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1.
Oncology ; 98(2): 61-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31846959

RESUMO

BACKGROUND: Radiation therapy is a cornerstone of the therapeutic modalities used in modern oncology. However, it is sometimes limited in its ability to achieve optimal tumor control by radiation-induced normal tissue toxicity. In delivering radiation therapy, a balance must be achieved between maximizing the dose to the tumor and minimizing any injury to the normal tissues. Amifostine was the first Food and Drug Administration (FDA)-approved clinical radiation protector intended to reduce the impact of radiation on normal tissue, lessening its toxicity and potentially allowing for increased tumor dose/control. Despite being FDA-approved almost 20 years ago, Amifostine has yet to achieve widespread clinical use. SUMMARY: A thorough review of Amifostine's development, mechanism of action, and current clinical status were conducted. A brief history of Amifostine is given, from its development at Walter Reid Institute of Research to its approval for clinical use. The mechanism of action of Amifostine is explored. The results of a complete literature review of all prospective randomized trials to date involving the use of Amifostine in radiation therapy are presented. The results are arranged by treatment site and salient findings discussed. Side effects and complications to consider in using Amifostine are reviewed. Key Messages: Amifostine has been explored as a radiation protectant in most radiation treatment sites. Studies have demonstrated efficacy of Amifostine in all treatment sites reviewed, but results are heterogeneous. The heterogeneity of studies looking at Amifostine as a clinical radiation protectant has precluded a definitive answer on its efficacy. Complicating its clinical use is its toxicity and delivery requirements. Amifostine has largely fallen out of use with the advent of intensity modulated radiation therapy (IMRT). However, side effects with IMRT remain a challenge and concern. The use of Amifostine in the IMRT era has been poorly explored and is worthy of future study.


Assuntos
Amifostina/uso terapêutico , Citoproteção/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Protetores contra Radiação/uso terapêutico , Amifostina/administração & dosagem , Amifostina/efeitos adversos , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Humanos , Especificidade de Órgãos , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Resultado do Tratamento
2.
Presse Med ; 48(12): 1489-1495, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757735

RESUMO

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Citoproteção/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Seleção de Pacientes , Preparações Farmacêuticas/classificação , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico
3.
J Biomed Sci ; 26(1): 63, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31470848

RESUMO

BACKGROUND: Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the cure rates for AML patients remain low, and the notorious adverse effects of chemotherapeutic drugs drastically reduce the life quality of patients. Penfluridol, a long-acting oral antipsychotic drug, has an outstanding safety record and exerts oncostatic effects on various solid tumors. Until now, the effect of penfluridol on AML remains unknown. METHODS: AML cell lines harboring wild-type (WT) Fms-like tyrosine kinase 3 (FLT3) and internal tandem duplication (ITD)-mutated FLT3 were used to evaluate the cytotoxic effects of penfluridol by an MTS assay. A flow cytometric analysis and immunofluorescence staining were employed to determine the cell-death phenotype, cell cycle profile, and reactive oxygen species (ROS) and acidic vesicular organelle (AVO) formation. Western blotting and chemical inhibitors were used to explore the underlying mechanisms involved in penfluridol-mediated cell death. RESULTS: We observed that penfluridol concentration-dependently suppressed the cell viability of AML cells with FLT3-WT (HL-60 and U937) and FLT3-ITD (MV4-11). We found that penfluridol treatment not only induced apoptosis as evidenced by increases of nuclear fragmentation, the sub-G1 populations, poly (ADP ribose) polymerase (PARP) cleavage, and caspase-3 activation, but also triggered autophagic responses, such as the light chain 3 (LC3) turnover and AVO formation. Interestingly, blocking autophagy by the pharmacological inhibitors, 3-methyladenine and chloroquine, dramatically enhanced penfluridol-induced apoptosis, indicating the cytoprotective role of autophagy in penfluridol-treated AML cells. Mechanistically, penfluridol-induced apoptosis occurred through activating protein phosphatase 2A (PP2A) to suppress Akt and mitogen-activated protein kinase (MAPK) activities. Moreover, penfluridol's augmentation of intracellular ROS levels was critical for the penfluridol-induced autophagic response. In the clinic, we observed that patients with AML expressing high PP2A had favorable prognoses. CONCLUSIONS: These findings provide a rationale for penfluridol being used as a PP2A activator for AML treatment, and the combination of penfluridol with an autophagy inhibitor may be a novel strategy for AML harboring FLT3-WT and FLT3-ITD.


Assuntos
Antipsicóticos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Penfluridol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Células HL-60 , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Transdução de Sinais , Células U937
4.
Food Chem Toxicol ; 133: 110798, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473340

RESUMO

In this work, the cytotoxicity of Beauvericin (BEA), lutein (LUT), zeaxanthin (ZEAX) and goji berries extract (GBE) rich in carotenoids, was investigated, as well as cytoprotective effects of these carotenoids against BEA induced-cytotoxicity on Caco-2 cells. Cytotoxicity was carried out using MTT and protein content (PC) assays during 24 and 48 h of exposure. Only BEA showed cytotoxic effect obtaining a reduction in cell proliferation range from 6.5 to 92.8%. Simultaneous combination of LUT and ZEAX with BEA slightly increased cell proliferation compared to BEA tested alone. LUT, ZEAX and GBE showed cytoprotective effects against cytotoxicity induced by BEA on Caco-2 cells. Pre-treatment assays showed the highest cytoprotection effect at the highest dose of BEA assayed (2.5 µM) in 29%, 31% and 35% for LUT, ZEAX and LUT + ZEAX, respectively; GBE showed a cytoprotection of 20%, for the same dose of BEA. The interaction between LUT, ZEAX and BEA studied by means of CI-isobologram method showed a synergism and antagaonism effect for all the combinations tested. These findings highlight that food containing high level of carotenoids, as goji berries, could contribute to reduce the toxicological risk that natural contaminant as BEA mycotoxin in diet can produce to the humans.


Assuntos
Depsipeptídeos/toxicidade , Luteína/farmacologia , Lycium/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Zeaxantinas/farmacologia , Células CACO-2 , Citoproteção/efeitos dos fármacos , Sinergismo Farmacológico , Frutas/química , Humanos , Luteína/toxicidade , Micotoxinas/toxicidade , Extratos Vegetais/toxicidade , Substâncias Protetoras/toxicidade , Zeaxantinas/toxicidade
5.
Life Sci ; 234: 116735, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394124

RESUMO

AIMS: The present study was to investigate the protective effects of Zn supplementation in OTA-induced apoptosis of Madin-Darby canine kidney (MDCK) epithelial cells and explore the potential mechanisms. Aiming to provides a new insight into the treatment strategy of OTA-induced nephrotoxicity by nutritional regulation. MAIN METHODS: Initially, through MTT and LDH assay revealed that Zn supplementation significantly suppressed OTA-induced cytotoxicity in MDCK cells. Then, the production of reactive oxygen species (ROS) was detected by using a DCFH-DA assay. Annexin V-FITC/PI, Hoechst 33258 staining and Flow cytometry were used to detect the apoptosis. The expressions of apoptosis-related molecules were determined by RT-PCR, Western blotting. Interestingly, OTA treatment slightly increased the levels of Metallothionein-1 (MT-1) and Metallothionein-2 (MT-2) by using RT-PCR, Western blotting assay; while Zn supplementation further improved the increase of MT-1 and MT-2 induced by OTA. However, the inhibitive effects of Zn supplementation were significantly blocked after double knockdown of MT-1 and MT-2 by using Small Interfering RNA (siRNA) Transfection method. KEY FINDINGS: Our study provides supportive data for the potential roles of Zn in reducing OTA-induced oxidative stress and apoptosis in MDCK cells. SIGNIFICANCE: Zn is one of the key structural components of many proteins, which plays an important role in several physiological processes such as cell survival and apoptosis. This metal is expected to contribute to the conservative and adjuvant treatment of kidney disease and should therefore be investigated further.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Metalotioneína/genética , Ocratoxinas/toxicidade , Substâncias Protetoras/farmacologia , Zinco/farmacologia , Animais , Citoproteção/efeitos dos fármacos , Cães , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Madin Darby de Rim Canino , Estresse Oxidativo/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Phytother Res ; 33(11): 2996-3007, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31418509

RESUMO

The present study evaluated the contribution of mango fiber (MF) and mango phenolic compounds (MP) to the hepatoprotective effect of freeze-dried mango pulp (FDM) cultivar (cv.) "Ataulfo" diets in high cholesterol/sodium cholate (HCC)-fed rats. Male Wistar rats were fed with a HCC diet for 12 weeks, either untreated, or supplemented with MF, MP, FDM, or a control diet (no HCC; n = 6/group). All mango treatments significantly decreased hepatic cholesterol deposition and altered its fatty acid profile, whereas MF and MP mitigated adipose tissue hypertrophy. MF caused a lower level of proinflammatory cytokines (IL-1α/ß, IFN-γ, TNF-α) whereas FDM increased the anti-inflammatory ones (IL-4, 6, 10). Mango treatments increased catalase (CAT) activity and its mRNA expression; superoxide dismutase (SOD) activity was normalized by MF and FDM, but its activity was unrelated to its hepatic mRNA expression. Changes in CAT and SOD mRNA expression were unrelated to altered Nrf2 mRNA expression. Higher hepatic PPARα and LXRα mRNA levels were found in MP and MF. We concluded that MF and MP are highly bioactive, according to the documented hepatoprotection in HCC-fed rats; their mechanism of action appears to be related to modulating cholesterol and fatty acid metabolism as well as to stimulating the endogenous antioxidant system.


Assuntos
Citoproteção/efeitos dos fármacos , Fibras na Dieta/farmacologia , Fígado/efeitos dos fármacos , Mangifera/química , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fenóis/farmacologia , Animais , Antioxidantes/farmacologia , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Dieta/efeitos adversos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/metabolismo , Fenóis/isolamento & purificação , Ratos , Ratos Wistar , Colato de Sódio/administração & dosagem , Colato de Sódio/efeitos adversos
7.
Phytother Res ; 33(11): 2821-2840, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31429152

RESUMO

Nowadays in our developing and industrial world, humans' health or even their life is threatened by exposure to poisons. In this situation, detecting a protective compound could be helpful and interesting. In the present article, we collected and reviewed all studies, which have been conducted so far about the protective effects of Ginkgo biloba L. (GB), one of the most ancient medicinal tree species, against toxicities induced by chemical toxic agents, natural toxins, and also radiation. In overall, investigations showed that GB exerts the antioxidant, antiinflammatory, antiapoptotic, and antigenotoxicity effects in different toxicities. There are also some special mechanisms about its protective effects against some specific toxic agents, such as acetylcholine esterase inhibition in the aluminium neurotoxicity or membrane-bond phosphodiesterase activation in the triethyltin toxicity. Ginkgolide A was the most investigated active ingredient of G. biloba leaf extract as a protective compound against toxicities, which had the similar effects of total extract. A few clinical studies have been conducted in this field, which demonstrated the beneficial effects of GB against toxic agents. However, the promising effects of this valuable herbal extract will practically remain useless without carrying out more clinical studies and proving its effects on human beings.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Ginkgo biloba/química , Extratos Vegetais/farmacologia , Lesões por Radiação/prevenção & controle , Toxinas Biológicas/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/toxicidade , Citoproteção/efeitos dos fármacos , Citoproteção/efeitos da radiação , Humanos , Protetores contra Radiação/farmacologia
8.
Int J Mol Sci ; 20(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426336

RESUMO

Reactive oxygen species (ROS) are generated from diverse cellular processes or external sources such as chemicals, pollutants, or ultraviolet (UV) irradiation. Accumulation of radicals causes cell damage that can result in degenerative diseases. Antioxidants remove radicals by eliminating unpaired electrons from other molecules. In skin health, antioxidants are essential to protect cells from the environment and prevent skin aging. (-)-Epigallocatechin-3-(3″-O-methyl) gallate (3″Me-EGCG) has been found in limited oolong teas or green teas with distinctive methylated form, but its precise activities have not been fully elucidated. In this study, we examined the antioxidant roles of 3″Me-EGCG in keratinocytes (HaCaT cells). 3″Me-EGCG showed scavenging effects in cell and cell-free systems. Under H2O2 exposure, 3″Me-EGCG recovered cell viability and increased the expression of heme oxygenase 1 (HO-1). Under ultraviolet B (UVB) and sodium nitroprusside (SNP) exposure, 3″Me-EGCG protected keratinocytes and regulated the survival protein AKT1. By regulating the AKT1/NF-κB pathway, 3″Me-EGCG augmented cell survival and proliferation in HaCaT cells. These results indicate that 3″Me-EGCG exhibits antioxidant properties, resulting in cytoprotection against various external stimuli. In conclusion, our findings suggest that 3″Me-EGCG can be used as an ingredient of cosmetic products or health supplements.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Citoproteção/efeitos dos fármacos , Ácido Gálico/análogos & derivados , Queratinócitos/efeitos dos fármacos , Antioxidantes/química , Catequina/química , Catequina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Citoproteção/efeitos da radiação , Ácido Gálico/química , Ácido Gálico/farmacologia , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Raios Ultravioleta/efeitos adversos
9.
Mol Cell Biochem ; 462(1-2): 107-114, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31463780

RESUMO

The aim of the work was to study the influence of vaspin on oxidative stress-induced apoptosis of mouse mesenchymal stem cells (MSCs). MSCs originated from bone marrow of C57BL/6 mouse were treated with vaspin and/or H2O2 in a dose-dependent manner. Cellular viability detected by CCK-8 and cell apoptosis studied by flow cytometry and TUNEL assay were observed in these cells. The protein expressions of PI3K, p-PI3K, Akt, p-Akt, T-ERK1/2, p-ERK1/2, p38, p-p38, JNK, and p-JNK were tested by Western blot. Vaspin had no significant effect on cellular viability, but significantly reduced H2O2-induced apoptosis. Western blot assay showed that pretreatment with vaspin promoted the activation of p-p38. Inhibition of p38 by SB203580 suppressed the protective effect of vaspin on oxidative stress-induced apoptosis. Vaspin inhibits oxidative stress-induced apoptosis of MSCs via the activation of MAPK/p38 signaling pathway. These findings indicate that vaspin is prone to osteoporosis protection.


Assuntos
Adipocinas/metabolismo , Apoptose , Citoproteção , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/enzimologia , Células-Tronco Mesenquimais/patologia , Estresse Oxidativo , Serpinas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adipocinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serpinas/farmacologia
10.
Can J Physiol Pharmacol ; 97(9): 880-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365282

RESUMO

The objective of this study was to analyze the cardioprotective roles of 3 wild blueberry genotypes and one commercial blueberry genotype by measuring markers of oxidative stress and cell death in H9c2 cardiac cells exposed to doxorubicin. Ripe berries of the 3 wild blueberry genotypes were collected from a 10-year-old clearcut forest near Nipigon, Ontario, Canada (49°1'39″N, 87°52'21″W), whereas the commercial blueberries were purchased from a local grocery store. H9c2 cardiac cells were incubated with 15 µg gallic acid equivalent/mL blueberry extract for 4 h followed by 5 µM doxorubicin for 4 h, and oxidative stress and active caspase 3/7 were analyzed. The surface area as well as total phenolic content was significantly higher in all 3 wild blueberry genotypes compared with the commercial species. Increase in oxidative stress due to doxorubicin exposure was attenuated by pre-treatment with all 3 types of wild blueberries but not by commercial berries. Furthermore, increase in caspase 3/7 activity was also attenuated by all 3 wild genotypes as well. These data demonstrate that wild blueberry extracts can attenuate doxorubicin-induced damage to H9c2 cardiomyocytes through reduction in oxidative stress and apoptosis, whereas the commercial blueberry had little effect.


Assuntos
Mirtilos Azuis (Planta)/química , Citoproteção/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Extratos Vegetais/química , Ratos
11.
Artif Cells Nanomed Biotechnol ; 47(1): 2940-2947, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31319730

RESUMO

Arbutin (ARB) has been widely used in skin pigmentation disorders. Nevertheless, the involvements of ARB in diabetic nephropathy (DN) are still unknown. We investigated the functions of ARB in high glucose (HG)-induced cell apoptosis and autophagy in HK-2 cells. Cell viability was examined through CCK-8 in HK-2 cells after disposal with 45 mM glucose and ARB (10-50 µM). Flow cytometry and western blot tested cell apoptosis and the related protein levels in HK-2 cells after 45 mM glucose and 50 µM ARB administration. RT-qPCR delved microRNA (miR)-27a expression in HG and ARB co-treated HK-2 cells. Effect of miR-27a on ARB affected cell apoptosis and autophagy was investigated after miR-27a inhibitor transfection. JNK and mTOR pathways were finally assessed by western blot. ARB alleviated HG-induced cell apoptosis, autophagy and regulated the related protein levels in HK-2 cells. MiR-27a expression was reduced in HG-treated cells, but was accelerated in HG and ARB co-treated HK-2 cells with the increased concentration. Inhibition of miR-27a apparently abolished the outcomes of ARB in HG-induced HK-2 cells apoptosis and autophagy. Besides, ARB blocked JNK and mTOR pathways by regulating miR-27a. The findings demonstrated that ARB alleviated apoptosis and autophagy in HG-treated HK-2 cells by regulating miR-27a/JNK/mTOR axis.


Assuntos
Apoptose/efeitos dos fármacos , Arbutina/farmacologia , Autofagia/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Glucose/efeitos adversos , MicroRNAs/genética , Regulação para Cima/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
12.
Artif Cells Nanomed Biotechnol ; 47(1): 2980-2988, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31322008

RESUMO

Background: Myocardial ischemia is a troublesome disease. Bilobalide possesses multiple biological functions. We researched the consequents of bilobalide in OGD-irritated H9c2 cells. Methods: OGD-stimulated H9c2 cells were treated by bilobalide, and/or transfected with miR-27a inhibitor or negative control. Use CCK-8 and flow cytometry to test cell activity and apoptosis, respectively. Luciferase activity experiment was to test targeting link between miR-27a and Tmub1. Levels of cell-cycle and apoptosis relative proteins and phosphorylation of PI3K/AKT and Wnt/ß-catenin related proteins were detected through western blot. Results: OGD stimulation reduced cell activity and negatively regulated the expression of CDK4, CDK6 and CyclinD1. Cell apoptosis was increased and its related proteins were affected by OGD. Bilobalide administration reversed all the results above caused by OGD. OGD negatively regulated miR-27a while bilobalide upregulated miR-27a. miR-27a's target gene was Tmub1. The protection consequents of bilobalide were suppressed when cells were transfected with a miR-27a inhibitor that cell activity was reduced and apoptosis was raised. Attenuation in the phosphorylation level of PI3K, AKT and ß-catenin by OGD was reversed by bilobalide, whereas there were opposite results after transfected with miR-27a inhibitor. Conclusion: Bilobalide relieved OGD-caused H9c2 cell damage, raising cell activity and attenuating apoptosis via upregulating miR-27a and activating of PI3K/AKT and Wnt/ß-catenin signal pathway. Highlights Bilobalide alleviates OGD-induced H9c2 cell injury. Bilobalide upregulates miR-27a expression in OGD-stimulated H9c2 cells. Bilobalide alleviates cell injury by upregulation of miR-27a. Bilobalide actuates PI3K/AKT and Wnt/ß-catenin pathways.


Assuntos
Ciclopentanos/farmacologia , Citoproteção/efeitos dos fármacos , Furanos/farmacologia , Ginkgolídeos/farmacologia , Glucose/deficiência , MicroRNAs/genética , Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Via de Sinalização Wnt/efeitos dos fármacos
13.
Mol Cell Biochem ; 460(1-2): 123-150, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313023

RESUMO

A series of nine tetrahydroacridine derivatives with iodobenzoic moiety were synthesized and evaluated for their cytotoxic activity against cancer cell lines-A549 (human lung adenocarcinoma), HT-29 (human colorectal adenocarcinoma) and somatic cell line-EA.hy926 (human umbilical vein cell line). All compounds displayed high cytotoxicity activity against A549 (IC50 59.12-14.87 µM) and HT-29 (IC50 17.32-5.90 µM) cell lines, higher than control agents-etoposide and 5-fluorouracil. Structure-activity relationship showed that the position of iodine in the substituent in the para position and longer linker most strongly enhanced the cytotoxic effect. Among derivatives, 1i turned out to be the most cytotoxic and displayed IC50 values of 14.87 µM against A549 and 5.90 µM against HT-29 cell lines. In hyaluronidase inhibition assay, all compounds presented anti-inflammatory activity, however, slightly lower than reference compound. ADMET prediction showed that almost all compounds had good pharmacokinetic profiles. 1b, 1c and 1f compounds turned out to act against chemoresistance in cisplatin-resistant 253J B-V cells. Compounds intercalated into DNA and inhibited cell cycle in G0/G1 phase-the strongest inhibition was observed for 1i in A549 and 1c in HT-29. Among compounds, the highest apoptotic effect in both cell lines was observed after treatment with 1i. Compounds caused DNA damage and H2AX phosphorylation, which was detected in A549 and HT-29 cells. All research confirmed anticancer properties of novel tetrahydroacridine derivatives and explained a few pathways of their mechanism of cytotoxic action.


Assuntos
Aminacrina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/patologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Iodobenzoatos/farmacologia , Neoplasias Pulmonares/patologia , Células A549 , Aminacrina/química , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Citoproteção/efeitos dos fármacos , DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HT29 , Histonas/metabolismo , Humanos , Hialuronoglucosaminidase/metabolismo , Concentração Inibidora 50 , Mutagênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Ensaio Tumoral de Célula-Tronco
14.
Artif Cells Nanomed Biotechnol ; 47(1): 2875-2881, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307231

RESUMO

Geniposide is an active ingredient with anti-apoptotic and anti-inflammatory properties. This study was to examine the effects of geniposide on a cell model of spinal cord injury (SCI). PC12 cells were administrated with geniposide before subjected to LPS. The effects of geniposide were analyzed by utilizing CCK-8 assay, apoptosis assay, ELISA, RT-qPCR and Western blot. We found that PC12 cells viability was unchanged by treating with geniposide. However, geniposide with concentrations of 200 or 300 µg/mL significantly mitigated LPS-evoked viability loss. Meanwhile, apoptosis driven by LPS was mitigated by geniposide, which accompanied with p53, Bax and cleaved caspase-3 down-regulation, and Bcl-2 up-regulation. Besides this, the expression and release of IL-1ß, IL-6, IL-8 and TNF-α evoked by LPS were mitigated by geniposide. miR-145-5p was a target of geniposide. miR-145-5p expression was up-regulated by geniposide, and geniposide did not protect PC12 cells against LPS injury when miR-145-5p was silenced. Moreover, geniposide inhibited NF-κB and JNK pathways via up-regulating miR-145-5p. In short, the present work described the neuroprotective effects of geniposide by targeting miR-145-5p. Further mechanisms involved in geniposide's beneficial effects are correlated with the inhibited NF-κB and JNK pathways. Highlights Geniposide prevents LPS-induced injury in PC12 cells; Geniposide up-regulates miR-145-5p; Geniposide protects PC12 cells via up-regulation of miR-145-5p; Geniposide inhibits NF-κB and JNK pathways via up-regulation of miR-145-5p.


Assuntos
Citoproteção/efeitos dos fármacos , Iridoides/farmacologia , Lipopolissacarídeos/efeitos adversos , MicroRNAs/genética , Regulação para Cima/efeitos dos fármacos , Animais , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos
15.
Artif Cells Nanomed Biotechnol ; 47(1): 2900-2908, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307239

RESUMO

The aim of the present study was to investigate the effect of Lycopus lucidus Turcz (LT) on diabetic retinopathy (DR) and its underlying mechanisms. SD rats and human retinal microvascular endothelial cells (HRECs) were applied for establishment DR model. HE and TUNEL staining were used to evaluate the pathological changes and apoptosis of retinal ganglion cells. Additionally, retinal vessels were detected by immunofluorescence staining with CD31 and VEGF. The function of BRB was observed using Evans blue. Moreover, the oxidative stress, inflammation and angiogenesis associated factors were measured respectively. The expression of p38-MAPK/NF-κB signalling proteins were detected by Western blot. The results demonstrated that pathological changes and retinal optic disc cells apoptosis in retinas of diabetic rats, both of which were reduced in the LT-treated group. And LT treatment attenuated the levels of oxidative stress, inflammation and angiogenesis factors. Importantly, the expression levels of p-p38, p-ERK, p-JNK and NF-κB were decreased. After treatment with TNF-α combined with LT, the levels of inflammatory factors were decreased but higher than the negative control. Taken together, the results suggested that LT treatment is of therapeutic benefit by ameliorating oxidative stress, inflammation and angiogenesis of DR via p38-MAPK/NF-κB signaling pathway.


Assuntos
Retinopatia Diabética/patologia , Lycopus/química , Extratos Vegetais/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Citoproteção/efeitos dos fármacos , Retinopatia Diabética/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Biomed Res Int ; 2019: 4348973, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275971

RESUMO

Diabetic nephropathy is the complication of diabetes mellitus that can lead to chronic renal failure. Reactive oxygen species (ROS) production plays an important role in its pathological process. Previous studies showed that carnosine may reduce diabetic nephropathy by antioxidant effect. However, the molecular mechanism of its antioxidant was not fully understood. In the current study, we developed high glucose containing different concentrations of carnosine to reduce ROS levels and podocytes apoptosis, and Cell Counting Kit-8 test was used to observe the cell viability. Carnosine (5-20mM) was found to protect mouse podocytes (MPC5) cells from HG-induced injury. Quantitative real-time PCR, Western blotting, and immunofluorescence staining revealed that high glucose induced ROS levels and podocytes apoptosis were downregulated by PI3K/AKT and Nrf2 signaling pathways. The current findings suggest that carnosine may reduce ROS levels and MPC5 cells apoptosis by PI3K/AKT and Nrf2 signaling pathways activation.


Assuntos
Apoptose/efeitos dos fármacos , Carnosina/farmacologia , Glucose/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Podócitos/patologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Camundongos , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
Artif Cells Nanomed Biotechnol ; 47(1): 2775-2782, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31284768

RESUMO

Atherosclerosis is a chronic inflammatory disease of the blood vasculature. Endothelial dysfunction is an early event in the development of atherosclerosis and the endothelium plays an important role in the innate immune defense in the pathology of cardiovascular diseases. New therapies are being developed based on the involvement of the immune system in atherosclerosis. In this study, we demonstrate that a commonly used anti-rheumatic drug, tofacitinib, possesses vascular protective properties in cultured primary human aortic endothelial cells (HAECs). Tofacitinib ameliorates oxidized low-density lipoprotein (ox-LDL)-induced adhesion of THP-1 cells to HAECs, suppresses the expression of vascular adhesion molecules and production of cytokines, including vascular cell adhesion molecule 1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Moreover, tofacitinib inhibits elevation of endothelial lectin-like ox-LDL receptor-1 (LOX-1) and production of reactive oxygen species (ROS) triggered by ox-LDL. As a result, the presence of tofacitinib reduces ox-LDL-induced cytotoxicity and improves endothelial viability. Mechanistically, we demonstrate that tofacitinib suppresses ox-LDL-mediated activation of NF-κB inhibitor α (IκB-α), accumulation of nuclear p65 and activation of nuclear factor κB (NF-κB) promoter, indicating that tofacitinib inhibits NF-κB activation. Collectively, our data support that tofacitinib possesses a novel protective function in endothelial cells, implying that tofacitinib could have the therapeutic potential to modulate inflammation in cardiovascular diseases.


Assuntos
Adesão Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Monócitos/citologia , Monócitos/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Linhagem Celular , Citoproteção/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Artif Cells Nanomed Biotechnol ; 47(1): 2746-2753, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282213

RESUMO

Puerarin has been reported to be useful in protection against hypoxia-induced injury. In our current study, we attempted to explore the protective effects of puerarin against hypoxia-caused damages in neural stem cells (NSCs). Additionally, the relative molecular underpinning studies preliminarily proceeded. NSCs were pre-incubated with puerarin before the hypoxic stimulus. MicroRNA-214 (miR-214) inhibitor was transfected into NSCs. Subsequently, the viability of NSCs was assessed by CCK-8 assay. Flow cytometry was employed to detect apoptotic cells after staining. qRT-PCR was performed to quantify miR-214. Western blot was applied for analyzing the expression of apoptosis-relative proteins and regulators. We found that puerarin alleviated hypoxia-induced apoptosis and maintained cell viability. Hypoxia-evoked up-regulation of miR-214 was further enhanced by puerarin. By contrast, miR-214-deficient NSCs showed the reduction in cell viability and the facilitation in apoptosis progress after pre-treatment with puerarin and stimulation in a hypoxia circumstance. Additionally, puerarin restored the phosphorylation of relative regulators, which was originally blunted by hypoxia. However, puerarin did not evidently restore the phosphorylation for response to hypoxia in miR-214-silenced NSCs. In conclusion, puerarin might be applied as a novel agent to ameliorate hypoxia-evoked damages in NSCs. Molecularly, miR-214 might be implicated in the protective roles of puerarin.


Assuntos
Isoflavonas/farmacologia , MicroRNAs/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Citoproteção/efeitos dos fármacos , Citoproteção/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células-Tronco Neurais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
19.
Molecules ; 24(13)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262066

RESUMO

Grafting a bioactive peptide onto a disulfide-rich scaffold is a promising approach to improve its structure and metabolic stability. The ginkgo plant-derived ß-ginkgotide ß-gB1 is a highly unusual molecule: Small, hyperdisulfide, and found only in selected ancient plants. It also contains a conserved 16-amino-acid core with three interlocking disulfides, as well as a six-amino-acid inter-cysteine loop 2 suitable for grafting peptide epitopes. However, very little is known about this recently-discovered family of molecules. Here, we report the biophysical and functional characterizations of the ß-ginkgotide ß-gB1 from G. biloba. A circular dichroism spectroscopy analysis at 90 °C and proteolytic treatments of ß-gB1 supported that it is hyperstable. Data mining revealed that the ß-gB1 loop 2 contains the canonical LC3 interacting region (LIR) motif crucial for selective autophagy. Cell-based assays and pull-down experiments showed that ß-gB1 is an adaptogen, able to maintain cellular homeostasis through induced autophagosomes formation and to protect cells by targeting intracellular proteins from stress-mediated damage against hypoxia and the hypoxia-reoxygenation of induced cell death. This is the first report of an LIR-containing peptide natural product. Together, our results suggest that the plant-derived ß-ginkgotide is cytoprotective, capable of targeting intracellular proteins, and holds promise as a hyperdisulfide scaffold for engineering peptidyl therapeutics with enhanced structural and metabolic stability.


Assuntos
Citoproteção/efeitos dos fármacos , Ginkgo biloba/química , Peptídeos , Proteínas de Plantas , Animais , Autofagossomos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Camundongos , Estrutura Molecular , Peptídeos/química , Peptídeos/farmacologia , Proteínas de Plantas/química , Proteínas de Plantas/farmacologia , Ratos
20.
Eur J Pharmacol ; 859: 172542, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31319070

RESUMO

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with additional antioxidant properties. Doxorubicin (DOX) is an anticancer drug that exerts oxidation-mediated adverse cardiovascular effects. This study examined the effects of nicorandil on DOX-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and underlying intracellular signaling mechanisms. Cultured HUVECs were pretreated with nicorandil (0.1, 0.3, 1, 3, and 10 µM) for 12 h and then treated with DOX (1 µM) for 24 h. Cell viability and cytotoxicity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. Cell apoptosis was examined using a caspase-3 activity assay, and DNA fragmentation was detected through TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Western blot analysis was conducted to determine the related protein expression. DOX markedly increased reactive oxygen species production, p53 expression, caspase-3 activity, cleaved caspase-3 levels, and TUNEL-positive cell numbers but reduced Bcl-2 expression and intracellular antioxidant enzyme levels; these effects were effectively antagonized through nicorandil (3 µM, 12 h) pretreatment, which resulted in HUVECs being protected from DOX-induced apoptosis. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, was induced by nicorandil (3 µM). Furthermore, nicorandil (3 µM) enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. ATF3 short interfering RNA significantly attenuated nicorandil-mediated Nrf2 translocation, HO-1 expression, and inhibitory effects on DOX-stimulated reactive oxygen species production and cell apoptosis. In summary, nicorandil may protect HUVECs from DOX-induced apoptosis, in part through ATF3-mediated Nrf2/HO-1 signaling pathways, which potentially protect the vessels from severe DOX toxicity.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Nicorandil/farmacologia , Fator 3 Ativador da Transcrição/metabolismo , Antioxidantes/metabolismo , Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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