RESUMO
This study concerned with assessing the effect of restoring p53 using PRIMA-1 on the anti-cancer activity of olaparib against TP53-mutant triple negative breast cancer (TNBC) cells and exploring the optimum synergistic concentrations and the underlying mechanism. Human BC cell lines, MDA-MB-231 with mutated TP53 gene, and MCF-7 with wild-type TP53 gene were treated with olaparib and/or PRIMA-1. The IC50 value for olaparib was significantly decreased by PRIMA-1 in MDA-MB-231 cells compared to MCF-7 cells. Contrary to MCF-7 cells, co-treatment with olaparib and PRIMA-1 had a synergistic anti-proliferative effect in MDA-MB-231 at all tested concentrations with the best synergistic combination at 45 and 8.5 µM, respectively, and furthermore PRIMA-1 enhanced olaparib-induced apoptosis. This synergistic apoptotic effect was associated with a significant boost in mRNA expression of TP53 gene, cell cycle arrest at G2/M phase, modulation of BRCA-1, BAX and Bcl2 proteins expressions, and induction of active caspase-3. These results present a clue for the utility of combined olaparib and PRIMA-1 in treatment of TP53-mutant TNBC invitro. PRIMA-1 triggers olaparib-induced MDA-MB-231 cell death in a synergistic manner via restoring TP53, decreasing BRCA-1 expression, cell cycle arrest, and enhancement of apoptosis via p53/BAX/Bcl2/caspase 3 pathway.
Assuntos
Neoplasias de Mama Triplo Negativas , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Genes p53 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Proteína X Associada a bcl-2/metabolismo , Linhagem Celular Tumoral , Apoptose , Morte Celular , Divisão Celular , Ciclo Celular , Proliferação de CélulasRESUMO
We describe an 81-year-old gentleman presenting with mild myelopathic symptoms in the upper limbs. Imaging showed a C1-3 intradural extramedullary lesion initially thought to be an arachnoid cyst. A C1 + 2 hemilaminectomy and partial excision was performed with histology revealing a neurenteric cyst (NC). NCs are congenital tumours that usually present within the third decade of life, they account for 1% of all spinal tumours. A literature search was conducted and we found that the age of presentation might actually be earlier than previously described. We also found that there has never before been a case described in the eighth decade of life, making this the oldest known symptomatic presentation of this rare condition.
Assuntos
Cistos Aracnóideos , Defeitos do Tubo Neural , Neoplasias da Medula Espinal , Masculino , Humanos , Idoso de 80 Anos ou mais , Defeitos do Tubo Neural/diagnóstico por imagem , Defeitos do Tubo Neural/cirurgia , Laminectomia , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/cirurgia , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: This study aims to comprehensively evaluate olfactory and gustatory dysfunctions during the COVID-19 pandemic regarding onset, course, associated symptoms, prognosis and relation to patients' demographics, treatment received and other symptoms. PATIENTS& METHODS: This is a prospective study conducted on patients proven to be infected with COVID-19 and with olfactory/gustatory dysfunction symptoms. Detailed history was taken from each patient about the onset of this dysfunction, associated symptoms. Then follow-up survey was done after 6 months to evaluate the prognosis. RESULTS: 1031 patients were included in the study, aged 18 to 69 years old, with 31.8% were male. Olfactory/gustatory dysfunctions occurred after other COVID-19 symptoms in 43.5% of cases, occurred suddenly in 80.4% and gradually in 19.6%. These dysfunctions were anosmia & ageusia in 50.2%, hyposmia & hypogeusia in 23.3%, anosmia alone in 17.7%, phantosmia in 18%, Parosmia in 28.4%. In terms of recovery 6-month follow up, 680 patients (66%) recovered completely, 22.1% recovered partially while 11.9% did not recover. Most improvement occurred in the first two weeks. Headache, malaise, nasal obstruction and rhinorrhea were the commonest COVID-19 symptoms associated. CONCLUSION: Most recovery of olfactory/gustatory dysfunction in COVID-19 infection occurs at the first two weeks and is unrelated to patient demographics, treatment or olfactory training. Parosmia is an independent predictor for complete recovery, while phantosmia is significantly associated with lower probability of complete recovery.
Assuntos
COVID-19/complicações , Transtornos do Olfato/virologia , Distúrbios do Paladar/virologia , Adolescente , Adulto , Idoso , COVID-19/epidemiologia , Egito/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/epidemiologia , Pandemias , Prognóstico , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2 , Distúrbios do Paladar/epidemiologiaRESUMO
Diabetic neuropathic pain is characterized by spontaneous pain with hyperalgesia and allodynia. We investigated whether (-)-epigallocatechin-3-O-gallate could improve diabetic neuropathic pain development through hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. Diabetes was induced in rats by streptozotocin (55 mg/kg/once) and treated with (-)-epigallocatechin-3-O-gallate (25 mg/kg/orally/once/daily/5 weeks). Diabetic rats showed an increase in serum levels of glucose, nitric oxide, triglyceride, total cholesterol, and low-density lipoprotein-cholesterol with a decrease in high-density lipoprotein-cholesterol and body weight. Also, there was an elevation in brain malondialdehyde with a marked reduction in brain levels of glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase. Furthermore, diabetic rats showed a clear reduction in plasma levels of insulin and an increase in plasma cytokines (interleukin-6 and tumor necrosis factor-α). Moreover, diabetic rats exhibited hyperalgesia as indicated by a hot plate, tail immersion, formalin, and carrageenan-induced edema tests as well as brain histopathological changes (neuron degeneration, gliosis, astrocytosis, congestion and hemorrhage). (-)-Epigallocatechin-3-O-gallate treatment ameliorated alterations in body weight, biochemical parameters, pain sensation, and histopathological changes in brain tissue. (-)-Epigallocatechin-3-O-gallate offers promising hypoglycemic, hypolipidemic, antioxidant and anti-inflammatory effects, which can prevent the development and progression of diabetic neuropathic pain.
Assuntos
Catequina/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Catequina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Masculino , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , RatosRESUMO
The protective effects of honey bee (HB) and pollen grains against cyclophosphamide (CPM) -induced cytotoxic and genotoxic effects in mice were investigated. This was achieved through study the effects of CPM and HB on oxidative status, chromosomal aberrations and gene expression of the tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL1ß), interleukin 17A (IL-17A) and interferon-gamma (IFN-γ) in mice. In addition, the levels of reduced glutathione (GSH) and malondialdehyde were determined. The results of this study revealed that CPM decrease in GSH level and increase in malondialdehyde (MDA) level in the liver and kidney tissues. Moreover, CPM induced sperm abnormality, chromosomal aberrations and down regulated the expression of the studied cytokine genes. HB treatment in association with CPM ameliorates GSH, MDA, chromosomal aberrations and regulated the expression of IL-1-ß, IL-17A, IL-6, TNF-α and IFN-γ. Thus, HB inhibits the cytotoxic and genotoxic risks associated with CPM treatment in mice.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Abelhas , Ciclofosfamida/toxicidade , Citocinas/genética , Dano ao DNA/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pólen , Animais , Antioxidantes , Expressão Gênica , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Interferon gama/efeitos dos fármacos , Interferon gama/genética , Interleucina-17/genética , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-6/genética , Rim/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genéticaRESUMO
Heart failure (HF) is one of diabetic complications. This work was designed to investigate the possible modulatory effect of curcumin against streptozotocin-induced diabetes and consequently HF in rats. Rats were divided into control, vehicle-treated, curcumin-treated, diabetic-untreated, diabetic curcumin-treated, and diabetic glibenclamide-treated groups. Animal treatment was started 5 days after induction of diabetes and extended for 6 weeks. Diabetic rats showed significant increase in serum glucose, triglycerides, total cholesterol, low-density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, nitric oxide, lactate dehydrogenase, cardiac malondialdehyde, plasma levels of interleukin-6, and tumor necrosis factor-alpha, and also showed marked decrease in serum high-density lipoprotein-cholesterol, cardiac reduced glutathione, and cardiac antioxidant enzymes (catalase, superoxide dismutase, and glutathione-S-transferase). However, curcumin or glibenclamide treatment significantly mitigated such changes. In conclusion, curcumin has a beneficial therapeutic effect in diabetes-induced HF, an effect that might be attributable to its antioxidant and suppressive activity on cytokines.
Assuntos
Antioxidantes/uso terapêutico , Curcumina/uso terapêutico , Diabetes Mellitus Experimental/complicações , Insuficiência Cardíaca/prevenção & controle , Animais , Antioxidantes/farmacologia , Glicemia , Curcumina/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Glutationa/metabolismo , Glibureto/farmacologia , Glibureto/uso terapêutico , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/etiologia , Mediadores da Inflamação/sangue , Interleucina-6/sangue , L-Lactato Desidrogenase/sangue , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico/sangue , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo , Ratos Wistar , Estreptozocina , Fator de Necrose Tumoral alfa/sangueRESUMO
In this study, endothelial nitric oxide synthase activity and nitric oxide (NO) production by human erythrocytes in the presence and absence of mercuric chloride (HgCl2 ), L-arginine (L-ARG), N ω- nitro-L-arginine methyl ester (L-NAME), and naringin (NAR) were investigated. In addition, the levels of reduced glutathione (GSH) and related enzymes were estimated in erythrocytes hemolysate. The protein carbonyl content (PCC) and thiobarbituric acid-reactive substances (TBARS) levels were also determined. The results of this study revealed that the treatment of erythrocytes with either HgCl2 or L-NAME induced a significant decrease in NOS activity and nitrite levels compared with control cells. Furthermore, mercury exposure significantly increased the levels of PCC and TBARS but reduced the GSH level. The activities of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase (GST) were inhibited. The exposure of erythrocytes to HgCl2 in combination with L-ARG, NAR, or both ameliorated the investigated parameters compared with erythrocytes incubated with HgCl2 alone. These results indicate that mercury exposure decreased both erythrocyte NOS activity and nitrite production, and that these parameters might be indicative of mercury exposure. The data also suggest that concomitant treatment with NAR can restore NO bioavailability through either its metal-chelating properties or its antioxidant activity.
Assuntos
Antioxidantes/farmacologia , Poluentes Ambientais/toxicidade , Eritrócitos/efeitos dos fármacos , Flavanonas/farmacologia , Cloreto de Mercúrio/toxicidade , Óxido Nítrico Sintase/metabolismo , Arginina/farmacologia , Biomarcadores/metabolismo , Eritrócitos/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Hemólise , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Oxirredução , Carbonilação Proteica , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Polyps are well-known cancer precursors identified by colonoscopy. However, variability in their size, appearance, and location makes the detection of polyps challenging. Moreover, colonoscopy surveillance and removal of polyps are highly operator-dependent procedures and occur in a highly complex organ topology. There exists a high missed detection rate and incomplete removal of colonic polyps. To assist in clinical procedures and reduce missed rates, automated methods for detecting and segmenting polyps using machine learning have been achieved in past years. However, the major drawback in most of these methods is their ability to generalise to out-of-sample unseen datasets from different centres, populations, modalities, and acquisition systems. To test this hypothesis rigorously, we, together with expert gastroenterologists, curated a multi-centre and multi-population dataset acquired from six different colonoscopy systems and challenged the computational expert teams to develop robust automated detection and segmentation methods in a crowd-sourcing Endoscopic computer vision challenge. This work put forward rigorous generalisability tests and assesses the usability of devised deep learning methods in dynamic and actual clinical colonoscopy procedures. We analyse the results of four top performing teams for the detection task and five top performing teams for the segmentation task. Our analyses demonstrate that the top-ranking teams concentrated mainly on accuracy over the real-time performance required for clinical applicability. We further dissect the devised methods and provide an experiment-based hypothesis that reveals the need for improved generalisability to tackle diversity present in multi-centre datasets and routine clinical procedures.
Assuntos
Crowdsourcing , Aprendizado Profundo , Pólipos , Humanos , Colonoscopia , ComputadoresRESUMO
The role of phosphodiesterase inhibitor, pentoxifylline, in the prevention of cyclophosphamide-induced hemorrhagic cystitis was evaluated in a rat model. Hemorrhagic cystitis was induced in rats by an intraperitoneal (i.p.) injection of a single dose of cyclophosphamide (150 mg/kg). Pentoxifylline (150 mg/kg/day/ip) was administered for 10 days followed by cyclophosphamide. Hemorrhagic cystitis was well characterized macroscopically, microscopically, and biochemically. Cyclophosphamide induced bladder injury including acute severe inflammation, vascular congestion, severe edema, hemorrhage, inflammatory cell infiltration in the lamina propria, and epithelial denudation; as well as it notably elevated serum inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), bladder content of malondialdehyde and total nitrate, accompanied with depletion of bladder antioxidant enzymes activities (glutathione peroxidase, superoxide dismutase, glutathione-S-transferase, and catalase). Prior administration of pentoxifylline improved all biochemical and histologic alterations induced by the cytotoxic drug cyclophosphamide. In conclusion, pentoxifylline has proven uroprotective efficacy in the cyclophosphamide-induced hemorrhagic cystitis model, possibly through modulating the release of inflammatory cytokines and nitric oxide and restoring the oxidant/antioxidant balance.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Cistite , Sequestradores de Radicais Livres/farmacologia , Hemorragia , Pentoxifilina/farmacocinética , Animais , Antineoplásicos Alquilantes/farmacologia , Antioxidantes/metabolismo , Ciclofosfamida/farmacologia , Cistite/sangue , Cistite/induzido quimicamente , Cistite/patologia , Cistite/prevenção & controle , Citocinas/sangue , Modelos Animais de Doenças , Hemorragia/sangue , Hemorragia/induzido quimicamente , Hemorragia/patologia , Hemorragia/prevenção & controle , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Oxirredutases/metabolismo , Ratos , Bexiga Urinária/metabolismo , Bexiga Urinária/patologiaRESUMO
Chloroacetonitrile is a disinfectant by-product of chlorination of drinking water and is considered as a direct-acting mutagenic and carcinogenic agent. Time-course and dose-response studies were performed to examine the mechanism of chloroacetonitrile-induced hepatotoxicity. In the time-course study, animals were scarified at 2, 4, 6 and 12 h after a single oral dose of chloroacetonitrile (38 mg/kg, p.o.). In the dose-response study, rats were scarified at 2 h after a single oral dose of chloroacetonitrile (9, 19, 38, and 76 mg/kg). In the time-course study chloroacetonitrile induced a significant decrease of hepatic glutathione, and activities of glutathione-S-transferase, glutathione proxidase and superoxide dismutase accompanied with an increase of hepatic malondialdehyde, plasma cytokines (IL-6 & 10 and TNF-α), serum aminotransferases and total bilirubin after 2 h of administration. Maximal alteration of the estimated parameters was observed at 4 h and returned to normal value at 6 h and/or 12 h after chloroacetonitrile treatment. Moreover, the alterations in oxidant, antioxidant parameters, inflammatory cytokines and the liver function tests were dose dependant. Histopathological findings supported the biochemical results. These data indicate that the mechanism of chloroacetonitrile-induced hepatotoxicity may be mediated through depletion of antioxidants, induction of oxidative stress and inflammatory cytokines.
Assuntos
Acetonitrilas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Purificação da Água , Animais , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Mediadores da Inflamação/sangue , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fatores de Tempo , Transaminases/sangueRESUMO
Background: In 2017, inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC) affected more than 6.8 million people worldwide, with increased incidence in newly industrialized countries. Although treatment options were previously limited to symptom reduction, current approaches benefit from disease-modifying biologics. In this study, we aimed to explore disease characteristics, treatment, and outcomes of patients with CD or UC treated with infliximab or golimumab in routine clinical practice in the Middle East and Northern Africa. Methods: HARIR was a prospective, observational, multicenter study (NCT03006198), in patients who were treatment naïve or who received two or fewer biologic agents. Observed data from routine clinical practice were presented descriptively. Results: Data from 86 patients enrolled from five countries (Algeria, Egypt, Kuwait, Qatar, and Saudi Arabia) were analyzed, 62 with CD and 24 with UC. All patients received infliximab. Clinically meaningful efficacy data were observed only for the CD group (up to Month 3) due to limited patient numbers. Crohn's Disease Activity Index (CDAI) scores at Month 3 indicated a positive response to treatment (reduced score of ≥70 and ≥25% compared with baseline) for 14/48 (29.2%) patients; notably, 28/52 (53.8%) patients had CDAI score <150 at baseline. Rates of serious and severe adverse events (AEs) were low in both groups. The most common AEs were gastrointestinal disorders. Conclusion: Infliximab treatment was well tolerated in this Middle Eastern and Northern African population, and a clinical response was observed for 29.2% of CD patients. Limited accessibility to biologics and concomitant treatments restricted study conduct.
Assuntos
Anticorpos Monoclonais , Produtos Biológicos , Colite Ulcerativa , Fármacos Gastrointestinais , Doenças Inflamatórias Intestinais , Infliximab , Humanos , África do Norte , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Infliximab/uso terapêutico , Oriente Médio/epidemiologia , Estudos Prospectivos , Anticorpos Monoclonais/uso terapêutico , Resultado do Tratamento , Fármacos Gastrointestinais/uso terapêuticoRESUMO
Polyps in the colon are widely known cancer precursors identified by colonoscopy. Whilst most polyps are benign, the polyp's number, size and surface structure are linked to the risk of colon cancer. Several methods have been developed to automate polyp detection and segmentation. However, the main issue is that they are not tested rigorously on a large multicentre purpose-built dataset, one reason being the lack of a comprehensive public dataset. As a result, the developed methods may not generalise to different population datasets. To this extent, we have curated a dataset from six unique centres incorporating more than 300 patients. The dataset includes both single frame and sequence data with 3762 annotated polyp labels with precise delineation of polyp boundaries verified by six senior gastroenterologists. To our knowledge, this is the most comprehensive detection and pixel-level segmentation dataset (referred to as PolypGen) curated by a team of computational scientists and expert gastroenterologists. The paper provides insight into data construction and annotation strategies, quality assurance, and technical validation.
Assuntos
Neoplasias do Colo , Pólipos do Colo , Humanos , Pólipos do Colo/diagnóstico , Colonoscopia/métodosRESUMO
Reactive oxygen species and cytokines have been implicated in the nephrotoxicity induced by doxorubicin. The goal of the present study was to determine protective effect of aminoguanidine on doxorubicin-induced nephrotoxicity in rats. Different groups of male Wistar rats received doxorubicin (67.75 mg/kg/i.p./2 days), aminoguanidine alone and aminoguanidine (200 and 400 mg/kg/i.p./30 days) prior to doxorubicin, respectively. Doxorubicin significantly increased serum creatinine (505%), blood urea nitrogen (333%), nitric oxide (406%), and plasma tumor necrosis factor-alpha (706%) as well as urinary albumin (452%) and N-acetyl-ß-D-glucosaminidase (415%) compared to control. Moreover, renal glutathione (334%), superoxide dismutase (283%), and catalase (513%) were significantly reduced accompanied with elevation in renal malondialdehyde compared to control. Pretreatment with aminoguanidine mitigated such changes in all mentioned parameters. Histopathological changes showed that doxorubicin-caused significant structural damages to kidneys that were reduced with aminoguanidine. Results indicate that reactive oxygen species and cytokines are involved in doxorubicin-induced nephrotoxicity, which can be reduced by aminoguanidine.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Sequestradores de Radicais Livres/uso terapêutico , Guanidinas/uso terapêutico , Nefropatias/prevenção & controle , Acetilglucosamina/urina , Albuminúria/prevenção & controle , Animais , Nitrogênio da Ureia Sanguínea , Catalase/metabolismo , Creatinina/sangue , Glutationa/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/urina , Peroxidação de Lipídeos , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/sangue , Estresse Oxidativo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
Hemorrhagic cystitis (HC) is considered a fatal complication of cyclophosphamide (CP). Down-regulation of Nrf2 and induction of pro-inflammatory mediators are the main pathological factors. Recently, ameliorative potential of the angiotensin II (AII) type-1 (AT1) receptor blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines was reported. The current study aims to investigate the possible protective effect of OLM on CP-induced HC in Wistar rats. The animals were divided into the control group (0.5% W/V carboxymethylcellulose, p.o.); OLM group (20 mg/kg, p.o., for 21 days); CP group (a single dose of 100 mg/kg, i.p.); and the remaining groups that received CP i.p. with oral OLM 5, 10 and 20 mg/kg for 21 days, respectively. The bladder tissue was collected for histopathology, immunohistochemistry, ELISA, Western blot, and oxidative stress assay. The OLM at doses of 10 and 20 mg/kg attenuated increase in TNF-α, IL-6, NF-kB, iNOS, and COX-2 induced by CP. Additionally, it up-regulated the Nrf2/HO-1 pathway, bladder GSH content, and CAT and SOD activities. The data indicated that OLM inhibited ROS-induced NF-kB, which caused inhibition of pro-inflammatory cytokines and activation of the Nrf2/HO-1 pathway. Hence, OLM holds great promise for preventing CP-induced HC.
Assuntos
Cistite , Fator 2 Relacionado a NF-E2 , Angiotensina II/metabolismo , Animais , Carboximetilcelulose Sódica , Ciclo-Oxigenase 2 , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Cistite/patologia , Citocinas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Imidazóis , Mediadores da Inflamação/metabolismo , Interleucina-6/farmacologia , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Transdução de Sinais , Superóxido Dismutase/metabolismo , Tetrazóis , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical-mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile-induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile-induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile-induced hepatotoxicity through its antioxidant activity.
Assuntos
Acrilonitrila/toxicidade , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Quercetina/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peróxidos Lipídicos/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Quercetina/administração & dosagem , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Osteoporosis is the most prevalent bone complication in beta-thalassemic patients despite regular transfusions and iron chelation therapy. Although its etiology is multi-factorial, genetic factors play an important role in pathogenesis. These factors have not yet been clearly defined, however, osteoporosis may be related to vitamin D receptor gene BsmI polymorphism. In this study, BsmI vitamin D receptor gene polymorphism was analyzed using polymerase chain reaction and BsmI restriction fragment length polymorphism in 42 regularly treated-beta-thalassemic patients of different ages. Bone mineral density was measured by peripheral quantitative ultrasound at the heel of the foot. Serum levels of alkaline phosphatase, calcium, phosphorus, ferritin and 25-hydroxyvitamin D3 were determined. Patients were divided into two groups according to pubertal signs: group I (22 children), and group II (20 adolescents and adults). The Z-scores of bone mineral density in both groups were -1.32 +/- -0.9 and -2.30 +/- -1.02 respectively, with a significant difference between the two groups. The height standard deviation and 25-hydroxyvitamin D3 were significantly decreased in group II compared to group I. Moreover, significantly lower bone mineral density and height standard deviation were detected among patients with BB vitamin D receptor genotype. Therefore, this genotype may be considered as a risk factor for osteoporosis in beta-thalassemic patients.
Assuntos
Densidade Óssea/fisiologia , Receptores de Calcitriol/genética , Talassemia beta , Adolescente , Adulto , Envelhecimento/genética , Fosfatase Alcalina/sangue , Estatura/genética , Estatura/fisiologia , Calcifediol/sangue , Cálcio/sangue , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Genótipo , Humanos , Masculino , Osteoporose/complicações , Osteoporose/etiologia , Fósforo/sangue , Polimorfismo de Fragmento de Restrição , Puberdade/sangue , Puberdade/genética , Puberdade/fisiologia , Fatores de Risco , Talassemia beta/complicações , Talassemia beta/genética , Talassemia beta/metabolismo , Talassemia beta/fisiopatologiaRESUMO
BACKGROUND: Diabetic cardiomyopathy (DCM) is a nonischemic myocardial disorder characterized by metabolic disturbances and oxidative stress in diabetic patients. The present paper aims to determine the protective effect of the phlebotrophic drug, diosmin, on DCM in a model of high-fat diet-fed and streptozotocin-induced type 2 diabetes in the rat. MATERIALS AND METHODS: The animals were divided into 4 groups (8 rats/group) as follows: vehicle-treated nondiabetic control group, vehicle-treated diabetic group, diosmin (50 mg/kg)-treated diabetic group and diosmin (100 mg/kg)-treated diabetic group. Treatment was given once daily orally by gavage for 6 weeks. Oxidant and antioxidant stress markers, inflammatory markers and proapoptotic and antiapoptotic gene expression using quantified real-time polymerase chain reaction were investigated. RESULTS: Diosmin treatment in diabetic rats lowered elevated blood glucose levels, homeostatic model assessment for insulin resistance, cardiac creatine kinase and lactate dehydrogenase enzymes, cardiac malondialdehyde and nitric oxide. Moreover, diosmin increased plasma insulin and c-peptide levels, cardiac glutathione content, superoxide dismutase, catalase and glutathione S-transferase activities. Also, diosmin treatment significantly (P < 0.05) lowered the levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), down-regulated cardiac Bcl-2-associated X protein and caspase 3 and 9 and up-regulated B-cell lymphoma 2 mRNA expression levels. CONCLUSIONS: Diosmin may have a sizeable therapeutic potential in the treatment of DCM due to antidiabetic, antioxidative stress, anti-inflammatory and antiapoptotic effects. Detailed studies are needed to disclose the precise mechanisms motivating the protective effect of diosmin .
Assuntos
Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Diosmina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Biomarcadores/sangue , Glicemia , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diosmina/administração & dosagem , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase , Insulina/sangue , Resistência à Insulina , RatosRESUMO
Free radicals have been implicated in the pathogenesis of diabetes mellitus leading to various complications including atherosclerosis. Propolis was reported to have oxygen radical scavenging activity. The present study was designed to investigate the possible antidiabetic, hypolipidemic and antioxidant effects of ethanolic extract of propolis (EEP). Type capital I, Ukrainian diabetes was induced in rats by injection of streptozotocin (STZ) in a dose of 60 mg/kg bwt, i.p. for 3 consecutive days. After 5 weeks of STZ injection, there were an apparent reduction in the animal body weight amounting to 21% and significant increases in serum glucose (184%), triglycerides (63%), total cholesterol (43%) and low density lipoprotein-cholesterol (LDL-C) (148%) with a concomitant decrease in serum high density lipoprotein-cholesterol (HDL-C) (51%) as compared to the control normal group. In addition, there was significant elevation in pancreatic lipid peroxides measured as malondialdehyde (MDA) and serum nitric oxide (NO) amounting to 185% and 224%, respectively with marked reduction in serum reduced glutathione (GSH) and catalase (CAT) (66% and 31%, respectively) and pancreatic superoxide dismutase (SOD) (54%) in STZ-treated rats. On the other hand, oral daily treatment of animals with EEP in a dose of 200 mg/kg bwt for a period of 5 weeks ameliorated STZ-induced alterations in the animal body weight as well as in serum glucose, lipids, lipoproteins, NO, GSH & CAT and pancreatic MDA & SOD. In conclusion, propolis extract offers promising antidiabetic and hypolipidemic effects that may be mainly attributed to its potent antioxidant potential. Further studies will be needed in future in order to determine which one(or more) of its active constituents has the main antidiabetic and hypolipidemic effects.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Sequestradores de Radicais Livres/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Própole/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/isolamento & purificação , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/isolamento & purificação , Hipolipemiantes/administração & dosagem , Hipolipemiantes/isolamento & purificação , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Própole/administração & dosagem , Própole/química , Ratos , Ratos WistarRESUMO
Oxidative stress may play a key role in the pathogenesis of diabetic nephropathy. Propolis and its extract have antioxidant properties. The effect of ethanolic extract of propolis against experimental diabetes mellitus-associated changes was examined. Diabetes was induced experimentally in rats by i.p. injection of streptozotocin (STZ) in a dose of 60 mg/kg bwt for 3 successive days. Blood urea nitrogen (BNU), creatinine, glucose, lipid profile, malondialdehyde (MDA) and urinary albumin were measured. Superoxide dimutase (SOD), glutathione (GSH), catalase (CAT) and MDA were measured in the renal tissue. The results showed decreased body weight and increased kidney weight in diabetic animals. Compared to the control normal rats, diabetic rats had higher blood glucose, BNU, creatinine, total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), MDA and urinary albumin and lower high-density lipoprotein-cholesterol (HDL-C) levels. Moreover, renal tissue MDA was markedly increased while SOD, GSH and CAT were significantly decreased. Oral administration of propolis extract in doses of 100,200 & 300 mg/kg bwt improved the body and kidney weights, serum glucose, lipid profile, MDA and renal function tests. Renal GSH, SOD and CAT were significantly increased while MDA was markedly reduced. These results may suggest a strong antioxidant effect of propolis which can ameliorate oxidative stress and delay the occurrence of diabetic nephropathy in diabetes mellitus.
Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Própole/farmacologia , Albuminúria/etiologia , Albuminúria/prevenção & controle , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Relação Dose-Resposta a Droga , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Garlic contains many sulfhydryl compounds that act as antioxidants. However, the role of nitric oxide (NO) in inflammation is controversial. The aim of the present study is to investigate the possible protective effect of garlic against acetic acid-induced ulcerative colitis in rats, as well as the probable modulatory effect of L-arginine (NO precursor) on garlic activity. Intra-rectal inoculation of rats with 4% acetic acid for 3 consecutive days caused a significant increase in the colon weight and marked decrease in the colon length. In addition, acetic acid induced a significant increase in serum levels of nitrate as well as colonic tissue content of malondialdehyde (MDA). Moreover, colonic tissue contents of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were markedly reduced. On the other hand, pre-treatment of rats with garlic (0.25 g/kgbwt, orally) for 4 consecutive weeks and 3 days during induction of colitis significantly reduced the increase in the colon weight induced by acetic acid and ameliorated alterations in oxidant and antioxidant parameters. Interestingly, oral co-administration of garlic (0.25 g/kgbwt) and L-arginine (625 mg/kgbwt) for the same period of garlic administration mitigated the changes in both colon weight and length induced by acetic acid and increased garlic effect on colon tissue contents of MDA and GSH. In conclusion, L-arginine can augment the protective effect of garlic against ulcerative colitis; an effect that might be mainly attributed to its NO donating property resulting in enhancement of garlic antioxidant effect. Further studies will be needed to determine which one of the active ingredients of garlic has the main antioxidant effect to be used with L-arginine.