関: fluoromethyl ketone

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English Journal

UVB-induced anti-survival and pro-apoptotic effects on HaCaT human keratinocytes via caspase- and PKC-dependent downregulation of PKB, HIAP-1, Mcl-1, XIAP and ER stress.

Park YK, Jang BC.Author information Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu, Daegu 704-701, Republic of Korea.AbstractEvidence suggests that solar ultraviolet B (UVB) radiation inhibits growth and/or induces apoptosis of human skin cells. However, mechanisms underlying the UVB-induced anti-survival and pro-apoptotic effects on human skin cells remain unclear. In this study, we investigated the effect of UVB radiation on survival and apoptosis of HaCaT human keratinocytes and determined possible molecular, cellular and signaling mechanisms including cross-regulation, which are responsible for the UVB's anti-survival and/or pro-apoptotic effects. The results showed that UVB radiation at 400 mJ/cm2 for 8 h largely decreased cell survival and induced DNA fragmentation, an index of apoptosis, in HaCaT human keratinocytes. On a mechanistic level, UVB radiation triggered the activation of caspase-9, cleavage of poly(ADP‑ribose) polymerase, and downregulation of myeloid cell leukemia-1 (Mcl-1), human inhibitor of apoptosis protein-1 (HIAP-1), X-linked IAP (XIAP), and protein kinase B (PKB), but did not affect the expression of B-cell lymphoma-2 in HaCaT cells. UVB radiation also upregulated the expression of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) stress marker, in HaCaT cells. Of note, results of pharmacological inhibition studies have demonstrated that pretreatment with z-VAD-fmk, a pan‑caspase inhibitor strongly attenuated UVB-induced apoptosis, the activation of caspase-9, downregulation of Mcl-1, XIAP and PKB (but not HIAP-1), and upregulation of GRP78, while pretreatment with GF109203 or GO6983, pan-PKC inhibitors, substantially blocked the UVB-induced reduction of cell survival, activation of caspase-9, downregulation of HIAP-1, XIAP, and PKB (but not Mcl-1), and GRP78 upregulation in HaCaT cells. Collectively, these results demonstrated that UVB has strong anti-survival and pro-apoptotic effects on HaCaT cells and the effects were largely mediated via the activation of caspase-9 and protein kinase Cs, which subsequently downregulated PKB, XIAP, HIAP-1 and Mcl-1, and triggered ER stress.
International journal of molecular medicine.Int J Mol Med.2014 Mar;33(3):695-702. doi: 10.3892/ijmm.2013.1595. Epub 2013 Dec 19.
Evidence suggests that solar ultraviolet B (UVB) radiation inhibits growth and/or induces apoptosis of human skin cells. However, mechanisms underlying the UVB-induced anti-survival and pro-apoptotic effects on human skin cells remain unclear. In this study, we investigated the effect of UVB radiat
PMID 24356997

Efficacy of Chlorin e6-Mediated Sono-Photodynamic Therapy on 4T1 Cells.

Li Q, Wang X, Wang P, Zhang K, Wang H, Feng X, Liu Q.Author information 1 Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Xi'an, China .AbstractAbstract Purpose: The present study aims to investigate the antitumor effect and possible mechanisms of chlorin e6 (Ce6)-mediated sono-photodynamic therapy (Ce6-SPDT) on murine 4T1 mammary cancer cells in vitro. Materials: Cellular uptake and intracellular distribution of Ce6 in 4T1 cells were detected by flow cytometry and confocal microscope. Cells after loading with 1 μg/mL Ce6 were exposed to ultrasound at 1.0 MHz for up to 1 minute with an intensity of 0.36 W/cm(2) and laser light with total radiation dose of 1.2 J/cm(2). Cell viability and clonogenicity were determined by MTT assay and colony formation assay. Apoptosis was analyzed by DAPI staining, Western blots were used to detect the activity of Caspase-3. DNA damage, mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) of 4T1 cells were also evaluated by flow cytometry. FD500 was employed to detect changes of membrane permeability after ultrasound. Results: Ce6 rapidly entered 4T1 cells within 4 hours after it has been added and displayed a mitochondria-localization pattern. Compared with sonodynamic therapy (SDT) and photodynamic therapy (PDT) alone, the combined SPDT treatment further enhanced cell viability loss, DNA damage, and clonogenicity inhibition. DAPI staining and western blots analysis reflected that cells with apoptotic morphological characteristics and the activity of Caspase-3 were apparently increased in the combined group. Besides, SPDT caused obvious MMP loss and intracellular ROS generation at early 1 hour post treatment. Interestingly, the SPDT induced cell viability loss and cell apoptosis was greatly inhibited by pre-treatment with ROS scavenger N-acetylcysteine and Caspase inhibitor z-VAD-fmk. FD500 detection showed that ultrasound enhanced cell membrane permeability, implying much higher uptake of Ce6 might be involved in PDT therapy by pre-ultrasound treatment. Conclusions: The findings demonstrated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, a Caspase-dependent apoptosis and loss of MMP, generation of ROS may be involved.
Cancer biotherapy & radiopharmaceuticals.Cancer Biother Radiopharm.2014 Feb;29(1):42-52. doi: 10.1089/cbr.2013.1526. Epub 2013 Nov 9.
Abstract Purpose: The present study aims to investigate the antitumor effect and possible mechanisms of chlorin e6 (Ce6)-mediated sono-photodynamic therapy (Ce6-SPDT) on murine 4T1 mammary cancer cells in vitro. Materials: Cellular uptake and intracellular distribution of Ce6 in 4T1 cells were detec
PMID 24206161

Radiation-induced cytochrome c release and the neuroprotective effects of the pan-caspase inhibitor z-VAD-fmk in the hypoglossal nucleus.

Li J1, Wang Y2, DU L2, Xu C2, Cao J2, Wang Q2, Liu Q2, Fan F2.Author information 1Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Nankai, Tianjin 300192, P.R. China ; Department of Human Anatomy, The Medical School of Inner Mongolia University for the Nationalities, Tongliao, Neimenggu 028041, P.R. China.2Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Nankai, Tianjin 300192, P.R. China.AbstractNumerous studies have demonstrated that neuronal cell death occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Radiation induces caspase activation fundamentally via the mitochondrial pathway. To investigate the role of caspase, a cell permeable pan-caspase inhibitor, z-VAD-fmk [N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone], was used to investigate the effects of caspase blockade in vivo following irradiation. Adult male Sprague-Dawley rats (weight, 250-300 g) underwent irradiation at room temperature with a 4-Gy dose of radiation. Since z-VAD-fmk does not penetrate the blood-brain barrier, it was applied intracerebroventricularly via a bolus injection (0.2 μg/h for 1 h). Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) demonstrated that z-VAD-fmk reduced the numbers of TUNEL-positive cells within the hypoglossal nucleus, suggesting that intervention in the caspase cascade following radiation may have therapeutic applications. The caspase inhibitor z-VAD-fmk reduced the expression and activation of caspase-3, caspase-8 and caspase-9 in the irradiated rats, indicating that caspase may be a potential therapeutic target in the treatment of brain radiation injury. Treatment with z-VAD-fmk also reduced the appearance of cytochrome c within the cytosolic fraction following radiation. The hypoglossal nucleus may be used as a model of radiation-induced injury in the central nervous system, providing visual information and displaying apoptotic nuclear morphology.
Experimental and therapeutic medicine.Exp Ther Med.2014 Feb;7(2):383-388. Epub 2013 Nov 20.
Numerous studies have demonstrated that neuronal cell death occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Radiation induces caspase activation fundamentally via the mitochondrial pathway. To investigate the role of caspase, a cell permeable pan-caspase inhibitor, z-VA
PMID 24396410

Japanese Journal

Augmentation of RANKL-induced osteoclast differentiation by Z-VAD-fmk, a pan-caspase inhibitor

Katao Yuko,Sawai Hirofumi,Shishido Mika,Omae Aki,Liao Wen,Inami Kaoru,Matsumoto Naoyuki
Journal of Osaka Dental University 47(1), 41-46, 2013-04
… In contrast with the previous report, co-treatment with Z-VAD-fmk, a pan-caspase inhibitor, augmented RANKL-induced osteoclast differentiation in RAW264 cells. … Augmentation of RANKL-induced osteoclast differentiation by Z-VAD-fmk was also detected in mouse bone marrow macrophages. …
NAID 110009603277

Phaseoloideside E, a Novel Natural Triterpenoid Saponin Identified From Entada phaseoloides, Induces Apoptosis in Ec-109 Esophageal Cancer Cells Through Reactive Oxygen Species Generation

Mo Shasha,Xiong Hui,Shu Guangwen,Yang Xinzhou,Wang Jianxia,Zheng Congyi,Xiong Wei,Mei Zhinan
Journal of Pharmacological Sciences 122(3), 163-175, 2013
… Further investigations revealed that PE reduced the ratio of Bcl-2 to Bax and increased the activities of caspase-3 and -9, but this was prevented by Z-VAD-fmk. …
NAID 130003362717

Sulphur Antioxidants Inhibit Oxidative Stress Induced Retinal Ganglion Cell Death by Scavenging Reactive Oxygen Species but Influence Nuclear Factor (Erythroid-Derived 2)-Like 2 Signalling Pathway Differently

Majid Aman Shah Abdul,Yin Zheng Qin,Ji Dan
Biological and Pharmaceutical Bulletin 36(7), 1095-1110, 2013
… In addition, the pan caspase inhibitor, benzoylcarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk) attenuated the negative effect of serum deprivation while the necroptosis inhibitor (necrostatin-1) counteracted solely an insult of GB. …
NAID 130003361470