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1.
J Cell Mol Med ; 28(16): e70025, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39164826

RESUMO

Metastasis is a crucial stage in tumour progression, and cancer-associated fibroblasts (CAFs) support metastasis through their participation in extracellular matrix (ECM) stiffness. CD248 is a possible biomarker for non-small cell lung cancer (NSCLC)-derived CAFs, but its role in mediating ECM stiffness to promote NSCLC metastasis is unknown. We investigated the significance of CD248+ CAFs in activating the Hippo axis and promoting connective tissue growth factor (CTGF) expression, which affects the stromal collagen I environment and improves ECM stiffness, thereby facilitating NSCLC metastasis. In this study, we found that higher levels of CD248 in CAFs induced the formation of collagen I, which in turn increased extracellular matrix stiffness, thereby enabling NSCLC cell infiltration and migration. Hippo axis activation by CD248+ CAFs induces CTGF expression, which facilitates the formation of the collagen I milieu in the stromal matrix. In a tumour lung metastasis model utilizing fibroblast-specific CD248 gene knockout mice, CD248 gene knockout mice showed a significantly reduced ability to develop tumour lung metastasis compared to that of WT mice. Our findings demonstrate that CD248+ CAFs activate the Hippo pathway, thereby inducing CTGF expression, which in turn facilitates the collagen I milieu of the stromal matrix, which promotes NSCLC metastasis.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Fator de Crescimento do Tecido Conjuntivo , Matriz Extracelular , Via de Sinalização Hippo , Neoplasias Pulmonares , Camundongos Knockout , Proteínas Serina-Treonina Quinases , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Animais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Matriz Extracelular/metabolismo , Camundongos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Linhagem Celular Tumoral , Antígenos CD/metabolismo , Antígenos CD/genética , Metástase Neoplásica , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Microambiente Tumoral
2.
J Cell Mol Med ; 28(4): e18185, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38396325

RESUMO

Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.


Assuntos
Antineoplásicos , Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Interleucina-8 , Neoplasias Pulmonares , Animais , Camundongos , Antígenos CD , Antígenos de Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Interleucina-8/genética , Interleucina-8/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , NF-kappa B , Humanos
3.
Mol Cancer ; 23(1): 11, 2024 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-38200551

RESUMO

Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality of aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an R-loop scoring model to characterize the R-loop state according to the identified R-loop regulators related to EGFR mutations, tissue origins, and TNM stage. We then evaluated the relationships of the R-loop score with the tumor microenvironment (TME) and treatment response. Furthermore, the potential roles of FANCI-mediated R-loops in LUAD were explored using a series of in vitro experiments. Results showed that malignant cells with low R-loop scores displayed glycolysis and epithelial-mesenchymal transition pathway activation and immune escape promotion, thereby hampering the antitumor therapeutic effects. Cell communication analysis suggested that low R-loop scores contributed to T cell exhaustion. We subsequently validated the prognostic value of R-loop scores by using bulk transcriptome datasets across 33 tumor types. The R-loop scoring model well predicted patients' therapeutic response to targeted therapy, chemotherapy, or immunotherapy in 32 independent cohorts. Remarkably, changes in R-loop distribution mediated by FANCI deficiency blocked the activity of Ras signaling pathway, suppressing tumor-cell proliferation and dissemination. In conclusion, this study reveals the underlying molecular mechanism of metabolic reprogramming and T cell exhaustion under R-loop score patterns, and the changes in R-loops mediated by R-loop regulators resulting in tumor progression. Therefore, incorporating anticancer methods based on R-loop or R-loop regulators into the treatment schemes of precision medicine may be beneficial.


Assuntos
Adenocarcinoma de Pulmão , Anemia de Fanconi , Neoplasias Pulmonares , Humanos , Estruturas R-Loop , Reprogramação Metabólica , Evasão da Resposta Imune , Adenocarcinoma de Pulmão/genética , Comunicação Celular , Análise de Célula Única , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética
4.
Gastroenterology ; 165(6): 1488-1504.e20, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37634735

RESUMO

BACKGROUND & AIMS: Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS: Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS: SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS: The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.


Assuntos
Células Acinares , Pancreatite Crônica , Animais , Camundongos , Receptores de Esfingosina-1-Fosfato , Células Estreladas do Pâncreas , Pancreatite Crônica/induzido quimicamente , Autofagia , Proteínas Quinases Ativadas por AMP , Fibrose , Monofosfato de Adenosina , Hipóxia , Mamíferos
5.
Environ Sci Technol ; 58(8): 4019-4028, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38366980

RESUMO

Humic acid (HA) ubiquitously existing in aquatic environments has been reported to significantly impact permanganate (KMnO4) decontamination processes. However, the underlying mechanism of the KMnO4/HA system remained elusive. In this study, an enhancing effect of HA on the KMnO4 oxidation of diclofenac (DCF) was observed over a wide solution pH range of 5-9. Surprisingly, the mechanism of HA-induced enhancement varied with solution pH. Quenching and chemical probing experiments revealed that manganese intermediates (Mn(III)-HA and MnO2) were responsible for the enhancement under acidic conditions but not under neutral and alkaline conditions. By combining KMnO4 decomposition, galvanic oxidation process experiments, electrochemical tests, and FTIR and XPS analysis, it was interestingly found that HA could effectively mediate the electron transfer from DCF to KMnO4 in neutral and alkaline solutions, which was reported for the first time. The formation of an organic-catalyst complex (i.e., HA-DCF) with lower reduction potential than the parent DCF was proposed to be responsible for the accelerated electron transfer from DCF to KMnO4. This electron transfer likely occurred within the complex molecule formed through the interaction between HA-DCF and KMnO4 (i.e., HA-DCF-KMnO4). These results will help us gain a more comprehensive understanding of the role of HA in the KMnO4 oxidation processes.


Assuntos
Óxidos , Poluentes Químicos da Água , Óxidos/química , Compostos de Manganês/química , Substâncias Húmicas/análise , Diclofenaco/química , Elétrons , Oxirredução , Poluentes Químicos da Água/análise
6.
Cell Mol Life Sci ; 80(10): 283, 2023 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-37688662

RESUMO

Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs' immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.


Assuntos
Doenças Autoimunes , Metformina , Humanos , Metformina/farmacologia , Metabolismo dos Lipídeos , Ciclo do Ácido Cítrico , Ácidos Graxos , Células Dendríticas
7.
Biochem Genet ; 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38334875

RESUMO

There is a potential link between rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). The aim of this study is to investigate the molecular processes that underlie the development of these two conditions by bioinformatics methods. The gene expression samples for RA (GSE77298) and IPF (GSE24206) were retrieved from the Gene Expression Omnibus (GEO) database. After identifying the overlapping differentially expressed genes (DEGs) for RA and IPF, we conducted functional annotation, protein-protein interaction (PPI) network analysis, and hub gene identification. Finally, we used the hub genes to predict potential medications for the treatment of both disorders. We identified 74 common DEGs for further analysis. Functional analysis demonstrated that cellular components, biological processes, and molecular functions all played a role in the emergence and progression of RA and IPF. Using the cytoHubba plugin, we identified 7 important hub genes, namely COL3A1, SDC1, CCL5, CXCL13, MMP1, THY1, and BDNF. As diagnostic indicators for RA, SDC1, CCL5, CXCL13, MMP1, and THY1 showed favorable values. For IPF, COL3A1, SDC1, CCL5, CXCL13, THY1, and BDNF were favorable diagnostic markers. Furthermore, we predicted 61 Chinese and 69 Western medications using the hub genes. Our research findings demonstrate a shared pathophysiology between RA and IPF, which may provide new insights for more mechanistic research and more effective treatments. These common pathways and hub genes identified in our study offer potential opportunities for developing more targeted therapies that can address both disorders.

8.
Int J Mol Sci ; 25(11)2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38891796

RESUMO

Among various non-covalent interactions, selenium-centered chalcogen bonds (SeChBs) have garnered considerable attention in recent years as a result of their important contributions to crystal engineering, organocatalysis, molecular recognition, materials science, and biological systems. Herein, we systematically investigated π-hole-type Se∙∙∙O/S ChBs in the binary complexes of SeO2 with a series of O-/S-containing Lewis bases by means of high-level ab initio computations. The results demonstrate that there exists an attractive interaction between the Se atom of SeO2 and the O/S atom of Lewis bases. The interaction energies computed at the MP2/aug-cc-pVTZ level range from -4.68 kcal/mol to -10.83 kcal/mol for the Se∙∙∙O chalcogen-bonded complexes and vary between -3.53 kcal/mol and -13.77 kcal/mol for the Se∙∙∙S chalcogen-bonded complexes. The Se∙∙∙O/S ChBs exhibit a relatively short binding distance in comparison to the sum of the van der Waals radii of two chalcogen atoms. The Se∙∙∙O/S ChBs in all of the studied complexes show significant strength and a closed-shell nature, with a partially covalent character in most cases. Furthermore, the strength of these Se∙∙∙O/S ChBs generally surpasses that of the C/O-H∙∙∙O hydrogen bonds within the same complex. It should be noted that additional C/O-H∙∙∙O interactions have a large effect on the geometric structures and strength of Se∙∙∙O/S ChBs. Two subunits are connected together mainly via the orbital interaction between the lone pair of O/S atoms in the Lewis bases and the BD*(OSe) anti-bonding orbital of SeO2, except for the SeO2∙∙∙HCSOH complex. The electrostatic component emerges as the largest attractive contributor for stabilizing the examined complexes, with significant contributions from induction and dispersion components as well.


Assuntos
Calcogênios , Bases de Lewis , Oxigênio , Selênio , Enxofre , Bases de Lewis/química , Calcogênios/química , Selênio/química , Enxofre/química , Oxigênio/química , Modelos Moleculares , Ligação de Hidrogênio , Óxidos de Selênio/química , Termodinâmica
9.
Int J Mol Sci ; 25(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38791191

RESUMO

Cancer immunotherapy relies on the insight that the immune system can be used to defend against malignant cells. The aim of cancer immunotherapy is to utilize, modulate, activate, and train the immune system to amplify antitumor T-cell immunity. In parallel, the immune system response to damaged tissue is also crucial in determining the success or failure of an implant. Due to their extracellular matrix mimetics and tunable chemical or physical performance, hydrogels are promising platforms for building immunomodulatory microenvironments for realizing cancer therapy and tissue regeneration. However, submicron or nanosized pore structures within hydrogels are not favorable for modulating immune cell function, such as cell invasion, migration, and immunophenotype. In contrast, hydrogels with a porous structure not only allow for nutrient transportation and metabolite discharge but also offer more space for realizing cell function. In this review, the design strategies and influencing factors of porous hydrogels for cancer therapy and tissue regeneration are first discussed. Second, the immunomodulatory effects and therapeutic outcomes of different porous hydrogels for cancer immunotherapy and tissue regeneration are highlighted. Beyond that, this review highlights the effects of pore size on immune function and potential signal transduction. Finally, the remaining challenges and perspectives of immunomodulatory porous hydrogels are discussed.


Assuntos
Hidrogéis , Neoplasias , Hidrogéis/química , Humanos , Porosidade , Animais , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Imunomodulação/efeitos dos fármacos , Engenharia Tecidual/métodos , Agentes de Imunomodulação/química , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/uso terapêutico , Microambiente Tumoral/imunologia
10.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(1): 81-86, 2024 Jan 20.
Artigo em Zh | MEDLINE | ID: mdl-38322517

RESUMO

Objective: To construct type Ⅰ collagen gels with different stiffness and to investigate the effects of three-dimensional (3D) culture environments of the gels on the morphology, free migration ability, and cell killing function of natural killer (NK) cells. Methods: Type Ⅰ collagen was isolated from the tails of Sprague Dawley (SD) rats and collagen gels with different levels of stiffnesses were prepared accordingly. The microstructure of the collagen gels was observed by laser confocal microscopy. The stiffness of the collagen gels was assessed by measuring the plateau modulus with a rheometer. NK-92MI cells were cultured in collagen gels with different levels of stiffness. The morphology of NK-92MI cells was observed by inverted microscope. High content imaging system was used to record the free migration process of NK-92MI cells and analyze the migration speed and distance. NK-92MI cells were cultured with type Ⅰ collagen gels with different levels of stiffness for 24 h and 48 h and, then, co-cultured with human colorectal DLD-1, a human adenocarcinoma epithelial cell line. CCK8 assay was performed to determine the proliferation rate of DLD-1 cells and analyze the cell killing ability of NK-92MI cells. Results: Low-stiffness type Ⅰ collagen gel and high-stiffness type Ⅰ collagen gel with the respective stiffness of (10.970±2.10) Pa and (114.50±3.40) Pa were successfully prepared. Compared with those cultured with the low-stiffness type Ⅰ collagen gel, the NK-92MI cells in the high-stiffness type Ⅰ collagen gel showed a more elongated shape (P<0.05), the mean area of the cells was reduced ([69.88±26.97] µm2 vs. [46.59±21.62] µm2, P<0.05), the roundness of the cells decreased (0.82±0.12 vs. 0.78±0.18, P<0.05), cell migration speed decreased ([2.50±0.91] µm/min vs. [1.70±0.72] µm/min, P<0.001) and the migration distance was shortened ([147.10±53.74] µm vs. [98.03± 40.95] µm, P<0.0001), with all the differences being statistically significant. Compared with those cultured with the low-stiffness type Ⅰ collagen gel, NK-92MI cells cultured with high-stiffness type Ⅰ collagen gel for 24 h could promote DLD-1 cell proliferation, with the proliferation rate being (46.39±12.79)% vs. (65.87±4.45)% (P<0.05) and reduce the cell killing ability. Comparison of the cells cultured for 48 h led to similar results, with the proliferation rates being (31.36±2.88)% vs. (74.57±2.16)% (P<0.05), and the differences were all statistically significant. Conclusion: The 3D culture environment of type Ⅰ collagen gels with different levels of stiffness alters the morphology, migration ability, and killing function of NK-92MI cells. This study provides the research basis for exploring and understanding the mechanisms by which the biomechanical microenvironment affects the immune response of NK cells, as well as laying the theoretical foundation for optimizing immunotherapy protocols.


Assuntos
Colágeno Tipo I , Células Matadoras Naturais , Ratos , Animais , Humanos , Colágeno Tipo I/metabolismo , Linhagem Celular Tumoral , Ratos Sprague-Dawley , Células Matadoras Naturais/metabolismo , Colágeno/química , Géis
11.
J Cell Mol Med ; 27(3): 456-469, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36651490

RESUMO

Among breast cancer patients, metastases are the leading cause of death. Despite decades of effort, little progress has been made to improve the treatment of breast cancer metastases, especially triple-negative breast cancer (TNBC). The extracellular matrix plays an important role in tumour growth and metastasis by causing its deposition, remodelling, and signalling. As we know, the process of fibrosis results in excessive amounts of extracellular matrix being deposited within the cells. So, it will be interesting to study if the use of anti-fibrotic drugs in combination with conventional chemotherapy drugs can produce synergistic antitumor effects. In this study, we assessed the efficacy of Pirfenidone (PFD), an FDA-approved medication for the treatment of idiopathic pulmonary fibrosis, on TNBC cells as well as its anti-tumour effects in xenograft tumour model. PFD inhibited in a dose-dependent manner breast cancer cell proliferation, migration, and invasion, while promoted their apoptosis in vitro. PFD also suppressed TGF-ß-induced activation of Smad signalling pathway and expression level of EMT-inducing transcription factors (e.g. SNAI2, TWIST1, ZEB1) as well as the mesenchymal genes such as VIMENTIN and N-Cadherin. On the contrary, the expression level of epithelial marker gene E-Cadherin was up-regulated in the presence of PFD. In vivo, PFD alone exerted a milder but significant anti-tumour effect than the chemotherapy drug nanoparticle albumin-bound paclitaxel (nab-PTX) did in the breast cancer xenograft mouse model. Interestingly, PFD synergistically boosted the cancer-killing effect of nab-PTX. Furthermore, Our data suggest that PFD suppressed breast cancer metastasis by inhibiting the activity of the TGFß/SMAD pathway.


Assuntos
Fator de Crescimento Transformador beta , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Proteínas Smad/metabolismo
12.
Cancer Sci ; 114(9): 3623-3635, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37488751

RESUMO

Pancreatic cancer (PC) development faces significant metabolic stress due to metabolic reprogramming and a distinct hypovascular nature, often leading to glucose and glutamine depletion. However, the adaption mechanisms by which PC adapts to these metabolic challenges have not yet been completely explored. Here, we found that metabolic stress induced by glucose and glutamine deprivation led to an overexpression of ZNFX1 antisense RNA 1 (ZFAS1). This overexpression played a significant role in instigating PC cell epithelial-mesenchymal transition (EMT) and metastasis. Mechanistically, ZFAS1 enhanced the interaction between AMPK, a key kinase, and ZEB1, the primary regulator of EMT. This interaction resulted in the phosphorylation and subsequent stabilization of ZEB1. Interestingly, ZEB1 also reciprocally influenced the transcription of ZFAS1 by binding to its promoter. Furthermore, when ZFAS1 was depleted, the nutrient deprivation-induced EMT of PC cells and lung metastasis in nude mice were significantly inhibited. Our investigations also revealed that ZFAS1-rich exosomes released from cells suffering glucose and glutamine deprivation promoted the EMT and metastasis of recipient PC cells. Corroborating these findings, a correlated upregulation of ZFAS1 and ZEB1 expression was observed in PC tissues and was associated with a poor overall survival rate for patients. Our findings highlight the involvement of a long noncoding RNA-driven metabolic adaptation in promoting EMT and metastasis of PC, suggesting ZFAS1 as a promising novel therapeutic target for PC metabolic treatment.


Assuntos
MicroRNAs , Neoplasias Pancreáticas , RNA Longo não Codificante , Animais , Camundongos , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Transição Epitelial-Mesenquimal/genética , Camundongos Nus , Glutamina/metabolismo , Neoplasias Pancreáticas/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proliferação de Células/genética , Neoplasias Pancreáticas
13.
Altern Ther Health Med ; 29(8): 286-291, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37573602

RESUMO

Objective: To observe the comprehensive treatment effect of Traditional Chinese Medicine on ventilator-related diseases. Methods: From January 2021 to August 2022, a total of 80 patients with ventilator-associated pneumonia were selected and divided into a test group and a matched control group based on the random number table, with 40 cases in each group. The control group received traditional Western medical care, and all patients were given tigecycline intravenously. The patients in the test group were treated with integrated traditional Chinese and Western medicine, and all patients were given tigecycline for injection by intravenous drip combined with Qingfei Huatan decoction orally. The two groups' therapeutic outcomes were contrasted, namely: procalcitonin (PCT), tumor necrosis factor (TNF)-α, hypersensitive C-reactive protein (CRP), blood oxygen saturation (PaO2), and white blood cell (WBC) count. Acute physiology and persistent health scores, clinical lung infection score, mechanical ventilation time, body temperature recovery time, and hospitalization time were recorded. Results: The effective Of cure in the test group was 37/40 (92.50%) and in the control group it was 30/40 (75.00%). The test group outperformed the control group by a considerable margin (P < .05). The levels of PCT, TNF-α, and hs-CRP were lower in the two groups, and the levels of TNF-α, PCT, and hs-CRP reduced with treatment (P < .05). The white blood cell and PaO2 levels were lower in the experimental group. APACHE II and CPIS scores decreased (P < .05). two groups,Postoperative body temperature recovery time, mechanical ventilation time, and hospital stay were all shortened (P < .05). Conclusion: The combination of traditional Chinese medicine and Western medicine has a positive clinical impact on ventilator-related diseases.


Assuntos
Proteína C-Reativa , Fator de Necrose Tumoral alfa , Humanos , Medicina Tradicional Chinesa , Tigeciclina , Prognóstico , Pró-Calcitonina , Ventiladores Mecânicos , Oxigênio
14.
Int J Mol Sci ; 24(22)2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-38003384

RESUMO

In recent years, the non-covalent interactions between chalcogen centers have aroused substantial research interest because of their potential applications in organocatalysis, materials science, drug design, biological systems, crystal engineering, and molecular recognition. However, studies on π-hole-type chalcogen∙∙∙chalcogen interactions are scarcely reported in the literature. Herein, the π-hole-type intermolecular chalcogen∙∙∙chalcogen interactions in the model complexes formed between XO2 (X = S, Se, Te) and CH3YCH3 (Y = O, S, Se, Te) were systematically studied by using quantum chemical computations. The model complexes are stabilized via one primary X∙∙∙Y chalcogen bond (ChB) and the secondary C-H∙∙∙O hydrogen bonds. The binding energies of the studied complexes are in the range of -21.6~-60.4 kJ/mol. The X∙∙∙Y distances are significantly smaller than the sum of the van der Waals radii of the corresponding two atoms. The X∙∙∙Y ChBs in all the studied complexes except for the SO2∙∙∙CH3OCH3 complex are strong in strength and display a partial covalent character revealed by conducting the quantum theory of atoms in molecules (QTAIM), a non-covalent interaction plot (NCIplot), and natural bond orbital (NBO) analyses. The symmetry-adapted perturbation theory (SAPT) analysis discloses that the X∙∙∙Y ChBs are primarily dominated by the electrostatic component.


Assuntos
Calcogênios , Calcogênios/química , Ligação de Hidrogênio , Teoria Quântica , Eletricidade Estática
15.
Zhongguo Yi Liao Qi Xie Za Zhi ; 47(2): 201-203, 2023 Feb 08.
Artigo em Zh | MEDLINE | ID: mdl-37096476

RESUMO

With the development of medical aesthetics industry in China, sodium hyaluronic is injected into the facial dermis with multi needles to relieve wrinkles, thick pores, skin relaxation and other aging problems, is more and more popular nowadays. The wide application of mesotherapy for cosmetic injection and the subsequent adverse events are widely reported. This study attempts to explore the adverse events and countermeasures for the application of mesotherapy from the perspective of medical device supervision.


Assuntos
Técnicas Cosméticas , Mesoterapia , Técnicas Cosméticas/efeitos adversos , Agulhas , Pele , Injeções
16.
Cancer Sci ; 113(10): 3633-3636, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35965405

RESUMO

Four types of A-related RNA modification regulators interact with each other and even the crosstalk between the regulators could characterize the tumor immune microenvironment infiltration patterns, chemosensitivity, and cancer prognosis in patients with pan-cancer.


Assuntos
Adenosina , Neoplasias , Humanos , Neoplasias/patologia , Prognóstico , RNA/genética , Microambiente Tumoral/genética
17.
Mutagenesis ; 37(3-4): 213-225, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-35869703

RESUMO

Two prototypical genotoxicants, benzo[a]pyrene (B[a]P) and colchicine (COL), were selected as model compounds to deduce their quantitative genotoxic dose-response relationship at low doses in a multi-endpoint genotoxicity assessment platform. Male Sprague-Dawley rats were treated with B[a]P (2.5-80 mg/kg bw/day) and COL (0.125-2 mg/kg bw/day) daily for 28 days. The parameters included were as follows: comet assay in the peripheral blood and liver, Pig-a gene mutation assay in the peripheral blood, and micronucleus test in the peripheral blood and bone marrow. A significant increase was observed in Pig-a mutant frequency in peripheral blood for B[a]P (started at 40 mg/kg bw/day on Day 14, started at 20 mg/kg bw/day on Day 28), whereas no statistical difference for COL was observed. Micronucleus frequency in reticulocytes of the peripheral blood and bone marrow increased significantly for B[a]P (80 mg/kg bw/day on Day 4, started at 20 mg/kg bw/day on Days 14 and 28 in the blood; started at 20 mg/kg bw/day on Day 28 in the bone marrow) and COL (started at 2 mg/kg bw/day on Day 14, 1 mg/kg bw/day on Day 28 in the blood; started at 1 mg/kg bw/day on Day 28 in the bone marrow). No statistical variation was found in indexes of comet assay at all time points for B[a]P and COL in the peripheral blood and liver. The dose-response relationships of Pig-a and micronucleus test data were analyzed for possible point of departures using three quantitative approaches, i.e., the benchmark dose, breakpoint dose, and no observed genotoxic effect level. The practical thresholds of the genotoxicity of B[a]P and COL estimated in this study were 0.122 and 0.0431 mg/kg bw/day, respectively, and our results also provided distinct genotoxic mode of action of the two chemicals.


Assuntos
Benzo(a)pireno , Colchicina , Ratos , Animais , Masculino , Benzo(a)pireno/toxicidade , Colchicina/toxicidade , Ratos Sprague-Dawley , Eritrócitos , Testes para Micronúcleos/métodos , Ensaio Cometa/métodos , Reticulócitos , Dano ao DNA , Relação Dose-Resposta a Droga , Testes de Mutagenicidade/métodos
18.
J Cardiovasc Pharmacol ; 80(5): 709-717, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36070614

RESUMO

ABSTRACT: Cardiac hypertrophy is a feature of hypertrophic cardiomyopathy (HCM), which could lead to heart failure and other cardiovascular diseases. Cardiomyocyte hypertrophy (CH) is the primary characteristic of cardiac hypertrophy. Long noncoding RNA (lncRNA, lincRNA) plays an important role in CH. In this study, the expression of linc-RMRP and its correlation with cardiac hypertrophy were analyzed in cardiac tissues of patients with HCM. Real-time qPCR and western blotting measured the expressions of lincf-RMRP, miR-1, and hypertrophic marker genes. RNA pulldown and luciferase reporter gene assays were performed to validate the combination between linc-RMRP and miR-1. We confirmed that Linc-RMRP was upregulated in both cardiac hypertrophy tissues and phenylephrine (PE)-induced CH cells, and the cells presented hypertrophic features, enlarged cell surface area and volume, elevated total protein contents, and increased expressions of ANP, BNP, ß-MHC, and activated p70S6K and 4EBP1. Bioinformatic analysis found that linc-RMRP directly bonds to miR-1. RNA pulldown, mutation, and luciferase reporter gene assays verified this combination. Silencing linc-RMRP significantly attenuated hypertrophic responses induced by PE while the expression of miR-1 was released. However, the transfection of miR-1 inhibitor reversed the effects of linc-RMRP knockdown exerted on PE-treated cardiomyocytes. In summary, our study identified the modulatory role linc-RMRP played in regulating PE-induced CH by means of binding miR-1, and this might provide a new target for cardiac hypertrophy therapy.


Assuntos
MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Miócitos Cardíacos , Fenilefrina/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiotônicos/farmacologia , Luciferases/metabolismo , Luciferases/farmacologia
19.
BMC Pulm Med ; 22(1): 458, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456932

RESUMO

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS: Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION: Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Fibrose Pulmonar , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fatores de Risco
20.
Molecules ; 27(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36234943

RESUMO

Polygonum capitatum, known as "Tou Hua Liao" (Chinese name), is a crucial source of Hmong medicinal plants that has benefited human health for a long time. This folk-medicinal plant is widely distributed in the south-west of China for the treatment of various urologic disorders including urinary tract infections, pyelonephritis, and urinary calculus. The purpose of this paper was to provide a systematic and comprehensive overview of the traditional usages, botany, phytochemistry, pharmacology, pharmacokinetics and clinical applications of this flora. Up until the end of 2022, at least 91 compounds had been reported from P. capitatum, mainly covering the classes of flavonoids, lignanoids, phenols and other components. The compounds and extracts isolated from P. capitatum exhibit a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, antimicrobial, anticancer, analgesic, hypothermic, diuretic and other pharmacological effects. Qualitative and quantitative chemical analyses were also covered. Furthermore, the possible development trends and perspectives for future research on this medicinal plant were also discussed.


Assuntos
Plantas Medicinais , Polygonum , Anti-Inflamatórios/farmacologia , Antioxidantes/uso terapêutico , Diuréticos , Etnofarmacologia , Flavonoides/análise , Humanos , Fenóis , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Plantas Medicinais/química , Polygonum/química
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