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BACKGROUND: Worldwide, cancer is still the primary cause of death, and one of the most widely used anthracyclines for treating cancer is doxorubicin (DOX). But a major worry is DOX-induced cardiomyopathy, which is primarily resulted from an excess of reactive oxygen species. Heart sarcoplasmic reticulum calcium ion ATPase2a (SERCA2a) controls the amount of calcium ions stored in the sarcoplasmic reticulum (SR). This study aims to evaluate and compare the efficacy of SERCA2a gene modified adipose mesenchymal stem cell-derived exosomes (AMSCs-dE) to nontransfected AMSCs-dE, in DOX induced cardiomyopathy in adult male albino rat. MATERIALS AND METHODS: Thirty one adult male albino rats were randomly divided into control group and DOX group that further subdivided into three DOX, AMSCs-dE and SERCA2a AMSCs-dE subgroups. AMSCs-dE were administered intravenously (IV). The levels of serum creatine kinase MB (CK-MB) were assessed after DOX injection and before sacrifice. Cardiac muscle samples were taken for histological analysis using Masson's trichrome and hematoxylin and eosin stains two months after the experiment. Proliferating cell nuclear antigen (PCNA) and connexin 43 were stained using immunohistochemistry. The expression of TNF and SERCA2a genes and proteins was measured by real-time polymerase chain reaction (PCR) and Western blot (Wb) analysis, respectively. Fluorescent microscopy demonstrated non-transfected and transfected exosomes labeled with PKH26 and GFP, respectively, in culture and cardiac muscle. RESULTS: DOX induced myocarditis progressing to degenerative and fibrotic changes in cardiac muscle that regressed in response to AMSCs-dE therapy. However, SERCA2a gene modified AMSCs-dE treatment reversed the mentioned parameters to nearly its normal level. CONCLUSIONS: These findings suggest that SERCA2a gene modification enhances the therapeutic efficacy of AMSCs-dE in treating DOX-induced cardiomyopathy.

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BACKGROUND: Preeclampsia is a systemic, multi-organ endotheliopathy, associated with oxidative injury to the blood-brain barrier (BBB). Preeclampsia initiates a cascade of events that include neuroinflammation. Recently, it was documented that Wnt/ß-catenin signaling pathway exerts neuroprotective effects and maintain BBB integrity. We investigate the protective effect of omega-3 against neurovascular complication of preeclampsia and its relation to Wnt/ß-catenin signaling pathway. METHODOLOGY: After confirmation of day 0 pregnancy (G0), 24 adult pregnant female Wistar rats were divided into four groups control pregnant, pregnant supplemented with omega-3, preeclampsia (PE); female rats received N (ω)-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day SC from day 7 to day 16 of pregnancy for induction of preeclampsia) and PE rats supplemented with omega-3. The intake of omega-3 started on day zero (0) of pregnancy until the end of the study (144 mg/kg\day orally). RESULTS: We found that omega-3 supplementation significantly improved cognitive functions and EEG amplitude, decreased blood pressure, water contents of brain tissues, sFlt-1, oxidative stress, proteinuria, and enhanced Wnt\ß-catenin proteins. Histological examination showed improved cerebral microangiopathy, increased expression of claudin-1 and -3, CD31, and VEGF in the cerebral cortical microvasculature and choroid plexus in PE rats treated with omega-3. A positive correlation between protein expression level of Wnt \ß-catenin and cognitive functions, and a negative correlation between claudin-5 relative expression, claudin-1 and -3 area % from one side and water content of the brain tissues from the other side were observed. CONCLUSION: Wnt/ß-catenin signaling pathway suspected to have an important role to improve BBB integrity. Neuroprotective, antioxidant, and anti-inflammatory effects of omega-3 were observed and can be suggested as protective supplementation for preeclampsia.

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Aging causes morphological and functional changes in the cerebellum. This work aimed to demonstrate the implication of JAK1/STAT3/SOCS3 on aging-induced changes of rat cerebellum. Thirty male rats were divided into: adult (12 months), early senile (24 months) and late senile (32 months) groups. Immunohistochemical reaction of the cerebellum to GFAP and caspase-3 was assessed and the expression of JAK1, STAT3, SOCS3 proteins was also evaluated. TNFα as well as the activities of malondialdehyde (MDA) and reduced glutathione (GSH) in cerebellar tissue were also measured. The cerebellum of late senile rats revealed more degenerative changes than early senile rats in the form of increase in GFAP and caspase-3 immunoreaction. Additionally, there was decrease in JAK1and STAT3 expression in early and late senile rats and increase in SOCS3 when compare early and late senile groups with adult one. Enhancement of TNFα was noticed with aging as well as significant decrease in GSH and increase in MDA in early senile group. Moreover, late senile group revealed significant decrease in GSH and increase in MDA. It could be concluded that aging resulting in variable changes of the cerebellum as detected by morphological changes, immunohistochemical reactions of caspase-3 and GFAP and expression of JAK1/STAT3/SOCS3 proteins. Additionally, inflammatory marker TNFα and the activity of oxidative/antioxidative stress markers; malondialdehyde (MDA) and reduced glutathione (GSH) were also affected with aging.

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Radiotherapy is one of the most effective modalities for treatment of neoplastic diseases. Radiation damage is to a large extent caused by overproduction of reactive oxygen species. To improve the therapeutic index, identifying effective substances for prevention or treatment of postirradiation intestinal and bone marrow injury should be prompted. This study was designed to evaluate the protective effects of cimetidine on the in rats exposed to γ-irradiation (5 Gy) and exploring the B-cell lymphoma 2 (Bcl2)/Bcl2 associated X (bax) pathway as a probable underlying mechanism. Eighteen adult male rats were randomly grouped into three: control, untreated irradiated rats, and irradiated rats pretreated with cimetidine. Seven days postirradiation the rats were culled, the bone marrow (BM) and jejunum tissue samples were collected for biochemical, histological, and immunohistological evaluation of BM cell count (BMCs), intestinal fibrosis, oxidative stress, tumor necrosis factor-α, Bcl2, and Bax. Cimetidine pretreatment significantly reversed the loss of BMCs, intestinal lining destruction, and fibrosis seen in the untreated irradiated rats and significantly decreased the underlying oxidative stress, inflammation, and Bax/Bcl2 ratio. There was a significant differential correlation between Bax/Bcl2 ratio, tissue oxidative stress level, and tissue injury. Cimetidine represents a very promising radioprotective agent with a potential differential beneficial effect on both cancer cells (inducing apoptosis) as previously proved through different studies and adjacent healthy cells (providing radioprotection via inhibiting apoptosis) as clearly demonstrated through this study, via its antioxidant effect and subsequent regulation of type 2 apoptotic pathway through modulation of Bax/Bcl2 ratio.

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INTRODUCTION: The cardiotoxicity of doxorubicin is incompletely understood. We investigated the prophylactic effect of nebivolol on doxorubicin-induced cardiac toxicity. MATERIAL AND METHODS: Thirty rats were divided into a control group, doxorubicin-treated group and nebivolol + doxorubicin-treated group. The specimens were examined using H + E and Masson's trichrome, caspase 3, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and tumor necrosis factor factor-α (TNF-α). The mean area percentage of collagen fiber content, caspase-3, eNOS, iNOS and TNF-α immunoactivities was measured. RESULTS: The doxorubicin-treated group showed marked myocyte distortion and fragmentation, congestion and cytoplasmic lysis in most fibers. These changes were less intense in the nebivolol-treated group. The mean area percentage of collagen fiber in the nebivolol-treated group was non-significantly smaller (p = 0.07) than that in the doxorubicin-treated group. The expression of caspase-3 (p = 0.03), eNOS (p ≤ 0.001), iNOS (p < 0.001) and TNF-α (p = 0.003) immunoreactivity was improved in the nebivolol-treated group. CONCLUSIONS: Nebivolol exerted a significant protective effect from doxorubicin toxicity. The protective effect appears to be mediated mainly through caspase-3, eNOS, iNOS and TNF-α modulation.

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INTRODUCTION: Aging causes morphological and functional changes in the thyroid gland. Free radicals play a key role in the pathology of normal aging. Vimentin and cytokeratin are cytoskeletal intermediate filaments that are often used as indirect indices of tissue injury. The aim of the study was to clarify the age-related alterations in the structure and function of the thyroid gland. The relationship between oxidative/antioxidative stress markers and cytoskeletal intermediate filaments (vimentin and cytokeratin) and oxidative/antioxidative stress markers as well as vascular endothelial growth factor (VEGF) during aging were elucidated. Finally, the role of Nigella sativa (NS) oil in ameliorating age-related alterations of the structure and function of the thyroid gland was studied. MATERIAL AND METHODS: Thirty Sprague-Dawley albino rats were divided into five groups: young adult control, young adult NS-treated, late adult control, late adult NS-treated, and senile. The age of young adult, late adult, and senile rats was nearly 7, 18 and 22 months, respectively. NS oil was added to food pellets and was administered at a daily dose of 0.1 g/kg body weight for one month. The thyroid gland was dissected and fixed immediately in 10% formalin saline. The assessment of thyroid structure was based on hematoxylin and eosin, and Masson's trichrome stainings, and histomorphometric analysis of the deparaffinized sections. Localization and distribution of vimentin and cytokeratin filaments was assessed by immunohistochemistry. Measurements of VEGF gene expression by qPCR and oxidative/antioxidative markers (malondialdehyde and glutathione content, superoxide dismutase activity) in thyroid gland homogenates were performed. Serum concentration of thyroid hormones (T3, T4) and TSH were assessed by radioimmunoassay. RESULTS: Follicles in the late adult control group were dilated and disrupted. Follicular cells showed cytoplasmic vacuolation. Follicles in the thyroids of senile rats were of irregular shape, often with cellular exfoliations. Many follicles were dilated and lined with flattened cells. A notable amelioration of these morphological alterations was observed in late adult NS-treated rats. Decrease in serum T3 and T4 levels and increase in TSH levels were observed in the late adult control and senile groups. A clear shift of the oxidative/antioxidative markers (MDA/ /GSH, SOD) was observed in the late adult control and senile groups in favor of oxidants. Administration of NS to late adult rats resulted in normalization of these parameters. Increased area of collagen fibers, immunoreactivity of vimentin and cytokeratin filaments and VEGF gene expression were observed in the thyroids of late adult and senile rat groups as compared to young animals. The mean number of follicular cells decreased in the late adult control and senile groups. Administration of NS to the late adult rats returned these parameters to the level of the young adult rats. CONCLUSIONS: Aging-related alterations in both structure and function of the rat thyroid gland that are associated with increased indices of oxidative stress might be abrogated by administration of antioxidative agents present in Nigella sativa oil.

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INTRODUCTION: Indomethacin is a non steroidal anti-inflammatory drug (NSAID) which is capable of producing injury to gastric mucosa. To prevent of NSAID-induced gastropathy, it is important to evaluate the risk factors. One of them is steroid. The aim is to study time dependent effects of glucocorticoids (GC) on indomethacin induced gastric ulcer. MATERIAL AND METHODS: Forty-nine albino rats were used. They were divided into control and experimental groups. The experimental group was subgroup I (rats were given indomethacin and were sacrificed 1 day after drug intake), subgroup II (rats were given indomethacin + dexamethasone and were sacrificed 1 day after drug intake), subgroup III (rats were given indomethacin + dexamethasone and were sacrificed 3 days after drug intake) and subgroup IV (rats were given indomethacin + dexamethasone and were sacrificed 7 days day after drug intake). Histological, scanning electron microscopy and morphometric studies were used. RESULTS: Indomethacin induced gastric ulceration with shredding of the superficial epithelial cells. The fundic glands were dilated in the subgroups II, III, IV. The surface epithelial cells were shredded and the ulcer sizes were big in subgroup IV. All subgroups exhibited abnormal surface epithelial cells within the gastric ulcer area. CONCLUSIONS: Indomethacin is capable of producing injury to gastrointestinal mucosa. With prolonged use of GC the surface epithelial cells became more affected and the ulcer sizes became bigger. Concomitant use of both medications will delay the healing of the indomethacin induced gastric ulcer and induce more gastric complication.