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1.
J Transl Med ; 21(1): 15, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627705

RESUMO

BACKGROUND: The 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) remains < 50%. Hypoxia patterns are a hallmark of HNSCC that are associated with its occurrence and progression. However, the precise role of hypoxia during HNSCC, such as the relationship between hypoxia, tumor immune landscape and cell communication orchestration remains largely unknown. The current study integrated data from bulk and single-cell RNA sequencing analyses to define the relationship between hypoxia and HNSCC. METHODS: A scoring system named the hypoxia score (HS) was constructed based on hypoxia-related genes (HRGs) expression. The predictive value of HS response for patient outcomes and different treatments was evaluated. Single-cell datasets and cell communication were utilized to rule out cell populations which hypoxia targeted on. RESULTS: The survival outcomes, immune/Estimate scores, responses to targeted inhibitors, and chemotherapeutic, and immunotherapy responses were distinct between a high HS group and a low HS group (all P < 0.05). Single-cell datasets showed different distributions of HS in immune cell populations (P < 0.05). Furthermore, HLA-DPA1/CD4 axis was identified as a unique interaction between CD4 + T Conv and pDC cells. CONCLUSIONS: Altogether, the quantification for hypoxia patterns is a potential biomarker for prognosis, individualized chemotherapeutic and immunotherapy strategies. The portrait of cell communication characteristics over the HNSCC ecosystem enhances the understanding of hypoxia patterns in HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Hipóxia Tumoral , Humanos , Biomarcadores Tumorais/genética , Neoplasias de Cabeça e Pescoço/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
2.
Micromachines (Basel) ; 14(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36677241

RESUMO

Since the effect of the facet braiding phenomenon, the display quality of reconstructed image degrades with increasing depth of field in tabletop three-dimensional light-field display. Here, to analysis the facet braiding, the imaging process of the tabletop 360-degree three-dimensional light-field display based on conical lens array is mathematically modeled. A viewpoint-fitting encoding algorithm is proposed to reduce the effect of the facet-braiding phenomenon and improve the range of depth of field, which is optimized to form the best synthetic encoded image by fitting the reconstructed image seen by the simulated human eye to the parallax image captured at the corresponding location. The effectiveness of the proposed optimization algorithm is verified by simulation analysis and optical experiments, respectively. In the experiment, the clear depth of field range of the display system is increased from 13 cm to 15 cm, and the visualization effect of the reconstructed three-dimensional image is enhanced.

3.
Front Microbiol ; 13: 1044676, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36578566

RESUMO

The HIV-1 Rev response element (RRE) is a cis-acting RNA element that facilitates the nuclear export of mRNA-containing introns by binding specifically to the Rev protein, enabling a critical step in the viral replication cycle. This study aims to determine the subtype-specific loci of HIV-1 subtype B RRE circulating in China and to analyze their effects on Rev-RRE function and HIV-1 replication. We amplified 71 HIV-1 subtype B RRE full-length sequences from the HIV patients' blood samples collected in China, analyzed the subtype-specific loci on them by comparing them with subtype B in the United States, and predicted their RNA secondary structures. Rev-RRE activity assay was used to test the binding activity of Rev and different RREs. Infectious clones were mutated to test the effect of the subtype-specific loci on replication capacity. In this study, two sites were determined to be the subtype-specific loci of HIV-1 subtype B RRE circulating in China. Both site 186 and site 56-57insAAC can significantly increase the viral mRNA transcription and Rev-RRE activity, but only the site 186 can significantly improve viral replication ability. Collectively, the subtype-specific loci of subtype B RRE circulating in China have a significant effect on the Rev-RRE activity and viral replication. This study investigates the subtype-specific loci of RRE, which are unique to retroviruses and essential for viral replication, and will help to explore the reasons why subtype B circulating in China is more widespread and persistent than American subtype B in China at the genetic level, and will provide theoretical support for the development of more inclusive detection and treatment methods for subtype B circulating in China. At the same time, it will also provide insight into the impact of different subtype HIV-1 genetic characteristics on viral replication.

4.
Front Immunol ; 13: 977630, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36479128

RESUMO

Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by bnAbs contribute to their autoreactivity. Here, we back-mutated all known changes made by a prototype CD4 binding site-directed bnAb lineage, CH103-106, during its later maturation steps. Strikingly, of 29 mutations examined, only four were crucial for increased autoreactivity, with minimal or no impact on neutralization. Furthermore, three of these residues were clustered in the heavy chain complementarity-determining region 2 (HCDR2). Our results demonstrate that broad neutralization activity and autoreactivity in the CH103-106 bnAb lineage can be governed by a few, distinct mutations during maturation. This provides strong rationale for developing immunogens that favor bnAb lineages bearing "neutralization-only" mutations into current HIV-1 vaccine designs.


Assuntos
HIV-1 , Vacinas , HIV-1/genética
5.
Front Immunol ; 13: 922183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325324

RESUMO

ß-Carbolines are potentially strong alkaloids with a wide range of bioactivities, and their dimers exhibit stronger antitumor activity other than the monomers. However, the detailed mechanisms of the ß-carboline dimers in inhibiting sarcoma (SARC) remain unclear. The results showed that ß-carboline-3-carboxylic acid dimers Comp1 and Comp2, which were synthesized in our lab and modified at the N9 position and linked at the C3 position, exhibited effective inhibition activity on MG-63 proliferation (IC50 = 4.6µM). Meanwhile, the large scale transcriptome profiles of SARC from The Cancer Genome Atlas (TCGA) were analyzed, and found that abnormal expression of genes relevant to apoptosis, cell cycle, and signaling pathways of Hedgehog, HIF, Ras involved in the SARC pathogenesis. Interestingly, both dimers could promote the apoptosis and arrest the cell cycle in S phase to inhibit proliferation of MG-63. Moreover, Comp1 and Comp2 inhibited the expression CDK2, CCNA2, DBF4, and PLK1 associated with various immune cells and cell cycle in MG-63. Remarkably, drug-target interaction network analysis showed that numerous proteins involved in cell cycle were the potential targets of Comp1 and Comp2, especially CCNA2. Further molecular docking, isothermal titration calorimetry (ITC) and Cellular Thermal Shift Assay (CETSA) confirmed that both dimers could directly interact with CCNA2, which is significantly correlated with CD4+ T cells, by strong hydrophobic interactions (Kd=5.821 ×106 N). Meanwhile, the levels of CCNA2 and CDK2 were inhibited to decrease in MG-63 by both dimer treatments at transcription and protein levels, implying that Comp1 and Comp2 blocked the interaction between CCNA2 and CDK2 through competitive binding with CCNA2 to arrest the cell cycle of MG-63 cells in the S phase. Additionally, the transcriptome profiles of ß-carboline-treated mice from Gene Expression Omnibus (GEO) were obtained, and found that similar antitumor mechanism was shared among ß-carboline derivatives. Overall, our results elucidated the antitumor mechanisms of Comp1 and Comp2 through dual-suppressing the function of CCNA2 to profoundly arrest cell cycle of MG-63, then effectively inhibited cell proliferation of MG-63. These results provide new insights into the antitumor mechanism of ß-carboline dimers and new routes of various novel cancer-related drug targets for future possible cancer therapy.


Assuntos
Antineoplásicos , Sarcoma , Animais , Camundongos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Carbolinas/farmacologia , Carbolinas/química , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química
6.
Life Sci ; 309: 121021, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36208658

RESUMO

AIMS: Anticoagulation in disease treatment has been wildly studied in recent years. The intrinsic coagulation pathway is attracting attention of research community due to its low bleeding risk, and inhibitors against intrinsic coagulation factor XIIa (FXIIa) or XIa (FXIa) have been extensively studied. However, studies to develop anticoagulant inhibitors simultaneous targeting FXIIa and FXIa have not been reported. Our study aimed to evaluate the anticoagulation effect of the dual targeting of FXIIa and FXIa. MAIN METHODS: A fusion protein Infestin-PN2KPI (IP) was designed by linking FXIIa inhibitor Infesin4 and FXIa inhibitor PN2KPI through a rigid linker, and was cloned, expressed and characterized. The binding of IP to FXIIa and FXIa was verified by SPR, and inhibitory ability of IP against FXIIa and FXIa was verified by chromogenic substrate method. And then, the anticoagulation and antithrombotic functions of IP were extensively evaluated by aPTT assay, FeCl3-induced carotid artery thrombosis model and transient occlusion of the middle cerebral artery model. KEY FINDINGS: IP significantly prolonged aPTT, inhibited thrombosis and prevented stroke at a dose of at least 1/2 lower than the effective dose of its component Infestin4 or PN2KPI, and did not cause bleed risk. SIGNIFICANCE: The bifunctional fusion protein IP showed good anticoagulation effects, and simultaneous targeting FXIIa and FXIa is a promising strategy for anticoagulation drug development.


Assuntos
Fator XIIa , Fator XIa , Humanos , Fator XIa/química , Fator XIa/metabolismo , Fibrinolíticos/farmacologia , Compostos Cromogênicos , Anticoagulantes/farmacologia , Hemorragia
7.
World J Gastroenterol ; 28(36): 5265-5279, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36185635

RESUMO

The intestinal mucosa is a highly compartmentalized structure that forms a direct barrier between the host intestine and the environment, and its dysfunction could result in a serious disease. As T cells, which are important components of the mucosal immune system, interact with gut microbiota and maintain intestinal homeostasis, they may be involved in the process of intestinal barrier dysfunction. P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effects of extracellular adenosine triphosphate and is expressed by most innate or adaptive immune cells, including T cells. Current evidence has demonstrated that P2X7R is involved in inflammation and mediates the survival and differentiation of T lymphocytes, indicating its potential role in the regulation of T cell function. In this review, we summarize the available research about the regulatory role and mechanism of P2X7R on the intestinal mucosa-derived T cells in the setting of intestinal barrier dysfunction.


Assuntos
Intestinos , Receptores Purinérgicos P2X7 , Trifosfato de Adenosina , Humanos , Inflamação , Mucosa Intestinal
8.
Commun Biol ; 5(1): 1052, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192483

RESUMO

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second-deadliest infectious disease worldwide. Emerging evidence shows that the elongation factor EF-Tu could be an excellent target for treating Mtb infection. Here, we report the crystal structures of Mtb EF-Tu•EF-Ts and EF-Tu•GDP complexes, showing the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. Mtb EF-Tu binds with EF-Ts at a 1:1 ratio in solution and crystal packing. Mutation and SAXS analysis show that EF-Ts residues Arg13, Asn82, and His149 are indispensable for the EF-Tu/EF-Ts complex formation. The GDP binding pocket of EF-Tu dramatically changes conformations upon binding with EF-Ts, sharing a similar GDP-exchange mechanism in E. coli and T. ther. Also, the FDA-approved drug Osimertinib inhibits the growth of M. smegmatis, H37Ra, and M. bovis BCG strains by directly binding with EF-Tu. Thus, our work reveals the structural basis of Mtb EF-Tu in polypeptide synthesis and may provide a promising candidate for TB treatment.


Assuntos
Mycobacterium tuberculosis , Fator Tu de Elongação de Peptídeos , Vacina BCG , Escherichia coli/genética , Escherichia coli/metabolismo , Guanosina Difosfato/química , Guanosina Difosfato/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Fator Tu de Elongação de Peptídeos/genética , Fator Tu de Elongação de Peptídeos/metabolismo , Fatores de Alongamento de Peptídeos/química , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Biossíntese de Proteínas , Espalhamento a Baixo Ângulo , Difração de Raios X
9.
Front Endocrinol (Lausanne) ; 13: 889858, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35957809

RESUMO

Objective: Non-alcoholic fatty liver disease (NAFLD) can be attributed to the dysregulation of hepatic lipid metabolism; however, its cellular and molecular mechanisms remain unclear. This study aims to explore the effect of long non-coding RNA growth arrest specific 5 (GAS5) on hepatic lipid metabolism in fatty liver models. Methods: Obese mice, high fat diet-fed mice and free fatty acid-stimulated cells were used for GAS5 expression detection. GAS5 overexpression or knockdown models were established to elucidate the regulatory function of GAS5 in de novo lipogenesis (DNL) and mitochondrial function. Bioinformatic analyses and dual luciferase assays were used to investigate the interaction between GAS5, miR-26a-5p and phosphodiesterase (PDE) 4B. The involvement of the cyclic adenosine monophosphate (cAMP)/cAMP-response element-binding protein (CREB) pathway was evaluated using H89 and forskolin treatment. Results: GAS5 was activated in vitro and in vivo fatty liver models. Knockdown of GAS5 reduced lipid droplet accumulation, DNL associated enzymes and preserved mitochondrial function, while GAS5 overexpression exacerbated hepatic lipid accumulation. Mechanistically, GAS5 sponged miR-26a-5p to increase PDE4B expression and subsequently modulated DNL and mitochondrial function via the cAMP/CREB pathway. Conclusion: Downregulation of GAS5 can activate the cAMP/CREB pathway through miR-26a-5p/PDE4B axis to mitigate hepatic lipid accumulation. This study provides evidence that downregulation of GAS5 may be a potential therapeutic option for the treatment of NAFLD.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , RNA Longo não Codificante , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ácidos Graxos não Esterificados , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
10.
J Biomed Nanotechnol ; 18(3): 909-916, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35715911

RESUMO

As a severe neurological disease of trauma, traumatic brain injury (TBI) leads to other disorders, such as depression, dementia and epilepsy. This study investigated whether poly d,l-(lactic-co-glycolic) acid (PLGA) PEGylated isoliquiritigenin could alleviate TBI. One hundred and eighty-three patients with clinical brain trauma were divided into two groups with or without intracranial injury in magnetic resonance imaging. The clinical results showed that serum cyclooxygenase 2 (COX-2) levels were obviously increased in the TBI patients compared to the patients with head trauma only or healthy individuals. Intracranial injection of isoliquiritigenin in TBI rats reversed TBI induced increase of COX-2 level, significantly reduced water content and contusion volume. Our findings suggest that PLGA PEG nanoparticles loaded with isoliquiritigenin can achieve the same effects as intracranial administration of isoliquiritigenin in reducing serum COX-2 level.


Assuntos
Lesões Encefálicas Traumáticas , Ácido Láctico , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Chalconas , Ciclo-Oxigenase 2 , Humanos , Polietilenoglicóis , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos
11.
Public Health Nutr ; : 1-9, 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35581171

RESUMO

OBJECTIVE: To determine if limb lengths, as markers of early life environment, are associated with the risk of diabetes in China. DESIGN: We performed a cohort analysis using data from the China Health and Retirement Longitudinal Study (CHARLS), and multivariable-adjusted Cox proportional hazard regression models were used to examine the associations between baseline limb lengths and subsequent risk of diabetes. SETTING: The CHARLS, 2011-2018. PARTICIPANTS: The study confined the eligible subject to 10 711 adults aged over 45 years from the CHARLS. RESULTS: During a mean follow-up period of 6·13 years, 1358 cases of incident diabetes were detected. When controlling for potential covariates, upper arm length was inversely related to diabetes (hazard ratio (HR) 0·95, 95 % CI (0·91, 0·99), P = 0·028), and for every 1-cm difference in knee height, the risk of diabetes decreased by about 4 % (HR 0·96, 95 % CI (0·93, 0·99), P = 0·023). The association between upper arm length and diabetes was only significant among females while the association between knee height and diabetes was only significant among males. In analyses stratified by BMI, significant associations between upper arm length/knee height and diabetes only existed among those who were underweight (HR 0·91, 95 % CI (0·83, 1·00), P = 0·049, HR 0·92, 95 % CI (0·86, 0·99), P = 0·031). CONCLUSIONS: Inverse associations were observed between upper arm length, knee height and the risk for diabetes development in a large Asian population, suggesting early life environment, especially infant nutritional status, may play an important role in the determination of future diabetes risk.

12.
J Environ Manage ; 316: 115198, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35537270

RESUMO

With rapid urbanization and industrialization, environmental pollution caused by such activities has drawn much attention due to its adverse impacts on environmental quality and public health. Therefore, under the current background of China's ecological civilization construction, promoting the precise and scientific treatment of environmental pollution holds great significance. This paper proposes an improved perpetual inventory method to systematically measure the capital stock of urban and industrial pollution control. The efficiency of urban and industrial pollution control is measured by adopting the global data envelopment analysis (DEA) model. Then, the influencing factors of pollution control efficiency are empirically analyzed by using the spatial Tobit regression model. The results reveal that, first, the growth rate of the capital input scale of urban pollution control is greater than that of industrial pollution control, and the spatial distribution of capital input is unbalanced. Second, the efficiency of urban and industrial pollution control from 1991 to 2019 was generally low. The current efficiency values of urban and industrial pollution control are less than 0.2 and 0.5, respectively, indicating that urban and industrial pollution control are far from efficient. Third, the efficiency of urban and industrial pollution control is significantly positively related to the level of urbanization and industrialization, has a U-shaped relationship with the economic development level, and has heterogeneous effects on technology, energy intensity, government influence and foreign trade. On this basis, we provide constructive suggestions for optimizing the performance of pollution control.


Assuntos
Desenvolvimento Econômico , Poluição Ambiental , China , Eficiência , Indústrias , Urbanização
13.
Chronic Dis Transl Med ; 8(1): 36-40, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35620164

RESUMO

Background: The most common etiologies of Cushing's syndrome (CS) are adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients. Methods: A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009-2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups. Results: Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, p = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two. Conclusions: Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics.

14.
Nanomaterials (Basel) ; 12(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35407273

RESUMO

The flexible pressure sensor has attracted much attention due to its wearable and conformal advantage. All the same, enhancing its electrical and structural properties is still a huge challenge. Herein, a flexible integrated pressure sensor (FIPS) composed of a solid silicone rubber matrix, composited with piezoelectric powers of polyacrylonitrile/Polyvinylidene fluoride (PAN/PVDF) and conductive silver-coated glass microspheres is first proposed. Specifically, the mass ratio of the PAN/PVDF and the rubber is up to 4:5 after mechanical mixing. The output voltage of the sensor with composite PAN/PVDF reaches 49 V, which is 2.57 and 3.06 times that with the single components, PAN and PVDF, respectively. In the range from 0 to 800 kPa, its linearity of voltage and current are all close to 0.986. Meanwhile, the sensor retains high voltage and current sensitivities of 42 mV/kPa and 0.174 nA/kPa, respectively. Furthermore, the minimum response time is 43 ms at a frequency range of 1-2.5 Hz in different postures, and the stability is verified over 10,000 cycles. In practical measurements, the designed FIPS showed excellent recognition abilities for various gaits and different bending degrees of fingers. This work provides a novel strategy to improve the flexible pressure sensor, and demonstrates an attractive potential in terms of human health and motion monitoring.

15.
Appl Opt ; 61(3): 844-850, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35200793

RESUMO

The discovery of monolayer graphene allows the unprecedented chance for exploring its Goos-Hänchen (GH) shift. However, most of the pronounced GH shifts are achieved in various structures with two-dimensional continuous monolayer graphene. Here, we report on the giant GH shift of reflected wave in monolayer graphene strips by constructing the multilayer dielectric grating structure under them. The observed GH shift here is as high as 7000 times that of the incident wave at the near-infrared frequency region, whose magnification is significantly larger than that of the monolayer graphene ribbon array. We further elucidate that the enhanced GH shift originates from the guided mode resonance of the dielectric grating structure and its magnitude and sign can be manipulated by chemical potential of the monolayer graphene strip. Our work enables a promising route for enhancing and controlling the GH shifts of reflected wave in monolayer graphene strips, which might contribute to their applications in biosensors and detectors.

16.
Cell Death Dis ; 13(2): 98, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110535

RESUMO

Long non-coding RNAs (lncRNAs) play critical functions in various cancers. Firre intergenic repeating RNA element (FIRRE), a lncRNA located in the nucleus, was overexpressed in colorectal cancer (CRC). However, the detailed mechanism of FIRRE in CRC remains elusive. Results of RNA sequence and qPCR illustrated overexpression of FIRRE in CRC cell lines and tissues. The aberrant expression of FIRRE was correlated with the migration, invasion, and proliferation in cell lines. In accordance, it was also associated with lymphatic metastasis and distant metastasis in patients with CRC. FIRRE was identified to physically interact with Polypyrimidine tract-binding protein (PTBP1) by RNA pull-down and RNA immunoprecipitation (RIP). Overexpression of FIRRE induced the translocation of PTBP1 from nucleus to cytoplasm, which was displayed by immunofluorescence and western blot. In turn, delocalization of FIRRE from nucleus to cytoplasm is observed after the loss of PTBP1. The RNA-protein complex in the cytoplasm directly bound to BECN1 mRNA, and the binding site was at the 3' end of the mRNA. Cells with FIRRE and PTBP1 depletion alone or in combination were treated by Actinomycin D (ACD). Results of qPCR showed FIRRE stabilized BECN1 mRNA in a PTBP1-medieated manner. In addition, FIRRE contributed to autophagy activity. These findings indicate FIRRE acts as an oncogenic factor in CRC, which induces tumor development through stabilizing BECN1 mRNA and facilitating autophagy in a PTBP1-mediated manner.


Assuntos
Autofagia , Proteína Beclina-1/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Oncogenes/fisiologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Biochem Biophys Res Commun ; 579: 129-135, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34597996

RESUMO

Phosphofructokinase B (PfkB) belongs to the ribokinase family, which uses the phosphorylated sugar as substrate, and catalyzes fructose-6-phosphate into fructose-1,6-diphosphate. However, the structural basis of Mycobacterium marinum PfkB is not clear. Here, we found that the PfkB protein was monomeric in solution, which was different from most enzymes in this family. The crystal structure of PfkB protein from M. marinum was solved at a resolution of 2.21 Å. The PfkB structure consists of two domains, a major three-layered α/ß/α sandwich-like domain characteristic of the ribokinase-like superfamily, and a second domain composed of four-stranded ß sheets. Structural comparison analysis suggested that residues G236, A237, G238, and D239 could be critical for ATP catalysis and substrate binding of PfkB. Our current work provides new insights into understanding the mechanism of the glycolysis in M. marinum.


Assuntos
Mycobacterium marinum/enzimologia , Fosfofrutoquinase-2/metabolismo , Catálise , Cromatografia em Gel , Cristalografia por Raios X , Escherichia coli , Frutosefosfatos/química , Glicólise , Concentração de Íons de Hidrogênio , Conformação Molecular , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/química , Conformação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Espalhamento de Radiação , Temperatura
18.
BMC Cancer ; 21(1): 1297, 2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34863141

RESUMO

BACKGROUND: Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12-/- mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12-/- mice on a weekly basis, their weight were not significantly different from those of WT mice. METHODS: ApcMin/+; MMP12-/- mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 -/-) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. RESULTS: MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. CONCLUSIONS: MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.


Assuntos
Caquexia/genética , Metaloproteinase 12 da Matriz/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Animais , Genótipo , Humanos , Camundongos , Camundongos Knockout
19.
Nanomaterials (Basel) ; 11(11)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34835624

RESUMO

Metastable cellular structures (MCSs) play a crucial role for the mechanical performance in concentrated alloys during non-equilibrium solidification process. In this paper, typifying the heterogeneous 316L stainless steel by laser additive manufacturing (LAM) process, we examine the microstructures in cellular interiors and cellular boundaries in detail, and reveal the interactions of dislocations and twins with cellular boundaries. Highly ordered coherent precipitates present along the cellular boundary, resulting from spinodal decomposition by local chemical fluctuation. The co-existences of precipitates and high density of tangled dislocations at cellular boundaries serve as walls for extra hardening. Furthermore, local chemical fluctuation in MCSs inducing variation in stacking fault energy is another important factor for ductility enhancement. These findings shed light on possible routines to further alter nanostructures, including precipitates and dislocation structures, by tailoring local chemistry in MCSs during LAM.

20.
Nanomaterials (Basel) ; 11(10)2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34685200

RESUMO

In this paper, we designed a triboelectric acceleration sensor with excellent multiple parameters. To more easily detect weak vibrations, the sensor was founded on a multilayer suspension structure. To effectively improve the electrical properties of the sensor, a surface roughening and internal doping friction film, which was refined with a room temperature vulcanized silicone rubber (RTV) and some thermoplastic polyurethanes (TPU) powder in a certain proportion, was integrated into the structure. It was found that the optimization of the RTV film increases the open circuit voltage and short circuit current of the triboelectric nanogenerator (TENG) by 223% and 227%, respectively. When the external vibration acceleration is less than 4 m/s2, the sensitivity and linearity are 1.996 V/(m/s2) and 0.999, respectively. Additionally, when it is in the range between 4 m/s2 and 15 m/s2, those are 23.082 V/(m/s2) and 0.975, respectively. Furthermore, the sensor was placed in a simulated truck vibration environment, and its self-powered monitoring ability validated by experiments in real time. The results show that the designed sensor has strong practical value in the field of monitoring mechanical vibration acceleration.

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