Jia Li

Sun Yat-Sen University, Shengcheng, Guangdong, China

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Publications (210)635.19 Total impact

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    ABSTRACT: Microtubule affinity-regulating kinase 2 (MARK2)/PAR-1b and protein kinase A (PKA) are both involved in the regulation of microtubule stability and neurite outgrowth, but whether a direct crosstalk exists between them remains unclear. Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. PKA could not reverse the microtubule disruption effect induced by a serine 409 to alanine (Ala) mutant of MARK2 (MARK2 S409A). In contrast, mutation of MARK2 Serine 409 to glutamic acid (Glu) (MARK2 S409E) did not affect microtubule stability and neurite outgrowth. We propose that PKA functions as an upstream inhibitor of MARK2 in regulating microtubule stability and neurite outgrowth by directly interacting and phosphorylating MARK2. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    The Journal of biological chemistry. 12/2014;
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    ABSTRACT: Three diterpenoids, including a pair of epimers, racemobutenolids A and B (1 and 2), and 4′,5′-dehydrodiodictyonema A (3), an α-tocopheroid, α-tocoxylenoxy (8), and an 28-oxostigmastane steroid, (23E)-3β-hydroxy-stigmasta-5,23-dien-28-one (11), together with 12 known compounds, were isolated from the green alga Caulerpa racemosa. The structures of the new compounds were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. The epimers (1 and 2) are two unusual diterpenoid lactones bearing a β-methyl-γ-substituted butenolide moiety, and 3 and 8 represent the first naturally occurring natural products with a hematinic acid ester group and 3,5-dimethylphenoxy functionality, respectively. The enzyme inhibitory activities of the isolated compounds were evaluated in vitro against PTP1B and related PTPs (TCPTP, CDC25B, LAR, SHP-1, and SHP-2). Compounds 3, 5, 6, and 9–14 exhibited different levels of PTP1B inhibitory activities with IC50 values ranging from 2.30 to 50.02 μM. Of these compounds, 3, 9, and 11 showed the most potent inhibitory activities towards PTP1B with IC50 values of 2.30, 3.85, and 3.80 μM, respectively. More importantly, the potent PTP1B inhibitors 3, 9, and 11 also displayed high selectivity over the highly homologous TCPTP and other PTPs. Also, the neuroprotective effects of the isolates against Aβ25-35-induced cell damage in SH-SY5Y cells were investigated. Compounds 10, 11, and 14 exhibited significant neuroprotective effects against Aβ25-35-induced SH-SY5Y cell damage with 11.31%–15.98% increases in cell viability at 10 μM. In addition, the cytotoxic activities of the isolated compounds were tested against the human cancer cell lines A-549 and HL-60.
    Bioorganic & Medicinal Chemistry. 11/2014;
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    ABSTRACT: Background & Aims As the main detoxifying organ of the body, the liver possesses a remarkable ability to regenerate after toxic injury, tissue resection or viral infection. A growing number of cellular signaling pathways have been implicated in orchestrating the process of liver regeneration. Here we investigated the role of inositol-requiring enzyme-1α (IRE1 α), a key signal transducer of the unfolded protein response (UPR), in liver regeneration. Methods Utilizing mice with hepatocyte-specific deletion of IRE1 α, we examined the role of IRE1 α in liver regeneration after challenges with carbon tetrachloride (CCl4) or hepatic surgery. We also investigated if IRE1 α deficiency could affect the activation state of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. Using co-immunoprecipitation and glutathione S-transferase (GST) pull-down assays, we analyzed whether IRE1 α could interact with STAT3 to regulate its phosphorylation. Results We found that in response to CCl4-induced liver damage or after two thirds partial hepatectomy (PH), abrogation of IRE1 α caused marked exacerbation of liver injury and impairment in regenerative proliferation of hepatocytes in mice. Furthermore, IRE1 α deficiency resulted in dampened STAT3 activation, and restoration of IRE1 α expression led to sustained phosphorylation of STAT3 in IRE1 α -null hepatocytes. Additionally, IRE1 α could directly and constitutively associate with STAT3, leading to elevated phosphorylation when stimulated by IL-6. Conclusions These results suggest that IRE1 α may promote liver regeneration through acting as a signaling platform to regulate the STAT3 pathway.
    Journal of Hepatology. 10/2014;
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    ABSTRACT: A novel minor bisindole alkaloid, racemosin C (1), characterized by a naturally unprecedented 8-hydroxy-2,4,6-cyclooctatrienone ring fused with two indole systems, was isolated from the green alga Caulerpa racemosa, together with one known related metabolite, caulersin (2). The structure of 1 was elucidated on the basis of extensive spectroscopic analysis, and by comparison with the data of related known compounds. A plausible biosynthetic pathway of 1 was proposed. Compounds 1 and 2 exhibited significant PTP1B inhibitory activity with IC50 values of 5.86 ± 0.57 and 7.14 ± 1.00 μM, respectively, compared with the positive control oleanolic acid (IC50 = 3.03 ± 0.20 μM). On the basis of the data obtained, the Caulerpa bisindole alkaloids may be considered as a new class of PTP1B inhibitors.
    Journal of Asian natural products research. 10/2014;
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    ABSTRACT: By rational design and modification, compound 9l showed excellent DPP4 inhibitory activity, good selectivity and efficacy in OGTTs in ICR mice, did not block the hERG channel and no inhibition of live metabolic enzyme like CYP2C9.
    European Journal of Medicinal Chemistry 10/2014; 86:242–256. · 3.43 Impact Factor
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    ABSTRACT: A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC50=1.18-8.01μg/mL) and PTP1B (IC50=0.85-8.75μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC50 values of 1.18 and 0.85μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na3VO4 (IC50=0.93μg/mL) and oleanolic acid (IC50=0.85μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor.
    Bioorganic & medicinal chemistry letters. 07/2014;
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    ABSTRACT: Two new apotirucallane-type triterpenoids, cedrodorols A-B (1 and 2), along with seven known compounds (3-9), were isolated from the twigs and leaves of Cedrela odorata. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 1 and 2 showed significant inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with the IC50 values of 13.09 and 3.93 μg/ml, respectively.
    Journal of Asian natural products research 05/2014; · 0.61 Impact Factor
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    ABSTRACT: 5-Hydroxymethylcytosine (5hmC), converted from 5-methylcytocine (5mC) by Tet family of dioxygenases (Tet1, Tet2, and Tet3), is enriched in the embryonic stem cells (ESCs) and in the brain. However, the role of 5hmC and Tet family in the process of ESC differentiation especially neuronal differentiation remains elusive. Here, we showed the evidence that Tet3 is critical in neural progenitor cell (NPC) maintenance and terminal differentiation of neurons. We found that Tet3 expression is basically undetectable in ESCs, but its level increases rapidly during neuronal differentiation. Tet3 knockout ESCs appear normal in self-renewal and maintenance but impaired in neuronal differentiation. NPCs could be induced efficiently from Tet3 knockout ESCs, as the expression of NPC marker Pax6 and nestin is comparable with NPCs from wild-type ESCs, but undergo apoptosis rapidly, and the terminal differentiation of neurons is greatly reduced. Our results indicate that Tet3 is important for NPC maintenance and terminal differentiation of neurons.
    Molecular Neurobiology 05/2014; · 5.47 Impact Factor
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    ABSTRACT: Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure-activity relationship study showed that the amine derivatives at the 24-position (groups I-VI) can improve the potency (EC50: 0.7-2.3 μM) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 μM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model.
    European Journal of Medicinal Chemistry 04/2014; 79C:340-349. · 3.43 Impact Factor
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    ABSTRACT: A series of novel di- and tripeptidyl epoxyketone derivatives composed of β-amino acids were designed, synthesized, and evaluated for their proteasome inhibitory activities and anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929 and normal cells (peripheral blood mononucleated cells, PBMC). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC50 values ranging from 0.97±0.05~1.85±0.11μM. In addition, all the four compounds showed anti-proliferation activities with IC50 values at low micromolar levels against two MM cell lines and weak activities against normal cells. Furthermore, western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e. All the experimental results validated that the β-amino acid building block has potential for the development of proteasome inhibitors.This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 04/2014; · 2.47 Impact Factor
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    ABSTRACT: A first example of 1,4-conjugate addition of β, γ-unsaturated N-sulfonyl imines via the oxonium ylides trapping process was developed. This method afforded a novel and efficient access for the high regio- and diastereoselective construction of α-hydroxyl-δ-amino esters derivatives, which exhibit inhibitory activity on PTP1B and SIRT1 enzymes in vitro. The synthetic potentials and the biological activity of the resulting products were well demonstrated to be promising for drug discovery.
    The Journal of Organic Chemistry 04/2014; · 4.56 Impact Factor
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    ABSTRACT: A novel series of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives was designed and synthesized. All compounds were evaluated the DPP4 inhibitory activities and selectivity. Compounds 6h and 6n showed excellent DPP4 inhibitory activities and selectivity. Besides, the binding mode, oral glucose tolerance test, chronic effect, and pharmacokinetics of these two compounds were investigated. Moreover, hERG and liver metabolic enzymes P450 of compounds 6h and 6n were tested.
    European Journal of Medicinal Chemistry 03/2014; 75:111–122. · 3.43 Impact Factor
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    ABSTRACT: Two new sarsolenane diterpenes, dihydrosarsolenone (2), methyl dihydrosarsolenoneate (3), and two new capnosane diterpenes, sarsolilides B (5) and C (6), were isolated together with the known analogue, sarsolilide A (4), from the Hainan soft coral Sarcophyton trocheliophorum Marenzeller. Their structures were elucidated by detailed spectroscopic analysis and by comparison with reported data, leading to a structure revision of sarsolenone (1). The absolute configurations of 2 and 5 were determined by TDDFT ECD calculations, and they could be used as ECD reference compounds in the determination of the absolute configuration of their related derivatives. Compounds 4 and 5 exhibited inhibitory activity in vitro against protein tyrosine phosphatases 1B (PTP1B), representing the first report of PTP1B inhibitory activity for capnosane diterpenes.
    Annalen der Chemie und Pharmacie 01/2014; · 3.10 Impact Factor
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    ABSTRACT: Chaetoglobosin Y (1), was isolated from the endolichenic fungal strain Chaetomium globosum (No. 64-5-8-2), along with related six known cytochalasans, chaetoglobosin Fex (2), chaetoglobosin E (3), isochaetoglobosin D (4), chaetoglobosin G (5), cytoglobosin B (6), and cytoglobosin C (7). Their structures were determined by detailed spectroscopic analyses and comparison with those of the closely related compounds previously reported. The cytotoxicity to HCT-116 cell line of 2-7 was evaluated in vitro with doxorubicin as positive control.
    Fitoterapia 01/2014; · 2.23 Impact Factor
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    ABSTRACT: A new alterporriol-type anthranoid dimer, alterporriol S (1), along with seven known anthraquinone derivatives, (+)-aS-alterporriol C (2), hydroxybostrycin (3), halorosellinia A (4), tetrahydrobostrycin (5), 9α-hydroxydihydrodesoxybostrycin (6), austrocortinin (7) and 6-methylquinizarin (8), were isolated from the culture broth of the mangrove fungus, Alternaria sp. (SK11), from the South China Sea. Their structures and the relative configurations were elucidated using comprehensive spectroscopic methods, including 1D and 2D NMR spectra. The absolute configurations of 1 and the axial configuration of 2 were defined by experimental and theoretical ECD spectroscopy. 1 was identified as the first member of alterporriols consisting of a unique C-10-C-2' linkage. Atropisomer 2 exhibited strong inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with an IC50 value 8.70 μM.
    Marine Drugs 01/2014; 12(5):2953-69. · 3.98 Impact Factor
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    ABSTRACT: Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF), has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2) in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN), attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.
    PLoS ONE 01/2014; 9(7):e100685. · 3.53 Impact Factor
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    ABSTRACT: Ubiquitin-proteasome pathway (UPP) plays a very important role in the degradation of proteins. Finding novel UPP inhibitors is a promising strategy for treating multiple myeloma (MM). Ub-YFP reporter assays were used as cellular UPP models. MM cell growth, apoptosis and overall death were evaluated with the MTS assay, Annexin V/PI dual-staining flow cytometry, poly (ADP-ribose) polymerase (PARP) cleavage, and PI uptake, respectively. The mechanism of UPP inhibition was analyzed by western blotting for ubiquitin, in vitro and cellular proteasomal and deubiquitinases (DUBs) activity assays. Cellular reactive oxygen species (ROS) were measured with H2DCFDA. Curcusone D, identified as a novel UPP inhibitor, causes cell growth inhibition and apoptosis in MM cells. Curcusone D induced the accumulation of poly-ubiquitin-conjugated proteins but could not inhibit proteasomal activity in vitro or in cells. Interestingly, the mono-ubiquitin level and the total cellular DUB activity were significantly downregulated following curcusone D treatment. Furthermore, curcusone D could induce ROS, which were closely correlated with DUB inhibition that could be nearly completely reversed by NAC. Finally, curcusone D and the proteasomal inhibitor bortezomib showed a strong synergistic effect against MM cells. Curcusone D is novel UPP inhibitor that acts via the ROS-induced inhibition of DUBs to produce strong growth inhibition and apoptosis of MM cells and synergize with bortezomib. The anti-MM molecular mechanism study of curcusone D will promote combination therapies with different UPP inhibitors against MM and further support the concept of oxidative stress regulating the activity of DUBs.
    Biochimica et Biophysica Acta (BBA) - General Subjects 01/2014; · 3.85 Impact Factor
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    ABSTRACT: Although the mammalian IRE1α-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1α signalling in vivo remains poorly understood. Here we show that hepatic IRE1α functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1α-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1α results in impairment of fatty acid β-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1α null mice. XBP1s directly binds to and activates the promoter of PPARα, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1α promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial β-oxidation and ketogenesis through the XBP1s-PPARα axis.
    Nature Communications 01/2014; 5:3528. · 10.74 Impact Factor
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    ABSTRACT: Resveratrol has recently been used as a supplemental treatment for several neurological and nonneurological diseases. It is not known whether resveratrol has neuroprotective effect on amyotrophic lateral sclerosis (ALS). To assess the effect of resveratrol on the disease, we tested this agent on an ALS model of SOD1(G93A) transgenic mouse. Rotarod measurement was performed to measure the motor function of the ALS mice. Nissl staining and SMI-32 immunofluorescent staining were used to determine motor neurons survival in the spinal cord of the ALS mice. Hematoxylin-eosin (H&E), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) staining were applied to pathologically analyze the skeletal muscles of the ALS mice. We found that resveratrol treatment significantly delayed the disease onset and prolonged the lifespan of the ALS mice. Furthermore, resveratrol treatment attenuated motor neuron loss, relieved muscle atrophy, and improved mitochondrial function of muscle fibers in the ALS mice. In addition, we demonstrated that resveratrol exerted these neuroprotective effects mainly through increasing the expression of Sirt1, consequently suppressing oxidative stress and downregulating p53 and its related apoptotic pathway. Collectively, our findings suggest that resveratrol might provide a promising therapeutic intervention for ALS.
    BioMed Research International 01/2014; 2014:483501. · 2.71 Impact Factor
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    ABSTRACT: Graphical abstract A series of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid, as exemplified by compound 20h, were designed and synthesized. Several compounds exhibited potent proteasome inhibitory activities together with anti-proliferation activities against two multiple myeloma cell lines.
    Bioorganic & medicinal chemistry 01/2014; · 2.82 Impact Factor

Publication Stats

2k Citations
635.19 Total Impact Points

Institutions

  • 2011–2014
    • Sun Yat-Sen University
      • • School of Pharmaceutical Science
      • • Department of Chemical Engineering
      Shengcheng, Guangdong, China
    • Ruijin Hospital North
      Shanghai, Shanghai Shi, China
    • University of South China
      Heng-nan, Hunan, China
  • 2005–2014
    • Chinese Academy of Sciences
      • National Center for Drug Screening
      Peping, Beijing, China
    • East China Normal University
      • Department of Chemistry
      Shanghai, Shanghai Shi, China
    • Sichuan University
      • Department of Pharmaceutical and Biochemical Engineering
      Hua-yang, Sichuan, China
  • 2004–2014
    • Shanghai Institutes for Biological Sciences
      • Institute of Health Sciences
      Shanghai, Shanghai Shi, China
  • 2013
    • Zhejiang University of Technology
      Hang-hsien, Zhejiang Sheng, China
    • Fudan University
      Shanghai, Shanghai Shi, China
    • National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention
      Peping, Beijing, China
    • Jiangxi Agricultural University
      Jiangxi, Gansu Sheng, China
    • Changsha Medical University
      Ch’ang-sha-shih, Hunan, China
    • Fourth Military Medical University
      • Department of Gynaecology and Obstetrics
      Xi’an, Liaoning, China
  • 2007–2013
    • East China University of Science and Technology
      • School of Pharmacy
      Shanghai, Shanghai Shi, China
  • 2003–2013
    • Northeast Institute of Geography and Agroecology
      • • State Key Laboratory of Drug Research
      • • National Center for Drug Screening
      • • Institute of Health Sciences
      • • Research Center for Modernization of Traditional Chinese Medicine
      Beijing, Beijing Shi, China
  • 2012
    • University of Texas MD Anderson Cancer Center
      • Department of Molecular Carcinogenesis
      Houston, TX, United States
    • Jinan University (Guangzhou, China)
      Shengcheng, Guangdong, China
  • 2011–2012
    • Chinese Center For Disease Control And Prevention
      • Institute for Viral Disease Control and Prevention
      Beijing, Beijing Shi, China
    • Yanbian University
      Yang-chi-t'eng, Jilin Sheng, China
  • 2009–2011
    • Zhejiang University
      • College of Pharmaceutical Sciences
      Hangzhou, Zhejiang Sheng, China
    • Shanghai Research Institute of Materials
      Shanghai, Shanghai Shi, China
    • Henan Provincial People’s Hospital
      Cheng, Henan Sheng, China
  • 2010
    • Chinese Academy of Tropical Agricultural Sciences
      Hoihau, Hainan, China
    • University of Jinan (Jinan, China)
      Chi-nan-shih, Shandong Sheng, China