Chronic Alcohol Ingestion Enhances Tumor Necrosis Factor-α Expression and Salivary Gland Apoptosis

We investigated the extent of induction in sublingual salivary gland cells apoptosis and tumor necrosis factor-α (TNF-α) expression with chronic ethanol ingestion. The experiments were conducted on rats pair-fed for 8 weeks with alcohol-containing and control liquid diet. The animals were killed, their sublingual glands dissected, and the glandular tissue used for quantitization of TNF-α expression and the assays of acinar cells apoptosis employing sandwich enzyme immunoassay for histone-associated DNA fragments. The mean value for TNF-α in sublingual gland of the control group was 22.3 pg/mg of protein and showed a 1.6-fold increase in the chronic ethanol diet group to 36.5 pg/mg of protein. In comparison with the controls, the sublingual gland of the chronic ethanol diet group also exhibited a 3.4-fold enhancement in acinar cell apoptosis. These findings suggest that chronic ethanol ingestion causes the enhancement in TNF-α expression and leads to the induction in salivary gland acinar cells apoptosis. Thus, the diminished secretion of saliva in alcoholics may be a direct result of increased salivary gland apoptosis.     

Participation of Phosphoinositides in Gastric Mucosal Protection by Colloidal Bismuth Subcitrate against Ethanol-Induced Injury

The mechanism of gastric mucosal protection by an antiulcer agent, colloidal bismuth subcitrate (CBS), against ethanol-induced injury was investigated using in vivo and in vitro systems. The experiments in vivo were conducted with groups of rats with and without indomethacin pretreatment, and the animals received either a dose of CBS (100 mg/kg) or a vehicle (saline), followed 30 min later by ethanol. In the in vitro studies, gastric mucosa segments were cultured in the presence of CBS, ethanol, or both. The results of in vivo experiments revealed that in the absence of CBS, ethanol caused extensive gastric hemorrhagic lesions which were significantly reduced following CBS pretreatment and this effect of CBS was not prevented by indomethacin. The data obtained with gastric mucosal culture established that in comparison to the controls, ethanol caused a 27% decrease in mucin synthesis, while mucin synthesis in the presence of CBS increased by 48%. The increase in mucin synthesis evoked by CBS was accompanied by the enhanced metabolism of mucosal phosphoinositides, as reflected by a decrease in PI (15%) and PIP2 (30%), and an increase in IP1 (26%) and IP3 (67%). In contrast, ethanol, which exhibited detrimental effect on mucin synthesis, caused a decrease in PIP (35%), IP2 (47%) and IP3 (38%), and an increase in PIP2 (80%), and IP1 (51%). However, when the mucosal culture was carried out in the presence of both CBS and ethanol, the detrimental changes evoked by ethanol on mucin synthesis were prevented, and the phosphoinositide and inositide phosphate distribution patterns were quite similar to those in the mucosa cultured in the presence of CBS only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome

The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer-associated systemic syndrome (CASS) and prevented death in tumor-bearing mice. Surprisingly, VEGFR2 blockage improved survival by rescuing mice from CASS without significantly compromising tumor growth, suggesting that “off-tumor” VEGF targets are more sensitive than the tumor vasculature to anti-VEGF drugs. Similarly, VEGF-induced CASS occurred in a spontaneous breast cancer mouse model overexpressing neu. Clinically, VEGF expression and CASS severity positively correlated in various human cancers. These findings define novel therapeutic targets of anti-VEGF agents and provide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.     

Glutathione and glutathione peroxidase activities in blood of patients in early stages following kidney transplantation

This study focuses on glutathione (GSH) level in red blood cells, as well as on glutathione peroxidases (GSH-Px) activities in red blood cells and in plasma of chronic renal failure (CRF) patients following renal transplantation. We want to focus our main attention on plasma GSH-Px, the selenoenzyme that is synthesized primarily in the kidney. In CRF patients, activity of this enzyme is significantly reduced, and the reduction decreases with the progress of the disease, reaching in the end-stage 20% to 30% of the activity of healthy patients. We have shown that following renal transplantation the activity of plasma GSH-Px is restored very rapidly, and 2 weeks after surgery it reached the value of the control group. Red blood cell GSH level is significantly higher in CRF patients, and following transplantation, no significant changes were observed. Red blood cell GSH-Px activity before transplantation was the same as in healthy patients and did not change significantly after surgery.     

Neuromuscular response of young boys versus men during sustained maximal contraction

PURPOSE: This study was designed to compare neuromuscular response between boys and men during sustained maximal voluntary contraction (MVC). METHODS: Fifteen boys (YB, 10.5 +/- 0.9 yr) and 12 men (AM, 21.5 +/- 4.5 yr) participated in the experiment. Arm's cross sectional area (CSA) and maximal force (F(max)) of elbow flexor were measured before subjects performed a 30-s sustained MVC. Mean power frequency (MPF) and muscle fiber conduction velocity (MFCV) were calculated from myoelectric signals of the biceps brachii. F(max)/CSA, MPF, and MFCV changes were expressed by slopes of linear regressions. Maximal MPF (I-MPF) and MFCV (I-MFCV) were derived from the intercept of each regression. RESULTS: AM had significantly greater F(max)/CSA (P < 0.05), I-MPF (P < 0.05), and I-MFCV (P < 0.01) than YB. F(max)/CSA (P < 0.001), MPF (P < 0.001), and MFCV (P < 0.01) declined significantly more for AM than YB. MPF/MFCV ratio increased, i.e., MPF decreased more than MFCV, for both groups but this was significantly (P < 0.001) more pronounced for AM. CONCLUSION: Taken together, those results suggest that more fatigable Type II motor units are involved in men, resulting in greater lactic acid and ions accumulations during fatigue. This difference in muscle's metabolic and ionic state could be responsible for a greater reflex-induced decrease of motor units firing rates in men compared with boys. This firing rate decrease could be explained using the "muscular wisdom" hypothesis and would express a nervous command adaptation to sustain a maximal contraction.     

Zur Phylotektonik der respiratorischen Muskulatur der Reptilien und S?ugetiere

Ohne ZusammenfassungMit 8 Textabbildungen     

Natural and Prosthetic Heart Valve Calcification: Morphology and Chemical Composition Characterization

Calcification is the most common cause of damage and subsequent failure of heart valves. Although it is a common phenomenon, little is known about it, and less about the inorganic phase obtained from this type of calcification. This article describes the scanning electron microscopy (SEM)/energy dispersive X‐ray spectroscopy and Ca K‐edge X‐ray absorption near edge structure (XANES) characterization performed in natural and bioprosthetic heart valves calcified in vivo (in comparison to in vitro‐calcified valves). SEM micrographs indicated the presence of deposits of similar morphology, and XANES results indicate, at a molecular level, that the calcification mechanism of both types of valves are probably similar, resulting in formation of poorly crystalline hydroxyapatite deposits, with Ca/P ratios that increase with time, depending on the maturation state. These findings may contribute to the search for long‐term efficient anticalcification treatments.     

Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.     

Fetal stromal-dependent paracrine and intracrine vascular endothelial growth factor-a/vascular endothelial growth factor receptor-1 signaling promotes proliferation and motility of human primary myeloma cells

Induction of neoangiogenesis plays an important role in the pathogenesis of multiple myeloma. However, the mechanism by which expression of vascular endothelial growth factor (VEGF)-A and its receptors modulate the interaction of multiple myeloma cells with stromal cells is not known. Here, we describe a novel in vitro coculture system using fetal bone stromal cells as a feeder layer, which facilitates the survival and growth of human primary multiple myeloma cells. We show that stromal-dependent paracrine VEGF-A signaling promotes proliferation of human primary multiple myeloma cells. Primary multiple myeloma cells only expressed functional VEGF receptor (VEGFR)-1, but not VEGFR-2 or VEGFR-3. VEGFR-1 expression was detected in the cytoplasm and the nuclei of proliferating multiple myeloma cells. Inhibition of VEGFR-1 abrogated multiple myeloma cell proliferation and motility, suggesting that the functional interaction of VEGF-A with its cognate receptor is essential for the growth of primary multiple myeloma cells. Collectively, our results suggest that stromal-dependent paracrine and intracrine VEGF-A/VEGFR-1 signaling contributes to human primary multiple myeloma cell growth and therefore, VEGFR-1 blockade is a potential therapeutic strategy for the treatment of multiple myeloma.     

Vascular Endothelial Growth Factor Receptor-3 Mediates Induction of Corneal Alloimmunity

There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery.