect of miR-185 mimics compared with inhibitor. The molecular features associated with loss of ARID1A and its association with tumor prognosis were analyzed using multi-platform data from The Cancer Genome Atlas (TCGA), and gene set enrichment analysis (GSEA) to identify potential signaling pathways associated with ARID1A alterations in colon cancer. Kaplan-Meier survival curve showed that a low level of ARID1A was closely related to low survival rate in patients with COAD. Results showed that inhibiting miR-185 expression in the COAD cell line significantly restored the expression of ARID1A. Further, the increased expression of ARID1A significantly improved the prolonged overall survival of COAD. We noticed that there is a possible relationship between ARID1A high expression and tumor microenvironment infiltrating immune cells. Furthermore, the increase of ARID1A in tumor cells enhanced the response of inflammatory chemokines. In conclusion, this study demonstrates that ARID1A is a direct target of miR-185 in COAD that regulates the immune modulations in the microenvironment of COAD.
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http://dx.doi.org/10.3389/fonc.2021.679334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367751PMC
August 2021

[Roles of ERK/JNK in carbon black induced AP-1 cell signaling pathway changes].

Wei Sheng Yan Jiu 2021 Jul;50(4):533-538

National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China.

Objective: To investigate the role of ERK/JNK in the alteration of activator protein-1(AP-1) signaling pathway in human embryonic lung fibroblasts(HELFs) induced by carbon black.

Methods: HELFs were cultured in RPMI 1640 medium containing 0, 15, 30, 60, 120 or 240 μg/mL carbon black for 24 h, and the appropriate dose of carbon black was determined by MTT assay result. HELFs were divided into three groups: HELFs, HELFs transfected with ERK dominant negative mutant plasmid(DN-ERK) and HELFs transfected with JNK dominant negative mutant plasmid(DN-JNK). 100 μg/mL carbon black was used to treat HELFs(CB), DN-ERK HELFs(CB-DN-ERK), DN-JNK HELFs(CB-DN-JNK), and HELFs without any treatment were considered as control group. At 0, 1, 2, 4, 8, 12, 24 and 36 h of CB and control groups HELFs, the western blot was used to detect ERK, p-ERK, JNK, p-JNK, p38, p-p38, c-Jun, p-c-Jun, c-Fos, p-c-Fos protein expression levels, and AP-1 activity was detected by luciferase method. Whereas CB-DN-ERK and CB-DN-JNK HELFs were detected only at 24 h.

Results: Compared with the protein expression levels at 0 h, CB group HELFs ERK and p-ERK protein expression increased at each time point, whereas p38 protein expression decreased. AP-1 activity of CB group HELFs was declined to the lowest at 8 h(0.72±0.12), and upregulated to the peak at 36 h(1.38±0.11). CB group HELFs c-Fos, p-c-Fos and c-Jun protein expression levels at each time point from 1 h to 24 h were greater than those of 0 h, and p-c-Jun protein expression levels at 1 h, 2 h, 4 h, 8 h, 36 h were also greater than those of 0 h. CB group HELFs AP-1 activity, ERK, p-ERK, JNK, p-JNK, p38, p-p38, c-Jun, p-c-Jun, c-Fos, p-c-Fos protein expression levels changes followed biphasic patterns. There were no statistically significant differences in AP-1 activity between CB group HELFs(1.03±0.10) and CB-DN-ERK group(1.02±0.04) or CB-DN-JNK group(1.09±0.10) HELFs(t=0.16, P=0.88; t=0.73, P=0.50). However, compared with CB group HELFs, c-Fos(t=5.31, P=0.01), p-c-Fos(t=4.33, P=0.01), p-c-Jun(t=10.95, P& lt; 0.01)in CB-DN-JNK group, and c-Fos protein expression levels in CB-DN-ERK group(t=42.72, P& lt; 0.01)were significantly decreased.

Conclusion: While carbon black induces HELFs increased protein expression levels of ERK, p-ERK, c-Jun, p-c-Jun, c-Fos and p-c-Fos, JNK may upregulate c-Fos, p-c-Fos, p-c-Jun protein expression levels, and ERK may upregulate c-Fos protein expression level.
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http://dx.doi.org/10.19813/j.cnki.weishengyanjiu.2021.04.001DOI Listing
July 2021

Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3,4)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic.

J Med Chem 2021 07 21;64(13):9458-9483. Epub 2021 Jun 21.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Management of moderate to severe pain relies heavily on opioid analgesics such as morphine, oxycodone, and fentanyl in clinics. However, their prolonged use was associated with undesirable side effects. Many new strategies to reduce side effects have been proposed, but not without disadvantages. Using a hot plate model as a phenotypic screening method, our studies identified (3,4)- with a new scaffold as a potent analgesic with ED values of 0.54 mg/kg and 0.021 mg/kg in hot plate and antiwrithing models, respectively. Mechanistic studies showed that it elicited its analgesic effect via the active metabolite (3,4)-. The mechanism of (3,4)--induced activation of the μ opioid receptor (MOR) was proposed by means of molecular dynamics (MD) simulation.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00722DOI Listing
July 2021

Structure-Activity Relationship for the Picolinamide Antibacterials that Selectively Target .

ACS Med Chem Lett 2021 Jun 7;12(6):991-995. Epub 2021 May 7.

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.

is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics. To address the urgent need for treating recurrent infection, antibiotics that selectively target over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against . The structure-activity relationship of 108 analogues of isonicotinamide , a compound that is equally active against methicillin-resistant and , was investigated. Introduction of the picolinamide core as exemplified by analogue resulted in exquisite potency and selectivity against . The ability of the picolinamide class to selectively target and to prevent gut dysbiosis holds promise for the treatment of recurrent infection.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201750PMC
June 2021

Peptidome Analysis of Pancreatic Tissue Derived from T1DM Mice: Insights into the Pathogenesis and Clinical Treatments of T1DM.

Biomed Res Int 2021 21;2021:9987042. Epub 2021 May 21.

Department of Pediatrics, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, Jiangsu, China.

Bioactive peptides attract growing concerns for their participation in multiple biological processes. Their roles in the pathogenesis of type 1 diabetes mellitus remain poorly understood. In this study, we used LC-MS/MS technology to compare the peptide profiling between pancreatic tissue of T1DM mice and pancreatic tissue of matched control groups. A total of 106 peptides were differentially expressed in T1DM pancreatic tissue, including 43 upregulated and 63 downregulated peptides. Most of the precursor proteins are insulin. Further bioinformatics analysis (GO and pathway analysis) indicated that the potential functions of these differential peptides were tightly related to regulation of endoplasmic reticulum stress. In conclusion, this study highlights new candidate peptides and provides a new perspective for exploring T1DM pathogenesis and clinical treatments.
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http://dx.doi.org/10.1155/2021/9987042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164536PMC
May 2021

[Role of PTEN in FAK and α-SMA protein levels changes in human embryonic lung fibroblasts induced by silica].

Wei Sheng Yan Jiu 2021 Mar;50(2):223-229

National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China.

Objective: To investigate the roles of phosphatase and tensin homolog deleted on chromosome 10(PTEN) in focal adhesion kinase(FAK) and α-smooth muscle actin(α-SMA) protein levels changes in human embryonic lung fibroblasts(HELFs) induced by silica.

Methods: The HELF cells were cultured in low serum medium containing 0, 25, 50, 100 and 200 μg/cm~2 silica for 24 hours, and the cell counting kit-8(CCK8) experiment was used to determine the appropriate dose of silica for stimulation. Meanwhile, the effect of different doses of silica on the morphology of HELFs was observed under inverted microscope. 50 μg/cm~2 silica solution was used to culture HELFs for 0, 1, 2, 4, 8, 12 and 24 hours(h), and the control group were used as the control group. In addition, Western blot was used to detect HELFs PTEN, p-PTEN, FAK, p-FAK and α-SMA protein levels at each culture time. Besides, HELFs were cultured with 2×10~(-3) mol/L PTEN inhibitor(VO-Ohpic) and/or silica for 24 h, including HELFs group, HELFs plus silica group, and HELFs plus silica plus VO-Ohpic group, and the FAK, p-FAK and α-SMA in each group were also detected by Western blot.

Results: With the increase of silica dose, HELFs viability firstly increased and then decreased, and the cell viability of 50 μg/cm~2 group(144. 91±5. 10) was significantly higher than that of 0 μg/cm~2 group(101. 23±6. 57)(P<0. 05). Compared with the control group of silica treated HELFs, the expression levels of PTEN and p-PTEN at 12 h and 24 h were significantly decreased(PTEN: 0. 44±0. 08 at 12 h, 0. 25±0. 02 at 24 h; p-PTEN: 0. 09±0. 01 at 12 h, 0. 01±0. 00 at 24 h; all P values<0. 05); whereas, FAK at 12 h(0. 92±0. 05) and 24 h(0. 89±0. 01), and p-FAK(0. 77±0. 02) and α-SMA at 24 h(1. 32±0. 01) were significantly increased(all P values<0. 05). The expression levels of FAK(0. 25±0. 03), p-FAK(0. 40±0. 02) and α-SMA(0. 36±0. 01) of HELFs plus silica plus VO-Ohpic group were significantly higher than those of HELFs plus silica group(P<0. 05).

Conclusion: While silica induces HELFs FAK, p-FAK, and α-SMA increase, PTEN may downregulate FAK, p-FAK and α-SMA expression levels.
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http://dx.doi.org/10.19813/j.cnki.weishengyanjiu.2021.02.010DOI Listing
March 2021

[Effect of ERK/JNK cell signaling pathway in carbon black induced cytokine IL-6 and IL-8 expression changes].

Wei Sheng Yan Jiu 2021 Jan;50(1):46-50

National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China.

Objective: To investigate the roles of extracellular signal-regulated kinase(ERK)/c-Jun amino-terminal kinase(JNK) signaling pathway on the expression of interleukin-6(IL-6) and interleukin-8(IL-8) in human embryonic lung fibroblasts(HELF) induced by carbon black.

Methods: HELFs were cultured in RPMI-1640 medium containing 0, 15, 30, 60, 120 or 240 μg/mL carbon black for 24 h, and the appropriate dose of carbon black was determined by MTT assay result HELFs were divided into three groups: HELFs, HELFs transfected with ERK dominant negative mutant plasmid(DN-ERK) and HELFs transfected with JNK dominant negative mutant plasmid(DN-JNK). 100 μg/mL carbon black was used to treat HELFs(CB), DN-ERK HELFs(CB-DN-ERK), DN-JNK HELFs(CB-DN-JNK), and HELFs without any black carbon treatment were considered as control group. At 16 h after carbon black treatment, scanning electron microscope(SEM) was used to observe HELFs morphology and whether there were carbon black particless. At 0, 1, 2, 4, 8, 12, 24 and 36 h, the enzyme linked immunosorbent assay(ELISA) was used to detect CB and control groups HELFs IL-6 and IL-8 expression levels, whereas CB-DN-ERK and CB-DN-JNK HELFs were detected only at 24 h.

Results: SEM result showed no carbon black particles were observed in CB group HELFs, whereas their surface projections were increased. The CB group HELFs IL-6 expression levels at 2 h(44. 86±3. 65 ng/L) and 4 h(76. 52±3. 15 ng/L) were significantly lower than those of the control group(96. 78±2. 82 and 147. 32±3. 26 ng/L)(P<0. 05), whereas the IL-6 expression levels were significantly higher than those of the control group(105. 54±6. 10, 101. 27±5. 84 and 97. 15±5. 12 ng/L) at 16 h(202. 64±7. 20 ng/L), 24 h(200. 38±6. 20 ng/L) and 36 h(183. 54±4. 54 ng/L)(P<0. 001). At 24 h(136. 75±3. 81 ng/L) and 36 h(149. 12±2. 74 ng/L), the CB group IL-8 expression levels were significantly higher than those of the control group(75. 16±2. 84 and 73. 44±2. 15 ng/L)(P<0. 001). Compared with CB group HELFs, CB-DN-ERK and CB-DN-JNK groups HELFs had significantly lower IL-6 and IL-8 expression levels(P<0. 05).

Conclusion: While carbon black induced HELFs IL-6 and IL-8 expression levels changes, ERK and JNK may upregulate IL-6 and IL-8 expression levels.
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http://dx.doi.org/10.19813/j.cnki.weishengyanjiu.2021.01.008DOI Listing
January 2021

Facile Synthesis of Defect-Modified Thin-Layered and Porous g-CN with Synergetic Improvement for Photocatalytic H Production.

ACS Appl Mater Interfaces 2020 Nov 11;12(47):52603-52614. Epub 2020 Nov 11.

Key Laboratory of Semiconductor Materials Science, Beijing Key Laboratory of Low Dimensional Semiconductor Materials and Devices, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.

Modulating and optimizing the diverse parameters of photocatalysts synergistically as well as exerting these advantages fully in photocatalytic reactions are crucial for the sufficient utilization of solar energy but still face various challenges. Herein, a novel and facile urea- and KOH-assisted thermal polymerization (UKATP) strategy is first developed for the preparation of defect-modified thin-layered and porous g-CN (DTLP-CN), wherein the thickness of g-CN was dramatically decreased, and cyano groups, nitrogen vacancies, and mesopores were simultaneously introduced into g-CN. Importantly, the roles of thickness, pores, and defects can be targetedly modulated and optimized by changing the mass ratio of urea, KOH, and melamine. This can remarkably increase the specific area, improve the light-harvesting capability, and enhance separation efficiency of photoexcited charge carriers, strengthening the mass transfer in g-CN. Consequently, the photocatalytic hydrogen evolution efficiency of the DTLP-CN (1.557 mmol h g, λ > 420 nm) was significantly improved more than 48.5 times with the highest average apparent quantum yield (AQY) of 18.5% and reached as high as 0.82% at 500 nm. This work provides an effective strategy for synergistically regulating the properties of g-CN, and opens a new horizon to design g-CN-based catalysts for highly efficient solar-energy conversion.
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http://dx.doi.org/10.1021/acsami.0c14262DOI Listing
November 2020

Isoliquiritigenin attenuates diabetic cardiomyopathy via inhibition of hyperglycemia-induced inflammatory response and oxidative stress.

Phytomedicine 2020 Nov 1;78:153319. Epub 2020 Sep 1.

Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

Background: Inflammation and oxidative stress play essential roles in the occurrence and progression of diabetic cardiomyopathy (DCM). Isoliquiritigenin (ISL), a natural chalcone, exhibits strong anti-inflammatory and antioxidant activities.

Hypothesis/purpose: In this study, we aimed to investigate the protective effects of ISL on DCM using high glucose (HG)-challenged cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic mice.

Study Design And Methods: Embryonic rat heart-derived H9c2 cells challenged with a high concentration of glucose were used to evaluate the anti-inflammatory and antioxidant effects of ISL. STZ-induced diabetic mice were used to study the effects of ISL in DCM in vivo. Furthermore, cardiac fibrosis, hypertrophy, and apoptosis were explored both in vitro and in vivo.

Results: ISL effectively inhibited HG-induced hypertrophy, fibrosis, and apoptosis probably by alleviating the inflammatory response and oxidative stress in H9c2 cells. Results from in vivo experiments showed that ISL exhibited anti-inflammatory and antioxidant stress activities that were characterized by the attenuation of cardiac hypertrophy, fibrosis, and apoptosis, which resulted in the maintenance of cardiac function. The protective effects of ISL against inflammation and oxidative stress were mediated by the inhibition of mitogen-activated protein kinases (MAPKs) and induction of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, respectively.

Conclusion: Our results provided compelling evidence that ISL, by virtue of neutralizing excessive inflammatory response and oxidative stress, could be a promising agent in the treatment of DCM. Targeting the MAPKs and Nrf2 signaling pathway might be an effective therapeutic strategy for the prevention and treatment of DCM.
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http://dx.doi.org/10.1016/j.phymed.2020.153319DOI Listing
November 2020

Single gold nanoclusters: Formation and sensing application for isonicotinic acid hydrazide detection.

Talanta 2020 Dec 10;220:121376. Epub 2020 Jul 10.

Anhui Key Laboratory of Chemo/Biosensing, College of Chemistry and Materials Science, Anhui Normal University, Wuhu, 241000, PR China. Electronic address:

Nano-sized electrodes have their special advantages for sensing applications, such as small overall dimension, fast response and low background current. In this work, single gold nanoclusters (AuNCs) were controllably prepared on single Pt nanoelectrode surface by electrodeposition method. The AuNCs covered Pt nanoelectrode (AuNCs/PtNE) had steady-state voltammetric response in redox species solution, which was similar to micro-/nano-sized electrodes. It was interesting to find isonicotinic acid hydrazide (INH, also known as isoniazid) showed good electrochemical response on AuNCs/PtNE surface, which had investigated carefully by square wave voltammetry (SWV) and chronoamperometry. Moreover, the prepared single AuNCs/PtNEs showed the capability for INH sensing with good sensitivity, reproducibility and selectivity, which was demonstrated for INH detection in human urine samples.
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http://dx.doi.org/10.1016/j.talanta.2020.121376DOI Listing
December 2020

Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective μ Opioid Receptor Agonists.

ACS Chem Neurosci 2021 01 28;12(2):285-299. Epub 2020 Dec 28.

Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.

Pain was implicated in many diseases. Despite effectiveness to treat moderate to severe pain, opioid analgesics elicited many side effects, greatly limiting their prescription in clinics. Based on , an active metabolite of tramadol, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-4-ol analogues were designed, synthesized, and evaluated . Among all the compounds tested, compound was found to be a novel, highly selective, and potent MOR agonist ( = 0.0034 nM, EC = 0.68 nM, = 206.5%; = 41.67 nM; = 7.9 nM). Structure-activity relationship exploration showed that the linker between the piperidine ring and the phenyl ring as well as substituent pattern of the phenyl ring played a pivotal role in binding affinity and selectivity. (3, 4)- ( = 0.0021 ± 0.0001 nM, EC = 0.0013 ± 0.0001 nM, = 209.1 ± 1.4%; = 18.4 ± 0.7 nM, EC = 74.5 ± 2.8 nM, = 267.1 ± 1.4%; = 25.8 ± 0.2 nM, EC = 116.2 ± 4.4 nM, = 209.5 ± 1.4%) had more potent activity for opioid receptors than its enantiomer (3, 4)- and was found to be a potent, highly selective MOR agonist with novel scaffold. High binding affinity and selectivity of (3, 4)- for MOR over KOR and DOR and its mechanism of activating MOR were proposed by docking and molecular dynamics simulations, respectively.
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http://dx.doi.org/10.1021/acschemneuro.0c00487DOI Listing
January 2021

Exploration of the Structural Space in 4(3)-Quinazolinone Antibacterials.

J Med Chem 2020 05 8;63(10):5287-5296. Epub 2020 May 8.

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.

We report herein the syntheses of 79 derivatives of the 4(3)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound (()-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the β-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720656PMC
May 2020

Structure-Activity Relationship for the Oxadiazole Class of Antibacterials.

ACS Med Chem Lett 2020 Mar 3;11(3):322-326. Epub 2019 Oct 3.

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.

A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant (MRSA) infection. Oxadiazole shows potent antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073871PMC
March 2020

Effect of MicroRNA-126a-3p on Bone Marrow Mesenchymal Stem Cells Repairing Blood-brain Barrier and Nerve Injury after Intracerebral Hemorrhage.

J Stroke Cerebrovasc Dis 2020 May 9;29(5):104748. Epub 2020 Mar 9.

Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.

Objective: Intracerebral hemorrhage (ICH) is a disease that threatens human health due to its high morbidity and mortality. On behalf of finding the better methods in the treatment of ICH, researchers pay more attention to a new technology which is finding effective genes to modify stem cells.

Methods: In this study, we isolated, cultured and identified bone marrow mesenchymal stem cells (MSCs) in vitro. Further, the MSCs (transfected with lentivirus expressing microRNA-126a-3p (miR-126)) were injected into the type Ⅶ collagenase-induced ICH rats to investigate the recovery effects of blood-brain barrier (BBB) and nerve damage in vivo.

Results: The MSCs surface marker molecules (CD29: 98.5%; CD90: 96.5%) were highly expressed, and the blood cell surface molecule was negatively expressed (CD45: 2%). Meanwhile, it was verified that miR-126 facilitated the differentiation of MSCs into vascular endothelial cells, owing to the rise of markers (CD31 and VE-cadherin). The modified neurological severity score, modified limb placing test score, brain water content and evans blue content were reduced after transplanted miR-126-modified MSCs. It was found that miR-126 accelerated the differentiation of MSCs into vascular endothelial cells via immunohistochemical staining in vivo. HE staining indicated the area of edema was obviously decreased compared with that in ICH + vector-MSCs group. MiR-126-modified MSCs alleviated the cell apoptosis in brain tissues by TUNEL assay. In addition, the mRNA and protein expression of protease activated receptor-1 and matrix metalloproteinase-9 were diminished, whilst the expression of zonula occludens-1 (ZO-1) and claudin-5 were enhanced in ICH+miR-126-MSCs group. Immunofluorescence assay revealed that miR-126-modified MSCs decreased the disruption of tight junction (ZO-1 and claudin-5).

Conclusions: All data illustrate that miR-126-modified MSCs repair BBB and nerve injury after ICH.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104748DOI Listing
May 2020

Engineering protonation conformation of l-aspartate-α-decarboxylase to relieve mechanism-based inactivation.

Biotechnol Bioeng 2020 06 2;117(6):1607-1614. Epub 2020 Mar 2.

School of Pharmaceutical Science, Jiangnan University, Wuxi, China.

Mechanism-based inactivation of l-aspartate-α-decarboxylase (PanD), which leads to irreversible modification of active site, is a major challenge in the efficient production of β-alanine from L-aspartic acid. In this study, a semi-rational strategy that combined conformational dynamics and structural alignment was applied to increase the catalytic stability of Bacillus subtilis PanD (BsPanD). Using site-saturation and C-terminal deletion, the variant Q5 (BsPanD ) was generated. The catalytic half-life and the total turnover number (TTN) of Q5 were 3.48-fold and 2.52-fold higher, respectively, compared with that of the parent Q0. The reasons for the differences were the prolonged distance d1 between the phenolic group of Tyr58 and pyruvoyl group of Ser25 (4.9 Å in Q0 vs. 5.5 Å in Q5), an increased difficulty for incorrect protonation to occur, and the decreased flexibility of residues in regions A, B, and C, thereby enhancing the probability of correct protonation. Variant Q5, coupled with l-aspartase (AspA) in a 15-L bioreactor, generated a linear cascade system using fumaric acid as a substrate, yielding 118.6 g/L β-alanine with a product/catalyst (P/C) ratio of 5.9 g/g and a conversion > 99%. These results showed that reshaping the protonation conformation of PanD can efficiently relieve mechanism-based inactivation and boost catalytic stability.
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http://dx.doi.org/10.1002/bit.27316DOI Listing
June 2020

Nanopore-based Strategy for Selective Detection of Single Carcinoembryonic Antigen (CEA) Molecules.

Anal Chem 2020 02 4;92(4):3042-3049. Epub 2020 Feb 4.

Anhui Key Laboratory of Chemo/Biosensing, College of Chemistry and Materials Science , Anhui Normal University , Wuhu 241000 , P.R. China.

Nanopores have become one of the most important tools for single-molecule sensing, but the challenge for selective detection of specific biomolecules still exists. In this contribution, we develop a new technique for sensing carcinoembryonic antigen (CEA), one of the important cancer biomarkers, using solid-state nanopores as a tool. The method is based on the specific affinity between aptamer (Apt) modified magnetic FeO-Au nanoparticles (MNPs) and CEA, and the formed CEA-Apt-MNPs and remaining Apt-MNPs can transport the nanopores by applying a positive potential after magnetic separation. Due to the obvious particle size difference between CEA-Apt-MNPs and Apt-MPs, their corresponding blockage signals could be distinguished completely by the degree of the current decline. Moreover, the frequency of the blockage signals for CEA-Apt-MNPs is proportional to the concentration of CEA within certain limits, indicating that our designed nanopore sensing strategy can quantitatively detect CEA in complex samples. This work demonstrates that our designed nanopore-based strategy can be used for CEA sensing with good selectivity and sensitivity and also can be used to analyze other protein biomarkers for early diagnosis and monitoring of cancer, though the detection limit (0.6 ng/mL) is not relatively low. In future works, we plan to improve our detection limit by the improvement of the nanopipette preparation technology and detection method.
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http://dx.doi.org/10.1021/acs.analchem.9b04185DOI Listing
February 2020

Occupational exposure to silica and risk of heart disease: a systematic review with meta-analysis.

BMJ Open 2020 01 7;10(1):e029653. Epub 2020 Jan 7.

Department of Biomarkers and Molecular Epidemiology, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China

Objective: To search for evidence of the relationship between occupational silica exposure and heart disease.

Design: A systematic review and meta-analysis.

Background: Growing evidence suggests a relationship between occupational silica exposure and heart disease; however, the link between them is less clear.

Data Sources: PubMed, ScienceDirect, Springer and EMBASE were searched for articles published between 1 January 1995 and 20 June 2019. Articles that investigated the effects of occupational silica exposure on the risk of heart disease were considered.

Study Selection: We included cohort studies, including prospective, retrospective and retroprospective studies.

Data Extraction And Synthesis: We extracted data using a piloted data collection form and conducted random-effects meta-analysis and exposure-response analysis. The meta-relative risk (meta-RR), a measure of the average ratio of heart disease rates in those with and without silica exposure, was used as an inverse variance-weighted average of relative risks from the individual studies. The Newcastle-Ottawa Quality Assessment Scale for cohort studies was used for study quality assessment.

Outcome Measure: We calculated the risk of heart diseases such as pulmonary heart disease, ischaemic heart disease and others.

Results: Twenty cohort studies were included. The results suggest a significant increase in the risk of overall heart disease (meta-RR=1.08, 95% CI 1.03 to 1.13). Stronger evidence of association with pulmonary heart disease was found in the risk estimate of both categories of heart disease (meta-RR=1.24, 95% CI 1.08 to 1.43) and in the exposure-response analysis (meta-RR=1.39, 95% CI 1.19 to 1.62). Our subgroup analyses also revealed that the statistical heterogeneity among studies could be attributed mainly to the diversity in reference group, occupation and study quality score.

Conclusions: Silica-exposed workers are at an increased risk for overall heart disease, especially pulmonary heart disease. Further research is needed to better clarify the relationship between occupational silica exposure and ischaemic heart disease.

Prospero Registration Number: CRD42019124673.
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http://dx.doi.org/10.1136/bmjopen-2019-029653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955526PMC
January 2020

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from -Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept.

J Med Chem 2019 12 6;62(24):11054-11070. Epub 2019 Dec 6.

CAS Key Laboratory of Receptor Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science , 555 Zuchongzhi Road , Shanghai 201203 , China.

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of -cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound , SLL-039) as a highly selective and potent κ opioid agonist (κ, = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays and antinociceptive assays . The effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V118, W124, and E209.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00857DOI Listing
December 2019

Activation of CRHR1 contributes to cerebral endothelial barrier impairment via cPLA phosphorylation in experimental ischemic stroke.

Cell Signal 2020 02 9;66:109467. Epub 2019 Nov 9.

Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, China. Electronic address:

The activation of corticotrophin-releasing hormone receptor (CRHR) 1 is implicated in neuronal injury in experimental stroke. However, little is known about the relationship between CRHR1 activation and brain endothelial barrier impairment after ischemia and reperfusion (I/R). Recently we have demonstrated that the activation of extracellular signal-regulated kinase (Erk) 1/2 as well as p38 is required for hydrogen peroxide (HO)-increased cytosolic phospholipase A (cPLA) phosphorylation in bEnd3 cells. Using this in vitro ischemic-like model, we found that both blockade and interference of CRHR1 inhibited HO-enhancd p38, Erk1/2 and cPLA phosphorylation and in turn suppressed monolayer hyperpermeability and ZO-1 redistribution. Then using the transient middle cerebral artery occlusion (tMCAO) mouse model, we revealed that CRHR1 antagonist NBI27914 pretreatment attenuated cPLA phosphorylation, Evans blue dye (EBD) extravasation, tight junction disruption and mitochondrial cytochrome c release. CRHR1 interference also inhibited cortical vascular hyperpermeability. Furthermore, NBI27914 administration attenuated neurovascular injury. After 30 min MCAO with 7 days reperfusion CRHR1 interference alleviated hippocampal blood-brain barrier (BBB) leakage and improved spatial cognitive dysfunction. Thus, our study demonstrates that during ischemic stroke the activation of endothelial CRHR1 contributes to BBB impairment via cPLA phosphorylation.
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http://dx.doi.org/10.1016/j.cellsig.2019.109467DOI Listing
February 2020

Susceptibility of Methicillin-Resistant Staphylococcus aureus to Five Quinazolinone Antibacterials.

Antimicrob Agents Chemother 2019 12 20;64(1). Epub 2019 Dec 20.

Area of Biochemistry and Molecular Biology, University of La Rioja, Logroño, Spain

The activities of five quinazolinone antibacterials, compounds Q1 to Q5, were tested against 210 strains of methicillin-resistant (MRSA). The MIC/MIC values (in μg/ml) were as follows: Q1, 0.5/2; Q2, 1/4; Q3, 2/4; Q4, 0.06/0.25; and Q5, 0.125/0.5. Several strains with high MIC values (from 8 to >32 μg/ml) for some of these compounds exhibited amino acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.
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http://dx.doi.org/10.1128/AAC.01344-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187613PMC
December 2019

Absorption lines measurements of carbon disulfide at 4.6 μm with quantum cascade laser absorption spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Jan 19;225:117478. Epub 2019 Aug 19.

Key Laboratory of Environmental Optics and Technology, Anhui Institute of Optics and Fine Mechanics, Chinese Academy of Science, Hefei, Anhui 230031, China; Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences, Changchun 130033, China. Electronic address:

We report measured line intensities and air- and self-broadening coefficients for fifty-one carbon disulfide transitions in the ν1 + ν3 band near 4.6 μm. This spectral region was chosen due to the strong carbon disulfide absorption strength and in the range of the mid-infrared atmospheric window for laser-based sensing applications. Spectroscopic parameters were determined by spectra measuring with quantum cascade laser direct absorption spectroscopy and multi-line fitting with Voigt lineshape. These measured results would facilitate the development of calibrated-free mid-infrared carbon disulfide sensors.
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http://dx.doi.org/10.1016/j.saa.2019.117478DOI Listing
January 2020

Cinnamonitrile Adjuvants Restore Susceptibility to β-Lactams against Methicillin-Resistant .

ACS Med Chem Lett 2019 Aug 1;10(8):1148-1153. Epub 2019 Jul 1.

Department Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.

β-Lactams are used routinely to treat infections. However, the emergence of methicillin-resistant (MRSA) renders them clinically precarious. We describe a class of cinnamonitrile adjuvants that restore the activity of oxacillin (a penicillin member of the β-lactams) against MRSA. The lead adjuvants were tested against six important strains of MRSA, one vancomycin-intermediate (VISA) strain, and one linezolid-resistant strain. Five compounds out of 84 total compounds showed broad potentiation. At 8 μM ()-3-(5-(3,4-dichlorobenzyl)-2-(trifluoromethoxy)phenyl)-2-(methylsulfonyl)acrylonitrile () potentiated oxacillin with a >4000-fold reduction of its MIC (from 256 to 0.06 mg·L). This class of adjuvants holds promise for reversal of the resistance phenotype of MRSA.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691485PMC
August 2019

Inhibition of EGFR-STAT3 attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes.

J Endocrinol 2019 09;242(3):199-210

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Emerging evidence implicates elevated activity of STAT3 transcription factor in driving the development and progression of diabetic cardiomyopathy (DCM). We hypothesized that the fibrosis-promoting and hypertrophic actions of STAT3 are linked to the activation by epidermal growth factor receptor (EGFR). We tested this hypothesis by challenging cultured cardiomyocytes to high-concentration glucose and heart tissues of streptozotocin (STZ)-induced type 1 diabetic mice. Our results indicated that, in diabetic mice, the blockade of STAT3 or EGFR using selective inhibitors S3I-201 and erlotinib, respectively, abrogated the increased activating STAT3 phosphorylation and the induction of genes regulating fibrosis and hypertrophy in myocardial tissue. S3I-201 and erlotinib significantly reduced myocardial structural and functional deficits in diabetic mice. In cultured cardiomyocytes, high-concentration glucose induced EGFR-mediated STAT3 phosphorylation. We further showed that blockade of STAT3 or EGFR using selective inhibitors and siRNAs significantly reduced the increased expression of genes known to promote fibrosis and hypertrophy in cardiomyocytes. These results provide novel evidence that the EGFR-STAT3 signaling axis likely plays a crucial role in the development and progression of DCM.
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http://dx.doi.org/10.1530/JOE-19-0058DOI Listing
September 2019

Hydrogen sulfide inhibited L-type calcium channels (CaV1.2) via up-regulation of the channel sulfhydration in vascular smooth muscle cells.

Eur J Pharmacol 2019 Sep 13;858:172455. Epub 2019 Jun 13.

Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China. Electronic address:

Hydrogen sulfide (HS) exerts different effects on the cardiovascular system by modulating ion channels. The present study was to ascertain whether HS affects L-type calcium (Ca) channels in vascular smooth muscle cells (VSMCs) and the subsequent signaling pathways. Here, CaV1.2 L-type Ca currents (I) were inhibited by sodium hydrosulfide (NaHS, an HS donor) in A7r5 cell lines using the whole-cell patch-clamp technique. Then NaHS significantly reduced intracellular Ca concentration ([Ca]) in Bayk8644-stimulated CaV1.2-HEK293 cells by using flow cytometry. However, NaHS did not affect the ryanodine-induced elevation of [Ca] by means of confocal microscopy, ruling out its influence on the intracellular Ca release. In the following, the sulfhydration of L-type Ca channels was determined by Ellman's Test. The results showed that NaHS decreased the number of free sulfhydryls, which was further strengthened by the oxidant sulfhydryl modifier diamide (DM) and significantly counteracted by the reductant sulfhydryl modifier dithiothreitol (DTT). DTT also partly reversed the NaHS-reduced [Ca] in CaV1.2-HEK293 cells. Additionally, NaHS did not change CaV1.2 expression. Furthermore, NaHS increased phosphorylation of PKC and ERK in both a concentration- and a time-dependent manner in VSMCs. Isradipine, L-type Ca channel specific blocker, further increased HS-induced phosphorylation of PKC and ERK, showing an additive effect with HS. Therefore, our results suggest that HS reduced I & [Ca] and hence influenced the downstream PKC/ERK pathway, which was likely through regulating the sulfhydration of L-type Ca channels in VSMCs.
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http://dx.doi.org/10.1016/j.ejphar.2019.172455DOI Listing
September 2019

Enhancing singlet oxygen generation in semiconducting polymer nanoparticles through fluorescence resonance energy transfer for tumor treatment.

Chem Sci 2019 May 11;10(19):5085-5094. Epub 2019 Apr 11.

Key Laboratory for Organic Electronics and Information Displays , Institute of Advanced Materials (IAM) , Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM) , Nanjing University of Posts and Telecommunications (NUPT) , Nanjing 210023 , P. R. China . Email: ; Email:

Photosensitizers (PSs) are of particular importance for efficient photodynamic therapy (PDT). Challenges for PSs simultaneously possessing strong light-absorbing ability, high O generation by effective intersystem crossing from the singlet to the triplet state, good water-solubility and excellent photostability still exist. Reported here are a new kind of dual-emissive semiconducting polymer nanoparticles (SPNs) containing fluorescent BODIPY derivatives and near-infrared (NIR) phosphorescent iridium(iii) complexes. In the SPNs, the BODIPY units serve as the energy donors in the fluorescence resonance energy transfer (FRET) process for enhancing the light absorption of the SPNs. The NIR emissive iridium(iii) complexes are chosen as the energy acceptors and efficient photosensitizers. The ionized semiconducting polymers can easily self-assemble to form hydrophilic nanoparticles and homogeneously disperse in aqueous solution. Meanwhile, the conjugated backbone of SPNs provides effective shielding for the two luminophores from photobleaching. Thus, an excellent overall performance of the SPN-based PSs has been realized and the high O yield (0.97) resulting from the synergistic effect of BODIPY units and iridium(iii) complexes through the FRET process is among the best reported for PSs. In addition, owing to the phosphorescence quenching of iridium(iii) complexes caused by O, the SPNs can also be utilized for O mapping and , which assists in the evaluation of the PDT process and provides important instructions in early-stage cancer diagnosis.
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http://dx.doi.org/10.1039/c8sc05501gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524665PMC
May 2019

MD2 blockade prevents oxLDL-induced renal epithelial cell injury and protects against high-fat-diet-induced kidney dysfunction.

J Nutr Biochem 2019 08 2;70:47-55. Epub 2019 May 2.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address:

There is a strong epidemiological link between obesity, a growing worldwide concern, and kidney disease. Emerging evidence indicates that the pathogenic basis of obesity-related kidney disease may be attributed to Toll-like receptor 4 (TLR4) of the innate immune system. We hypothesized that renal epithelial cell injury in response to oxidized low-density lipoprotein (oxLDL) requires myeloid differentiation factor 2 (MD2), a co-receptor of TLR4. Moreover, we also hypothesized that renal dysfunction is MD2-dependent in the high-fat diet (HFD) mouse model. Results indicated that the MD2 selective inhibitor (L6H21) abrogated the oxLDL-induced formation of MD2-TLR4 dimerization in the renal proximal tubular epithelial cell line NRK-52E. Further, MD2 blockade in NRK-52E cells using siRNA target sequences or L6H21 prevented oxLDL-induced cell injury as indicated by expression of profibrotic molecules, autophagic activity and apoptosis. Similarly, TLR4 knockdown in NRK-52E cells using siRNA target sequences prevented oxLDL-induced cell injury. In the HFD mouse model, MD2 knockout protected against development of kidney dysfunction and renal tissue injury, corroborating the observations observed in NRK-52E cells. Thus, the oxLDL-induced renal tubular epithelial cell profibrotic responses, autophagy and apoptosis were dependent on MD2, as were the renal dysfunction and tissue impairment in HFD mice. These are new findings indicating that the MD2-TLR4 immune signaling complex is a critical pathogenic factor in the development of kidney disease related to obesity or metabolic syndrome.
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http://dx.doi.org/10.1016/j.jnutbio.2019.04.003DOI Listing
August 2019

Schizandrin B attenuates angiotensin II induced endothelial to mesenchymal transition in vascular endothelium by suppressing NF-κB activation.

Phytomedicine 2019 Sep 11;62:152955. Epub 2019 May 11.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

Background: Angiotensin II (Ang II)-induced chronic inflammation and oxidative stress often leads to irreversible vascular injury, in which the endothelial to mesenchymal transition (EndMT) in the endothelial layers are involved. Schisandrin B (Sch B), a natural product isolated from traditional Schisandra chinensis, has been reported to exert vascular protective properties with unclear mechanism.

Hypothesis/purpose: This study investigated the protective effects and mechanism of Sch B against Ang II-induced vascular injury.

Methods: C57BL/6 mice were subcutaneous injected of Ang II for 4 weeks to induce irreversible vascular injury. In vitro, Ang II-induced HUVECs injury was used to study the underlying mechanism. The markers of EndMT, inflammation and oxidative stress were studied both in vitro and in vivo.

Results: Pre-administration of Sch B effectively attenuated phenotypes of vascular EndMT and fibrosis in Ang II-treated animals, accompanied with decreased inflammatory cytokine and ROS. The in vitro data from HUVECs suggest that Sch B directly targets NF-κB activation to suppress Ang II-induced EndMT and vascular injury. The activation of EndMT in the presence of Ang II is regulated by the NF-κB, a common player in inflammation and oxidative stress. Ang II-induced inflammation and oxidative stress also contributed to vascular EndMT development and Sch B inhibited inflammation/ROS-mediated EndMT by suppressing NF-κB.

Conclusion: EndMT contributes to vascular injury in Ang II-treated mice, and it can be prevented via suppressing NF-κB activation by Sch B treatment. These results also imply that NF-κB might be a promising target to attenuate vascular remodeling induced by inflammation and oxidative stress through an EndMT mechanism.
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http://dx.doi.org/10.1016/j.phymed.2019.152955DOI Listing
September 2019

[Role of p53/p21 signal transduction pathway in the malignant transformation of human embryonic lung fibroblasts induced by quartz].

Wei Sheng Yan Jiu 2019 Mar;48(2):187-192

National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China.

Objective: To observe the expression of p53 protein and investigate the roles of p53 in the expressions and interactions of p21, cyclin D1 and cyclin dependent kinase 4(CDK4) proteins in malignant transformation of human embryonic lung fibroblasts(T-HELF) induced by quartz.

Methods: The cytosolic protein and nuclear protein of both HELF and T-HELF cells were extracted by the separation technique of cytoplasm and nuclei. The distribution and expression of p53, phosphorylated p53 and p21 proteins were detected by Western blot. Based on the RNA interference technique, p53 siRNA was transfected into T-HELF cells to observe the protein expression and change of p53, phosphorylated p53, p21, cyclin D1 and CDK4, while the control group was conducted by transfecting the CMV-neo blank vector into the plasmid. The expression levels of p21, cyclin D1 and CDK4 protein complex in HELF and T-HELF cells were detected by immunoprecipitation. After adding 20 μmol/L of p53 chemical inhibitor pifithrin-α(PFT-α) and 2 μg of p53 siRNA into T-HELF cells respectively, the effect of p53 protein inhibition on p21, cyclin D1 and CDK4 protein complex was also observed.

Results: Quartz stimulation of HELF caused a significant increase in the expression of p53 and phosphorylated p53 protein in the nucleus(P<0. 05). The protein expression of p53 in the nucleus of T-HELF was significantly lower than that of HELF(P<0. 05). After transfection of p53 siRNA, the expression of p53 protein was decreased and the expression of p21 and cyclin D1 protein was increased compared with the control group(P<0. 05), while the change of expression in CDK4 was not observed(P>0. 05). Additionally, the result of immunoprecipitation showed that the inhibition of p53 expression could down-regulate the expression level of the binding complex between p21 and cyclin D1 protein(P<0. 05). However, this effect on p21-CDK4 and cyclin D1-CDK4 protein complex was not observed(P>0. 05).

Conclusion: By regulating the expression and protein-protein interaction between p21 and cyclin D1, p53 would participate in quartz-induced malignant transformation.
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March 2019

STRIP2 silencing inhibits vascular smooth muscle cell proliferation and migration via P38-AKT-MMP-2 signaling pathway.

J Cell Physiol 2019 12 15;234(12):22463-22476. Epub 2019 May 15.

Department of Pharmacology, Nanjing Medical University, Nanjing, China.

STRIP2 (FAM40B) was reported to regulate tumor cell migration. Our study aims to discuss the effect of STRIP2 in mouse aortic smooth muscle cell (MOVAS) proliferation and migration processes, which contributes greatly to atherosclerosis formation. In MOVAS cells, STRIP2 depletion suppressed cell proliferation and migration, which were related to a remarkable decrease in matrix metalloproteinases-2 (MMP-2)/MMP-9 expression. Additionally, P38 mitogen-activated protein kinases and Protein kinase B (AKT) are inactivated while extracellular signal-regulated kinase (ERK1/2) and jun N-terminal kinase (JNK) are activated upon STRIP2 silencing. SB203580 (P38 inhibitor) further reduced AKT phosphorylation (p-AKT) while dehydrocorydaline chloride (Dc; P38 activator) reversed this effect. Furthermore, Dc significantly recovered MMP-2 expression in STRIP2-knockdown cells. As expected, overexpressing STRIP2 exhibited a contrary effect. Dc and AKT activator SC79 reversed the inhibition of cell proliferation and migration induced by STRIP2 silencing. Interestingly, STRIP2 depletion increased vascular endothelial growth factor level significantly. Taken together, STRIP2 contributed to cell proliferation and migration through P38-AKT-MMP-2 signaling in MOVAS cells, indicating the importance of STRIP2 in atherosclerosis.
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http://dx.doi.org/10.1002/jcp.28810DOI Listing
December 2019

Luteolin protects against diabetic cardiomyopathy by inhibiting NF-κB-mediated inflammation and activating the Nrf2-mediated antioxidant responses.

Phytomedicine 2019 Jun 28;59:152774. Epub 2018 Nov 28.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address:

Background: Diabetes mellitus is a well-known risk factor for the development of heart failure. Inflammation and oxidative stress play a key role in the development of diabetic cardiomyopathy (DCM), and this nexus represents an attractive target to combat this disease. Naturally occurring flavonoid luteolin exhibits both anti-inflammatory and antioxidant activities in various systems.

Hypothesis/purpose: In this study, we aimed to investigate potential cardioprotective effects of luteolin in cultured cardiomyocytes and in mice with type 1 diabetes.

Methods: C57BL/6 mice were intraperitoneal injection of streptozotocin (STZ) to induce DCM. High glucose (HG) was used to induce H9C2 cells injury in vitro. Cardiac fibrosis, hypertrophy, inflammation and oxidative stress were studied both in vitro and in vivo.

Results: Our studies show that luteolin significantly reduces HG-induced inflammatory phenotype and oxidative stress in H9C2 cardiomyocytes. We found that the mechanisms involved inhibition of nuclear factor-kappa B (NF-κB) pathway and the activation of antioxidant nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway. Modulation of these pathways resulted in reduced expression of matrix proteins and cellular hypertrophy. Luteolin also prevented cardiac fibrosis, hypertrophy, and dysfunction in STZ-induced diabetic mice. These readouts were also associated with reduced levels of inflammatory cytokines and oxidative stress biomarkers.

Conclusion: Our results indicate that luteolin protects heart tissues in STZ-induced diabetic mice through modulating Nrf2-mediated oxidative stress and NF-κB-mediated inflammatory responses. These findings suggest that luteolin may be a potential therapeutic agent for DCM.
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http://dx.doi.org/10.1016/j.phymed.2018.11.034DOI Listing
June 2019
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