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Pollen Typhae Total Flavone Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis in Human Aortic-Vascular Smooth Muscle Cells through Down-Regulating PERK-eIF2α-ATF4-CHOP Pathway
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作者 CHEN Ming-tai HUANG Ruo-lan +6 位作者 OU Li-jun CHEN Ying-nan MEN Ling CHANG Xiao WANG Ling YANG Yu-zhu ZHANG Zhong 《中国结合医学杂志:英文版》 SCIE CAS CSCD 2019年第8期604-612,共9页
Objective: To test the hypothesis that the inhibition of endoplasmic reticulum(ER) stress-induced apoptosis in oxidized low-density lipoproteins(ox-LDL)-induced human aortic-vascular smooth muscle cells(HA-VSMCs) was ... Objective: To test the hypothesis that the inhibition of endoplasmic reticulum(ER) stress-induced apoptosis in oxidized low-density lipoproteins(ox-LDL)-induced human aortic-vascular smooth muscle cells(HA-VSMCs) was associated with suppression of the protein kinase RNA-like ER kinase(PERK)-eukaryotic translation initiation factor 2α(e IF2α)-activating transcription factor 4(ATF4)-CCAAT/enhancer binding protein homologous protein(CHOP) signaling pathway by Pollen Typhae total flavone(PTF). Methods: Primary HA-VSMCs were cultured and identified. The cultured HA-VSMCs were randomized into 5 groups, including a normal control group, an ox-LDL group(70 μg/m L high ox-LDL), an HPTF group(70 μg/m L high ox-LDL+500 μg/m L PTF), an MPTF group(70 μg/m L high ox-LDL+250 μg/m L PTF), and a LPTF group(70 μg/m L high ox-LDL+100 μg/m L PTF) in the first part;and a normal control group, an ox-LDL group(70 μg/mL high ox-LDL), an MPTF group(70 μg/m L high ox-LDL+250 μg/m L PTF), a sh RNA group(transducted with PERK shRNA lentiviral particles), a scramble shRNA group(transducted with control shRNA lentiviral particles), an MPTF+ox-LDL+shRNA group(250 μg/mL PTF+70 μg/mL high ox-LDL+PERK shRNA lentiviral particles) and an ox-LDL+shRNA group(70 μg/mL high ox-LDL+PERK shRNA lentiviral particles) in the second part. The protein expression levels of ER-associated apoptosis proteins were detected by Western blot, and their m RNA expression levels were detected by quantitative real-time reverse transcription-polymerase chain reaction. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay was applied to test cel viability, and the level of apoptosis was monitored by flow cytometry. Results: The MTT assay and flow cytometry showed that the ox-LDL group had a significant increase in apoptosis, which was attenuated in PTF treatment groups and sh RNA groups. Moreover, the ox-LDL group had increased protein and m RNA levels of binding immunoglobulin protein and ER-associated apoptosis proteins, such as PERK, 展开更多
关键词 Pollen Typhae total flavone endoplasmic reticulum stress PROTEIN KINASE RNA-like endoplasmic reticulum kinase-eukaryotic translation initiation FACTOR 2a -activating transcription FACTOR 4-CCAAT/enhancer binding PROTEIN homologous PROTEIN PATHWAY apoptosis vulnerable atherosclerotic plaque
A11, a novel diaryl acylhydrazone derivative, exerts neuroprotection against ischemic injury in vitro and in vivo
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作者 Hong-xuan Feng Chun-pu Li +2 位作者 Shuang-jie Shu Hong Liu Hai-yan Zhang 《中国药理学报:英文版》 SCIE CAS CSCD 2019年第2期160-169,共10页
There is an urgent need to develop effective therapies for ischemic stroke, but the complicated pathological processes after ischemia make doing so difficult. In the current study, we identified a novel diaryl acylhyd... There is an urgent need to develop effective therapies for ischemic stroke, but the complicated pathological processes after ischemia make doing so difficult. In the current study, we identified a novel diaryl acylhydrazone derivative, A11, which has multiple neuroprotective properties in ischemic stroke models. First, A11 was demonstrated to induce neuroprotection against ischemic injury in a dose-dependent manner (from 0.3 to 3 μM) in three in vitro experimental ischemic stroke models: oxygen glucose deprivation (OGD), hydrogen peroxide, and glutamate-stimulated neuronal cell injury models. Moreover, A11 was able to potently alleviate three critical pathological changes, apoptosis, oxidative stress, and mitochondrial dysfunction, following ischemic insult in neuronal cells. Further analysis revealed that A11 upregulated the phosphorylation levels of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in OGD-exposed neuronal cells, suggesting joint activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MEK)/ERK pathways. In rats with middle cerebral artery occlusion, single-dose administration of A11 (3 mg/kg per day, i.v.) at the onset of reperfusion significantly reduced the infarct volumes and ameliorated neurological deficits. Our study, for the first time, reports the anti-ischemic effect of diaryl acylhydrazone chemical entities, especially A11, which acts on multiple ischemia-associated pathological processes. Our results may provide new clues for the development of an effective therapeutic agent for ischemic stroke. 展开更多
关键词 ischemic stroke NEUROPROTECTION diaryl ACYLHYDRAZONE oxygen glucose DEPRIVATION middle cerebral artery OCCLUSION protein KINASE B extracellular SIGNAL-REGULATED KINASE
Effect of Yanggan Jiedu Sanjie formula on human hepatocellular carcinoma Bel-7402 cells
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作者 Hu Bing Zhang Tong +5 位作者 An Hongmei Zheng Jialu Yan Xia Huang Xiaowei Tian Jianhui Li Miao 《中医杂志:英文版》 SCIE CAS CSCD 2019年第1期26-33,共8页
OBJECTIVE: To observe the effect of Yanggan Jiedu Sanjie(YGJDSJ) formula on human hepatocellular carcinoma Bel-7402 cells.METHODS: Bel-7402 cells were treated with YGJDSJ. Cell proliferation was detected by cell count... OBJECTIVE: To observe the effect of Yanggan Jiedu Sanjie(YGJDSJ) formula on human hepatocellular carcinoma Bel-7402 cells.METHODS: Bel-7402 cells were treated with YGJDSJ. Cell proliferation was detected by cell counting kit-8 assay. Cell apoptosis was identified by Hoechst 33258 staining and flow cytometric analysis. Cell cycle distribution was quantified by flow cytometric analysis. Caspase activities were measured by commercial kit. Cell senescence was detected by senescence-associated β-galactosidase(SA-β-gal)staining. Protein expression and phosphorylation were identified by Western blot. Protein expression was knocked-down by siRNA.RESULTS: YGJDSJ inhibited proliferation of Bel-7402 cells in a dose-and time-dependent manner.YGJDSJ induced apoptosis and activated caspase-3, 8, and 9 in Bel-7402 cells. YGJDSJ-induced apoptosis was completely abrogated by a pan caspase inhibitor, Z-VAD-FMK. YGJDSJ also induced cell senescence, up-regulated cyclin-dependent kinase inhibitor 1 a(CDKN1 a) and CDKN2 a expression and down-regulated retinoblastoma protein(RB) phosphorylation in Bel-7402 cells. Specific knockdown of CDKN1 a and CDKN2 a significantly reduced YGJDSJ-induce cell senescence in Bel-7402 cells.CONCLUSION: YGJDSJ inhibited cell proliferation,induced caspase-dependent apoptosis and CDKN1 a/CDKN2 a-RB signalling mediated cell senescence in Bel-7402 cells. Our findings suggest that YGJDSJ might be potential for hepatocellular carcinoma treatment. 展开更多
关键词 Carcinoma hepatocellular Chinese herbal FORMULA Apoptosis CELL SENESCENCE CELL cycle Cyclin-dependent KINASE INHIBITOR p21 Cyclindependent KINASE INHIBITOR p16 RETINOBLASTOMA protein
Treadmill training improves neurological deficits and suppresses neuronal apoptosis in cerebral ischemic stroke rats 预览
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作者 Li-Mei Cao Zhi-Qiang Dong +1 位作者 Qiang Li Xu Chen 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第8期1387-1393,共7页
RehabilNation training is believed to be beneficial to patients with stroke, but its molecular mechanism is still unclear. Rat models of cerebral ischemic stroke were established by middle cerebral artery occlusion/re... RehabilNation training is believed to be beneficial to patients with stroke, but its molecular mechanism is still unclear. Rat models of cerebral ischemic stroke were established by middle cerebral artery occlusion/reperfusion, and then received treadmill training of different intens让ies, twice a day for 30 minutes for 1 week. Low-intensity training was conducted at 5 m/min, with a 10-minute running, 10-minute rest, and 10-minute running cycle. In the moderate-intensity training, the intensity gradually increased from 5 m/min to 10 m/min in 5 minutes, with the same rest cycle as above. In high-intensity training, the intensity gradually increased from 5 m/min to 25 m/min in 5 minutes, with the same rest cycle as above. The Bederson scale was used to evaluate the improvement of motor function. Infarct volume was detected using 2,3,5-triphenyltetrazolium chloride staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining was applied to detect the apoptosis of nerve cells in brain tissue. Western blot assay was employed to analyze the activation of cyclic adenosine monophosphate (cAMP)/protein kinase A and Akt/glycogen synthase kinase-3卩 signaling pathways in rat brain tissue. All training intensities reduced the neurological deficit score, infarct volume, and apoptosis in nerve cells in brain tissue of stroke rats. Training intensities activated the cAMP/protein kinase A and Akt/glycogen synthase kinase-3 beta signaling pathways. This activation was more obvious with higher training intensities. These changes were reversed by intracerebroventricular injection of protein kinase A inhibitor Rp-cAMP. Our findings indicate that the neuroprotective effect of rehabilitation training is achieved via activation of the cAMP/ protein kinase A and Akt/glycogen synthase kinase-3 beta signaling pathways. This study was approved by the Ethics Committee of Animal Experimentation in Shanghai No. 8 Peoples Hospital, China. 展开更多
关键词 nerve REGENERATION ischemic stroke TREADMILL training neuronal DEFICIT apoptosis cyclic adenosine MONOPHOSPHATE protein kinase A GLYCOGEN synthase kinase-3^ NEUROPROTECTIVE effect neural REGENERATION
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Significant benefits of osimertinib in treating acquired resistance to first-generation EGFR-TKIs in lung squamous cell cancer:A case report 预览
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作者 Yan Zhang Hui-Min Chen +6 位作者 Yong-Mei Liu Feng Peng Min Yu Wei-Ya Wang Heng Xu Yong-Sheng Wang You Lu 《世界临床病例杂志》 2019年第10期1221-1229,共9页
BACKGROUND Lung squamous cell cancer(LSCC)rarely harbors epidermal growth factor receptor(EGFR)mutations,even much rarer for acquired T790M mutation.Although clinical trials of AURA series illustrated that non-small c... BACKGROUND Lung squamous cell cancer(LSCC)rarely harbors epidermal growth factor receptor(EGFR)mutations,even much rarer for acquired T790M mutation.Although clinical trials of AURA series illustrated that non-small cell lung cancer(NSCLC)with EGFR T790M mutation can benefit from osimertinib,only five LSCC patients were enrolled in total;moreover,the efficacy for LSCC was not shown in the results.Therefore,the response of LSCC to osimertinib is still unclear to date.CASE SUMMARY We report an LSCC case with T790M-related acquired resistance after treatments with first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)and benefited from osimertinib significantly.A 63-year-old Chinese man was diagnosed with stage IV(cT2N2M1b)LSCC harboring an EGFR exon 19-deletion mutation.Following disease progression after gefitinib and multi-line chemotherapy,rebiopsy was conducted.Molecular testing of EGFR by amplification refractory mutation system-polymerase chain reaction detected the exon 19-deletion without T790M mutation.Therefore,the patient was given erlotinib,but progression developed only 3 mo later.Then the frozen re-biopsy tissue was tested by next-generation sequencing(NGS),which detected an EGFR T790M mutation.However,he was very weak with symptoms of dysphagia and cachexia.Fortunately,osimertinib was started,leading to alleviation from the symptoms.Four months later,normal deglutition was restored and partial response was achieved.Finally,the patient achieved an overall survival time period of 29 mo.CONCLUSION Our findings highlight that EGFR T790M mutation may also be an important acquired drug resistance mechanism for LSCC and offer direct evidence of the efficacy of osimertinib in LSCC with T790M mutation.NGS and better preservation conditions may contribute to higher sensitivity of EGFR T790M detection. 展开更多
关键词 LUNG SQUAMOUS cell CANCER LUNG CANCER EPIDERMAL growth factor receptor mutation T790M Osimertinib TYROSINE kinase inhibitor Targeted therapy Case report
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Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study
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作者 Peng Wei Bo Liu +11 位作者 Ruifeng Wang Yinglei Gao Lanlan Li Yuchi Ma Zhiwei Qian Yuelei Chen Maosheng Cheng Meiyu Geng Jingkang Shen Dongmei Zhao Jing Ai Bing Xiong 《药学学报:英文版》 CSCD 2019年第2期351-368,共18页
Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investiga... Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development. 展开更多
关键词 Fibroblast growth factor TYROSINE kinase receptor STRUCTURE-BASED CRYSTALLOGRAPHY Selectivity Hybrid 5-Hydrosulfonyl-5Hpyrrolo[2 3-b]pyrazine Inhibitor
Broussonin E suppresses LPS-induced inflammatory response in macrophages via inhibiting MAPK pathway and enhancing JAK2-STAT3 pathway
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作者 HUANG Shao-Peng GUAN Xin +6 位作者 KAI Guo-Yin XU Ya-Zhou XU Yuan WANG Hao-Jie PANG Tao ZHANG Lu-Yong LIU Ying 《中国天然药物:英文版》 SCIE CAS CSCD 2019年第5期372-380,共9页
Macrophages play an important role in inflammation, and excessive and chronic activation of macrophages leads to systemic inflammatory diseases, such as atherosclerosis and rheumatoid arthritis. In this paper, we expl... Macrophages play an important role in inflammation, and excessive and chronic activation of macrophages leads to systemic inflammatory diseases, such as atherosclerosis and rheumatoid arthritis. In this paper, we explored the anti-inflammatory effect of broussonin E, a novel phenolic compound isolated from the barks of Broussonetia kanzinoki, and its underlying molecular mechanisms. We discovered that Broussonin E could suppress the LPS-induced pro-inflammatory production in RAW264.7 cells, involving TNF-α, IL-1β、IL-6, COX-2 and iNOS. And broussonin E enhanced the expressions of anti-inflammatory mediators such as IL-10, CD206 and arginase-1 (Arg-1) in LPS-stimuIated RAW264.7 cells. Further, we demonstrated that broussonin E inhibited the LPS-stimulated phosphorylation of ERK and p38 MAPK. Moreover, we found that broussonin E could activate janus kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3. Downregulated pro-inflammatory cytokines and upregulated anti-inflammatory factors by broussonin E were abolished by using the inhibitor of JAK2-STAT3 pathway, WP1066. Taken together, our results showed that broussonin E could suppress inflammation by modulating macrophages activation state via inhibiting the ERK and p38 MAPK. and enhancing JAK2-STAT3 signaling pathway, and can be further developed as a promising drug for the treatment of inflammation- related diseases such as atherosclerosis. 展开更多
关键词 Broussonin E MACROPHAGE polarization Inflammation JANUS kinase 2 Signal TRANSDUCER and ACTIVATOR of transcription 3
The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction
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作者 Min Chui Cho Junghoon Lee +5 位作者 Juhyun Park Sohee Oh Ji Sun Chai Hwancheol Son Jae-Seung Paick Soo Woong Kim 《亚洲男性学杂志:英文版》 SCIE CAS CSCD 2019年第5期493-500,共8页
We aimed to determine whether combination of LIM-kinase 2 inhibitor(LIMK2i)and phosphodiesterase type-5 inhibitor(PDE5i)could restore erectile function through suppressing cavernous fibrosis and improving caver nous a... We aimed to determine whether combination of LIM-kinase 2 inhibitor(LIMK2i)and phosphodiesterase type-5 inhibitor(PDE5i)could restore erectile function through suppressing cavernous fibrosis and improving caver nous apoptosis in a rat model of cavernous nerve crush injury(CNCI).Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows:(1)sham surgery(Group S),(2)CNCI(Group I),(3)CNCI treated with daily intraperitoneal administration of 10.0 mg kg^-1 LIMK2i(Group I+L),(4)daily oral administration of 20.0 mg kg-1 udenafil,PDE5i(Group I+U),and(5)combined administration of 10.0 mg kg^-1 LIMK2i and 20.0 mg kg^-1 udenafil(Group I+L+U).Rats in Groups I+L,I+U,and I+L+U were treated with respective regimens for 2 weeks after CNCI.At 2 weeks after surgery,erectile response was assessed using electrostimulation.Penile tissues were processed for histological studies and western blot.Group I showed lower intracavernous pressure(ICP)/mean arterial pressure(MAP),lower area under the curve(AUC)/MAP,decreased immunohistochemical staining for alpha-smooth muscle(SM)actin,higher apoptotic index,lower SM/collagen ratio,increased phospho-LIMK2-positive fibroblasts,decreased protein kinase B/endothelial nitric oxide synthase(Akt/eNOS)phosphorylation,increased LIMK2/cofilin phosphorylation,and increased protein expression of fibronectin,compared to Group S.In all three treatment groups,erectile responses,protein expression of fibronectin,and SM/collagen ratio were improved.Group I+L+U showed greater improvement in erectile response than Group I+L.SM content and apoptotic index in Groups I+U and I+L+U were improved compared to those in Group I.However,Group I+L did not show a significant improvement in SM content or apoptotic index.The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I+L and I+L+U,but not in Group I+U.Akt/eNOS phosphorylation was improved in Groups I+U and I+L+U,but not in Group I+L.LIMK2/cofilin phosphorylation was improved in Groups I+L and I+L+U,but not in Group 展开更多
关键词 APOPTOSIS erectile dysfunction FIBROSIS LIM kinase PHOSPHODIESTERASE
Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer
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作者 Bing Cui Patrick A.Eyers +30 位作者 Leonard L.Dobens Nguan Soon Tan Peter D.Mace Wolfgang A.Link Endre Kiss-Toth Karen Keeshan Takuro Nakamura Warren S.Pear Yodit Feseha Jessica Johnston Arkatiz Carracedo Marcel Scheideler Zabran llyas Robert C.Bauer Jorge D.Erusalimsky Dominika Grzesik Juan Salamanca-Viloria Xiaoxi Lv Yishi Jin Ke Li Guillermo Velasco Shuang Shang Jose M.Lizcano Xiaowei Zhang Jichao Zhou Jiaojiao Yu Fang Hua Feng Wang Shanshan Liu Jinmei Yu Zhuowei Hu 《药学学报:英文版》 CSCD 2019年第2期443-454,共12页
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of ... The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases. 展开更多
关键词 Tribbles IMMUNOLOGY METABOLISM Cell biology Kinase inhibitor TUMORIGENESIS Metastasis TRIB1 TRIB2 TRIB3 Pseudokinase Inflammation Atomic structure Protein quality control Ubiqutin
Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein
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作者 Jian Meng Xiao-yun Liu +11 位作者 Sheng Ma Hua Zhang Song-da Yu Yi-fan Zhang Mei-xia Chen Xiao-yu Zhu Yi Liu Ling Yi Xiao-liang Ding Xiao-yan Chen Li-yan Miao Da-fang Zhong 《中国药理学报:英文版》 SCIE CAS CSCD 2019年第7期980-988,共9页
Pyrotinib is a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor that is used to treat HER2-positive breast cancer. In this study we investigated the metabolism and disposition of pyrotinib in six healthy Ch... Pyrotinib is a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor that is used to treat HER2-positive breast cancer. In this study we investigated the metabolism and disposition of pyrotinib in six healthy Chinese men after a single oral dose of 402?mg of [14C]pyrotinib. At 240?h postdose, the mean cumulative excretion of the dose radioactivity was 92.6%, including 1.7% in urine and 90.9% in feces. In feces, oxidative metabolites were detected as major drug-related materials and the primary metabolic pathways were O-depicoline (M1), oxidation of pyrrolidine (M5), and oxidation of pyridine (M6-1, M6-2, M6-3, and M6-4). In plasma, the major circulating entities identified were pyrotinib, SHR150980 (M1), SHR151468 (M2), and SHR151136 (M5), accounting for 10.9%, 1.9%, 1.0%, and 3.0%, respectively, of the total plasma radioactivity based on the AUC0–∞ ratios. Approximately 58.3% of the total plasma radioactivity AUC0–∞ was attributed to covalently bound materials. After incubation of human plasma with [14C]pyrotinib at 37?°C for 2, 5, 8, and 24?h, the recovery of radioactivity by extraction was 97.4%, 91.8%, 69.6%, and 46.7%, respectively, revealing covalent binding occurred independently of enzymes. A group of pyrotinib adducts, including pyrotinib-lysine and pyrotinib adducts of the peptides Gly-Lys, Lys-Ala, Gly-Lys-Ala, and Lys-Ala-Ser, was identified after HCl hydrolysis of the incubated plasma. Therefore, the amino acid residue Lys190 of human serum albumin was proposed to covalently bind to pyrotinib via Michael addition. Finally, the covalently bound pyrotinib could dissociate from the human plasma protein and be metabolized by oxidation and excreted via feces. 展开更多
关键词 pyrotinib EGFR/HER2 dual TYROSINE kinase inhibitor breast cancer DRUG METABOLISM DRUG DISPOSITION human plasma COVALENT binding
Sphingosine kinase 1 knockout alleviates hepatic ischemia/reperfusion injury by attenuating inflammation and oxidative stress in mice 预览
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作者 Guang-Hui Qiang Zhong-Xia Wang +5 位作者 An-Lai Ji Jun-Yi Wu Yin Cao Guang Zhang Yi-Yang Zhang Chun-Ping Jiang 《国际肝胆胰疾病杂志:英文版》 SCIE CAS CSCD 2019年第3期255-265,共11页
Background: Hepatic ischemia/reperfusion(I/R) injury remains a significant problem in clinical practice. Sphingosine kinase 1(Sph K1) phosphorylates sphingosine to sphingosine-1-phosphate(S1 P) which participates in m... Background: Hepatic ischemia/reperfusion(I/R) injury remains a significant problem in clinical practice. Sphingosine kinase 1(Sph K1) phosphorylates sphingosine to sphingosine-1-phosphate(S1 P) which participates in multiple bioactive processes. However, little is known about the role of Sph K1 in hepatic I/R injury. This study aimed to investigate the effect of Sph K1 knockout on liver I/R injury and to explore underlying mechanisms. Methods: Sph K1 knockout and wild type mice were subjected to 70% partial hepatic I/R. Serum alanine aminotransferase was determined to indicate the degree of liver damage. Hematoxylin-eosin staining and TUNEL assay were used to assess histological changes and hepatocellular apoptosis, respectively. Immunohistochemistry was performed to detect the expression and translocation of phosphorylated p65 and signal transducer and activator of transcription 3(STAT3). Western blotting was used to determine the expression of S1 P receptor 1(S1 PR1), phosphorylated p65 and STAT3. Real-time PCR was used to demonstrate the changes of proinflammatory cytokines. Oxidative stress markers were also determined through biochemical assays. Results: Sph K1 knockout significantly ameliorated I/R-induced liver damage, mitigated liver tissue necrosis and apoptosis compared with wild type control. I/R associated inflammation was alleviated in Sph K1 knockout mice as demonstrated by attenuated expression of S1 PR1 and reduced phosphorylation of nuclear factor kappa B p65 and STAT3. The proinflammatory cytokines interleukin-1 β, interleukin-6 and tumor necrosis factor-α were also inhibited by Sph K1 genetic deletion. The oxidative stress markers were lower in Sph K1 knockout mice after I/R injury than wild type mice. Conclusions: Knockout of Sph K1 significantly alleviated damage after hepatic I/R injury, possibly through inhibiting inflammation and oxidative stress. Sph K1 may be a novel and potent target in clinical practice in I/R-related liver injury. 展开更多
关键词 ISCHEMIA/REPERFUSION injury SPHINGOSINE KINASE 1 INFLAMMATION Oxidative stress
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Clinical Benefit of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors Plus Radiotherapy for Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small Cell Lung Cancer: A Retrospective Analysis on Real World Data
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作者 Wang Ranlin Li Tao +2 位作者 Lv Jiahua Sun Chang Shi Qiuling 《肿瘤预防与治疗》 2019年第5期385-394,共10页
Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC)... Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC),compared with TKIs alone.Methods: A total of 103 patients with stage Ⅳ EGFR-mutated NSCLC treated from February 2015 to May 2017 at Sichuan Cancer Hospital were analyzed retrospectively. Fifty patients were treated with EGFR-TKIs( gefitinib or erlotinib) plus radiotherapy( the TKI +RT group) and 53 patients received EGFR-TKIs alone( the TKI group). Tumor response,survival and toxicities were compared between the two groups. Results: Median follow-up time was 11. 7 months( 2. 8-36. 3 months). The overall response rate( ORR) and disease control rate( DCR) in the TKI + RT group vs the TKI group were 62% vs 37. 7%( P = 0. 014) and 88% vs 75. 5%( P =0. 101),respectively. The median progression-free survival( PFS) and median overall survival( OS) in the TKI + RT group were superior to those of the TKI group( 18. 87 months vs 12. 80 months,P = 0. 035 and 23. 10 months vs 18. 30 months,P = 0. 011). OS rates in the TKI + RT group and the TKI group were 56. 0% vs 35. 8% at year 1( P = 0. 04) and 16. 0% vs 3. 8% at year 2( P =0. 036). Multivariate Cox model found that TKI + RT related to significantly better OS( hazard ratio = 0. 209;95% CI,0. 066 to0. 661;P = 0. 008) than TKI alone. Adverse events did not differ significantly between the two groups( P > 0. 050). Conclusion:Compared with EGFR-TKIs alone,EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumor response and survival for EGFR mutation-positive metastatic NSCLC patients. 展开更多
关键词 RADIOTHERAPY NON-SMALL cell lung cancer EPIDERMAL growth factor receptor-tyrosine kinase inhibitor Effectiveness
Functional Metagenomics to Mine Soil Microbiome for Novel Cadmium Resistance Genetic Determinants
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作者 ZHENG Xin CHEN Liang +2 位作者 CHEN Miaomiao CHEN Jinghao LI Xiaofang 《土壤圈:英文版》 SCIE CAS CSCD 2019年第3期298-310,共13页
Metal resistance genes are valuable resources for genetic engineering of bioremediation tools. In this study, novel genetic determinants involved in cadmium(Cd) resistance were identified using a small-insert metageno... Metal resistance genes are valuable resources for genetic engineering of bioremediation tools. In this study, novel genetic determinants involved in cadmium(Cd) resistance were identified using a small-insert metagenomic DNA library constructed from an arable soil microbiome. A total of 16 recombinant plasmids harboring 49 putative open reading frames(ORFs) were found to be associated with enhanced Cd tolerance. In addition to several ORFs for ion transport/chelation and stress response, most ORFs were assumed to be associated with non-direct metal resistance mechanisms such as energy metabolism, protein/amino acid metabolism,carbohydrate/fatty acid metabolism, and signal transduction. Furthermore, 13 ORFs from five clones selected at random were cloned and subject to Cd resistance assay. Eight of these ORFs were positive for Cd resistance when expressed in Escherichia coli, among which four ORFs significantly reduced Cd accumulation and one increased Cd enrichment of the host cells. Notably, C1-ORF1, potentially encoding a histidine kinase-like adenosine triphosphatase, was the most effective Cd resistance determinant and reduced host Cd accumulation by 33.9%. These findings highlight the vast capacity of soil microbiome as a source of gene pool for bioengineering.The novel genetic determinants for Cd resistance identified in this study merit further systematic explorations into their molecular mechanisms. 展开更多
关键词 BIOREMEDIATION GENETIC engineering HISTIDINE kinase metal resistance gene open reading frame recombinant PLASMID
Ginsenoside Rb1 Ameliorates Autophagy of Hypoxia Cardiomyocytes from Neonatal Rats via AMP-Activated Protein Kinase Pathway
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作者 DAI Sheng-nan HOU Ai-jie +4 位作者 ZHAO Shu-mei CHEN Xiao-ming HUANG Hua-ting CHEN Bo-han KONG Hong-liang 《中国结合医学杂志:英文版》 SCIE CAS CSCD 2019年第7期521-528,共8页
Objective: To investigate whether ginsenoside-Rb1(Gs-Rb1) improves the CoCl2-induced autophagy of cardiomyocytes via upregulation of adenosine 5’-monophosphate-activated protein kinase(AMPK) pathway. Methods: Ventric... Objective: To investigate whether ginsenoside-Rb1(Gs-Rb1) improves the CoCl2-induced autophagy of cardiomyocytes via upregulation of adenosine 5’-monophosphate-activated protein kinase(AMPK) pathway. Methods: Ventricles from 1-to 3-day-old Wistar rats were sequentially digested, separated and incubated in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum for 3 days followed by synchronization. Neonatal rat cardiomyocytes were randomly divided into 7 groups: control group(normal level oxygen), hypoxia group(500 μmol/L CoCl2), Gs-Rb1 group(200 μmol/L Gs-Rb1 + 500 μmol/L CoCl2), Ara A group(500 μmol/L Ara A + 500 μmol/L CoCl2), Ara A+ Gs-Rb1 group(500 μmol/L Ara A + 200 μmol/L Gs-Rb1 + 500 μmol/L CoCl2), AICAR group [1 mmol/L 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR)+ 500 μmol/L CoCl2], and AICAR+Gs-Rb1 group(1 mmol/L AICAR + 200 μmol/L Gs-Rb1 + 500 μmol/L CoCl2). Cel s were treated for 12 h and cell viability was determined by methylthiazolyldiphenyl-tetrazolium bromide(MTT) assay and cardiac troponin I(cTnI) levels were detected by enzyme-linked immunosorbent assay(ELISA). AMPK activity was assessed by 2’,7’-dichlorofluorescein diacetate(DCFH-DA) ELISA assay. The protein expressions of Atg4 B, Atg5, Atg6, Atg7, microtubule-associated protein 1 A/1 B-light chain 3(LC3), P62, and active-cathepsin B were measured by Western blot. Results: Gs-Rb1 significantly improved the cell viability of hypoxia cardiomyocytes(P<0.01). However, the viability of hypoxia-treated cardiomyocytes was significantly inhibited by Ara A(P<0.01). Gs-Rb1 increased the AMPK activity of hypoxia-treated cardiomyocytes. The AMPK activity of hypoxia-treated cadiomyocytes was inhibited by Ara A(P<0.01) and was not affected by AICAR(P=0.983). Gs-Rb1 up-regulated Atg4B, Atg5, Beclin-1, Atg7, LC3B Ⅱ, the LC3BⅡ/Ⅰ ratio and cathepsin B activity of hypoxia cardiomyocytes(P<0.05), each of these protein levels was significantly enhanced by Ara A(all P<0.01), but was not affected by AICAR(all P 展开更多
关键词 CARDIOMYOCYTES ginsenosides-Rb1 HYPOXIA ADENOSINE 5'-monophosphate-activated protein KINASE autophagic flux
Extract of Fructus Schisandrae chinensis Inhibits Neuroinflammation Mediator Production from Microglia via NF-κB and MAPK Pathways
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作者 SONG Fang-jiao ZENG Ke-wu +4 位作者 CHEN Jin-feng LI Yuan SONG Xiao-min TU Peng-fei WANG Xue-mei 《中国结合医学杂志:英文版》 SCIE CAS CSCD 2019年第2期131-138,共8页
Objective: To investigate the anti-neuroinflammation effect of extract of Fructus Schisandrae chinensis(EFSC) on lipopolysaccharide(LPS)-induced BV-2 cells and the possible involved mechanisms. Methods: Primary cortic... Objective: To investigate the anti-neuroinflammation effect of extract of Fructus Schisandrae chinensis(EFSC) on lipopolysaccharide(LPS)-induced BV-2 cells and the possible involved mechanisms. Methods: Primary cortical neurons were isolated from embryonic(E17-18) cortices of Institute of Cancer Research(ICR) mouse fetuses. Primary microglia and astroglia were isolated from the frontal cortices of newborn ICR mouse. Different cells were cultured in specific culture medium. Cells were divided into 5 groups: control group, LPS group(treated with 1 μg/mL LPS only) and EFSC groups(treated with 1 μg/mL LPS and 100, 200 or 400 mg/mL EFSC, respectively). The effect of EFSC on cells viability was tested by methylthiazolyldiphenyltetrazolium bromide(MTT) colorimetric assay. EFSC-mediated inhibition of LPS-induced production of pro-inflammatory mediators, such as nitrite oxide(NO) and interleukin-6(IL-6) were quantified and neuron-protection effect against microglia-mediated inflammation injury was tested by hoechst 33258 apoptosis assay and crystal violet staining assay. The expression of pro-inflammatory marker proteins was evaluated by Western blot analysis or immunofluorescence. Results: EFSC(200 and 400 mg/mL) reduced NO, IL-6, inducible nitric oxide synthase(iN OS) and cyclooxygenase 2(COX-2) expression in LPS-induced BV-2 cel s(P<0.01 or P<0.05). EFSC(200 and 400 mg/mL) reduced the expression of NO in LPS-induced primary microglia and astroglia(P<0.01). In addition, EFSC al eviated cel apoptosis and inflammation injury in neurons exposed to microglia-conditioned medium(P<0.01). The mechanistic studies indicated EFSC could suppress nuclear factor(NF)-κB phosphorylation and its nuclear translocation(P<0.01). The anti-inflammatory effect of EFSC occurred through suppressed activation of mitogen-activated protein kinase(MAPK) pathway(P<0.01 or P<0.05). Conclusion: EFSC acted as an anti-inflammatory agent in LPS-induced glia cel s. These effects might be realized through blocking of NF-κB activity and inhibition of M 展开更多
关键词 NEUROINFLAMMATION MICROGLIA Fructus Schisandrae CHINENSIS nuclear factor-κB mitogen- activated protein KINASE
TrkA regulates the regenerative capacity of bone marrow stromal stem cells in nerve grafts 预览
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作者 Mei-Ge Zheng Wen-Yuan Sui +8 位作者 Zhen-Dan He Yan Liu Yu-Lin Huang Shu-Hua Mu Xin-Zhong Xu Ji-Sen Zhang Jun-Le Qu Jian Zhang Dong Wang 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第10期1765-1771,共7页
We previously demonstrated that overexpression of tropomyosin receptor kinase A(TrkA)promotes the survival and Schwann celllike differentiation of bone marrow stromal stem cells in nerve grafts,thereby enhancing the r... We previously demonstrated that overexpression of tropomyosin receptor kinase A(TrkA)promotes the survival and Schwann celllike differentiation of bone marrow stromal stem cells in nerve grafts,thereby enhancing the regeneration and functional recovery of the peripheral nerve.In the present study,we investigated the molecular mechanisms underlying the neuroprotective effects of TrkA in bone marrow stromal stem cells seeded into nerve grafts.Bone marrow stromal stem cells from Sprague-Dawley rats were infected with recombinant lentivirus vector expressing rat TrkA,TrkA-shRNA or the respective control.The cells were then seeded into allogeneic rat acellular nerve allografts for bridging a 1-cm right sciatic nerve defect.Then,8 weeks after surgery,hematoxylin and eosin staining showed that compared with the control groups,the cells and fibers in the TrkA overexpressing group were more densely and uniformly arranged,whereas they were relatively sparse and arranged in a disordered manner in the TrkA-shRNA group.Western blot assay showed that compared with the control groups,the TrkA overexpressing group had higher expression of the myelin marker,myelin basic protein and the axonal marker neurofilament 200.The TrkA overexpressing group also had higher levels of various signaling molecules,including TrkA,pTrkA(Tyr490),extracellular signal-regulated kinases 1/2(Erkl/2),pErk1/2(Thr202/Tyr204),and the anti-apoptotic proteins Bcl-2 and Bcl-xL.In contrast,these proteins were downregulated,while the pro-apoptotic factors Bax and Bad were upregulated,in the TrkA-shRNA group.The levels of the TrkA effectors Akt and pAkt(Ser473)were not different among the groups.These results suggest that TrkA enhances the survival and regenerative capacity of bone marrow stromal stem cells through upregulation of the Erk/Bcl-2 pathway.All procedures were approved by the Animal Ethical and Welfare Committee of Shenzhen University,China in December 2014(approval No.AEWC-2014-001219). 展开更多
关键词 NERVE REGENERATION bone marrow stromal stem cells TROPOMYOSIN RECEPTOR kinase A RECEPTOR LENTIVIRAL vector shRNA extracellular SIGNAL-REGULATED protein kinases 1/2 Bcl-2 NERVE grafts peripheral NERVE REGENERATION survival neural REGENERATION
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Effect of Soothing Gan(Liver) and Invigorating Pi(Spleen) Recipes on TLR4-p38 MAPK Pathway in Kupffer Cells of Non-alcoholic Steatohepatitis Rats
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作者 GONG Xiang-wen XU Yong-jian +4 位作者 YANG Qin-he LIANG Yin-ji ZHANG Yu-pei WANG Guan-long LI Yuan-yuan 《中国结合医学杂志:英文版》 SCIE CAS CSCD 2019年第3期216-224,共9页
Objective: To investigate the mechanism of inflammatory-mediated toll-like receptor 4(TLR4)-p38 mitogen-activated protein kinase(p38 MAPK) pathway in Kupffer cells(KCs) of non-alcoholic steatohepatitis(NASH) rats and ... Objective: To investigate the mechanism of inflammatory-mediated toll-like receptor 4(TLR4)-p38 mitogen-activated protein kinase(p38 MAPK) pathway in Kupffer cells(KCs) of non-alcoholic steatohepatitis(NASH) rats and the intervention effect of soothing Gan(Liver) and invigorating Pi(Spleen) recipes on this pathway. Methods: After 1 week of acclimatization, 120 Sprague-Dawley male rats were randomly divided into 8 groups using a random number table(n=15 per group): normal group, model group, low-dose Chaihu Shugan Powder(柴胡疏肝散, CHSG) group(3.2 g/kg), high-dose CHSG group(9.6 g/kg), low-dose Shenling Baizhu Powder(参苓白术散, SLBZ) group(10 g/kg), high-dose SLBZ(30 g/kg) group, and low-and highdose integrated recipe(L-IR, H-IR) groups. All rats in the model and treatment groups were fed with a high-fat diet(HFD). The treatments were administrated by gastrogavage once daily and lasted for 26 weeks. The liver tissues were detected with hematoxylin-eosin(HE) and oil red O staining. Levels of liver lipids, serum lipids and transaminases were measured. KCs were isolated from the livers of rats to evaluate the mRNA expressions of TLR4 and p38 MAPK by real-time fluorescence quantitative polymerase chain reaction, and proteins expressions of TLR4, p-p38 MAPK and p38 MAPK by Western blot. Levels of inflammatory cytokines including tumor necrosis factor α(TNF-α), interleukin(IL)-1 and IL-6 in KCs were measured by enzyme-linked immunosorbent assay. Results: After 26 weeks of HFD feeding, HE and oil red O staining showed that the NASH model rats successfully reproduced typical pathogenesis and histopathological features. Compared with the normal group, the model group exhibited significant increases in body weight, liver weight, liver index, serum levels of total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol, and aspartate aminotransferase as well as TC and TG levels in liver tissues, and significant decrease in serum level of high-density lipoprotein cholesterol(P<0.05 or P<0.01), whi 展开更多
关键词 non-alcoholic steatohepatitis soothing GAN (Liver)and invigorating PI (Spleen)recipes Kupffer cel toll-like receptor 4-p38 MITOGEN-ACTIVATED protein kinase signaling pathway inflammation Chinese medicine
Development and validation of an LC-MS/MS method for tyrphostin A9 预览
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作者 Lyndsey F. Meyer Dhaval K. Shah 《药物分析学报:英文版》 CAS CSCD 2019年第3期163-169,共7页
Here we have presented a sensitive and selective LC-MS/MS method for the quantification of tyrphostin A9, which is a selective inhibitor for platelet derived growth factor receptor tyrosine kinase and has been investi... Here we have presented a sensitive and selective LC-MS/MS method for the quantification of tyrphostin A9, which is a selective inhibitor for platelet derived growth factor receptor tyrosine kinase and has been investigated in vitro as a potent oxidative phosphorylation uncoupler. The murine analytical method was developed for three biological matrices: cell culture media, 3T3-L1 cell lysate, and murine plasma. For each matrix the limit of detection and the limit of quantification were found to be 0.5 ng/mL and 1.0 ng/ mL, respectively. The range of standard curve for each matrix was 1.0-100 ng/mL, linearity was >0.99, and the precision and accuracy were within 20%. 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propanoic acid was found to be the most suitable internal standard. The validated LC-MS/MS method was used to investigate stability and in vitro pharmacokinetics of tyrphostin A9. It was found that tyrphostin A9 is susceptible to hydrolysis, and the degradation product was identified as 3,5-di-tert-butyl-4- hydroxybenzaldehyde. Tyrphostin A9 was not stable in biological matrices, and the rate of its degradation in murine plasma was faster than that in cell culture media. In vitro pharmacokinetic studies revealed that tyrphostin A9 concentrations in the cell culture media declined in a bi-exponential manner and the concentrations inside the adipocytes remained constant, suggesting tyrphostin A9 has an intracellular binding site and is retained within the cell. The LC-MS/MS method presented here paves the way for further quantitative investigations involving tyrphostin A9. 展开更多
关键词 TYRPHOSTIN 9/ A9/AG-9/Malonoben/SF6847 LC-MS/MS Stability PHARMACOKINETICS TYROSINE KINASE inhibitor
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Overexpression of PtPEPCK1 gene promotes nitrogen metabolism in poplar 预览
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作者 Lina Wang Miao He +4 位作者 Song Chen Kean Wang Donghai Cui Xin Huang Lijie Liu 《林业研究:英文版》 CAS CSCD 2019年第6期2289-2303,共15页
To understand the function of phosphoenolpyruvate carboxylase kinase,we introduced PtPEPCK1 gene under the control of 35S promoter into 84K poplar(Populus alba×P.glandulosa).PtPEPCK1 gene is well-known for its ro... To understand the function of phosphoenolpyruvate carboxylase kinase,we introduced PtPEPCK1 gene under the control of 35S promoter into 84K poplar(Populus alba×P.glandulosa).PtPEPCK1 gene is well-known for its role in gluconeogenesis.However,our data confi rmed that it has signifi cant eff ects on amino acid biosynthesis and nitrogen metabolism.Immunohistochemistry and fl uorescence microscopy indicate that PtPEPCK1 is specifi cally expressed in the cytoplasm of the spongy and palisade tissues.Overexpression of PtPEPCK1 was characterized through transcriptomics and metabolomics.The metabolites concentration of the ornithine cycle and its precursors also increased,of which N-acetylornithine was up-regulated almost 50-fold and ornithine 33.7-fold.These were accompanied by a massive increase in levels of several amino acids.Therefore,overexpression of PtPEPCK1 increases amino acid levels with urea cycle disorder. 展开更多
关键词 Amino acid METABOLISM METABOLOME Nitrogen METABOLISM PHOSPHOENOLPYRUVATE CARBOXYLASE kinase TRANSCRIPTOME Urea cycle
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Protective Effect of GRK2 and Effect of Sanguis Draconis Flavones on Focal Cerebral Ischemia-Reperfusion Injury in Rats 预览
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作者 Rui LI Huiyu JIA +2 位作者 Deyun JIA Min SI Dewu JIA 《药用植物研究(英文版)》 2019年第4期44-48,50共6页
[Objectives] To explore the protective effect of Sanguis Draconis flavones (SDF) on rat focal cerebral ischemia-reperfusion injury (CIRI) models established by middle cerebral artery occlusion (MCAO).[Methods] A total... [Objectives] To explore the protective effect of Sanguis Draconis flavones (SDF) on rat focal cerebral ischemia-reperfusion injury (CIRI) models established by middle cerebral artery occlusion (MCAO).[Methods] A total of 60 healthy adult male Sprague-Dawley rats were selected. They were evenly and randomly divided into sham group, model group, edaravone group (12 mg/kg) and SDF group (360 mg/kg), and administered intragastrically and intraperitoneally. The middle cerebral artery of each rat was blocked by suture-occluded method to establish a CIRI model. After ischemia for 2 h and reperfusion for 48 h, the pathological injury on the ischemic side was observed by HE staining;the neuron and myelin sheath structure was observed by transmission electron microscopy;the expression of G protein-coupled receptor kinase 2 (GRK2) was preserved by immunohistochemistry;and the transfer of GRK2 was detected by western-blot.[Results] After 48 h of CIRI, the nuclei of the penumbral cortical neurons shrank, the chromatin was unevenly distributed, the nuclear membrane was dissolved and the mitochondria in the cytoplasm were swollen and vacuolated. The myelin layer was disordered. With this change, the distribution of GRK2 subcellular cells in the penumbra of the injured lateral cortex transferred from the cytoplasm to the membrane. SDF can effectively restore neuronal and myelin sheath structural damage and reduce the functional (membrane coupling) expression of GRK2.[Conclusions] GRK2 may be an effective target for SDF to protect the impaired blood-brain barrier (BBB) in CIRI. 展开更多
关键词 Sanguis DRACONIS flavones Cerebral ISCHEMIA-REPERFUSION injury G protein-coupled receptor kinase 2 Blood-brain barrier Matrix METALLOPROTEINASES
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