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1.
JCI Insight ; 9(17)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39253973

RESUMO

Elevated numbers of antibody-secreting cells (ASCs) and anti-double-stranded DNA (anti-dsDNA) antibodies are found in nasal polyp (NP) tissue. The presence of anti-dsDNA IgG in tissue prospectively predicts recurrent NP but the characteristics of the source ASCs are unknown. Here, we investigated whether NP B cells expressing the extrafollicular marker EBI2 have increased propensity for autoantibody production and evaluated the molecular characteristics of NP ASCs. NPs showed increased frequencies of anti-dsDNA IgG and total IgG ASCs compared with tonsils, with more pronounced differences among EBI2+ cells. In NPs, EBI2+ cells were frequently double negative (IgD-CD27-) and ASCs. Single-cell RNA-Seq analysis of tonsils and NPs revealed substantial differences in B lineage composition, including differences in percentages of ASCs, germinal centers, proliferative cells, and non-ASCs. NPs exhibited higher expression of specific isotypes (IGHE, IGHA1, IGHA2, and IGHG4) and mature plasma genes, including SDC1 and XBP1, than tonsils. Gene Ontology biological processes indicated upregulated NF-κB and downregulated apoptosis pathways in NP ASCs. Together, these data indicate that NP EBI2+ ASCs secret increased total and anti-dsDNA IgG compared with those from tonsils and had molecular features of mature plasma cell differentiation.


Assuntos
Células Produtoras de Anticorpos , Imunoglobulina G , Pólipos Nasais , Humanos , Pólipos Nasais/imunologia , Pólipos Nasais/patologia , Pólipos Nasais/metabolismo , Células Produtoras de Anticorpos/imunologia , Células Produtoras de Anticorpos/metabolismo , Masculino , Feminino , Adulto , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Pessoa de Meia-Idade , Tonsila Palatina/imunologia , Tonsila Palatina/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Antígenos de Histocompatibilidade Menor/imunologia , Anticorpos Antinucleares/imunologia , Idoso , Adulto Jovem
2.
Tissue Barriers ; : 2399235, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39225375

RESUMO

BACKGROUND: Oncostatin M (OSM) may be involved in the promotion of mucosal epithelial barrier dysfunction in patients with eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) by inducing matrix metalloproteinase (MMP) -1 and -7. The aim was to evaluate the roles and mechanisms of action of OSM on MMP-1 and -7 synthesis from nasal epithelial cells (NECs). METHODS: OSM, OSM receptor (OSMR), MMP-1 and -7 expression was evaluated in nasal mucosa or primary NECs from scrapings by quantitative polymerase chain reaction (qPCR), immunofluorescence and immunohistochemistry. OSM and other cytokines were used to stimulate air-liquid interface (ALI) cultured NECs. qPCR, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence were used to evaluate the expression of OSMR, MMP-1, -7 and occludin in NECs. RESULTS: Elevated levels of OSMRß, MMP-1 and -7 were found in the tissues and scraped NECs of Eos CRSwNP in comparison to them obtained from the inferior turbinate (IT) and control subjects. The levels of OSM and OSMRß mRNA in tissues were positively correlated with the levels of MMP-1 and -7. OSM stimulation of NECs increased the expression of MMP-1 and -7, and the responses were suppressed by a STAT3 inhibitor, and a PI3K inhibitor respectively. In parallel studies, we found that stimulation with OSM disrupted the localization of occludin, a tight junction protein in NECs. The response was suppressed by a pan-MMP inhibitor. CONCLUSION: OSM induces the synthesis and release of MMP-1 and -7 in NECs. Furthermore, MMP-1 and -7 promote mucosal epithelial barrier dysfunction in patients with Eos CRSwNP.

3.
Int Immunopharmacol ; 142(Pt A): 113089, 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39244897

RESUMO

Interleukin-10 (IL-10) exerts complex effects on tumor growth, exhibiting both pro- and anti-tumor properties. Recent focus on the anti-inflammatory properties of IL-10 has highlighted its potential anti-tumor properties, particularly through the enhancement of CD8+ T cell activity. However, further research is needed to fully elucidate its other anti-tumor mechanisms. Our study investigates novel anti-tumor mechanisms of IL-10 in a murine mammary carcinoma model (4T1). We found that IL-10 overexpression in mouse 4T1 cells suppressed tumor growth in vivo. This suppression was accompanied by an increase in IFN-γ-secreting CD8+ T cells and a decrease in myeloid-derived suppressor cells (MDSCs) in tumor tissue. In vitro experiments showed that IL-10-rich tumor cell-derived supernatants inhibited myeloid cell differentiation into monocytic and granulocytic MDSCs while reducing MDSCs migration. In addition, IL-10 overexpression downregulated CXCL5 expression in 4T1 cells, resulting in decreased CXCR2+ MDSCs infiltration. Using RAG1-deficient mice and CXCL5 knockdown tumor models, we demonstrated that the anti-tumor effects of IL-10 depend on both CD8+ T cells and reduced MDSC infiltration. IL-10 attenuated the immunosuppressive tumor microenvironment by enhancing CD8+ T cell activity and inhibiting MDSCs infiltration. In human breast cancer, we observed a positive correlation between CXCL5 expression and MDSC infiltration. Our findings reveal a dual mechanism of IL-10-mediated tumor suppression: (1) direct enhancement of CD8+ T cell activity and (2) indirect reduction of immunosuppressive MDSCs through CXCL5 downregulation and inhibition of myeloid cell differentiation. This study provides new insights into the role of IL-10 in anti-tumor immunity and suggests potential strategies for breast cancer immunotherapy by modulating the IL-10-CXCL5-MDSCs axis.

4.
Int J Biol Sci ; 20(11): 4277-4296, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247810

RESUMO

Recent investigations have revealed that oxidative stress can lead to neuronal damage and disrupt mitochondrial and endoplasmic reticulum functions after intracerebral hemorrhage (ICH). However, there is limited evidence elucidating their role in maintaining neuronal homeostasis. Metabolomics analysis, RNA sequencing, and CUT&Tag-seq were performed to investigate the mechanism underlying the interaction between the PERK/ATF4 branch of the endoplasmic reticulum stress (ERS) and mitochondrial one-carbon (1C) metabolism during neuronal resistance to oxidative stress. The association between mitochondrial 1C metabolism and the PERK/ATF4 branch of the ERS after ICH was investigated using transcription factor motif analysis and co-immunoprecipitation. The findings revealed interactions between the GRP78/PERK/ATF4 and mitochondrial 1C metabolism, which are important in preserving neuronal homeostasis after ICH. ATF4 is an upstream transcription factor that directly regulates the expression of 1C metabolism genes. Additionally, the GRP78/PERK/ATF4 forms a negative regulatory loop with MTHFD2 because of the interaction between GRP78 and MTHFD2. This study presents evidence of disrupted 1C metabolism and the occurrence of ERS in neurons post-ICH. Supplementing exogenous NADPH or interfering with the PERK/ATF4 could reduce symptoms related to neuronal injuries, suggesting new therapeutic prospects for ICH.


Assuntos
Fator 4 Ativador da Transcrição , Hemorragia Cerebral , Estresse do Retículo Endoplasmático , Mitocôndrias , Neurônios , eIF-2 Quinase , Fator 4 Ativador da Transcrição/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Animais , Neurônios/metabolismo , eIF-2 Quinase/metabolismo , Hemorragia Cerebral/metabolismo , Mitocôndrias/metabolismo , Chaperona BiP do Retículo Endoplasmático/metabolismo , Carbono/metabolismo , Ratos , Camundongos , Masculino , Ratos Sprague-Dawley , Estresse Oxidativo
5.
Neuro Oncol ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093693

RESUMO

BACKGROUND: Self-renewal of glioma stem cells (GSCs) is responsible for glioblastoma (GBM) therapy-resistant and recurrence. Tumor necrosis factor α (TNFα) and TNF signaling pathway display an antitumor activity in preclinical models and in tumor patients. However, TNFα exhibits no significance for glioma clinical prognosis based on Glioma Genome Atlas database. This study aimed to explore whether TNFα of tumor microenvironment maintains self-renewal of GSCs and promotes worse prognosis in glioma patient. METHODS: Spatial transcriptomics, immunoblotting, sphere formation assay, extreme limiting dilution, and gene expression analysis were used to determine the role of TNFα on GSC's self-renewal. Mass spectrometry, RNA-sequencing detection, bioinformatic analyses, qRT-RNA, immunofluorescence, immunohistochemistry, single cell RNA sequencing, in vitro and in vivo models were used to uncover the mechanism of TNFα-induced GSC self-renewal. RESULTS: Low level of TNFα displays a promoting effect on GSC self-renewal and worse glioma prognosis. Mechanistically, Vasorin (VASN) mediated TNFα-induced self-renewal by potentiating glycolysis. Lactate produced by glycolysis inhibits the TNFα secretion of tumor-associated macrophages (TAMs) and maintains TNFα in a low level. CONCLUSIONS: TNFα-induced GSC self-renewal mediated by VASN provides a possible explanation for the failures of endogenous TNFα effect on GBM. Combination of targeting VASN and TNFα anti-tumor effect may be an effective approach for treating GBM.

6.
Ecotoxicol Environ Saf ; 283: 116970, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39216224

RESUMO

Most patients diagnosed with pancreatic cancer are initially at an advanced stage, and radiotherapy resistance impact the effectiveness of treatment. This study aims to investigate the effects of endocrine disruptor Di-(2-ethylhexyl) phthalate (DEHP) on various biological behaviors and the radiotherapy sensitivity of pancreatic cancer cells, as well as its potential mechanisms. Our findings indicate that exposure to DEHP promotes the proliferation of various cancer cells, including those from the lung, breast, pancreas, and liver, in a time- and concentration-dependent manner. Furthermore, DEHP exposure could influence several biological behaviors of pancreatic cancer cells in vivo and vitro. These effects include reducing cell apoptosis, causing G0/G1 phase arrest, increasing migration capacity, enhancing tumorigenicity, elevating the proportion of cancer stem cells (CSCs), and upregulating expression levels of CSCs markers such as CD133 and BMI1. DEHP exposure can also increase radiation resistance, which can be reversed by downregulating BMI1 expression. In summary our research suggests that DEHP exposure can lead to pancreatic cancer progression and radiotherapy resistance, and the mechanism may be related to the upregulation of BMI1 expression, which leads to the increase of CSCs properties.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Células-Tronco Neoplásicas , Neoplasias Pancreáticas , Tolerância a Radiação , Dietilexilftalato/toxicidade , Neoplasias Pancreáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação , Humanos , Linhagem Celular Tumoral , Disruptores Endócrinos/toxicidade , Tolerância a Radiação/efeitos dos fármacos , Animais , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Camundongos , Camundongos Nus , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Progressão da Doença
7.
ACS Pharmacol Transl Sci ; 7(7): 1951-1970, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-39022361

RESUMO

Corticotroph pituitary neuroendocrine tumors (PitNETs), associated with Cushing's disease (CD), have limited treatment options other than surgical resection. Bone morphogenetic protein 4 (BMP4), a potential therapeutic target, is decreased in patients with CD. Previous studies have identified BMPSB4 as a potent agonist of the BMP4 signaling pathway. Here, we investigated the effect of BMPSB4 on the corticotroph PitNET cell line AtT20/D16v-F2 and explored the underlying mechanisms and therapeutic potential. We verified the low expression patterns of BMP4 and downstream p-SMAD1/5/9 in CD samples at the transcriptional and protein levels. In addition, BMPSB4 activated SMAD1/5/9 in a time- and concentration-dependent manner, with concomitant inhibitory effects on AtT20/D16v-F2 cells. Further RNA sequencing, transmission electron microscopy (TEM), and transfection with the mRFP-EGFP-LC3 adenoviral vector revealed that BMPSB4 induced cellular autophagy, which was the basis for the inhibitory effect of BMPSB4. Moreover, we demonstrated that autophagy induced by BMPSB4 was achieved through the SMADs-dependent pathway. In vivo, BMPSB4 inhibited tumor growth and significantly reduced adrenocorticotrophin (ACTH) and corticosterone (CORT) secretion, thereby alleviating the CD phenotype. In conclusion, this study identified BMPSB4 as an effective therapeutic agent for CD. BMPSB4 activates autophagy through a SMADs-dependent pathway, which in turn promotes autophagy-mediated cell death. Our work further elucidates the mechanism of the BMP4 signaling pathway in CD and suggests broad prospects for the development and application of BMPSB4 in CD therapy.

8.
Sensors (Basel) ; 24(14)2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39065984

RESUMO

There are various indoor fingerprint localization techniques utilizing the similarity of received signal strength (RSS) to discriminate the similarity of positions. However, due to the varied states of different wireless access points (APs), each AP's contribution to RSS similarity varies, which affects the accuracy of localization. In our study, we analyzed several critical causes that affect APs' contribution, including APs' health states and APs' positions. Inspired by these insights, for a large-scale indoor space with ubiquitous APs, a threshold was set for all sample RSS to eliminate the abnormal APs dynamically, a correction quantity for each RSS was provided by the distance between the AP and the sample position to emphasize closer APs, and a priority weight was designed by RSS differences (RSSD) to further optimize the capability of fingerprint distances (FDs, the Euclidean distance of RSS) to discriminate physical distance (PDs, the Euclidean distance of positions). Integrating the above policies for the classical WKNN algorithm, a new indoor fingerprint localization technique is redefined, referred to as FDs' discrimination capability improvement WKNN (FDDC-WKNN). Our simulation results showed that the correlation and consistency between FDs and PDs are well improved, with the strong correlation increasing from 0 to 76% and the high consistency increasing from 26% to 99%, which confirms that the proposed policies can greatly enhance the discrimination capabilities of RSS similarity. We also found that abnormal APs can cause significant impact on FDs discrimination capability. Further, by implementing the FDDC-WKNN algorithm in experiments, we obtained the optimal K value in both the simulation scene and real library scene, under which the mean errors have been reduced from 2.2732 m to 1.2290 m and from 4.0489 m to 2.4320 m, respectively. In addition, compared to not using the FDDC-WKNN, the cumulative distribution function (CDF) of the localization errors curve converged faster and the error fluctuation was smaller, which demonstrates the FDDC-WKNN having stronger robustness and more stable localization performance.

9.
PLoS One ; 19(6): e0300632, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38917144

RESUMO

OBJECTIVES: Lu's approach for video-assisted thoracoscopic surgery (LVATS), which derives from UVATS, is a novel surgical approach for VATS and carries out micro-innovation for lung cancer resection. The objective of this study is to elucidate the safety, feasibility, and efficacy of this novel surgical approach. METHODS: The clinical data of patients with non-small cell lung cancer (NSCLC) who underwent a curative thoracoscopic lobectomy between Mar. 2021 and Mar. 2022, were retrospectively collected, and analyzed. According to whether applied Lu's approach during the VATS operation, patients were divided into the LVATS group and the UVATS group. The propensity score (PS) matching method was used to reduce selection bias by creating two groups. After generating the PSs, 1:1 ratio and nearest-neighbor score matching was completed. Perioperative variables, including the operation time, intraoperative blood loss, lymph node stations dissected, total drainage volume, drainage duration, postoperative hospital stay, pain score (VAS, Visual Analogue Scale) on the postoperative first day (POD1) and third day (POD3), and incidence of postoperative complications, were compared between the two groups. The data were analyzed statistically with P<0.05 defined as statistically significant. RESULTS: A total of 182 patients were identified, among whom 86 patients underwent LVATS and 96 UVATS. Propensity matching produced 62 pairs in this retrospective study. There were no deaths during perioperative period. Patients in the LVATS group experienced a shorter operation time (88 (75, 106) VS 122 (97, 144)min, P <0.001), less intraoperative blood loss(20 (20, 30) VS 25 (20, 50)ml, P = 0.021), shorten incision length (2.50 (2.50, 2.50) VS 3.00 (3.00, 3.50)cm, P <0.001), and more drainage volume (460 (310, 660) VS 345 (225, 600)ml, P = 0.041) than patients in the UVATS group. There was not significant difference in the lymph node stations dissected(5 (4, 5) VS 5 (4, 5), P = 0.436), drainage duration (3 (3, 4) VS 3 (3, 4)days, P = 0.743), length of postoperative hospital stay (4 (4, 5) VS 4 (4, 6)days, P = 0.608), VAS on the POD1(4 (4, 4) VS 4 (4, 4), P = 0.058)and POD3 (3 (3, 4) VS 4 (3, 4), P = 0.219), and incidence of postoperative complications (P = 0.521) between the two groups. CONCLUSIONS: Lu's approach is a safe and feasible approach for video-assisted thoracoscopic surgery for the lobectomy of NSCLC. This approach can shorten surgical time, reduce incision length and intraoperative blood loss.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Complicações Pós-Operatórias , Cirurgia Torácica Vídeoassistida , Humanos , Cirurgia Torácica Vídeoassistida/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/cirurgia , Estudos Retrospectivos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Duração da Cirurgia , Tempo de Internação , Pneumonectomia/métodos , Pontuação de Propensão , Resultado do Tratamento
10.
Cell Rep ; 43(4): 114032, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38568805

RESUMO

N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Carcinogênese , Retroalimentação Fisiológica , Proteínas Supressoras de Tumor , Proteínas Supressoras de Tumor/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Retroalimentação Fisiológica/fisiologia , Estabilidade Proteica , Fosforilação/genética , Glioblastoma/enzimologia , Glioblastoma/fisiopatologia , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Adenosina/análogos & derivados , Adenosina/metabolismo , Contagem de Células , Proteólise , Carcinogênese/genética , Carcinogênese/patologia
11.
Med Phys ; 51(8): 5479-5491, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38558279

RESUMO

BACKGROUND: Cushing's Disease (CD) is a rare clinical syndrome characterized by excessive secretion of adrenocorticotrophic hormone, leading to significant functional and structural brain alterations as observed in Magnetic Resonance Imaging (MRI). While traditional statistical analysis has been widely employed to investigate these MRI changes in CD, it has lacked the ability to predict individual-level outcomes. PURPOSE: To address this problem, this paper has proposed an interpretable machine learning (ML) framework, including model-level assessment, feature-level assessment, and biology-level assessment to ensure a comprehensive analysis based on structural MRI of CD. METHODS: The ML framework has effectively identified the changes in brain regions in the stage of model-level assessment, verified the effectiveness of these altered brain regions to predict CD from normal controls in the stage of feature-level assessment, and carried out a correlation analysis between altered brain regions and clinical symptoms in the stage of biology-level assessment. RESULTS: The experimental results of this study have demonstrated that the Insula, Fusiform gyrus, Superior frontal gyrus, Precuneus, and the opercular portion of the Inferior frontal gyrus of CD showed significant alterations in brain regions. Furthermore, our study has revealed significant correlations between clinical symptoms and the frontotemporal lobes, insulin, and olfactory cortex, which also have been confirmed by previous studies. CONCLUSIONS: The ML framework proposed in this study exhibits exceptional potential in uncovering the intricate pathophysiological mechanisms underlying CD, with potential applicability in diagnosing other diseases.


Assuntos
Substância Cinzenta , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Hipersecreção Hipofisária de ACTH , Humanos , Hipersecreção Hipofisária de ACTH/diagnóstico por imagem , Hipersecreção Hipofisária de ACTH/fisiopatologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Adulto , Masculino , Processamento de Imagem Assistida por Computador/métodos , Feminino , Pessoa de Meia-Idade
12.
Langmuir ; 40(17): 9028-9038, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38635954

RESUMO

Aqueous zinc-ion batteries (AZIBs) suffer from sharp cycling deterioration due to serious interfacial side reactions and corrosion problems on the zinc anode. Herein, an efficacious approach to construct hydrophobic ZnMoO4 coatings on Zn (denoted as Zn@ZMO) is proposed to mitigate direct contact between the zinc anode and electrolyte and enhance its cycle life. The hydrophobic ZnMoO4 layer (contact angle = 128°) with a honeycomb-like structure is prepared by an in situ liquid phase deposition method. The as-prepared ZnMoO4 coating exhibits persistent corrosion protection for Zn through 30 days of immersion in a 2 M ZnSO4 electrolyte, indicating excellent stability of the ZnMoO4 layer and ensuring its available application in AZIBs. Unique microchannels in this kind of honeycomb-like structured coating favor Zn2+ ion diffusion and ease of ion transport, especially at high current cycling. Its robust surface exclusion can effectively counter other side reactions induced by water, simultaneously. As a result, the Zn@ZMO symmetrical cell shows a remarkable cycle lifespan exceeding 2700 h at 1 mA cm-2/1 mA h cm-2, surpassing that of the bare zinc cell by more than 100 folds. At a current density of 5 A g-1, the Zn@ZMO//V2O5 cell can still achieve a specific capacity of 167.0 mA h g-1 after 500 cycles with a capacity retention rate of 88%, which demonstrates its long-term cycling stability.

13.
Cancer Lett ; 590: 216801, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38479552

RESUMO

The mesenchymal subtype of glioblastoma (GBM) cells characterized by aggressive invasion and therapeutic resistance is thought to be dependent on cell-intrinsic alteration and extrinsic cellular crosstalk. Tumor-associated macrophages (TAMs) are pivotal in tumor progression, chemo-resistance, angiogenesis, and stemness maintenance. However, the impact of TAMs on the shifts in glioma stem cells (GSCs) states remains largely uncovered. Herein, we showed that the triggering receptor expressed on myeloid cells-1 (TREM1) preferentially expressed by M2-like TAMs and induced GSCs into mesenchymal-like states by modulating the secretion of TGFß2, which activated the TGFßR/SMAD2/3 signaling in GSCs. Furthermore, we demonstrated that TREM1 was transcriptionally regulated by HIF1a under the hypoxic environment and thus promoted an immunosuppressive type of TAMs via activating the TLR2/AKT/mTOR/c-MYC axis. Collectively, this study reveals that cellular communication between TAMs and GSCs through the TREM1-mediated TGFß2/TGFßR axis is involved in the mesenchymal-like transitions of GSCs. Our study provides valuable insights into the regulatory mechanisms between the tumor immune microenvironment and the malignant characteristics of GBM, which can lead to potential novel strategies targeting TAMs for tumor control.


Assuntos
Células-Tronco Neoplásicas , Receptor Gatilho 1 Expresso em Células Mieloides , Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Animais , Linhagem Celular Tumoral , Transdução de Sinais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/imunologia , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Glioma/imunologia , Camundongos , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/imunologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regulação Neoplásica da Expressão Gênica , Proteína Smad2/metabolismo , Proteína Smad2/genética
14.
Lung Cancer (Auckl) ; 15: 9-17, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38328758

RESUMO

Purpose: Lu's approach for video-assisted thoracoscopic surgery (LVATS), which derives from Uniportal Video-Assisted Thoracoscopic Surgery(UVATS), is a novel surgical approach for VATS and carries out micro-innovation for lung cancer resection. The objective of this study is to elucidate the safety, feasibility, and efficacy of this novel surgical approach. Patients and Methods: The clinical data of patients with non-small cell lung cancer (NSCLC) who underwent a curative thoracoscopic lobectomy between Mar. 2021 and Mar. 2022, were retrospectively collected and analyzed. Patients were divided into the LVATS group and the UVATS group. Propensity score matching (PSM) was used to reduce selection bias and create two comparable groups. Perioperative variables were compared, and a p-value < 0.05 was deemed statistically significant. Results: A total of 182 patients were identified, among whom 86 patients underwent LVATS and 96 UVATS. Propensity matching produced 62 pairs in this retrospective study. There were no deaths during perioperative period. Patients in the LVATS group experienced a shorter operation time (88 (75, 106) VS 122 (97, 144) min, P <0.001), less intraoperative blood loss (20 (20, 30) VS 25 (20, 50) mL, P = 0.021), shorten incision length (2.50 (2.50, 2.50) VS 3.00 (3.00, 3.50) cm, P <0.001), and more drainage volume (460 (310, 660) VS 345 (225, 600) mL, P = 0.041) than patients in the UVATS group. There was not significant difference in the lymph node stations dissected (5 (4, 5) VS 5 (4, 5), P = 0.436), drainage duration (3 (3, 4) VS 3 (3, 4) days, P =0.743), length of postoperative hospital stay (4 (4, 5) VS 4 (4, 6) days, P = 0.608), VAS on the POD1 (4 (4, 4) VS 4 (4, 4), P=0.058) and POD3 (3 (3, 4) VS 4 (3, 4), P=0.219), and incidence of postoperative complications (P=0.521) between the two groups. Conclusion: Lu's approach for video-assisted thoracoscopic lobectomy is safe and feasible, potentially reducing surgery time, incision length, and intraoperative blood loss.

15.
Cell Signal ; 117: 111094, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38341123

RESUMO

Hypoxia-inducible transcription factors (HIFs) are key transcription factors for cellular response to low oxygen levels. However, the specific mediators responsible for activating downstream transcription are not well characterized. We previously identified Protein Arginine methyltransferase 2 (PRMT2), a highly expressed methyltransferase in glioblastoma multiforme, as a transcription co-activator. And we established a connection between PRMT2-mediated histone H3R8 asymmetric methylation (H3R8me2a) and transcription activation. Here we find that PRMT2 is activated by HIF1α under hypoxic conditions. And we demonstrate that PRMT2 and its H3R8me2a activity are required for the transcription activation of a significant subset of hypoxia-induced genes. Consequently, the inactivation of PRMT2 suppresses hypoxia-induced glioblastoma cell migration, attenuates tumor progression, and enhances chemotherapeutic sensitivity in mouse xenograft models. In addition, our analysis of clinical glioma specimens reveals a correlation between PRMT2 protein levels, HIF1α abundance, and an unfavorable prognosis. Our study establishes HIF1α-induced PRMT2 as a critical modulator in the activation of hypoxia-related transcriptional programs, ultimately driving malignant progression.


Assuntos
Glioblastoma , Humanos , Camundongos , Animais , Glioblastoma/genética , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Fatores de Transcrição/metabolismo , Metilação , Ativação Transcricional , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
16.
Acta Neurochir (Wien) ; 166(1): 68, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38319454

RESUMO

BACKGROUND: Schwannomas are the most common intrathoracic neurogenic tumors. In the past, they were often treated by traditional open surgery. Video-assisted thoracic surgery (VATS) has also been used for some large tumors. Recently, minimally invasive posterior neurosurgical technique provides a new option for some of these tumors. METHOD: Here, we describe the specific steps involved in the O-arm guided minimally invasive removal of intrathoracic epidural schwannoma, as well as its advantages and limitations. CONCLUSION: O-arm guided minimally invasive resection of intrathoracic epidural schwannoma is safe and effective and causes little damage.


Assuntos
Neurilemoma , Cirurgia Assistida por Computador , Humanos , Imageamento Tridimensional , Tomografia Computadorizada por Raios X , Neurilemoma/diagnóstico por imagem , Neurilemoma/cirurgia , Procedimentos Neurocirúrgicos
17.
J Am Chem Soc ; 146(3): 2257-2266, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38195401

RESUMO

Metallic Al has been deemed an ideal electrode material for aqueous batteries by virtue of its abundance and high theoretical capacity (8056 mAh cm-3). However, the development of aqueous Al metal batteries has been hindered by several side reactions, including water decomposition, Al corrosion, and passivation, which arise from the solvation reaction of Al and H2O in conventional aqueous electrolytes. In this work, we report that water activity in electrolyte can be suppressed by optimizing the Al3+ solvation structure through intercalation of polar pyridine-3-carboxylic acid in an aluminum trifluoromethanesulfonate aqueous environment. Furthermore, the pyridine-3-carboxylic acid molecules are inclined to alter the surface energy of Al, thus suppressing the random deposition of Al. As a result, the Al corrosion in the hybrid electrolyte is restrained, and the long-term electrochemical stability of the electrolyte is tremendously improved. These merits bring remarkable reversibility to aqueous Al batteries using Al-preintercalated MnO2 cathodes, delivering a retaining energy density of >250 Wh kg-1 at 0.2 A g-1 after 600 cycles.

18.
Sci Total Environ ; 912: 169265, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38086485

RESUMO

Herein, a novel N, S co-doped porous carbon (S5C5-AC) for Cr(VI) removal was prepared by co-hydrothermal carbonization (HTC) of sewage sludge (SS) and low-rank coal (LC) combining with KOH modification. The results showed that S5C5-AC had excellent adsorption performance on Cr(VI), and lower pH value, higher initial concentration and longer contact time were beneficial for Cr(VI) adsorption. The adsorption kinetics and isotherms revealed that Cr(VI) adsorption by S5C5-AC was homogeneous and dominated by chemisorption. The adsorption isotherm showed that the maximum equilibrium adsorption capacity of S5C5-AC for Cr(VI) was 382.04 mg/g at 25 °C. Furthermore, the results showed that the main mechanisms for Cr(VI) removal were the pore filling, electrostatic interaction and reduction. Moreover, the electron transfer mechanism during the adsorption and reduction process was further explored at the molecular and electronic levels by density functional theory (DFT) and front orbital theory (FOT) simulations. The analysis of DFT and FOT indicated that the synergistic effect between S and N functional groups was exhibited during the Cr(VI) removal process. Considering the existence of synergistic effects between N and S functional groups during adsorption, the S and N content and form were modified collaboratively. Increasing the relative content of pyrrolic N may be the most effective pathway for improving removal performance. Besides that, S5C5-AC exhibited excellent adsorption capacity over a high coexisting ion concentration range and various actual water bodies and regeneration performance, which indicated that S5C5-AC had promising potential for the remediation of wastewater in industrial applications.

19.
Adv Sci (Weinh) ; 11(7): e2305620, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38087889

RESUMO

Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin-binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self-renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Proteínas Musculares , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Neoplasias Encefálicas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Hipóxia/metabolismo , Células-Tronco Neoplásicas/metabolismo
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