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1.
Life Sci ; 347: 122627, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38614301

RESUMO

A high mortality rate makes hepatocellular carcinoma (HCC) a difficult cancer to treat. When surgery is not possible, liver cancer patients are treated with chemotherapy. However, HCC management and treatment are difficult. Sorafenib, which is a first-line treatment for hepatocellular carcinoma, initially slows disease progression. However, sorafenib resistance limits patient survival. Recent studies have linked HCC to programmed cell death, which has increased researcher interest in therapies targeting cell death. Pyroptosis, which is an inflammatory mode of programmed cell death, may be targeted to treat HCC. Pyroptosis pathways, executors, and effects are examined in this paper. This review summarizes how pyroptosis affects the tumor microenvironment (TME) in HCC, including the role of cytokines such as IL-1ß and IL-18 in regulating immune responses. The use of chemotherapies and their ability to induce cancer cell pyroptosis as alternative treatments and combining them with other drugs to reduce side effects is also discussed. In conclusion, we highlight the potential of inducing pyroptosis to treat HCC and suggest ways to improve patient outcomes. Studies on cancer cell pyroptosis may lead to new HCC treatments.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Piroptose , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sorafenibe/uso terapêutico , Sorafenibe/farmacologia
2.
Sci Rep ; 14(1): 2753, 2024 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-38307890

RESUMO

The emergence of SARS-CoV-2 variants diminished the efficacy of current antiviral drugs and vaccines. Hence, identifying highly conserved sequences and potentially druggable pockets for drug development was a promising strategy against SARS-CoV-2 variants. In viral infection, the receptor-binding domain (RBD) proteins are essential in binding to the host receptor. Others, Heparan sulfate (HS), widely distributed on the surface of host cells, is thought to play a central role in the viral infection cycle of SARS-CoV-2. Therefore, it might be a reasonable strategy for antiviral drug design to interfere with the RBD in the HS binding site. In this study, we used computational approaches to analyze multiple sequences of coronaviruses and reveal important information about the binding of HS to RBD in the SARS-CoV-2 spike protein. Our results showed that the potential hot-spots, including R454 and E471, in RBD, exhibited strong interactions in the HS-RBD binding region. Therefore, we screened different compounds in the natural product database towards these hot-spots to find potential antiviral candidates using LibDock, Autodock vina and furthermore applying the MD simulation in AMBER20. The results showed three potential natural compounds, including Acetoside (ACE), Hyperoside (HYP), and Isoquercitrin (ISO), had a strong affinity to the RBD. Our results demonstrate a feasible approach to identify potential antiviral agents by evaluating the binding interaction between viral glycoproteins and host receptors. The present study provided the applications of the structure-based computational approach for designing and developing of new antiviral drugs against SARS-CoV-2 variants.


Assuntos
COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , SARS-CoV-2/metabolismo , Antivirais/química , Desenvolvimento de Medicamentos , Ligação Proteica , Sítios de Ligação
3.
BMC Nurs ; 22(1): 447, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38017421

RESUMO

BACKGROUND: Nurses with busy workloads lack the time to maintain health, leading to a decline in physical and mental health and quality of life. It is widely accepted that self-perception of health triggers health-promoting behaviors and impacts the quality of life; however, the relationship between these factors among nurses is unclear. The purpose of this study was to investigate the ability of a health-promoting lifestyle to mediate the relationship between self-perceived health and quality of life among nurses. METHODS: A cross-sectional survey was conducted in four regional Taiwanese teaching hospitals with over 500 beds. The survey used stratified random sampling of 600 nurses who had worked for more than six months. The Self-Perceived Health Questionnaire, the Health-Promoting Lifestyle Profile, and the World Health Organization Quality of Life Scale were used to measure nurses' self-perceived health (SPH), health-promoting lifestyle (HPL), and quality of life (QoL). A Hayes PROCESS analysis and bootstrapping method were used for the mediation analysis. RESULTS: A total of 518 nurses' data was included in the analysis. Nurses perceived their health status as less favorable than their colleagues, but frequently adopted health promotion behaviors. Nurses reported a moderate QoL. QoL and SPH were correlated (r = .33) and a high correlation between QoL and HPL (r = .64) was found. SPH and HPL both affect QoL (B = 0.077 and 0.070). SPH and HPL explained 42.6% of the variation in QoL. HPL played a partial mediation role. CONCLUSIONS: The study confirmed that HPL has an important role in mediating nurses' SPH and QoL. Nurse administrators are advised to encourage nurses to monitor their health status and provide health promotion mechanisms to improve their quality of life.

4.
Nucleic Acids Res ; 50(15): 8867-8881, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35871296

RESUMO

The use of multiple drugs simultaneously targeting DNA is a promising strategy in cancer therapy for potentially overcoming single drug resistance. In support of this concept, we report that a combination of actinomycin D (ActD) and echinomycin (Echi), can interact in novel ways with native and mismatched DNA sequences, distinct from the structural effects produced by either drug alone. Changes in the former with GpC and CpG steps separated by a A:G or G:A mismatch or in a native DNA with canonical G:C and C:G base pairs, result in significant asymmetric backbone twists through staggered intercalation and base pair modulations. A wobble or Watson-Crick base pair at the two drug-binding interfaces can result in a single-stranded 'chair-shaped' DNA duplex with a straight helical axis. However, a novel sugar-edged hydrogen bonding geometry in the G:A mismatch leads to a 'curved-shaped' duplex. Two non-canonical G:C Hoogsteen base pairings produce a sharply kinked duplex in different forms and a four-way junction-like superstructure, respectively. Therefore, single base pair modulations on the two drug-binding interfaces could significantly affect global DNA structure. These structures thus provide a rationale for atypical DNA recognition via multiple DNA intercalators and a structural basis for the drugs' potential synergetic use.


Assuntos
DNA , Pareamento de Bases , DNA/química , DNA/genética , Ligação de Hidrogênio , Estrutura Molecular , Conformação de Ácido Nucleico
5.
J Mater Chem B ; 10(25): 4759-4770, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35670467

RESUMO

Psoriasis is a chronic inflammatory skin disease that can significantly impact the quality of human life. Various drug treatments are available; however, due to their long-term severe side effects the usage of these drugs is limited. Photodynamic therapy (PDT) has been clinically approved for skin diseases due to its non-invasive nature. We present novel NNO-tridentate vanadium(IV) complexes used in PDT for anti-inflammatory effects in an imiquimod-induced psoriasis-like skin disease mouse model. The vanadium(IV) complexes (1-4) were synthesized using the NNO-tridentate ligand with a benzo[i]dipyrido[3,2-a;2',3'-c]phenazine (dppn) moiety, and were characterized by UV/Visible spectroscopy, EPR spectroscopy, NMR (1H, and 13C) spectroscopy, electrospray ionization mass (ESI-MS) spectrometry and cyclic voltammetry (CV) studies. The photocytotoxicity of vanadium(IV) complexes (1-4) was low under dark conditions and complex (4) showed remarkable photocytotoxicity under blue light (430 nm, 8 W cm-2, 30 min) irradiation. Moreover, [VO(t-butylL)(dppn)] (4)-mediated PDT down-regulated inflammatory cytokines IL-17A and IL-22 in the psoriasis-like mouse model, which could evidence the significant relieving of the psoriatic-like symptoms in the mouse model. Overall, these results suggested that [VO(t-butylL)(dppn)] (4) could be a potential candidate for the treatment of psoriasis both in vitro and in vivo.


Assuntos
Fotoquimioterapia , Psoríase , Animais , Modelos Animais de Doenças , Imiquimode/uso terapêutico , Camundongos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Pele , Vanádio/efeitos adversos , Vanádio/química
6.
J Am Chem Soc ; 142(25): 11165-11172, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32478511

RESUMO

The potent DNA-binding compound triaminotriazine-acridine conjugate (Z1) functions by targeting T:T mismatches in CTG trinucleotide repeats that are responsible for causing neurological diseases such as myotonic dystrophy type 1, but its binding mechanism remains unclear. We solved a crystal structure of Z1 in a complex with DNA containing three consecutive CTG repeats with three T:T mismatches. Crystallographic studies revealed that direct intercalation of two Z1 molecules at both ends of the CTG repeat induces thymine base flipping and DNA backbone deformation to form a four-way junction. The core of the complex unexpectedly adopts a U-shaped head-to-head topology to form a crossover of each chain at the junction site. The crossover junction is held together by two stacked G:C pairs at the central core that rotate with respect to each other in an X-shape to form two nonplanar minor-groove-aligned G·C·G·C tetrads. Two stacked G:C pairs on both sides of the center core are involved in the formation of pseudo-continuous duplex DNA. Four metal-mediated base pairs are observed between the N7 atoms of G and CoII, an interaction that strongly preserves the central junction site. Beyond revealing a new type of ligand-induced, four-way junction, these observations enhance our understanding of the specific supramolecular chemistry of Z1 that is essential for the formation of a noncanonical DNA superstructure. The structural features described here serve as a foundation for the design of new sequence-specific ligands targeting mismatches in the repeat-associated structures.


Assuntos
Acridinas/química , DNA/química , Substâncias Intercalantes/química , Triazinas/química , Pareamento Incorreto de Bases , Pareamento de Bases , DNA/genética , Conformação de Ácido Nucleico , Timina/química , Repetições de Trinucleotídeos
7.
J Med Chem ; 63(6): 3131-3141, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32105468

RESUMO

Structure-based stabilization of protein-protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases.


Assuntos
Alcaloides/farmacologia , Antivirais/farmacologia , Indóis/farmacologia , Proteínas do Nucleocapsídeo/metabolismo , Multimerização Proteica/efeitos dos fármacos , Alcaloides/química , Alcaloides/metabolismo , Sequência de Aminoácidos , Animais , Antivirais/química , Antivirais/metabolismo , Chlorocebus aethiops , Proteínas do Nucleocapsídeo de Coronavírus , Cristalografia por Raios X , Desenho de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Indóis/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Simulação de Acoplamento Molecular , Proteínas do Nucleocapsídeo/química , Ligação Proteica , Domínios Proteicos , Alinhamento de Sequência , Células Vero
8.
J Inorg Biochem ; 194: 74-84, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30831392

RESUMO

Organometallic Ru(II)-arene complexes have emerged as potential alternatives to platinum appended agents due to their wide range of interesting features such as stability in solution and solid, significant activity, less toxicity and hydrophobic property of arene moiety, etc. Hence, a series of Ru(II)-p-cymene complexes, [(η6-p-cymene)Ru(η2-N,N-L1)Cl]Cl (1), [(η6-p-cymene)Ru(η1-N-L2)Cl2] (2) and [(η6-p-cymene)Ru(η1-N-L3)Cl2] (3) were prepared from pyrazole based ligands [2-(1H-pyrazol-3-yl)pyridine (L1), 3-(furan-2-yl)-1H-pyrazole (L2) and 3-(thiophen-2-yl)-1H-pyrazole (L3)], and [RuCl2-(η6-p-cymene)] dimer. The new Ru(II)-p-cymene complexes were well characterized by elemental analysis, and spectroscopic (FT-IR, UV-Visible, 1H NMR, 13C NMR and mass) and crystallographic methods. The Ru(II)-p-cymene complexes (1-3) were found to adopt their characteristic piano stool geometry around Ru(II) ion. The calf thymus DNA (CT-DNA) binding ability of the new complexes was investigated by electronic absorption spectroscopic titration and viscosity methods. The molecular docking study results showed that complex 1 strongly bound with targeted biomolecules than 2 and 3. Docked poses of bidentate pyrazole based Ru(II)-p-cymene complex 1 revealed that the complex formed a crucial guanine N7 position hydrogen bond with DNA receptor. Complexes 1-3 might hydrolyze under physiological conditions and form aqua complexes 4-8, and docking calculations showed that the aqua complexes bound strongly with the receptors than original complexes. The in vitro cytotoxicity of the Ru(II)-p-cymene complexes and cisplatin was evaluated against triple negative breast cancer (TNBC) MDA-MB-231 cells. Our results showed that the inhibitory effect of bidentate pyrazole based Ru(II)-p-cymene complex 1 on the growth of breast cancer cells was superior to other tested complexes.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA/metabolismo , Pirazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cimenos/química , DNA/química , Guanina/química , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/metabolismo , Substâncias Intercalantes/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Rutênio/química
9.
Plast Reconstr Surg ; 143(5): 1371-1382, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30807498

RESUMO

BACKGROUND: This study investigated whether a hyaluronic acid-povidone-iodine compound can enhance diabetic wound healing. METHODS: A dorsal skin defect (6 × 5 cm) in a streptozotocin-induced diabetes rodent model was used. Seventy male Wistar rats were divided into seven groups: I, normal control; II, diabetic control, no treatment; III, diabetic rats, lower molecular weight (100 kDa) hyaluronic acid; IV, rats, higher molecular weight (1000 kDa) hyaluronic acid; V, rats, 0.1% povidone-iodine; VI, rats, lower molecular weight hyaluronic acid plus povidone-iodine; and VII, rats, higher molecular weight hyaluronic acid plus povidone-iodine. Histologic examination was performed with hematoxylin and eosin staining. CD45, Ki-67, prolyl 4-hydroxylase, and vascular endothelial growth factor were evaluated with immunohistochemical staining. RESULTS: Compared with the control, higher molecular weight hyaluronic acid plus povidone-iodine-treated rats had significantly reduced wound area (p < 0.001). Higher molecular weight hyaluronic acid plus povidone-iodine increased wound healing time when compared with higher molecular weight hyaluronic acid, povidone-iodine, or lower molecular weight hyaluronic acid plus povidone-iodine. Histology revealed significantly increased neovessels and suppressed inflammatory response in the higher molecular weight hyaluronic acid plus povidone-iodine group when compared with the control group. Immunohistochemical staining revealed significantly increased Ki67, prolyl 4-hydroxylase, and vascular endothelial growth factor expression, and suppressed CD45 expression in the higher molecular weight hyaluronic acid plus povidone-iodine group when compared with the other groups. CONCLUSION: Higher molecular weight hyaluronic acid plus povidone-iodine complex dressing significantly facilitated diabetic wound healing via increasing neovascularization and tissue regeneration and suppressing a proinflammatory response.


Assuntos
Anti-Infecciosos Locais/farmacologia , Diabetes Mellitus Experimental/complicações , Ácido Hialurônico/farmacologia , Povidona-Iodo/farmacologia , Cicatrização/efeitos dos fármacos , Administração Cutânea , Animais , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/uso terapêutico , Bandagens , Diabetes Mellitus Experimental/induzido quimicamente , Pé Diabético/tratamento farmacológico , Pé Diabético/etiologia , Combinação de Medicamentos , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/uso terapêutico , Masculino , Peso Molecular , Povidona-Iodo/química , Povidona-Iodo/uso terapêutico , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/patologia , Estreptozocina/toxicidade , Resultado do Tratamento
10.
Phytomedicine ; 54: 109-119, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668360

RESUMO

BACKGROUND: Phytochemical naphtho[1,2-b] furan-4,5­dione (NFD) presenting in Avicennia marina exert anti-cancer effects, but little is known regarding about DNA damage-mediated apoptosis in non-small-cell lung carcinoma (NSCLC). PURPOSE: To examine whether NFD-induced apoptosis of NSCLC cells is correlated with the induction of DNA damage, and to investigate its underlying mechanism. STUDY DESIGN: The anti-proliferative effects of NFD were assessed by MTS Assay Kit FACS assay, and in vivo nude mice xenograft assay. The DNA damage related proteins, the Bcl-2 family and pro-apoptotic factors were examined by immunofluorescence assay, q-PCR, and western blotting. The activity of NF-κB p65 in nuclear extracts was detected using a colorimetric DNA-binding ELISA assay. The inhibitory activity of topoisomerase II (TOPO II) was evaluated by molecular docking and TOPO II catalytic assay. RESULTS: NFD exerted selective cytotoxicity against NSCLC H1299, H1437 and A549 cells rather than normal lung-embryonated cells MRC-5. Remarkably, we found that NFD activated the hull marker and modulator of DNA damage repairs such as γ-H2AX, ATM, ATR, CHK1, and CHK2 probably caused by the accumulation of intracellular reactive oxygen species (ROS) and inhibition of TOPO II activity. Furthermore, the suppression of transcription factor NF-κB by NFD resulted in significantly decreased levels of pro-survival proteins including Bcl-2 family Bcl-2, Bcl-xL and Mcl-1 and the endogenous inhibitors of apoptosis XIAP and survivin in H1299 cells. Moreover, the nude mice xenograft assay further validated the suppression of H1299 growth by NFD, which is the first report for evaluating the anti-cancer effect of NFD in vivo. CONCLUSION: These findings provide a novel mechanism indicating the inhibition of TOPO II activity and NF-κB signaling by NFD, leading to DNA damage and apoptosis of NSCLC tumor cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Furanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/química , Feminino , Furanos/química , Humanos , Neoplasias Pulmonares/genética , Camundongos Nus , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Naftoquinonas/química , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Mol Sci ; 19(7)2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29933620

RESUMO

Unfolded protein response (UPR) is a cytoprotective mechanism that alleviates the protein-folding burden in eukaryotic organisms. Moderate activation of UPR is required for maintaining endoplasmic reticulum (ER) homeostasis and profoundly contributes to tumorigenesis. Defects in UPR signaling are implicated in the attenuation of various malignant phenotypes including cell proliferation, migration, and invasion, as well as angiogenesis. This suggests UPR as a promising target in cancer therapy. The pharmacological effects of the plant Scindapsus cf. hederaceus on human cancer cell lines is not understood. In this study, we identified an ethyl acetate extract from Scindapsus cf. hederaceus (SH-EAE), which markedly altered the protein expression of UPR-related genes in human non-small cell lung cancer (NSCLC) cells. Treatment with the SH-EAE led to the dose-dependent suppression of colony forming ability of both H1299 and H460 cells, but not markedly in normal bronchial epithelial BEAS-2B cells. SH-EAE treatment also attenuated the migration and invasion ability of H1299 and H460 cells. Moreover, SH-EAE strikingly suppressed the protein expression of two ER stress sensors, including inositol requiring enzyme-1α (IRE-1α) and protein kinase R-like ER kinase (PERK), and antagonized the induction of C/EBP homologous protein (CHOP) expression by thapsigargin, an ER stress inducer. SH-EAE induced the formation of massive vacuoles which are probably derived from ER. Importantly, SH-EAE impaired the formation of intersegmental vessels (ISV) in zebrafish larvae, an index of angiogenesis, but had no apparent effect on the rate of larval development. Together, our findings demonstrate, for the first time, that the ability of SH-EAE specifically targets the two sensors of UPR, with significant anti-proliferation and anti-migration activities as a crude extract in human NSCLC cells. Our finding also indicates potential applications of SH-EAE in preventing UPR activation in response to Tg-induced ER stress. We suggest that SH-EAE attenuates UPR adaptive pathways for rendering the NSCLC cells intolerant to ER stress.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Araceae/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Neovascularização Fisiológica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Acetatos/química , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/genética , Endorribonucleases/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Larva/efeitos dos fármacos , Neovascularização Fisiológica/genética , Extratos Vegetais/isolamento & purificação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Solventes/química , Fator de Transcrição CHOP/antagonistas & inibidores , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Ensaio Tumoral de Célula-Tronco , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Peixe-Zebra , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
12.
Cell Transplant ; 26(8): 1418-1427, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28901186

RESUMO

Donor mesenchymal stem cells (MSCs) could prolong vascularized composite allotransplantation (VCA) survival in our previous studies. However, recipient adipose tissue is easier to harvest than donor tissue for preconditioning modulation. Hence, this study investigated the efficacy of recipient autologous adipose-derived stem cells (rADSCs) for VCA survival. The heterotopic hind-limb transplantation from female donor to male recipient was performed in outbred miniature swine. Group I ( n = 6) was untreated controls. Group II ( n = 4) obtained rADSCs infusions (given on weeks 0, +1, +2, and +3). Group III ( n = 4) obtained tacrolimus (FK506, weeks 0 to +4). Group IV ( n = 8) received irradiation (IR; day -1), FK506 (weeks 0 to +4), and rADSC infusions (weeks 0, +1, +2, and +3). The results revealed treatment with multiple injections of rADSCs along with IR and FK506 resulted in a statistically significant increase in allograft survival. The percentage of CD4+/CD25+/Foxp3+ regulatory T cells were significantly increased in the rADSC-IR-FK506 group as compared to controls. Analysis of recipient peripheral blood revealed that transforming growth factor ß1 (TGFß1) was significantly increased in the rADSC-IR-FK506 group. The polymerase chain reaction (PCR) analysis and immunohistochemical staining showed recipient sex-determining region of Y (SRY) chromosome gene expression existed in donor allotissues in the rADSC-IR-FK506 group. These results indicate that rADSCs in addition to IR and transient immunosuppressant could prolong allotransplant survival, modulate T-cell regulation, and enhance recipient cell engraftment into the allotransplant tissues.


Assuntos
Tecido Adiposo/transplante , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Feminino , Sobrevivência de Enxerto , Membro Posterior , Masculino , Transplante de Células-Tronco Mesenquimais/mortalidade , Análise de Sobrevida , Suínos , Porco Miniatura
13.
Plast Reconstr Surg ; 138(5): 1015-1023, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27391839

RESUMO

BACKGROUND: The authors' previous proteome study revealed that haptoglobin was involved in adipose-derived stem cell modulation of allotransplant survival and T-cell regulation to induce immune tolerance. This study investigated whether adipose-derived stem cells could modulate T-cell regulation through haptoglobin and the downstream heme oxgenase-1 pathway in vitro. METHODS: Splenocytes were isolated from Lewis rat spleens and then CD3 T cells were purified using anti-CD3 beads. Adipose-derived stem cells were harvested from Lewis rats and co-cultured with the T cells. After Transwell co-culture at different periods, the authors analyzed cell proliferation with a bromodeoxyuridine assay. Cell extractions and culture supernatants were collected for further analysis. Heme oxgenase-1 and related protein expression levels from the adipose-derived stem cells and T cells were detected using Western blotting. The related cytokine expression levels were analyzed with enzyme-linked immunosorbent assay kits. Flow cytometry was used to detect the regulatory T-cell proportion. RESULTS: The adipose-derived stem cells significantly suppressed T-cell proliferation. The regulatory T-cell percentages were significantly increased in the adipose-derived stem cells that were co-cultured with T cells compared with T cells alone without adipose-derived stem cell co-culture. Heme oxgenase-1 expression in concanavalin A-stimulated T cells that were co-cultured with adipose-derived stem cells revealed a significant increase compared with concanavalin A-stimulated T cells alone. Cytokine assays of the culture supernatants revealed that transforming growth factor-ß and interleukin-10 were significantly increased and interferon-γ was statistically decreased in the adipose-derived stem cell-co-cultured T-cell group compared with other groups; however, blockade with a heme oxgenase-1 inhibitor (zinc protoporphyrin IX) protected against these changes. CONCLUSION: Adipose-derived stem cells modulate T-cell proliferation and enhance regulatory T-cell expression, and this correlated with heme oxgenase-1 expression and related cytokine pathway changes.


Assuntos
Tecido Adiposo/citologia , Heme Oxigenase (Desciclizante)/fisiologia , Células-Tronco Mesenquimais/fisiologia , Subpopulações de Linfócitos T/imunologia , Animais , Divisão Celular , Técnicas de Cocultura , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Interferon gama/metabolismo , Interleucina-10/metabolismo , Células-Tronco Mesenquimais/enzimologia , Protoporfirinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/imunologia , Baço/citologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Plast Reconstr Surg ; 137(1): 187e-195e, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26710051

RESUMO

BACKGROUND: It is unclear whether diabetic angiopathy is related to oxidative stress-associated endothelial dysfunction. The authors investigated whether alteration of endothelin-1 and lipid peroxide production and activation of nuclear factor-κB expression were involved in lower limb amputation in type 2 diabetes mellitus patients. METHODS: A total of 135 subjects including 51 type 2 diabetes mellitus patients with major lower extremity amputations and 36 diabetes mellitus patients without limb and vascular complication and 48 normal controls were recruited for this study. The authors measured the plasma soluble endothelin-1 concentrations by a sandwich enzyme immunoassay, and measured oxidative stress as determined by the lipid peroxide byproduct malondialdehyde. Histologic staining and nuclear factor-κB activation determined by electrophoretic mobility shift assay of the amputated vessels were examined. RESULTS: Histologic staining revealed that severe arteriosclerosis with atheroma formation in the amputated diabetic arteries was significantly prominent compared with normal controls. Soluble endothelin-1 concentrations and malondialdehyde levels were increased significantly in diabetic amputation patients compared with other groups (p < 0.001). The nuclear factor-κB binding activity in amputated diabetic stump vessels was more prominent compared with healthy vessels without diabetes mellitus. There was a positive correlation between endothelin-1 and malondialdehyde in patients with diabetic amputation (r = 0.46, p = 0.001). CONCLUSIONS: These results suggest that elevation of endothelin-1 and lipid peroxide levels is involved in the pathogenesis of diabetic foot amputation. An increase of lipid peroxide and endothelin-1 associated with nuclear factor-κB activation plays an important role in the development of diabetic angiopathies.


Assuntos
Amputação Cirúrgica , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Endotelina-1/genética , Regulação da Expressão Gênica , Perna (Membro)/cirurgia , NF-kappa B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/cirurgia , Eletroforese , Endotelina-1/biossíntese , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , NF-kappa B/biossíntese , Reação em Cadeia da Polimerase , RNA/genética , Estudos Retrospectivos
15.
Integr Cancer Ther ; 13(3): NP18-28, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-22505597

RESUMO

Furano-1,2-naphthoquinone (FNQ), a biologically active component ofAvicennia marina, has been demonstrated to display anticancer activity. FNQ exerted cytotoxicity with the G2/M cell cycle arrest and apoptosis in Ca9-22 cells. FNQ-induced G2/M arrest was correlated with a marked decrease in the expression levels of cyclin A and cyclin B, and their activating partner cyclin-dependent kinases (CDK) 1 and 2 with concomitant induction of p27. FNQ-induced apoptosis was accompanied by Bax and Bad upregulation, and the downregulation of Bcl-2, Bcl-XL, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), resulting in cytochrome C release and sequential activation of caspase-9 and caspase-3. Mechanistic studies showed that FNQ suppressed Src phosphorylation, PI3K, and Akt activation in Ca9-22 cells. Moreover, the Src inhibitor PP2 reduced the phosphorylation of Src and activation of PI3K/Akt, which was comparable with FNQ treatment. The combined treatment of FNQ with PP2 enhanced the cell cycle arrest and apoptosis and also led to the downregulation of Bcl-XL, Mcl-1, XIAP, cyclin A, cyclin B, CDK1, and CDK2 and upregulation of p27, Bax, and Bad. These findings suggest that FNQ-mediated cytotoxicity of Ca9-22 cells is related with the G2/M cell cycle arrest and apoptosis via inactivation of Src and PI3K/Akt-mediated signaling pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Furanos/farmacologia , Neoplasias Bucais/tratamento farmacológico , Naftoquinonas/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Avicennia/química , Carcinoma de Células Escamosas/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Furanos/administração & dosagem , Furanos/isolamento & purificação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Neoplasias Bucais/patologia , Naftoquinonas/administração & dosagem , Naftoquinonas/isolamento & purificação , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo
16.
Life Sci ; 90(1-2): 54-65, 2012 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-22079475

RESUMO

AIM: The aim of this study is to determine whether cardiotoxin III (CTX III) inhibited the metastasis in MDA-MB-231 cells and to further explain its possible mechanisms. MAIN METHODS: The MTT assay, wound healing assay, Boyden chamber invasion assay, zymography analysis, reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), inhibitor assay, and Western blot analysis were used to reveal molecular events of CTX III in this study. KEY FINDINGS: During treatment with non-toxic doses of CTX III, not only cell migration and invasion were markedly suppressed but the expression/activity of matrix metalloproteinase-9 (MMP-9) was also significantly and selectively suppressed in a concentration-dependent manner. In addition, CTX III decreased the nuclear protein level of nuclear factor kappa B (NF-κB), and pretreatment with NF-κB inhibitor (PDTC) or IκB protease inhibitor (TPCK) also reduced MMP-9 expression/activity and cell migration. Our biochemical assays indicated that CTX III potently suppressed the phosphorylation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositide-3-kinase (PI3K) and Akt. Additionally, the treatment of inhibitors specific for p38 MAPK (SB203580) or PI3K (wortmannin) to cells could result in a reduced expression of NF-κB and MMP-9 expression, concomitantly with an inhibition on cell metastasis. SIGNIFICANCE: These results demonstrated that CTX III inhibition of MDA-MB-231 cells may occur through inactivation of both PI3K/Akt and p38 MAPK signaling pathways, exerting inhibitory effects on NF-κB transcriptional factor, thereby decreasing the activity of MMP-9 and then posing an anti-metastatic effect in the cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Proteínas Cardiotóxicas de Elapídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Proteínas Cardiotóxicas de Elapídeos/uso terapêutico , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Clin Exp Pharmacol Physiol ; 37(8): 833-40, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20456425

RESUMO

1. Cardiotoxin (CTX) III, a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential anticancer therapeutic activity. The aim of the present study was to investigate the apoptotic effect (and the underlying mechanism of action) of CTX III in human adenocarcinoma A549 cells. 2. It was found that CTX III induces apoptosis in A549 cells, as indicated by an increase in the sub-G(1) population, phosphatidylserine externalization, loss of mitochondrial membrane potential (Psi(m)) with cytochrome c release and activation of caspases 9 and 3. These actions were correlated with upregulation of Bax and Bad and downregulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, X-linked inhibitor of apoptosis protein (XIAP) and p-Bad in CTX III-treated cells. 3. The signal transduction pathways involved in the effects of CTX III in A549 cells were evaluated using 5 micromol/L AG1478, an inhibitor of the epidermal growth factor receptor (EGFR), and exposing cells to the drug for 8 h. The results indicated that CTX III suppresses phosphorylation of EGFR and activation of phosphatidylinositol 3-kinase (PI3-K)/Akt and Janus tyrosine kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, all of which are downstream molecules in the EGFR signalling pathway. 4. Exposure of cells for 8 h to the PI3-K inhibitor wortmannin (10 micromol/L) blocked JAK2 and STAT3 activation, whereas exposure of cells to the JAK2 inhibitor AG490 (5 micromol/L) decreased levels of phosphorylated (p-) JAK2 and p-STAT3 without affecting PI3-K/Akt activation. These observations suggest that PI3-K is an upstream activator of JAK2/STAT3. Furthermore, 5 micromol/L AG490 and 10 micromol/L wortmannin treatment of A549 cells for 8 h resulted in upregulation of Bax and Bad and downregulation of Bcl-2, Bcl-X(L), XIAP and p-Bad. 5. Together, the results of the present study indicate that CTX III induces apoptosis in A549 cells by inactivating the EGFR, PI3-K/Akt and JAK2/STAT3 signalling pathways.


Assuntos
Proteínas Cardiotóxicas de Elapídeos/toxicidade , Receptores ErbB/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Western Blotting , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Citometria de Fluxo , Humanos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
18.
Toxicon ; 56(4): 508-20, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20493203

RESUMO

Cardiotoxin III (CTX III), a basic polypeptide with 60-amino acid residues isolated from Naja naja atra venom, has been reported to have cytotoxic activity. CTX III exerted cytotoxicity with the S-phase cell cycle arrest, correlated with a marked decrease in the expression levels of cyclin A, cyclin B, and cyclin-dependent kinase 1 (CDK1), and apoptosis, accompanied with Bax and Bad up-regulation, and the down-regulation of Bcl-2, p-Bad, and X-linked inhibitor of apoptosis (XIAP) with cytochrome c release and sequential activation of caspase-9 and caspase-3 in Ca9-22 cells. Mechanistic studies showed that CTX III suppressed the phosphorylation of Src, EGFR, STAT3, STAT5, Akt, and activation of PI3 K (p110). Moreover, Src inactivation was observed earlier than that of the EGFR and the Src inhibitor PP2 suppressed the levels of phospho-EGFR, phospho-STAT3, phospho-STAT5, phospho-Akt, and PI3 K(p110). The PP2 also caused the S-phase arrest and apoptosis, and led to down-regulation of Bcl-2, p-Bad, XIAP, cyclin A, cyclin B, and CDK1, and up-regulation of Bax and Bad, similar to that observed in CTX III treatment. Taken together, these results indicate that CTX III induces apoptosis and S-phase arrest in Ca9-22 cells via concomitant inactivation of the Src, EGFR, STAT3, STAT5, PI3 K(p110), and Akt signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proteínas Cardiotóxicas de Elapídeos/farmacologia , Proteínas Proto-Oncogênicas pp60(c-src)/antagonistas & inibidores , Animais , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Proteínas Cardiotóxicas de Elapídeos/química , Proteínas Cardiotóxicas de Elapídeos/isolamento & purificação , Venenos Elapídicos/química , Elapidae , Ativação Enzimática/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Bucais , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/fisiologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Ativação Transcricional/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismo
19.
Eur J Pharmacol ; 636(1-3): 52-8, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20371243

RESUMO

Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exerts an anti-tumor effect. This study was performed to elucidate whether the epidermal growth factor (EGF) receptor and phosphatidylinositol-3-kinase (PI3K) signaling pathways are involved in NFD-induced apoptosis of oral squamous cell carcinoma (OSCC). Immunoblot showed that NFD suppressed the phosphorylation of EGF receptor and activation of PI3K/Akt, downstream molecules of EGF receptor signaling pathway, in Ca9-22 cells. The levels of downstream targets of Akt, including phospho-glycogen synthase kinase-3beta (p-GSK-3beta), GSK-3beta, forkhead transcription factor (FKHR), and cyclin D1, were also reduced after NFD treatment. Moreover, inactivation of nuclear factor-kappaB (NF kappaB), modulation of I kappa K beta and I kappaB alpha, up-regulation of Bad, and down-regulation of anti-apoptotic proteins including phospho-Bad, Bcl-X(L), myeloid cell leukemia-1(Mcl-1), and XIAP were found in NFD-treated cells. In addition, NFD treatment disrupted mitochondrial membrane potential (Delta Psi m), resulted in release of cytochrome c, and activation of both caspases-9 and caspase-3. Taken together, these results indicate that NFD induces apoptosis in Ca9-22 cells via inactivation of the EGF receptor-mediated survival pathway.


Assuntos
Carcinoma de Células Escamosas/patologia , Receptores ErbB/metabolismo , Neoplasias Bucais/patologia , Naftoquinonas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromos c/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Bucais/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos
20.
Toxicol In Vitro ; 24(4): 1158-67, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20197088

RESUMO

Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti-carcinogenic effect. NFD-induced apoptosis in MDA-MB-231 cells, as indicated by the accumulation of sub-G1 population, externalization of phosphatidylserine, loss of mitochondrial membrane potential (DeltaPsim) with subsequent release of cytochrome c, and activation of both capase-9 and caspase-3. This correlated with up-regulation in Bax and Bad, and down-regulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, and survivin in NFD-treated cells. In the analysis of signal transduction pathway, NFD suppressed the phosphorylation of JAK2 in MDA-MB-231 cells without altering the expression of JAK2 protein. Activation of STAT3, Src, and PI3K/Akt were also inhibited by NFD. Moreover, the JAK2 inhibitor AG490 blocked JAK2, STAT3, Src, PI3K, and Akt activation, whereas both Src inhibitor PP2 and PI3K inhibitor wortmannin did not affect JAK2 activation. This suggests that STAT3, Src, and PI3K/Akt are downstream molecules of the JAK2 signaling pathway. AG490 treatment also mimics the cytotoxic effects of NFD. Taken together, these results indicate that NFD disrupts JAK2 pathway and induces apoptosis in MDA-MB-231 cells.


Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Janus Quinase 2/metabolismo , Naftoquinonas/toxicidade , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas Inibidoras de Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Quinases da Família src/efeitos dos fármacos , Quinases da Família src/metabolismo
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