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1.
Phys Chem Chem Phys ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39028298

RESUMO

In recent years, 3-hydroxychromone (3-HC) and its derivatives have attracted much interest for their applications as molecular photoswitches and fluorescent probes. A clear understanding of their excited-state dynamics is essential for their applications and further development of new functional 3-HC derivatives. However, the deactivation mechanism of the photoexcited 3-HC family is still puzzling as their spectral properties are sensitive to the surrounding medium and substituents. The excited-state relaxation channels of 3-HC have been a matter of intense debate. In the current work, we thoroughly investigated the excited-state decay process of the 3-HC system in the gas phase using high-level electronic structure calculations and on-the-fly excited-state dynamic simulations intending to provide insight into the intrinsic photochemical properties of the 3-HC system. A new deactivation mechanism is proposed in the gas phase, which is different from that in solvents. The excited-state intramolecular proton transfer (ESIPT) process that occurs in solutions is not preferred in the gas phase due to the existence of a sizable energy barrier (∼0.8 eV), and thus, no dual fluorescence is found. On the contrary, the non-radiative decay process is the dominant decay channel, which is driven by photoisomerization combined with ring-puckering and ring-opening processes. The results coincide with the observations of an experiment performed in a supersonic jet by Itoh (M. Itoh, Pure Appl. Chem., 1993, 65(8), 1629-1634). The current work indicates that the solution environment plays an important role in regulating the excited-state dynamic behaviour of the 3-HC system. This study thus provides theoretical guidance for the rational design and improvement of the photochemical properties of the 3-HC system and paves the way for further investigation into its photochemical properties in complex environments.

2.
J Nanobiotechnology ; 22(1): 429, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39033109

RESUMO

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.


Assuntos
Antineoplásicos , Neoplasias da Mama , Indazóis , Macrófagos , Estruturas Metalorgânicas , Nanopartículas , Pirimidinas , Sulfonamidas , Animais , Feminino , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Humanos , Macrófagos/efeitos dos fármacos , Indazóis/farmacologia , Indazóis/química , Camundongos , Pirimidinas/farmacologia , Pirimidinas/química , Linhagem Celular Tumoral , Nanopartículas/química , Sulfonamidas/farmacologia , Sulfonamidas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos Endogâmicos BALB C , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Materials (Basel) ; 17(13)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38998298

RESUMO

This work explores the effect of a Zn1-xSnxOy (ZTO) layer as a potential replacement for CdS in Sb2(S,Se)3 devices. Through the use of Afors-het software v2.5, it was determined that the ZTO/Sb2(S,Se)3 interface exhibits a lower conduction band offset (CBO) value of 0.34 eV compared to the CdS/Sb2(S,Se)3 interface. Lower photo-generated carrier recombination can be obtained at the interface of the ZTO/Sb2(S,Se)3 heterojunction. In addition, the valence band offset (VBO) value at the ZTO/Sb2(S,Se)3 interface increases to 1.55 eV. The ZTO layer increases the efficiency of the device from 7.56% to 11.45%. To further investigate the beneficial effect of the ZTO layer on the efficiency of the device, this goal has been achieved by five methods: changing the S content of the absorber, changing the thickness of the absorber, changing the carrier concentration of ZTO, using various Sn/(Zn+Sn) ratios in ZTO, and altering the thickness of the ZTO layer. When the S content in Sb2(S,Se)3 is around 60% and the carrier concentration is about 1018 cm-3, the efficiency is optimal. The optimal thickness of the Sb2(S,Se)3 absorber layer is 260 nm. A ZTO/Sb2(S,Se)3 interface with a Sn/(Zn+Sn) ratio of 0.18 exhibits a better CBO value. It is also found that a ZTO thickness of 20 nm is needed for the best efficiency.

5.
Surgery ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38851900

RESUMO

BACKGROUND: Advanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination. METHODS: Gene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment. RESULTS: In total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune "cold" subtype and immune "hot" subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune "cold" subtype or immune "hot" subtype. Interestingly, patients with high risk scores had a higher proportion of immune "hot" subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified. CONCLUSION: The tumor-antigens-based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune "cold" subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.

6.
Drug Resist Updat ; 75: 101098, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38833804

RESUMO

Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.


Assuntos
Células Apresentadoras de Antígenos , Vacinas Anticâncer , Imunoterapia , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Nanopartículas/administração & dosagem , Células Apresentadoras de Antígenos/imunologia , Biomimética/métodos , Materiais Biomiméticos/administração & dosagem , Animais , Lipossomos , Nanovacinas
8.
Autophagy ; : 1-18, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38797513

RESUMO

The dysregulation of membrane protein expression has been implicated in tumorigenesis and progression, including hepatocellular carcinoma (HCC). In this study, we aimed to identify membrane proteins that modulate HCC viability. To achieve this, we performed a CRISPR activation screen targeting human genes encoding membrane-associated proteins, revealing TMX2 as a potential driver of HCC cell viability. Gain- and loss-of-function experiments demonstrated that TMX2 promoted growth and tumorigenesis of HCC. Clinically, TMX2 was an independent prognostic factor for HCC patients. It was significantly upregulated in HCC tissues and associated with poor prognosis of HCC patients. Mechanistically, TMX2 was demonstrated to promote macroautophagy/autophagy by facilitating KPNB1 nuclear export and TFEB nuclear import. In addition, TMX2 interacted with VDAC2 and VADC3, assisting in the recruitment of PRKN to defective mitochondria to promote cytoprotective mitophagy during oxidative stress. Most interestingly, HCC cells responded to oxidative stress by upregulating TMX2 expression and cell autophagy. Knockdown of TMX2 enhanced the anti-tumor effect of lenvatinib. In conclusion, our findings emphasize the pivotal role of TMX2 in driving the HCC cell viability by promoting both autophagy and mitophagy. These results suggest that TMX2 May serve as a prognostic marker and promising therapeutic target for HCC treatment.Abbreviation: CCCP: Carbonyl cyanide 3-chlorophenylhydrazone; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeat; ER: endoplasmic reticulum; HCC: hepatocellular carcinoma; KPNB1: karyopherin subunit beta 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; TFEB: transcription factor EB; TMX2: thioredoxin related transmembrane protein 2; VDAC2: voltage dependent anion channel 2; VDAC3: voltage dependent anion channel 3; WB: western blot.

9.
Pharmacol Res ; 204: 107218, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38768671

RESUMO

This study investigates the role of Stanniocalcin-1 (STC1) in melanoma progression, with a focus on its impact on metastasis, angiogenesis, and immune evasion. Systematic bioinformatics analysis revealed the potential influence of STC1 dysregulation on prognosis, immune cell infiltration, response to immune therapy, and cellular functions. In vitro assays were conducted to assess the proliferation, invasion, migration, and angiogenesis capabilities of A375 cells. In vivo experiments utilizing C57BL/6 J mice established a lung metastasis model using B16-F10 cells to evaluate macrophage infiltration and M2 polarization. A Transwell co-culture system was employed to explore the crosstalk between melanoma and macrophages. Molecular interactions among STC1, YAP, ßPIX, and CCL2 are investigated using mass spectrometry, Co-Immunoprecipitation, Dual-Luciferase Reporter Assay, and Chromatin Immunoprecipitation experiments. STC1 was found to enhance lung metastasis by promoting the recruitment and polarization of M2 macrophages, thereby fostering an immunosuppressive microenvironment. Mechanistically, STC1 competes with YAP for binding to ßPIX within the KER domain in melanoma cells, leading to YAP activation and subsequent CCL2 upregulation. CCL2-induced M2 macrophages secrete VEGFA, which enhances tumor vascularization and increases STC1 expression via the AKT signaling pathway in melanoma cells, establishing a pro-metastatic feedback loop. Notably, STC1-induced YAP activation increases PD-L1 expression, promoting immune evasion. Silencing STC1 enhances the efficacy of PD-1 immune checkpoint therapy in mice. This research elucidates STC1's role in melanoma metastasis and its complex interactions with tumor-associated macrophages, proposing STC1 as a potential therapeutic target for countering melanoma metastasis and augmenting the efficacy of PD-1 immunotherapy.


Assuntos
Quimiocina CCL2 , Glicoproteínas , Macrófagos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt , Fator A de Crescimento do Endotélio Vascular , Proteínas de Sinalização YAP , Animais , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Humanos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Macrófagos/metabolismo , Macrófagos/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas/genética , Camundongos , Melanoma/patologia , Melanoma/metabolismo , Melanoma/imunologia , Melanoma/genética , Retroalimentação Fisiológica , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Microambiente Tumoral , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/metabolismo , Progressão da Doença , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética
10.
Chemphyschem ; : e202400250, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38820005

RESUMO

The design and application of molecular photoswitches have attracted much attention. Herein, we performed a detailed computational study on the photoswitch benzylidene-oxazolone system based on static electronic structure calculations and on-the-fly excited-state dynamic simulations. For the Z and E isomer, we located six and four minimum energy conical intersections (MECIs) between the first excited state (S1) and the ground state (S0), respectively. Among them, the relaxation pathway driven by ring-puckering motion is the most competitive channel with the photoisomeization process, leading to the low photoisomerization quantum yield. In the dynamic simulations, about 88 % and 66 % trajectories decay from S1 to S0 for Z and E isomer, respectively, within the total simulation time of ~2 ps. The photoisomeization quantum yields obtained in our study (0.20 for Z→E and 0.12 for E→Z) agree well with the experimental measured values (0.25 and 0.11), even though the number of trajectories is limited to 50. Our study sheds light on the complexity of the benzylidene-oxazolone system 's deactivation process and the competitive mechanisms among different reaction channels, which provides theoretical guidance for further design and development of benzylidene-oxazolone based molecular photoswitches.

11.
ACS Appl Mater Interfaces ; 16(21): 27587-27595, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38748924

RESUMO

Optimizing the photon spectrum for photosynthesis concurrently with improving crop yields presents an efficient and sustainable pathway to alleviate global food shortages. Luminescent solar concentrators (LSCs), consisting of transparent host matrices doped with fluorophores, show excellent promise to achieve the desired spectral tailoring. However, conventional LSCs are predominantly engineered for photon concentration, which results in a limited outcoupling efficiency of converted photons. Here, we introduce a scheme to implement LSCs into horticulture (HLSC) by enhancing light extraction. The symmetry of the device is disrupted by incorporating microcone arrays on the bottom surface to mitigate total internal reflection. Both Monte Carlo ray tracing simulations and experimental results have verified that the greatest enhancements in converted light extraction, relative to planar LSCs, are achieved using microcone arrays (base width 50 µm, aspect ratio 1.2) with extruded and protruded profiles (85.15 and 66.55% improvement, respectively). Angularly resolved transmission measurements show that the HLSC device exhibits a broad angular radiation distribution. This characteristic indicates that the HLSC device emits diffuse light, which is conducive to optimal plant growth.

12.
Pharm Biol ; 62(1): 394-403, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38739003

RESUMO

CONTEXT: Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated. OBJECTIVE: This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP). MATERIALS AND METHODS: After tabersonine (10 µM) and/or CDDP (10 µM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial-mesenchymal transition (EMT) phenotypes. RESULTS: Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 µM for BT549 and 27.0 µM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine. DISCUSSION AND CONCLUSIONS: Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.


Assuntos
Aurora Quinase A , Cisplatino , Transição Epitelial-Mesenquimal , Alcaloides Indólicos , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Antineoplásicos/farmacologia , Aurora Quinase A/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Simulação de Acoplamento Molecular , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
13.
Ecotoxicol Environ Saf ; 277: 116372, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38669875

RESUMO

Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.


Assuntos
Adenosina , Carcinogênese , Poluentes Ambientais , Adenosina/análogos & derivados , Carcinogênese/induzido quimicamente , Poluentes Ambientais/toxicidade , Humanos , Metilação , Animais , RNA/genética , Metilação de RNA
14.
Transl Oncol ; 44: 101942, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38555741

RESUMO

Cisplatin resistance plays a significant role in the dismal prognosis and progression of muscle-invasive bladder cancer (MIBC). However, the strategies to predict prognosis and cisplatin resistance are inefficient, and it remains unclear whether cisplatin resistance is associated with tumor immunity. In this study, we integrated the transcriptional data from cisplatin-resistant cell lines and a TCGA-MIBC cohort to establish cisplatin-resistance-related cluster classification and a cisplatin-resistance-related gene risk score (CRRGRS). Kaplan-Meier survival curves showed that compared with those in low CRRGRS group, MIBC patients belonging to high CRRGRS group had worse prognosis in TCGA-MIBC cohort and external GEO cohorts. Meanwhile, CRRGRS was able to help forecast chemotherapy and immunotherapy response of MIBC patients in the TGCA cohort and IMvigor210 cohort. Moreover, compared with the low CRRGRS group, the high CRRGS group possessed a relatively immunosuppressive "cold tumor" phenotype with a higher tumor immune dysfunction and exclusion (TIDE) score, ESTIMATE score, stromal score and immune score and a lower immunophenoscore (IPS) score. The upregulated expression levels of immune checkpoint genes, including PD-1, PD-L1 and CTLA4, in the high CRRGRS group also further indicated that a relative immunosuppressive tumor microenvironment may exist in MIBC patients belonging to high CRRGRS group. In addition, we integrated CRRGRS and clinical characteristics with prognostic value to develop a nomogram, which could help forecast overall survival of MIBC patients. Furthermore, DIAPH3 was identified as a regulator of proliferation and cisplatin resistance in MIBC. The expression of DIAPH3 was increased in cisplatin-resistant cell lines and chemotherapy-unsensitive people. Further mechanism exploration revealed that DIAPH3 facilitated tumor proliferation and cisplatin resistance by regulating the NF-kB and epithelial-mesenchymal transition (EMT) pathways. In conclusion, the comprehensive investigations of CRRGRS increased the understanding of cisplatin resistance and provided promising insights to restrain tumor growth and overcome chemoresistance by targeting DIAPH3.

15.
Signal Transduct Target Ther ; 9(1): 58, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438346

RESUMO

Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.


Assuntos
Glioblastoma , Glioma , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Homeostase , Proteômica , Espécies Reativas de Oxigênio , Temozolomida/farmacologia , Ubiquitina-Proteína Ligases
16.
Front Oncol ; 14: 1301327, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38444673

RESUMO

Background: Notwithstanding the acknowledged interplay between atrial fibrillation (AF) and the emergence of digestive system neoplasms, the intricacies of this relationship remain ambiguous. By capitalizing univariable Mendelian Randomization (MR) complemented by a mediated MR tactic, our pursuit was to elucidate the causative roles of AF in precipitating digestive system malignancies and potential intermediary pathways. Method: This research endeavor seeks to scrutinize the causal clinical implications of whether genetic predispositions to AF correlate with an increased risk of digestive system malignancies, employing MR analytical techniques. Utilizing a dataset amalgamated from six studies related to AF, encompassing over 1,000,000 subjects, we performed univariable MR assessments, employing the random-effects inverse-variance weighted (IVW) methodology as our principal analytical paradigm. Subsequently, a mediated MR framework was employed to probe the potential mediating influence of AF on the nexus between hypertension (HT), heart failure (HF), ischemic stroke (IS), coronary artery disease (CAD), and digestive system neoplasms. Result: The univariable MR evaluation unveiled a notable causal nexus between the genetic inclination toward AF and the genetic susceptibility to colon, esophageal, and small intestine malignancies. The mediated MR scrutiny ascertained that the genetic inclination for AF amplifies the risk profile for colon cancer via IS pathways and partially explains the susceptibility to esophageal and small intestine tumors through the HF pathway. Conclusion: Our investigative endeavor has highlighted a definitive causative association between genetic inclination to AF and specific digestive system neoplasms, spotlighting IS and HF as instrumental mediators. Such revelations furnish pivotal perspectives on the complex genetic interconnections between cardiovascular anomalies and certain digestive tract tumors, emphasizing prospective therapeutic and diagnostic worthy of pursuit.

17.
Front Cardiovasc Med ; 11: 1327497, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38525192

RESUMO

Background: Pre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence. Methods: Two-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p < 5 × -8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p < 0.0083 considered significant evidence and a p within 0.083-0.05 considered suggestive evidence. Results: Critical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03-1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01-1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia. Conclusions: Our investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose-response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.

18.
Chem Biol Interact ; 393: 110958, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38493911

RESUMO

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, such as Olaparib, have been pivotal in treating BRCA-deficient ovarian cancer. However, their efficacy is limited in over 40% of BRCA-deficient patients, with acquired resistance posing new clinical challenges. To address this, we employed bioinformatics methods to identify key genes impacting Olaparib sensitivity in ovarian cancer. Through comprehensive analysis of public databases including GEO, CPTAC, Kaplan Meier Plotter, and CCLE, we identified CRABP2 as significantly upregulated at both mRNA and protein levels in ovarian cancer, correlating with poor prognosis and decreased Olaparib sensitivity. Using colony formation and CCK-8 assays, we confirmed that CRABP2 knockdown in OVCAR3 and TOV112D cells enhanced sensitivity to Olaparib. Additionally, 4D label-free quantitative proteomics analysis, GSEA, and GO/KEGG analysis revealed CRABP2's involvement in regulating oxidation signals. Flow cytometry, colony formation assays, and western blotting demonstrated that CRABP2 knockdown promoted ROS production by activating Caspase-8, thereby augmenting Olaparib sensitivity and inhibiting ovarian cancer cell proliferation. Moreover, in xenograft models, CRABP2 knockdown significantly suppressed tumorigenesis and enhanced Olaparib sensitivity, with the effect being reversed upon Caspase-8 knockdown. These findings suggest that CRABP2 may modulate Olaparib sensitivity in ovarian cancer through the Caspase-8/ROS axis, highlighting its potential as a target for Olaparib sensitization.


Assuntos
Neoplasias Ovarianas , Ftalazinas , Piperazinas , Feminino , Humanos , Apoptose , Caspase 8/genética , Caspase 8/metabolismo , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
J Nat Prod ; 87(4): 837-848, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38417401

RESUMO

Ovarian cancer (OVC) is one of the most aggressive gynecological malignancies worldwide. Although olaparib treatment has shown favorable outcomes against the treatment of OVC, its effectiveness remains limited in some OVC patients. Investigating new strategies to improve the therapeutic efficacy of olaparib against OVC is imperative. Our study identified tabersonine, a natural indole alkaloid, for its potential to increase the chemosensitivity of olaparib in OVC. The combined treatment of olaparib and tabersonine synergistically inhibited cell proliferation in OVC cells and suppressed tumor growth in A2780 xenografts. The combined treatment effectively suppressed epithelial-mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, and vimentin and induced DNA damage responses. Integrating quantitative proteomics, FHL1 was identified as a potential regulator to modulate EMT after tabersonine treatment. Increased expression of FHL1 was induced by tabersonine treatment, while downregulation of FHL1 reversed the inhibitory effects of tabersonine on OVC cells by mediating EMT. In vivo findings further reflected that the combined treatment of tabersonine and olaparib significantly inhibited tumor growth and OVC metastasis through upregulation of FHL1. Our findings reveal the role of tabersonine in improving the sensitivity of olaparib in OVC through FHL1-mediated EMT, suggesting that tabersonine holds promise for future application in OVC treatment.


Assuntos
Transição Epitelial-Mesenquimal , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas com Domínio LIM , Proteínas Musculares , Neoplasias Ovarianas , Ftalazinas , Piperazinas , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Quinolinas/farmacologia
20.
Front Psychol ; 15: 1265648, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38379627

RESUMO

Objectives: To understand the attitudes and health behaviors of middle-aged and older adults in China after receiving elevated results of tumor markers (TMs) test in the annual health examinations (AHEs) and explore the influencing factors. Methods: A three-section online questionnaire survey was conducted from March 1 to April 30, 2020 in Hangzhou, China, to people who were aged 45 and older and had at least one elevated result of TMs test. Clinical information was collected from the online survey and medical records. Descriptive statistics were carried out followed by regression analyses. Results: Of 380 participants, 76.1% were unwilling to quit the TMs test in AHEs, whereas 75.3% would take the doctor's advice and quit unnecessary TMs test; 67.4% felt stressed about their TMs. Among participants with elevated TMs, 76.8% changed lifestyle to keep healthy, 74.2% sought health information, 58.9% requested a TMs retest, and 50.3% did further tests to confirm a diagnosis. Family history of cancer was associated with lifestyle changing; education level, area of residence and health insurance were associated with health information seeking; comorbidity were associated with retests and sequential confirming tests. Conclusion: The application of the TMs test in AHEs among Chinese people may lead to positive and negative behavioral consequences and psychological distress. Doctors have a significant impact on patients' health behaviors. Accurate indications and adequate communication with patients before and after the TMs test are in great need.

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