Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary ...morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 μM CisPt challenged myotubes (4 h–8 h) before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Differently, 25 mM taurine pretreatment rescues the majority of myotubes size upon 50 μM CisPt at 24 h. Taurine appears to counteract atrophy by restoring regular microtubular apparatus and mitochondria and reducing the overload and the localization of autophagolysosomes. Such a promising taurine action in preventing atrophy needs further molecular and biochemical studies to best define its impact on muscle homeostasis and the maintenance of an adequate skeletal mass in vivo.
Mercury represents an ubiquitous environmental toxic metal. Heat shock proteins (HSP) and metallothioneins (MTs) help to protect cells against metal toxicity. Schisandrin B (Sch B), a lignoid from
...Schisandra chinensis, has been successfully used to treat hepatitis, but its effect against mercury hepatotoxicity remains unknown. We analyzed whether Sch B could protect rat liver against mercuric chloride (HgCl
2) intake by analyzing stress proteins and histopathological changes.
Wistar rats were administered Sch B (10
mg/kg/day by gavage) or vehicle (olive oil) for 10
days. A subset of each group also received low-dose HgCl
2 (0.1
mg/kg/day) for 3
days on days 8–10. Another group received Sch B for 10
days with a single high dose of HgCl
2 (1
mg/kg intraperitoneally) on day 10.
In rats treated with Sch B and HgCl
2, HSP72, HSP25 and MTs were overexpressed in liver zones 1 and 3 irrespective of HgCl
2 dosing schedules. Furthermore Sch B alone induced perinuclear rough endoplasmic reticulum alignment and if associated to HgCl
2, increased mitochondrial density and dense bodies, all signs of intense detoxification machinery. Taking together these data suggest that dietary Sch B counteracts HgCl
2 hepatotoxicity in the rat by stimulating chaperones responsible for anabolic activity.
Aluminium (Al) is a ubiquitous metal that is potentially toxic to the brain. Its effects on other fundamental organs are not completely understood. This morphological in vivo study sought to compare ...sublethal hepatotoxic changes and Al deposition in adult mice that orally ingested Al sulphate daily for 10 months, in age matched control mice that drank tap water and in senescent mice (24 months old). Livers were examined for collagen deposition using Sirius red and Masson, for iron accumulation using Perls’ stain. Light, electron microscopy and morphometry were used to assess fibrosis and vascular changes. Scanning transmission electron microscopy and EDX microanalysis were used to detect in situ elemental Al. Iron deposition, transferrin receptor expression were significantly altered following Al exposure and in the aged liver but were unaffected in age matched control mice. In Al treated mice as in senescent mice, endothelial thickness was increased and porosity was decreased like perisinusoidal actin. Furthermore, Al stimulated the deposition of collagen and laminin, mainly in acinar zones 1 and 3. Pseudocapillarization and periportal laminin in senescent mice were similar to Al treated adult liver. In conclusion, prolonged Al sulphate intake accelerates features of senescence in the adult mice liver.
Abstract Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effects in several organs, but its impact on the heart is still controversial. Small heat shock ...proteins (sHSPs), such as HSP25 and alpha B-crystallin, are cytoprotective stress proteins exceptionally represented in the heart. They act as myofibrillar chaperones that help actin and desmin to maintain their optimum configuration and stability, thereby antagonizing oxidative damage. The present study examined: (1) the cardiac distribution and abundance of HSP25 and alpha B-crystallin in rats receiving CsA at a therapeutic dosage (15 mg/kg/day) for 42 days and 63 days; (2) the presence of myofibrillar proteins, such as actin, alpha-actinin and desmin following the CsA treatments; (3) the subcellular effects of prolonged CsA exposure on the cardiomyocytes by histopathology and transmission electron microscopy. After 63 days CsA intake, sHSPs translocated from a regular sarcomeric pattern to peripheral sarcolemma and intercalated discs, together with actin and desmin. In contrast, the sarcomeric alpha-actinin pattern did not change in all experimental groups. The abundance of actin and HSP25 was unchanged in every time point of treatment while after 63 days CsA, alpha B-crystallin and desmin levels significantly decreased. Furthermore CsA induced fibrosis, irregular sarcomeric alignment and damaged desmosomes. These findings indicate that following prolonged CsA exposure, the cardiac muscle network was affected. In particular, the translocation of sHSPs to intercalated discs merits special consideration as a direct compensatory mechanism to limit CsA cardiotoxicity.
Stress proteins such as HSP70 members (HSP72 and GRP75) and metallothionein (MT) protect the kidney against oxidative damage and harmful metals, whereas inducible nitric oxide synthase (iNOS) ...regulates tubular functions. A single dose of mercuric chloride (HgCl2) can cause acute renal failure in rats, its main target being the proximal tubule. Oxidative damage has been proposed as one of its pathogenic mechanisms. In this study we tested whether melatonin (MEL), a powerful antioxidant compound, is effective against HgCl2 nephrotoxicity. Rats were treated with saline, HgCl2 (3.5 mg/kg), MEL (5 mg/kg), and MEL + HgCl2 and examined after 24 hr for HSP72, GRP75, MT, and iNOS by immunohistochemistry and immunoblotting. Tubular effects of the treatment were then characterized by ultrastructure. In the HgCl2 group, all markers were overexpressed in convoluted proximal tubules and sometimes in distal tubules. In the MEL + HgCl2 group, GRP75 and iNOS decreased in convoluted and straight proximal tubules, whereas HSP72 and MT persisted more than the saline and MEL-only groups. Tubular damage and mitochondrial morphometry were improved by MEL pretreatment. In conclusion, the beneficial effect of MEL against HgCl2 nephrotoxicity was outlined morphologically and by the reduction of the tubular expression of stress proteins and iNOS. These markers could represent sensitive recovery index against mercury damage. (J Histochem Cytochem 54:1149-1157, 2006)
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