Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Molecules ; 29(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474593

RESUMO

Lycorine is a kind of natural active ingredient with a strong antitumor effect. In this study, folate ligand-conjugated polyethylene glycol-block-poly(l-lactide) (PEG-PLLA) nanoparticles (FA-PEG-PLLA NPs) were designed to deliver lycorine to enhance its anti-glioma activity. The successful preparation of the FA-PEG-PLLA polymer was confirmed by 1H-NMR, FT-IR, XRD, TGA, and DSC. The optimal formulation for LYC@FA-PEG-PLLA NPs was determined by response surface analysis as follows: sodium dodecyl sulfate (SDS) of 1%, carrier material of 0.03 g, organic phase volume of 3 mL, and ultrasonic power of 20%. The LYC@FA-PEG-PLLA NPs exhibited an encapsulation efficiency of 83.58% and a particle size of 49.71 nm, demonstrating good stability. Hemolysis experiments, MTT assays, and cell scratch assays revealed excellent biocompatibility of FA-PEG-PLLA and superior anti-glioma activity of LYC@FA-PEG-PLLA NPs compared to the raw drug. Additionally, cell apoptosis assays, ROS experiments, and western blot analysis demonstrated that LYC@FA-PEG-PLLA NPs contributed to cell apoptosis by inducing ROS generation and increasing the expression of NF-κB inhibitory protein IκBα. These results suggested that LYC@FA-PEG-PLLA NPs hold promise for glioma treatment.


Assuntos
Alcaloides de Amaryllidaceae , Glioma , Nanopartículas , Fenantridinas , Humanos , Ácido Fólico/química , Espécies Reativas de Oxigênio , Espectroscopia de Infravermelho com Transformada de Fourier , Nanopartículas/química , Polietilenoglicóis/química , Portadores de Fármacos/química , Tamanho da Partícula , Linhagem Celular Tumoral
2.
Biomed Mater ; 19(3)2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38422539

RESUMO

A novel biodegradable amphiphilic triblock copolymer, polyphosphate, polyethylene glycol, and polylactic acid (PAEEP-PEG-PLLA), was synthesized by twice ring-opening polymerization and triphenylphosphine (TPP) was grafted onto the block copolymer to synthesize a carrier material TPP-PAEEP-PEG-PLLA, which was identified by1H-nuclear magnetic resonance (1H-NMR) spectroscopy. The TPP-PAEEP-PEG-PLLA nanoparticles encapsulated with ursolic acid (UA) were prepared by the emulsion-solvent evaporation method and characterized by dynamic light scattering. The mitochondrial targeting ability of fluorescently labeled nanoparticles was evaluated by laser confocal microscopy. The average particle size and surface charge of the UA -loaded nanoparticle solution were 180.07 ± 1.67 nm and +15.57 ± 1.33 mV, respectively. The biocompatibility of nanoparticles was briefly evaluated by erythrocyte hemolysis assay.In vitrocell proliferation assay and scratch migration assay were performed to compare the difference in anti-tumor effect between UA and UA nanoparticles. The results showed that TPP-modified triblock copolymers had good mitochondrial targeting and improved the low bioavailability of UA, and UA nanoparticles exhibited more pronounced anti-tumor capabilities. In summary, the results suggested that our UA nanoparticles were a promising drug-targeted delivery system for the treatment of tumors.


Assuntos
Nanopartículas , Neoplasias , Compostos Organofosforados , Humanos , Portadores de Fármacos/química , Polímeros/química , Polietilenoglicóis/química , Neoplasias/tratamento farmacológico , Nanopartículas/química , Tamanho da Partícula
3.
Front Biosci (Landmark Ed) ; 28(11): 293, 2023 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-38062833

RESUMO

BACKGROUND: Accumulative evidence suggests that pyroptosis plays a key role in mediating angiotensin II (Ang II)-induced cardiac remodeling However, the potential role of pyroptosis-related transcription factor (TF)-microRNA (miRNA)-gene regulatory networks in mediating Ang II-associated cardiac remodeling remains largely unknown. Therefore, we identified the pyroptosis-related hub genes and constructed a transcription factor (TF)-miRNA-target gene regulatory network using bioinformatic tools to elucidate the pathogenesis of Ang II-induced cardiac remodeling. METHODS: The pyroptosis-related differentially expressed genes (DEGs) were identified from the cardiac remodeling-related dataset GSE47420. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis were performed to identify the pyroptosis-related hub DEGs. A TF-miRNA-target gene network was constructed and further validated by quantitative real-time polymerase chain reaction (qRT-PCR) in animal experiments. The correlation between the pyroptosis-related hub DEGs and cardiac remodeling was evaluated using comparative toxicogenomics database. The drug-gene interaction analysis was performed to identify potential drugs that target the pyroptosis-related hub DEGs. RESULTS: A total of 32 pyroptosis-related DEGs were identified and enriched in the inflammation-related pathways by KEGG analysis. 13 of the 32 pyroptosis-related DEGs were identified as hub DEGs. Furthermore, a TF-miRNA-target gene regulatory network containing 16 TFs, 6 miRNAs, and 5 hub target genes was constructed. The five pyroptosis-related hub target genes (DDX3X, ELAVL1, YWHAZ, STAT3, and EED) were identified as crucial cardiac remodeling-related genes using the comparative toxicogenomics database (CTD) database. Five drugs including celecoxib were identified as potential drugs for the treatment of cardiac remodeling. Finally, the expression levels of two top-ranked TF-miRNA-target genes axis were verified by qRT-PCR in mice with Ang II-induced cardiac remodeling and found to be generally consistent with the microarray results. CONCLUSIONS: This study constructed a pyroptosis-related TF-miRNA-target gene regulatory network for Ang II-induced cardiac remodeling. Five pyroptosis-related genes (DDX3X, ELAVL1, YWHAZ, STAT3, and EED) can be considered the core genes associated with pyrotposis-related cardiac remodeling. The findings of this study provide new insights into the molecular mechanisms of Ang II-induced cardiac remodeling and may serve as potential biomarkers or therapeutic targets for Ang II-induced cardiac remodeling.


Assuntos
Redes Reguladoras de Genes , MicroRNAs , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Piroptose/genética , Remodelação Ventricular/genética , Mapas de Interação de Proteínas/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Biologia Computacional/métodos
4.
Pharmaceutics ; 15(12)2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38140034

RESUMO

Given that cancer mortality is usually due to a late diagnosis, early detection is crucial to improve the patient's results and prevent cancer-related death. Imaging technology based on novel nanomaterials has attracted much attention for early-stage cancer diagnosis. In this study, a new block copolymer, poly(ethylene glycol)-poly(l-lactide) diblock copolymer (PEG-PLLA), was synthesized by the ring-opening polymerization method and thoroughly characterized using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (H-NMR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The obtained PEG-PLLA was used to prepare nanoparticles encapsulated with perfluoropentane and salicylic acid by the emulsion-solvent evaporation method, resulting in a new dual-mode nano-image probe (PEG-PLLA@SA·PFP). The zeta potential and mean diameter of the obtained nanoparticles were measured using dynamic light scattering (DLS) with a Malvern Zetersizer Nano. The in vitro biocompatibility of the PEG-PLLA nanoparticles was evaluated with cell migration, hemolysis, and cytotoxicity assays. Ultrasonic imaging was performed using an ultrasonic imaging apparatus, and chemical exchange saturation transfer (CEST) MRI was conducted on a 7.0 T animal scanner. The results of IR and NMR confirmed that the PEG-PLLA was successfully synthesized. The particle size and negative charge of the nanoparticles were 223.8 ± 2.5 nm and -39.6 ± 1.9 mV, respectively. The polydispersity of the diameter was 0.153 ± 0.020. These nanoparticles possessed good stability at 4 °C for about one month. The results of cytotoxicity, cell migration, and hemolysis assays showed that the carrier material was biocompatible. Finally, PEG-PLLA nanoparticles were able to significantly enhance the imaging effect of tumors by the irradiation of ultrasound and saturation by a radiofrequency pulse, respectively. In conclusion, these nanoparticles exhibit promising dual-mode capabilities for US/CEST MR imaging.

5.
Immun Inflamm Dis ; 11(11): e1080, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38018593

RESUMO

BACKGROUND: Rhino-orbito-cerebral mucormycosis (ROCM) is an opportunistic pathogenic fungal disease caused by the fungus mucor, and it is a life-threatening fungal infection. The ulceration on the skin of the head and neck, accompanied by rhinitis, headache, orbital inflammation, and eyelid edema, should raise a high suspicion of Mucor infection in diabetic patients with inadequately controlled blood glucose. CASE DESCRIPTION: The clinical data of a patient with ROCM were analyzed retrospectively, and the clinical features were analyzed. The patient was admitted to the hospital with "diabetic hyperosmotic coma" after presenting with fatigue, poor appetite, and disturbances in consciousness as initial symptoms. After improving relevant examinations, controlling underlying diseases, and administering antifungal treatment, the final clinical outcome was death. CONCLUSION: ROCM is more prevalent in patients with uncontrolled diabetes and varied clinical manifestations. The characteristic feature is an eschar-like necrosis of the local skin or mucosa. The gold criteria for diagnosis are pathology and fungal culture; imaging examination does not reveal any specific manifestations. Early diagnosis and effective treatment are the keys.


Assuntos
Diabetes Mellitus , Mucormicose , Doenças Orbitárias , Humanos , Mucormicose/diagnóstico , Mucormicose/tratamento farmacológico , Estudos Retrospectivos , Doenças Orbitárias/diagnóstico , Doenças Orbitárias/tratamento farmacológico , Diabetes Mellitus/diagnóstico , Antifúngicos/uso terapêutico
6.
Future Microbiol ; 18: 911-916, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37584568

RESUMO

HSV can evade host defenses and cause lifelong infection and severe illness. Lysosomes are catabolic organelles that play an important role in the regulation of cellular homeostasis. Lysosomal dysfunction and alterations in the process of autophagy have been identified in a variety of diseases, including HSV infection, and targeting lysosomes is a potential anti-HSV therapeutic strategy. This article reviews the role of lysosomes and lysosome-associated proteins in HSV infection, providing attractive targets and novel strategies for the treatment of HSV infection.


Assuntos
Autofagia , Lisossomos , Homeostase , Lisossomos/metabolismo
7.
J Phys Chem Lett ; 14(32): 7229-7234, 2023 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-37552579

RESUMO

ZrO2-Cu-based catalysts are active in catalyzing the hydrogenation of CO2 to methanol. Herein, we report Cu facet effects on the catalytic performance of ZrO2/Cu inverse catalysts in CO2 hydrogenation to methanol using various Cu nanocrystals with well-defined Cu morphologies and facets. The ZrO2-Cu interface is the active site, in which the ZrO2-Cu{100} and ZrO2-Cu{110} interfaces exhibit similar apparent activation energies of ∼42.6 kJ/mol, smaller than that of the ZrO2-Cu{111} interface (∼64.5 kJ/mol). Temporal in situ diffuse reflectance infrared Fourier transform spectroscopy characterization results identify the bridge formate hydrogenation as the rate-determining elementary surface reaction under typical reaction temperatures, whose activation energy is similar at the ZrO2-Cu{100} (∼36.3 kJ/mol) and ZrO2-Cu{110} (∼40.5 kJ/mol) interfaces and larger at the ZrO2-Cu{111} interface (∼54.5 kJ/mol). This fundamental understanding suggests Cu facet engineering as a promising strategy to improve the catalytic performance of ZrO2/Cu inverse catalysts for CO2 hydrogenation to methanol.

8.
Int J Mol Med ; 51(5)2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37026522

RESUMO

Bone cancer pain (BCP) is mainly caused by bone metastasis and markedly impairs the functional capacity and daily functions of patients. Neuroinflammation plays a pivotal role in the pathogenesis and maintenance of chronic pain. Oxidative stress in the mitochondria is a key contributor to neuroinflammation and neuropathic pain. Herein, a rat model of BCP was established which was characterized by bone destruction, pain hypersensitivity and motor disability. In the spinal cord, phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) signaling was activated, and the inflammatory response and mitochondrial dysfunction were also observed. The intrathecal injection of LY294002, a selective inhibitor of PI3K/Akt signaling, decreased mechanical pain sensitivity, suppressed spontaneous pain and recovered the motor coordination of rats with BCP. Second, LY294002 treatment blocked spinal inflammation by reducing astrocytic activation and downregulating the expression levels of inflammatory factors, such as NF­κB, IL­1ß and TNF­α. Moreover, LY294002 treatment recovered mitochondrial function by activating the manganese superoxide dismutase enzyme, increasing NADH:ubiquinone oxidoreductase subunit B11 expression, and decreasing BAX and dihydroorotate dehydrogenase expression. LY294002 treatment also increased the mitochondrial membrane potential and decreased the mitochondrial reactive oxygen species levels in C6 cells. On the whole, the results of the present study suggest that the inhibition of PI3K/Akt signaling by LY294002 restores mitochondrial function, suppresses spinal inflammation and alleviates BCP.


Assuntos
Neoplasias Ósseas , Dor do Câncer , Pessoas com Deficiência , Transtornos Motores , Neuralgia , Osteossarcoma , Ratos , Animais , Humanos , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Doenças Neuroinflamatórias , Ratos Sprague-Dawley , Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Mitocôndrias/metabolismo
9.
PLoS One ; 18(4): e0284332, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37058473

RESUMO

Pain is the main symptom of osteoarthritis, which severely reduces the patients' quality of life. Stimulated neuroinflammation and elevated mitochondrial oxidative stress are associated arthritis pain. In the present study, arthritis model was established by intra-articular injection of complete Freund's adjuvant (CFA) on mice. Knee swelling, pain hypersensitivity and motor disability were observed in CFA-induced mice. In spinal cord, neuroinflammation was triggered and presented as severe infiltration of inflammatory cells and up-regulated expressions of glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-κB), PYD domains-containing protein 3 (NLRP3), cysteinyl aspartate specific proteinase (caspase-1) and interleukin-1 beta (IL-1ß). Mitochondrial function was disrupted and characterized as elevated expressions of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), dihydroorotate dehydrogenase (DHODH) and cytochrome C (Cyto C), and reduced expressions of Bcl-2 and Mn-superoxide dismutase (Mn-SOD) activity. Meanwhile, as a potential target for pain management, glycogen synthase kinase-3 beta (GSK-3ß) activity was up-regulated in CFA induced mice. To explore potential therapeutic options for arthritis pain, GSK-3ß inhibitor TDZD-8 was intraperitoneally injected for three days on CFA mice. Animal behavioral tests found that TDZD-8 treatment elevated mechanical pain sensitivity, suppressed spontaneous pain and recovered motor coordination. Morphological and protein expression analysis indicated that TDZD-8 treatment decreased spinal inflammation score and inflammatory related protein levels, recovered mitochondrial related protein levels, and increased Mn-SOD activity. In summary, TDZD-8 treatment inhibits GSK-3ß activity, reduces mitochondrial mediated oxidative stress, suppresses spinal inflammasome response, and alleviates arthritis pain.


Assuntos
Artrite , Pessoas com Deficiência , Transtornos Motores , Camundongos , Animais , Humanos , Glicogênio Sintase Quinase 3 beta , Espécies Reativas de Oxigênio , Doenças Neuroinflamatórias , Qualidade de Vida , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Mitocôndrias , Proteínas Proto-Oncogênicas c-bcl-2
10.
J Biomater Appl ; 36(6): 1064-1075, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34338057

RESUMO

Due to the low bioavailability and severe toxic side effects caused by the lack of selectivity of traditional chemotherapy drugs, the targeted delivery of chemotherapy drugs has become the key to tumor treatment. The activity and transmembrane potential of mitochondria in cancer cells were significantly higher than that of normal cells, making them a potential target for chemotherapeutic drug delivery. In this study, triphenylphosphine (TPP) based mitochondria targeting polylactic acid (PLLA) nanoparticles (TPP-PLLA NPs) were synthesized to improve the delivery efficiency of anticancer drugs. The carrier material was characterized by 1H NMR and FT-IR and 7-hydroxyl coumarin (7-HC) was successfully loaded into TPP-PLLA to form 7-HC/TPP-PLLA NPs. Further studies showed that TPP-PLLA NPs were primarily accumulated in the mitochondrial and 7-HC/TPP-PLLA NPs had higher antitumor activity. Taken together, our results indicated that TPP-PLLA NPs could be a promising mitochondria-targeted drug delivery system for cancer therapy.


Assuntos
Antineoplásicos , Nanopartículas , Antineoplásicos/química , Linhagem Celular Tumoral , Cumarínicos , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Mitocôndrias , Nanopartículas/química , Compostos Organofosforados , Poliésteres , Espectroscopia de Infravermelho com Transformada de Fourier
11.
J Biomater Appl ; 36(1): 15-25, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33287646

RESUMO

The proposed study was to develop the preparation of ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) modified with citric acid, with surface conjugated with lactoferrin (Lf), which used as a potential targeted contrast agent for magnetic resonance imaging (MRI) of brain glioma. USPIONs were prepared by the thermal decomposition method. The hydrophobic USPIONs were coated with citric acid by the ligand exchange method. Then, Lf was conjugated into the surface of USPIONs. The obtained Lf-USPIONs were analyzed by fourier transform infrared (FTIR) spectroscopy and polyacrylamide gel electrophoresis. The size, size distribution, shape and superparamagnetic property of Lf-USPIONs were investigated with TEM and vibrating sample magnetometer (VSM). Both FTIR and electrophoresis analysis demonstrated the successful conjugation of Lf to the surface of USPIONs. The average size of Lf-USPIONs was about 8.4 ± 0.5 nm, which was determined using the statistics of measured over 100 nanoparticles in the TEM image, with a negative charge of -7.3 ± 0.2 mV. TEM imaging revealed that Lf-USPIONs were good in dispersion and polygonal in morphology. VSM results indicated that Lf-USPIONs were superparamagnetic and the saturated magnetic intensity was about 69.8 emu/g. The Lf-USPIONs also showed good biocompatibility in hemolysis, cytotoxicity, cell migration and blood biochemistry studies. MR imaging results in vitro and in vivo indicated that Lf-USPIONs exhibited good negative contrast enhancement. Taken together, Lf-USPIONs hold great potential for brain gliomas MR imaging as a nanosized targeted contrast agent.


Assuntos
Ácido Cítrico/química , Dextranos/química , Glioma/tratamento farmacológico , Lactoferrina/química , Nanopartículas de Magnetita/química , Nanopartículas/química , Animais , Movimento Celular , Meios de Contraste/química , Glioma/diagnóstico por imagem , Hemólise , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Coelhos , Ratos
12.
J Environ Manage ; 272: 111077, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32854884

RESUMO

China needs to balance between current population pressures and a vulnerable marine environment, creating a national, political outline or management strategy dubbed an ecological civilization construction. The nation's effort to protect and maintain a sustainable ocean and address the relevant economic, resource and environmental issues relies on Marine Ecological Civilization (MEC) construction. The quantification of MEC progress is essential to track the management performance and guide the subsequent development and implementation. This study evaluates the performance of China's MEC from 2006 to 2016 based on a comprehensive index system. Our findings are as follows: During 2006-2016, the overall MEC performance score increased from 0.3426 to 0.4850 nationwide. Large space-time variations exist among the eleven coastal regions. The Shandong and Guangdong regions showed relatively good performances, whereas the Jiangsu, Guangxi and Shanghai regions had low scores. A decade long change in MEC scores showed that Hebei achieved the largest increase ratio. Marine management was improved by implementing various conservation strategies by China's government. Marine education and human talent introduction deserve more attention in less developed areas such as Hainan and Guangxi, and poor marine environmental quality was an urgent issue of the Yangtze river estuary economic zone. More accessible marine monitoring dataset are needed to track future space-time progress dynamics towards MEC construction. Our results provide a decade long retrospect of China's MEC achievements, and the quantified evaluation for each coastal region can provide valuable insight to policy-makers.


Assuntos
Civilização , Biologia Marinha , Logro , China , Humanos , Dinâmica Populacional
13.
Acta Biochim Biophys Sin (Shanghai) ; 52(3): 231-240, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32072182

RESUMO

Bone cancer pain (BCP) is induced by primary bone cancer and secondary bone metastasis. During BCP pathogenesis, activated spinal astrocytes release proinflammatory cytokines, which participate in pain information transmission. In this study, we found that BCP rats showed disruption of trabecular bone structure, mechanical allodynia, and spinal inflammation. Moreover, reduced adenosine monophosphate-activated protein kinase (AMPK) activity, increased mitochondrial fission-associated protein Drp1 GTPase activity accompanied by the dysfunction of mitochondrial function, and abnormal BAX and Bcl-2 expression were found in the spinal cord of BCP rats. Notably, these alterations are reversed by resveratrol (Res) administration. Cell experiment results demonstrated that Res promotes mitochondrial function by activating AMPK, decreasing Drp1 activity, and inhibiting tumor necrosis factor-α-induced mitochondrial membrane potential reduction. Taken together, these results indicate that Res suppresses BCP in rats by attenuation of the inflammatory responses through the AMPK/Drp1 signaling pathway.


Assuntos
Dor do Câncer/tratamento farmacológico , Dor do Câncer/fisiopatologia , Resveratrol/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Astrócitos/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Dinaminas/metabolismo , Feminino , Hiperalgesia/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Osteossarcoma/patologia , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Resveratrol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo
15.
Eur J Pharmacol ; 859: 172549, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325434

RESUMO

Recent studies have revealed critical roles of transforming growth factor-ß1 (TGF-ß1) and microRNA-132 (miR-132), a downstream mediator of TGF-ß1, in the pathogenesis of cardiac remodeling. In this study, we tested whether the antiaging protein klotho modifies angiotensin II (Ang II)-induced cardiac remodeling through regulating TGF-ß1-miR-132 axis. We found that both klotho and the TGF-ß1 inhibitor LY364947 significantly inhibited cardiac hypertrophy, fibrosis, and dysfunction in Ang II-infused mice, as evidenced by the ratios of heart weight to body weight (HW/BW), heart weight to tibial length (HW/TL), cardiomyocyte cross-sectional area, fibrotic area, and expression of prohypertrophic genes (ANP, ß-MHC) and fibrotic marker genes (α-SMA, collagen I), echocardiographic parameters. Meanwhile, klotho also significantly inhibited Ang II-induced protein expression of TGF-ß1 and phosphorylated Smad2/3 in the heart tissues and cultured cardiomyocytes and cardiac fibroblasts. In vitro experiments demonstrated that Ang II-induced cardiomyocyte hypertrophy and proliferation and activation of cardiac fibroblasts were markedly inhibited by klotho, LY364947 or the miR-132 inhibitor anti-miR-132. Both klotho and the TGF-ß1 inhibitor LY364947 downregulated the miR-132 expression. Additionally, klotho decreased Ang II-induced protein expressions of cardiac fibroblast growth factor (FGF)23 in vivo and in vitro. The decreased protein levels of klotho in serum and renal tissues of Ang II-infused mice were elevated by klotho. Klotho downregulated the protein levels of TGF-ß1 in renal tissues of Ang II-infused mice. In conclusion, our results suggest that klotho prevents Ang II-induced cardiac remodeling and dysfunction through modifying the TGF-ß1-miR-132 axis, providing an experimental basis for clinical treatment on cardiac remodeling.


Assuntos
Angiotensina II/farmacologia , Cardiomegalia/metabolismo , Glucuronidase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Animais , Cardiomegalia/patologia , Regulação para Baixo/efeitos dos fármacos , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Fibrose , Proteínas Klotho , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Remodelação Ventricular/efeitos dos fármacos
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(3): 587-598, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579931

RESUMO

Bone cancer pain (BCP) is the pain induced by primary bone cancer or tumor metastasis. Increasing evidence and our previous studies have shown that mammalian silent information regulator 2 homolog (SIRT1) is involved in periphery sensitization and central sensitization of BCP, and the underlying mechanism of SIRT1 in bone cancer pain may provide clues for pain treatment. Dynamin-related protein 1 (Drp1) is an essential regulator for mitochondrial fission. In this research, BCP model rats were established by injecting MRMT-1 rat mammary gland carcinoma cells into the left tibia of female Sprague-Dawley rats and validated by tibia radiographs, histological examination and mechanical pain test. As a result BCP rats exhibited bone destruction and sensitivity mechanical pain. BCP increased inflammatory cells infiltration and apoptosis, reduced SIRT1 protein expression and phosphorylation, and elevated Drp1 expression in spinal cord. An agonist of SIRT1 named SRT1720 intrathecal treatment in BCP rats increased SIRT1 phosphorylation, reduced the up-regulated Drp1 expression, and reversed pain behavior. SRT1720 also regulated Bcl-2/BAX and cleaved caspase-3 expressions, and inhibited mitochondrial apoptosis in spinal cord of BCP rats. For in vitro research, SRT1720 treatment decreased Drp1 expression in a dose-dependent manner, blocked CCCP-induced mitochondrial membrane potential change, consequently reduced apoptosis and promoted proliferation. These data suggest that SIRT1 activation by SRT1720 attenuated bone cancer pain via preventing Drp1-mediated mitochondrial fission. Our results provide new targets for therapeutics of bone cancer pain.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Dor do Câncer/tratamento farmacológico , Dinaminas/fisiologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/genética , Animais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Dor do Câncer/genética , Dor do Câncer/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Dinaminas/genética , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/metabolismo
17.
Acta Biochim Biophys Sin (Shanghai) ; 50(6): 597-604, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29701752

RESUMO

Although doxorubicin has become a key drug in cancer treatment, the resistance of colorectal carcinoma to doxorubicin is a major problem in clinical practice. F-box and WD repeat domain-containing 7 (FBXW7) plays important roles in human cancers and is one of the major causes of drug resistance. The miR-223/FBXW7 pathway has been reported to be a crucial clue to the mechanism of chemoresistance in many human cancers, such as gastric cancer, breast cancer, and non-small cell lung cancer. However, it is unclear whether similar mechanisms of doxorubicin resistance are involved in colorectal cancer (CRC). The aim of the current study was to evaluate the role of miR-223/FBXW7 pathway in chemosensitivity in different CRC cell lines and to investigate the relevant underlying mechanisms. We found that high levels of FBXW7 expression were associated with increased doxorubicin sensitivity in different CRC cell lines, and FBXW7 was regulated by miR-223. Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of CRC cells to doxorubicin, while suppression of miR-223 had the opposite effect. Moreover, epithelial-mesenchymal transition (EMT) was proved to be regulated by miR-223/FBXW7 pathway and involved in the drug resistance. In conclusion, miR-223/FBXW7 axis regulates doxorubicin sensitivity through EMT in CRC, which may lead to the development of individualized treatment in clinical practice.


Assuntos
Neoplasias Colorretais/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteína 7 com Repetições F-Box-WD/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Antibióticos Antineoplásicos/farmacologia , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Homologia de Sequência do Ácido Nucleico
18.
Acta Biochim Biophys Sin (Shanghai) ; 49(11): 1008-1014, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29036449

RESUMO

Bone cancer pain (BCP) is one of the most common pains in patients with malignant cancers. The mechanism underlying BCP is largely unknown. Our previous studies and the increasing evidence both have shown that acid-sensing ion channels 3 (ASIC3) is an important protein in the pathological pain state in some pain models. We hypothesized that the expression change of ASIC3 might be one of the factors related to BCP. In this study, we established the BCP model through intrathecally injecting rat mammary gland carcinoma cells (MRMT-1) into the left tibia of Sprague-Dawley female rats, and found that the BCP rats showed bone destruction, increased mechanical pain sensitivities and up-regulated ASIC3 protein expression levels in L4-L6 dorsal root ganglion. Then, resveratrol, which was intraperitoneally injected into the BCP rats on post-operative Day 21, dose-dependently increased the paw withdrawal threshold of BCP rats, reversed the pain behavior, and had an antinociceptive effect on BCP rats. In ASIC3-transfected SH-SY5Y cells, the ASIC3 protein expression levels were regulated by resveratrol in a dose- and time-dependent manner. Meanwhile, resveratrol also had an antinociceptive effect in ASIC3-mediated pain rat model. Furthermore, resveratrol also enhanced the phosphorylation of AMPK, SIRT1, and LC3-II levels in ASIC3-transfected SH-SY5Y cells, indicating that resveratrol could activate the AMPK-SIRT1-autophagy signal pathway in ASIC3-transfected SH-SY5Y cells. In BCP rats, SIRT1 and LC3-II were also down-regulated. These findings provide new evidence for the use of resveratrol as a therapeutic treatment during BCP states.


Assuntos
Canais Iônicos Sensíveis a Ácido/análise , Autofagia/efeitos dos fármacos , Neoplasias Ósseas/fisiopatologia , Dor do Câncer/tratamento farmacológico , Estilbenos/farmacologia , Proteínas Quinases Ativadas por AMP/fisiologia , Canais Iônicos Sensíveis a Ácido/fisiologia , Animais , Linhagem Celular Tumoral , Feminino , Ratos , Ratos Sprague-Dawley , Resveratrol , Transdução de Sinais/efeitos dos fármacos
19.
Materials (Basel) ; 10(3)2017 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-28772641

RESUMO

In this paper, a TiC reinforcement metal matrix composite coating is produced using nickel and graphite mixing powder on the surface ofTi-6Al-4V alloy by laser radiation. The microstructure of the coatings is investigated by XRD, SEM and EDS. Results show that most of the TiC phase is granular, with a size of several micrometers, and a few of the TiC phases are petals or flakes. At the cross-section of the coatings, a few special TiC patterns are found and these TiC patterns do not always occur at the observed cross-section. The even distribution of the TiC phase in the coatings confirms that the convection of the laser-melted pool leads to the homogenization of titanium atoms from the molten substrate, and carbon atoms from the preplace powder layer, by the mass transfer. The characteristics of the TiC pattern confirm that the morphology and distribution of the primary TiC phase could be influenced by convection. Two main reasons for this are that the density of the TiC phase is lower than the liquid melt, and that the primary TiC phase precipitates from the pool with a high convection speed at high temperature.

20.
Biochem Biophys Res Commun ; 473(2): 455-61, 2016 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-26970306

RESUMO

Myocardial hypertrophy is an independent risk factor for cardiac morbidity and mortality. The antiaging protein klotho reportedly possesses a protective role in cardiac diseases. However, the precise mechanisms underlying the cardioprotective effects of klotho remain unknown. This study was aimed to determine the effects of klotho on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and the possible mechanism of actions. We found that klotho significantly inhibited Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by decreased [(3)H]-Leucine incorporation, cardiomyocyte surface area and ß-myosin heavy chain (ß-MHC) mRNA expression. Meanwhile, klotho inhibited Ang II-stimulated activation of the Wnt/ß-catenin pathway in cardiomyocytes, as evidenced by decreased protein expression of active ß-catenin, downregulated protein and mRNA expression of the ß-catenin target genes c-myc and cyclin D1, and increased ß-catenin phosphorylation. Inhibition of the Wnt/ß-catenin pathway by the specific inhibitor XAV939 markedly attenuated Ang II-induced cardiomyocyte hypertrophy. The further study revealed that klotho treatment significantly downregulated protein expression of Ang II receptor type I (AT1R) but not type II (AT2R). The AT1R antagonist losartan inhibited Ang II-stimulated activation of the Wnt/ß-catenin pathway and cardiomyocyte hypertrophy. Our findings suggest that klotho inhibits Ang II-induced cardiomyocyte hypertrophy through suppression of the AT1R/ß-catenin signaling pathway, which may provide new insights into the mechanism underlying the protective effects of klotho in heart diseases, and raise the possibility that klotho may act as an endogenous antihypertrophic factor by inhibiting the Ang II signaling pathway.


Assuntos
Angiotensina II/metabolismo , Cardiomegalia/metabolismo , Glucuronidase/metabolismo , Miócitos Cardíacos/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Animais , Cardiomegalia/patologia , Células Cultivadas , Proteínas Klotho , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA