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Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.
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Antígeno B7-H1 , Fibrose Pulmonar Idiopática , Animais , Humanos , Regulação para Cima , Vimentina/genética , Vimentina/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Pulmão , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Transição Epitelial-Mesenquimal , BleomicinaRESUMO
PURPOSE: High explosives are used to produce blast waves to study their biological effects. The lungs are considered as the critical target organ in blast-effect studies. The degree of lung hemorrhaging is related to both the explosive power and the increased lung weight. We studied the characteristics of the biological effects from an air explosion of a thermobaric bomb in a high-altitude environment and the lethality and lung injury severity of goats in different orientations and distances. METHODS: Goats were placed at 2.5, 3, 4, and 5 m from the explosion center and exposed them to an air blast at an altitude of 4700-meter. A group of them standing oriented to the right side and the other group seated facing the explosion center vertically. The lung injuries were quantified according to the percentage of surface area contused, and using the pathologic severity scale of lung blast injury (PSSLBI) to score the 4 injury categories (slight, moderate, serious and severe) as 1, 2, 3, and 4, respectively. The lung coefficient (lung weight [g]/body weight [kg]) was the indicator of pulmonary edema and was related to lung injury severity. Blast overpressure data were collected using blast test devices placed at matching locations to represent loadings to goats. All statistical analyses were performed using SPSS, version 26.0, statistical software (SPSS, Inc., Chicago, IL, USA). RESULTS: In total, 127 goats were involved in this study. Right-side-standing goats had a significantly higher mortality rate than those seated vertical-facing (p < 0.05). At the 2.5 m distance, the goat mortality was nearly 100%, whereas at 5 m, all the goats survived. Lung injuries of the right-side-standing goats were 1 - 2 grades more serious than those of seated goats at the same distances, the scores of PSSLBI were significantly higher than the seated vertical-facing goats (p < 0.05). The lung coefficient of the right-side-standing goats were significantly higher than those of seated vertical-facing (p < 0.05). Mortality, PSSLBI, and the lung coefficient results indicated that the right-side-standing goats experienced severer injuries than the seated vertical-facing goats, and the injuries were lessened as the distance increased. The blast overpressure was consistent with these results. CONCLUSION: The main killing factors of the thermobaric bomb in the high-altitude environment were blast overpressure, blast wind propulsions and burn. The orientation and distances of the goats significantly affected the blast injury severity. These results may provide a research basis for diagnosing, treating and protecting against injuries from thermobaric explosions.
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Traumatismos por Explosões , Lesão Pulmonar , Animais , Lesão Pulmonar/etiologia , Cabras , Explosões , Pulmão/patologiaRESUMO
BACKGROUND: Cotton fiber is a single cell that arises from the epidermis of ovule. It is not only a main economic product of cotton, but an ideal material for studying on the growth and development of plant cell. Our previous study indicated that phytosterol content and the ratio of campesterol to sitosterol fluctuated regularly in cotton fiber development. However, what effects of modified phytosterol content and composition on the growth and development of cotton fiber cell is unknown. In this study, we overexpressed the GhSMT2-1, a cotton homologue of sterol C-24 methyltransferase 2 gene in transgenic upland cotton plants to modify phytosterol content and composition in fiber cells and investigated the changes on fiber elongation and secondary cell wall deposition. RESULTS: GhSMT2-1 overexpression led to changes of phytosterol content and the ratio of campesterol to sitosterol in fiber cell. At the rapid elongation stage of fiber cell, total phytosterol and sitosterol contents were increased while campesterol content was decreased in transgenic fibers when compared to control fibers. Accordingly, the ratio of campesterol to sitosterol declined strikingly. Simultaneously, the transgenic fibers were shorter and thicker than control fibers. Exogenous application of sitosterol or campesterol separately inhibited control fiber cell elongation in cotton ovule culture system in vitro. In addition, campesterol treatment partially rescued transgenic fiber elongation. CONCLUSION: These results elucidated that modification of phytosterol content and composition influenced fiber cell elongation and secondary cell wall formation. High sitosterol or low ratio of campesterol to sitosterol suppresses fiber elongation and/or promote secondary cell wall deposition. The roles of sitosterol and campesterol were discussed in fiber cell development. There might be a specific ratio of campesterol to sitosterol in different developmental stage of cotton fibers, in which GhSMT2-1 play an important role. Our study, at a certain degree, provides novel insights into the regulatory mechanisms of fiber cell development.
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Gossypium/química , Gossypium/fisiologia , Fitosteróis/química , Proteínas Arqueais/genética , Proteínas Arqueais/metabolismo , Crescimento Celular , Parede Celular , Fibra de Algodão , Gossypium/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/química , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/fisiologiaRESUMO
There are two main types of fluid in bone tissue: blood and interstitial fluid. The metabolism of cells mainly relies on the microenvironment of the interstitial fluid. Researches of osteonal fluid seepage behavior based on the microstructure of bone tissue have become a hot point. The aim of the present research work is to assess the effect of blood pressure oscillation on the osteonal interstitial fluid seepage behavior. We established finite element osteon models for a hollow and that considering blood pressure oscillation, respectively, with COMSOL Multiphysics software in order to compare their fluid flow behavior under the axial loading. The results predicted that the interstitial fluid pressure field was enlarged considering the blood pressure oscillation, while the velocity filed changed little. Specifically, the increase of blood pressure oscillatory amplitude could result in the increase of osteonal interstitial fluid pressure, while the blood pressure oscillatory frequency had limited effects on the osteonal pore fluid pressure. Moreover, the blood pressure oscillatory amplitude and frequency had no effect on the osteonal interstitial fluid velocity. The finite element model can be used for the study of the poroelastic behaviors of the osteon under non-axisymmetric loads and microcracks, and can also be a new way to study the mechanism of bone mechanotransduction and electromechanotransduction.
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Acute lung injury (ALI) has high mortality and still lacks novel and efficient therapies. Zinc finger E-box binding homeobox 1 and 2 (ZEB1/2) are highly expressed in the early stage of ALI and are positively correlated with the progression of pulmonary fibrosis. Herein, we developed a nanoscale Zr(IV)-based porphyrin metal-organic (ZPM) framework to deliver small interfering ZEB1/2 (siZEB1/2) to alleviate early pulmonary fibrosis during ALI. This pH-responsive nano-ZPM system could effectively protect siRNAs during lung delivery until after internalization and rapidly trigger siRNA release under the mildly acidic environment of the endo/lysosome (pH 4.0-6.5) for transfection and gene silencing. Furthermore, the in vivo studies confirmed that this nano-ZPM system could anchor in inflamed lungs. Moreover, the ZEB1/2 silencing led to increased E-cadherin and decreased α-SMA levels. Overall, the nano-ZPM system was an excellent non-viral vector system to deliver siRNAs to alleviate early pulmonary fibrosis during ALI.
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Background: Pulmonary fibrosis is difficult to treat. Early diagnosis and finding potential drug therapy targets of pulmonary fibrosis are particularly important. There were still various problems with existing pulmonary fibrosis markers, so it is particularly important to find new biomarkers and drug treatment targets. m6A (N6,2'-O-dimethyladenosine) RNA methylation was the cause of many diseases, and it is regulated by m6A methylation regulators. So, whether RNA methylation regulators can be a diagnostic marker and potential drug therapy target of early pulmonary fibrosis needs to be explored. Materials and Methods: Using GSE110147 and GSE33566 in the GEO database to predict the m6A methylation regulators that may be related to the development of pulmonary fibrosis, we used 10 mg/ml bleomycin to induce mouse pulmonary fibrosis models and human pulmonary fibrosis samples, to confirm whether this indicator can be an early diagnostic marker of pulmonary fibrosis. Results: According to the database prediction results, METTL3 can predict the occurrence and development of pulmonary fibrosis, and the results of MASSON and HE staining show that the fibrosis model of mice is successful, and the fibrosis of human samples is obvious. The results of immunohistochemistry showed that the expression of METTL3 was significantly reduced in pulmonary fibrosis. Conclusions: The m6A methylation regulator METTL3 can be considered as an important biomarker for diagnosing pulmonary fibrosis occurrence, furthermore it could be considered as a drug target because of its low expression in pulmonary fibrosis.
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BACKGROUND: Spinal cord injury (SCI) is a challenge worldwide, but there are no effective treatments or therapeutic methods in the clinic. Recent studies have shown that type I arginase (Arginase1, Arg1) is closely associated with the treatment of SCI. The classical treatment for SCI involves filling the local area of SCI with activated M2a macrophages to allow the repair and regeneration of some synapses, but the specific mechanism of action of Arg1 is not clear. METHOD: In the present study, we first induced the polarization of RAW264.7 macrophages to M2a-type cells using IL-4 and constructed an Arg1 knockout cell line through the use of shRNA; we used these cells to treat a rat model of SCI. Finally, the present study explored the mechanism and pathway by which Arginase 1 regulates spinal repair by immunoblotting and immunohistochemistry. RESULT: Suspended M2a (Arg1-/+) macrophages were transplanted into the injury site in a rat model of contusion SCI. Compared with the model group and the shArg1 group, the shScramble (shSc) group exhibited higher Basso, Beattie, Bresnahan motor function scores, more compact structures and more Nissl bodies. Immunohistochemical results showed that the shSc group expressed higher levels of NeuN (a neuronal marker) and tau (an axonal marker), as well as the up-regulation of Cdc42, N-WASP, Arp2/3 and tau, as determined by Western blot. CONCLUSION: The study found that the polarization of M2a macrophages promoted the expression of Arginase 1, which restored axonal regeneration, promoted axonal regeneration, and promoted the structural and functional recovery of the contused spinal cord.
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Arginase/metabolismo , Axônios/patologia , Ativação de Macrófagos , Macrófagos/transplante , Regeneração Nervosa , Traumatismos da Medula Espinal/terapia , Medula Espinal/fisiopatologia , Proteína 2 Relacionada a Actina/metabolismo , Animais , Arginase/genética , Axônios/metabolismo , Modelos Animais de Doenças , Feminino , Interleucina-4/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Camundongos , Atividade Motora , Células RAW 264.7 , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Proteína Neuronal da Síndrome de Wiskott-Aldrich/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas tau/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic disease with a high rate of infection and mortality; however, its etiology and pathogenesis remain unclear. Studies have revealed that epithelial-mesenchymal transition (EMT) is a crucial cellular event in IPF. Here, we identified that the pulmonary fibrosis inducer bleomycin simultaneously increased the expression of bFGF and TGF-ß1 and inhibited epithelial-specific regulatory protein (ESRP1) expression in vivo and in vitro. In addition, in vitro experiments showed that bFGF and TGF-ß1 down-regulated the expression of ESRP1 and that silencing ESRP1 promoted EMT in A549 cells. Notably, we determined that bFGF activates PI3K/Akt signaling, and treatment with the PI3K/Akt inhibitor LY294002 inhibited bleomycin-induced cell morphology changes and EMT. In addition, the effects of LY294002 on bleomycin-induced EMT were inhibited by ESRP1 silencing in A549 cells. Taken together, these findings suggest that bleomycin induced EMT through down-regulating ESRP1 by simultaneously increasing bFGF and TGF-ß1 in pulmonary fibrosis. Additionally, our findings indicated that bFGF inhibits ESRP1 by activating PI3K/Akt signaling.
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Bleomicina , Transição Epitelial-Mesenquimal , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/enzimologia , Pulmão/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células A549 , Animais , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
In this paper, a superparamagnetic Fe3O4 core encapsulated into a metal-organic framework shell, Fe3O4@MIL-100(Fe), was successfully synthesized taking advantage of layer-to-layer method. The thickness of the shell can be controlled by self-assembly cycles between FeCl3·6H2O and 1,3,5-benzenetricarboxylic acid (H3BTC). The composites were characterized by Powder X-ray diffracrion (XRD), transmission electron microscopy (TEM), fourier transform infrared spectroscopy (FTIR) and N2 adsorption/desorption isotherms. Then, the synthesized material was firstly used to fabricate a novel electrochemical sensor for chlorogenic acid (CGA). Under the optimal conditions, this electrochemical sensor can detect CGA quantitatively in the range of 0.1-10.0⯵molâ¯L-1 and 10.0-460⯵molâ¯L-1. The limit of detection (LOD) can be as low as 0.05 µmolâ¯L-1. Considering there are little common interfering materials, this novel chlorogenic acid sensor was further applied in real samples to detect the content of CGA.
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BACKGROUND: The D2 dopamine receptor (DRD2) has been extensively investigated and has been associated with the occurrence of neuropsychiatric disorders. Polymorphisms in the DRD2 gene have also been determined as a possible predisposing component for major depressive disorders (MDD). The present study focused on evaluating the connection of polymorphisms inside the whole DRD2 gene in MDD patients as well as in non-MDD participants in a group selected from the Chinese Han population. MATERIALS AND METHODS: In total, 831 unrelated Chinese adults from the Han population were sampled, including 497 non-MDD participants and 334 MDD patients for this evaluation. After the haplotype bins were built, 14 tag single-nucleotide polymorphisms (tSNPs) and the two most investigated SNP were chosen for the whole DRD2 gene. An improved multiplex ligation detection reaction (iMLDR) technique was used to choose the genotypes. Following this, the allelic frequencies and clinical features were contrasted between the two independent Chinese Han populations. Transcriptional enhancer activities were measured to assess the functionality of the rs7131056 polymorphism. RESULTS: Sixteen SNPs were identified, including the two most examined in the Chinese Han population, and all were recurrent SNPs. Of the 16 SNPs, two (rs4648317 and rs7131056) were significantly connected to MDD. Patients with MDD were more apt to carry the rs4648317G and rs7131056A allele in contrast to the non-MDD controls (P < 0.05). The genetic risk effect on MDD occurrence was associated with the haplotype GTGATCGCGCAGGC of fourteen tag SNPs (OR = 1.52, 95% CI: 1.06 to 2.18, P = 0.02). Moreover, the rs7131056 polymorphism contained intronic silencer activities. CONCLUSIONS: This case-control evaluation involving the Chinese Han population suggests that the rs4648317 and rs7131056 polymorphisms and the haplotype GTGATCGCGCAGGC inside the DRD2 gene could be possible markers to forecast vulnerability to MDD.
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PHD finger protein 19 (PHF19), a critical component of the polycomb repressive complex 2 (PRC2), is crucial for maintaining the repressive transcriptional activity of several developmental regulatory genes and plays essential roles in various biological processes. Abnormal expression of PHF19 causes dysplasia or serious diseases, including chronic myeloid disorders and tumors. However, the biological functions and molecular mechanisms of PHF19 in glioblastoma (GBM) remain unclear. Here, we demonstrated that PHF19 expression was positively associated with GBM progression, including cell proliferation, migration, invasion, chemosensitivity, and tumorigenesis. Using XAV-939, a Wnt/ß-catenin inhibitor, we found that the effects of PHF19 on GBM cells were ß-catenin-dependent. We also demonstrated that PHF19 expression was positively correlated with cytoplasmic ß-catenin expression. PHF19 stabilized ß-catenin by inhibiting the transcription of seven in absentia homolog 1 (SIAH1), an E3 ubiquitin ligase of ß-catenin, through direct binding to the SIAH1 promoter region. Taken together, our results revealed the novel PHF19-SIAH1-ß-catenin axis as a potential and promising therapeutic target.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias Encefálicas/genética , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Proteínas Nucleares/genética , Ubiquitina-Proteína Ligases/genética , beta Catenina/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/patologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Nucleares/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismoRESUMO
It is generally known that glioblastoma is the most common primary malignant brain tumor and that it is highly aggressive and deadly. Although surgical and pharmacological therapies have made longterm progress, glioblastoma remains extremely lethal and has an uncommonly low survival rate. Therefore, further elucidation of the molecular mechanisms of glioblastoma initiation and its pathological processes are urgent. Arsenic resistance protein 2 (Ars2) is a highly conserved gene, and it has been found to play an important role in microRNA biosynthesis and cell proliferation in recent years. Furthermore, absence of Ars2 results in developmental death in Drosophila, zebrafish and mice. However, there are few studies on the role of Ars2 in regulating tumor development, and the mechanism of its action is mostly unknown. In the present study, we revealed that Ars2 is involved in glioblastoma proliferation and we identified a potential mechanistic role for it in cell cycle control. Our data demonstrated that Ars2 knockdown significantly repressed the proliferation and tumorigenesis abilities of glioblastoma cells in vitro and in vivo. Further investigation clarified that Ars2 deficiency inhibited the activation of the MAPK/ERK pathway, leading to cell cycle arrest in the G1 phase, resulting in suppression of cell proliferation. These findings support the conclusion that Ars2 is a key regulator of glioblastoma progression.
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Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Nucleares/metabolismo , Animais , Neoplasias Encefálicas/dietoterapia , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Nucleares/genética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-ß/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.
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Processamento Alternativo/efeitos dos fármacos , Fibrose Pulmonar Idiopática/genética , Proteínas de Ligação a RNA/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Animais , Bleomicina/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Camundongos Transgênicos , Isoformas de Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45α (GADD45α) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45α prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and apoptosis. More importantly, our data show that the overexpression of GADD45α significantly enhances the radiosensitivity of radioresistant cervical cancer cells. These data show that GADD45α decreases the cytoplasmic distribution of APE1, thereby enhancing the radiosensitivity of cervical cancer cells. Furthermore, we show that GADD45α inhibits the production of nitric oxide (NO), a nuclear APE1 export stimulator, by suppressing both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) in cervical cancer cells. In conclusion, our findings suggest that decreased GADD45α expression significantly contributes to the development of radioresistance and that ectopic expression of GADD45α sensitizes cervical cancer cells to radiotherapy. GADD45α inhibits the NO-regulated cytoplasmic localization of APE1 through inhibiting eNOS and iNOS, thereby enhancing the radiosensitivity of cervical cancer cells.
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Proteínas de Ciclo Celular/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Tolerância a Radiação , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia , Animais , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Radioterapia , Neoplasias do Colo do Útero/patologiaRESUMO
Inflammatory response following spinal cord injury (SCI) is important in regulation of the repair process. Olfactory ensheathing cells (OECs) and Schwann cells (SCs) are important donor cells for repairing SCI in different animal models. However, synergistic or complementary effects of co-transplantation of both cells for this purpose have not been extensively investigated. In the present study, we investigated the effects of co-transplantation of OECs and SCs on expression of pro- or anti-inflammatory factor and polarization of macrophages in the injured spinal cord of rats. Mixed cell suspensions containing OECs and SCs were transplanted into the injured site at 7 days after contusion at the vertebral T10 level. Compared with the DMEM, SC, or OEC group, the co-transplantation group had a more extensive distribution of the grafted cells and significantly reduced number of astrocytes, microglia/macrophage infiltration, and expression of chemokines (CCL2 and CCL3) at the injured site. The co-transplantation group also significantly increased arginase+/CD206+ macrophages (IL-4) and decreased iNOS+/CD16/32+ macrophages (IFN-γ), which was followed by higher IL-10 and IL-13 and lower IL-6 and TNF-α in their expression levels, a smaller cystic cavity area, and improved motor functions. These results indicate that OEC and SC co-transplantation could promote the shift of the macrophage phenotype from M(IFN-γ) to M(IL-4), reduce inflammatory cell infiltration in the injured site, and regulate inflammatory factors and chemokine expression, which provide a better immune environment for SCI repair.
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Microambiente Celular/fisiologia , Bulbo Olfatório/fisiologia , Bulbo Olfatório/transplante , Células de Schwann/fisiologia , Células de Schwann/transplante , Traumatismos da Medula Espinal/terapia , Animais , Feminino , Inflamação/patologia , Inflamação/terapia , Regeneração Nervosa/fisiologia , Bulbo Olfatório/citologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Sepsis is one of the most common diseases that seriously threaten human health. Although a large number of markers related to sepsis have been reported in the last two decades, the diagnostic accuracy of these biomarkers remains unclear due to the lack of similar baselines among studies. Therefore, we conducted a large systematic review and meta-analysis to evaluate the diagnostic value of biomarkers from studies that included non-infectious systemic inflammatory response syndrome patients as a control group. METHODS: We searched Medline, Embase and the reference lists of identified studies beginning in April 2014. The last retrieval was updated in September 2016. RESULTS: Ultimately, 86 articles fulfilled the inclusion criteria. Sixty biomarkers and 10,438 subjects entered the final analysis. The areas under the receiver operating characteristic curves for the 7 most common biomarkers, including procalcitonin, C-reactive protein, interleukin 6, soluble triggering receptor expressed on myeloid cells-1, presepsin, lipopolysaccharide binding protein and CD64, were 0.85, 0.77, 0.79, 0.85, 0.88, 0.71 and 0.96, respectively. The remaining 53 biomarkers exhibited obvious variances in diagnostic value and methodological quality. CONCLUSIONS: Although some biomarkers displayed moderate or above moderate diagnostic value for sepsis, the limitations of the methodological quality and sample size may weaken these findings. Currently, we still lack an ideal biomarker to aid in the diagnosis of sepsis. In the future, biomarkers with better diagnostic value as well as a combined diagnosis using multiple biomarkers are expected to solve the challenge of the diagnosis of sepsis.
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The epithelial-to-mesenchymal transition (EMT) is a crucial cellular event in wound healing, tissue repair, and cancer progression in adult tissues, with the interactions with numerous signals. In this study, we aimed to determine whether bleomycin (BLM), an agent that causes pulmonary fibrosis, induces the EMT of the alveolar epithelial cell line A549 and investigated the possible mechanisms. We examined the EMT involved changes in cell morphology, isoform switching of the fibroblast growth factor receptor 2 (FGFR2) by alternative splicing, and expression of the phenotypic markers including E-cadherin, vimentin, and α-SMA using RT-PCR, Western blotting, and immunofluorescence assays. A TGF-ß/Smad inhibitor was used to determine whether coculture with BLM would inhibit the EMT of A549 cells. The results showed that BLM induced the EMT of A549 cells possibly via the TGF-ß/Smad signaling pathway, evident from the decrease in the expression of E-cadherin and increase in the expression on vimentin.
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The development of high-energy weapons could increase the velocity of projectiles to well over 1000 m/s. The nature of the injuries caused by the ballistic impact of projectiles at velocities much faster than 1000 m/s is unclear. This study characterizes the mechanical and biochemical alterations caused by high-speed ballistic impact generated by spherical steel ball to the hind limbs of the pig. That the local and distal injuries caused by hypervelocity ballistic impact to the living body are also identified. It is showed that the severity of the injury was positively correlated with the velocity of the projectile. And 4000 m/s seems to be the critical velocity for the 5.6 mm spherical steel ball, which would cause severe damage to either local or distal organs, as below that speed the projectile penetrated the body while above that speed it caused severe damage to the body. In addition, vaporization prevented the projectile from penetrating the body and the consequent pressure wave seems to be the causal factor for the distant damage.
RESUMO
BACKGROUND: Gene variations related to the dopaminergic pathway have been implicated in a number of neuropsychiatric disorders, including post-traumatic stress disorder (PTSD). Dopamine D2 receptor (DRD2) has been shown to significantly contribute to neuropsychiatric disorders and may specifically contribute to predisposition to PTSD. This study aimed to evaluate the association of polymorphisms within the entire DRD2 gene with PTSD in a case-control study. MATERIALS AND METHODS: A total of 834 unrelated Han Chinese adults, including 497 healthy volunteers and 337 patients with PTSD, were used in this study. Fifteen tag single-nucleotide polymorphisms (tSNPs) were selected spanning the entire DRD2 gene through the construction of haplotype bins. Genotypes were gathered using an improved multiplex ligation detection reaction (iMLDR) technique. Allelic frequencies and clinical characteristics were compared in two independent Han Chinese populations. Moreover, the functionality of the rs2075652 and rs7131056 polymorphisms were assessed by measuring transcriptional enhancer activities. RESULTS: Fifteen tag SNPs were identified in the Han Chinese population and all were common SNPs. Among 15 tSNPs, two of them (rs2075652 and rs7131056) significantly associated with PTSD. PTSD individuals were more likely to carry the rs2075652A and rs7131056A allele compared to the controls (P<0.05). The haplotype GTGATCGCGCAGGCG, had a risk effect on PTSD occurrence (OR=1.75, 95% CI: 1.24-2.48, P=0.002). Additionally, the rs2075652 polymorphism contained intronic enhancer activities. CONCLUSIONS: The rs2075652 and rs7131056 polymorphisms, and the haplotype GTGATCGCGCAGGCG within the DRD2 gene, may be potential markers to predict susceptibility to PTSD.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Dopamina D2/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Alelos , Estudos de Casos e Controles , China , Citocinas/sangue , Elementos Facilitadores Genéticos/genética , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , Receptores de Dopamina D2/sangue , Fatores de RiscoRESUMO
BACKGROUND: Free radical-induced oxidative damage of the brain has been implicated in a number of psychiatric disorders, including post-traumatic stress disorder (PTSD). Catalase (CAT) is a major antioxidant enzyme and a number of polymorphisms in CAT have been shown to be associated with several diseases, including hypertension, diabetes mellitus, Alzheimer's disease, and vitiligo. The aim of this study was to evaluate the association of CAT gene polymorphisms with PTSD in a case-control study. MATERIALS AND METHODS: A total of 460 unrelated adult Chinese Han adults, including 287 healthy volunteers and 173 patients with PTSD. Six tag single-nucleotide polymorphisms (tSNPs) were selected from the entire CAT gene through construction of haplotype bins, and they were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. Allelic frequencies and clinical characteristics were compared in two independent Chinese Han populations. RESULTS: Six tag SNPs were identified in the Chinese Han population and all were common SNPs. However, we could detect no evidence of genetic association between six tag SNPs in the CAT gene and PTSD in the Chinese Han population. CONCLUSIONS: This result suggests that six tag SNPs of the CAT gene may not be associated with PTSD, and that CAT gene might not influence the development of PTSD in patients following exposure to a traumatic event, also may be the sample sizes too small to allow a meaningful test.