Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.
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PMID:Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. 1151 46

Dysfunction of the heterogeneous ribonucleoprotein TAR DNA binding protein 43 (TDP-43) is associated with neurodegeneration in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we examine the effects of a series of 4-aminoquinolines with affinity for TDP-43 upon caspase-7-induced cleavage of TDP-43 and TDP-43 cellular function. These compounds were mixed inhibitors of biotinylated TG6 binding to TDP-43, binding to both free and occupied TDP-43. Incubation of TDP-43 and caspase-7 in the presence of these compounds stimulated caspase-7 mediated cleavage of TDP-43. This effect was antagonized by the oligonucleotide TG12, prevented by denaturing TDP-43, and exhibited a similar relation of structure to function as for the displacement of bt-TG6 binding to TDP-43. In addition, the compounds did not affect caspase-7 enzyme activity. In human neuroglioma H4 cells, these compounds lowered levels of TDP-43 and increased TDP-43 C-terminal fragments via a caspase-dependent mechanism. Subsequent experiments demonstrated that this was due to induction of caspases 3 and 7 leading to increased PARP cleavage in H4 cells with similar rank order of the potency among the compounds tests for displacement of bt-TG6 binding. Exposure to these compounds also reduced HDAC-6, ATG-7, and increased LC3B, consistent with the effects of TDP-43 siRNA described by other investigators. These data suggest that such compounds may be useful biochemical probes to further understand both the normal and pathological functions of TDP-43, and its cleavage and metabolism promoted by caspases.
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PMID:Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function. 2265 71

Oxidative stress plays a central role in the common pathophysiology of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases. Compounds derived from natural sources may offer the potential for new treatment options. Semen Celosiae is a traditional Chinese edible herbal medicine with a long history in China and exhibits wide-reaching biological activities such as hepatoprotective, anti-tumor, anti-diarrheal, anti-diabetic, anti-oxidant, etc. In this study, nine saponins and two phenylacetonitrile glycosides were isolated from Semen Celosiae and their structures were identified using ESI-MS and NMR techniques. Among them, compounds 1 and 2 have not been previously reported. The total concentrations of the five triterpenoid saponins and the two phenylacetonitrile glycosides were 3.348 mg g-1 and 0.187 mg g-1, respectively, suggesting that Semen Celosiae is a novel viable source of the two kinds of compounds. These compounds were observed to significantly attenuate t-BHP-induced neuronal damage by effectively enhancing cell viability and decreasing reactive oxygen species generation and cell apoptosis rate in NSC-34 cells. Furthermore, compounds 1 and 7 reduced the ratios of cleaved caspase-3: caspase-3 and cleaved caspase-7: caspase-7 and the level of cytochrome C, while they increased the levels of SOD1 and Beclin 1. These findings suggest that compounds 1-11 are potent inhibitors of neuron injury elicited by t-BHP, possibly via inhibition of oxidative stress and apoptosis, and activation of autophagy; therefore they may be valuable leads for future therapeutic development.
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PMID:Chemical compounds with a neuroprotective effect from the seeds of Celosia argentea L. 3319 16