BB-Cl-Amidine as a novel therapeutic for canine and feline mammary cancer via activation of the endoplasmic reticulum stress pathway
Melissa M. LedetRobyn AndersonRebecca M. HarmanAaron MuthPaul R. ThompsonScott A. CoonrodGerlinde R. Van de Walle
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Mammary cancer is highly prevalent in dogs and cats and results in a poor prognosis due to critically lacking viable treatment options. Recent human and mouse studies have suggested that inhibiting peptidyl arginine deiminase enzymes (PAD) may be a novel breast cancer therapy. Based on the similarities between human breast cancer and mammary cancer in dogs and cats, we hypothesized that PAD inhibitors would also be an effective treatment for mammary cancer in these animals.Canine and feline mammary cancer cell lines were treated with BB-Cl-Amidine (BB-CLA) and evaluated for viability and tumorigenicity. Endoplasmic reticulum stress was tested by western blot, immunofluorescence, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Canine and feline mammary cancer xenograft models were created using NOD scid gamma (NSG) mice, and were treated with BB-CLA for two weeks.We found that BB-CLA reduced viability and tumorigenicity of canine and feline mammary cancer cell lines in vitro. Additionally, we demonstrated that BB-CLA activates the endoplasmic reticulum stress pathway in these cells by downregulating 78 kDa Glucose-regulated Protein (GRP78), a potential target in breast cancer for molecular therapy, and upregulating the downstream target gene DNA Damage Inducible Transcript 3 (DDIT3). Finally, we established a mouse xenograft model of both canine and feline mammary cancer in which we preliminarily tested the effects of BB-CLA in vivo.We propose that our established mouse xenograft models will be useful for the study of mammary cancer in dogs and cats, and furthermore, that BB-CLA has potential as a novel therapeutic for mammary cancer in these species.Keywords:
Surgical oncology
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Abstract The testicular interstitial cells of mice contain an abundant agranular endoplasmic reticulum occurring as a network of interconnected tubules. Unusual features of the reticulum are occasional extensive whorls of concentric membranes and the occurrence of bundles of parallel double‐walled tubules. The mitochondria have tubular cristae and are occasionally very large. In contrast to the interstitial cells of other species that have been described, the mouse interstitial cells show a segregation of the cytoplasm into areas of dense agranular reticulum and other areas where the agranular reticulum is relatively sparse. The latter areas contain scattered cistenae of granular reticulum, many free ribosomes in clusters, mitochondria, lipid droplets and small granules. The mitochondria and lipid droplets are often encircled by cisternae of the reticulum. Biochemical evidence from other laboratories, taken with the present results, indicates that the membranes of the endoplasmic reticulum in mouse interstitial cells are the site of the enzymes that mediate the synthesis of testosterone from progesterone. There is also an indication that cholesterol biosynthesis is associated with the agranular reticulum. The membranes of the agranular reticulum may also serve as a reservoir for the storage of cholesterol.
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Objective To study the role of endoplasmetic reticulum in aluminium-induced apoptosis.Methods Neurons from 0-3 day newborn rats were cultured and treated with different concentration of aluminium chloride(AlCl_3).(1)Morphologic changes of neurons and endoplasmic reticulum were observed under light and transmission electron microscope;(2)Contents of apoptosis proteins,caspase and Ctyc in endoplasmic reticulum were measured.Results(1)Typical morphologic changes in neurons apoptosis and endoplamic reticulum were found under light and transmission electron microscope;(2)Active caspase-3 contents were significantly increased in Al-treated groups comparing with the control group(P0.01,r=0.902).There were significant higher CtyC contents in control group than those in Al-treated groups(P0.05).Conclusion Al may induce neurons apoptosis,and endoplasmic reticulum plays an important role in the apoptosis progression.
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健常者および諸種出血性素因患者血小板の微細構造を検索した. 1)健常者: granulomer αの大きさは平均長径0.23μ,短径0.15μで電子密度が高く,均質な基質を有する.ミトコンドリアは極めて小さく,二重の限界膜およびcristae mitochondriaiesを有する. endoplasmic reticulum, Golgi野の存在を確認した.いわゆる空胞の他に特異な空胞を認めた. 2)血小板無力症: granuleomer αの電子密度の増強及び変形, endoplasmic reticulumの腫脹増大などの変化が認められた. 3)血友病A: granulomer αの電子密度の増強および数の減少,ミトコンドリアの膨化および数の減少, endoplasmic reticulumの減少などの変化が認められた. 4)血友病B:一部血友病Aに共通した変化を有する他は健常者血小板により近い所見を有する. 5) Willebrand-Jürgens型出血性素因:本症に特異的と想われる所見は見出し得なかつた.
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Dense, homogeneous granules of 250 to 350 mµ in diameter have been found inside the cavities of the endoplasmic reticulum in the acinar cells of the pancreas of the guinea pig. They apparently correspond to the fine granules described in the same material in light microscopy by Mankowski and Bensley. The location of these granules indicates that the endoplasmic reticulum is a cavitary system and suggests its participation in secretory processes.
Exocrine pancreas
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ObjectiveTo investigate effects of iron on the endoplasm ic reticulum and mitochondria of the myocardial cells.MethodsTo use model of cultured fetal mouse heart,in v itro,the fetal mouse hearts were cultured in culture liquid with 140?μg FeSO 4/ml for 12?h. ResultsInjury of endoplasmic reticulum was ahead of mito chondria.Structure of mitochondria around endoplasmic reticulum damaged lightly was complete and their cristae were clear.However,cristae of mitochondria around endoplasmic reticulum damaged severely were unclear. ConclusionUnsynchronism injury of endoplasmic reticulum and mitochondria may be related to three-dimensional structure between two organ ellae and,to regulative disorder of Ca 2+ -ATPase between two organellae.
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Бұл зерттеужұмысындaКaно моделітурaлы жәнеоғaн қaтыстытолықмәліметберілгенжәнеуниверситетстуденттерінебaғыттaлғaн қолдaнбaлы (кейстік)зерттеужүргізілген.АхметЯссaуи университетініңстуденттеріүшін Кaно моделіқолдaнылғaн, олaрдың жоғaры білімберусaпaсынa қоятынмaңыздытaлaптaры, яғнисaпaлық қaжеттіліктері,олaрдың мaңыздылығытурaлы жәнесaпaлық қaжеттіліктерінеқaтыстыөз университетінқaлaй бaғaлaйтындығытурaлы сұрaқтaр қойылғaн. Осы зерттеудіңмaқсaты АхметЯсaуи университетіндетуризмменеджментіжәнеқaржы бaкaлaвриaт бaғдaрлaмaлaрыныңсaпaсынa қaтыстыстуденттердіңқaжеттіліктерінaнықтaу, студенттердіңқaнaғaттaну, қaнaғaттaнбaу дәрежелерінбелгілеу,білімберусaпaсын aнықтaу мен жетілдіружолдaрын тaлдaу болыптaбылaды. Осы мaқсaтқaжетуүшін, ең aлдыменКaно сaуaлнaмaсы түзіліп,116 студенткеқолдaнылдыжәнебілімберугежәнеоның сaпaсынa қaтыстыстуденттердіңтaлaптaры мен қaжеттіліктерітоптықжұмыстaрaрқылыaнықтaлды. Екіншіден,бұл aнықтaлғaн тaлaптaр мен қaжеттіліктерКaно бaғaлaу кестесіменжіктелді.Осылaйшa, сaпa тaлaптaры төрт сaнaтқa бөлінді:болуытиіс, бір өлшемді,тaртымдыжәнебейтaрaп.Соңындa,қaнaғaттaну мен қaнaғaттaнбaудың мәндеріесептелдіжәнестуденттердіңқaнaғaттaну мен қaнaғaттaнбaу деңгейлерінжоғaрылaту мен төмендетудеосытaлaптaр мен қaжеттіліктердіңрөліaйқын aнықтaлды.Түйінсөздер:сaпa, сaпaлық қaжеттіліктер,білімберусaпaсы, Кaно моделі.
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The electron microscope has been used to examine a diagnostic biopsy of frontal neocortex which showed the light microscopic features of Alzheimer's disease. In addition to plaques and tangles, the biopsy showed some neurons which contained abnormal tubular profiles specifically associated with their granular endoplasmic reticulum. In transverse section the profiles consisted of two concentric layers of trilaminar unit membrane with an overall diameter of approximately 75 nm and they appeared to lie within the cisternae of granular endoplasmic reticulum. When cut longitudinally, the structures appeared as elongated tubes lying within the endoplasmic reticulum, but a number of ends were found where the inner membrane formed a closed tube and the outer membrane folded back and was continuous with the membrane forming the outer layer of the sac of endoplasmic reticulum. These profiles do not appear to have been described previously although similarities between their ultrastructure and that of the coat of certain unusual forms of Rhabdovirus are noted.
Neocortex
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