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Prolonged exposure to different occupational or environmental toxicants triggered oxidative stress and inflammatory reactions mediated lung damage. This study was designed to explore the influence and protective impact of flavone on lung injury in rats intoxicated with nicotine (NIC) and exposed to radiation (IR). Forty rats were divided into four groups; group I control, group II flavone; rats were administered with flavone (25 mg/kg/day), group III NIC + IR; rats were injected intraperitoneally with NIC (1 mg/kg/day) and exposed to γ-IR (3.5 Gy once/week for 2 weeks) while group IV NIC + IR + flavone; rats were injected with NIC, exposed to IR and administered with flavone. Redox status parameters and histopathological changes in lung tissue were evaluated. Nuclear factor-kappa B (NF-κB), forkhead box O-class1 (FoxO1) and nucleotide-binding domain- (NOD-) like receptor pyrin domain-containing-3 (NLRP3) gene expression were measured in lung tissues. Moreover, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and phosphatidylinositol three kinase (PI3K) were measured using ELISA kits. Our data demonstrates, for the first time, that flavone protects the lung from NIC/IR-associated cytotoxicity, by attenuating the disrupted redox status and aggravating the antioxidant defence mechanism via activation of the PI3K/Nrf2. Moreover, flavone alleviates pulmonary inflammation by inhibiting the inflammatory signaling pathway FOXO1/NF-κB/NLRP3- Inflammasome. Collectively, the obtained results exhibited a notable efficiency of flavone in alleviating lung injury induced by NIC and IR via modulating PI3K/Nrf2 and FoxO1/NLRP3 Inflammasome.
Assuntos
Flavonas , Inflamassomos , Lesão Pulmonar , Nicotina , Animais , Masculino , Ratos , Flavonas/farmacologia , Proteína Forkhead Box O1 , Raios gama , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Nicotina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Melissa officinalis (MO) is a well-known medicinal plant species used in the treatment of several diseases; it is widely used as a vegetable, adding flavour to dishes. This study was designed to evaluate the therapeutic effect of MO Extract against hyperthyroidism induced by Eltroxin and γ-radiation. METHODS: Hyperthyroidism was induced by injecting rats with Eltroxin (100 µg/kg/ day) for 14 days and exposure to γ-radiation (IR) (5 Gy single dose). The hyperthyroid rats were orally treated with MO extract (75 mg/kg/day) at the beginning of the second week of the Eltroxin injection and continued for another week. The levels of thyroid hormones, liver enzymes and proteins besides the impaired hepatic redox status and antioxidant parameters were measured using commercial kits. The hepatic gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein-1(Keap-1) in addition to hepatic inflammatory mediators including tumor necrosis factor-α (TNF- α), Monocyte chemoattractant protein-1 (MCP-1) and fibrogenic markers such as transforming growth factor-beta1 (TGF-ß1) were determined. RESULTS: MO Extract reversed the effect of Eltroxin + IR on rats and attenuated the thyroid hormones. Moreover, it alleviated hyperthyroidism-induced hepatic damage by inhibiting the hepatic enzymes' activities as well as enhancing the production of proteins concomitant with improving cellular redox homeostasis by attenuating the deranged redox balance and modulating the Nrf2/Keap-1 pathway. Additionally, MO Extract alleviated the inflammatory response by suppressing the TNF- α and MCP-1 and prevented hepatic fibrosis via Nrf2-mediated inhibition of the TGF-ß1/Smad pathway. CONCLUSION: Accordingly, these results might strengthen the hepatoprotective effect of MO Extract in a rat model of hyperthyroidism by regulating the Nrf-2/ Keap-1 pathway.
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Hipertireoidismo , Hepatopatias , Melissa , Extratos Vegetais , Animais , Ratos , Expressão Gênica , Hipertireoidismo/complicações , Hipertireoidismo/tratamento farmacológico , Inflamação/metabolismo , Fígado , Melissa/química , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Hormônios Tireóideos/metabolismo , Tiroxina/genética , Tiroxina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Hepatopatias/etiologia , Hepatopatias/terapiaRESUMO
INTRODUCTION: The clinical use of 5-fluorouracil (5-FU), a routinely used chemotherapy medication, has a deleterious impact on the liver. Therefore, it is necessary to find a less harmful alternative to minimize liver damage. This study was designed to see how 5-fluorouracil nanogel influenced 5-FU-induced liver damage in rats. METHODS: To induce liver damage, male albino rats were injected intraperitoneally with 5-FU (12.5 mg/kg) three doses/week for 1 month. The histopathological examination together with measuring the activities of serum alanine and aspartate aminotransferase enzymes (ALT and AST) were used to evaluate the severity of liver damage besides, hepatic oxidative stress and antioxidant markers were also measured. The hepatic gene expression of heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein-1(Keap-1) in addition to hepatic inflammatory mediators including tumor necrosis factor-α (TNF- α) and interleukins (IL-1ß, IL-6) were detected. RESULTS: 5-Fu nanogel effectively attenuated 5-FU-induced liver injury by improving the hepatic structure and function (ALT and AST) besides the suppression of the hepatic inflammatory mediators (TNF- α, IL-1ß and IL-6). Additionally, 5-FU nanogel alleviated the impaired redox status and restored the antioxidant system via maintaining the cellular homeostasis Keap-1/Nrf2/HO-1 pathway. CONCLUSION: Consequently, 5-Fu nanogel exhibited lower liver toxicity compared to 5-FU, likely due to the alleviation of hepatic inflammation and the regulation of the cellular redox pathway.
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Antioxidantes , Doença Hepática Induzida por Substâncias e Drogas , Polietilenoglicóis , Polietilenoimina , Ratos , Masculino , Animais , Antioxidantes/metabolismo , Fluoruracila/toxicidade , Fator 2 Relacionado a NF-E2 , Interleucina-6/metabolismo , Nanogéis , Fígado , Estresse Oxidativo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Mediadores da Inflamação/metabolismoRESUMO
The purpose of this study was to demonstrate the neuroprotective effect of Melissa officinalis extract (MEE) against brain damage associated with hypothyroidism induced by propylthiouracil (PTU) and/or γ-radiation (IR) in rats. Hypothyroidism induction and/or exposure to IR resulted in a significant decrease in the serum levels of T3 and T4 associated with increased levels of lipid peroxidation end product, malondialdehyde (MDA), and nitrites (NO) in the brain tissue homogenate. Also, hypothyroidism and /or exposure to IR markedly enhance the endoplasmic reticulum stress by upregulating the gene expressions of the protein kinase RNA-like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF6), endoplasmic reticulum-associated degradation (ERAD), and CCAAT/enhancer-binding protein homologous protein (CHOP) in the brain tissue homogenate associated with a proapoptotic state which indicated by the overexpression of Bax, BCl2, and caspase-12 that culminates in brain damage. Meanwhile, the PTU and /or IR-exposed rats treated with MEE reduced oxidative stress and ERAD through ATF6. Also, the MEE treatment prevented the Bax and caspase-12 gene expression from increasing. This treatment in hypothyroid animals was associated with neuronal protection as indicated by the downregulation in the gene expressions of the microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) in the brain tissue. Furthermore, the administration of MEE ameliorates the histological structure of brain tissue. In conclusion, MEE might prevent hypothyroidism-induced brain damage associated with oxidative stress and endoplasmic reticulum stress.
Assuntos
Hipotireoidismo , Melissa , Ratos , Animais , Melissa/metabolismo , Degradação Associada com o Retículo Endoplasmático , Proteína X Associada a bcl-2/metabolismo , Caspase 12/metabolismo , Encéfalo/metabolismo , Apoptose , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Estresse do Retículo EndoplasmáticoRESUMO
Objective: Hepatocellular carcinoma (HCC) is one of the most leading causes of death worldwide. Previous studies reported that gallium alone and cetyltrimethylammonium bromide (CTAB) have antineoplastic activities; therefore, this study aimed to evaluate the activity of copper-cetyl tri-methyl ammonium bromide with gallium oxide nanoparticles (Cu-CTAB+GaO-NPs) against HCC by using in vitro and in vivo studies. Methods: In vitro study was performed to evaluate the cytotoxic effects of Cu-CTAB+GaO-NPs and GaO-NPs on HepG-2 cell line using crystal violet dye assay. In vivo study was done on diethyl nitrosamine (DEN) induced HCC Wister rats. Rats were randomly divided into eight groups; control, Cu-CTAB, GaO-NPs, Cu-CTAB+GaONPs, DEN, DEN+Cu-CTAB, DEN+GaO-NPs and DEN+Cu-CTAB+GaO-NPs. Histopathological examination of liver and biochemical parameters such as liver function markers, oxidative stress-antioxidants markers, tumor makers, apoptosis makers were studied. Results: Results obtained from in vitro study revealed that Cu-CTAB+GaO-NPs and GaO-NPs affect the cell viability of HepG-2 cancer cell with IC50 0.2 µg/ml and 360 µg/ml, respectively. Cu-CTAB+GaO-NPs exerted an antiproliferative effect in experimental rat models of HCC, as demonstrated both histologically, since it facilitated the tissue recovery of the damaged liver, and biochemically as showed by the reduction of liver function markers (ALT & AST), oxidative stress markers (MDA) and tumor makers (AFP,TGF-ß1,α-L-Fucosidase); while antioxidants markers (SOD), apoptosis markers (caspase-3 mRNA) and araginase activity were elevated in DEN+Cu-CTAB, DEN+GaO-NPs and DEN+Cu-CTAB+GaO-NPs groups when compared to DEN group. Conclusion: The present study demonstrated that both Cu-CTAB alone and/or combined with GaO-NPs exerted cytotoxic effects against DEN-induced HCC, which would in turn, speculate a possible therapeutic role of the novel Cu-CTAB+GaO-NPs compound.
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Antineoplásicos , Carcinoma Hepatocelular , Gálio , Neoplasias Hepáticas , Nanopartículas , Ratos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Cobre/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Antioxidantes/farmacologia , Cetrimônio/efeitos adversos , Ratos Wistar , Antineoplásicos/uso terapêutico , Gálio/efeitos adversos , Nanopartículas/químicaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disorder. The naturally occurring phytosterol; ß-sitosterol has antiobesogenic and anti-diabetic properties. The purpose of this study was to explore the role of ß-sitosterol in preventing hepatic steatosis induced by a high-fat diet (HFD) in rats. In the current study, to induce NAFLD in the female Wister rats, an HFD was administered to them for 8 weeks. The pathogenic severity of steatosis in rats receiving an HFD diet was dramatically decreased by oral administration of ß-sitosterol. After administering ß-sitosterol to HFD-induced steatosis for three weeks, several oxidative stress-related markers were then assessed. We showed that ß-sitosterol reduced steatosis and the serum levels of triglycerides, transaminases (ALT and AST) and inflammatory markers (IL-1ß and iNOS) compared to HFD-fed rats. Additionally, ß-sitosterol reduced endoplasmic reticulum stress by preventing the overexpression of inositol-requiring enzyme-1 (IRE-1α), X-box binding protein 1(sXBP1) and C/EBP homologous protein (CHOP) genes which, showing a function in the homeostatic regulation of protein folding. Also, it was found that the expression of the lipogenic factors; peroxisome proliferator-activated receptor (PPAR-α), sterol regulatory element binding protein (SREBP-1c) and carnitine palmitoyltransferase-1(CPT-1), which are involved in the regulation of the fatty acid oxidation process, may be regulated by ß-sitosterol. It can be concluded that ß-sitosterol may prevent NAFLD by reducing oxidative stress, endoplasmic reticulum stress and inflammatory responses, which supports the possibility of using ß-sitosterol as an alternative therapy for NAFLD. Together, ß-sitosterol may be an option for NAFLD prevention.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Feminino , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/genética , Metabolismo dos Lipídeos , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ratos Wistar , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Inflamação/metabolismoRESUMO
INTRODUCTION: Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease, and until now therapeutic agents for UC still cannot exert satisfied effects. Therefore, this study aimed to investigate the ameliorative effect of boswellic acid coated zinc nanoparticles (BAs-ZnNPs) on dextran sodium sulphate (DSS) induced-UC in rats. METHODS: Rats were divided into five groups; control, BAs-ZnNPs, DSS, DSS+BAs, and DSS + BAs-ZnNPs. The activity of alkaline phosphatase (ALP) was determined colorimetrically, while the concentration of IgM, IgG, TNF-α, IL-1ß, and IL-8 were measured by ELISA. Levels of gene expression of NF-κB and COX-2 genes were evaluated by RT-qPCR, while the expression of protein levels of PI3K and STAT-3 were done by western blotting. Finally, histopathological examination of colon tissues of different groups of rats was done. RESULTS: The depicted ball-like structure of the BAs-ZnNPs in the TEM images ranging in size from 50 to 100 nm in diameter while their formation was confirmed by UV-visible spectroscopy with a sharp peak of maximum absorbance at 266 nm. Our results revealed that BAs-ZnNPs exerted an anti-inflammatory effect in the experimental model of colitis, demonstrated histologically and biochemically as shown by the improvement of ALP, IgM, IgG, and the gene expression levels of NF-κB and COX-2. Also, this beneficial effect was associated with the reduction in the expression of TNF-α, IL-1ß, IL-8, PI3K, and STAT-3. Thus, this effect improves the altered immune response associated with the colonic inflammation. CONCLUSION: BAs-ZnNPs can be proposed as a therapeutic candidate to attenuate UC. The potential underlying mechanism includes suppression of ALP, IgM, IgG, IL-1ß, and IL-8 levels via regulation of NF-κB and COX-2 gene expression and STAT-3 and PI3K protein expression in a UC rat model.
Assuntos
Colite Ulcerativa , Nanopartículas Metálicas , Zinco , Animais , Ratos , Doença Crônica , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Imunoglobulina G , Imunoglobulina M , Inflamação , Interleucina-8 , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases , Fator de Necrose Tumoral alfa/metabolismo , Zinco/uso terapêuticoRESUMO
The endoplasmic reticulum (ER) controls many biological functions besides maintaining the function of liver cells. Various studies reported the role of the ER stress and UPR signaling pathway in various liver diseases via triggering hepatocytes apoptosis. This study aims to investigate the suppressive effect of ß-sitosterol (ßS) on apoptosis associated with liver injury and ER stress. METHODS: Liver damage in rats was induced by TAA (150 mg/kg I.P twice a week/3 weeks) and γ-irradiation (single dose 3.5 Gy) and treated with ßS (20 mg/kg daily for 30 days). Serum aminotransferase activity, lipid profile and lipid metabolic factors were measured beside liver oxidative stress and inflammatory markers. Moreover, the hepatic expression of ER stress markers (inositol-requiring enzyme 1 alpha (IRE1α), X-box-binding protein 1 (XBP1) and CCAAT/enhancer binding protein homologous protein (CHOP) and apoptotic markers were detected together with histopathological examination. RESULTS: ßS diminished the aminotransferase activity, the oxidative stress markers as well as the inflammatory mediators. Furthermore, ßS lowered the circulating TG and TC and the hepatic lipotoxicity via the suppression of lipogenesis (Srebp-1c) and improved the ß-oxidation (Pparα and Cpt1a) together with the mitochondrial biogenesis (Pgc-1 α). Moreover, the upregulated levels of ER stress markers were reduced upon treatment with ßS, which consequently attenuated hepatic apoptosis. CONCLUSION: ßS relieves hepatic injury, ameliorates mitochondrial biogenesis, and reduces lipotoxicity and apoptosis via inhibition of CHOP and ER stress response.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Estresse do Retículo Endoplasmático , Endorribonucleases , Hepatócitos , Sitosteroides , Animais , Ratos , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Hepatócitos/efeitos dos fármacos , Fígado/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Sitosteroides/farmacologia , Tioacetamida/metabolismo , Tioacetamida/farmacologia , Transaminases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
BACKGROUND: The natural compound's alternative and complementary uses have increased hopes for hepatocellular cancer treatment (HCC). OBJECTS: The goal of this study was to see if Piceatannol (PIC) in combination with cisplatin has a synergistic effect on N, N-nitrosodiethylamine (DEN)-induced HCC in rats. METHODS: Tissue antioxidant enzymes, malondialdehyde (MDA), and nuclear factor erythroid 2 related factors 2 (Nrf2) and tumor necrosis factor α (TNF-α) gene expression were all measured. Nuclear Factor Kabba B (NF-κB) was also tested, as well as hepatic caspase 3 and NAD (P) H quinone oxidoreductase 1 (NQO1). Liver specimens were subjected to histopathological analysis. RESULTS: When compared to the HCC group, piceatannol and/or cisplatin caused a significant improvement in liver function tests, as well as a significant modulation in Nrf2 gene expression and antioxidant enzyme activities, as well as a significant decrease in tissue MDA, TNF-α, NF-κB levels, NQO1 activity, and prompt and caspase-3 activities. When the PIC and/or cisplatin combination was compared to each of these compounds alone, the results were substantial. CONCLUSION: PIC in combination with cisplatin has been shown to have a synergistic anticancer impact through modulating Nrf2 and redox state. In addition, adding PIC to an HCC therapy plan that includes chemotherapeutic medicines may boost the efficacy of cisplatin while reducing its negative effects.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratos , Animais , Dietilnitrosamina/toxicidade , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino , Fator 2 Relacionado a NF-E2 , Antioxidantes , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B , Fator de Necrose Tumoral alfa , OxirreduçãoRESUMO
BACKGROUND: Bisphenol (BPA) and ionizing radiation exposure (IR) are potent oxidants that cause free radical induction, leading to signaling pathway activation that alters cell growth. Due to the insufficient knowledge of the impact of BPA and IR on the lungs, the current study determined the impact of BPA and IR on the lung tissue of adult female Wistar rats. METHODS: Forty Wister female rats were used in this study and were randomly divided into four groups. The rats received BPA (150 mg/kg body weight/day for 6 weeks) and were exposed to IR at 2 Gy/week up to 12 Gy for 6 weeks. RESULTS: It was found that BPA and IR possess a harmful effect on the lungs via induction of oxidative stress, confirmed by increasing levels of malondialdehyde (MDA), nitric oxide, myeloperoxidase (MPO), and lactate dehydrogenase (LDH). Exposure to BPA and IR activates inflammatory cytokines TNF-α, IL-6, IL-1ß, growth factors such as TGF-ß, and gastrin-releasing peptides. BPA/IR exposures induced phosphorylated expression p-ERK1/2 and p-MEK1/2 associated with triggering of the GPER/EGFR/KRAS signaling factors, resulting in matrix metalloproteinase-2 and 9 overexpression and the development of lung tumors. Our findings support the causal role of two deleterious environmental pollutants BPA and IR, via the cytotoxicity in the respiratory system in the form of severe lung damage resulting in cancerous cells.
Assuntos
Sistema de Sinalização das MAP Quinases , Metaloproteinase 2 da Matriz , Animais , Carcinogênese , Receptores ErbB , Feminino , Incidência , Pulmão , Proteínas Proto-Oncogênicas p21(ras) , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
Cancer is a mortality contributor worldwide, and breast cancer is the most common among women. Despite the numerous breast cancer therapeutic strategies, they either have limitations or sometimes are resisted by cancer, so new approaches are needed to tackle those restrictions. Nanotechnology offers exciting leaps in the diagnosis and treatment of cancer, especially breast cancer. The main objective of this study was to investigate the effect of the newly synthesized gallium nanoparticles coated by Ellagic acid (EA-GaNPs) on the induced mammary gland carcinogenesis in female rats and their antibacterial activities comparison with standard antibiotics (Ketoconazole (100 µg/ml) and Gentamycin (4 µg/ml)) by disc diffusion method using eight different microbial species. The antitumor efficacy of EA-GaNPs was conducted both in vitro and in in vivo. The result of antimicrobial activity of EA-Ga NPs (1 mg/1 mL) revealed moderate toxicity behavior against Gram-positive {Staphylococcus aureus, Bacillus subtilis, Bacillus cereus) and Gram-negative pathogenic bacteria {Escherichia coli, Proteus vulgarfs) also, antifungal activity was detected against {Aspergillus terreus). In vitro study showed that EA-GaNPs inhibited human breast cancer cell line (MCF-7) proliferation with IC50 of 2.86 µg/ml. Although in vivo; the administration of EA-GaNPs to DMBA-treated rats ameliorated the hyperplastic state of mammary gland carcinogenesis induced by DMBA. Additionally, EA-GaNPs administration significantly modulated the activities of ALT and AST, as well as the levels of urea and creatinine in serum. Also, EA-GaNPs administration improved the antioxidant state by increasing Superoxide dismutase activity and GSH content, and decreasing malondialdehyde content in the mammary tissue, besides enhancing the apoptotic activity through elevating the levels of caspase-3 and decreasing the protein intensities of protein kinase B & phosphatidyl inositide 3-kinases. Furthermore, a significant decrease in serum Total iron-binding capacity accompanied by a significant increase in the level of calcium was noted. So, it can be concluded that the newly synthesized nanoparticles EA-GaNPs have an efficient antitumor activity that was manifested by reduction of the viability on the human breast cancer cell line (MCF-7) in vitro. Also, in vivo against the chemically induced mammary gland carcinogenesis in a female rat model. Histopathological findings were in harmony with biochemical and molecular results showing the effectiveness of EA-GaNPs against mammary carcinogenesis. Therefore, EA-GaNPs could be a promising, potent anti-cancer compound.
RESUMO
BACKGROUND AND OBJECTIVE: Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern. METHODS: This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks. RESULTS: Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination. CONCLUSION: our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Pancreatite Crônica/terapia , Amilases/metabolismo , Animais , Arginina , Proteína C-Reativa/análise , Citocinas , Dinoprostona/sangue , Lipase/metabolismo , Metabolismo dos Lipídeos , Masculino , Pâncreas/enzimologia , Pâncreas/patologia , Pancreatite Crônica/sangue , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/metabolismo , Ratos Wistar , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Combining chemotherapy with radiotherapy potentiates the outcome of cancer treatment for the more comprehensive attack. In the current study, we continued to assess the therapeutic efficaciousness of the newly synthesized gallium nanoparticles (GaNPs) combined with low level of gamma radiation (IR), on the incidence of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. Oral administration of GaNPs (1 mg/Kg b.wt.) 5 times per week for 6 weeks combined with IR to rats treated with DEN (20 mg/Kg b.wt. 5 times per week for 6 weeks) significantly reduced serum levels of alpha-fetoprotein (AFP), aspartate transferase (AST), alanine transferase (ALT), and gamma-glutamyltransferase (GGT). In addition, the immunoblotting results of matrix metalloproteinase-9 (MM-9) showed a marked downregulation of protein expression along with a significant decrease in the hepatic level of transforming growth factor ß (TGF-ß). Furthermore, GaNPs and/or low dose of radiation significantly elevated the level of caspase-3 gene transcript accompanied with evoked DNA fragmentation in rats treated with DEN. The ameliorative effect of GaNPs and IR well appreciated with the histopathological alteration finding in DEN groups. It can be concluded that the combination of GaNPs and/or IR can serve as a good therapeutic agent for the treatment of HCC, which ought to attract more studies.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Metaloproteinase 9 da Matriz/genética , Fator de Crescimento Transformador beta/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/radioterapia , Caspase 3/genética , Fragmentação do DNA/efeitos dos fármacos , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Gálio/administração & dosagem , Raios gama , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/radioterapia , Nanopartículas Metálicas/administração & dosagem , Doses de Radiação , RatosRESUMO
Guided treatments with nanoparticles and radiotherapy are a new approach in cancer therapy. This study evaluated the beneficial antitumor effects of γ-radiation together with gallium nanoparticles against solid Ehrlich carcinoma in female mice. Gallium nanoparticles were biologically synthesized using Lactobacillus helveticus cells. Transmission electron microscopy showed gallium nanoparticles with size range of 8-20 nm. In vitro study of gallium nanoparticles on MCF-7 revealed IC50 of 8.0 µg. Gallium nanoparticles (0.1 mg/kg body weight) were injected intraperitoneally daily on the seventh day of Ehrlich carcinoma cells inoculation. Whole-body γ-radiation was carried out at a single dose of 0.25 Gy on eighth day after tumor inoculation. Biochemical analysis showed that solid Ehrlich carcinoma induced a significant increase in alanine aminotransferase activity and creatinine level in serum, calcium, and iron concentrations in liver tissue compared to normal control. Treatment of Ehrlich carcinoma-bearing mice with gallium nanoparticles and/or low dose of γ-radiation exposure significantly reduced tumor volume, decreased alanine aminotransferase and creatinine levels in serum, increased lipid peroxidation, and decreased glutathione content as well as calcium and iron concentrations in liver and tumor tissues with intense DNA fragmentation accompanied compared to untreated tumor cells. Moreover, mitochondria in the treated groups displayed a significant increase in Na+/K+-ATPase, complexes II and III with significant reduction in CYP450 gene expression, which may indicate a synergistic effect of gallium nanoparticles and/or low dose of γ-radiation combination against Ehrlich carcinoma injury, and this results were well appreciated with the histopathological findings in the tumor tissue. We conclude that combined treatment of gallium nanoparticles and low dose of gamma-radiation resulted in suppressive induction of cytotoxic effects on cancer cells.
Assuntos
Carcinoma de Ehrlich/radioterapia , Gálio/uso terapêutico , Raios gama/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Alanina Transaminase/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Creatinina/sangue , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Fragmentação do DNA/efeitos da radiação , Feminino , Glutationa/metabolismo , Humanos , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos da radiação , Fígado/metabolismo , Células MCF-7 , Camundongos , Mitocôndrias/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Irradiação Corporal TotalRESUMO
ß-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated ß-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated ß-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated ß-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated ß-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated ß-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of ß-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both ß-glucan therapeutic and preventive treatments. In conclusion, irradiated ß-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal-regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis.