更新于：2024-11-01

Top II x PKC

更新于：2024-11-01

基本信息

关联

项与 Top II x PKC 相关的药物

AD-198

靶点

PKC x Top II

作用机制

PKC抑制剂 [+1]

在研机构-

原研机构

University of Tennessee

在研适应症-

非在研适应症

肺癌 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Top II x PKC 相关的临床结果

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100 项与 Top II x PKC 相关的转化医学

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0 项与 Top II x PKC 相关的专利（医药）

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项与 Top II x PKC 相关的文献（医药）

2017-04-01·Molecular Carcinogenesis2区 · 医学

Survivin inhibitor YM155 induces mitochondrial dysfunction, autophagy, DNA damage and apoptosis in Bcl‐xL silenced glioma cell lines

2区 · 医学

Article

作者: Jane, Esther P. ; Premkumar, Daniel R. ; Cavaleri, Jonathon M. ; Pollack, Ian F. ; Sutera, Philip A.

Because the anti‐apoptotic protein Bcl‐xL is overexpressed in glioma, one might expect that inhibiting or silencing this gene would promote tumor cell killing. However, our studies have shown that this approach has limited independent activity, but may tip the balance in favor of apoptosis induction in response to other therapeutic interventions. To address this issue, we performed a pharmacological screen using a panel of signaling inhibitors and chemotherapeutic agents in Bcl‐xL silenced cells. Although limited apoptosis induction was observed with a series of inhibitors for receptor tyrosine kinases, PKC inhibitors, Src family members, JAK/STAT, histone deacetylase, the PI3K/Akt/mTOR pathway, MAP kinase, CDK, heat shock proteins, proteasomal processing, and various conventional chemotherapeutic agents, we observed a dramatic potentiation of apoptosis in Bcl‐xL silenced cells with the survivin inhibitor, YM155. Treatment with YM155 increased the release of cytochrome c, smac/DIABLO and apoptosis inducing‐factor, and promoted loss of mitochondrial membrane potential, activation of Bax, recruitment of LC3‐II to the autophagosomes and apoptosis in Bcl‐xL silenced cells. We also found an additional mechanism for the augmentation of apoptosis due to abrogation of DNA double‐strand break repair mediated by Rad51 repression and enhanced accumulation of γH2AX. In summary, our observations may provide a new insight into the link between Bcl‐xL and survivin inhibition for the development of novel therapies for glioma. © 2016 Wiley Periodicals, Inc.

2017-02-01·Neurourology and Urodynamics3区 · 医学

l‐Theanine inhibits proinflammatory PKC/ERK/ICAM‐1/IL‐33 signaling, apoptosis, and autophagy formation in substance P‐induced hyperactive bladder in rats

3区 · 医学

Article

作者: Yu, Hong‐Jeng ; Tsai, Wen‐Hsin ; Chien, Chiang‐Ting ; Wu, Chung‐Hsin

Aims: Upregulation of substance P (SP) and neurokinin‐1 receptor (NK1R) activation induces pro‐inflammatory bladder hyperactivity through the PKC/ERK/NF‐κB/ICAM‐1/IL‐33 signaling pathways to increase the leukocyte infiltration and adhesion leading to reactive oxygen species (ROS) production, autophagy, and apoptosis. l‐Theanine is a unique non‐protein‐forming amino acid present in tea (Camellia sinensis [L.] O. Kuntze) with its antioxidant, anti‐inflammatory, and relaxation effects to improve cognition, mood, gastric ulcer injury, and cerebral ischemia/reperfusion injury, and posttraumatic stress disorder. We explored the protective effect of l‐theanine on SP‐induced bladder hyperactivity.Methods: In urethane‐anesthetized female Wistar rats, we explored the transcystometrogram, pelvic nerve activity, proinflammatory PKC/ERK/NF‐κB/ICAM‐1/IL‐33 signaling, apoptosis‐related Caspase 3/poly‐(ADP‐ribose)‐polymerase (PARP), and autophagy‐mediated LC3 II expression by Western blot, electrophoretic‐mobility shift assay and immunohistochemistry, bladder ROS amount by a ultrasensitive chemiluminescence method, and possible ROS sources from the different leukocytes by specific stains in SP‐evoked hyperactive bladder.Results:l‐Theanine dose‐dependently depressed H2O2 and HOCl activity in vitro. In urethane‐anesthetized female Wistar rats, intra‐arterial SP through NK1R activation increased voiding frequency (shortened intercontraction intervals) associated with the increase in bladder nerve activity, proinflammatory PKC/ERK/NF‐κB/ICAM‐1/IL‐33 signaling, Caspase 3/PARP‐mediated apoptosis, LC3 II‐mediated autophagy, ROS amount, neutrophils adhesion, CD68 (monocyte/macrophage) infiltration, and mast cells degranulation in the hyperactive bladder. Intragastrical l‐theanine (15 mg/kg) twice daily for 2 weeks efficiently ameliorated all the enhanced parameters in the SP‐treated hyperactive bladder.Conclusions: In conclusion, l‐theanine through antioxidant and anti‐inflammatory actions ameliorates SP‐induced bladder hyperactivity via the inhibition of proinflammatory PKC/ERK/NF‐κB/ICAM‐1/IL‐33 signaling, oxidative stress, bladder nerve hyperactivity, apoptosis, and autophagy. Neurourol. Urodynam. 36:297–307, 2017. © 2016 Wiley Periodicals, Inc.

2016-06-01·Neuroscience3区 · 医学

Intrinsic plasticity induced by group II metabotropic glutamate receptors via enhancement of high-threshold KV currents in sound localizing neurons

3区 · 医学

Article

作者: Y. Lu ; W.R. Hamlet

Intrinsic plasticity has emerged as an important mechanism regulating neuronal excitability and output under physiological and pathological conditions. Here, we report a novel form of intrinsic plasticity. Using perforated patch clamp recordings, we examined the modulatory effects of group II metabotropic glutamate receptors (mGluR II) on voltage-gated potassium (KV) currents and the firing properties of neurons in the chicken nucleus laminaris (NL), the first central auditory station where interaural time cues are analyzed for sound localization. We found that activation of mGluR II by synthetic agonists resulted in a selective increase of the high-threshold KV currents. More importantly, synaptically released glutamate (with reuptake blocked) also enhanced the high-threshold KV currents. The enhancement was frequency-coding region dependent, being more pronounced in low-frequency neurons compared to middle- and high-frequency neurons. The intracellular mechanism involved the Gβγ signaling pathway associated with phospholipase C and protein kinase C. The modulation strengthened membrane outward rectification, sharpened action potentials, and improved the ability of NL neurons to follow high-frequency inputs. These data suggest that mGluR II provides a feedforward modulatory mechanism that may regulate temporal processing under the condition of heightened synaptic inputs.