Aluminum bone toxicity in immature rats exposed to simulated high altitude

Aluminum (Al) is an element to which humans are widely exposed. Chronic administration induces a negative effect on bone tissue, affecting collagen synthesis and matrix mineralization. Its toxic effects are cumulative. Hypobaric hypoxia induces stress erythropoiesis, leading to hypertrophy of the erythropoietic marrow affecting the bone. This study was designed to evaluate the risk of Al bone toxicity among immature rats maintained at simulated high altitude (SHA) by mechanical assessment of stiffness and strength, calculation of some indicators of bone material and geometrical properties, as well as blood determinations. Forty growing rats were divided into control and experimental groups whether injected with vehicle or Al, as Al(OH)₃, three times a week for 3 months. Half of each group was exposed to hypobaric conditions (HX) by placing the animals in a SHA chamber. Both treatments negatively affected structural properties of bones, decreasing the maximum capacity to withstand load, the limit elastic load and the capacity of absorbing energy in elastic conditions. Al administration significantly depressed mandible structural stiffness, although diaphyseal stiffness was not modified. Indicators of bone material intrinsic properties, elastic modulus and stress, were significantly reduced by Al or HX. Treatments increased the diaphyseal sectional bending moment of inertia, suggesting that femur, but not mandible, compensates for the decline in the material properties with an adaptation of its architecture to maintain structural properties. The different biomechanical behaviors between the two kinds of bone are probably due to their different embryological origin and specific functions, as mandible is a bone that adjusts its strength to biting forces, whereas femur is designed to support load.     

Angiogenic and anti-angiogenic therapy for gastrointestinal ulcers: new challenges for rational therapeutic predictions and drug design

Gastrointestinal (GI) ulcers are essentially internal wounds that resist normal healing processes. Since their pathogenesis is poorly understood, and the etiologic (e.g., gastric acid, aspirin-like drugs, stress) and aggravating factors (e.g., H. pylori) are not well characterized, the remaining therapeutic option is to accelerate healing. Superficial mucosal lesions, i.e., erosions usually heal by epithelial regeneration and restitution, but when ulcers involve the muscularis propria, smooth muscle cells do not divide/regenerate. These deep lesions are filled by granulation tissue, i.e., angiogenesis followed by proliferation of connective tissue fibroblasts that deposit collagen over which adjacent surviving and dividing epithelial cells migrate to complete the healing. Our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the GI tract. Indeed, daily treatment of rats with bFGF, PDGF or VEGF markedly improved the healing of cysteamine-induced chronic duodenal ulcers, without any reduction in gastric acid secretion. These results were reproduced by a single dose of gene therapy by adenoviral vectors encoding PDGF or VEGF genes. The molar potency of angiogenic growth factors was 2-7 million times better than the antiulcerogenic effect of antisecretory H2 antagonists. Since histologically & pathologically gastroduodenal ulcers look similar to ulcers in the lower GI tract, we also predicted that the healing of experimental ulcerative colitis might be also improved by these angiogenic growth factors. Rectal enemas containing bFGF or PDGF indeed accelerated the healing of chemically induced ulcerative colitis in rats. VEGF, also known as VPF (vascular permeability factor), however, had no effect or slightly aggravated the colonic lesions. Injection of anti-VEGF neutralizing antibodies, however, counteracted the increased vascular permeability in the early stages of experimental ulcerative colitis and subsequently decreased the number of inflammatory cells in colonic ulcers in rats, resulting in significantly improved healing in the lower GI tract lesions. Thus, the three angiogenic growth factors tested exerted beneficial effect on gastroduodenal ulcers, and rectal enemas with bFGF or PDGF also accelerated the healing of experimental ulcerative colitis. Surprisingly, we achieved the latter effect with anti-VEGF antibodies, most likely because of the pro-inflammatory actions of VEGF in the pathogenesis of ulcerative colitis.     

Damage of testicular cell macromolecules and reproductive capacity of male rats following co-administration of ethambutol, rifampicin, isoniazid and pyrazinamide

The necessity to minimize adverse effects of tuberculosis chemotherapy requires a comprehensive evaluation of the effects of antituberculosis drugs on the reproductive system and testicular cell macromolecules. The epidemiological situation of tuberculosis in Central and Eastern Europe is getting worse. Data on adverse effects of antituberculosis drugs are scare concerning particularly their effects on the reproductive system. The aim of the present study was to investigate the potential effect of ethambutol, rifampicin, isoniazid and pyrazinamide co-administration on lipid peroxidation, glutathione content and protein SH-groups, DNA fragmentation levels, the reproductive capacity of Wistar male rats and the antenatal development of their posterity. The rats (150-170 g) were divided into two groups: group I - received antituberculosis drugs suspended in 1% starch gel per os: ethambutol - 155 mg/kg b.w./day, rifampicin - 74.4 mg/kg b.w./day, isoniazid - 62 mg/kg b.w./day, pyrazinamide - 217 mg/kg b.w./day, group II (control) - received only starch gel in corresponding volumes. The contents of TBA-active compounds, glutathione and protein SH-groups in testis and sperm were determined spectrophotometrically, the DNA-fragmentation was determined using an UV transilluminator (BIORAD, USA), reproductive system indices were measured by standard methods. The co-administration of therapeutic doses of ethambutol, isoniazid, rifampicin and pyrazinamide to male rats during the period of spermatogenesis caused an increase in the rate of thiobarbituric acid reactive substances formation in testis and sperm, decrease of testis glutathione and protein SH-group contents, significant changes in DNA fragmentation, fatal decrease of male fertilizing capacity and fertility, and increase of pre- and post-implantation embryo lethality. The changes in reproductive indices could be the result of direct or indirect effects of one or more drugs investigated.