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1.
Expert Opin Ther Targets ; 28(4): 237-250, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38650383

RESUMO

INTRODUCTION: Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T cells, B cells, dendritic cells, and other immune cells. Loss of HPK1 kinase activity results in exacerbated cytokine secretion, enhanced T cell signaling, improved viral clearance, and thus increased restraint of tumor growth. These findings highlight HPK1 as a promising target for immuno-oncology treatments, culminating in the advancement of candidate compounds targeting HPK1 to clinical trials by several biotech enterprises. AREAS COVERED: Through searching PubMed, Espacenet-patent search, and clinicaltrials.gov, this review provides a comprehensive analysis of HPK1, encompassing its structure and roles in various downstream signaling pathways, the consequences of constitutive activation of HPK1, and potential therapeutic strategies to treat HPK1-driven malignancies. Moreover, the review outlines the patents issued for small molecule inhibitors and clinical investigations of HPK1. EXPERT OPINION: To enhance the success of tumor immunotherapy in clinical trials, it is important to develop protein degraders, allosteric inhibitors, and antibody-drug conjugates based on the crystal structure of HPK1, and to explore combination therapy approaches. Although several challenges remain, the development of HPK1 inhibitors display promising in preclinical and clinical studies.


Assuntos
Imunoterapia , Terapia de Alvo Molecular , Neoplasias , Proteínas Serina-Treonina Quinases , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Imunoterapia/métodos , Transdução de Sinais , Antineoplásicos/farmacologia , Patentes como Assunto , Inibidores de Proteínas Quinases/farmacologia , Desenvolvimento de Medicamentos
2.
Angew Chem Int Ed Engl ; 63(16): e202319856, 2024 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354272

RESUMO

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.


Assuntos
Níquel , Níquel/química , Catálise , Oxirredução
3.
Environ Sci Technol ; 58(3): 1752-1762, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38190653

RESUMO

The widespread presence of formaldehyde (HCHO) pollutant has aroused significant environmental and health concerns. The catalytic oxidation of HCHO into CO2 and H2O at ambient temperature is regarded as one of the most efficacious and environmentally friendly approaches; to achieve this, however, accelerating the intermediate formate species formation and decomposition remains an ongoing obstacle. Herein, a unique tandem catalytic system with outstanding performance in low-temperature HCHO oxidation is proposed on well-structured Pd/Mn3O4-MnO catalysts possessing bifunctional catalytic centers. Notably, the optimized tandem catalyst achieves complete oxidation of 100 ppm of HCHO at just 18 °C, much better than the Pd/Mn3O4 (30%) and Pd/MnO (27%) counterparts as well as other physical tandem catalysts. The operando analyses and physical tandem investigations reveal that HCHO is primarily activated to gaseous HCOOH on the surface of Pd/Mn3O4 and subsequently converted to H2CO3 on the Pd/MnO component for deep decomposition. Theoretical studies disclose that Pd/Mn3O4 exhibits a favorable reaction energy barrier for the HCHO → HCOOH step compared to Pd/MnO; while conversely, the HCOOH → H2CO3 step is more facilely accomplished over Pd/MnO. Furthermore, the nanoscale intimacy between two components enhances the mobility of lattice oxygen, thereby facilitating interfacial reconstruction and promoting interaction between active sites of Pd/Mn3O4 and Pd/MnO in local vicinity, which further benefits sustained HCHO tandem catalytic oxidation. The tandem catalysis demonstrated in this work provides a generalizable platform for the future design of well-defined functional catalysts for oxidation reactions.


Assuntos
Formaldeído , Paládio , Temperatura , Domínio Catalítico , Oxirredução , Catálise , Paládio/química
4.
Sci Total Environ ; 904: 166319, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37586509

RESUMO

Amorphousness effectively improves the electron transfer rate of zero-valent iron. In this study, a novel kaolinite loading amorphous zero-valent iron composite (K-AZVI) was prepared and applied to the remediation of soils with cadmium (Cd) pollution concentrations of 20, 50, and 100 mg/kg respectively. The results showed that the application of K-AZVI increased the pH and cation exchange capacity (CEC) of soil, and decreased the dissolved organic carbon (DOC) and organic matter (OM) of soil, thus indirectly promoting the adsorption of Cd in the soil. After 28 days of stabilization, the stabilizing efficiency of K-AZVI on the water-soluble Cd content in soil reached 98.72 %. Under the amendment of 0.25 %-1.0 % (w/w), the available Cd content in 20-100 mg/kg contaminated soil decreased by 46.47 %-62.23 %, 24.10 %-41.52 %, and 16.09 %-30.51 % respectively compared with CK. More importantly, the addition of K-AZVI promoted the transformation of 33.18 %-48.42 % exchangeable fraction (EXC) to 10.09 %-20.14 % residual fraction (RES), which increased the abundance and diversity of soil bacterial communities. Comprehensive risk assessment showed that adding 1.0 % K-AZVI provided the best remediation on contaminated soil. In addition, the results of scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) of K-AZVI before and after the reaction showed that the stabilization mechanism of K-AZVI to Cd in soil is mainly the stable metal species (Cd(OH)2, CdO and CdFe2O4) formed by the direct complexation and coprecipitation of a large number of iron oxides formed by the rapid corrosion of amorphous zero-valent iron (AZVI). Overall, this work provides a promising approach to the remediation of Cd-contaminated soil using K-AZVI composites.

5.
Langmuir ; 39(27): 9488-9502, 2023 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-37368460

RESUMO

Amorphous zerovalent iron (AZVI) has gained considerable attention due to its remarkable reactivity, but there is limited research on sulfidated amorphous zerovalent iron (SAZVI) and the influence of different sulfur precursors on its reactivity remains unclear. In this study, SAZVI materials with an amorphous structure were synthesized using various sulfur precursors, resulting in significantly increased specific surface area and hydrophobicity compared to AZVI. The Cr(VI) removal efficiency of SAZVI-Na2S, which exhibited the most negative free corrosion potential (-0.82 V) and strongest electron transfer ability, was up to 8.5 times higher than that of AZVI. Correlation analysis revealed that the water contact angle (r = 0.87), free corrosion potential (r = -0.92), and surface Fe(II) proportion (r = 0.98) of the SAZVI samples played crucial roles in Cr(VI) removal. Furthermore, the enhanced elimination ability of SAZVI-Na2S was analyzed, primarily attributed to the adsorption of Cr(VI) by the FeSx shell, followed by the rapid release of internal electrons to reduce Cr(VI) to Cr(III). This process ultimately led to the precipitation of FeCr2O4 and Cr2S3 on the surface of SAZVI-Na2S, resulting in their removal from the water. This study provides insights into the influence of sulfur precursors on the reactivity of SAZVI and offers a new strategy for designing highly active AZVI for efficient Cr(VI) removal.

6.
Front Immunol ; 14: 1145706, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37251413

RESUMO

Background: Diffuse intrinsic pontine gliomas (DIPGs) are rare and fatal pediatric brainstem gliomas with no cure. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have been proven effective in treating glioblastoma (GBM) in preclinical studies. However, there are no relevant studies on the CAR-NK treatment for DIPG. Our study is the first to evaluate the anti-tumor activity and safety of GD2-CAR NK-92 cells treatment for DIPG. Methods: Five patient-derived DIPG cells and primary pontine neural progenitor cell (PPC) were used to access disialoganglioside GD2 expression. Cell killing activity of GD2-CAR NK-92 cells was analyzed by in vitro cytotoxicity assays. Two DIPG patient-derived xenograft models were established to detect the anti-tumor efficacy of GD2-CAR NK-92 cells in vivo. Results: Among the five patient-derived DIPG cells, four had high GD2 expression, and one had low GD2 expression. In in vitro assays, GD2-CAR NK-92 cells could effectively kill DIPG cells with high GD2 expression while having limited activity against DIPG cells with low GD2 expression. In in vivo assays, GD2-CAR NK-92 cells could inhibit tumor growth in TT150630 DIPG patient-derived xenograft mice (high GD2 expression) and prolong the overall survival of the mice. However, GD2-CAR NK-92 showed limited anti-tumor activity for TT190326DIPG patient-derived xenograft mice (low GD2 expression). Conclusion: Our study demonstrates the potential and safety of GD2-CAR NK-92 cells for adoptive immunotherapy of DIPG. The safety and anti-tumor effect of this therapy need to be further demonstrated in future clinical trials.


Assuntos
Glioma Pontino Intrínseco Difuso , Glioma , Receptores de Antígenos Quiméricos , Humanos , Camundongos , Animais , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Células Matadoras Naturais , Imunoterapia Adotiva , Glioma/tratamento farmacológico
7.
Langmuir ; 39(11): 4026-4036, 2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-36877598

RESUMO

Amorphous zero-valent iron (AZVI) has attracted wide attention due to its high-efficiency reduction ability. However, the effect of different EDA/Fe(II) molar ratios on the physicochemical properties of the synthesized AZVI requires further investigation. Herein, series of AZVI samples were prepared by changing the molar ratio of EDA/Fe(II) to 1/1 (AZVI@1), 2/1 (AZVI@2), 3/1 (AZVI@3), and 4/1 (AZVI@4). When the EDA/Fe(II) ratio increased from 0/1 to 3/1, the Fe0 proportion on the AZVI surface increased from 26.0 to 35.2% and the reducing ability was enhanced. As for AZVI@4, the surface was severely oxidized to form a large amount of Fe3O4, and the Fe0 content was only 74.0%. Moreover, the removal ability of Cr(VI) was in the order AZVI@3 > AZVI@2 > AZVI@1 > AZVI@4. The isothermal titration calorimetry results revealed that the increase of the molar ratio of EDA/Fe(II) would lead to the stronger complexation of EDA with Fe(II), which resulted in the gradual decrease of the yield of AZVI@1 to AZVI@4 and the gradual deterioration of water pollution after the synthesis. Therefore, based on the evaluation of all indicators, AZVI@2 was the optimal material, not only because its yield was as high as 88.7% and the secondary water pollution level was low, but most importantly, the removal efficiency of Cr(VI) by AZVI@2 was excellent. Furthermore, the actual Cr(VI) wastewater with the concentration of 14.80 mg/L was treated with AZVI@2, and the removal rate of 97.0% was achieved after only a 30 min reaction. This work clarified the effect of different ratios of EDA/Fe(II) on the physicochemical properties of AZVI, which provided insights for guiding the reasonable synthesis of AZVI and is also conducive to investigating the reaction mechanism of AZVI in Cr(VI) remediation.

8.
Hepatobiliary Pancreat Dis Int ; 22(3): 282-287, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35246397

RESUMO

BACKGROUND: The risk factors for the recurrent choledocholithiasis after endoscopic retrograde cholangiopancreatography (ERCP) have not been well studied. The aim of this study was to explore the risk factors of recurrent choledocholithiasis. METHODS: We carried out a retrospective analysis of data collected between January 1, 2010 and January 1, 2020. Univariate analysis and multivariate analysis were used to explore the independent risk factors of recurrent choledocholithiasis following therapeutic ERCP. RESULTS: In total, 598 patients were eventually selected for analysis, 299 patients in the recurrent choledocholithiasis group and 299 patients in the control group. The overall rate of recurrent choledocholithiasis was 6.91%. Multivariate analysis showed that diabetes [odds ratio (OR) = 3.677, 95% confidence interval (CI): 1.875-7.209; P < 0.001], fatty liver (OR = 4.741, 95% CI: 1.205-18.653; P = 0.026), liver cirrhosis (OR = 3.900, 95% CI: 1.358-11.201; P = 0.011), history of smoking (OR = 3.773, 95% CI: 2.060-6.908; P < 0.001), intrahepatic bile duct stone (OR = 4.208, 95% CI: 2.220-7.976; P < 0.001), biliary stent (OR = 2.996, 95% CI: 1.870-4.800; P < 0.001), and endoscopic papillary balloon dilation (EPBD) (OR = 3.009, 95% CI: 1.921-4.715; P < 0.001) were independent risk factors of recurrent choledocholithiasis. However, history of drinking (OR = 0.183, 95% CI: 0.099-0.337; P < 0.001), eating light food frequently (OR = 0.511, 95% CI: 0.343-0.760; P = 0.001), and antibiotic use before ERCP (OR = 0.315, 95% CI: 0.200-0.497; P < 0.001) were independent protective factors of recurrent choledocholithiasis. CONCLUSIONS: Patients with the abovementioned risk factors are more likely to have recurrent CBD stones. Patients who eat light food frequently and have a history of drinking are less likely to present with recurrent CBD calculi.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Coledocolitíase , Humanos , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Coledocolitíase/diagnóstico por imagem , Coledocolitíase/cirurgia , Estudos Retrospectivos , Cateterismo , Fatores de Risco , Esfinterotomia Endoscópica
9.
Environ Sci Technol ; 56(18): 13379-13390, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36074134

RESUMO

The evaluation of the poisoning effect of complex components in practical gas on DCM (dichloromethane) catalytic ozonation is of great significance for enhancing the technique's environmental flexibility. Herein, Ca, Pb, As, and NO/SO2 were selected as a typical alkaline-earth metal, heavy metal, metalloid, and acid gas, respectively, to evaluate their interferences on catalytic behaviors and surface properties of an optimized urchin-like CuMn catalyst. Ca/Pb loading weakens the formation of oxygen vacancies, oxygen mobility, and acidity due to the fusion of Mn-Ca/Pb-O, leading to their inferior catalytic performance with poor CO2 selectivity and mineralization rate. Noticeably, the presence of As induces excessively strong acidity, facilitating the inevitable formation of byproducts. Catalytic co-ozonation of NO/DCM is achieved with stoichiometric ozone addition. Unfortunately, SO2 introduction brings irreversible deactivation due to strong competition adsorption and the loss of active sites. Unexpectedly, Ca loading protects active sites from an attack by SO2. The formation of unstable sulfites and the released Mn-O structure offset the negative effect from SO2. Overall, the catalytic ozonation of DCM exhibits a distinctive priority in the antipoisoning of metals with the maintenance of DCM conversion. The construction of more stable acid sites should be the future direction of catalyst design; otherwise, catalytic ozonation should be arranged together with post heavy metal capture and a deacidification system.


Assuntos
Metaloides , Ozônio , Dióxido de Carbono , Catálise , Chumbo , Cloreto de Metileno , Ozônio/química , Sulfitos
10.
Drug Dev Res ; 83(3): 755-768, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34981843

RESUMO

Cervical cancer (CC) is a common malignancy in gynecology. Emerging evidence has demonstrated that circular RNAs (circRNAs) act as vital mediators in CC. However, the roles of circRNA ring finger protein 121 (circRNF121) in CC are largely unknown. Herein, we focused on the exact function and underlying mechanism of circRNF121 in CC development. Our results showed that circRNF121 was highly expressed in CC tissues and cells. Knockdown of circRNF121 suppressed cell growth, metastasis, epithelial-mesenchymal transition (EMT), autophagy, and wnt/ß-catenin pathway in CC cells in vitro and blocked tumor formation in vivo. For mechanism investigation, circRNF121 could affect activating transcription factor 2 (ATF2) expression by decoying miR-153-3p, thereby accelerating CC cell development. In conclusion, circRNF121 exerted the tumor-suppressive role in CC progression by altering miR-153-3p/ATF2 axis. These results suggested that circRNF121 might be a possible circ-targeted therapy for patients with CC.


Assuntos
MicroRNAs , RNA Circular , Neoplasias do Colo do Útero , Via de Sinalização Wnt , beta Catenina , Fator 2 Ativador da Transcrição/genética , Fator 2 Ativador da Transcrição/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , beta Catenina/genética , beta Catenina/metabolismo
11.
J Colloid Interface Sci ; 612: 132-145, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-34992014

RESUMO

Though the highest CO2 capture capacity belongs to liquid amine-solutions, solid matters capable of CO2 capture are also highly sought, providing that, they offer at least analogous CO2 adsorption capacity and CO2/N2 selectivity. Herein, a surprisingly high-performance Ni-based metal-organic framework for CO2 adsorption, namely MOF-74(Ni), was synthesized by a facile condensation reflux approach. It was found that the structure and CO2 adsorption isosteric heat of MOF-74(Ni) could tune upon varying the synthesis duration under various temperatures. The optimized MOF-74(Ni)-24-140 (synthesized at 140 °C for 24 h) displays outstanding CO2 adsorption capacity of 8.29/6.61 mmol/g at 273/298 K under normal pressure of 1.0 bar, several times higher than previously reported MOF-74-Ni (2.0/2.1 times), UTSA-16 (1.5/1.6 times), and DA-CMP-1 (3.6/4.9 times) under similar conditions. The excellent CO2 capture capacity is associated to the abundant adsorption sites (mainly arising from the cationic Ni2+ ions) and narrow micropore channels (mainly arising from the cage structure of Ni2+ ions coordinated with organic linkers). Offering a high CO2 selectivity (CO2/N2 = 49) and a well-tuned isosteric heat of CO2 adsorption (27-52 kJ/mol) besides its decent CO2 capture capacity, MOF-74(Ni) strongly stands out as an efficient and strong CO2 capturing material with industrial scale applicability.

12.
Cancer Res ; 81(22): 5678-5691, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34593522

RESUMO

Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer. Previous studies have reported on the role of long noncoding RNA (lncRNA) in tumorigenesis of pancreatic cancer, however, the involvement of lncRNA in the development of GEM resistance of pancreatic cancer remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF1α (HIF1A-AS1) was significantly elevated in the GEM-resistant pancreatic cancer cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of pancreatic cancer cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF1α expression and thus promoted glycolysis to enhance GEM resistance of pancreatic cancer cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box-binding protein 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF1α mRNA that consequently promoted translation of HIF1α. Furthermore, HIF1α promoted HIF1A-AS1 transcription by directly binding to the HIF1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF1α were upregulated in pancreatic cancer tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF1α that contributes to GEM resistance of pancreatic cancer and indicate that HIF1A-AS1 might serve as a novel therapeutic target for GEM resistance of pancreatic cancer. SIGNIFICANCE: These findings show that a reciprocal feedback of HIF1A-AS1 and HIF1α promotes gemcitabine resistance of pancreatic cancer, which provides an applicable therapeutic target.


Assuntos
Biomarcadores Tumorais/metabolismo , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glicólise , Neoplasias Pancreáticas/tratamento farmacológico , RNA Longo não Codificante/genética , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Desoxicitidina/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Gencitabina
13.
Oncol Lett ; 22(2): 577, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34122628

RESUMO

Colorectal cancer (CRC) is the third most common cancer worldwide. Long non-coding RNA (lncRNA) small nucleolar RNA host gene 8 (SNHG8) acts as an oncogene in different types of cancer, including prostate, breast and ovarian cancer. SNHG8 promotes the tumorigenesis of CRC; however, its underlying molecular mechanism remains unclear. The present study aimed to explore the mechanism of SNHG8 on CRC development via various assays, including western blot, pull-down, PCR and immunofluorescence assays. The results of the present study demonstrated that SNHG8 expression was substantially upregulated in primary tumor tissues from The Cancer Genome Atlas dataset. Western blot and immunofluorescence analyses demonstrated that SNHG8 facilitated cell proliferation and autophagy in CRC cells. Notably, the function of SNHG8 in enhancing autophagy was dependent on autophagy-related gene 7 (ATG7). In addition, western blot analysis indicated that the effect of SNHG8 on autophagy in CRC cells was dependent on the miR-588/ATG7 axis. Taken together, the results of the present study suggest that SNHG8 promotes autophagy in CRC cells.

14.
Front Immunol ; 12: 630318, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790902

RESUMO

Macrophages comprise the front line of defense against various pathogens. Classically activated macrophages (M1), induced by IFN-γ and LPS, highly express inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4 and IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Ak4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP and maintains the homeostasis of cellular nucleotides which is essential for cell functions. However, its role in regulating the function of macrophages is not fully understood. Here we report that Ak4 expression is induced in M1 but not M2 macrophages. Suppressing the expression of Ak4 in M1 macrophages with shRNA or siRNA enhances ATP production and decreases ROS production, bactericidal ability and glycolysis in M1 cells. Moreover, Ak4 regulates the expression of inflammation genes, including Il1b, Il6, Tnfa, Nos2, Nox2, and Hif1a, in M1 macrophages. We further demonstrate that Ak4 inhibits the activation of AMPK and forms a positive feedback loop with Hif1α to promote the expression of inflammation-related genes in M1 cells. Furthermore, RNA-seq analysis demonstrates that Ak4 also regulates other biological processes in addition to the expression of inflammation-related genes in M1 cells. Interestingly, Ak4 does not regulate M1/M2 polarization. Taken together, our study uncovers a potential mechanism linking energy consumption and inflammation in macrophages.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Adenilato Quinase/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Inflamação/etiologia , Macrófagos/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Polaridade Celular , Células Cultivadas , Feminino , Glicólise , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
15.
Ecotoxicol Environ Saf ; 191: 110145, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954214

RESUMO

Arsenic (As) and antimony (Sb) are listed as the priority pollutants by the U.S. Environmental Protection Agency (EPA) and the European Union (EU) due to their toxicity and potential carcinogenicity. It is necessary to investigate their adsorption over soil as such a behavior affects their mobility and bioavailability. In this study, the effect of pH on the adsorption of As(V) and Sb(V) by the black soil was investigated with three systems: the Single system, Binary system, and Sequence system. The operating pH was set at 4.0, 7.0 and 10.0. Based on the Langmuir isothermal and the pseudo-second-order kinetic models, the adsorption for As(V) was always better than Sb(V) in the whole pH range; the best adsorption performance for the two sorbates was achieved at pH of 4.0, followed by 7.0 and 10.0 in the three systems. The reasons could be that the atomic radius of arsenic is smaller than that of antimony, and the positively charged functional groups carried by the inorganic colloids in the soil contributed to binding with the negatively charged As(V)/Sb(V). A lower pH promoted the inorganic colloids to carry more positive charges. Compared to Single system, the maximum adsorption capacity (qm) and the initial adsorption rates (k2qe,cal2) of As(V) and Sb(V) in Binary system decreased obviously, suggesting competitive adsorption occurred when As(V) and Sb(V) coexisted. The findings of this workimprove the understanding of As(V)/Sb(V) adsorption behavior in soil under different situations and would facilitate a comprehensive evaluation on the risk assessment of arsenic and antimony.


Assuntos
Antimônio/análise , Arsênio/análise , Poluentes do Solo/análise , Adsorção , Concentração de Íons de Hidrogênio , Cinética , Solo/química
16.
Medicine (Baltimore) ; 98(44): e17381, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689744

RESUMO

BACKGROUND: This study will assess the effectiveness of electroacupuncture (EA) for pain in patients with osteosarcoma post surgery (OSPS). METHODS: In this study, we will comprehensively search the following electronic databases from inception to the present without language restrictions: Cochrane Library, EMBASE, MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database. Two authors will independently carry out study selection, data extraction, and methodological assessments. RevMan 5.3 software will be used for statistical analysis. RESULTS: The primary outcome is pain intensity. The secondary outcomes consist of event-free survival, overall survival, quality of life, and adverse events. CONCLUSION: The findings of this study will provide helpful evidence of EA treatment for patients with OSPS. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019146696.


Assuntos
Dor do Câncer/terapia , Eletroacupuntura/métodos , Osteossarcoma/terapia , Intervalo Livre de Doença , Eletroacupuntura/efeitos adversos , Humanos , Osteossarcoma/cirurgia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
17.
Cancer Res ; 79(7): 1398-1412, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30563888

RESUMO

Cancer cells are known to undergo metabolic reprogramming, such as glycolysis and glutamine addiction, to sustain rapid proliferation and metastasis. It remains undefined whether long noncoding RNAs (lncRNA) coordinate the metabolic switch in pancreatic cancer. Here we identify a nuclear-enriched antisense lncRNA of glutaminase (GLS-AS) as a critical regulator involved in pancreatic cancer metabolism. GLS-AS was downregulated in pancreatic cancer tissues compared with noncancerous peritumor tissues. Depletion of GLS-AS promoted proliferation and invasion of pancreatic cancer cells both in vitro and in xenograft tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via formation of double stranded RNA with GLS pre-mRNA through ADAR/Dicer-dependent RNA interference. GLS-AS expression was transcriptionally downregulated by nutrient stress-induced Myc. Conversely, GLS-AS decreased Myc expression by impairing the GLS-mediated stability of Myc protein. These results imply a reciprocal feedback loop wherein Myc and GLS-AS regulate GLS overexpression during nutrient stress. Ectopic overexpression of GLS-AS inhibited proliferation and invasion of pancreatic cancer cells by repressing the Myc/GLS pathway. Moreover, expression of GLS-AS and GLS was inversely correlated in clinical samples of pancreatic cancer, while low expression of GLS-AS was associated with poor clinical outcomes. Collectively, our study implicates a novel lncRNA-mediated Myc/GLS pathway, which may serve as a metabolic target for pancreatic cancer therapy, and advances our understanding of the coupling role of lncRNA in nutrition stress and tumorigenesis.Significance: These findings show that lncRNA GLS-AS mediates a feedback loop of Myc and GLS, providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1.large.jpg.See related commentary by Mafra and Dias, p. 1302.


Assuntos
Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Animais , Glutaminase , Camundongos , Camundongos Nus , Nutrientes
18.
Dis Markers ; 2018: 8431219, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581500

RESUMO

AIMS: The study is aimed at studying the incidence of acute kidney injury (AKI) and exploring the potential predictor for AKI in patients with acute pancreatitis. METHODS: A retrospective study adopting a stratified cohort sampling design was performed in a cohort of patients (n = 237) diagnosed with acute pancreatitis without any renal injury. The following information including age, gender, serum creatinine, serum urea nitrogen, serum uric acid, serum cystatin C, fasting serum glucose, serum amylase, serum lipase, serum choline esterase, total protein, albumin, globulin, total bilirubin, direct bilirubin, total bile acids, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, gamma glutamyl transpeptidase, and alkaline phosphatase were collected from each patient when they were diagnosed with acute pancreatitis. Student t-test was conducted to figure out the difference between patients with and without AKI. Univariate and multivariate logistic regression analyses were used for investigating the predictors for AKI in patients with acute pancreatitis. RESULTS: 18 (7.6%) patients in total had developed AKI among the study group. Compared with patients without AKI (1.01 ± 0.26 mg/L), the level of baseline serum cystatin C (CYS-C) was significantly higher in patients with AKI (3.64 ± 2.17 mg/L, P < 0.001). Baseline serum CYS-C (OR = 203.594, P < 0.001) was the independent and significant predictor for AKI in patients with acute pancreatitis. AKI in patients with acute pancreatitis could be identified with a sensitivity of 88.9% at specificity of 100% (AUC = 0.948, 95% CI 0.879-1.000) by baseline serum CYS-C (cut-off value = 1.865 mg/L). CONCLUSIONS: Baseline serum CYS-C shall be adopted to predict the potential risk of AKI in patients with acute pancreatitis.


Assuntos
Injúria Renal Aguda/sangue , Biomarcadores/sangue , Cistatina C/sangue , Pancreatite/complicações , Injúria Renal Aguda/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Estudos Retrospectivos
19.
Oncogene ; 37(44): 5811-5828, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29970904

RESUMO

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/fisiologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Fator 1 Induzível por Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/secundário , RNA Longo não Codificante/metabolismo , Transcrição Gênica , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
20.
J Pathol ; 245(3): 349-360, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29708271

RESUMO

Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1α (HIF-1α) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1α recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1α, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Histona Desacetilases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Repressoras/metabolismo , Acetilação , Adenocarcinoma/genética , Adenocarcinoma/secundário , Animais , Antígenos CD/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/metabolismo , Histona Desacetilases/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Proteínas Repressoras/genética , Elementos de Resposta , Transdução de Sinais , Transcrição Gênica , Carga Tumoral
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