Jia Li

Sun Yat-Sen University, Shengcheng, Guangdong, China

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Publications (205)620.44 Total impact

  • [Show abstract] [Hide abstract]
    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;
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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. · 3.27 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: 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. · 3.73 Impact Factor
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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. 01/2014; 86:242–256.
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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 01/2014; 75:111–122. · 3.27 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. · 10.02 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. · 2.88 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
  • European Journal of Medicinal Chemistry. 01/2014; 79:340–349.
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    ABSTRACT: 7-O-methylvariecolortide A (1), variecolortide B (2), and variecolortide C (3), the rare variecolortides existing in racemic manner, were isolated from an endolichenic fungal strain Eurotium sp. (No. 17-11-8-1). With the chiral HPLC technology, (-)-(S)-7-O-methylvariecolortide A (1a), (+)-(R)-7-O-methylvariecolortide A (1b), (-)-(S)-variecolortide B (2a), (+)-(R)-variecolortide B (2b), (-)-(S)-variecolortide C (3a), (+)-(R)-variecolortide C (3b), were successfully separated and obtained. Their absolute configurations were firstly assigned by ECD experiment and ECD calculation. According to the relation of isolated compounds, a plausible biosynthetic pathway for variecolortides was proposed. In caspase-3 enzymatic assay, compounds 1-3 showed inhibitory activity, with IC50 values of 1.7, 0.8 and 15.7μM, respectively.
    Fitoterapia 12/2013; · 2.23 Impact Factor
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    ABSTRACT: Previously, we have documented that prenatal hypoxia can aggravate the cognitive impairment and Alzheimer's disease (AD) neuropathology in APP(Swe) /PS1(A246E) (APP/PS1) transgenic mice, and valproic acid (VPA) can prevent hypoxia-induced down-regulation of β-amyloid (Aβ) degradation enzyme neprilysin (NEP) in primary neurons. In this study, we have investigated the molecular mechanisms of VPA's anti-AD effects and found that VPA can reduce the prenatal hypoxia-induced neuritic plaque formation and improve the learning deficits in the AD mouse model. The pregnant APP/PS1 transgenic mice were exposed in a hypobaric chamber. Neuritic plaque staining, Morris water maze, and enzyme-linked immunosorbent assay (ELISA) were used to detect the effects of VPA on Aβ neuropathology, learning, and memory. Chromatin immunoprecipitation (ChIP) assays and real-time PCR (RT-PCR) were used to determine the effect of VPA on the histone3 acetylation (H3-Ace). We found that VPA can inhibit neuritic plaque formation and improve the learning and memory in the prenatal hypoxic APP/PS1 transgenic mice. In addition, VPA treatment can decrease the soluble and insoluble Aβ42 levels and increase the NEP expression via up-regulation of H3-Ace in the APP/PS1 transgenic mice. Valproic acid is able to attenuate the prenatal hypoxia-induced Aβ neuropathology and learning and memory deficits via inhibiting the activation of histone deacetylase 1 (HDAC1), preventing the decrease in H3-Ace in the NEP promoter regions and reducing the down-regulation of NEP.
    CNS Neuroscience & Therapeutics 12/2013; · 4.46 Impact Factor
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    ABSTRACT: The chemokine receptor 4 (CXCR4) plays an important role in the growth, angiogenesis and metastasis of various cancers, including epithelial ovarian cancer (EOC). However, the correlation between CXCR4 and the clinical response of EOC patients to chemotherapy remains unknown. 124 EOC patients were recruited to assess the relationship between CXCR4 and the response to cisplatin-based chemotherapy. The results showed that patients with a higher CXCR4 expression had a significantly lower chemosensitivity, a poorer progression-free survival and a lower overall survival than those with lower CXCR4 expression. In addition, knockdown of CXCR4 by small interfering RNA suppressed cell proliferation and resulted in G1/S arrest, increased apoptosis and chemosensitivity in both cisplatin-sensitive A2780 cells and cisplatin-resistant cell A2780/cis in vitro. Our data suggest that CXCR4 is one of the key molecules in cisplatin-based chemotherapy for EOC patients and that CXCR4 inhibition is a potential strategy to address the chemoresistance of EOC.
    BMB reports 11/2013; · 1.63 Impact Factor
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    ABSTRACT: The liver plays a central role in cholesterol homeostasis. It exclusively receives and metabolizes oxysterols, which are important metabolites of cholesterol and are more cytotoxic than free cholesterol, from all extrahepatic tissues. Hepatocellular carcinomas (HCCs) impair certain liver functions and cause pathological alterations in many processes including cholesterol metabolism. However, the link between an altered cholesterol metabolism and HCC development is unclear. Human ACAT2 is abundantly expressed in intestine and fetal liver. Our previous studies have shown that ACAT2 is induced in certain HCC tissues. Here, by investigating tissue samples from HCC patients and HCC cell lines, we report that a specific cholesterol metabolic pathway, involving induction of ACAT2 and esterification of excess oxysterols for secretion to avoid cytotoxicity, is established in a subset of HCCs for tumor growth. Inhibiting ACAT2 leads to the intracellular accumulation of unesterified oxysterols and suppresses the growth of both HCC cell lines and their xenograft tumors. Further mechanistic studies reveal that HCC-linked promoter hypomethylation is essential for the induction of ACAT2 gene expression. We postulate that specifically blocking this HCC-established cholesterol metabolic pathway may have potential therapeutic applications for HCC patients.
    Journal of Molecular Cell Biology 10/2013; · 7.31 Impact Factor

Publication Stats

2k Citations
620.44 Total Impact Points


  • 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
    • 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
    • Fourth Military Medical University
      • Department of Gynaecology and Obstetrics
      Xi’an, Liaoning, China
    • Fudan University
      Shanghai, Shanghai Shi, China
    • Changsha Medical University
      Ch’ang-sha-shih, Hunan, China
    • Jiangxi Agricultural University
      Jiangxi, Gansu Sheng, 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
    • Yanbian University
      Yang-chi-t'eng, Jilin Sheng, China
    • Chinese Center For Disease Control And Prevention
      • Institute for Viral Disease Control and Prevention
      Beijing, Beijing Shi, 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
  • 2005–2011
    • East China Normal University
      • Department of Chemistry
      Shanghai, Shanghai Shi, China
  • 2010
    • Chinese Academy of Tropical Agricultural Sciences
      Hoihau, Hainan, China
    • University of Jinan (Jinan, China)
      Chi-nan-shih, Shandong Sheng, China