RESUMEN
Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP & NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy.
Asunto(s)
Acetilcisteína , Alopecia , Ciclofosfamida , Modelos Animales de Enfermedad , Folículo Piloso , Ratones Endogámicos C57BL , Animales , Alopecia/inducido químicamente , Alopecia/tratamiento farmacológico , Alopecia/patología , Alopecia/metabolismo , Ratones , Folículo Piloso/metabolismo , Folículo Piloso/efectos de los fármacos , Folículo Piloso/patología , Femenino , Acetilcisteína/farmacología , Antineoplásicos AlquilantesRESUMEN
Ethanol-producing dysbiotic gut microbiota could accelerate the progress of non-alcoholic fatty liver disease (NAFLD). Metformin demonstrated some benefits in NAFLD. In the present study, we tested the ability of metformin to modify ethanol-producing gut bacterial strains and, consequently, retard the progress of NAFLD. This 12-week study included forty mice divided into four groups (n = 10); normal diet, Western diet, Western diet with intraperitoneal metformin, and Western diet with oral metformin. Oral metformin has a slight advantage over intraperitoneal metformin in ameliorating the Western diet-induced changes in liver function tests and serum levels of different cytokines (IL-1ß, IL-6, IL-17, and TNF-α). Changes in liver histology, fibrosis, lipid content, Ki67, and TNF-α were all corrected as well. Faecal ethanol contents were increased by the Western diet but did not improve after treatment with metformin although the numbers of ethanol-producing Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli) were decreased by oral metformin. Metformin did not affect bacterial ethanol production. It does not seem that modification of ethanol-producing K. pneumoniae and E. coli bacterial strains by metformin could have a significant impact on the therapeutic potentials of metformin in this experimental model of NAFLD.
RESUMEN
Doxorubicin (Dox) is an anthracycline antibiotic that treats a variety of malignancies. Unfortunately, its cardiotoxicity limits its therapeutic usefulness. Coenzyme Q10 (CoQ10) has effectively treated and prevented various cardiac diseases and toxicities. This study aimed to evaluate the possible antioxidative and anti-apoptotic cardioprotective effects of CoQ10 against doxorubicin-induced histopathological and molecular changes in cardiomyocytes. Twenty-eight adult Wistar rats were divided into positive control, negative control, Dox-treated group, and Dox+CoQ10-treated. On the 16th day after the start of treatment, the hearts of all rats were dissected, and the left ventricles were processed for histological evaluation; immunohistochemical staining with caspase-3 and inducible nitric oxide synthase (iNOS); ultrastructural examination of cardiomyocytes; molecular assessment of proapoptotic gene Bax and anti-apoptotic gene expression Bcl-2; and biochemical study of malondialdehyde (MDA). The Dox-treated group had disorganized cardiomyocytes with increased interstitial space, vacuolated cytoplasm, and multiple small-sized pyknotic nuclei. A significant increase in caspase-3 and iNOS immunoexpression was observed. Ultrastructurally, the mitochondria were large with abnormal shapes, vacuolated cytoplasm, multiple vacuoles and autophagosomes, collagen fibril accumulation, and multiple small hyperchromatic nuclei. The intercalated discs were disorganized with loss of desmosome junction. The cardiomyocytes also showed significantly increased MDA levels and upregulation of Bax/Bcl-2 gene expression ratio. Co-administration of CoQ10 resulted in significant improvement in the histopathological picture, with a significant decrease in caspase-3 and iNOS immunoexpression and downregulation of the Bax/Bcl-2 gene expression ratio. In conclusion, CoQ10 protects against Dox-induced cardiotoxicity through the regulation of proapoptotic and anti-apoptotic gene expression.
Asunto(s)
Antioxidantes , Cardiomiopatías , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Caspasa 3/metabolismo , Caspasa 3/uso terapéutico , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/metabolismo , Ratas Wistar , Proteína X Asociada a bcl-2/uso terapéutico , Cardiomiopatías/inducido químicamente , Cardiomiopatías/prevención & control , Doxorrubicina/efectos adversos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/uso terapéuticoRESUMEN
BACKGROUND: Oral mucositis is the most debilitating and troublesome adverse effect of irinotecan (CPT-11) treatment. It adversely affects the patient quality of life. The aim of this work was to study the histological, immunohistochemical, and molecular changes in the oral mucosa by CPT-11 and the possible alleviated role of atorvastatin. METHODS: Rats were randomly divided into control, CPT-11-treated group, and CPT-11+ atorvastatin-treated group. At the end of the experiment, the anterior two-thirds of the tongue was dissected out and divided into two parts: one part for light microscopic examination and the second for molecular study. RESULTS: CPT-11-treated group revealed loss of normal mucosal organization, areas of ulceration and inflammation, and loss of architecture of lingual papillae. A significant decrease in immunohistochemical and molecular gene expression of Ki-67 and antiapoptotic Bcl-2 levels was observed. A significant increase in NF-κB immunohistochemical and mRNA gene expression level and a nonsignificant increase in Nrf2 gene expression were detected. Coadministration of atorvastatin showed remarkable improvement in the histopathological picture with a significant increase in Ki-67 and Bcl-2, a significant decrease in NF-κB protein and gene expression, and a significant increase in Nrf2 gene expression. CONCLUSION: Atorvastatin substantially attenuates CPT-11-induced oral mucositis through the initiation of the antiapoptotic gene, modulation of the inflammatory, and antioxidant gene expression.
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Antineoplásicos/efectos adversos , Antioxidantes/administración & dosificación , Atorvastatina/administración & dosificación , Irinotecán/efectos adversos , Mucosa Bucal/efectos de los fármacos , Estomatitis/inducido químicamente , Estomatitis/tratamiento farmacológico , Lengua/efectos de los fármacos , Animales , Expresión Génica/efectos de los fármacos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Mucosa Bucal/metabolismo , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estomatitis/genética , Estomatitis/metabolismo , Lengua/metabolismo , Resultado del TratamientoRESUMEN
Dedifferentiation of tubular epithelial cells is involved in both regeneration and fibrosis following acute kidney injury (AKI). Prostaglandin E2 receptor 4 (EP4 ) antagonist can inhibit the dedifferentiation of renal tubular cells. The present study investigated whether the time of blockage of EP4 receptors, using grapiprant, could affect the tubular regeneration or interstitial fibrosis in AKI. Cisplatin was used to induce AKI in 72 C57BL/6 adult female mice. Animals were assigned to four groups; control, cisplatin-treated, cisplatin-treated with early grapiprant intervention and cisplatin-treated with late grapiprant intervention. AKI was assessed by kidney function tests and histopathology. Fibrosis was evaluated by Masson's trichrome and alpha smooth muscle actin (α-SMA) expression. Markers of dedifferentiation, CD133, and epithelial to mesenchymal transition (EMT), vimentin were assessed. Early intervention with grapiprant significantly ameliorated AKI more efficiently than late intervention. However, even late intervention was useful in reducing the overall fibrosis as demonstrated by Masson's trichrome and α-SMA expression. In both grapiprant-treated groups, a parallel reduction of dedifferentiation (CD133) and EMT (vimentin) was evident. It seems that the progressive fibrotic changes that follow AKI could still be reduced possibly by targeting dedifferentiation and/or EMT.
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Lesión Renal Aguda , Transición Epitelial-Mesenquimal , Animales , Fibrosis , Masculino , Ratones , ProstaglandinasRESUMEN
Fibromyalgia (FM) is a common chronic pain syndrome that affects 1% to 5% of the population. We aimed to investigate the role of endothelial dysfunction and autophagy in fibromyalgia-related vascular and cerebral cortical changes in a reserpine-induced rat model of fibromyalgia at the histological and molecular levels and to study the ameliorative effect of fisetin. Forty adult female albino rats were divided into four groups (10 each): two control groups, the reserpine-induced fibromyalgia group, and the fisetin-treated group. The carotid arteries and brains of the animals were dissected. Frozen tissue samples were used for total RNA extraction and qPCR analysis of eNOS, caspase-3, Bcl-2, LC-3, BECN-1, CHOP, and TNF-α expression. Histological, immunohistochemical (eNOS), and ultrastructure studies were conducted. The carotid arteries revealed excessive autophagy and endothelial, vascular, and apoptotic changes. The cerebral cortex showed similar findings apart from endoplasmic reticulum stress. Additionally, there was decreased gene expression of eNOS and Bcl-2 and increased expression of caspase-3, LC-3, BECN-1, CHOP, and TNF-α. In the fisetin-treated rats, improvements in the histological and molecular results were detected. In conclusion, oxidative stress, enhanced apoptosis, and excessive autophagy are fundamental pathophysiologic mechanisms of reserpine-induced fibromyalgia. Moreover, fisetin has an ameliorative effect against fibromyalgia.
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Autofagia , Vasos Sanguíneos/patología , Vasos Sanguíneos/fisiopatología , Corteza Cerebral/patología , Endotelio Vascular/fisiopatología , Fibromialgia/complicaciones , Flavonoles/farmacología , Animales , Autofagia/efectos de los fármacos , Vasos Sanguíneos/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Arterias Carótidas/fisiopatología , Arterias Carótidas/ultraestructura , Corteza Cerebral/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Femenino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Sprague-DawleyRESUMEN
Endoplasmic reticulum (ER) stress could participate in high-fat diet (HFD)-induced hepatic steatosis. The current study aims to investigate the role of ER stress as well as inflammation as possible pathophysiologic mechanisms of HFD-induced hepatic steatosis at ultrastructure and molecular levels. Fifteen control rats on ordinary diet and 30 HFD-fed rats were enrolled in the study. Histological and EM examinations of rats' liver were carried out. Molecular study of TNF-α, CRP, and HNF4α by RT qPCR as well as biochemical investigation of liver function and lipids profile were done. Hepatic steatosis was induced with lipid droplets accumulation at histological level and mega-mitochondria with reduced ER-mitochondrial distance at EM level. Increased gene expression of TNF-α and CRP was significantly correlated with the reduced HNF4α expression and with other ER stress markers. In conclusion, endoplasmic reticulum stress, confirmed at ultrastructure level, plays an important role in pathogenesis of HFD-induced hepatic steatosis. HNF4α downregulation as well as increased expression of hs-CRP and TNF-α enforce the concept of interplay between ER stress, hepatic subclinical inflammation, and disturbed gene expression regulation in the pathogenesis of HFD-induced hepatic steatosis.
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Estrés del Retículo Endoplásmico , Hígado Graso/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Mediadores de Inflamación/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/fisiopatología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The mother-infant relation is important for brain development and maturation. To investigate hippocampus changes, we used 18 male rat pups from three dams. Pups were divided into a maternal care (control) group, a maternal separation (MS) group and a MS plus fluoxetine (MS + Fl) treated group. On postnatal day 22, pups were weaned and their serum corticosterone level measured. At 2 months, the hippocampus was removed and processed for histological, immunohistochemical and ultrastructural study. MS caused significant elevation of serum corticosterone level and a significant decrease in the thickness of the pyramidal and granular layers of the cornu ammonis 3 (CA3) and dentate gyrus (DG) areas of the hippocampus. Both CA3 and DG areas exhibited degenerative changes in nerve cells, which were shrunken with pyknotic nucleus and darkly stained cytoplasm. Electron microscopy showed condensed chromatin, degenerated mitochondria, cytoplasmic vacuoles and electron lucent cytoplasm with loss of most polyribosomes. Immunohistochemical staining showed significantly increased numbers of glial fibrillary acid protein-positive cells in the CA3 and DG, and numbers of Ki-67stained cells in the DG in the MS group compared to the control group. All adverse changes were ameliorated in the MS + Fl group. Our findings corroborate the importance of the mother-infant relation to hippocampal development and demonstrate a protective role for Fl in MS pups.
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Fluoxetina/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/lesiones , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Animales , Cortisona/sangre , Femenino , Masculino , RatasRESUMEN
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disease characterized by defect in verbal and nonverbal communications. As, the cerebellum has the greatest number of neurons and synapses in the central nervous system so, the cerebellum has emerged as one of the target brain areas affected in autism. The aim of this work was to study the biochemical, immunohistochemical and ultrastructural characteristics of autism and the possible neuroprotective role of grape seed extract. In this study 28 male pups were divided into Control groups; Group I (saline), Group II (GSE 400â¯mg/kg), Group III (VPA 500â¯mg/kg) and Group IV (VPA and GSE). Cerebellar hemispheres were dissected out and prepared to determine the oxidative stress markers, histological, immunohistochemical and morphometric study were done. A significant elevation in oxidative stress markers in off spring of VPA treated rats in comparison to control group was detected. A significant decrease in the Purkinje cell count and nuclear size were observed. Numerous shrunken cells with hyperchromatic nuclei and ultrastructural degeneration of cytoplasmic organelles were detected. A significant rise in the area percentage of GFAP-positive immune stained cells in comparison to that of the control groups was seen. Strikingly, GSE revealed significant improvement in the oxidative stress markers and then the histological and morphometric picture of the cerebellum. GSE has neuroprotective effect on the cerebellum of VPA treated rats through its potent antioxidant effect.