Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacological management of heart failure has evolved during the last decade from therapies focused on improving haemodynamics to others that modulate neurohormonal systems which are activated in the setting of left ventricular dysfunction. Despite optimal inhibition of these systems with drugs such as ACE inhibitors, beta-blockers, digoxin and, most recently, spironolactone, the mortality rate remains unacceptably high. Calcium antagonists have long been investigated for use in a variety of cardiovascular diseases, including ischaemic heart disease, hypertension, and heart failure. However, concern has arisen with regard to the use of calcium antagonists in the treatment of left ventricular dysfunction--particularly those agents with negative inotropic activity. In addition, first generation dihydropyridines have also generated concern because of their profound vasodilatory effects and the fact that they have been shown to increase noradrenaline (norepinephrine) levels and neurohormonal activity. The third generation dihydropyridine calcium antagonists appear to be more promising therapies for heart failure, given their pharmacological properties of higher vascular selectivity and their minimal effects on neurohormonal activation. Several trials have been conducted with third generation dihydropyridines and additional trials are ongoing. A new class of calcium antagonists, which blocks the T-type calcium channel, was introduced in 1998. The prototype drug, mibefradil, was rigorously tested for use in heart failure in the Mortality Assessment in Congestive Heart Failure (MACH-1) trial. It was expected that calcium antagonists blocking the T-type calcium channel would be of benefit, because of their lack of negative inotropic effects and their ability to induce regression of hypertrophy. The results of the MACH-1 trial were disappointing, and the trial was prematurely discontinued as a result of excess mortality in the mibefradil arm. The purpose of this review is to examine the evidence-based pharmacotherapeutic strategies in the management of heart failure, and to discuss current and potential roles for calcium antagonists in the therapeutic regimen.
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PMID:[Calcium antagonists in the treatment of heart failure. Re-evaluation of therapeutic strategies]. 1100 55

A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-alpha or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-alpha, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
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PMID:Apoptosis and heart failure: mechanisms and therapeutic implications. 1472 98

Phytochemicals in some foods are a potential source of bioactive safe compounds for cancer chemoprevention and suppression of tumor initiation, promotion, and metastasis. In the present study, we evaluated hot water (HWE), microwaved 50% ethanol (MWE), acidic (ACE), and alkaline (AKE) extracts of the fruitbody (sporocarp) of Hericium erinaceus (Yamabushitake, Lion's Mane) mushrooms for their ability to induce apoptosis (programmed cell death) in U937 human monocytic leukemia cells. Cell culture, cell viability, cytotoxicity, flow cytometry, chromosomal DNA integrity, mitochondrial membrane potential, expression of pro- and anti-apoptotic proteins, and activation and inhibition of caspase assays were carried out to help define the mechanism of observed apoptosis. The aqueous and aqueous/ethanolic extracts were active in all assays, whereas the acidic and alkaline extracts with the similar proximate compositions were both inactive. The results of the bioassays with the active extracts are consistent with an apoptosis mechanism governing suppression of the cell proliferation pathway that involves activation of mitochondria-mediated caspase-3 and caspase-9 but not caspase-8. Proximate analysis of the freeze-dried mushroom powder showed that it contains high amounts of proteins, carbohydrates, and minerals. The results indicate that H. erinaceus mushrooms may have therapeutic potential against human leukemia.
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PMID:Mechanism of Hericium erinaceus (Yamabushitake) mushroom-induced apoptosis of U937 human monocytic leukemia cells. 2177 73