S-CMC-Lys-dependent stimulation of electrogenic glutathione secretion by human respiratory epithelium.

Glutathione (GSH) is one of the most important defense mechanisms against oxidative stress in the respiratory epithelial lining fluid. Considering that GSH secretion in respiratory cells has been postulated to be at least partially electrogenic, and that the mucoregulator S-carbocysteine lysine salt monohydrate (S-CMC-Lys) can cause an activation of epithelial Cl(-) conductance, the purpose of this study was to verify whether S-CMC-Lys is able to stimulate GSH secretion. Experiments have been performed by patch-clamp technique, by high-performance liquid chromatography (HPLC) assay, and by Western blot analysis on cultured lines of human respiratory cells (WI-26VA4 and CFT1-C2). In whole-cell configuration, after cell exposure to 100 microM S-CMC-Lys, a current due to an outward GSH flux was observed, which was inhibitable by 5-nitro-2-(3-phenylpropylamino)-benzoate and glibenclamide. This current was not observed in CFT1-C2 cells, where a functional cystic fibrosis transmembrane conductance regulator (CFTR) is lacking. Inside-out patch-clamp experiments (GSH on the cytoplasm side, Cl(-) on the extracellular side) showed the activity of a channel, which was able to conduct current in both directions: the single channel conductance was 2-4 pS, and the open probability (P(o)) was low and voltage-independent. After preincubation with 100 microM S-CMC-Lys, there was an increase in P(o), in the number of active channels present in each patch, and in the relative permeability to GSH vs Cl(-). Outwardly directed efflux of GSH could also be increased by protein kinase A, adenosine 5'-triphosphate, and cyclic adenosine monophosphate (cAMP) added to the cytoplasmic side (whole-cell configuration). The increased secretion of GSH observed in the presence of S-CMC-Lys or 8-bromoadenosine-3',5'-cyclic monophosphate was also confirmed by HPLC assay of GSH on a confluent monolayer of respiratory cells. Western blot analysis confirmed the presence of CFTR in WI-26VA4 cells. This study suggests that S-CMC-Lys is able to stimulate a channel-mediated GSH secretion by human respiratory cells: electrophysiological and pharmacological characteristics of this channel are similar to those of the CFTR channel.

Phenotypic differentiation during migration of dopaminergic progenitor cells to the olfactory bulb.

A possible source for transplantable neurons in Parkinson's disease are adult olfactory bulb (OB) dopamine (DA) progenitors that originate in the anterior subventricular zone and reach the OB through the rostral migratory stream. We used adult transgenic mice expressing a lacZ reporter directed by an 8.9 kb tyrosine hydroxylase (TH) promoter to investigate the course of DAergic differentiation. Parallel transgene and intrinsic TH mRNA expression occurred during migration of DA interneurons through the mitral and superficial granule cell layers before these cells reached their final periglomerular position. Differential transgene and calcium-calmodulin-dependent protein kinase IV expression distinguished two nonoverlapping populations of interneurons. Transgenic mice carrying a TH8.9kb/lacZ construct with a mutant AP-1 site demonstrated that this element confers OB DA-specific TH gene regulation. These results indicate that DA phenotypic determination is specific to a subset of mobile OB progenitors.

Ion transport across the gallbladder epithelium.

The function of the gallbladder is not only to store bile, but also to concentrate it during the interdigestive phase by means of salt-dependent water reabsorption. On the contrary, secretions of water and salt take place during the digestive phase. Dysregulation of ion absorption or secretion are common in many gallbladder diseases, such as colelithiasis. Transepithelial absorptions are determined by the Na+/K+ pump on the basolateral membrane, and by several apical membrane Na(+)-coupled transporters. Among these, some isoforms of Na+/H+ and Cl-/HCO3(-) exchangers have been studied. The presence of a Na(+)-Cl(-) simport has been molecularly and functionally characterized in some animal species. The ion transepithelial secretion is mainly dependent on an apical chloride transport attributable to a CFTR-like cAMP-activated channel with high permeability to HCO3(-). The apical membrane electrical potential is one of the factors influencing anion secretion and is maintained by the activity of cAMP-dependent K+ channels. The regulation of the activity of these channels is complex, because of their sensitivity to voltage, and to intracellular calcium and pH. The coordinated interplay underlying the regulation of transporters and channels needs to be clarified yet, as well as the interactions between transporters, channels and aquaporins.

Clinical study of niceritrol on serum lipids in the treatment of hyperlipidemia.

The effects of niceritrol, a nicotinic acid derivative, on the levels of HDL-cholesterol (HDL-Ch) and a mixture of VLDL- and LDL-Ch (VLDL- + LDL-Ch) were studied in hyperlipidemic patients. Serum total cholesterol (sTC) and serum triglyceride (sTG) were significantly reduced during niceritrol administration. Lipoprotein electrophoresis showed that niceritrol increased the alpha:beta ratio. HDL-Ch showed a significant increase of 12.5% by the 16th week of therapy. This increase was more marked in patients with lower pre-treatment HDL-Ch levels and significant in patients whose pre-treatment sTG levels were in excess of 200 mg/dl. Females displayed higher pre-treatment HDL-Ch levels (38.5 mg/dl) than males (30.6 mg/dl). However, niceritrol increased HDL-Ch significantly in both groups. At 16 weeks, the VLDL- + LDL-Ch level showed a significant decrease of 9.2%; the HDL-Ch:VLDL + LDL-Ch and HDL-CH:sTC ratios were significantly increased throughout niceritrol administration. Niceritrol is thought to be effective in preventing the development and progression of atherosclerosis because it raises the level of anti-atherogenic HDL-Ch and lowers the level of atherogenic VLDL- + LDL-Ch.

Multiple gastric carcinoids and pituitary adenoma in type A gastritis.

A 48-year-old male with type A atrophic gastritis developed multiple gastric carcinoids and a pituitary adenoma. Laboratory tests revealed high levels of serum gastrin and growth hormone (GH). He underwent subtotal gastrectomy, resulting in a return of the previously elevated gastrin level to normal. Serum GH concentration remained high. Three months after the surgery, the pituitary tumor, composed greatly of GH-immunoreactive cells, was partially removed. Since hypergastrinemia plays a pivotal role in gastric carcinoid formation and induces GH-releasing factor (GHRH) release resulting in GH-producing pituitary tumor formation, GH-producing pituitary adenoma might be a clinical manifestation in type A gastritis.

The ICln interactome.

The many different functional phenotypes described in mammalian cells can only be explained by an intense interaction of the underlying proteins, substantiated by the fact that the number of independently expressed proteins in living cells seems not to exceed 25 K, a number way too small to explain the >250 K different phenotypes on a one-protein-one-function base. Therefore, the study of the interactome of the different proteins is of utmost importance. Here, we describe the present knowledge of the ICln interactome. ICln is a protein, we cloned and whose function was reported to be as divers as (i) ion permeation, (ii) cytoskeletal organization, and (iii) RNA processing. The role of ICln in these different functional modules can be described best as being a 'connector hub' with 'date hub' function.

Myocardial sarcoidosis with a tumor-like left atrial thrombus.

We report here an elderly woman who started vague complaints around the age of 50, was proved to be a sarcoidosis by negative skin reaction with purified protein derivative, bilateral hilar lymphadenopathy, and sarcoid lesions in biopsied liver and lymph nodes, and died of cardiac insufficiency after 15 years of the illness. Necropsy revealed a huge tumor-like left atrial thrombus with nonspecific fibrous lesions throughout the myocardium, a pulmonary hamartoma, pneumonia, liver cell necrosis, and cholecystopathy. To our knowledge, this may be the first case of myocardial sarcoidosis associated with this kind of atrial thrombus, although the sarcoidosis and thrombus may have occurred independently.