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1.
J Adv Res ; 33: 127-140, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34603784

RESUMO

Introduction: Pancreatic adenocarcinoma (PAAD) is an aggressive malignancy, with a major mortality resulting from the rapid progression of metastasis. Unfortunately, no effective treatment strategy has been developed for PAAD metastasis to date. Thus, unraveling the mechanisms involved in PAAD metastatic phenotype may facilitate the treatment for PAAD patients. Objectives: PIK3CB is an oncogene implicated in cancer development and progression but less is known about whether PIK3CB participates in PAAD metastasis. Therefore, the objective of this study is to explore the mechanism(s) of PIK3CB in PAAD metastasis. Methods: In our study, we examined the PIK3CB expression pattern using bioinformatic analysis and clinical material derived from patients with PAAD. Subsequently, a series of biochemical experiments were conducted to investigate the role of PIK3CB as potential mechanism(s) underlying PAAD metastasis in vivo using nude mice and in vitro using cell lines. Results: We observed that PIK3CB was involved in PAAD progression. Notably, we identified that PIK3CB was involved in PAAD metastasis. Downregulation of PIK3CB significantly reduced PAAD metastatic potential in vivo. Furthermore, a series of bioinformatic analyses showed that PIK3CB was involved in cell adhesion in PAAD. Notably, PIK3CB depletion inhibited invasion potential specifically via suppressing cell adhesion to collagen I in PAAD cells. Conclusion: Collectively, our findings indicate that PIK3CB is involved in PAAD metastasis through cell-matrix adhesion. We proposed that PIK3CB is a potential therapeutic target for PAAD therapy.

2.
Small ; : e2103214, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34590404

RESUMO

Proton exchange membrane fuel cells (PEMFCs) are promising devices for clean power generation in fuel cell electric vehicles applications. The further request of high-efficiency and cost competitive technology make high-temperature proton exchange membranes utilizing phosphoric acid-doped polybenzimidazole be favored because they can work well up to 180 °C without extra humidifier. However, they face quick loss of phosphoric acid below 120 °C and resulting in the limits of commercialization. Herein UiO-66 derived carbon (porous carbon-ZrO2 ), comprising branched poly(4,4'-diphenylether-5,5'-bibenzimidazole) and polyacrylamide hydrogels self-assembly (BHC1-4) membranes for wide-temperature-range operation (80-160 °C) is presented. These two-phase membranes contained the hygroscopicity of polyacrylamide hydrogels improve the low-temperature proton conductivity, relatively enable the membrane to function at 80 °C. An excellent cell performance of BHC2 membrane with high peak power density of 265 and 656 mW cm-2 at both 80 and 160 °C can be achieved. Furthermore, this membrane exhibits high stability of frequency cold start-ups (from room temperature to 80 °C) and long-term cell test at 160 °C. The improvement of cell performance and stability of BHC2 membrane indicate a progress of breaking operated temperature limit in existing PEMFCs systems.

3.
Small ; : e2103514, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34590421

RESUMO

2D metal-halide perovskites have attracted intense research interest due to superior long-term stability under ambient environments. Compared to their 3D analog, the alternate arrangement of organic and inorganic layers leads to forming a multilayer quantum well (MQW), which endows 2D perovskites with anisotropic optoelectronic properties. In addition, the spacer layer functions as a hydrophobic barrier to effectively prevent 2D perovskite films from ion migration and moisture penetrating, thus realizing outstanding stability. Recently, 2D perovskites have been widely developed with abundant species. The stunning photovoltaic performance with the coexistence of long-term stability and high-power conversion efficiency (PCE) has been realized in 2D perovskite solar cells (PSCs), which paves an avenue for commercialization of PSCs. This review begins with an introduction of crystal structure and crystallization kinetics to illustrate the unique layer characters in 2D perovskites. Then, electron structure, excitons, dielectric confinement, and intrinsic stability properties are discussed in detail. Next, the photovoltaic performance based on recent Ruddlesden-Popper (RP), Dion-Jacobson (DJ), and alternating cations in the interlayer (ACI) phase 2D-PSCs is comprehensively summarized. Finally, the confronting challenges and strategies toward structural design and optoelectronic studies of 2D perovskites are proposed to offer insight into the advanced underlying properties of this family of materials.

5.
Pathol Res Pract ; 227: 153615, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34562827

RESUMO

BACKGROUND: CircRNAs are a new subset of noncoding RNAs formed by covalent closed loops and play crucial roles in the regulation of cancer gene expression. However, the roles and underlying mechanisms of circRNAs in gastric cancer (GC) remain indistinct. This study aimed to explore the role and mechanism of hsa_circ_0006421 (circPTK2) in GC. METHODS: The differential expression of circRNAs between GC tissues and adjacent normal tissues were identified by a circRNA expression profiling. Associations of circPTK2 or miR-134-5p expression with clinicopathological characteristics and prognosis of GC patients were analyzed by chi-square of Fisher's exact tests and Kaplan-Meier analysis. CCK8, colony formation, EdU assays and animal models were performed to assess the effects of circPTK2 on proliferation and invasion of GC cells. CircPTK2-specific probes were used to purify the RNA pulled down from the circPTK2, and enrichment of circPTK2 and miR-134-5p was detected by qRT-PCR. The effects of circPTK2 on miR-134-5p expression and CELF2/PTEN signaling were examined by qRT-PCR and Western blotting analysis. RESULTS: Low expression of circPTK2 and high expression of miR-134-5p were related to the poor survival, and high expression of miR-134-5p was related to the tumor recurrence in GC patients. Overexpressing circPTK2 suppressed the proliferation, colony formation, DNA synthesis and cell invasion as well as xenograft tumor growth and lung metastasis in vitro and in vivo, whereas silencing circPTK2 had the opposite effects. Moreover, circPTK2 was negatively correlated and co-localized with miR-134-5p in the cytoplasm of GC tissue cells. circPTK2 bound to and sponged miR-134-5p in GC cells, and miR-134-5p facilitated cell growth and invasion but attenuated circPTK2 induced tumor suppressive effects and CELF2/PTEN signaling activation in GC cells. CONCLUSIONS: circPTK2 functions as a tumor suppressor in GC by sponging miR-134-5p and activating the CELF2/PTEN axis.

6.
Eur J Endocrinol ; 185(4): 565-576, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374650

RESUMO

Objective: Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown. Methods: We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence. Results: We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS-) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS- cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS-. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS- cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS- cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining. Conclusion: Our data demonstrate defective insulin maturation in patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proinsulina/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Adulto , Aldeído Oxirredutases/metabolismo , Estudos de Casos e Controles , Desdiferenciação Celular/fisiologia , China , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia
7.
J Virol ; 95(21): e0074521, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34406859

RESUMO

Feline infectious peritonitis virus (FIPV) is the etiologic agent of feline infectious peritonitis (FIP) and causes fatal disease in cats of almost all ages. Currently, there are no clinically approved drugs or effective vaccines for FIP. Furthermore, the pathogenesis of FIP is still not fully understood. There is an urgent need for an effective infection model of feline infectious peritonitis induced by FIPV. Here, we constructed a field type I FIPV full-length cDNA clone, pBAC-QS, corresponding to the isolated FIPV QS. By replacing the FIPV QS spike gene with the commercially available type II FIPV 79-1146 (79-1146_CA) spike gene, we established and rescued a recombinant virus, designated rQS-79. Moreover, we constructed 79-1146_CA infectious full-length cDNA pBAC-79-1146_CA, corresponding to recombinant feline coronavirus (FCoV) 79-1146_CA (r79-1146_CA). In animal experiments with 1- to 2-year-old adult cats orally infected with the recombinant virus, rQS-79 induced typical FIP signs and 100% mortality. In contrast to cats infected with rQS-79, cats infected with 79-1146_CA did not show obvious signs. Furthermore, by rechallenging rQS-79 in surviving cats previously infected with 79-1146_CA, we found that there was no protection against rQS-79 with different titers of neutralizing antibodies. However, high titers of neutralizing antibodies may help prolong the cat survival time. Overall, we report the first reverse genetics of virulent recombinant FCoV (causing 100% mortality in adult cats) and attenuated FCoV (causing no mortality in adult cats), which will be powerful tools to study pathogenesis, antiviral drugs, and vaccines for FCoV. IMPORTANCE Tissue- or cell culture-adapted feline infectious peritonitis virus (FIPV) usually loses pathogenicity. To develop a highly virulent FIPV, we constructed a field isolate type I FIPV full-length clone with the spike gene replaced by the 79-1146 spike gene, corresponding to a virus named rQS-79, which induces high mortality in adult cats. rQS-79 represents the first described reverse genetics system for highly pathogenic FCoV. By further constructing the cell culture-adapted FCoV 79-1146_CA, we obtained infectious clones of virulent and attenuated FCoV. By in vitro and in vivo experiments, we established a model that can serve to study the pathogenic mechanisms of FIPV. Importantly, the wild-type FIPV replicase skeleton of serotype I will greatly facilitate the screening of antiviral drugs, both in vivo and in vitro.

8.
Cell Death Dis ; 12(7): 678, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226501

RESUMO

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-ß-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.


Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Movimento Celular , Colangiocarcinoma/enzimologia , Ubiquitina Tiolesterase/metabolismo , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/genética , Colangiocarcinoma/secundário , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitinação
9.
Nat Commun ; 12(1): 3997, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183666

RESUMO

Despite obesity being a predisposing factor for pancreatic ß-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood. In this study, we identify an islet-enriched long non-coding RNA (lncRNA), which we name ß-cell function and apoptosis regulator (ßFaar). ßFaar is dramatically downregulated in the islets of the obese mice, and a low level of ßFaar is necessary for the development of obesity-associated ß-cell dysfunction and apoptosis. Mechanistically, ßFaar promote the synthesis and secretion of insulin by upregulating islet-specific genes Ins2, NeuroD1, and Creb1 through sponging miR-138-5p. In addition, using quantitative mass spectrometry, we identify TRAF3IP2 and SMURF1 as interacting proteins that are specifically associated with ßFaar. We demonstrate that SMURF1 ubiquitin ligase activity is essential for TRAF3IP2 ubiquitination and activation of NF-κB-mediate ß-cell apoptosis. Our experiments provide direct evidence that dysregulated ßFaar contributes to the development of obesity-induced ß-cell injury and apoptosis.


Assuntos
Apoptose/genética , Células Secretoras de Insulina/metabolismo , Insulina/biossíntese , Obesidade/patologia , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/genética , Secreção de Insulina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/genética , NF-kappa B/metabolismo , Obesidade/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia
10.
Life Sci ; 281: 119720, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34144056

RESUMO

AIMS: Asthma is characterized by chronic inflammation and airway hyperresponsiveness (AHR). It is controllable, but not curable. Ubiquitin-specific peptidase 4 (USP4) has been verified as a regulator of regulatory T (Treg) cells and Th17 cells in vitro. In this study, we aim to investigate whether USP4 could serve as a therapeutic target for asthma. MAIN METHODS: Age-matched USP4 wild-type and knockout mice received an intraperitoneal injection of 100 µg ovalbumin (OVA) mixed in 2 mg aluminum hydroxide in 1 × PBS on days 0, 7 and 14. On days 21 to 27, the mice were challenged with aerosolized 1% OVA in 1 × PBS for 30 min. Tissue histology, ELISA and flow cytometry were applied 24 h after the last OVA challenge. KEY FINDINGS: USP4 deficiency protected mice from OVA-induced AHR and decreased the production of several inflammatory cytokines in T cells in vivo. Compared to the lung cells isolated from WT mice, Usp4-/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro. Meanwhile, the percentage of CD4+Foxp3+ Treg cells was elevated, with more CCR6+Foxp3+ Treg cells accumulating in the lungs of OVA-challenged USP4 deficient mice than in their wild-type counterparts. Treatment with the USP4 inhibitor, Vialinin A, reduced inflammatory cell infiltration in the lungs of OVA-challenged mice in vivo. SIGNIFICANCE: We found USP4 deficiency contributes to attenuated airway inflammation and AHR in allergen-induced murine asthma, and Vialinin A treatment alleviates asthma pathogenesis and may serve as a promising therapeutic target for asthma.


Assuntos
Asma/imunologia , Linfócitos T Reguladores/imunologia , Proteases Específicas de Ubiquitina/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/citologia , Proteases Específicas de Ubiquitina/genética
11.
FEBS Lett ; 595(14): 1962-1974, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080184

RESUMO

Regulatory T cells (Tregs) are indispensable for the maintenance of immunological self-tolerance and homeostasis. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is required for optimal Treg induction. Here, we reveal that human-induced Tregs (iTregs) lacking hnRNPA1 show reduced expression of the transcription factor FOXP3, increased ubiquitination level of FOXP3, and impaired suppressive abilities. Human naïve CD4 T cells with hnRNPA1 knockdown show a decreased Treg differentiation ratio. hnRNPA1 could interact with FOXP3 as well as with the E3 ligase Stub1. The phosphorylation at hnRNPA1 S199 could increase both interactions. The overexpression of FOXP3 in Tregs containing shhnRNPA1 could not recover the phenotype caused by hnRNPA1 knockdown. Therefore, there might be multiple essential pathways regulated by hnRNPA1 in Tregs. In conclusion, we present a new role of hnRNPA1 in promoting Treg function, indicating it as a promising target for tumor therapies.


Assuntos
Fatores de Transcrição Forkhead/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Ubiquitina-Proteína Ligases/genética , Diferenciação Celular , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Células HEK293 , Ribonucleoproteína Nuclear Heterogênea A1/antagonistas & inibidores , Ribonucleoproteína Nuclear Heterogênea A1/imunologia , Homeostase/imunologia , Humanos , Fosforilação , Cultura Primária de Células , Ligação Proteica , Estabilidade Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Tolerância a Antígenos Próprios/genética , Transdução de Sinais , Linfócitos T Citotóxicos/citologia , Linfócitos T Reguladores/citologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação
12.
Xenobiotica ; 51(7): 818-830, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33952086

RESUMO

Diabetes mellitus is a chronic metabolic disorder with multiple complications, patients who receive metformin may have a simultaneous intake of herbal medicine containing rutaecarpine due to cardiovascular protection and hypolipidemic effects of rutaecarpine. There might be drug interactions between metformin and rutaecarpine. This study aimed to investigate the effects of rutaecarpine on the pharmacodynamics and pharmacokinetics of metformin in diabetic rats.The diabetic rat model was induced with high-fat diet and low dose streptozotocin. Metformin with or without rutaecarpine was administered by oral gavage for 42 days. Pharmacodynamics and pharmacokinetics parameters were evaluated.The pharmacodynamics results revealed that co-administration of rutaecarpine with metformin resulted in a remarkable reduction of serum glucose and lipid profiles in diabetic rats compared to metformin treated alone. The pharmacokinetics results showed that co-treatments of rutaecarpine with metformin did not affect the systemic exposure and renal distribution of metformin, but increased metformin concentration in liver. Furthermore, rutaecarpine increased Oct1-mediated metformin uptake into hepatocytes by upregulation of Oct1 expression in the liver.The above data indicate that rutaecarpine enhanced the anti-diabetic effect of metformin, which may be associated with the increased hepatic distribution of metformin through up-regulation of Oct1 in response to rutaecarpine.


Assuntos
Diabetes Mellitus Experimental , Metformina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Alcaloides Indólicos , Fígado , Metformina/farmacologia , Quinazolinas , Ratos , Regulação para Cima
13.
Artigo em Inglês | MEDLINE | ID: mdl-33944548

RESUMO

Polyacrylamide is widely employed in constructing functional hydrogels. However, the volume expansion of this hydrogel in water weakens its mechanical properties and restricts its application. Herein, we report a strategy to convert the swollen and weak polyacrylamide/carboxymethyl chitosan hydrogel into a strong and tough one by hydrolysis in acid solution with an elevated temperature. The obtained hydrolyzed hydrogels possess a high strength, toughness, and tearing fracture energy of 5.9 MPa, 22 MJ/m3 and 7517 J/m2, which are 254, 535 and 186 times higher than those of the original swollen one, respectively. In addition, the gels demonstrate low residual strain and rapid self-recovery abilities. Moreover, the gels have good shape memory behavior controlled by temperature. Furthermore, the gels can be worked as strain sensors with a broad strain window, high sensitivity, excellent linear response, and great durability in monitoring human motions after immersing treatment in a normal saline solution. This work provides a new method for preparing the stretchable and tough polyacrylamide-based hydrogels used in the areas of soft actuators and flexible electronics.

14.
Int Arch Allergy Immunol ; 182(9): 852-862, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33895737

RESUMO

The prevalence of food allergy (FA) is increasing, and there is an urgent need to take effective measures against it. One important measure is the avoidance diet, which shows a disadvantage, especially in case of accidental exposure. Oral tolerance restoration sheds new light on the control of FA. Oral tolerance is naturally a state of systemic unresponsiveness of the gastrointestinal tract to food antigens and its restoration can be a clinical therapy for FA. Its immune basis lies on the intestinal mucosal immune system and factors, such as gut microbiota and food processing methods, are also important. This review presents recent advances in oral tolerance and its closely related factors.


Assuntos
Alérgenos/imunologia , Dessensibilização Imunológica , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/terapia , Tolerância Imunológica , Administração Oral , Alérgenos/administração & dosagem , Animais , Dessensibilização Imunológica/métodos , Hipersensibilidade Alimentar/diagnóstico , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
15.
Front Immunol ; 12: 647540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897695

RESUMO

The treatment and prognosis of advanced colorectal cancer (CRC) remain a challenging clinical research focus. Here, we describe a new CRC tumor suppressor and potential therapeutic target: thymocyte selection associated high mobility group box (TOX) protein. The expression of TOX was lower in CRC than para-CRC. With the increase of tumor stage, TOX expression decreased, indicating the presence of TOX relates to better overall survival (OS). TOX suppressed the mechanistic target of rapamycin kinase (mTOR) signaling to inhibit cell proliferation, migration, invasion, and change the epithelial-mesenchymal transition (EMT) process. In addition, TOX promoted apoptosis. As tumor mutation burden and tumor microenvironment play vital roles in the occurrence and development of tumors, we analyzed the TOX expression in the immune microenvironment of CRC. The high TOX expression was negatively correlated with TumorPurity. Moreover, it was positively related to ImmuneScore, StromalScore, microsatellite instability (MSI) status, and Consensus Molecular Subtypes (CMS) 3 typing. Based on gene set enrichment analysis (GSEA), the reduced expression of TOX activated mTOR. We found rapamycin, a mTOR inhibitor, partly inhibited cell proliferation, invasion, and migration in shTOX HCT116 cells. Lastly, TOX suppressed tumorigenesis and lung metastasis of CRC in vivo. Rapamycin alone or combined with PD1 inhibitor is more effective than PD1 inhibitor alone in a tumor model. Taken together, these findings highlight the tumor-suppressive role of TOX in CRC, especially in MSI CRC, and provide valuable information that rapamycin alone or combined with PD1 inhibitor has therapeutic potential in CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Genes Supressores de Tumor , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Transfecção , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Int Med Res ; 49(4): 3000605211002003, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33794678

RESUMO

OBJECTIVE: The long-term effect of extracorporeal shock wave lithotripsy (SWL) is still controversial. A previous meta-analysis showed no association between new-onset hypertension and entire upper urinary urolithiasis after SWL. Recently, there have been some reports on this topic. Therefore, we aimed to examine the association between new-onset hypertension and nephrolithiasis after SWL therapy. METHODS: Embase, the Cochrane Central Search Library, and PubMed were used to search for reports on new-onset hypertension and patients with nephrolithiasis after SWL. A meta-analysis of the association between new-onset hypertension and nephrolithiasis after SWL was carried out. The data of relevant research were synthesized and the relative risk was computed. RESULTS: Seven eligible studies were included in our meta-analysis. There was a significant association between nephrolithiasis after SWL and new-onset hypertension. The overall relative risk with a 95% confidence interval was 1.21 (1.11-1.31) in a fixed-effects model. CONCLUSION: Our meta-analysis suggests an association between new-onset hypertension and patients with nephrolithiasis after SWL, which is in contrast with the finding of a previous meta-analysis.


Assuntos
Hipertensão , Cálculos Renais , Litotripsia , Urolitíase , Humanos , Hipertensão/etiologia , Cálculos Renais/etiologia , Cálculos Renais/terapia , Litotripsia/efeitos adversos , Urolitíase/etiologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-33797361

RESUMO

OBJECTIVE: The goal of this study was to investigate the status of FEN1 in Colorectal cancer (CRC) and determine the potential correlation between FEN1 expression level and clinicopathological parameters in CRC patients. METHODS: Expression of FEN1 in CRC tissue on tissue microarray was detected using immunohistochemistry (IHC). The relationship between FEN1 expression status and clinicopathologic characteristics of CRC was analyzed by Chi-square test. The survival data of TCGA Colon Cancer (COAD) were obtained from ucsc xena browser (https://xenabrowser.net/). Patients were separated into higher and lower expression groups by median FEN1 expression. The association with prognosis of CRC patients was determined by Kaplan-Meier survival analysis with Log-rank test. RESULTS: FEN1expression level and cellular localization had wide variability among different individuals, we classified the staining results into four types: both positive in nucleus and cytoplasm, both negative in nucleus and cytoplasm, only positive in nucleus, only positive in cytoplasm. Moreover, FEN1 expression status only correlated with patient's metastasis status, and the patients in NLCL group showed more risk of cancer cell metastasis. CONCLUSION: Our results indicate that FEN1 expression level and cellular localization had wide variability in CRC and is not a good biomarker in CRC.

19.
J Colloid Interface Sci ; 594: 54-63, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33756368

RESUMO

Organic dye-containing wastewater has become an increasingly serious environmental problem due to the rapid development of the printing and dyeing industry. Hydrogel is a promising adsorbent for organic dyes because of its unique three-dimension network structure and versatile functional groups. Though many efforts have been made in hydrogel adsorbents recently, there is still a critical challenge to fabricate hydrogel adsorbent with high adsorption capacity and high efficiency at the same time. To address this concern, we developed a calcium hydroxide nano-spherulites/poly(acrylic acid -[2-(Methacryloxy)ethyl]trimethyl ammonium chloride) hydrogel adsorbent with novel villi-like structure. The hydrogels were prepared through a simple free radical copolymerization method using calcium hydroxide nano-spherulites as crosslinker. The resultant hydrogel adsorbents showed a maximum adsorption capacity of 2249 mg/g in a 400 mg/L methylene blue solution and a high removal ratio of 98% in 1 h for a 50 mg/L methylene blue solution. In addition, the adsorption behaviors of our hydrogel adsorbents could be well described by pseudo-second-order kinetic model and Langmuir adsorption isotherm model. Furthermore, this kind of hydrogel adsorbent showed selective adsorption behavior for methylene blue. Altogether, the hydrogel adsorbent developed in this work has a high capacity and high efficiency in organic dye removing and promised a great potential in wastewater treatment application.

20.
BMC Endocr Disord ; 21(1): 47, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711989

RESUMO

BACKGROUND: NKX6.1 is a transcription factor for insulin, as well as a marker for ß cell maturity. Abnormal NKX6.1 expression in ß cells, such as translocation from the nucleus to cytoplasm or lost expression, has been shown as a marker for ß cell dedifferentiation. METHODS: We obtained pancreatic sections from organ donors and immunofluorescence staining with NKX6.1 and insulin was performed to characterize NKX6.1 expression in subjects with or without type 2 diabetes mellitus (T2DM). RESULTS: Our results showed that cells with insulin expression but no nucleic NKX6.1 expression (NKX6.1Nuc-Ins+), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1cytIns-) were significantly increased in T2DM subjects and positively correlated with glycated hemoglobin (HbA1c), indicating the elevated ß cell dedifferentiation with NKX6.1 inactivation in T2DM. To investigate whether ß cell dedifferentiation has initiated in subjects with higher risks for T2DM, we next analyzed the association between ß-cell dedifferentiation level in ND subjects with different ages, body mass index, and HbA1c. The results showed the absolute number and percentage of dedifferentiated ß cells with NKX6.1 inactivation did not significantly change in subjects with advanced aging, obesity, or modest hyperglycemia, indicating that the ß cell dedifferentiation might mainly occur after T2DM was diagnosed. CONCLUSION: Our results suggested that NKX6.1 expression in ß cells was changed in type 2 diabetic subjects, evidenced by significantly increased NKX6.1Nuc-Ins+ and NKX6.1cytIns- cells. This abnormality did not occur more frequently in subjects with a higher risk for T2DM, suggesting that ß cell dedifferentiation might be secondary to the pathological changes in T2DM.

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