We have identified and characterized Mtd, a novel regulator of apoptosis. Sequence analysis revealed that Mtd is a member of the Bcl-2 family of proteins containing conserved BH1, BH2, BH3, and BH4 regions and a carboxyl-terminal hydrophobic domain. In adult tissues, Mtd mRNA was predominantly detected in the brain, liver, and lymphoid tissues, while in the embryo Mtd mRNA was detected in the liver, thymus, lung, and intestinal epithelium. Expression of Mtd promoted the death of primary sensory neurons, 293T cells and HeLa cells, indicating that Mtd is a proapoptotic protein. Unlike all other known death agonists of the Bcl-2 family, Mtd did not bind significantly to the survival-promoting proteins Bcl-2 or Bcl-X L . Furthermore, apoptosis induced by Mtd was not inhibited by Bcl-2 or Bcl-X L . A Mtd mutant with glutamine substitutions of highly conserved amino acids in the BH3 domain retained its ability to promote apoptosis, further indicating that Mtd does not promote apoptosis by heterodimerizing with Bcl-2 or Bcl-X L . Mtd-induced apoptosis was not blocked by broad range synthetic caspase inhibitors z-VAD-fmk or a viral protein CrmA. Mtd is the first example of a naturally occurring Bcl-2 family member that can activate apoptosis independently of heterodimerization with survival-promoting Bcl-2 and Bcl-X L .Apoptosis, a morphologically distinguished form of programmed cell death, is critical not only during development and tissue homeostasis but also in the pathogenesis of a variety of diseases (1). Several regulatory components of the apoptotic pathway have been identified in various living organisms, including man (1, 2). bcl-2, the first member of an evolutionary conserved family of apoptosis regulatory genes, was initially isolated from the t(14;18) chromosomal translocation found in human B-cell follicular lymphomas and was subsequently shown to repress cell death triggered by a diverse array of stimuli (3-6). Several members of the family, including Bcl-2 and Bcl-X L , share conserved regions termed Bcl-2 homology domains 1, 2, 3 and 4 (BH1, BH2, BH3, and BH4) and function by repressing apoptosis (for review, see Ref. 7). The biochemical process by which Bcl-2 family members regulate cell death are poorly understood. The crystal structures of human and rat Bcl-X L have revealed a significant similarity to the pore-forming domains of diphtheria toxin and bacterial colicins, suggesting that Bcl-2 family members could function as channels for ions, proteins, or both (8, 9). Experiments with synthetic membranes have shown that recombinant Bcl-2, Bcl-X L , and Bax exhibit ion channel activity, suggesting that Bcl-2-related proteins could regulate apoptosis by regulating trafficking of molecules through intracellular membranes (10 -12). However, the significance of these latter findings is unclear as there is no evidence that Bcl-2 or related proteins form ion-channels in vivo.Analyses of the nematode cell death regulators CED-3, CED-4, and CED-9 has provided important insight into the biochemical mechanism ...
The abnormalities underlying diabetic neuropathy appear to be multiple and involve metabolic neuronal and vasomediated defects. The accumulation of long-chain fatty acids and impaired  -oxidation due to deficiencies in carnitine and/or its esterified derivatives, such as acetyl-L -carnitine, may have deleterious effects. In the present study, we examined, in the diabetic bio-breeding Worcester rat, the shortand long-term effects of acetyl-L -carnitine administration on peripheral nerve polyols, myoinositol, Na ϩ /K ϩ -ATPase, vasoactive prostaglandins, nerve conduction velocity, and pathologic changes. Short-term prevention (4 mo) with acetyl-L -carnitine had no effects on nerve polyols, but corrected the Na ϩ /K ϩ -ATPase defect and was associated with 63% prevention of the nerve conduction defect and complete prevention of structural changes. Long-term prevention (8 mo) and intervention (from 4 to 8 mo) with acetyl-Lcarnitine treatment normalized nerve PGE 1 whereas 6-keto PGF 1 ␣ and PGE 2 were unaffected. In the prevention study, the conduction defect was 73% prevented and structural abnormalities attenuated. Intervention with acetyl-L -carnitine resulted in 76% recovery of the conduction defect and corrected neuropathologic changes characteristic of 4-mo diabetic rats. Acetyl-L -carnitine treatment promoted nerve fiber regeneration, which was increased two-fold compared to nontreated diabetic rats. These results demonstrate that acetyl-L -carnitine has a preventive effect on the acute Na ϩ / K ϩ -ATPase defect and a preventive and corrective effect on PGE 1 in chronically diabetic nerve associated with improvements of nerve conduction velocity and pathologic changes. (
Asthma represents a serious health problem particularly for inner city children, and recent studies have identified that cockroach allergens trigger many of these asthmatic attacks. This study tested the concept that asthma-like pulmonary inflammation may be induced by house dust containing cockroach allergens. An aqueous extract was prepared from a house dust sample containing endotoxin and high levels of cockroach allergens. BALB/c mice were immunized with the house dust extract (HDE) and received two additional pulmonary challenges. Bronchoalveolar lavage (BAL) eosinophil counts and eotaxin levels were significantly increased in immunized mice exposed to the HDE, whereas neutrophils were the predominant BAL inflammatory cell in the unimmunized mice. Kinetics studies in immunized mice demonstrated a peak pulmonary inflammatory response 48 h after the last challenge. The allergic response in this model was further confirmed by histological and physiological studies demonstrating a significant influx of eosinophils and lymphocytes in the peribronchial area, and severe airway hyperreactivity through whole-body plethysmography. The specificity of the response was established by immunizing with HDE and challenging with purified cockroach allergen, which induced pulmonary eosinophilia and airway hyperreactivity. Ab inhibition of eotaxin significantly inhibited the number of BAL eosinophils. These data describe a novel murine model of asthma-like pulmonary inflammation induced by house dust containing endotoxin and cockroach allergens and further demonstrate that eotaxin represents the principal chemoattractant for the recruitment of the pulmonary eosinophils.
These findings indicate that retinal ET-1, ET-3, ET(A) and ET(B) mRNA expression in increased in the chronically diabetic BB/W rat. Augmented gene expression of ETs and their receptors potentially may be of importance in the pathogenesis of retinal microangiopathy in diabetes.
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