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Lithium metal batteries (LMBs) with high-voltage nickel-rich cathodes show great potential as energy storage devices due to their exceptional capacity and power density. However, the detrimental parasitic side reactions at the cathode electrolyte interface result in rapid capacity decay. Herein, a polymerizable electrolyte additive, pyrrole-1-propionic acid (PA), which can be in situ electrochemically polymerized on the cathode surface and involved in forming cathode electrolyte interphase (CEI) film during cycling is proposed. The formed CEI film prevents the formation of microcracks in LiNi0.8Co0.1Mn0.1O2 (NCM811) secondary particles and mitigates parasitic reactions. Additionally, the COO- anions of PA promote the acceleration of Li+ transport from cathode particles and increase charging rates. The Li||NCM811 batteries with PA in the electrolyte exhibit a high capacity retention of 83.83% after 200 cycles at 4.3 V, and maintain 80.88% capacity after 150 cycles at 4.6 V. This work provides an effective strategy for enhancing interface stability of high-voltage nickel-rich cathodes by forming stable CEI film.
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Substantial evidence has clearly demonstrated the role of the IL-6-NF-κB signaling loop in promoting aggressive phenotypes in breast cancer. However, the exact mechanism by which this inflammatory loop is regulated remains to be defined. Here, we report that integrin-linked kinase (ILK) acts as a molecular switch for this feedback loop. Specifically, we show that IL-6 induces ILK expression via E2F1 upregulation, which, in turn, activates NF-κB signaling to facilitate IL-6 production. shRNA-mediated knockdown or pharmacological inhibition of ILK disrupted this IL-6-NF-κB signaling loop, and blocked IL-6-induced cancer stem cells in vitro and estrogen-independent tumor growth in vivo Together, these findings establish ILK as an intermediary effector of the IL-6-NF-κB feedback loop and a promising therapeutic target for breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais , HumanosRESUMO
BACKGROUND: Cancer stem cells (CSCs) are considered responsible for the recurrence and chemoresistance of cancer. Dysregulated autophagy is highly prevalent in many types of cancer including pancreatic cancer and has been implicated in cytoprotection and tumor promotion. This study aimed to investigate the role of autophagy in regulating cancer stemness and chemoresistance of pancreatic cancer. METHODS: The correlation between autophagy and CSCs and its clinical significance were analyzed using pancreatic cancer tissue microarrays. Genetic and pharmacological approaches were applied to explore the function of autophagy on CSC activity and gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. RESULTS: LC3 expression positively correlated with the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), CD44, and CD133 in pancreatic cancer tissues. High coexpression of LC3/ALDH1 was associated with both poor overall survival and progression-free survival. In pancreatic cancer cell lines, higher LC3-II expression was observed in the sphere-forming cells than in the bulk cells. Blockade of autophagy by silencing ATG5, ATG7, and BECN1 or the administration of autophagy inhibitor chloroquine markedly reduced the CSC populations, ALDH1 activity, sphere formation, and resistance to gemcitabine in vitro and in vivo. Furthermore, osteopontin (OPN) was found to stimulate LC3-II, ALDH1, CD44, and CD133 expression in PANC-1 cells, whereas this effect could be prevented by OPN knockdown and autophagy blockade. After treatment with various inhibitors against the major signaling pathways downstream of OPN, only the inhibitor of NF-κB activation, BAY 1170-82, could effectively counteract OPN-induced autophagy and CSC activity. According to the histochemical results, pancreatic cancer patients manifesting high levels of OPN/LC3/ALDH1 and OPN/CD44/CD133 had poor survival. CONCLUSIONS: Induction of autophagy mediated by OPN/NF-κB signaling is required for maintenance of pancreatic CSC activity. Combination of gemcitabine with pharmacological autophagy inhibitors is a promising therapeutic strategy for pancreatic cancer.
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Antimetabólitos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , GencitabinaRESUMO
Visual pH-responsive packaging material is particularly important in food supply chain safety monitoring due to their non-destructive monitoring method and intuitive result. However, it has always been limited by the instability performance of pH-response components and carriers, which further hinders its wide food safety application. To address these challenges, we selected cellulose with remarkable biocompatibility and mechanical properties as the carrier, and high pH-responsive curcumin to develop a smart packaging material (RC/GC composite film) with real-time food safety monitoring. Compared with pure cellulose film, the RC/GC composite film exhibited excellent mechanical properties (4-fold enhancement) and thermal stability (100⯰C increasing). Meanwhile, based on the first reported strategy of curcumin in-situ growth during cellulose film formation, the RC/GC composite film exhibited exceptional antioxidant activity (89.2â¯%), antimicrobial property (91.6â¯%), and significant pH-responsive sensitivity (within 15â¯s). This innovative approach offers a new strategy for easy-to-use and effective monitoring of food spoilage in packaging materials.
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Ionic thermocells convert heat into electricity and are promising power sources for electronic devices. However, discontinuous and small electricity output limits practical use under varying environmental conditions. Here, a thermogalvanic ionogel with a high Seebeck coefficient (32.4 mV K-1) is designed. Thermocells that combine thermogalvanic ionogel-based thermocells, which realize all-weather power generation via passive radiative cooling, are also developed. These thermocells generate electricity continuously under varying weather conditions and over a wide temperature range (-40 to 90 °C), with a normalized power density of 25.84 mW m-2 K-2. Advanced characterization shows that the chaotropic effect enhances the Seebeck coefficient, while the self-supplying temperature difference given the radiative cooling structure enables all-weather power generation. These results provide an effective strategy for developing practical thermocells suitable for diverse daily and seasonal variations.
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The performance of cellulose-based materials is highly dependent on the choice of solvent systems. Exceptionally, cellulose dissolution and derivatization by efficient solvent have been considered as a key factor for large-scale industrial applications of cellulose. However, cellulose dissolution and derivatization often requires harsh reaction conditions, high energy consumption, and complex solubilizing, resulting in environmental impacts and low practical value. Here we address these limitations by using a low-temperature oxalic acid/sulfuric acid solvent to enable cellulose dissolution and derivatization for high-performance cellulose films. The dissolution and derivatization mechanism of the mixed acid is studied, demonstrating that cellulose is firstly socked by oxalic acid, then more hydrogen bonds ionized by sulfuric acid break cellulose chain, and finally the esterification reaction between oxalic acid and cellulose is catalyzed by sulfuric acid. Solutions containing 8 %-10 % cellulose are obtained and can be stored for a long time at -18 °C without significant degradation. Moreover, the cellulose film exhibits a higher tensile strength of up to 66.1 MPa, thermal stability, and degree of polymerization compared to that fabricated by sulfuric acid. These unique advantages provide new paths to utilize renewable resources for alternative food packaging materials at an industrial scale.
Assuntos
Celulose , Embalagem de Alimentos , Ácido Oxálico , Ácidos Sulfúricos , Ácidos Sulfúricos/química , Celulose/química , Embalagem de Alimentos/métodos , Ácido Oxálico/química , Resistência à Tração , Solubilidade , Solventes/químicaRESUMO
Hydrogels with excellent high-water uptake and flexibility have great potential for wound dressing. However, pure hydrogels without fiber skeleton faced poor water retention, weak fatigue resistance, and mechanical strength to hinder the development of the dressing as next-generation functional dressings. We prepared an ultrafast gelation (6 s) Fe3+/TA-CNC hydrogel (CTFG hydrogel) based on a self-catalytic system and bilayer self-assembled composites. The CTFG hydrogel has excellent flexibility (800% of strain), fatigue resistance (support 60% compression cycles), antibacterial, and self-adhesive properties (no residue or allergy after peeling off the skin). CTFG@S bilayer composites were formed after electrospun silk fibroin (SF) membranes were prepared and adhesive with CTFG hydrogels. The CTFG@S bilayer composites had significant UV-shielding (99.95%), tensile strain (210.9 KPa), and sensitive humidity-sensing properties. Moreover, the integrated structure improved the mechanical properties of electrospun SF membranes. This study would provide a promising strategy for rapidly preparing multifunctional hydrogels for wound dressing.
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Celulose , Fibroínas , Polifenóis , Cimentos de Resina , Bandagens , Antibacterianos/farmacologia , Hidrogéis , ÁguaRESUMO
Industrial waste steam is one of the major sources of global energy losses. Therefore, the collection and conversion of waste steam energy into electricity have aroused great interest. Here, a "two-in-one" strategy is reported that combines thermoelectric and moist-electric generation mechanisms for a highly efficient flexible moist-thermoelectric generator (MTEG). The spontaneous adsorption of water molecules and heat in the polyelectrolyte membrane induces the fast dissociation and diffusion of Na+ and H+ , resulting in the high electricity generation. Thus, the assembled flexible MTEG generates power with a high open-circuit voltage (Voc ) of 1.81 V (effective area = 1cm2 ) and a power density of up to 4.75±0.4 µW cm-2 . With efficient integration, a 12-unit MTEG can produce a Voc of 15.97 V, which is superior to most known TEGs and MEGs. The integrated and flexible MTEGs reported herein provide new insights for harvesting energy from industrial waste steam.
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Thermo-sensitive composite microspheres (TPCP) were developed to achieve the on-demand release of drugs. The TPCP microspheres were synthesized using Oil-in-Water (O/W) emulsion evaporation technique and then impregnated with thermo-sensitive polyethylene glycol (PEG). The addition of cellulose nanocrystals (CNCs) significantly enhance thermal stability, crystallization ability, and surface hydrophilicity of TPCP microspheres due to heterogeneous nucleation effect and hydrogen bonding interaction, resulting in stable microsphere structure. The thermal degradation temperature (Tmax) increased by 13.8 °C, and the crystallinity improved by 20.9 % for 10 % TPCP. The thermo-sensitive composite microspheres showed the regulated cumulative release according to in vitro human physiological temperature changes. Besides, four release kinetics and possible release mechanism of TPCP microspheres were provided. Such thermo-responsive composite microspheres with control microsphere sizes and high encapsulation rate may have the potential to the development of on-demand and advanced controlled-release delivery systems.
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Celulose , Nanopartículas , Humanos , Liberação Controlada de Fármacos , Microesferas , CinéticaRESUMO
Nowadays, non-degradable plastic packaging materials have caused serious environmental pollution, posing a threat to human health and development. Renewable eco-friendly nanocellulose hybrid (NCs-hybrid) composites as an ideal alternative to petroleum-based plastic food packaging have been extensively reported in recent years. NCs-hybrids include metal, metal oxides, organic frameworks (MOFs), plants, and active compounds. However, no review systematically summarizes the preparation, processing, and multi-functional applications of NCs-hybrid composites. In this review, the design and hybridization of various NCs-hybrids, the processing of multi-scale nanocomposites, and their key properties in food packaging applications were systematically explored for the first time. Moreover, the synergistic effects of various NCs-hybrids on several properties of composites, including mechanical, thermal, UV shielding, waterproofing, barrier, antimicrobial, antioxidant, biodegradation and sensing were reviewed in detailed. Then, the problems and advances in research on renewable NCs-hybrid composites are suggested for biodegradable food packaging applications. Finally, a future packaging material is proposed by using NCs-hybrids as nanofillers and endowing them with various properties, which are denoted as "PACKAGE" and characterized by "Property, Application, Cellulose, Keen, Antipollution, Green, Easy."
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Embalagem de Alimentos , Nanocompostos , Humanos , Antioxidantes , Biodegradação Ambiental , CeluloseRESUMO
SARS-CoV-2 pandemic has profound impacts on human life and global economy since the outbreak in 2019. With the new variants continue to emerge with greater immune escaping capability, the protectivity of the available vaccines is compromised. Therefore, development a vaccine that is capable of inducing immunity against variants including omicron strains is in urgent need. In this study, we developed a protein-based vaccine BCVax that is consisted of antigen delta strain spike protein and QS21-based adjuvant AB801 in nanoparticle immune stimulation complex format (AB801-ISCOM). Results from animal studies showed that high level of anti-S protein IgG was induced after two doses of BCVax and the IgG was capable of neutralizing multiple variants of pseudovirus including omicron BA.1 or BA.2 strains. In addition, strong Th1 response was stimulated after BCVax immunization. Furthermore, BCvax with AB801-ISCOM as the adjuvant showed significant stronger immunity compared with the vaccine using aluminum hydroxide plus CpG 1018 as the adjuvant. BCVax was also evaluated as a booster after two prior vaccinations, the IgG titers and pseudovirus neutralization activities against BA.2 or BA.4/BA.5 were further enhanced suggesting BCVax is a promising candidate as booster. Taken together, the pre-clinical data warrant BCVax for further development in clinic.
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COVID-19 , ISCOMs , Animais , Humanos , Vacinas contra COVID-19 , SARS-CoV-2 , Subunidades Proteicas , COVID-19/prevenção & controle , Glicoproteína da Espícula de Coronavírus/genética , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Animais de Laboratório , Imunoglobulina G , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
We have reported both T-cell-dependent and -independent hepatitis in immunocompetent and immunodeficiency mice, respectively, after intravenous injection of Con A in mice. The mode of hepatocyte cell death is different: autophagy for T-cell-independent hepatitis in contrast to apoptosis for T-cell-dependent one. In this study, we further demonstrate that liver blood vessels are the first target in both modes. The infused Con A bond to the hepatic vascular endothelial cells and cause its damage with autophagy. Before the elevation of the serum alanine aminotransferase at 6 h post-injection, the plasma leakage and hemorrhage occur at 1-3 h without inflammation. Con A induces autophagy of endothelial cells and hemorrhage that is enhanced by IFN-gamma. Using the endothelial cell line HMEC-1, a dose- and time-dependent cell death with autophagic LC3-II (microtubule-associated protein light chain 3) conversion was induced by Con A and was enhanced by IFN-gamma. In conclusion, Con A induced autophagy on hepatic endothelial cells; the damage of liver blood vessel occurs before the induction of T-cell-dependent hepatitis via apoptosis or T-cell-independent hepatitis via autophagy.
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Autofagia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A , Células Endoteliais/patologia , Hepatócitos/patologia , Interferon gama/imunologia , Animais , Western Blotting , Sobrevivência Celular , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Células Endoteliais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Fatores de TempoRESUMO
Globo H (GH), a hexasaccharide, is expressed at low levels in normal tissues but is highly expressed in multiple cancer types, rendering it a promising target for cancer immunotherapy. OBI-999, a novel antibody-drug conjugate, is derived from a conjugation of a GH-specific mAb with a monomethyl auristatin E (MMAE) payload through a site-specific ThioBridge and a cleavable linker. OBI-999 high homogeneity with a drug-to-antibody ratio of 4 (>95%) was achieved using ThioBridge. OBI-999 displayed GH-dependent cellular internalization and trafficked to endosome and lysosome within 1 and 5 hours, respectively. Furthermore, OBI-999 showed low nanomolar cytotoxicity in the assay with high GH expression on tumor cells and exhibited a bystander killing effect on tumor cells with minimal GH expression. Tissue distribution indicated that OBI-999 and free MMAE gradually accumulated in the tumor, reaching maximum level at 168 hours after treatment, whereas OBI-999 and free MMAE decreased quickly at 4 hours after treatment in normal organs. Maximum MMAE level in the tumor was 16-fold higher than in serum, suggesting that OBI-999 is stable during circulation and MMAE is selectively released in the tumor. Excellent tumor growth inhibition of OBI-999 was demonstrated in breast, gastric, and pancreatic cancer xenograft or lung patient-derived xenograft models in a dose-dependent manner. The highest nonseverely toxic dose in cynomolgus monkeys is 10 mg/kg determined by a 3-week repeated-dose toxicology study demonstrating an acceptable safety margin. Taken together, these results support further clinical development of OBI-999, which is currently in a phase I/II clinical study in multiple solid tumors (NCT04084366). OBI-999, the first GH-targeting ADC, displayed excellent tumor inhibition in animal models across multiple cancer types, including breast, gastric, pancreatic, and lung cancers, warranting further investigation in the treatment of solid tumors.
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Imunoconjugados/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunoconjugados/farmacologia , CamundongosRESUMO
Liver cirrhosis and hepatocellular carcinomas are two major causes of morbidity and mortality worldwide, and can synergistically interact to expedite the tumor progression. How fibrosis promotes the hepatoma growth remains completely unexplained. Using an in situ murine hepatoma model together with fibrosis induction by thioacetamide (TAA), the hepatoma growth and the immune factors in the fibrotic liver were analyzed. We found that TAA-fibrosis induction enhanced hepatoma cell growth in the liver and increased the mortality of hepatoma-bearing mice. The tumor-infiltrating CD4(+) or CD8(+) T cells are downregulated by fibrosis induction. The Foxp3(+) regulatory T cells (Treg) cells were induced. We conclude that fibrosis induction causes further immunosuppression, in which Treg cells exert a downregulation effect on the antitumor immunity.
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Carcinoma Hepatocelular/patologia , Cirrose Hepática/imunologia , Neoplasias Hepáticas Experimentais/patologia , Neoplasias/patologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Carcinógenos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Fatores de Transcrição Forkhead/imunologia , Tolerância Imunológica , Cirrose Hepática/patologia , Neoplasias Hepáticas Experimentais/imunologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Tioacetamida , Evasão TumoralRESUMO
Relative to several other p21-activated kinase (PAK) family members, the role of PAK3 in regulating cancer cell functions remains unclear. Our study obtained evidence that PAK3 regulates the Akt-GSK3ß-ß-catenin signaling by acting as Ser473-Akt kinase in several pancreatic cancer cell lines. Specifically, knockdown of PAK3 or overexpression of dominant-negative PAK3 inhibited the phosphorylation of Ser473-Akt and GSK3ß, resulting in the proteasomal degradation of ß-catenin. Conversely, overexpression of PAK3 led to activation of Akt signaling and increased ß-catenin expression. These changes, however, were not noted with the silencing and/or overexpression of PAK1, PAK2, or PAK4, which underlies the impetus of PAK3 as a key effector in governing malignant phenotypes in these pancreatic cancer cells, including cancer stem cell (CSC) expansion. Accordingly, PAK3 depletion effectively suppresses tumorsphere formation, ALDH activity, and the expression of CSC surface markers. Moreover, we used a stable knockdown clone of AsPC-1â¯cells to demonstrate the in vivo efficacy of PAK3 inhibition in suppressing tumorigenesis and xenograft tumor growth. Together, these findings suggest the potential role of PAK3 as a target for pancreatic cancer therapy, which warrants further investigations.
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Proliferação de Células , Glicogênio Sintase Quinase 3 beta/metabolismo , Células-Tronco Neoplásicas/enzimologia , Neoplasias Pancreáticas/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Serina , Transdução de Sinais , Esferoides Celulares , Carga Tumoral , beta Catenina/genética , Quinases Ativadas por p21/genéticaRESUMO
alpha-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several diseases, including hepatic disorder and diabetic polyneuropathy. However, the effects of LA or its reduced form, dihydrolipoic acid (DHLA), on cancer chemoprevention has seldom been studied. Tetrachlorohydroquinone (TCHQ) is a toxic metabolite of pentachlorophenol (PCP) that was proven to be a tumor promoter in our previous study. We recently reported that DHLA can inhibit DMBA/TPA-induced skin tumor formation through its anti-inflammatory and anti-oxidizing functions. In the present study, we further examined the effects of DHLA on DMBA/TCHQ-induced skin tumor formation and the possible mechanisms. We found that DHLA significantly inhibited tumor incidence and tumor multiplicity in DMBA/TCHQ-induced skin tumor formation. Administration of DHLA prevented ROS generation, cytotoxicity, genotoxicity and apoptotic cell death in cells treated with TCHQ. In addition, activation of JNK and p38 MAPK may be involved in TCHQ-mediated apoptosis. Nonetheless, the detailed mechanisms of DHLA in attenuating TCHQ-induced skin tumor promotion are still unclear and need to be further investigated. We conclude that DHLA may be a useful protective agent against TCHQ-induced toxicity in epithelial cells, and for reversing TCHQ-induced damage in mouse skin.
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Anticarcinógenos , Antioxidantes/farmacologia , Carcinógenos/antagonistas & inibidores , Carcinógenos/toxicidade , Hidroquinonas/antagonistas & inibidores , Hidroquinonas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Epididimo/patologia , Citometria de Fluxo , Imuno-Histoquímica , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células NIH 3T3 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/prevenção & controle , Ácido Tióctico/farmacologiaRESUMO
Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.
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Ceruletídeo/efeitos adversos , Janus Quinases/metabolismo , Células Estreladas do Pâncreas/metabolismo , Pancreatite Crônica/etiologia , Pancreatite Crônica/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Pancreatite Crônica/patologia , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Integrin-linked kinase (ILK) is a serine-threonine kinase that regulates interactions between the cell and the extracellular matrix. In many cancers, overexpression of ILK leads to increased cell proliferation, motility, and invasion. We hypothesized that ILK functions as a regulator of viability and migration in thyroid cancer cells. METHODS: Eleven human thyroid cancer cell lines were screened for ILK protein expression. The cell lines with the greatest expression were treated with either ILK small interfering RNA (siRNA) or a novel ILK inhibitor, T315, and the effects were evaluated via Western blot and migration assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays were performed to assess cell viability. RESULTS: siRNA against ILK decreased phosphorylation of downstream effectors Akt and MLC, as well as decreased migration. Treatment with T315 showed a dose-related decrease in both Akt and MLC phosphorylation, as well as decreased migration. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays showed T315 to have an half maximal inhibitory concentration of less than 1 µM in cell lines with high ILK expression. CONCLUSION: ILK is expressed differentially in thyroid cancer cell lines. Both ILK siRNA and T315 inhibit motility of thyroid cancer cell lines, and T315 is shown to be cytotoxic at low concentrations. Altogether, our study suggests that ILK may represent an important kinase in aggressive thyroid cancers.
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Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases , RNA Interferente Pequeno/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Transdução de SinaisRESUMO
Extensive researches have found that the mutation of p53 tumor suppressor gene is the most frequent event in many human cancers and associated with a poor clinical outcome in lung cancer patients. Because the p53 molecular mutation involved in tumorigenesis of patients with lung cancer in Taiwan remains poorly defined, the aim of this study was to assess the p53 mutation spectrum and possible etiological factors of Taiwan's patients with Non-Small Cell Lung Cancer (NSCLC). Cancer specimens were obtained surgically from 61 patients with pathologically proven NSCLC. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing were used to study p53 mutations in exon 4-8. We also performed immunohistochemistry (IHC) to detect p53 protein expression. Our results provided that 34 mutations of p53 gene were found in 27 cases with a mutation rate of 44% (27/61). There were six cases having more than two p53 mutations. Among the 34 mutations, 19 were point mutations (56%, 19/34) consisted of a majority of missense mutations including transversion (13/19, 68%) and transitions (6/19, 32%) with four cases (4/6, 67%) occurring in the CpG sequence. One of the most important finding in our study was the high frequency of frameshift (44%, 15/34) which included 11 insertions and 4 deletions of p53 in NSCLC in Taiwan. Surprisingly, our results disclosed distinct novel mutations at codon 181, 185, 208 (Exon 5-6) of p53. Especially, 4 cases with mutation at codon181 and codon 185 seemed to have more advanced clinical outcome with survival time less than 6 months. In addition, there were two recurring mutations at codon 168 and three at condon193. The different mutation spectrum in our series, including a high frequency of frameshift mutations and distinctly novel hot spots suggested the heterogenous entity of exogenous mutagens in NSCLC in Taiwan.
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Carcinoma Pulmonar de Células não Pequenas/genética , Mutação da Fase de Leitura , Genes p53 , Neoplasias Pulmonares/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/etiologia , Transformação Celular Neoplásica , Análise Mutacional de DNA , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Prognóstico , TaiwanRESUMO
A technique for synthesizing biocompatible hydrogels by cross-linking calcium-form poly(γ-glutamic acid), alginate sodium, and Pluronic F-127 was created, in which alginate can be cross-linked by Ca(2+) from Ca-γ-PGA directly and γ-PGA molecules introduced into the alginate matrix to provide pH sensitivity and hemostasis. Mechanical properties, swelling behavior, and blood compatibility were investigated for each hydrogel compared with alginate and for γ-PGA hydrogel with the sodium form only. Adding F-127 improves mechanical properties efficiently and influences the temperature-sensitive swelling of the hydrogels but also has a minor effect on pH-sensitive swelling and promotes anticoagulation. MG-63 cells were used to test biocompatibility. Gelation occurred gradually through change in the elastic modulus as the release of calcium ions increased over time and caused ionic cross-linking, which promotes the elasticity of gel. In addition, the growth of MG-63 cells in the gel reflected nontoxicity. These results showed that this biocompatible scaffold has potential for application in bone materials.