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1.
Mol Cell Biochem ; 457(1-2): 83-91, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30825051

RESUMO

Epithelial-mesenchymal transition (EMT) leads to tumor dissemination and metastasis. Metadherin (MTDH) is an oncogene that plays an important role in metastasis regulation. This study tries to investigate the effect of MTDH gene up-regulation on the activation of EMT in colorectal cancer (CRC) cells and identify the role of NF-κB p65. The CaCO2 cells were divided into three groups: one control group of cultured CaCO2 cells (C1), and two groups of CaCO2 cells co-transfected using human MTDH expression plasmid with either siRNA targeting human NF-κB p65 or its negative control (C2 and C3 respectively). The gene modification was confirmed by qPCR and the effect of gene modification on CRC aggravation was studied. MTDH up-regulation significantly promoted CRC cell proliferation, activated anaerobic respiration (glucose consumption and lactate production), and increased gene expression of multidrug resistance gene (MDR1), Snail transcription factor and NF-κB p65, but decreased the gene expression of E-cadherin. Moreover, MTDH up-regulation led to a significant increase in the acquisition of surface markers of CRC stem cells. Interference with NF-κB p65 gene expression reversed the action of MTDH gene up-regulation on MDR1 and E-cadherin gene expression and anaerobic respiration. Moreover, NF-κB p65 interference significantly decreased MTDH-induced cell proliferation and acquisition of surface markers of CRC stem cells but didn't affect the Snail transcription factor. MTDH-dependent EMT in CRC is activated via NF-κB p65 and is mediated by up-regulation of Snail. These results identify a pathway by which MTDH regulates NF-κB p65 induced EMT during CRC cell metastasis.


Assuntos
Moléculas de Adesão Celular/biossíntese , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Fator de Transcrição RelA/biossíntese , Células CACO-2 , Moléculas de Adesão Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Proteínas de Membrana , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Ligação a RNA , Fator de Transcrição RelA/genética
2.
Mol Cell Biochem ; 444(1-2): 161-168, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29198019

RESUMO

Skeletal muscle atrophy occurs in different catabolic conditions and mostly accompanied with upregulation of Muscle ring finger 1 (MuRF1) gene which is one of the master regulatory genes in muscle atrophy. Taurine amino acid is widely distributed in different tissues and has anti-inflammatory and antioxidant effects. This study aimed to investigate the potential influence of taurine on muscle atrophy induced by reduced mechanical loading. Twenty-eight Albino mice were used, and divided equally into four groups: group I (control); group II (immobilization); group III (immobilization + taurine); and group IV (taurine). Quadriceps muscle sections were taken for histopathology, immunohistochemical analysis of caspase 3 expression, and qRT-PCR of MuRF1 gene. Our data revealed Zenker necrosis associated with axonal injury of the nerve trunk of the immobilized muscle together with increase of caspase 3 expression and upregulation of MuRF1 gene. While, taurine supplementation alleviated the muscular and neural tissues damage associated with disuse skeletal muscle atrophy through downregulation of MuRF1 gene and decrease of tissue caspase 3 expression. In conclusion, taurine may be helpful to counteract apoptosis and up-regulated MuRF1 gene expression related to muscle atrophy, which might be hopeful for a large number of patients.


Assuntos
Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteólise/efeitos dos fármacos , Taurina/farmacologia , Proteínas com Motivo Tripartido/biossíntese , Ubiquitina-Proteína Ligases/biossíntese , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Masculino , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/patologia
3.
Tumour Biol ; 39(2): 1010428317692254, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28218036

RESUMO

Bladder cancer remains a huge concern for the medical community because of its incidence and prevalence rates, as well as high percentage of recurrence and progression. Omega-3 polyunsaturated fatty acids and atorvastatin proved anti-inflammatory effects through peroxisome proliferator-activated receptor gamma mechanism. However, their chemopreventive effect still remained to be examined and clarified. In this study, bladder cancer was induced in rats by the chemical carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid: 2:3 w/w; 1200 mg/kg) and/or atorvastatin (6 mg/kg) were given orally daily to rats for eight consecutive weeks concomitantly with N-butyl-N-(4-hydroxybutyl)nitrosamine and continued for further 4 weeks after cessation of N-butyl-N-(4-hydroxybutyl)nitrosamine administration. The histopathological examination of rat bladder revealed the presence of tumors and the absence of apoptotic bodies in sections from N-butyl-N-(4-hydroxybutyl)nitrosamine group, while tumors were absent and apoptotic bodies were clearly observed in sections from rat groups treated with omega-3 polyunsaturated fatty acids, atorvastatin, or both drugs. The study of the molecular mechanisms illustrated downregulation of COX-2 and P53 (mutant) genes and suppression of transforming growth factor beta-1 and the lipid peroxidation product malondialdehyde in serum of rats of the three treated groups. This chemopreventive effect was confirmed by and associated with lower level of bladder tumor antigen in urine. However, the combined treatment with both drugs exhibited the major protective effect and nearly corrected the dyslipidemia that has been induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. Collectively, omega-3 polyunsaturated fatty acids and atorvastatin, besides having anti-inflammatory properties, proved a chemopreventive effect against bladder cancer, which nominates them to be used as adjuvant therapy with other chemotherapeutics.


Assuntos
Atorvastatina/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Neoplasias da Bexiga Urinária/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Butilidroxibutilnitrosamina , Proliferação de Células/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologia
4.
Nutr Cancer ; 68(6): 1044-51, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27383944

RESUMO

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The current work was designed to elucidate the molecular mechanisms underlying the antitumorigenic effect of pomegranate hull extract (PHE) in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) with emphasis on oxidative stress, proliferation, and apoptosis. Male albino rats were divided into three groups: normal control, DENA group, and PHE group. PHE was given to rats orally 3 times weekly for 10 wk, 4 wk before and 6 wk after DENA (200 mg/kg, single i.p. dose). The results indicated a prophylactic effect of PHE against neoplastic changes in the liver, which was evidenced by the decrease of tumor size, liver index, and the anti-apoptotic protein Bcl-2; and the increase of glutathione. PHE group also showed decreased expression of liver cyclin D1 and ß-catenin genes compared with DENA group. It is proved that PHE has antitumorigenic effect and could be a candidate for anticancer drugs.


Assuntos
Anticarcinógenos/uso terapêutico , Carcinoma Hepatocelular/prevenção & controle , Suplementos Nutricionais , Neoplasias Hepáticas/prevenção & controle , Fígado/metabolismo , Lythraceae/química , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Carcinógenos/toxicidade , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/dietoterapia , Carcinoma Hepatocelular/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Dietilnitrosamina/toxicidade , Frutas/química , Frutas/economia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/patologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Ratos , Taxa de Sobrevida , Carga Tumoral/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismo
5.
Clin Nutr ESPEN ; 61: 253-265, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38777441

RESUMO

BACKGROUND: Pomegranate seed oil (PSO) and avocado seed oil (ASO) are natural polyphenols with established anti-inflammatory activity. PURPOSE: This study aimed to investigate the molecular mechanisms underlying the therapeutic efficacy of PSO and ASO in experimental ulcerative colitis (UC) with reference to sulfasalazine (SLZ). METHODS: Eighty male albino rats were divided equally into 8 groups; Normal, PSO, ASO, SLZ, UC-control, (UC + PSO), (UC + ASO) and (UC + SLZ) groups. Colitis was induced by intra-rectal injection of acetic acid. PSO (0.5ml/200g), ASO (1ml/250g) and SLZ (100 mg/kg) were administered orally once/day for 14 days, 24h after colitis induction. Colitis was evaluated by measuring disease activity index (DAI), colon weight/length ratio and histologic inflammatory score. Vascular endothelial growth factor receptor-2 (VEGFR-2), colonic macrophage migration inhibitory factor (MIF), and malondialdehyde (MDA) were determined. Colonic gene expression of TNF-α, VEGF and heme oxygenase-1 (HO-1) were also estimated. RESULTS: PSO and ASO treatments to UC rats significantly reduced DAI, weight/length ratio, VEGFR-2, and colon histologic inflammatory score versus UC-controls. ASO significantly suppressed MIF levels and TNF-α expression greater than PSO. However, PSO was more significant than ASO in reducing MDA levels and up-regulating HO-1 expression. Both oils significantly down-regulated VEGF expression. The obtained biochemical and histological changes induced by UC were nearly corrected by SLZ. CONCLUSION: The proved beneficial effect of PSO and ASO as anti-inflammatory, anti-angiogenic, and antioxidant in UC rats could be mediated by suppression of TNF-α, VEGF, and MIF and up-regulation of HO-1.


Assuntos
Anti-Inflamatórios , Colite Ulcerativa , Persea , Óleos de Plantas , Punica granatum , Animais , Colite Ulcerativa/tratamento farmacológico , Masculino , Persea/química , Ratos , Punica granatum/química , Óleos de Plantas/farmacologia , Anti-Inflamatórios/farmacologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Malondialdeído/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sementes/química , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Inflamação/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Modelos Animais de Doenças
6.
Life Sci ; 336: 122339, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38097110

RESUMO

AIMS: Breast cancer (BC) is the most frequently occurring cancer in women worldwide. BC patients are often diagnosed at advanced stages which are characterized by low survival rates. Distant metastasis is considered a leading cause of mortalities among BC patients. Epithelial-to-mesenchymal transition (EMT) is a transdifferentiation program that is necessary for cancer cells to acquire metastatic potential. In the last decade, long noncoding RNAs (lncRNAs) proved their significant contribution to different hallmarks of cancer, including EMT and metastasis. The primary aim of our review is to analyze recent studies concerning the molecular mechanisms of lncRNAs implicated in EMT regulation in BC. MATERIALS AND METHODS: We adopted a comprehensive search on databases of PubMed, Web of Science, and Google Scholar using the following keywords: lncRNAs, EMT, breast cancer, and therapeutic targeting. KEY FINDINGS: The different roles of lncRNAs in the mechanisms and signaling pathways governing EMT in BC were summarized. LncRNAs could induce or inhibit EMT through WNT/ß-catenin, transforming growth factor-ß (TGF-ß), Notch, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways as well as via their interaction with histone modifying complexes and miRNAs. SIGNIFICANCE: LncRNAs are key regulators of EMT and BC metastasis, presenting potential targets for therapeutic interventions. Further research is necessary to investigate the practical application of lncRNAs in clinical therapeutics.


Assuntos
Neoplasias da Mama , MicroRNAs , RNA Longo não Codificante , Humanos , Feminino , Neoplasias da Mama/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , MicroRNAs/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica
7.
Gene ; 928: 148785, 2024 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-39053658

RESUMO

Prostate cancer is the most frequent solid tumor in terms of incidence and ranks second only to lung cancer in terms of cancer mortality among men. It has a considerably high mortality rate; around 375,000 deaths occurred worldwide in 2020. In 2024, the American Cancer Society estimated that the number of new prostate cancer cases will be around 299,010 cases, and the estimated deaths will be around 32,250 deaths only in the USA. Cell cycle dysregulation is inevitable in cancer etiology and is targeted by various therapies in cancer treatment. MicroRNAs (miRNAs) are small, endogenous, non-coding regulatory molecules involved in both normal and abnormal cellular events. One of the cellular processes regulated by miRNAs is the cell cycle. Although there are some exceptions, tumor suppressor miRNAs could potentially arrest the cell cycle by downregulating several molecular machineries involved in catalyzing the cell cycle progression. In contrast, oncogenic miRNAs (oncomirs) help the cell cycle to progress by targeting various regulatory proteins such as retinoblastoma (Rb) or cell cycle inhibitors such as p21 or p27, and hence may contribute to prostate cancer progression; however, this is not always the case. In this review, we emphasize how a dysregulated miRNA expression profile is linked to an abnormal cell cycle progression in prostate cancer, which subsequently paves the way to a new therapeutic option for prostate cancer.


Assuntos
Ciclo Celular , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias da Próstata , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Masculino , Ciclo Celular/genética
8.
Nutrition ; 126: 112517, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39146583

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a seriously increasing liver disorder affecting nearly 32% of adults globally. Hepatic triglycerides (TG) accumulation is the hallmark of MASLD, which results from dysregulated lipid and fatty acid uptake, increased de novo lipogenesis (DNL), and decreased lipid removal. More recently, selective autophagy of lipid droplets (LDs), termed lipophagy, has emerged to be closely associated with disrupted hepatic lipid homeostasis. Recent studies have indicated that a series of natural products have shown promise as an alternative approach in attenuating MASLD via regulating lipophagy in vivo and in vitro. Therefore, lipophagy could be a new approach for natural products to be used to improve MASLD. This article aims to provide a comprehensive overview on the interrelationship between dysregulated lipid metabolism, lipophagy, and MASLD pathogenesis. In addition, the role of some natural products as lipophagy modulators and their impact on MASLD will be discussed.


Assuntos
Autofagia , Produtos Biológicos , Metabolismo dos Lipídeos , Fígado , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Autofagia/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Animais , Lipogênese/efeitos dos fármacos , Triglicerídeos/metabolismo , Gotículas Lipídicas/metabolismo
9.
Pathol Res Pract ; 251: 154907, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37925819

RESUMO

With 8.8 million deaths worldwide, cancer is the major reason for the high rate of fatalities. Malignancy's commencement, progression, development, metastasis, and therapy resistance have all been correlated with the epithelial-to-mesenchymal transition (EMT) pathway. EMT promotes the cancer cells' metastatic spread and starts the development of treatment resistance. Sirtuin-1 (SIRT1) is a histone deacetylase that is important for signaling, cell persistence, and apoptosis. It does this by deacetylating important cell signaling molecules and proteins that are associated with apoptosis. The function of SIRT1 in EMT and cancer progression, as well as the emerging therapeutic strategy of treating cancer through the inhibition of SIRT1 and EMT will be discussed in detail.


Assuntos
Neoplasias , Sirtuína 1 , Humanos , Sirtuína 1/metabolismo , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Transdução de Sinais
10.
Curr Drug Saf ; 18(3): 345-354, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35507797

RESUMO

BACKGROUND: Lactoferrin (LF) is a member of the transferrin family, which is known for its immunomodulatory properties. LF has been widely used as an anticancer medication in various cancers including breast cancer. AIMS: The current study aimed to examine the molecular mechanisms underlying the therapeutic potential of recombinant human lactoferrin (rhLF), either alone or combined with epirubicin (EPI), in mice bearing solid Ehrlich carcinoma (SEC). METHODS: SEC-bearing female mice (n=40) were divided into 4 equal groups. Mice were given rhLF orally (100mg/kg/mouse) daily and/or EPI i.p (8mg/kg/mouse). The experiment lasted 14 days, after which samples were collected to measure IL-18 and phosphorylated c-Jun N-terminal kinase (p-JNK) by ELISA and p53 gene expression by real-time PCR. RESULTS: Administration of rhLF, either alone or combined with EPI, markedly decreased the tumor volume and increased tumor inhibition rate as well as survival rate compared to either tumor control group or EPI-mono treated group. In addition, co-administration of rhLF and EPI increased the level of activated JNKs and expression of p53 in tumor tissues compared to the tumor, control group, exhibiting their pro-apoptotic properties. Moreover, the combined treatment with rhLF and EPI elevated IL-18 level in the intestinal mucosa compared to other experimental groups with a possible immune-enhancing effect. CONCLUSION: Recombinant human lactoferrin exhibited potential anticancer and immune-enhancing properties in mice with breast cancer. Co-treatment with rhLF and EPI proved to be a promising strategy in cancer treatment.


Assuntos
Neoplasias da Mama , Carcinoma , Animais , Camundongos , Humanos , Feminino , Lactoferrina/farmacologia , Lactoferrina/genética , Lactoferrina/metabolismo , Epirubicina/farmacologia , Interleucina-18/metabolismo , Carcinoma/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Proteínas Recombinantes/farmacologia
11.
Int Immunopharmacol ; 119: 110148, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37044036

RESUMO

BACKGROUND: Breast cancer is usually associated with metastatic features, poor prognosis, and high mortality. The epithelial-mesenchymal transition (EMT) process has been implicated in the initiation and metastasis of breast cancer. OBJECTIVE: The study aimed to investigate the possible role of montelukast (Mont), the cysteinyl leukotriene receptor (CystLT1R) antagonist, in mitigating EMT in triple-negative breast cancer (TNBC) (in vitro study) and solid Ehrlich carcinoma (SEC) bearing mice (in vivo study) as well as to clarify the underlying molecular mechanisms in the presence and absence of sirtuin-1 inhibitor (sirtinol; Sirt). METHODS: TNBC MDA-MB-231 cells were treated with either 5 µM Mont or 25 µM Sirt or both for 48 h. Alternatively, SEC cells were inoculated in mice to induce breast cancer. After 12 days, the mice were divided into four groups: Untreated SEC group (vehicle), Sirt group (1 mg/kg), Mont group (10 mg/kg), and cotreatment Sirt/Mont group. The mice groups received the assigned treatment for the consequent 16 days. RESULTS: Mont and/or Sirt decreased cell proliferation, migration and suppressed EMT in both in vitro and in vivo experiments. All treatments downregulated sirtuin-1 and vimentin expression but upregulated E-cadherin expression. Furthermore, all treatments retarded angiogenesis as evidenced by decreased VEGF expression. These findings were associated with suppressing active protein kinase B (p-AKT). CONCLUSION: Cotreatment with Sirt and Mont proved more effective anti-tumor activity in TNBC cell line and in SEC bearing mice than either treatment alone, which could be attributed to the inhibition of sirtuin-1 and AKT- activated pathways, with the subsequent inhibition of EMT.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transição Epitelial-Mesenquimal , Sirtuína 1/metabolismo , Transdução de Sinais , Proliferação de Células , Linhagem Celular Tumoral , Movimento Celular
12.
Med Int (Lond) ; 2(3): 14, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36698506

RESUMO

Diabetes mellitus is the most common chronic metabolic disorder worldwide. The present study was designed to investigate the potential role of cinnamon bark extract oligomeric proanthocyanidins (OPCs) in controlling streptozotocin (STZ)-induced hyperglycemia and to clarify the underlying molecular mechanisms underlying its effects. For this purpose, 60 male rats were equally divided into six groups as follows: The normal control group; OPC control group (non-diabetic rats treated with OPC at 300 mg/kg orally for 21 days); the untreated diabetic control group; the wortmannin control group [diabetic rats treated with wortmannin at 1 mg/kg, intraperitoneal (i.p.) on the final day of the experiment]; the OPC diabetic group (diabetic rats treated with OPC at 300 mg/kg orally for 21 days); and the OPC diabetic + wortmannin co-treated group (diabetic rats treated with OPC at 300 mg/kg/day for 21 consecutive days and then 24 h after the final OPC dose treated with a single wortmannin injection at 1 mg/kg, i.p.). The results indicated that OPC ameliorated the diabetic state, as evidenced by a significant decrease in serum glucose levels, and a significant increase in the levels of insulin, amylin, insulin receptor phosphorylation, glycogen and glucose transporter-4 translocation; it also improved the lipid profile in STZ-diabetic rats. On the whole, the findings of the present study provide biochemical evidence that OPC treatment is effective as an anti-diabetic and anti-hyperlipidemic agent by enhancing glucose uptake through the activation of insulin receptor kinase activity and the PI3K/Akt pathway.

13.
Curr Drug Saf ; 17(3): 250-258, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34814819

RESUMO

BACKGROUND: Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis. METHODS: A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level < 10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Prespecified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed. RESULTS: Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients. CONCLUSION: Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.


Assuntos
Anemia , Eritropoetina , Falência Renal Crônica , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Darbepoetina alfa/efeitos adversos , Egito , Epoetina alfa/efeitos adversos , Eritropoetina/efeitos adversos , Hemoglobinas/uso terapêutico , Humanos , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/complicações , Falência Renal Crônica/tratamento farmacológico , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia
14.
Asian Pac J Cancer Prev ; 23(11): 3763-3770, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36444589

RESUMO

OBJECTIVE: The study aimed to investigate the anticancer effect of E-prostanoid receptor 1 (EP1) antagonist, SC19220, alone or in combination with the COX-2 inhibitor Celecoxob(CXB)® in mice bearing solid Ehrlich carcinoma (SEC). METHODS: The tumors were induced in 40 female mice, which were divided randomly into four equal groups (n= 10 in each group): Tumor control, CXB, EP1 antagonist, and co-treatment. CXB (10mg/kg) and EP1 antagonist (2mg/kg) were given intraperitoneally every three days, six times in total, then tissue was extracted and prepared for histopathology and measurement of weight, PGE2, and gene expression of EP1 and ß 1 integrin. RESULTS: Both inhibitors, alone or in combination, showed a significant (p<0.001) antitumorigenic effect by decreasing, significantly (p<0.001), each of the tumor weights, tumor volumes, PGE2 levels, EP1 and ß1-integrin gene expression along with increasing, significantly (p<0.001), the P53 tumor suppressor protein. The survival rate was improved from 80% in the control group to reach 100% in the treated groups. The co-treatment by CXB and EP1 antagonist showed a marked decrease in tumor weights and volumes as compared with the single treatment. In parallel, the histopathological findings showed enhanced apoptosis and diminished necrosis in the co-treated group. CONCLUSION: EP1 antagonist proved an antitumorigenic effect alone or combined with CXB and could play a new therapeutic strategy against breast cancer.


Assuntos
Carcinoma , Dinoprostona , Feminino , Camundongos , Animais , Receptores de Prostaglandina , Modelos Animais de Doenças , Integrinas
15.
PLoS One ; 16(5): e0251408, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33984042

RESUMO

AIM: Nephrolithiasis is a chronic metabolic condition affecting 10% of population worldwide. The present study aimed to investigate the possible protective role of candesartan (CAND) and sodium thiosulfate (STS) in ameliorating ethylene glycol (EG) induced nephrolithiasis. METHODS: One hundred male Wistar rats were divided into five groups: Normal control group, nephrolithiasis (EG) group (1% EG in drinking water), Cystone (CYS) group (EG + 750 mg/kg CYS, orally, once daily), STS group (EG + 0.4 gm/kg STS, intraperitoneally, 3 times/week) and CAND group (EG + 70 µg/mL CAND in drinking water). Treatments and EG administration commenced on the same day and continued for 28 days. CYS was used as reference drug. Urine, blood, and renal tissues were collected at the end of the experiment for assessment of kidney function tests (serum creatinine and urea), urinary (8-hydroxydeoxyguanosine (8-OHdG), calcium and oxalate), inflammatory and oxdative stress biomarkers (transforming growth factor beta (TGF-ß), osteopontin (OPN) and ratio of reduced glutathione to oxidized glutathione (GSH/GSSG)) in renal tissue. RESULTS: Serum (creatinine and urea), urinary (8-OHdG and oxalate) and renal (OPN and TGF-ß) were significantly reduced in CAND and STS groups compared to EG group. Furthermore, renal GSH/GSSG and urinary calcium were significantly increased in CAND and STS groups compared to EG group. Histopathological results support the biochemical findings; CAND and STS groups showed less retention of crystals and necrotic damage in kidney. Also, microscopic examination of urine revealed less crystal for CAND and STS groups. CONCLUSION: Candesartan and sodium thiosulfate exhibited protective effect against nephrolithiasis.


Assuntos
Benzimidazóis/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Nefrolitíase/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Tetrazóis/uso terapêutico , Tiossulfatos/uso terapêutico , Animais , Etilenoglicol , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Nefrolitíase/induzido quimicamente , Nefrolitíase/patologia , Ratos Wistar
16.
Chem Biol Interact ; 333: 109330, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33245929

RESUMO

AIM: Benzo[a]pyrene [BP] is one of the major carcinogenic precursors of cigarette smoke that primary affects the lung at its first proximity. The goal of the current research was to elucidate new mechanisms underlying the tumorigenic impact of oral BP in the lung of mice, with focus on immunosuppressive effects and cancer stemming properties. METHODS: Female albino mice (n = 44) were divided into 2 groups: normal control and BP group. BP was administered orally to mice (50 mg/kg body weight), twice a week for four weeks in succession. At the end of experiment (22 weeks), gene expression were measured for transforming growth factor-ß (TGF-ß), cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death ligand 1(PD-L1), forkhead box protein P3 (FOXP3) and interleukin 12 (IL-12) and CD83+, CD8+ and CD166+ cell percentage were measured in lung tissue. RESULTS: The results indicated the tumorigenic role of BP in the lung which was evidenced by histopathological examination. BP group also showed immunosuppressive role which evidenced by increased expression of lung TGF-ß, CTLA-4, PD-L1, FOXP3 genes and decreased expression of lung IL-12 gene compared with normal control group. BP group also showed decreased CD83+ cells, CD8+ cells and increased number of CD166+ cells. CONCLUSION: Our findings indicated that BP has immunosuppressive role in lung cancer besides increasing the percentage of cancer stem like cells.


Assuntos
Benzo(a)pireno/farmacologia , Carcinogênese/efeitos dos fármacos , Imunossupressores/farmacologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Animais , Antígenos CD/metabolismo , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-12/genética , Camundongos , Análise de Sobrevida , Fator de Crescimento Transformador beta/genética , Carga Tumoral/efeitos dos fármacos
17.
Toxicol Rep ; 8: 1530-1537, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408972

RESUMO

Prostaglandin E2 (PGE2) and ß1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ ß1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-Ò¡B and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and ß1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-Ò¡B were added followed by measurement of ß1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased ß1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, ß1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-Ò¡B suppressed 17 -PT-PGE2-mediated ß1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-Ò¡B, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-Ò¡B inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.

18.
Pathol Oncol Res ; 26(3): 1947-1956, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31902118

RESUMO

Benign prostatic hyperplasia (BPH) is considered a normal part of the aging process in men, and is characterized by an imbalance between cell proliferation and apoptosis. Our study aimed to investigate the potential protective role of silymarin (SIL) against testosterone-induced BPH in rats and to elucidate the molecular mechanisms underlying SIL pro-apoptotic and anti-proliferative effects. Forty adult male Wistar rats were divided equally into four groups: control group, BPH group (3 mg/kg testosterone propionate, s.c. for 14 days, SIL group (50 mg/kg SIL, orally, once daily concomitantly with 3 mg/kg testosterone propionate s.c.) and inhibitor group (50 mg/kg SIL orally concomitantly with 3 mg/kg testosterone, s.c. and 0.5 mg/rat Z-VAD-FMK, i.p.). Silymarin induced caspase-dependent apoptosis in BPH as SIL significantly reduced prostatic Bcl-2 protein and increased Bax protein concentration. Also, SIL down-regulated survivin (Inhibitor of apoptosis protein (IAPs) gene expression in rat prostate assisting mainly caspase-dependent pathway. Silymarin significantly decreased cytochrome-c cytosolic concentration and increased caspase 3 activity compared to BPH group. Silymarin significantly increased the content of p27/kip1 (Cyclin dependent kinase inhibitor (CDKIs) promoting cell cycle arrest. The histological features of BPH such as hypertrophy, papillary projections formation, improved in SIL group. Silymarin showed a significant anti-proliferative and pro-apoptotic role in BPH and accordingly it could be effectively and safely used as a treatment tool in cases of BPH or prostatic disorders.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Hiperplasia Prostática/patologia , Silimarina/farmacologia , Animais , Masculino , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Ratos , Ratos Wistar , Testosterona/toxicidade
19.
Life Sci ; 259: 118212, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768581

RESUMO

AIMS: Autophagy plays a complex role in breast cancer by suppressing or improving the efficiency of treatment. Triple-negative breast cancer (TNBC) cell line (MDA-MB-231) is associated with aggressive response and developing therapy resistance. MDA-MB-231 cells depend on autophagy for survival. Also, the potential benefits of autophagy inhibition in ameliorating developed chemotherapy resistance towards MDA-MB-231 remains to be elucidated. Despite showing anti-tumorigenic activities, the use of lovastatin and docosahexaenoic acid (DHA) for treating different types of cancers is still limited. We aimed to investigate the protective effect of autophagy inhibition by chloroquine (CQ) in MDA-MB-231 cells resistance treated with lovastatin or DHA. MAIN METHODS: MDA-MB-231 cells were treated with 30 µM lovastatin and/or 100 µM DHA for 48 h plus 20 µM CQ. Autophagic flux was assessed in association with the expression of multidrug resistance gene 1 (MDR1), transforming growth factor beta 1 gene (TGF-ß1), and autophagy-related 7 gene (ATG7). KEY FINDINGS: Both drugs exhibited dose-dependent cytotoxicity, enhanced the autophagic flux represented by increased LC3BII protein concentration and decreased p62 protein concentration, and up-regulated the expression of MDR1, TGF-ß1, and ATG7 genes. CQ addition enhanced the cytotoxicity of drugs and inhibited the autophagic flux which is detected by higher levels of LC3BII and p62 correlated with the reverted MDR1, TGF-ß1 and ATG7 genes expression. SIGNIFICANCE: Autophagy inhibition by CQ showed an ameliorative effect on lovastatin- and DHA-induced resistance and enhanced their cytotoxicity, providing a promising strategy in breast cancer therapy.


Assuntos
Autofagia/efeitos dos fármacos , Cloroquina/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cloroquina/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Humanos , Lovastatina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/fisiopatologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-32181246

RESUMO

More attention has been recently directed toward glutathione peroxidase and s-transferase enzymes because of the great importance they hold with respect to their applications in the pharmaceutical field. This work was conducted to optimize the production and characterize glutathione peroxidase and glutathione s-transferase produced by Lactobacillus plantarum KU720558 using Plackett-Burman and Box-Behnken statistical designs. To assess the impact of the culture conditions on the microbial production of the enzymes, colorimetric methods were used. Following data analysis, the optimum conditions that enhanced the s-transferase yield were the De Man-Rogosa-Sharp (MRS) broth as a basal medium supplemented with 0.1% urea, 0.075% H2O2, 0.5% 1-butanol, 0.0125% amino acids, and 0.05% SDS at pH 6.0 and anaerobically incubated for 24 h at 40°C. The optimum s-transferase specific activity was 1789.5 U/mg of protein, which was ~12 times the activity of the basal medium. For peroxidase, the best medium composition was 0.17% urea, 0.025% bile salt, 7.5% Na Cl, 0.05% H2O2, 0.05% SDS, and 2% ethanol added to the MRS broth at pH 6.0 and anaerobically incubated for 24 h at 40°C. Furthermore, the optimum peroxidase specific activity was 612.5 U/mg of protein, indicating that its activity was 22 times higher than the activity recorded in the basal medium. After SDS-PAGE analysis, GST and GPx showed a single protein band of 25 and 18 kDa, respectively. They were able to retain their activities at an optimal temperature of 40°C for an hour and pH range 4-7. The 3D model of both enzymes was constructed showing helical structures, sheet and loops. Protein cavities were also detected to define druggable sites. GST model had two large pockets; 185Å3 and 71 Å3 with druggability score 0.5-0.8. For GPx, the pockets were relatively smaller, 71 Å3 and 32 Å3 with druggability score (0.65-0.66). Therefore, the present study showed that the consortium components as well as the stress-based conditions used could express both enzymes with enhanced productivity, recommending their application based on the obtained results.

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