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1.
Anticancer Res ; 39(10): 5515-5524, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570445

RESUMO

BACKGROUND/AIM: Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin. MATERIALS AND METHODS: To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated. RESULTS: Cisplatin increased the accumulation of ROS, leading to excessive ER stress. In presence of cisplatin, treatment of TH-1 cells with fucoidan significantly reduced the ER stress by maintaining the complex of GRP78 with PERK and IRE1α. In particular, fucoidan enhanced the antioxidative capacity through up-regulation of PrPC Furthermore, fucoidan suppressed cisplatin-induced apoptosis and cell-cycle arrest, whereas silencing of PRNP blocked these effects of fucoidan. CONCLUSION: Fucoidan may be a potential adjuvant therapy for cancer patients treated with cisplatin as it preserves renal functionality.


Assuntos
Cisplatino/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Regulação para Cima/efeitos dos fármacos , eIF-2 Quinase/metabolismo
2.
J Agric Food Chem ; 67(41): 11428-11435, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31589037

RESUMO

Diosgenin and diosgenyl saponins as the major bioactive compounds isolated from dietary fenugreek seeds, yam roots, etc. possessed strong antitumor effects. To understand their detailed antitumor mechanisms, a fluorophore-appended derivative of diosgenin [Glc/CNHphth-diosgenin (GND)] was synthesized, starting from diosgenin and glucosamine hydrochloride in overall yields of 7-12% over 7-10 steps. Co-localization of GND with organelle-specific stains, transmission electron microscopy, and relative protein analyses demonstrated that GND crossed the plasma membrane through organic anion-transporting polypeptide 1B1 and distributed in the endoplasmic reticulum (ER), lysosome, and mitochondria. In this process, GND induced ER swelling, mitochondrial damage, and autophagosome and upregulating IRE-1α to induce autophagy and apoptosis. Furthermore, autophagy inhibitor chloroquine delayed the appearance of cleaved poly(ADP-ribose) polymerase and inhibited cleaved caspase 8, which indicated that GND induced autophagy to activate caspase-8-dependent apoptosis. These observations suggested that diosgenyl saponin was a potent anticancer agent that elicited ER stress and mitochondria-mediated apoptotic pathways in liver cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Hepáticas/fisiopatologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/genética , Lisossomos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo
3.
Postepy Biochem ; 65(2): 118-127, 2019 06 06.
Artigo em Polonês | MEDLINE | ID: mdl-31642650

RESUMO

Recent studies aimed at understanding the molecular mechanisms of human disease indicate that in the pathogenesis of many metabolic disorders, including inflammatory processes, aging of the organism, as well as cancer and neurodegenerative disorders, endoplasmic reticulum stress plays a significant role that is associated with the accumulation of misfolded proteins in the lumen of endoplasmic reticulum. In response to endoplasmic reticulum stress, the unfolded protein response pathway, that has a dualistic role, is induced. The unfolded protein response can restore endoplasmic reticulum homeostasis by degradation of unfolded proteins, inhibition of translation, and mobilization of chaperons, but it can also promote apoptosis when endoplasmic reticulum stress is prolonged. The unfolded protein response signaling pathways may be activated via three transmembrane receptors such as: PERK, IRE1 and ATF6. The most promising for development of new therapies of many human diseases, in particular cancer and neurodegeneration is PERK pathway, that inhibition shows positive therapeutic effects both in in vitro and in vivo studies.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , eIF-2 Quinase/antagonistas & inibidores , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/enzimologia , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
4.
Gene ; 721: 144095, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476403

RESUMO

Penehyclidine hydrochloride (PHC) is a novel anticholinergic drug applied broadly in surgeries as a preanesthetic medication. A substantial amount of research indicates that PHC has lung defensive properties. Considering that endoplasmic reticulum (ER) stress exerts a crucial function in cell apoptosis associated with the lipopolysaccharides (LPS)-induced acute lung injury (ALI) model, we aimed to determine whether regulation of ER stress in the LPS-induced ALI model was associated with the lung defensive role of PHC. Adult male SD rats were administered LPS (5 mg/kg, intratracheally) followed by PHC (1.0 mg/kg, intravenously) for 24 h. The NR8383 alveolar macrophages were randomly separated into Sham, LPS (100 ng/mL), and PHC (1, 2.5, or 5 µg/mL) + LPS groups. PHC (1, 2.5, or 5 µg/mL) + LPS groups were treated with PHC alone for 1 h after LPS exposure. Posttreatment with PHC relieved LPS-induced pulmonary impairment and blocked LPS-mediated lung apoptosis, indicated by the downregulation of the lung apoptotic indicators malondialdehyde and superoxide dismutase in serum at 24 h after LPS-induced ALI. PHC (1-5 µg/mL) did not influence the activity of cultivated NR8383 alveolar macrophages in vitro. However, postconditioning with PHC dosage-dependently reduced LPS-mediated cell apoptosis. Additionally, many studies have indicated that PHC administration inhibits ER stress and initiates hairy and enhancer of split 1 (Hes1)/(Notch1) signaling by decreasing phosphorylated α subunit of eukaryotic initiation factor 2α (p-eIF2α)/eukaryotic translation initiation factor 2α (eIF2α) and Phospho-protein kinase R-like ER kinase (p-PERK)/ protein kinase R-like ER kinase (PERK) proportions; inhibiting C/EBP-homologous protein (CHOP), activating transcription factor 4 (ATF4), caspase-3, and Bcl2-associated x (Bax) activity; and enhancing notch1 intracellular domain (NICD), Notch1, B-cell lymphoma-2 (Bcl-2), and Hes1 activity in vivo and in vitro. In addition, the defensive functions of PHC on LPS-activated NR8383 alveolar macrophages were abrogated through the Notch1 pathway antagonist [(3,5-difluorophenacetyl)-1-alanyl] -phenylglycine-butyl ester (DAPT). In conclusion, PHC alleviates LPS-induced ALI by ameliorating ER stress-mediated apoptosis and promoting Hes1/Notch1 signaling in vivo and in vitro.


Assuntos
Lesão Pulmonar Aguda , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hialuronan Sintases/metabolismo , Lipopolissacarídeos/toxicidade , Quinuclidinas/farmacologia , Receptor Notch1/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
5.
Life Sci ; 234: 116739, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400352

RESUMO

AIM: This study aimed to investigate the effect of icariin (referred as ICA) on Alzheimer's disease (AD) model through endoplasmic reticulum (ER) stress pathway. MAIN METHODS: Nine months male APP/PS1 and wild-type (WT) mice were randomly divided into four groups: APP/PS1 control, APP/PS1 + ICA, WT control and WT + ICA groups. The treated mice were given ICA 60 mg/kg/d and control mice were received the same volume distilled water for consecutive 3 months. The Morris water maze and Novel object recognition were used to detect animals' behavior. Nissl staining was used to observe the neuronal morphology in hippocampus area. Aß deposition in hippocampal region was observed by immunofluorescence staining. TUNEL staining was used to observe apoptosis. Detection of expression of ER stress related factors by Western blot and real time RT-PCR. KEY FINDINGS: Chronically administrated with ICA compared with APP/PS1 control mice significantly improved the behavior performance, reduced neuronal apoptosis, as well as suppressing the ER stress signaling pathway, including that decreased the level of glucose-regulated protein 78, phosphorylated ER-regulated kinase and phosphorylated eukaryotic initiation factor α, as well activating transcription factor-4, C/EBP homologous protein, DNA damage inducible protein 34 and tribbles homologous protein 3. SIGNIFICANCE: Our data indicated that ICA suppressed the ER stress signaling to protect against AD animal model, these findings suggest that a potential point for researching the effect of ICA on neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Cognição/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonoides/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória/efeitos dos fármacos , Camundongos
6.
Chem Commun (Camb) ; 55(72): 10776-10779, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31432809

RESUMO

Herein, we present a dual-site ratiometric fluorescent probe based on the ICT-PET-FRET mechanism for the detection of pH in the ER. The probe showed a highly sensitive response to pH in the range of 5.0-7.2, and could be applied for the quantitative measurement of the pH values in the ER during ER stress and dexamethanose-induced stimulation.


Assuntos
Retículo Endoplasmático/metabolismo , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Dexametasona/farmacologia , Transporte de Elétrons , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio
7.
J Agric Food Chem ; 67(34): 9618-9629, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31381342

RESUMO

Astrocytes provide nutritional support, regulate inflammation, and perform synaptic functions in the human brain. Although butylated hydroxyanisole (BHA) is a well-known antioxidant, several studies in animals have indicated BHA-mediated liver toxicity, retardation in reproductive organ development and learning, and sleep deficit. However, the specific effects of BHA on human astrocytes and the underlying mechanisms are yet unclear. Here, we investigated the antigrowth effects of BHA through cell cycle arrest and downregulation of regulatory protein expression. The typical cell proliferative signaling pathways, phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase 1/2, were downregulated in astrocytes after BHA treatment. BHA increased the levels of pro-apoptotic proteins, such as BAX, cytochrome c, cleaved caspase 3, and cleaved caspase 9, and decreased the level of anti-apoptotic protein BCL-XL. It also increased the cytosolic calcium level and the expression of endoplasmic reticulum stress proteins. Treatment with BAPTA-AM, a calcium chelator, attenuated the increased levels of ER stress proteins and cleaved members of the caspase family. We further performed an in vivo evaluation of the neurotoxic effect of BHA on zebrafish embryos and glial fibrillary acidic protein, a representative astrocyte biomarker, in a gfap:eGFP zebrafish transgenic model. Our results provide clear evidence of the potent cytotoxic effects of BHA on human astrocytes, which lead to disruption of the brain and nerve development.


Assuntos
Astrócitos/efeitos dos fármacos , Hidroxianisol Butilado/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurotoxinas/toxicidade , Animais , Astrócitos/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
8.
J Agric Food Chem ; 67(39): 10832-10843, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31464433

RESUMO

Excessive fluoride mainly causes skeletal lesions. Recently, it has been reported that an appropriate level of calcium can alleviate fluorosis. However, the appropriate concentration and mechanism of calcium addition is unclear. Hence, we evaluated the histopathology and ultrastructure, DNA fragmentation, hormonal imbalances, biomechanical levels, and expression of apoptosis-related genes after treating the rats with 150 mg/L NaF and different concentrations of CaCO3. Our results suggested that NaF induced the histopathological and ultrastructural injury, with a concomitant increase in the DNA fragmentation (P < 0.05) and serum OC (17.5 ± 0.89 pmoL/L) at 120 days. In addition, the qRT-PCR and western blotting results indicated that NaF exposure upregulated the mRNA and protein expression of Bax, Calpain, Caspase 12, Caspase 9, Caspase 7, Caspase 3, CAD, PARP, and AIF while downregulated Bcl-2 (P < 0.01) and decreased the bone ultimate load by 27.1%, the ultimate stress by 10.1%, and the ultimate deformity by 23.3% at 120 days. However, 1% CaCO3 supplementation decreased the serum OC (14.7 ± 0.65 pmoL/L), bone F content (P < 0.01), and fracture and breakage of collagen fibers and changed the expression of endoplasmic reticulum pathway-related genes and proteins at 120 days. Further, 1% CaCO3 supplementation increased the bone ultimate load by 20.9%, the ultimate stress by 4.89%, and the ultimate deformity by 21.6%. In summary, we conclude that 1% CaCO3 supplementation alleviated fluoride-induced bone damage by inhibiting endoplasmic reticulum stress and mitochondrial dysfunction.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fluoretos/toxicidade , Mitocôndrias/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Caspases/genética , Caspases/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Int J Nanomedicine ; 14: 6103-6115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447555

RESUMO

Purpose: Myocardial delivery of magnetic iron oxide nanoparticles (MNPs) might produce iron overload-induced myocardial injury, and the oxidative stress was regarded as the main mechanism. Therefore, we speculated antioxidant modification might be a reasonable strategy to mitigate the toxicity of MNPs. Methods and results: Antioxidant N-acetylcysteine (NAC) was loaded into magnetic mesoporous silica coated Fe3O4 nanoparticles. Neonatal rat hypoxia/reoxygenation (H/R) cardiomyocytes were incubated with nanoparticles for 24 hrs. NAC can effectively mitigate iron-induced oxidative injury of cardiomyocytes, evidenced by reduced production of MDA, 8-iso-PGF2α, and 8-OHDG and maintained concentrations of SOD, CAT, GSH-Px, and GSH in ELISA and biochemical tests; downregulated expression of CHOP, GRP78, p62, and LC3-II proteins in Western Blot, and less cardiomyocytes apoptosis in flow cytometric analysis. Conclusions: NAC modifying could suppress the toxic effects of Fe3O4 nanoparticles in H/R cardiomyocytes model in vitro, indicating a promising strategy to improve the safety of iron oxide nanoparticles.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Compostos Férricos/toxicidade , Nanopartículas de Magnetita/toxicidade , Miócitos Cardíacos/patologia , Oxigênio/farmacologia , Animais , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nanopartículas de Magnetita/ultraestrutura , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Porosidade , Ratos , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade
10.
Life Sci ; 232: 116612, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260687

RESUMO

AIMS: Accumulating evidence suggest that endoplasmic reticulum (ER) stress is an important mechanism underlying the development of diabetes. We have reported that sustained treatment with N-methyl-d-aspartate (NMDA) results in apoptotic ß-cell death and impairs insulin secretion. However, the molecular mechanism responsible for NMDA-induced ß-cell dysfunction remains largely obscure. Thus, this study aimed to determine whether sustained activation of NMDA receptors (NMDARs) causes ß-cell dysfunction through ER stress. MAIN METHODS: Primary mouse islets and MIN6 mouse pancreatic ß-cells were treated with NMDA for 24 h or high-glucose for 72 h. After the treatment, glucose-stimulated insulin secretion (GSIS) and the expression of ER stress markers were measured, respectively. In vivo, the expression of ER stress markers was measured in the pancreas of diabetic mice treated with or without NMDARs inhibitor Memantine. KEY FINDINGS: NMDA treatment caused an increase in the expression of ER stress markers (ATF4, CHOP, GRP78, and Xbp1s) in primary islets. While, tauroursodeoxycholic acid (TUDCA), an inhibitor of ER stress, significantly attenuated NMDA-induced ß-cell dysfunction, including the loss of glucose-stimulated insulin secretion and reduction of pancreas duodenum homeobox factor-1 (Pdx-1) mRNA expression, a transcription factor regulating insulin synthesis. Besides, NMDA-induced ER stress strongly promoted pro-inflammatory cytokines synthesis (IL-1ß and TNF-α) in ß cells. Interestingly, knockdown of CHOP attenuated ß-cell dysfunction evoked by NMDA. Furthermore, we demonstrated that blockade of NMDARs ameliorated high-glucose-induced ER stress in vitro and in vivo. SIGNIFICANCE: This study confirms that ER stress is actively involved in the activation of NMDARs-related ß-cell dysfunction.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Células Secretoras de Insulina/metabolismo , Fator de Transcrição CHOP/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glucose/metabolismo , Proteínas de Choque Térmico/metabolismo , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , N-Metilaspartato/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Proteína 1 de Ligação a X-Box/metabolismo
11.
Chem Biol Interact ; 310: 108733, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276663

RESUMO

Plumbagin (PLB) is an active secondary metabolite extracted from the roots of Plumbago rosea. In this study, we report that plumbagin effectively induces paraptosis by triggering extensive cytoplasmic vacuolation followed by cell death in triple negative breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and non-small lung cancer cells (A549) but not in normal lung fibroblast cells (WI-38). The vacuoles originated from the dilation of the endoplasmic reticulum (ER) and were found to be empty. The cell death induced by plumbagin was neither apoptotic nor autophagic. Plumbagin induced ER stress mainly by inhibiting the chymotrypsin-like activity of 26S proteasome as also evident from the accumulation of polyubiquitinated proteins. The vacuolation and cell death were found to be independent of reactive oxygen species generation but was effectively inhibited by thiol antioxidant suggesting that plumbagin could modify the sulfur homeostasis in the cellular milieu. Plumbagin also resulted in a decrease in mitochondrial membrane potential eventually decreasing the ATP production. This is the first study to show that Plumbagin induces paraptosis through proteasome inhibition and disruption of sulfhydryl homeostasis and thus further opens up the lead molecule to potential therapeutic strategies for apoptosis-resistant cancers.


Assuntos
Morte Celular/efeitos dos fármacos , Naftoquinonas/farmacologia , Neoplasias/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Homeostase , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Compostos de Sulfidrila/metabolismo , Vacúolos/metabolismo
12.
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
13.
Environ Pollut ; 253: 429-438, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325888

RESUMO

Recently, the essentiality and fatalness of cardiovascular diseases is attracting much attention. Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants, which could induce the toxic effect and have been implicated in the occurrence and development of cardiovascular diseases. However, it is unclear how autophagy and apoptosis induced by BDE-209 in endothelial cells are regulated. The aim of the present study was to investigate the effects of BDE-209 on human umbilical vein endothelial cells (HUVECs) and elucidate the mechanisms involved. HUVECs were treated with a wide range concentration of BDE-209 for 24 h. The appearance of autophagy was tested by the testing index such as outcomes of monodansylcadaverine (MDC) staining and lysotracker staining, observation of autophagosomes and conversion between autophagy marker light chain 3 (LC3)-I and LC3-II. Besides, the apoptotic cell rate was detected with flow cytometry. In addition, BDE-209 induced endoplasmic reticulum (ER) stress was detected by transmission electron microscopy (TEM). Our data suggest that the exposure of BDE-209 could induce autophagy, which was confirmed by MDC staining, transmission electron microscopy observation, lysotracker staining and LC3-I/LC3-II conversion. Besides, the ER stress-related inositol-requiring enzyme 1α (IRE1α)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway could be activated by reactive oxygen species (ROS) to regulate autophagy. Moreover, the apoptosis of endothelial cells was alleviated when autophagy was blocked by 3-Methyladenine (3-MA). The results demonstrated that BDE-209 could induce the production of ROS and ER stress, activate autophagy through IRE1α/AKT/mTOR signaling pathway and ultimately induce apoptosis of vascular endothelial cells. These findings indicate that exposure to PBDE is possible to be a potential risk factor for cardiovascular diseases.


Assuntos
Poluentes Ambientais/toxicidade , Éteres Difenil Halogenados/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inositol , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Testes de Toxicidade , Veias Umbilicais
14.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1876-1881, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342716

RESUMO

This study is aimed to investigate the intervention effect and possible mechanism of ophiopogonin D( OPD) in protecting cardiomyocytes against ophiopogonin D'( OPD')-induced injury,and provide reference for further research on toxicity difference of saponins from ophiopogonins. CCK-8 assay was used to evaluate the effect of OPD and OPD' on cell viability. The effect of OPD on OPD'-induced cell apoptosis was measured by flow cytometry. Morphologies of endoplasmic reticulum were observed by endoplasmic reticulum fluorescent probe. PERK,ATF-4,Bip and CHOP mRNA levels were detected by Real-time quantitative polymerase chain reaction( PCR) analysis. ATF-4,phosphorylated PERK and e IF2α protein levels were detected by Western blot assay. RESULTS:: showed that treatment with OPD'( 6 µmol·L-1) significantly increased the rate of apoptosis; expressions of endoplasmic reticulum stress related genes were increased. The morphology of the endoplasmic reticulum was changed. In addition,different concentrations of OPD could partially reverse the myocardial cell injury caused by OPD'. The experimental results showed that OPD'-induced myocardial toxicity may be associated with the endoplasmic reticulum stress,and OPD may modulate the expression of CYP2 J3 to relieve the endoplasmic reticulum stress caused by OPD'.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Espirostanos/farmacologia , Apoptose , Cardiotônicos/farmacologia , Células Cultivadas , Humanos
15.
Chem Pharm Bull (Tokyo) ; 67(7): 648-653, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257320

RESUMO

Diabetic embryopathy is a diabetic complication, in which maternal hyperglycemia in early pregnancy causes birth defects in newborn infants. Under maternal diabetic conditions, hyperglycemia disturbs intracellular molecular activities and organelles functions. These include protein misfolding in the endoplasmic reticulum (ER), overproduction of reactive oxygen species (ROS) in mitochondria, and high levels of nitric oxide (NO). The resultant ER, oxidative, and nitrosative stresses activate apoptotic machinery to cause cell death in the embryo, ultimately resulting in developmental malformations. Based on the basic research data, efforts have been made to develop interventional strategies to alleviate the stress conditions and to reduce embryonic malformations. One of the challenges in birth defect prevention is to identify effective and safe agents to be used in pregnancy. One approach is to search and characterize naturally occurring phytochemicals, including flavonoids, curcuminoids and stilbenoids, for use in prevention of diabetic embryopathy.


Assuntos
Anormalidades Congênitas/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Gravidez em Diabéticas/prevenção & controle , Curcumina/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Gravidez , Estilbenos/química , Estilbenos/farmacologia , Estilbenos/uso terapêutico
16.
Chem Biol Interact ; 309: 108675, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31150632

RESUMO

Liver fibrosis is a progression of chronic liver disease with lacks effective therapies at present. Schisandrin B (Sch B), a bioactive compound extracted from the traditional Chinese medicine Schisandra chinensis, was reported to benefit liver diseases. This study aimed to investigate the therapeutic effects and molecular mechanisms of Sch B against CCl4-induced liver fibrosis in rats. RNA sequencing and transcriptome analysis were performed collaboratively, including analysis of differential gene expression, gene ontology (GO) analysis, pathway analysis and pathway-act-network analysis. The results demonstrated that Sch B effectively alleviated CCl4-induced liver damage and fibrosis in rats, as evidenced by improved liver function and decreased extracellular matrix deposition. Furthermore, 4440 (1878 up-regulated, 2562 down-regulated) genes in the model group versus (vs) normal group, 4243 (2584 up-regulated, 1659 down-regulated) genes in Sch B-treated group vs model group were identified as differentially expressed genes (DEGs). Subsequently, GO analysis revealed that DEGs were mainly enriched in metabolism, oxidation-reduction, endoplasmic reticulum stress and apoptosis-related biological processes. Pathway analysis suggested that Sch B up-regulated cytochrome P450 drug metabolism, PPAR signaling pathways, and down-regulated glutathione metabolism pathways. In addition, the regulatory patterns of Sch B on key genes and pathways were also confirmed. In conclusion, our study demonstrated Sch B alleviated CCl4-induced liver fibrosis by multiple modulatory mechanisms, which provide new clues for further pharmacological study of Sch B.


Assuntos
Lignanas/farmacologia , Cirrose Hepática/patologia , Fígado/metabolismo , Compostos Policíclicos/farmacologia , Transcriptoma , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica , Lignanas/química , Lignanas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa , Compostos Policíclicos/química , Compostos Policíclicos/uso terapêutico , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Ratos , Ratos Wistar , Schisandra/química , Schisandra/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos
17.
Life Sci ; 231: 116551, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185236

RESUMO

Octreotide (OCT) shows clinical efficacies in the treatment of liver cirrhosis complicated with gastrointestinal hemorrhage. Experiments were designed to investigate its function mechanism associated with endoplasmic reticulum stress (ERS)-induced autophagy and microRNA (miR). Protein associated with ERS and autophagy was detected by western blot. miR-101 was examined by qRT-PCR. Besides, miR-101 or G protein-coupled receptor 78 (GPR78)-silenced Caco-2 cells were established by transfection. Furthermore, western blot was used to determine TGF-beta activated kinase 1 (TAK1), AMPK, mTOR, p70S6K as well as their phosphorylated forms. Lipopolysaccharide (LPS) enforced the expression of GPR78. Besides, LPS triggered the production of Beclin-1 and LC3-II while mitigated the accumulation of p62. Then all these above results were reversed by OCT pretreatment. Moreover, miR-101 expression was downregulated by LPS while upregulated by OCT. Further, miR-101 knockdown strengthened ERS and promoted autophagy. GPR78 silence retarded autophagy process. In the end, OCT mitigated phosphorylation of TAK1, AMPK while enhanced the phosphorylated expression of mTOR and p70S6K in LPS-treated Caco-2 cells. The anti-autophagy property of OCT was mediated by miR-101-induced suppression of GPR78 in LPS-treated Caco-2 cells.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , MicroRNAs/metabolismo , Octreotida/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Proteína Beclina-1/genética , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/genética , Octreotida/metabolismo , Fosforilação , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
18.
Int J Oncol ; 55(1): 331-339, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180536

RESUMO

Thyroid cancer is among the most common types of malignant tumor of the endocrine system. The role of metformin in the inhibition of cancer cell proliferation and induction of apoptosis is widely accepted. The present study explored the effect and the underlying mechanisms of metformin on human thyroid cancer TPC­1 cells. Following treatment of TPC­1 cells with different concentrations of metformin, cell proliferation and apoptosis were analyzed by cell counting kit­8 (CCK­8) assay and flow cytometry, respectively. Reverse transcription­quantitative PCR and western blotting were used to detect alterations in the mRNA and protein expression levels, respectively, for heat shock protein family A member 5 (HSPA5, also known as Bip), DNA damage­inducible transcript 3 (DDIT3, also known as CHOP) and caspase­12. The results demonstrated that treatment with metformin inhibited proliferation and induced apoptosis in a concentration and time­dependent manner. In addition, treatment with metformin increased the expression of Bip, CHOP and caspase­12 in vitro, activating endoplasmic reticulum (ER) stress. Thapsigargin treatment enhanced the apoptosis induced by metformin. Inhibition of ER stress by 4­phenylbutyrate reversed the metformin­induced apoptosis. Finally, treatment with metformin inhibited thyroid cancer growth and increased the expression of Bip and CHOP in a TPC­1 cell xenograft model. These results indicated that metformin increased the apoptotic rate of thyroid cancer cells via ER stress­associated mechanisms.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metformina/farmacologia , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
19.
Chem Commun (Camb) ; 55(52): 7474-7477, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31184664

RESUMO

Inspired by clinical studies on alcohol abuse induced endoplasmic reticulum disruption, we designed a N-hydroxylethyl peptide assembly to regulate the ER stress response in cancer cells. Upon coupling with a coumarin derivative via an ester linkage, a prodrug was synthesized to promote esterase-facilitated self-delivery of N-hydroxylethyl peptide assemblies around the ER, inducing ER dilation. Following this, ER-specific apoptosis was effectively and efficiently activated in various types of cancer cells including drug resistant and metastatic ones.


Assuntos
Citosol/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Peptídeos/farmacologia , Apoptose/efeitos dos fármacos , Carboxilesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Humanos , Microscopia de Fluorescência , Peptídeos/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia
20.
J Dairy Sci ; 102(8): 7359-7370, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155263

RESUMO

Disruption of endoplasmic reticulum (ER) homeostasis, often termed ER stress, is intrinsically linked with perturbation of lipid metabolism in humans and mice. Whether ER homeostasis is affected in cows experiencing fatty liver is unknown. The aim of this study was to investigate the potential role of ER stress in hepatic lipid accumulation in calf hepatocytes and ER stress status in dairy cows with severe fatty liver. In vitro experiments were conducted in which hepatocytes were isolated from calves and treated with different concentrations of fatty acids, tauroursodeoxycholic acid (TUDCA; a canonical inhibitor of ER stress), or both. The increase in phosphorylation level of protein kinase RNA-like ER kinase (PERK) and inositol requiring protein-1α (IRE1α) proteins, and the cleavage of activating transcription factor-6 (ATF6) protein in response to increasing doses of fatty acids (which were reversed by TUDCA treatment) in primary hepatocytes underscored a mechanistic link between fatty acids and ER stress. In addition, fatty acid treatment increased the abundance of sterol regulatory element-binding protein 1c, acetyl-CoA carboxylase-α, fatty acid synthase, and diacylglycerol acyltransferase 1, and lipid accumulation in calf primary hepatocytes, whereas inhibition of ER stress by incubating with TUDCA significantly weakened these effects. Overall, results in vitro indicate that inhibition of ER stress in calf hepatocytes alleviates fatty acid-induced lipid accumulation by downregulating the expression of lipogenic genes. In vivo experiments, liver and blood samples were collected from cows diagnosed as healthy (n = 15) or with severe fatty liver (n = 15). The phosphorylation level of PERK and IRE1α, the cleavage of ATF6 protein, and the abundance of several unfolded protein response genes (78 kDa glucose-regulated protein, AMP-dependent transcription factor 4, and spliced X-box binding protein 1) were greater in liver of cows with severe fatty liver. The present in vivo study confirms the occurrence of ER stress in dairy cows with severe fatty liver. Considering the causative role of fatty acid-induced ER stress in hepatic lipid accumulation in calf hepatocytes, the existence of ER stress in the liver of severe fatty liver cows may presage its participation in fatty liver progression in dairy cows. However, the mechanistic relationship between ER stress and fatty liver in dairy cows remain to be determined.


Assuntos
Doenças dos Bovinos/fisiopatologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos/administração & dosagem , Fígado Gorduroso/veterinária , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fator 6 Ativador da Transcrição/metabolismo , Animais , Bovinos , Células Cultivadas , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipogênese/genética , Fígado/efeitos dos fármacos , Camundongos , Fosforilação , Ácido Tauroquenodesoxicólico/administração & dosagem , Resposta a Proteínas não Dobradas/genética , eIF-2 Quinase/metabolismo
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