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Nerve growth factor-induced gene B (Nur77) has been shown to ameliorate several biological processes in chronic diseases, including inflammatory response, cellular proliferation, and metabolism. Chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis for which no targeted therapies are available as yet. In this study, we performed in vivo and in vitro experiments to demonstrate that Nur77 targets fibrosis signals and attenuates renal tubulointerstitial fibrosis during the aging process. We observed that the TGF-ß/Smads signal pathway was significantly suppressed by Nur77, suggesting that Nur77 controlled the activation of key steps in TGF-ß/Smads signaling. We further showed that Nur77 interacted with Smad7, the main repressor of nuclear translocation of Smad2/3, and stabilized Smad7 protein homeostasis. Nur77 deficiency resulted in Smad7 degradation, aggravating Smad2/3 phosphorylation, and promoting transcription of its downstream target genes, ACTA2 and collagen I. Our findings demonstrate that Nur77 is a potential therapeutic target for age-related kidney diseases including CKD. Maintenance of Nur77 may be an effective strategy for blocking renal tubulointerstitial fibrosis and improving renal function in the elderly.
Assuntos
Envelhecimento/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Envelhecimento/genética , Animais , Fibrose , Camundongos , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Insuficiência Renal Crônica/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: So far, the diagnosis of acute artery of percheron (AOP) infarction is uncommon. In this study, patients with acute AOP infarction were studied to explore the relationship of imaging findings, clinical manifestations and prognosis of acute AOP infarction. MATERIALS: A total of 23 patients with acute AOP infarction in our institution from 2014 to 2019 were reviewed retrospectively. All cases were evaluated by computed tomography (CT) and magnetic resonance imaging (MRI). The modified Rankin scale (MRS), blood examination, electrocardiogram and transthoracic echocardiography were used for detailed clinical and prognostic evaluation. All standard risk factors for these patients were recorded. The MRS scores were performed 90 days after discharge. RESULTS: Four different types of acute AOP infarction were identified: (a) bilateral paramedian thalamic infarction (BPTI, 52%); (b) bilateral paramedian thalamic with rostral midbrain infarction (BPTRMI, 30%), (c) bilateral paramedian and anterior thalamic infarction (BPATI, 13%), and (d) bilateral paramedian thalamic with red nuclei infarction (BPTRNI, 4%). These patients had consciousness disorder, memory dysfunctions, vertical gaze paresis and mesencephalothalamic syndrome. The 65% of patients with BPTI and BPATI experienced relatively good functional recovery and could carry out daily life activities (MRS score ≤ 2). However, patients with BPTRMI may have an unfavorable outcome. CONCLUSIONS: Although the clinical features are variable, DWI or ADC map can improve the diagnosis of acute AOP infarction patterns. Acute AOP occlusion requires immediate diagnosis and treatment to obtain more favorable outcome and avoid additional unnecessary procedures.
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Infarto Cerebral , Tálamo , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Tálamo/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: In recent decades, considerable attention has been paid to exploring the population genetic characteristics of Han Chinese, mainly documenting a north-south genetic substructure. However, the central Han Chinese have been largely underrepresented in previous studies. AIM: To infer a comprehensive understanding of the homogenisation process and population history of Han Chinese. SUBJECTS AND METHODS: We collected samples from 122 Han Chinese from seven counties of Hubei province in central China and genotyped 534,000 genome-wide SNPs. We compared Hubei Han with both ancient and present-day Eurasian populations using Principal Component Analysis, ADMIXTURE, f statistics, qpWave and qpAdm. RESULTS: We observed Hubei Han Chinese are at a genetically intermediate position on the north-south Han Chinese cline. We have not detected any significant genetic substructure in the studied groups from seven different counties. Hubei Han show significant evidence of genetic admixture deriving about 63% of ancestry from Tai-Kadai or Austronesian-speaking southern indigenous groups and 37% from Tungusic or Mongolic related northern populations. CONCLUSIONS: The formation of Han Chinese has involved extensive admixture with Tai-Kadai or Austronesian-speaking populations in the south and Tungusic or Mongolic speaking populations in the north. The convenient transportation and central location of Hubei make it the key region for the homogenisation of Han Chinese.
Assuntos
Etnicidade/genética , Genótipo , Migração Humana , Polimorfismo de Nucleotídeo Único , China , Humanos , Análise de Componente PrincipalRESUMO
Gastric cancer (GC) is a common cause of cancer-related death worldwide. As a result of the lack of reliable diagnostic or prognostic biomarkers for GC, patient prognosis is still poor. Therefore, there is an urgent need for studies examining the underlying pathogenesis of GC in order to find effective biomarkers. LRRN1 (leucine-rich repeat neuronal protein-1) is a type I transmembrane protein that plays an important role in the process of nerve development and regeneration. However, its role in cancer, especially in GC, remains unclear. In the present study, we found that LRRN1 expression is upregulated in GC tissues and that high LRRN1 expression is associated with poor prognosis. siRNA and shRNA-mediated knockdowns of LRRN1 expression promoted GC cell apoptosis and activation of the Fas/FasL pathway. LRRN1 knockdown also resulted in upregulation of JUN, a subunit of the transcription factor AP-1 (activator protein-1). This suggests that LRRN1 suppresses GC cell apoptosis by downregulating AP-1, resulting in inhibition of the Fas/FasL pathway. These results confirm that LRRN1 plays a significant role in GC pathogenesis. Moreover, LRRN1 may be a potential prognostic biomarker and therapeutic target for GC.
Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Regulação para Cima , Animais , Apoptose , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Proteínas do Tecido Nervoso , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Fator de Transcrição AP-1/metabolismo , Receptor fas/metabolismoRESUMO
A variety of solid tumors are surrounded by a hypoxic microenvironment, which is known to be associated with high metastatic capability and resistance to various clinical therapies, contributing to a poor survival rate for cancer patients. Although the majority of previous studies on tumor-associated hypoxia have focused on acute hypoxia, chronic hypoxia more closely mimics the actual hypoxic microenvironment of a tumor. In this study, two novel hypoxia-resistant gastric cancer (HRGC) cell lines which could grow normally in 2% oxygen were established. The long non-coding RNA UCA1 was upregulated in HRGC cells, which promoted their migration. Bioinformatics analysis and a luciferase reporter assay showed that miR-7-5p could bind to specific sites of UCA1 to regulate the target EGFR through competitive endogenous RNA function. UCA1 directly interacted with miR-7-5p and decreased the binding of miR-7-5p to the EGFR 3'-untranslated region, which suppressed the degradation of EGFR mRNA by miR-7-5p. Therefore, long-term hypoxia induced UCA1 to promote cell migration by enhancing the expression of EGFR. This study thus reveals a new mechanism by which a hypoxic microenvironment promotes tumor metastasis, and highlights UCA1 as a potential biomarker for predicting the metastasis of gastric cancer to guide clinical treatment.
Assuntos
Hipóxia Celular/genética , Movimento Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Regulação para Cima/genética , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , RNA Mensageiro/genética , Ativação Transcricional/genética , Microambiente Tumoral/genéticaRESUMO
Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma and regulators of tumor progression. However, the molecular mechanism by which CAFs promote gastric cancer progression should be further explored. In our study, we found that interleukin-11 (IL-11) secretion was significantly increased when CAFs were co-cultured with gastric cancer cells. Co-culture system-derived IL-11 promoted the migration and invasion of gastric cancer cells, whereas the increase of migration and invasion was attenuated by a neutralizing antibody of IL-11 or inhibition of JAK/STAT3 and MAPK/ERK pathways with specific inhibitors. Taken together, these results revealed that CAFs play a significant role in the gastric cancer progression in the tumor microenvironment through IL-11-STAT3/ERK signaling by upregulating MUC1. Also, IL-11 targeted therapy can achieve an effective treatment against gastric cancer indirectly by exerting their action on stromal fibroblasts.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Interleucina-11/metabolismo , Mucina-1/metabolismo , Metástase Neoplásica/patologia , Neoplasias Gástricas/metabolismo , Regulação para Cima/fisiologia , Animais , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Neoplasias Gástricas/patologia , Ativação Transcricional/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
BACKGROUND: Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells. METHODS: Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells. RESULTS: Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished. CONCLUSIONS: CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.
Assuntos
Antígeno B7-H1/genética , Quimiocinas CXC/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Biologia Computacional/métodos , Humanos , Imuno-Histoquímica , Anotação de Sequência Molecular , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR3/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologiaRESUMO
The ATM and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) pathway plays a pivotal role in DNA damage sensor and modulating homologous recombination. Recently, emerging evidence demonstrated that Chk1 phosphorylation was associated with chemotherapy and radiotherapy resistance. In this study, we explored the effect of ATR/Chk1 pathway on regulating lapatinib sensitivity in human epidermal growth factor receptor-2 (HER2)-positive gastric cancer cell lines. We selected two HER2-positive gastric cancer cell lines, and NCI-N87 cells exhibited higher sensitivity than MKN7 cells. Application of lapatinib inhibited phosphorylated HER2 and EGFR and the formation of epidermal growth factor receptor (EGFR)/HER2 complex in both cells. In NCI-N87 cells, lapatinib induced G1 arrest and reduced Chk1 phosphorylation through inhibiting the expression of DNA topoisomerase 2-binding protein 1 (TopBP1). While in MKN7 cells, no significant cell cycle transition was found and phosphorylated Chk1 was mildly upregulated. Inhibition of Chk1 phosphorylation enhanced the lapatinib sensitivity of MKN7 cells, which was shown by potentiated anti-proliferative effect, G1 arrest, downregulation of phosphorylated AKT and ERK along with aggravated DNA damage. In addition, increased Chk1 phosphorylation in NCI-N87 cells attenuated lapatinib-induced anti-proliferative effect and G1 arrest, and abrogated reduced phosphorylated AKT and ERK. Taken together, our study provides a novel mechanism for regulating lapatinib sensitivity in HER2 positive gastric cancer cells, suggesting a new strategy in clinical treatment.
Assuntos
Antineoplásicos/farmacologia , Quinase 1 do Ponto de Checagem/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Lapatinib , FosforilaçãoRESUMO
Dysregulation of histone acetylation plays an important role in tumor development. Histone acetylation regulates gene transcription and expression, which is reversibly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). As an HDAC inhibitor, 4-phenylbutyric acid (4-PBA) can increase histone acetylation levels by inhibiting HDAC activity. While 4-PBA inhibits proliferation of tumor cells in vitro, clinical trials have failed to show benefits of 4-PBA for refractory solid tumors. Here, we found that 4-PBA could enhance the migration capacity of gastric cancer cells. Upregulation of HER3/HER4 and activation of HER3/HER4-ERK pathway was shown to be involved in 4-PBA-induced gastric cancer cell migration. Knockdown of HER3/HER4 blocked HER3/HER4-ERK activation and partially prevented 4-PBA-induced cell migration. Consistently, the ERK inhibitor PD98059 also partially prevented 4-PBA-induced cell migration. Moreover, enhanced levels of acetyl-histones were detected following 4-PBA-treatment, and histone3 acetylation in promoter regions of HER3 and HER4 were confirmed by ChIP. These results demonstrate that 4-PBA promotes gastric cancer cells migration through upregulation of HER3/HER4 subsequent to increased levels of acetyl-histone and activation of ERK signaling. These novel findings provide important considerations for the use of 4-PBA in cancer therapeutics.
Assuntos
Movimento Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Fenilbutiratos/farmacologia , Receptor ErbB-3/metabolismo , Receptor ErbB-4/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Acetilação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Regiões Promotoras Genéticas , Receptor ErbB-3/genética , Receptor ErbB-4/genética , Neoplasias Gástricas/enzimologia , Ativação Transcricional , Regulação para Cima/efeitos dos fármacosRESUMO
In this study, we report a novel mcr-1 gene variant, named mcr-1.6, carried by an IncP plasmid in a colistin-resistant Salmonella enterica serovar Typhimurium isolate from a healthy person. Compared with mcr-1, the mcr-1.6 gene contains two single-nucleotide polymorphisms, one of which results in an arginine to histidine variation (Arg536âHis). The plasmid carrying the mcr-1.6 gene was designated pMCR1.6_P053 and is similar to a recently discovered mcr-1-bearing plasmid found in Klebsiella pneumoniae.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Etanolaminofosfotransferase/genética , Plasmídeos/genética , Salmonella typhimurium/genética , Substituição de Aminoácidos/genética , Sequência de Bases , Conjugação Genética/genética , DNA Bacteriano/genética , Feminino , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Proteínas de Membrana/genética , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Polimorfismo de Nucleotídeo Único/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/isolamento & purificação , Análise de Sequência de DNARESUMO
In order to meet the requirements of uniform illumination for optical palm/fingerprint instruments and overcome the shortcomings of the poor uniform illumination on the working plane of the optical palm/fingerprint prism, a novel secondary optical lens with a free-form surface, compact structure, and high uniformity is presented in this paper. The design of the secondary optical lens is based on emission properties of the near-infrared light-emitting diode (LED) and basic principles of non-imaging optics, especially considering the impact of the thickness of the prism in the design. Through the numerical solution of Snell's law in geometric optics, we obtain the profile of the free-form surface of the lens. Using the optical software TracePro, we trace and simulate the illumination system. The results show that the uniformity is 89.8% on the working plane of the prism, and the test results show that the actual uniformity reaches 85.7% in the experiment, which provides an effective way for realizing a highly uniform illumination system with high-power near-infrared LED.
RESUMO
An accelerated aging test is the main method in evaluation of the reliability of light-emitting diodes (LEDs), and the first goal of this study is to investigate how the junction temperature (Tj) of the LED varies during accelerated aging. The Tj measured by the forward voltage method shows an upward trend over the aging time, which gives a variation about 6°C-8°C after 3,000 h of aging under an ambient temperature of 80°C. The second goal is to investigate how the variation of Tj affects the lifetime estimation. It is verified that at a certain aging stage, as Tj increases, the normalized luminous flux linearly decreases with variation rate of microns (µ) (1/°C). Then, we propose a method to modify the luminous flux degradation with the Tj and µ to meet the requirements of a constant degradation rate in the data fitting. The experimental results show that with the proposed method, the accelerated lifetimes of samples are bigger than that of the current method with increment values from 8.8% to 21.4% in this research.
RESUMO
The accelerated aging tests under electric stress for one type of LED lamp are conducted, and the differences between online and offline tests of the degradation of luminous flux are studied in this paper. The transformation of the two test modes is achieved with an adjustable AC voltage stabilized power source. Experimental results show that the exponential fitting of the luminous flux degradation in online tests possesses a higher fitting degree for most lamps, and the degradation rate of the luminous flux by online tests is always lower than that by offline tests. Bayes estimation and Weibull distribution are used to calculate the failure probabilities under the accelerated voltages, and then the reliability of the lamps under rated voltage of 220 V is estimated by use of the inverse power law model. Results show that the relative error of the lifetime estimation by offline tests increases as the failure probability decreases, and it cannot be neglected when the failure probability is less than 1%. The relative errors of lifetime estimation are 7.9%, 5.8%, 4.2%, and 3.5%, at the failure probabilities of 0.1%, 1%, 5%, and 10%, respectively.
RESUMO
To observe the solar corona, stray light in the coronagraph, arising primarily from an external occulter and diaphragm illuminated directly by the Sun, should be strongly suppressed. A toothed occulter and diaphragm can be used to suppress stray light because they diffract much less light in the central area than a circular disk. This study develops a method of computing the light diffracted by a toothed occulter and diaphragm, obtaining the optimum shape using this method. To prove the method's feasibility, the diffracted fields of circular and rectangular disks are computed and compared with those calculated by a conventional method.
RESUMO
Sirt1 is an NAD+ -dependent deacetylase that protects against premature aging and cell senescence. Aging accompanied by oxidative stress leads to a decrease in Sirt1 levels and activity, but the regulatory mechanism that connects these events remains unclear. Here, we reported that Nur77, which shares similar biological pathways with Sirt1, was also decreased with age in multiple organs. Our in vivo and in vitro results revealed that Nur77 and Sirt1 decreased during aging and oxidative stress-induced cell senescence. Deletion of Nr4a1 shortened the lifespan and accelerated the aging process in multiple mouse tissues. Overexpression of Nr4a1 protected the Sirt1 protein from proteasomal degradation through negative transcriptional regulation of the E3 ligase MDM2. Our results showed that Nur77 deficiency markedly aggravated aging-related nephropathy and elucidated a key role for Nur77 in the stabilization of Sirt1 homeostasis during renal aging. We proposed a model wherein a reduction of Nur77 in response to oxidative stress promotes Sirt1 protein degradation through MDM2, which triggers cell senescence. This creates additional oxidative stress and provides positive feedback for premature aging by further decreasing Nur77 expression. Our findings reveal the mechanism by which oxidative stress reduces Sirt1 expression during aging and offers an attractive therapeutic strategy for targeting aging and homeostasis in organisms.
Assuntos
Senilidade Prematura , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Sirtuína 1 , Animais , Camundongos , Envelhecimento/metabolismo , Senescência Celular/fisiologia , Homeostase , Estresse Oxidativo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismoRESUMO
Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression for further interaction with CtIP for DDR, which promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that de-ubiquitination of SAMHD1 by USP7 promotes DDR to overcome oncogenic stress and affect chemotherapy sensitivity.
Assuntos
Dano ao DNA , Reparo do DNA , Humanos , Peptidase 7 Específica de Ubiquitina/genética , Proteína 1 com Domínio SAM e Domínio HD/genética , UbiquitinaçãoRESUMO
Curcumin (Cur) plays a key role in photodynamic antibacterial activity as a photosensitizer. On the other hand, the antimicrobial potential of graphene oxide (GO) has been reported controversially, and how to improve its antimicrobial ability has become an meaningful study. In this study, we prepared polydopamine-curcumin (PDA-Cur) by pi-pi stacking and loaded it onto the GO surface to obtain GO/PDA-Cur composite nanomaterials. GO/PDA-Cur was characterized by physical and optical means, and GO/PDA-Cur possessed good dispersion and stability in water. In vitro antibacterial results showed that GO/PDA-Cur mediated photodynamic therapy significantly reduced Gram-positive Staphylococcus aureus (S. aureus) by 4 orders of magnitude with a bactericidal rate of 99.99 %. The antibacterial mechanism stems from the fact that GO/PDA-Cur can generate reactive oxygen species (ROS) under white light irradiation (405-780 nm), which causes bacterial outer membrane breakage and cellular deformation. In addition, GO/PDA-Cur has good biocompatibility. The antibacterial ability of graphene oxide was significantly improved by combining it with PDA-Cur, which allows it to be used as a photodynamic antibacterial material.
Assuntos
Curcumina , Nanoestruturas , Antibacterianos/farmacologia , Curcumina/farmacologia , Grafite , Indóis , Polímeros , Staphylococcus aureusRESUMO
AIMS: Radiofrequency ablation (RFA) is the first-line option for early-stage hepatocellular carcinoma (HCC). However, the residual tumor attributed to insufficient RFA (iRFA) led to tumor recurrence and metastasis. Novel combination strategies are urgently needed to enhance efficiency of RFA. MAIN METHODS: For in vitro iRFA models, HCC cells were placed in a water bath at 46 °C for 10 min and then returned to the original incubator. For in vivo models, HCC cells were implanted subcutaneously into nude mice. The nude mice were then randomly assigned into 4 groups: control group, XL888 group, iRFA group, combination of XL888 and iRFA group. CCK8 was performed to detect cell viability; Hoechst 33258 was used to explore nuclear morphology; The expression levels of proteins were demonstrated by western blotting; Co-localization of HSP90 and STAT3 was elucidated by immunofluorescence confocal microscopy; Immunohistochemistry was used to explore expression levels of proteins at tissue level. KEY FINDINGS: XL888 promoted apoptosis of HCC cells induced by heat via inhibiting expression levels of Mcl-1 and cleaved-caspase 3 in vivo and in vitro. XL888 attenuated the complex formation of HSP90 and STAT3, leading to decreased expression levels of STAT3 and p-STAT3. In human HCC tissues, IHC scores of HSP90 were positively correlated with those of STAT3. Overexpression of STAT3 rescued cell apoptosis induced by co-treatment of XL888 and heat. SIGNIFICANCE: We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.
Assuntos
Apoptose/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Ácidos Ftálicos/farmacologia , Fator de Transcrição STAT3/genética , Animais , Compostos Azabicíclicos/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Camundongos Endogâmicos BALB C , Camundongos Nus , Ácidos Ftálicos/uso terapêutico , Ablação por RadiofrequênciaRESUMO
BACKGROUND: Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear. METHODS: We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy. RESULTS: Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM. CONCLUSIONS: Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.
Assuntos
Autofagia , Fibronectinas/metabolismo , Hipóxia/fisiopatologia , Integrina alfa5/metabolismo , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Movimento Celular , Proliferação de Células , Epitélio/metabolismo , Epitélio/patologia , Feminino , Fibronectinas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Integrina alfa5/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Breast cancer is the most lethal malignancy in women. N-acetylgalactosaminyltransferase 6 (GALNT6) is an enzyme which mediates the initial step of mucin-type O-glycosylation, and has been reported to be involved in mammary carcinogenesis. However, the molecular mechanism of GALNT6 in breast cancer metastasis has not been fully explored. In this study, based on online database analyses and tissue microarrays, the overall survival (OS) of breast cancer patients with high expression of GALNT6 was found to be shorter than those with low expression of GALNT6. Also, high GALNT6 expression was positively correlated with advanced pN stage and pTNM stage. GALNT6 was shown to be able to promote the migration and invasion of breast cancer cells, and enhance the level of mucin-type O-glycosylation of substrates in the supernatants of breast cancer cells. Qualitative mucin-type glycosylomics analysis identified α2M as a novel substrate of GALNT6. Further investigation showed that GALNT6 increased O-glycosylation of α2M, and the following activation of the downstream PI3K/Akt signaling pathway was involved in the promotion of migration and invasion of breast cancer cells. This study identified a new substrate of GALNT6 and provides novel understanding of the role of GALNT6 in promoting metastasis and poor prognosis in breast cancer.