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1.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500626

RESUMO

We investigated the protective effect and mechanisms of apigenin against cognitive impairments in a scopolamine-injected mouse model. Our results showed that intraperitoneal (i.p.) injection of scopolamine leads to learning and memory dysfunction, whereas the administration of apigenin (synthetic compound, 100 and 200 mg/kg/day) improved cognitive ability, which was confirmed by behavioral tests such as the T-maze test, novel objective recognition test, and Morris water maze test in mice. In addition, scopolamine-induced lipid peroxidation in the brain was attenuated by administration of apigenin. To further evaluate the protective mechanisms of apigenin on cognitive and memory function, Western blot analysis was carried out. Administration of apigenin decreased the B-cell lymphoma 2-associated X/B-cell lymphoma 2 (Bax/Bcl-2) ratio and suppressed caspase-3 and poly ADP ribose polymerase cleavage. Furthermore, apigenin down-regulated the ß-site amyloid precursor protein-cleaving enzyme, along with presenilin 1 (PS1) and PS2 protein levels. Apigenin-administered mice showed lower protein levels of a receptor for advanced glycation end-products, whereas insulin-degrading enzyme, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) expression were promoted by treatment with apigenin. Therefore, this study demonstrated that apigenin is an active substance that can improve cognitive and memory functions by regulating apoptosis, amyloidogenesis, and BDNF/TrkB signaling pathways.


Assuntos
Apigenina/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Neurônios/efeitos dos fármacos , Escopolamina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
PLoS One ; 16(9): e0251951, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34473709

RESUMO

The purpose of this study was to explore potential mechanisms of cytotoxicity towards HeLa and HT29 cells displayed by Pediocin PA-1. We did this by carrying out sequence alignments and 3D modelling of related bacteriocins which have been studied in greater detail: Microcin E492, Enterocin AB heterodimer and Divercin V41. Microcin E492 interacts with Toll-Like Receptor 4 in order to activate an apoptosis reaction, sequence alignment showed a high homology between Pediocin PA-1 and Microcin E492 whereas 3D modelling showed Pediocin PA-1 interacting with TLR-4 in a way reminiscent of Microcin E492. Furthermore, Pediocin PA-1 had the highest homology with the Enterocin heterodimer, particularly chain A; Enterocin has also shown to cause an apoptotic response in cancer cells. Based on this we are led to strongly believe Pediocin PA-1 interacts with TLRs in order to cause cell death. If this is the case, it would explain the difference in cytotoxicity towards HeLa over HT29 cells, due to difference in expression of particular TLRs. Overall, we believe Pediocin PA-1 exhibits a dual effect which is dose dependant, like that of Microcin. Unfortunately, due to the COVID-19 pandemic, we were unable to carry out experiments in the lab, and the unavailability of important data meant we were unable to provide and validate out solid conclusions, but rather suggestions. However, bioinformatic analysis is still able to provide information regarding structure and sequence analysis to draw plausible and evidence based conclusions. We have been able to highlight interesting findings and how these could be translated into future research and therapeutics in order to improve the quality of treatment and life of cancer patients.


Assuntos
Bacteriocinas/química , Bacteriocinas/farmacologia , Pediocinas/química , Pediocinas/farmacologia , Conformação Proteica , Sequência de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Bacteriocinas/genética , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Células HeLa , Humanos , Modelos Moleculares , Pandemias , Pediocinas/genética , SARS-CoV-2/fisiologia , Homologia de Sequência de Aminoácidos , Receptor 4 Toll-Like/metabolismo
3.
Cancer Genomics Proteomics ; 18(5): 661-673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34479918

RESUMO

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Virulence ; 12(1): 2214-2227, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34494942

RESUMO

An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry. 4 F also reduced associated cellular apoptosis and secretion of IL-6 in both SARS-CoV-2 infected Vero-E6 and Calu3 cells. Thus, 4 F attenuates in vitro SARS-CoV-2 replication, associated apoptosis in epithelial cells and secretion of IL-6, a major cytokine related to COVID-19 morbidity. Given established safety of 4 F in humans, clinical studies are warranted to establish 4 F as therapy for COVID-19.


Assuntos
Antivirais/farmacologia , Peptídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Basigina/metabolismo , Citocinas/metabolismo , Células Epiteliais , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Inflamação , Interferons/metabolismo , Estresse Oxidativo/efeitos dos fármacos , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
5.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361566

RESUMO

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that new four benzo[f]indole-4,9-dione derivatives reduce TNBC cell viability by reactive oxygen species (ROS) accumulation stress in vitro. Further analyses showed that LACBio1, LACBio2, LACBio3 and LACBio4 exert cytotoxic effects on MDA-MB 231 cancer cell line by inducing the intrinsic apoptosis pathway, activating caspase 9 and Bax/Bcl-2 pathway in vitro. These results provide evidence that these new four benzo[f]indole-4,9-dione derivatives could be potential therapeutic agents against TNBC by promoting ROS stress-mediated apoptosis through intrinsic-pathway caspase activation.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Citotoxinas , Indóis , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Feminino , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo
6.
J Photochem Photobiol B ; 222: 112258, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34399205

RESUMO

Photodynamic therapy (PDT) is an approved therapeutic approach and an alternative to conventional chemotherapy for the treatment of several types of cancer with the advantages of reducing the side effects and developing resistance mechanisms. Here, was evaluated the photosensitization capabilities of 5,10,15,20-tetrakis[4-(pyridinium-1-yl-methyl)phenyl]porphyrin (3), its N-confused isomer (4) and of the neutral precursors (1) and (2) and the results were compared with the ones obtained with the cationic 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). Both regular porphyrin derivatives 1 and 3 showed higher efficiency to generate singlet oxygen than TMPyP. The PDT assays towards MCF-7 cells under red light irradiation (λ > 640 nm, 23.7 mW cm-2) demonstrated that the cationic porphyrin 3 is an efficient photosensitizer to kill MCF-7 breast cancer cells. The study of the cell death mechanisms induced by the photodynamic process showed that the studied porphyrin 3 and TMPyP caused cell death by autophagic flux and necrosis.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Apoptose/efeitos da radiação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Luz , Células MCF-7 , Microscopia Confocal , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/uso terapêutico , Oxigênio Singlete/metabolismo
7.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445078

RESUMO

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Purinas/farmacologia , Receptor Smoothened/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Proteínas Hedgehog/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Purinas/química , Purinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/metabolismo
8.
J Enzyme Inhib Med Chem ; 36(1): 1715-1731, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34425716

RESUMO

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 µM (MGC-803 cells), 0.70 µM (HCT-116 cells), 1.04 µM (PC-3 cells), and 0.81 µM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.


Assuntos
Antineoplásicos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Nus , Estrutura Molecular , Quinazolinas/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1056-1064, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362482

RESUMO

OBJECTIVE: To investigate the cytotoxic effect and its mechanism of the micromolecule compound on the leukemia cells. METHODS: The cytotoxic effects of 28 Nilotinib derivatives on K562, KA, KG, HA and 32D cell lines were detected by MTT assays, and the compound Nilo 22 was screen out. Cell apoptosis and cell cycle on leukemia cells were detected by flow cytometry. The effect of compound screened out on leukemogenesis potential of MLL-AF9 leukemia mice GFP+ cells was tested by colony-forming units assays (CFU). The cytotoxic effect was further detected by transplant assays ex vivo. Telomerase activity assay, C-circle assay were used to measure the effects of compound on the length mechanism of telomere, RT-PCR was used to detected the changes of telomere. RESULTS: Nilo 22 serves as the most outstanding candidate out of 28 Nilotinib derivatives, which impairs leukemia cell lines, but spares normal hematopoietic cell line. Comparing with Nilotinib, Nilo 22 could induce the apoptosis of GFP+ cells significantly, slightly arrests the cell cycle at G0/G1 phase, and significantly inhibits colony formation and prolong the progression in MLL-AF9 leukemia mice model. The expression showed that the compound could slow the disease progression in MLL-AF9 leukemia mice significantly. Mechanistically, Nilo 22 could reduce the length of telomere by inhibiting telomerase activity and alternative lengthening of telomere (ALT). CONCLUSION: Nilo 22 shows a significant cytotoxic effect on mice and human leukemia cells, especially for drug resistance cells. Nilo 22 is a promising anti-leukemia agent to solve the common clinical problems of drug resistance and relapse of leukemia.


Assuntos
Leucemia , Telomerase/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Proteína de Leucina Linfoide-Mieloide/genética , Telomerase/metabolismo , Telômero/metabolismo
10.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
11.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443605

RESUMO

Extracts derived from the Ceratonia siliqua L. (carob) tree have been widely studied for their ability to prevent many diseases mainly due to the presence of polyphenolic compounds. In this study, we explored, for the first time, the anti-cancer properties of Cypriot carobs. We produced extracts from ripe and unripe whole carobs, pulp and seeds using solvents with different polarities. We measured the ability of the extracts to inhibit proliferation and induce apoptosis in cancer and normal immortalized breast cells, using the MTT assay, cell cycle analysis and Western Blotting. The extracts' total polyphenol content and anti-oxidant action was evaluated using the Folin-Ciocalteu method and the DPPH assay. Finally, we used LC-MS analysis to identify and quantify polyphenols in the most effective extracts. Our results demonstrate that the anti-proliferative capacity of carob extracts varied with the stage of carob maturity and the extraction solvent. The Diethyl-ether and Ethyl acetate extracts derived from the ripe whole fruit had high Myricetin content and also displayed specific activity against cancer cells. Their mechanism of action involved caspase-dependent and independent apoptosis. Our results indicate that extracts from Cypriot carobs may have potential uses in the development of nutritional supplements and pharmaceuticals.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Fabaceae/química , Fenóis/química , Fenóis/farmacologia , Solventes/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Frutas/química , Humanos , Sementes/química
12.
FASEB J ; 35(9): e21842, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418159

RESUMO

Retinopathy of prematurity (ROP) remains one of the major causes of blindness in children worldwide. While current ROP treatments are mostly disruptive to reduce proliferative neovascularization by targeting the hypoxic phase, protection against early hyperoxia-induced retinal vascular loss represents an effective therapeutic window, but no such therapeutic strategy is available. Built upon our recent demonstration that the protection against oxygen-induced retinopathy by adenosine A2A receptor (A2A R) antagonists is most effective when administered at the hyperoxia (not hypoxic) phase, we here uncovered the cellular mechanism underlying the A2A R-mediated protection against early hyperoxia-induced retinal vascular loss by reversing the inhibition of cellular proliferation via possibly multiple signaling pathways. Specifically, we revealed two distinct stages of the hyperoxia phase with greater cellular proliferation and apoptosis activities and upregulation of adenosine signaling at postnatal 9 day (P9) but reduced cellular activities and adenosine-A2A R signaling at P12. Importantly, the A2A R-mediated protection at P9 was associated with the reversal of hyperoxia-induced inhibition of progenitor cells at the peripheral retina at P9 and of retinal endothelial proliferation at P9 and P12. The critical role of cellular proliferation in the hyperoxia-induced retinal vascular loss was validated by the increased avascular areas by siRNA knockdown of the multiple signaling molecules involved in modulation of cellular proliferation, including activin receptor-like kinase 1, DNA-binding protein inhibitor 1, and vascular endothelial growth factor-A.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Proliferação de Células/efeitos dos fármacos , Hiperóxia/metabolismo , Substâncias Protetoras/farmacologia , Receptor A2A de Adenosina/metabolismo , Neovascularização Retiniana , Vasos Retinianos/efeitos dos fármacos , Receptores de Activinas Tipo II/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína 1 Inibidora de Diferenciação/metabolismo , Camundongos , Neovascularização Patológica , Oxigênio/efeitos adversos , Retina/citologia , Retina/efeitos dos fármacos , Retina/patologia , Vasos Retinianos/citologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
13.
FASEB J ; 35(9): e21789, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383983

RESUMO

Normal pregnancy is essential for human reproduction. However, BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) could cause dysfunctions of human trophoblast cells and might further induce miscarriage. Yet, the underlying mechanisms remain largely unknown. Herein, we identified a novel upregulated lnc-HZ04 and a novel downregulated miR-hz04 in villous tissues of unexplained recurrent miscarriage (RM) relative to those in healthy control tissues and also in BPDE-treated human trophoblast cells. Lnc-HZ04 directly and specifically bound with miR-hz04, diminished the reduction effects of miR-hz04 on IP3 R1 mRNA expression level and on IP3 R1 mRNA stability, and then activated the Ca2+ -mediated IP3 R1 /p-CaMKII/SGCB pathway, which further promoted trophoblast cell apoptosis. The miR-hz04 target site on lnc-HZ04 played crucial roles in these regulations. In normal trophoblast, relatively less lnc-HZ04 and more miR-hz04 suppressed this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in RM tissues, p53 was upregulated, which might promote p53-mediated lnc-HZ04 transcription. Relatively more lnc-HZ04 and less miR-hz04 activated this apoptosis pathway and might further induce miscarriage. BaP could also induce mice miscarriage by upregulating its corresponding murine apoptosis pathway. Therefore, BPDE-induced apoptosis of human trophoblast cells was associated with the occurrence of miscarriage. This work discovered the regulation roles of lnc-HZ04 and miR-hz04 and provided scientific and clinical understanding of the occurrence of unexplained miscarriage.


Assuntos
Aborto Habitual/genética , Apoptose/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Trofoblastos/metabolismo , Regulação para Cima/genética , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/farmacologia , Aborto Habitual/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Sarcoglicanas/genética , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
14.
Biomed Res Int ; 2021: 1340281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336999

RESUMO

The purpose of this study was to develop an efficient vitrification system for cryopreservation of dog skin tissues as a source of stable autologous stem cells. In this study, we performed vitrification using four different cryoprotectants, namely, ethylene glycol (EG), dimethyl-sulfoxide (Me2SO), EG plus Me2SO, and EG plus Me2SO plus sucrose, and analyzed the behaviors of cells established from warmed tissues. Tissues vitrified with 15% EG, 15% Me2SO, and 0.5 M sucrose had a normal histological appearance and the highest cell viability after cell isolation, and thus, this cocktail of cryoprotectants was used in subsequent experiments. We evaluated proliferation and apoptosis of cells derived from fresh and vitrified tissues. These cells had a normal spindle-like morphology after homogenization through subculture. Dog dermal skin stem cells (dDSSCs) derived from fresh and vitrified tissues had similar proliferation capacities, and similar percentages of these cells were positive for mesenchymal stem cell markers at passage 3. The percentage of apoptotic cell did not differ between dDSSCs derived from fresh and vitrified tissues. Real-time PCR analysis revealed that dDSSCs at passage 3 derived from fresh and vitrified tissues had similar expression levels of pluripotency (OCT4, SOX2, and NANOG), proapoptotic (BAX), and antiapoptotic (BCL2 and BIRC5) genes. Both types of dDSSCs successfully differentiated into the mesenchymal lineage (adipocytes and osteocytes) under specific conditions, and their differentiation potentials did not significantly differ. Furthermore, the mitochondrial membrane potential of dDSSCs derived from vitrified tissues was comparable with that of dDSSCs derived from fresh tissues. We conclude that vitrification of dog skin tissues using cocktail solution in combination of 15% EG, 15% Me2SO, and 0.5 M sucrose allows efficient banking of these tissues for regenerative stem cell therapy and conservation of genetic resources.


Assuntos
Células-Tronco Mesenquimais/citologia , Pele/citologia , Vitrificação , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Crioprotetores/farmacologia , Derme/citologia , Cães , Feminino , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo
15.
Biomed Res Int ; 2021: 5522964, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337019

RESUMO

Ziziphora (Cacotti in Persian) belongs to the Lamiaceae family (mint group) and is vastly found in Iran and Asia. This traditional medicinal plant is normally used as analgesic and for treatment of particular gastrointestinal diseases. Since colorectal cancer is one of the most common causes of death in the world and the second leading cause of cancer death among adults, there is a pressing need to inhibit this malignancy by using methods with minimal side effects. One of these methods is the use of natural resources such as medical plants. This study is aimed at investigating the expression of apoptosis-related genes in the adjacent culture of colorectal cancer epithelial cells (HT-29) with Ziziphora essential oil (ZEO). The essential oil was extracted from Ziziphora leaves, and its compounds were determined and then added to the HT-29 culture medium at different concentrations. After 24 hours, the HT-29 cells were harvested from the medium and cytotoxicity was analyzed by MTT assay. After MTT assay and determination of the percentage of apoptosis by flow cytometry, RNA extraction was performed and the expression levels of Bax, Bcl-2, caspase 3 (C3), and caspase 9 (C9) were analyzed using newly designed primers by reverse transcription (RT) qPCR method and GeniX6 software. Also, specific antibodies were used for western blot analyses of those molecules. GC analysis revealed 42 different compounds in the ZEO, including pulegone (26.65%), menthone (5.74%), thymol (5.51%), and menthol (1.02%). MTT assay showed that the concentration of 200 µg/ml of ZEO had the highest HT-29 cell death during 24 hours. After incubation with the concentration of 50 µg/ml of ZEO for 24 and 48 hours, caspase 3 and 9 gene expressions in the treated group increased compared to those in the control group (P < 0.001), while the Bcl-2 expression decreased. The results showed that having anticancer compounds, ZEO can increase C3 and C9 and decrease Bcl-2 expressions, causing apoptosis in HT-29 cells in vitro. This can lead to the use of ZEO as a factor for colorectal cancer treatment.


Assuntos
Apoptose , Neoplasias Colorretais/patologia , Lamiaceae/química , Óleos Voláteis/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Monoterpenos Cicloexânicos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Cromatografia Gasosa-Espectrometria de Massas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Biológicos , Proteína X Associada a bcl-2/metabolismo
16.
Biomolecules ; 11(7)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34356601

RESUMO

In this study, the total phenolic compounds content and profile, the nutritional value, the antioxidant and antiproliferative activities of avocado peel, seed coat, and seed extracts were characterized. Additionally, an in-silico analysis was performed to identify the phenolic compounds with the highest intestinal absorption and Caco-2 permeability. The avocado peel extract possessed the highest content of phenolic compounds (309.95 ± 25.33 mMol GA/100 g of extract) and the lowest effective concentration (EC50) against DPPH and ABTS radicals (72.64 ± 10.70 and 181.68 ± 18.47, respectively). On the other hand, the peel and seed coat extracts had the lowest energy densities (226.06 ± 0.06 kcal/100 g and 219.62 ± 0.49 kcal/100 g, respectively). Regarding the antiproliferative activity, the avocado peel extract (180 ± 40 µg/mL) showed the lowest inhibitory concentration (IC50), followed by the seed (200 ± 21 µg/mL) and seed coat (340 ± 32 µg/mL) extracts. The IC50 of the extracts induced apoptosis in Caco-2 cells at the early and late stages. According to the in-silico analysis, these results could be related to the higher Caco-2 permeability to hydroxysalidroside, salidroside, sakuranetin, and luteolin. Therefore, this study provides new insights regarding the potential use of these extracts as functional ingredients with antioxidant and antiproliferative properties and as medicinal agents in diseases related to oxidative stress such as cancer.


Assuntos
Antioxidantes , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Frutas/química , Alimento Funcional , Persea/química , Extratos Vegetais , Antioxidantes/química , Antioxidantes/farmacologia , Células CACO-2 , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
17.
Biomolecules ; 11(7)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34356602

RESUMO

Cadmium (Cd) is a potential pathogenic factor in the nervous system associated with various neurodegenerative disorders. Puerarin (Pur) is an isoflavone purified from the Chinese medical herb, kudzu root, and exhibits antioxidant and antiapoptotic properties in the brain. In this study, the detailed mechanisms underlying the neuroprotective potential of Pur against Cd-induced neuronal injury was evaluated for the first time in vivo in a rat model and in vitro using primary rat cerebral cortical neurons. The results of the in vivo experiments showed that Pur ameliorated Cd-induced neuronal injury, reduced Cd levels in the cerebral cortices, and stimulated Cd excretion in Cd-treated rats. We also observed that the administration of Pur rescued Cd-induced oxidative stress, and attenuated Cd-induced apoptosis by concomitantly suppressing both the Fas/FasL and mitochondrial pathways in the cerebral cortical neurons of rats both in vivo and in vitro. Our results demonstrate that Pur exerted its neuroprotective effects by stimulating Cd excretion, ameliorating Cd-induced oxidative stress and apoptosis in rat cerebral cortical neurons.


Assuntos
Apoptose/efeitos dos fármacos , Cádmio , Córtex Cerebral , Isoflavonas/farmacologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Cádmio/farmacocinética , Cádmio/toxicidade , Córtex Cerebral/lesões , Córtex Cerebral/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
18.
Toxicol Lett ; 350: 240-248, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34333065

RESUMO

Certain medicines including anticancer drugs, NSAIDs and antiepileptic drugs are known to cause drug-induced nephropathy. For example, antiepileptic drugs such as carbamazepine (CBZ) and valproic acid have been reported to cause damage to the proximal tubular cells. Although there has been a great deal of research concerning the nephrotoxicity of CBZ, little is known about that of oxcarbazepine (OXC), a derivative of CBZ. To investigate the molecular mechanism underlying renal proximal tubular cell death caused by OXC, we examined alterations in the gene expression profile of NRK-52E proximal tubular cells during OXC exposure. DNA microarray analysis revealed that the levels of genes related to mitotic processes including chromosomal and cytoplasmic segregation, progression to G2/M phase, and formation of the mitotic spindle are increased after exposure to 50 µM OXC for 6 h. Cell cycle analysis by flow cytometry showed that OXC at concentrations between 25 and 100 µM induces G2/M arrest. We also found that OXC significantly increases histone H3 phosphorylation, indicative of mitotic cells. These results imply that OXC induces cell cycle arrest at the mitotic phase. Immunofluorescence analysis showed monopolar spindles, which are formed in response to centrosome separation defects, in OXC-treated cells. We also show that OXC suppresses the phosphorylation of PLK1, which is involved not only in the activation of the kinesin family of motor proteins for centrosome separation and bipolar spindle assembly, but also in the cleavage of centrosomal proteins. Thus, our results indicate that OXC inhibits centrosome separation by reducing the activation of PLK1, which leads to the formation of an abnormal spindle and induces mitotic catastrophe and apoptosis in NRK-52E cells.


Assuntos
Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Apoptose/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Túbulos Renais Distais/efeitos dos fármacos , Mitose/efeitos dos fármacos , Oxcarbazepina/toxicidade , Animais , Humanos , Modelos Animais , Ratos
19.
Molecules ; 26(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34361649

RESUMO

Hispolon, a polyphenol compound isolated from Phellinus linteus, has been reported to exhibit antioxidant, antiproliferative, and antitumor activities. This study aimed to explore the antitumor effects of hispolon on glioblastoma multiforme (GBM) cells in vitro and in vivo. The results revealed that hispolon significantly inhibited GBM cell proliferation and induced apoptosis through caspase-9 and caspase-3 activation and PARP cleavage. Hispolon also induced cell cycle G2/M phase arrest in GBM cells, as supported by flow cytometry analysis and confirmed by a decrease in cyclin B1, cdc2, and cdc25c protein expressions in a dose- and time-dependent manner. Furthermore, hispolon suppressed the migration and invasion of GBM cells by modulating epithelial-mesenchymal transition (EMT) markers via wound healing, transwell assays, and real-time PCR. Moreover, hispolon significantly reduced tumor growth in DBTRG xenograft mice and activated caspase-3 in hispolon-treated tumors. Thus, our findings revealed that hispolon is a potential candidate for the treatment of GBM.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Catecóis/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Animais , Basidiomycota/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ratos
20.
Inorg Chem ; 60(17): 13051-13061, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34369147

RESUMO

The facile modification of the ligands in organometallic Ru(II)-arene complexes offers more opportunities to optimize their pharmacological profiles. Herein, three Ru(II)-arene complexes containing a glutathione S-transferase (GST) inhibitor (NBDHEX) in chelate ligand have been designed and synthesized in this study. In vitro results indicated that the ligation with NBDHEX significantly increased the activities and selectivities of the organometallic Ru(II)-arene complexes against tumor cells, especially complex 3, which was the most active compound among the tested compounds. DFT calculations and hydrolysis results demonstrated that complex 3 with more alkyl groups in the arene ligand has increased electron density at the Ru(II) center as compared with complexes 1 and 2, thus resulting in the improved hydrolysis rate, which may be responsible for its higher anticancer activity. Further studies showed that complexes 1-3 can cause the loss of the mitochondrial membrane potential and upregulate the expression of Bcl-2 and Bax in A549 cells, suggesting that complexes 1-3-induced cell death may be mediated via the mitochondrial apoptotic pathway. Thus, these findings suggested that simultaneous modification of the chelate ligands and arene rings in the organometallic Ru(II)-arene complexes is an effective way to improve their pharmacological properties.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
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