RESUMO
Mesenchymal stem cells have therapeutic properties that are related to their potentials for trans-differentiation, immunomodulation, anti-inflammatory, inhibitory effect on tumor proliferation, and induction of apoptosis. This study was performed to analyze the role of mesenchymal stem cells as an alternative for cellular signaling growth factors involved in the pathogenesis of leukemogenesis in rats. Treatment of rats with 7,12-dimethyl benz [a] anthracene induced leukemogenesis appeared as a significant decrease in hematological parameters with concomitant significant increase in bone marrow oxidative and inflammatory indices (transforming growth factor beta and interleukin-6) in comparison with normal groups. On the contrary, Western immunoblotting showed a significant increase in the signaling growth factors: PI3K, AKT, mTOR proteins and a significant decrease in PTEN in 7,12-dimethyl benz [a] anthracene-treated group. In addition, a significant increase in the transcript levels of B cell lymphoma-2 protein gene in the 7,12-dimethyl benz [a] anthracene group, while that of C-X-C motif chemokine receptor-4 and B cell lymphoma-2 protein associated x-protein were significantly downregulated compared to controls. Meanwhile, therapeutic mesenchymal stem cells treatment predict a significant improvement versus 7,12-dimethyl benz [a] anthracene group through the modulation of growth factors that confront bone marrow dysplasia. In the same direction treatment of 7,12-dimethyl benz [a] anthracene group with mesenchymal stem cells, it induced apoptosis and increased the homing efficacy to bone marrow. In conclusion, mesenchymal stem cells improve hematopoiesis and alleviate inflammation, and modulated PI3K/AKT signaling pathway contributed to experimental leukemogenesis.
Assuntos
Leucemia/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteína Oncogênica v-akt/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Apoptose/genética , Células da Medula Óssea/patologia , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Humanos , Leucemia/induzido quimicamente , Leucemia/genética , Leucemia/patologia , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases/genética , Ratos , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
Previous studies have shown that aspirin is used in colon cancer treatment. However, long-term of Aspirin usage is limited to gastric and renal toxicity. Luteolin (LUT) has cancer prevention and anti-inflammatory effects. The present study was designed to investigate the effect of LUT supplementation and Aspirin treatment in dimethylhydrazine (DMH)-induced carcinogenesis in rats. DMH (20 mg/kg BW/week) treated rats received gavages with Aspirin (50 mg/kg BW/week) and LUT (0.2 mg/kg BW/day) for 15 weeks. DMH injections induce colon polyps and renal bleeding, significantly increasing carcinoembryonic antigen (CEA), cyclooxygenase-2 (COX-2), oxidative stress, and kidney function tests and reducing antioxidant markers. Either Aspirin or LUT gavages alone or combined produce a significant decrease in colon polyp number and size, significantly decreasing CEA, COX-2, and oxidative stress and increasing antioxidant markers. In conclusion, the supplementations of LUT adjacent to Aspirin in the treatment of DMH-induced carcinogenesis in rats reflect a better effect than the use of Aspirin alone.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aspirina/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Luteolina/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antígeno Carcinoembrionário/biossíntese , Carcinogênese/efeitos dos fármacos , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/biossíntese , Dimetilidrazinas/toxicidade , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
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.
Assuntos
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
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
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
Breast cancer is one of the most prevalent and deadliest cancers among women in the world because of its aggressive behavior and inadequate response to conventional therapies. Mesenchymal stem cells (MSCs) combined with green nanomaterials could be an efficient tool in cell cancer therapy. This study examined the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) with selenium nanoparticles (SeNPs) coated with fermented soymilk and a low dose of gamma radiation (LDR) in DMBA-induced mammary gland carcinoma in female rats. DMBA-induced mammary gland carcinoma as marked by an elevation of mRNA level of cancer promoter genes (Serpin and MIF, LOX-1, and COL1A1) and serum level of VEGF, TNF-α, TGF-ß, CA15-3, and caspase-3 with the reduction in mRNA level of suppressor gene (FST and ADRP). These deleterious effects were hampered after treatment with BM-MSCs (1 × 106 cells/rat) once and daily administration of SeNPs (20 mg/kg body weight) and exposure once to (0.25 Gy) LDR. Finally, MSCs, SeNPs, and LDR notably modulated the expression of multiple tumor promoters and suppressor genes playing a role in breast cancer induction and suppression.
Assuntos
Carcinoma , Células-Tronco Mesenquimais , Nanopartículas , Selênio , Ratos , Feminino , Animais , Selênio/farmacologia , Selênio/metabolismo , Microambiente Tumoral , Raios gama , Carcinogênese/metabolismo , Carcinogênese/patologia , Transformação Celular Neoplásica/metabolismo , Carcinoma/metabolismo , Carcinoma/patologiaRESUMO
The use of 5-fluorouracil (5-FU) is associated with multifaceted challenges and poor pharmacokinetics. Accordingly, our study was designed to prepare 5-FU nanogel as a new form of the colon cancer chemotherapeutic drug 5-FU using polyacrylic acid and gelatin hybrid nanogel as efficient drug carriers. Alongside the in vivo chemotherapeutic evaluation, the anti-proliferative and anti-apoptotic efficacy were carried out for 5-FU nanogel against 1,2-dimethylhydrazine (DMH, 20 mg/kg) and γ-radiation (4 Gy)-prompted colon dysplasia in rats compared to 5-FU. The morphology and size of 5-FU nanogel were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) in addition to cytotoxicity assay. The expression of phosphoinositide-3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR); Toll-like receptor2 (TLR2)/nuclear factor kappa B), adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream autophagy-related genes in addition to apoptotic markers were measured in colon tissues. Results: 5-FU nanogel reduced the levels of the TLR2/ NF-κß as well as the expression of PI3K/AKT/mTOR. Moreover, it promoted autophagy through the activation of the AMPK and its downstream targets which consequently augmented the intrinsic and extrinsic apoptotic pathways. Conclusion: Collectively, these data might strengthen the therapeutic potential of 5-FU nanogel which can be used as an antitumor product for colon cancer.
RESUMO
Nattokinase (NK), a protease enzyme produced by Bacillus subtilis, has various biological effects such as lipid-lowering activity, antihypertensive, antiplatelet/anticoagulant, and neuroprotective effects. Exposure to environmental toxicants such as bisphenol A (BPA) or γ-radiation (IR) causes multi-organ toxicity through several mechanisms such as impairment of oxidative status, signaling pathways, and hepatic and neuronal functions as well as disruption of the inflammatory responses. Therefore, this study is designed to evaluate the ameliorative effect of NK against BPA- or IR-induced liver and brain damage in rats. Serum ammonia level and liver function tests were measured in addition to brain oxidative stress markers, amyloid-beta, tau protein, and neuroinflammatory mediators. Moreover, relative quantification of brain nuclear factor-erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) genes, as well as apoptotic markers in brain tissue, was carried out in addition to histopathological examination. The results showed that NK improved liver functions, impaired oxidative status, the cholinergic deficits, and minified the misfolded proteins aggregates. Furthermore, NK alleviated the neuroinflammation via modulating NF-κB/Nrf2/HO-1 pathway and glial cell activation in addition to their antiapoptotic effect. Collectively, the current results revealed the protective effect of NK against hepatic and neurotoxicity derived from BPA or IR.
Assuntos
Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Subtilisinas , Animais , Ratos , Amônia/metabolismo , Compostos Benzidrílicos/toxicidade , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Lipídeos , Fígado , Fármacos Neuroprotetores/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Fenóis/toxicidade , Subtilisinas/farmacologia , Proteínas tau/metabolismo , Raios gama/efeitos adversosRESUMO
Alzheimer's disease (AD) is a brain disorder associated with a gradual weakening in neurocognitive functions, neuroinflammation, and impaired signaling pathways. Resveratrol (RSV) has neuroprotective properties, but with low bioavailability, and low solubility in vivo. Selenium (Se) is an essential micronutrient for brain function. Thus, this study aimed to evaluate the role of formulated RSV-Se nanoparticles (RSV-SeNPs) on neurochemical and histopathological approaches associated with the AD model in rats induced by Aluminum chloride (AlCl3) at a dose of 100 mg/kg/day for 60 days. RSV-SeNPs supplementation attenuates the impaired oxidative markers and mitochondrial dysfunction. The ameliorative effect of RSV-SeNPs on cholinergic deficits was associated with clearance of amyloid ß (Aß). Furthermore, activation of phosphatidylinositol 3 kinase (PI3K) deactivates glycogen synthase kinase 3 beta (GSK-3ß)-mediated tau hyperphosphorylation. Additionally, RSV-SeNPs downregulate signal transducer and activator of transcription (STAT3) expression as well as interleukin-1ß (IL-1ß) levels, therefore alleviating neuroinflammation in AD. Moreover, RSV-SeNPs upregulate the expression of Sirtuin-1 (SIRT1) and lower that of microRNA-134, consequently increasing neurite outgrowth. Eventually, the obtained results showed that nano-formulation of resveratrol with selenium maximized the therapeutic potential of RSV against Alzheimer's disease not only by their antioxidant but also by anti-inflammatory effect improving the neurocognitive function and modulating the signaling pathways.
Assuntos
Doença de Alzheimer , MicroRNAs , Nanopartículas , Síndromes Neurotóxicas , Selênio , Cloreto de Alumínio , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Colinérgicos , Glicogênio Sintase Quinase 3 beta , Interleucina-1beta , Micronutrientes/uso terapêutico , Nanopartículas/química , Doenças Neuroinflamatórias , Síndromes Neurotóxicas/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Ratos , Resveratrol/farmacologia , Selênio/farmacologia , Selênio/uso terapêutico , Sirtuína 1/metabolismoRESUMO
Acute Pancreatitis (AP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluate the role the of Cinnamic acid nanoparticles (CA-NPs) as a modulator for the redox signaling pathway involved in the development of pancreatitis. AP in rats was induced by L-arginine and exposure to gamma radiation. The pancreatic injury was evaluated using biochemical and histological parameters. Upon the oral administration of CA-NPs, both the severity of acute pancreatitis and the serum levels of amylase and lipase were decreased. Furthermore, the malondialdehyde (MDA) levels of the pancreatic tissue were significantly reduced and the depletion of glutathione was considerably restored. The injury and apoptosis of pancreatic tissues were markedly improved by the reduction of the caspase-3 levels. Additionally, the alleviation of pancreatic oxidative damage by CA-NPs was accompanied by a down-regulation of the NLRP3, NF-κB, and ASK1/MAPK signaling pathways. Collectively, the current findings showed that CA-NPs could protect the pancreatic acinar cell from injury not only by its antioxidant, anti-inflammatory effect but also by modulation of the redox-sensitive signal transduction pathways contributed to acute pancreatitis severity. Accordingly, cinnamic acid nanoparticles have therapeutic potential for the management of acute pancreatitis.