Cyclosporine A (CsA) is the most widely used immunosuppressive drug for preventing graft rejection and autoimmune disease. However, the therapeutic treatment induces several side effects such as ...nephrotoxicity, cardiotoxicity, hypertension and hepatotoxicity. Among possible mechanisms of CsA-induced hepatic damage, oxidative stress has been suggested. Melatonin (Mel) has been successfully used as a potent antioxidant against many pathophysiological states. This experimental study was performed to test, during CsA treatment, the alterations of some heat shock proteins (HSP) and the Mel antioxidant properties against CsA-induced injury. Rats were divided into four groups, which were treated respectively with olive oil, Mel alone, CsA and CsA plus Mel for 30 days. At the end of the treatments, the animals were killed and hepatic tissue was treated for morphological (haematoxylin–eosin), biochemical (reduced glutathione, GSH and malondialdehyde, MDA) and immunohistochemical (HSP60, HSP72, GRP75 and MT) analyses. The results indicate that CsA-induced hepatotoxicity was characterised by morphological alterations in tissue architecture, changes in GSH and MDA levels and increase in stress protein expression. In conclusion, our data suggest that the imbalance between production of free oxygen radicals and antioxidant defence systems, due to CsA administration, is a mechanism responsible for oxidative stress. Moreover, we show that Mel plays a protective action against CsA-induced oxidative stress, as supported by biochemical and immunohistochemical results.
Abstract The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play ...crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice ( ob/ob ) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a dysregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.
This study evaluated the role of cyclophilin A (CyPA) in early phase of atherosclerosis and also examined the atheroprotective effects of melatonin due to its antioxidant properties.
APOE null mice ...at 6 and 15weeks of age were treated with melatonin at a dose of 0.1mg/kg/day or 10mg/kg/day. We evaluated both histopathological alterations in endothelial and vascular smooth muscle cells by CyPA and rolling mononuclear cell expression during the early phase of atherosclerosis development.
Our study showed that CyPA expression increases and may modulate inflammatory cell adhesion and interleukin-6 expression inducing vascular smooth muscle cell migration and inflammatory cell extravasation in a time-dependent manner. Moreover, we observed an indirect atheroprotective effect of melatonin on vascular injury; it inhibited CyPA mediated inflammatory cell extravasation and oxidative stress.
The melatonin treatment may represent a new atheroprotective approach that contributes to reducing the early phase of atherosclerosis involving the rolling of monocytes, their passage to subendothelial space and inhibition of CyPA expression.
Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain and an extensive array of other symptoms including disordered sleep, fatigue, depression and anxiety. Important ...factors involved in the pathogenic process of fibromyalgia are inflammation and oxidative stress, suggesting that ant-inflammatory and/or antioxidant supplementation might be effective in the management and modulation of this syndrome. Recent evidence suggests that melatonin may be suitable for this purpose due to its well known ant-inflammatory, antioxidant and analgesic effects. Thus, in the current study, the effects of the oral supplementation of melatonin against fibromyalgia-related skeletal muscle alterations were evaluated. In detail, 90 Sprague Dawley rats were randomly treated with reserpine, to reproduce the pathogenic process of fibromyalgia and thereafter they received melatonin. The animals treated with reserpine showed moderate alterations at hind limb skeletal muscles level and had difficulty in moving, together with significant morphological and ultrastructural alterations and expression of inflammatory and oxidative stress markers in the gastrocnemius muscle. Interestingly, melatonin, dose and/or time dependently, reduced the difficulties in spontaneous motor activity and the musculoskeletal morphostructural, inflammatory, and oxidative stress alterations. This study suggests that melatonin in vivo may be an effective tool in the management of fibromyalgia-related musculoskeletal morphofunctional damage.
Since lupus nephritis (LN) etiopathogenesis is not fully understood, herein we investigated the morphological basis of LN in mice induced with pristane.
To evaluate the melatonin effects in these ...animals, we studied the renal cytoarchitecture by means of morphological analyses, immunofluorescence expression of specific markers related to fibrosis, oxidative stress, inflammation and apoptosis.
We observed that pristane-LN mice have serious alterations in the kidney cytoarchitecture, i.e. tubular degeneration, glomerular hypercellularity, matrix mesangial expansion and interstitial inflammation. The pristane-induced LN mice treated with melatonin exhibited a well preserved cytoarchitecture.
Our results document that LN etiopathogenesis is related to both tubular damage and glomerular lesions. We suggest that it is essential to take in consideration both these lesions for LN diagnosis and classification. Clearly, we show that the use of melatonin may be a possible therapeutic strategy for improvement the renal injury in this disorder.
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Abstract only Adult obesity is a worldwide pandemic condition that leads to the metabolic syndrome and a spectrum of irreversible cardiovascular, neurological, renal and digestive morbidities and ...cardiovascular diseases represent the leading cause of death in obese people. Cardiomyocytes are particularly sensitive to oxidative damage due to the link between mitochondria and sarcoplasmic reticulum necessary for calcium flux and contraction. Melatonin, versatile and pleiotropic indoleamine with multiple actions, has also important cardioprotective properties. The present study defined mitochondria cardiomyocyte changes and relative oxidative stress pattern in ob/ob mice treated orally or not with melatonin at 100 mg/kg/day for 8 weeks. We observed that ob/ob mice mitochondria in cardiomyocytes sub-sarcolemmal and inter-myofibrillar compartments are often devoid of cristae and have an abnormal large size, so they are defined mega-mitochondria. Moreover, in ob/ob mice, we observed also alteration of peroxisome proliferator-activated receptor gamma coactivator-1α, protein that controls mitochondrial biogenesis, oxidative metabolism and inflammation, together with a deregulated endogenous antioxidant system, showing in particular altered heme oxygenase-1 cardyomiocyte expression. Melatonin oral treatment in ob/ob mice restores heart mitochondria and minimizes oxidative stress and inflammation. These preliminary data indicate a significant protective role of melatonin supplementation against obesity-related heart alterations.
Obesity is a worldwide epidemic disease that induces important structural and functional changes to the heart and predisposes a patient to devastating cardiac complications. Sirtuin1 (SIRT1) has been ...found to have roles in regulating cardiac function, but whether it can help in cardioprotection is not clear. The aim of the present study was to determine whether melatonin, by modulating SIRT1 and in turn mitochondria signaling, may alleviate obesity-induced cardiac injuries. We investigated 10 lean control mice and 10 leptin-deficient obese mice ( ob/ob ) orally supplemented with melatonin for 8 weeks, as well as equal numbers of age-matched lean and ob/ob mice that did not receive melatonin. Hearts were evaluated using multiple parameters, including biometric values, morphology, SIRT1 activity and expression of markers of mitochondria biogenesis, oxidative stress, and inflammation. We observed that ob/ob mice experienced significant heart hypertrophy, infiltration by inflammatory cells, reduced SIRT1 activity, altered mitochondrial signaling and oxidative balance, and overexpression of inflammatory markers. Notably, melatonin supplementation in ob/ob mice reverted these obesogenic heart alterations. Melatonin prevented heart remodeling caused by obesity through SIRT1 activation, which, together with mitochondrial pathways, reduced oxidative stress and inflammation.
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