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1.
Anticancer Res ; 39(8): 4095-4100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366493

RESUMO

BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively). CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição PAX8/genética , Simportadores/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/genética
2.
Anticancer Res ; 39(8): 4199-4206, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366506

RESUMO

BACKGROUND/AIM: We previously synthesized a glucose-conjugated chlorin compound e6 (G-chlorin e6), and reported that it has very strong antitumor effects. The aim of the present study was to synthesize acetylated glucose-conjugated chlorin (AcN003HP) and evaluate its antitumor effect and excretion. MATERIALS AND METHODS: To evaluate the antitumor effect of AcN003HP, its IC50 was calculated as well as its accumulation in cancer cells was examined by flow cytometry. Confocal microscopy was used to observe the intracellular localization of AcN003HP. The excretion and antitumor effects of AcN003HP were also evaluated in vivo. RESULTS: AcN003HP showed stronger antitumor effects and accumulation into cancer cells compared to talaporfin sodium, a conventional photosensitizer. AcN003HP was localized in the endoplasmic reticulum. In a xenograft tumor mouse model, AcN003HP showed longer excretion time from the body than G-chlorin e6, and photodynamic therapy using AcN003HP showed very strong antitumor effects. CONCLUSION: The safety, improved controllability, and robust antitumor effects suggest AcN003HP as a good next-generation photosensitizer.


Assuntos
Neoplasias Gastrointestinais/terapia , Glucose/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Retículo Endoplasmático/efeitos dos fármacos , Citometria de Fluxo , Neoplasias Gastrointestinais/patologia , Glucose/síntese química , Glucose/química , Humanos , Camundongos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfirinas/administração & dosagem , Porfirinas/síntese química , Porfirinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Biol Res ; 52(1): 45, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426853

RESUMO

BACKGROUND: Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process. RESULTS: In the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model. CONCLUSION: These results indicated that resveratrol reduced store-operated Ca2+ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1-STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Experimental/fisiopatologia , Canais de Cálcio/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Proteína ORAI1/efeitos dos fármacos , Resveratrol/farmacologia , Molécula 1 de Interação Estromal/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Animais , Canais de Cálcio/fisiologia , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Resveratrol/administração & dosagem
4.
Cell Physiol Biochem ; 53(3): 439-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31436397

RESUMO

BACKGROUND/AIMS: Among the assisted reproductive techniques, the in vitro maturation of oocytes (IVM) is less developed than other techniques, but its implementation would entail a qualitative advance. This technique consists in the extraction of immature oocytes from antral ovarian follicles with the patient under low hormone stimulation or without hormone to mature exogenously in culture media supplemented with different molecules to promote maturation. In this sense, we are interested in the role that cannabinoids could have as IVM promoters because cannabinoid's molecular pathway is similar to the one by which oocyte's meiosis resumption is activated. With the intention of advancing in the possible use of cannabinoids as supplements for the media for in vitro maturation of oocytes, we intend to deepen the study of the function of the phytocannabinoid Δ-9-tetrahydrocannabinol (THC) in the IVM process. METHODS: By immunocytochemistry, we detected the location pattern of cannabinoid receptor type 1 (CB1) and type 2 (CB2) during oocyte maturation in presence or absence of THC, as well as, the staining pattern of p-AKT and p-ERK. We used a genetic/ pharmacological approach generating knockout oocytes for CB1 and/or CB2 and they were incubated with THC during the oocyte maturation to visualize the physiological effects of THC, observing the rate of blastocyst achieved by oocyte. RESULTS: This study confirms that the incubation of oocytes with THC during IVM accelerated some events of that process like the phosphorylation pattern of ERK and AKT and was able to increase the blastocyst rate in response to IVF. Moreover, it seems that both CB1 and CB2 are necessary to maintain a healthy oocyte maturation. CONCLUSION: Our data suggest that THC may be useful IVM supplements in clinic as is more feasible and reliable than any synthetic cannabinoid.


Assuntos
Blastocisto/efeitos dos fármacos , Dronabinol/farmacologia , Oócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Blastocisto/citologia , Blastocisto/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fertilização In Vitro , Técnicas de Maturação in Vitro de Oócitos , Meiose/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oócitos/citologia , Oócitos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo
5.
Inorg Chem ; 58(16): 11076-11084, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31393117

RESUMO

Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Platina/farmacologia , Pró-Fármacos/farmacologia , Receptores LHRH/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta à Radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores LHRH/metabolismo , Relação Estrutura-Atividade
6.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
7.
Zhonghua Fu Chan Ke Za Zhi ; 54(8): 541-547, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31461811

RESUMO

Objective: To detect phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) protein expression in epithelial ovarian cancer and cell lines, and to examine the effects of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor AZD6244 on cell proliferation, apoptosis as well as cell cycle of ovarian cancer cells. To explore the function and significance of MAPK/extracellular signal-regulated kinase (ERK) signaling pathway in the development of ovarian cancer. Methods: (1) A total of 104 cases of patients with ovarian cancer who accepted the treatment of gynecological surgery and being confirmed by pathological examination in First Affiliated Hospital, Dalian Medical University from January 2004 to December 2013 were selected. The expressions of p-ERK1/2 protein were detected by immunohistochemistry in ovarian cancer specimens, and the relationship between the expressions of p-ERK1/2 and the clinical features of patients was analyzed. (2) p-ERK1/2 and other related proteins were determined by western blot in various ovarian cancer cells, including SKOV3, OV2008, C13, A2780S, A2780CP, OVCAR4, OVCAR5, OVCAR8 and CAOV3 treated with or without MEK inhibitor. The cellular proliferation, apoptosis and cell cycle of ovarian cancer cells after treatment with MEK inhibitor were analyzed by methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively. Results: (1) The immunohistochemical method showed that p-ERK1/2 between low grade serous carcinoma and clear cell carcinoma were not significantly higher expressed (P>0.05) . However, a lower level of the p-ERK1/2 expression were observed among high grade serous carcinoma, mucinous carcinoma and endometrioid carcinoma (all P<0.05) . There was no significant correlation between the protein expression of p-ERK1/2 and patients' age, pathological stage of surgery, and preoperative serum CA(125) level (P>0.05). (2) Western blot showed that the protein p-ERK1/2 was widely expressed in various ovarian cancer cell lines such as SKOV3, OV2008, C13, A2780S, A2780CP, OVCAR4, OVCAR5, OVCAR8 and CAOV3. After treatment with AZD6244 (5, 10 µmol/L), the level of p-ERK1/2 in OVCAR5 and OVCAR8 decreased significantly in dose-dependent manner. Additionally, we found a reduction of the expression level of cyclin D1, caspase-3 and appeared cleaved poly adenosine diphosphate ribose polymerase (PARP) in OVCAR5 and OVCAR8, compared with control groups. MTT assays showed that OVCAR5, OVCAR8 and A2780S were differently inhibited in the dose-dependent manner after being treated with different concentrations of AZD6244 (0, 2.5, 5, 10, 25, 50 and 100 µmol/L, all P<0.05). Further tested by flow cytometry, the results showed that AZD6244 (5, 10 µmol/L) was able to induce the apoptosis of OVCAR5, OVCAR8 and A2780S, as well as G(0)/G(1) phase arrest, both in a dose-dependent manner (P<0.05). Conclusions: As the main active and functional unit of MAPK/ERK signaling pathway, p-ERK1/2 protein is expressed in both the tissues and various ovarian cancer cell lines. AZD6244 could down-regulated the expression of p-ERK1/2 in ovarian cancer cells, accompanied by the decreased proliferation and increased cell apoptosis of ovarian cancer cells. In conclusion, MAPK/ERK signaling pathway might play a role in the development and progression of ovarian cancer, and may be provide a novel option for molecular targeted therapies of the disease.


Assuntos
Carcinoma Epitelial do Ovário , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Neoplasias Ovarianas/genética
8.
Am J Orthod Dentofacial Orthop ; 156(2): 193-202, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31375229

RESUMO

OBJECTIVES: To evaluate whether the effects on the mandibular condylar cartilage (MCC) and subchondral bone are transient of botulinum neurotoxin (Botox) injection into the masseter muscle. METHODS: Botox (0.3 U) was injected into the right masseter of 6-week-old female mice (C57BL/6; n = 16). In addition, 16 mice were used as control and received no injections. Experimental and matching control mice were killed 4 or 8 weeks after the single Botox injection. Mandibles and mandibular condyles were analyzed by means of microscopic computed tomography (microCT) and histology. Sagittal sections of condyles were stained for tartrate-resistant acid phosphatase (TRAP), toluidine blue, 5-ethynyl-2'-deoxyuridine (EdU), and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. RESULTS: Bone volume fraction was significantly decreased on the subchondral bone of the Botox-injected side, compared with the control side and control mice, 4 and 8 weeks after injection. Furthermore, histologic analysis revealed decrease in mineralization, cartilage thickness, TRAP activity, and EdU-positive cells in the MCC of the Botox-injected side 4 and 8 weeks after injection. CONCLUSIONS: The effects on the MCC and subchondral bone of Botox injection into the masseter muscle persisted for 8 weeks after injection and were not considered to be transient.


Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Côndilo Mandibular/efeitos dos fármacos , Músculo Masseter/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Injeções , Masculino , Mandíbula , Côndilo Mandibular/diagnóstico por imagem , Côndilo Mandibular/patologia , Músculo Masseter/diagnóstico por imagem , Músculo Masseter/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Articulação Temporomandibular
9.
Pestic Biochem Physiol ; 159: 144-153, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400776

RESUMO

Ivermectin is a pesticide that has been used for over 30 years in livestock. Although there are a number of studies on the therapeutic potential of ivermectin, little is known about the effects of the drug during the early stage of pregnancy. In this study, we investigated the detrimental effects of ivermectin on porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. Ivermectin not only inhibited the proliferation of both cells via the regulation of cell cycle-associated genes, but also induced apoptosis in pTr and pLE cells. We also verified its effect on mitochondrial dysfunction as shown by loss of mitochondrial membrane potential, mitochondrial Ca2+ overload, and reactive oxygen species (ROS) generation in pTr and pLE cells. As a mechanistic approach, we evaluated ivermectin-mediated cell signaling interactions including PI3K, AKT and MAPK pathways. Overall, our results suggest that constant exposure to and accumulation of ivermectin may cause abnormal fetal morphogenesis and placentation during the early stages of pregnancy. Our results may further provide a comprehensive understanding of the detrimental effects of ivermectin during pregnancy and will contribute to the establishment of a complete safety profile for ivermectin and its association with environmental pollution and public health in humans and livestock.


Assuntos
Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Ivermectina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Útero/citologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Suínos , Trofoblastos/citologia , Trofoblastos/efeitos dos fármacos
10.
Pestic Biochem Physiol ; 159: 163-172, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400778

RESUMO

Edifenphos (EDF) (O-ethyl-S, S-diphenyldithiophosphate) is an organophosphate pesticide that is extensively used as a fungicide in agricultural rice fields. However, EDF accumulated in various agricultural products and caused potential health hazards to human and other living organisms. Therefore, the present study was investigated to evaluate the ameliorative role of apigenin (APG); a natural antioxidant against EDF-induced hepato-renal toxicity in rats. Six groups with five male Wistar rats each, were used for this purpose; these groups included the control group (A) that received corn oil; (B) 10 mg/kg APG; (C) 10 mg/kg EDF; (D) 25 mg/kg EDF; (E) 10 mg/kg APG pretreatment for 1 h then 10 mg/kg EDF; (F) 10 mg/kg APG pretreatment for 1 h then 25 mg/kg EDF for 14 consecutive days. Oral administration of EDF led to disruption of the intracellular antioxidant machinery which cause the generation of intracellular reactive oxygen species (ROS). However, EDF promotes deleterious effects like oxidative stress, DNA damage, reduced mitochondrial membrane potential, generation of ROS production, activation of caspase 3/9 activities and causing hepato-renal histopathological changes. However, the pretreatment of APG ameliorated the EDF-induced oxidative damage and apoptosis, through their antioxidant activity or by directly scavenging free radical property. Overall, these results suggest that EDF exerts oxidative stress, and APG could be a potent dietary anti-oxidant regimen against EDF-induced toxicity.


Assuntos
Apigenina/farmacologia , Rim/metabolismo , Fígado/metabolismo , Compostos Organotiofosforados/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
11.
Cell Physiol Biochem ; 53(2): 388-399, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403269

RESUMO

BACKGROUND/AIMS: Doxorubicin, a chemotherapy drug used successfully for years, could induce cardiotoxicity. Euterpe oleracea Mart. (açai) is a fruit high in antioxidant properties. The aim of this study was to evaluate doxorubicin-induced cardiotoxicity prevention after açai administration. METHODS: A total of 64 male Wistar rats were allocated into 4 groups: control (C), açai (A), doxorubicin (D) and açai-doxorubicin (DA). Rats received regular chow (C and D groups) or chow supplemented with açai 5% (A and DA groups) for 4 weeks. Subsequently, rats received doxorubicin 20 mg/kg (D and DA groups) or saline (C and A groups). Euthanasia was performed 48 hours after doxorubicin injection. Left ventricular function was evaluated by echocardiography in vivo and by isolated heart study ex vivo. Oxidative stress, myocardial metabolism and nitric oxide metabolite were evaluated by spectrophotometry, MMP-2 activity by zymography and caspase-3 and Bcl-2 protein expression by Western blot. RESULTS: Doxorubicin induced decreases in body weight, food and water ingestion. We observed decreases in left ventricular fractional shortening in rats treated with doxorubicin. Additionally, the same rats showed lower +dP/dt and -dP/dt during isolated heart study than those who did not receive doxorubicin. Doxorubicin injection increased caspase-3 protein expression, myocardium lipid hydroperoxide concentration, MMP-2 activity, phosphofructokinase and lactate dehydrogenase activity, and decreased ß-hydroxyacyl-CoA dehydrogenase, pyruvate dehydrogenase, citrate synthase, complex I, complex II and ATP synthase activity in myocardium. Açai supplementation improved left ventricular fractional shortening, decreased myocardium lipid hydroperoxide concentration, MMP-2 activity, and improved ß-hydroxyacyl-CoA dehydrogenase, phosphofructokinase, citrate synthase, complex II and ATP synthase enzymatic activities. We did not observe differences in nitric oxide metabolite concentrations between groups. CONCLUSION: Doxorubicin induced left ventricular dysfunction, increases in oxidative stress, changes in myocardium metabolism and MMP-2 activation. Açai supplementation was able to prevent these alterations.


Assuntos
Doxorrubicina/toxicidade , Euterpe/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Suplementos Nutricionais , Ecocardiografia , Euterpe/metabolismo , Cardiopatias/etiologia , Cardiopatias/prevenção & controle , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/sangue , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Função Ventricular Esquerda/efeitos dos fármacos
12.
Pharm Res ; 36(10): 145, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396764

RESUMO

PURPOSE: The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a inhibition is a promising biological strategy for breast cancer therapy. METHODS: In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system. RESULTS: The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation. CONCLUSION: The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.


Assuntos
Antagomirs/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glipicanas/imunologia , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/imunologia , Nanopartículas/química , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , PPAR gama/metabolismo , Fosforilcolina/química , Polietilenoglicóis/química
13.
Anticancer Res ; 39(7): 3443-3451, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262868

RESUMO

BACKGROUND/AIM: This study aimed to investigate aclarubicin (ACR)-induced oxidative DNA damage and apoptosis. MATERIALS AND METHODS: ACR-induced apoptosis was analyzed using HL-60 leukemia cells and HP100 cells, hydrogen peroxide (H2O2)-resistant cells derived from HL-60 cells. ACR-induced DNA damage was analyzed using plasmid DNA. RESULTS: HL-60 cells were more sensitive to ACR than HP100 cells. In HP100 cells, DNA ladder formation and caspase-3/7 activity induced by ACR were suppressed or delayed in comparison to those in HL-60 cells. ACR-induced DNA damage occurred in the presence of Cu(II), and scavenger experiments showed that the reactive species causing DNA damage appeared to be generated from H2O2 and Cu(I). Moreover, we detected intracellular Cu(I) induced by ACR in HL-60 cells, using CopperGREEN™, a fluorescent probe for detection of Cu(I) ion specifically. CONCLUSION: ACR-induced DNA damage and apoptosis can be accounted for by the involvement of H2O2 and Cu(I).


Assuntos
Aclarubicina/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Cobre/farmacologia , Dano ao DNA , Peróxido de Hidrogênio/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias/metabolismo
14.
J Agric Food Chem ; 67(28): 7783-7792, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31267752

RESUMO

The increasing use of pesticides in agriculture and gardening has caused severe deterioration to both the ecosystem and the health of users (human beings), so there is an urgent need for eco- and user-friendly pesticides. Among a variety of herbicides, paraquat (PQ), frequently used as an effective herbicidal agent worldwide, is well-known for its serious toxicity that has killed, and harmed, thousands of people and countless wildlife such as fish. Herein, we present a facile supramolecular formulation of PQ@cucurbit[7]uril (PQ@CB[7]), prepared by simply mixing PQ with equivalent (molar) CB[7] in water. With addition of CB[7], PQ's cellular uptake was dramatically inhibited. The reactive oxygen species (ROS) generation and the associated apoptosis otherwise induced by PQ in cellular models were both reduced, resulting in increased cellular viability. In a wildtype zebrafish model that is a typical fragile wildlife species in the ecosystem, the supramolecular formulation exhibited significantly reduced hepatotoxicity and increased survival rate, in comparison with those of the fish exposed to free PQ. In a mouse model that is clinically relevant to human being, the administration of PQ@CB[7] significantly alleviated major organ injuries and unusual hematological parameters that were otherwise induced by free PQ, resulting in a significantly increased survival rate. Meanwhile, this formulation maintained effective herbicidal activity that was equivalent to that of free PQ. Taken together, this facile supramolecular PQ formulation is providing not only an extremely rare example of an eco- and user-friendly herbicide that has been desired for decades but also a practical solution for green agriculture.


Assuntos
Herbicidas/farmacologia , Paraquat/farmacologia , Animais , Apoptose/efeitos dos fármacos , Química Verde , Herbicidas/síntese química , Herbicidas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Paraquat/síntese química , Paraquat/química , Poaceae/efeitos dos fármacos , Poaceae/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
15.
Expert Opin Drug Metab Toxicol ; 15(8): 659-669, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31293190

RESUMO

Introduction: Although the hepatotoxicity of acetaminophen is a well-known problem, the search for reliable biomarker of toxicity is still a current issue as clinical tools are missing to assess patients intoxicated following chronic use, sequential ingestion, use of modified release formulations or in case of delayed arrival to hospital. The need for new specific and robust biomarkers for acetaminophen toxicity has prompted many studies exploring the use of blood levels of acetaminophen derivatives, mitochondrial damage markers, liver cell apoptosis and/or necrosis markers and circulating microRNAs. Areas covered: In this review, we present a concise overview of the most promising biomarkers currently under evaluation including descriptions of their properties with respect to exposure type, APAP specificity, and potential clinical application. In addition, we illustrate the power of new technologies for biomarker research and describe their current application to the field of acetaminophen-induced hepatotoxicity. Expert opinion: Recently the use of extracellular vesicles isolation in combination with omics techniques has opened a new perspective to the field of biomarker research. However, the potential of those new technologies for the prediction and monitoring of hepatic diseases and acetaminophen toxicity has not yet been fully taken into consideration.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Entorpecentes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Acetaminofen/administração & dosagem , Acetaminofen/farmacocinética , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/farmacocinética , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Humanos , MicroRNAs/metabolismo , Mitocôndrias/patologia , Projetos de Pesquisa
16.
Cell Physiol Biochem ; 53(2): 301-322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343125

RESUMO

BACKGROUND/AIMS: Propolis is one of the most promising natural products, exhibiting not only therapeutic but also prophylactic actions. Propolis has several biological and pharmacological properties, including hepatoprotective activities. The present study aimed to investigate the underlying molecular mechanisms of propolis against CCl4-mediated liver fibrosis. METHODS: Three groups of male BALB/c mice (n=15/ group) were used: group 1 comprised control mice; groups 2 and 3 were injected with CCl4 for the induction of liver fibrosis. Group 3 was then orally supplemented with propolis (100 mg/kg body weight) for four weeks. Different techniques were used to monitor the antifibrotic effects of propolis, including histopathological investigations using H&E, Masson's trichrome and Sirius red staining; Western blotting; flow cytometry; and ELISA. RESULTS: We found that the induction of liver fibrosis by CCl4 was associated with a significant increase in hepatic collagen and α-smooth muscle actin (α-SMA) expression. Moreover, CCl4-treated mice also exhibited histopathological alterations in the liver architecture. Additionally, the liver of CCl4-treated mice exhibited a marked increase in proinflammatory signals, such as increased expression of HSP70 and increased levels of proinflammatory cytokines and ROS. Mechanistically, the liver of CCl4-treated mice exhibited a significant increase in the phosphorylation of AKT and mTOR; upregulation of the expression of BAX and cytochrome C; downregulation of the expression of Bcl2; a significant elevation in the levels of TGF-ß followed by increased phosphorylation of SMAD2; and a marked increase in the expression of P53 and iNOS. Interestingly, oral supplementation of CCl4-treated mice with propolis significantly abolished hepatic collagen deposition, abrogated inflammatory signals and oxidative stress, restored CCl4-mediated alterations in the signaling cascades, and hence repaired the hepatic architecture nearly to the normal architecture observed in the control mice. CONCLUSION: Our findings revealed the therapeutic potential and the underlying mechanisms of propolis against liver fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Cirrose Hepática Experimental/patologia , Própole/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono/toxicidade , Citocinas/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
17.
Pharm Res ; 36(9): 133, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289919

RESUMO

PURPOSE: KRAS is the most frequently mutated gene in human cancers. Despite its direct involvement in malignancy and intensive effort, direct inhibition of KRAS via pharmacological inhibitors has been challenging. RNAi induced knockdown using siRNAs against mutant KRAS alleles offers a promising tool for selective therapeutic silencing in KRAS-mutant lung cancers. However, the major bottleneck for clinical translation is the lack of efficient biocompatible siRNA carrier systems. METHODS: Bovine serum albumin (BSA) nanoparticles were prepared by desolvation method to deliver siRNA targeting the KRAS G12S mutation. The BSA nanoparticles were characterized with respect to their size, zeta potential, encapsulation efficiency and nucleic acid release. Nanoparticle uptake, cellular distribution of nucleic acids, cytotoxicity and gene knock down to interfere with cancer hallmarks, uncontrolled proliferation and migration, were evaluated in KRAS G12S mutant A459 cells, a lung adenocarcinoma cell line. RESULTS: BSA nanoparticles loaded with siRNA resulted in nanoparticles smaller than 200 nm in diameter and negative zeta potentials, displaying optimal characteristics for in vivo application. Encapsulating and protecting the siRNA payload well, the nanoparticles enabled transport to A549 cells in vitro, could evade endosomal entrapment and mediated significant sequence-specific KRAS knockdown, resulting in reduced cell growth of siRNA transfected lung cancer cells. CONCLUSIONS: BSA nanoparticles loaded with mutant specific siRNA are a promising therapeutic approach for KRAS-mutant cancers.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Interferente Pequeno/farmacologia , Soroalbumina Bovina/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Bovinos , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Terapia Genética , Humanos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Transfecção
18.
Anticancer Res ; 39(7): 3493-3498, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262873

RESUMO

BACKGROUND/AIM: Pancreatic cancer is the most lethal cancer of the digestive system. IL-29 is a new member of the IFNλ family and well-known for its strong antiviral activity. However, its direct effect on pancreatic cancer is still unclear. This study was performed to investigate if IL-29 has any direct effect on Pan-48 pancreatic cancer cells. MATERIALS AND METHODS: Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the effects of IL-29 on cell survival, proliferation, and apoptosis of Pan-48 pancreatic cancer cells. RT-PCR and IHC were subsequently performed to explore IL-29's potential molecular mechanisms. RESULTS: The percentage of colonies of Pan-48 cells was decreased following the addition of IL-29. This was consistent with a decreased optical density (OD) value of cancer cells. Furthermore, the relative caspase-3 activity in cancer cells was increased after the addition of IL-29, indicating increased apoptosis of cancer cells. The anti-proliferative effect of IL-29 on cancer cells correlated with increased expression of the anti-proliferative molecule p21. The pro-apoptotic effect of IL-29 on cancer cells correlated with an increased expression of the pro-apoptotic molecule Bax. CONCLUSION: IL-29 constrains Pan-48 pancreatic cell growth via up-regulation of p21 and Bax. Our study suggests a potential use of IL-29 in immunotherapy for pancreatic cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Interleucinas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteína X Associada a bcl-2/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
19.
J Agric Food Chem ; 67(31): 8668-8676, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31271028

RESUMO

This study investigated the effect of Chlorella vulgaris (C. vulgaris) on genotoxicity, cytotoxicity, and apoptosis in Caco-2 and HT-29 cells. C. vulgaris significantly induced DNA damage in both cell lines at a concentration of 200 µg dry matter/mL (comet tail intensity CTI: 24.6 ± 4.7% for Caco-2, 16.6 ± 0.9% for HT-29). The application of processing (sonication, ball-milling) did not affect the genotoxicity negatively and lowered the lipid peroxidation in C. vulgaris preparations. C. vulgaris-induced intracellular formation of reactive oxygen species in human cell lines and might be responsible for the genotoxic effect. A solid fraction mainly triggered the observed DNA damage (CTI: 41.5 ± 1.9%), whereas a hydrophilic (CTI: 7.9 ± 1.7%) and lipophilic (CTI: 10.2 ± 2.1%) fraction revealed a significantly lower tail intensity. C. vulgaris significantly induced DNA damage in both cell lines possibly through intracellular formation of reactive oxygen species; however, it was repaired after a 2 h recovery time or was even avoided at lower concentrations. In addition, none of the preparations indicated an adverse effect on cell proliferation or revealed apoptotic activity.


Assuntos
Chlorella vulgaris/química , Dano ao DNA/efeitos dos fármacos , Células Epiteliais/citologia , Mutagênicos/toxicidade , Extratos Vegetais/toxicidade , Apoptose/efeitos dos fármacos , Processos Autotróficos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorella vulgaris/crescimento & desenvolvimento , Chlorella vulgaris/efeitos da radiação , Ensaio Cometa , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Luz , Peroxidação de Lipídeos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
20.
Biol Res ; 52(1): 34, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277690

RESUMO

BACKGROUND: Psoralen is a coumarin-like and coumarin-related benzofuran glycoside, which is a commonly used traditional Chinese medicine to treat patients with kidney and spleen-yang deficiency symptom. Psoralen has been reported to show estrogen-like activity, antioxidant activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. However, the antitumor mechanism of psoralen is not fully understood. This study aimed to investigate the therapeutic efficacy of psoralen in human hepatoma cell line SMMC7721 and the mechanism of antitumor effects. RESULTS: Psoralen inhibited proliferation of SMMC7721 in a dose- and time-dependent manner, and promoted apoptosis. Further, psoralen activated the ER stress signal pathway, including the expansion of endoplasmic reticulum, increasing the mRNA levels of GRP78, DDIT3, ATF4, XBP1, GADD34 and the protein levels of GDF15, GRP78, IRE1α, XBP-1s in a time-dependent manner. Psoralen induces cell cycle arrest at G1 phase by enhancing CyclinD1 and reducing CyclinE1 expression. Moreover, TUDC couldn't inhibit the psoralen-induced ER stress in SMMC7721 cells. CONCLUSIONS: Psoralen can inhibit the proliferation of SMMC7721 cells and induce ER stress response to induce cell apoptosis, suggesting that psoralen may represent a novel therapeutic option for the prevention and treatment hepatocellular carcinoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ficusina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ficusina/química , Ficusina/uso terapêutico , Humanos , Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
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