Yonghua Ji

Shanghai University, Shanghai, Shanghai Shi, China

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Publications (12)21.64 Total impact

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    ABSTRACT: Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels (VGSCs), how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Nav1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacainetriggered arrhythmia. Here, we investigated the effect of bupivacaine on Nav1.5 within the clinical concentration range. The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.
    Neuroscience Bulletin 07/2014; · 1.83 Impact Factor
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    ABSTRACT: Glioma is the most common primary central nervous system tumor. Despite considerable research effort, little progress has been made in the therapeutic treatment of this disease. Protein kinase Cε (PKCε), an important intracellular signaling molecule, modulates diverse cellular functions, including cell proliferation, apoptosis, invasion and differentiation. The aim of the study is to investigate whether knockdown of PKCε expression by RNA interference (RNAi) could affect the growth, apoptosis and invasion of human glioma cells, and the involvement of the signal transducer and activator of transcription 3 (Stat3) signaling pathway in these effects. Our data showed that knockdown of PKCε expression inhibited proliferation, induced apoptosis and decreased invasiveness of human glioma cell lines U251 and U87, as well as suppressed the growth of U87 cell-derived tumors in nude mice. Moreover, PKCε physically interacts with Stat3, and knockdown of PKCε expression attenuated Stat3Ser727 phosphorylation and B-cell lymphoma-extra large (Bcl-xL) expression in the two human glioma cell lines. These results support an important role for PKCε in glioma cell growth, apoptosis and invasion, and PKCε exerting its above effects at least in part through Stat3. Thus, PKCε has the potential to be an attractive therapeutic target for glioma therapy.
    Journal of Molecular Neuroscience 06/2014; · 2.76 Impact Factor
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    ABSTRACT: Malignant gliomas are highly invasive tumours associated with high levels of mortality, and the treatment of gliomas remains a major neurosurgical challenge. Stat3, a member of the signal transducer and activator of transcription family, has a critical role in a variety of cancer cells. We have previously shown that downregulation of Stat3 decreases invasiveness and induces apoptosis in U251 human glioma cells in vitro, but to date it has been unclear whether this treatment would be beneficial in vivo. In the present study, we found that downregulation of Stat3 via RNAi suppressed tumour growth in a xenograft mouse model by inducing apoptosis of U251 tumour cells and inhibiting tumour neo-angiogenesis. We also found that Stat3 RNAi suppresses the expression of Bcl-2 in vivo to induce apoptosis. These results indicate that Stat3 is a critical factor in the survival of patients with glioma, and that targeting Stat3 may offer a potential therapeutic approach.
    Journal of Clinical Neuroscience 03/2012; 19(3):443-6. · 1.32 Impact Factor
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    Zhirui Liu, Jie Tao, Pin Ye, Yonghua Ji
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    ABSTRACT: Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.
    Journal of Toxicology 01/2012; 2012:843787.
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    Yonghua Ji, Maria Elena De Lima
    Journal of Toxicology 01/2012; 2012:501438.
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    ABSTRACT: Acute myeloid leukemia (AML) is the most common myeloid leukemia. It is highly malignant, thus, most patients with AML will relapse and die after traditional treatment. Stat3, a member of the signal transducer and activator of transcription (Stat) family, is involved in the development and progression of many tumors. The purpose of the study was to investigate whether the down-regulation of Stat3 expression by RNA interference is effective against human leukemia HL-60 cells. The results indicated that constitutively expressed Stat3 is present in human leukemia HL-60 cells, and the down-regulation of Stat3 expression caused significant induction of apoptosis as well as inhibition of proliferation in HL-60 cells. These data further demonstrated that Stat3 plays a critical role in human leukemia HL-60 cell apoptosis and proliferation. Thus, targeting Stat3 may be a useful adjunctive treatment strategy in AML.
    Hematology 06/2011; 16(4):232-235. · 1.19 Impact Factor
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    ABSTRACT: BmK IT2 is regarded as a receptor site-4 modulator of sodium channels with depressant insect toxicity. It also displays anti-nociceptive and anti-convulsant activities in rat models. In this study, the potency and efficacy of BmK IT2 were for the first time assessed and compared among four sodium channel isoforms expressed in Xenopus oocytes. Combined with molecular approach, the receptor site of BmK IT2 was further localized. 2 µM BmK IT2 strongly shifted the activation of DmNa(v)1, the sodium channel from Drosophila, to more hyperpolarized potentials; whereas it hardly affected the gating properties of rNa(v)1.2, rNa(v)1.3 and mNa(v)1.6, three mammalian central neuronal sodium channel subtypes. (1) Mutations of Glu(896), Leu(899), Gly(904) in extracellular loop Domain II S3-S4 of DmNa(v)1 abolished the functional action of BmK IT2. (2) BmK IT2-preference for DmNa(v)1 could be conferred by Domain III. Analysis of subsequent DmNa(v)1 mutants highlighted the residues in Domain III pore loop, esp. Ile(1529) was critical for recognition and binding of BmK IT2. In this study, BmK IT2 displayed total insect-selectivity. Two binding regions, comprising domains II and III of DmNa(v)1, play separated but indispensable roles in the interaction with BmK IT2. The insensitivity of Na(v)1.2, Na(v)1.3 and Na(v)1.6 to BmK IT2 suggests other isoforms or mechanism might be involved in the suppressive activity of BmK IT2 in rat pathological models.
    PLoS ONE 01/2011; 6(1):e14510. · 3.53 Impact Factor
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    ABSTRACT: BmK I, a site-3-specific modulator of VGSCs (voltage-gated sodium channels) from the Chinese scorpion Buthus martensi Karsch, can induce spontaneous nociception and hyperalgesia and generate epileptiform responses in rats, which is attributed to the modulation of VGSCs in the neural system. However, which VGSC subtype is targeted by BmK I remains to be identified. Using two-electrode voltage-clamp recording, we studied the efficacy and selectivity of BmK I to three neuronal VGSCs co-expressed with the auxiliary β1 subunit in Xenopus oocytes. Results revealed that BmK I induced a large increase in both transient and persistent currents in mNav1.6α/β1 (where m indicates mouse), which correlated with a prominent reduction in the fast component of inactivating current. In comparison, BmK I-increased currents of rNav1.2α/β1 (where r indicates rat) and rNav1.3α/β1 were much smaller. The EC50 values of BmK I for rNav1.2α/β1 (252±60 nM) and mNav1.6α/β1 (214±30 nM) were similar and roughly half of that for rNav1.3α/β1 (565±16 nM). Moreover, BmK I only accelerated the slow inactivation development and delay recovery of mNav1.6α/β1 through binding to the channel in the open state. Residue-swap analysis verified that an acidic residue (e.g. Asp1602 in mNav1.6) within the domain IV S3-S4 extracellular loop of VGSCs was crucial for the selectivity and modulation pattern of BmK I. Our findings thus provide the molecular determinant explaining the divergent and intriguing behaviour of neuronal VGSCs in response to site-3-specific modulators, indicating that these subtypes play different roles in BmK I-induced hyperexcitablity in rat models.
    Biochemical Journal 10/2010; 431(2):289-98. · 4.78 Impact Factor
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    ABSTRACT: In pancreatic beta cells, ATP-sensitive potassium (K(ATP)) channels are metabolic sensors that couple cell metabolism to electrical activity, and therefore K(ATP) channels regulate insulin secretion. We assume that down-regulating the expression of Kir6.2 subunits of K(ATP) channels may change calcium influx induced by glucose and insulin secretion regulated by K(ATP) channels. In our study, we employ Kir6.2-shRNA plasmid to downregulate Kir6.2 expression in HIT-T15 cells. Then, we research the effect of downregulation of Kir6.2 on K(ATP) current, cytoplasmic free Ca2+ concentration and insulin secretion. All results illustrate that downregulation of Kir6.2 subunits of K(ATP) channels in HIT-T15 cells affects K(ATP) current and insulin secretion, and fails to promote calcium influx. The results demonstrate the function of Kir6.2 subunits in electrophysiology characteristic, insulin secretion and calcium influx, and RNA interference provides a feasible alternative to study the function of Kir6.2 subunits in K(ATP) channels in different kinds of diabetes.
    Journal of pediatric endocrinology & metabolism: JPEM 07/2010; 23(7):709-17. · 0.71 Impact Factor
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    ABSTRACT: Gliomas are the most common type of primary brain tumors. Despite the improvement in current treatments for gliomas, including surgical resection, radiation, and chemotherapy, there has been very little progress in curing this kind of disease. Stat3 is a member of signal transducer and activator of transcription family. It plays an important role in regulating cell survival, invasion, and apoptosis. This study investigated the influence of low-level expression of Stat3 on invasion and apoptosis in U251 cells. Our data showed that Stat3 is constitutively expressed in human gliomas cell line U251. The invasion activity in U251 cells was weakened and the apoptosis in U251 cells was induced after down-regulation of Stat3. In addition, down-regulation of Stat3 can suppress the expression of MMP-2, Bcl-xL and survivin but not 67LR. These results further indicate that Stat3 plays a key role in the invasion and apoptosis of human glioma cell line U251.
    Journal of Molecular Neuroscience 03/2010; 40(3):353-9. · 2.76 Impact Factor
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    ABSTRACT: Malignant gliomas are among the most intractable brain cancers. Neural stem cells (NSC) are tissue-specific stem cells with self-renewal capacity and the potential to differentiate into glia and neurons. It has been proposed that NSC could serve as a therapeutic vehicle for the treatment of gliomas. Previous studies showed that NSC, after being implanted into the brain, could migrate to the invading tumor border and target infiltrating tumor cells. These findings suggested that NSC and gliomas could interact, although the mechanism is still not well understood. Here we report that the stem-cell state of NSC is disrupted and NSCs become differentiated when they are co-cultured in vitro with a medium in which glioma cells have been cultured (conditioned medium). The ratio of neurons in these differentiated cells is significantly higher than that in the controls (NSC cultured in regular medium). Conditioned medium in which primary NSC have been grown can inhibit proliferation of glioma cells, an effect that was greater with NSC conditioned medium of embryonic mice than neonatal mice. These results suggest that glioma cells and NSC can interact at the niche or micro-environment level, potentially leading to proliferation and differentiation of NSC and suppression of proliferation of glioma cells. These findings may shed new light on the development of novel strategies for the treatment of malignant gliomas.
    Journal of Clinical Neuroscience 10/2009; 16(12):1619-23. · 1.32 Impact Factor
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    ABSTRACT: Glioma is the most common brain tumor in central nervous system. Traditional therapies are not effective to cure this disease. Stat3 is a member of the signal transducer and activator of transcription family, and it has the potential to mediate cell survival, growth and differentiation. In this study, we testified that Stat3 was constitutively expressed in glioma cell line SHG44 and then investigated the role of a low level of Stat3 expression in glioma cells by constructing an interfering RNA expression plasmid. The results showed that glioma cells underwent morphologic and biochemical changes after the RNAi treatment. We hypothesized that a low level of Stat3 expression could induce apoptosis of glioma cell, which further proved that Stat3 played an important role in growth, survival and proliferation of glioma cells. This study provides a new alternative to gene therapy for glioma treatment.
    Neurological Research 05/2008; 30(3):297-301. · 1.45 Impact Factor

Publication Stats

46 Citations
21.64 Total Impact Points


  • 2008–2012
    • Shanghai University
      • School of Life Sciences
      Shanghai, Shanghai Shi, China
  • 2010
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China