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1.
Liver Int ; 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39037259

RESUMO

BACKGROUND: Extracellular vesicles (EVs) facilitate cell-cell interactions in the tumour microenvironment. However, standard and efficient methods to isolate tumour tissue-derived EVs are lacking, and their biological functions remain elusive. METHODS: To determine the optimal method for isolating tissue-derived EVs, we compared the characterization and concentration of EVs obtained by three previously reported methods using transmission electron microscopy, nanoparticle tracking analysis, and nanoflow analysis (Nanoflow). Additionally, the differential content of small RNAs, especially tsRNAs, between hepatocellular carcinoma (HCC) and adjacent normal liver tissues (ANLTs)-derived EVs was identified using Arraystar small RNA microarray. The targets of miRNAs and tsRNAs were predicted, and downstream functional analysis was conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, non-negative matrix factorization and survival prediction analysis. RESULTS: A differential centrifugation-based protocol without cell cultivation (NC protocol) yielded higher EV particles and higher levels of CD9+ and CD63+ EVs compared with other isolation protocols. Interestingly, the NC protocol was also effective for isolating frozen tissue-derived EVs that were indistinguishable from fresh tissue. HCC tissues showed significantly higher EV numbers compared with ANLTs. Furthermore, we identified different types of small RNAs in HCC tissue-derived EVs, forming a unique multidimensional intercellular communication landscape that can differentiate between HCC and ANLTs. ROC analysis further showed that the combination of the top 10 upregulated small RNAs achieved better diagnostic performance (AUC = .950 [.895-1.000]). Importantly, most tsRNAs in HCC tissue-derived EVs were downregulated and mitochondria-derived, mainly involving in lipid-related metabolic reprogramming. CONCLUSION: The NC protocol was optimal for isolating EVs from HCC, especially from frozen tissues. Our study emphasized the different roles of small-RNA in regulating the HCC ecosystem, providing insights into HCC progression and potential therapeutic targets.

2.
Hepatology ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38779918

RESUMO

BACKGROUND AND AIMS: Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. APPROACH AND RESULTS: We identified CTC-platelet adhesions by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in patients with HCC. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from NK cell killing by upregulating inhibitory checkpoint CD155 (PVR cell adhesion molecule), therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK-cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another 2 receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK-cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. CONCLUSIONS: Our results demonstrated CTC evasion from NK-cell-mediated innate immunosurveillance mainly through immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.

4.
Pharmacol Res ; 204: 107195, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677532

RESUMO

Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of translation elongation for protein biosynthesis as well as a plethora of non-translational moonlighting functions for cellular homeostasis. In malignant cells, however, eEF1A becomes a pleiotropic driver of cancer progression via a broad diversity of pathways, which are not limited to hyperactive translational output. In the past decades, mounting studies have demonstrated the causal link between eEF1A and carcinogenesis, gaining deeper insights into its multifaceted mechanisms and corroborating its value as a prognostic marker in various cancers. On the other hand, an increasing number of natural and synthetic compounds were discovered as anticancer eEF1A-targeting inhibitors. Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics.


Assuntos
Antineoplásicos , Neoplasias , Fator 1 de Elongação de Peptídeos , Humanos , Fator 1 de Elongação de Peptídeos/metabolismo , Fator 1 de Elongação de Peptídeos/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Relevância Clínica
5.
J Exp Clin Cancer Res ; 43(1): 108, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600610

RESUMO

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Neoplasias Colorretais , Mupirocina , Humanos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos , Carcinogênese , Morte Celular , Transformação Celular Neoplásica , Neoplasias Colorretais/tratamento farmacológico
6.
Lung Cancer ; 190: 107541, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38531154

RESUMO

OBJECTIVE: Metabolic reprogramming is an important coordinator of tumor development and resistance to therapy, such as the tendency of tumor cells to utilize glycolytic energy rather than oxidative phosphorylation, even under conditions of sufficient oxygen. Therefore, targeting metabolic enzymes is an effective strategy to overcome therapeutic resistance. MATERIALS AND METHODS: We explored the differential expression and growth-promoting function of MDH2 by immunohistochemistry and immunoblotting experiments in lung cancer patients and lung cancer cells. Pentose phosphate pathway-related phenotypes (including ROS levels, NADPH levels, and DNA synthesis) were detected intracellularly, and the interaction of malate and proteinase 6PGD was detected in vitro. In vivo experiments using implanted xenograft mouse models to explore the growth inhibitory effect and pro-chemotherapeutic function of dimethyl malate (DMM) on lung cancer. RESULTS: We found that the expression of malate dehydrogenase (MDH2) in the tricarboxylic acid cycle (TCA cycle) was increased in lung cancer. Biological function enrichment analysis revealed that MDH2 not only promoted oxidative phosphorylation, but also promoted the pentose phosphate pathway (PPP pathway). Mechanistically, it was found that malate, the substrate of MDH2, can bind to the PPP pathway metabolic enzyme 6PGD, inhibit its activity, reduce the generation of NADPH, and block DNA synthesis. More importantly, DMM can improve the sensitivity of lung cancer to the clinical drug cisplatin. CONCLUSION: We have identified malate as a natural inhibitor of 6PGD, which will provide new leads for the development of 6PGD inhibitors. In addition, the metabolic enzyme MDH2 and the metabolite malate may provide a backup option for cells to inhibit their own carcinogenesis, as the accumulated malate targets 6PGD to block the PPP pathway and inhibit cell cycle progression.


Assuntos
Neoplasias Pulmonares , Animais , Humanos , Camundongos , DNA , Neoplasias Pulmonares/genética , Malatos/farmacologia , NADP/metabolismo
7.
Biochim Biophys Acta Mol Basis Dis ; 1870(3): 167013, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38199515

RESUMO

Inflammatory bowel disease (IBD) is an incurable and disabling bowel disease driven by multiple risk factors that severely limit patients' quality of life. We integrated the RNA-sequencing data of 1238 IBD patients, and investigated the pathogenesis of IBD by combining transcriptional element prediction analysis and immune-related analysis. Here, we first determined that KIAA1109 is inhibited in IBD patients. The expression of KIAA1109 and NOD2, the key receptor of NOD-like receptors, showed a negative correlation. The NOD-like receptor signaling pathway is activated and exerts transcriptional regulation on the chemokines CXCL1 and CXCL2 through the activation of the transcription factors NFκB and AP1. Analysis of immune infiltration revealed that the expression of chemokines CXCL1 and CXCL2 may regulate the inflammatory response induced by immune cells. These findings suggest that the KIAA1109-NOD2-NFκB/AP1-CXCL1/CXCL2 regulatory axis is the molecular mechanism of IBD pathogenesis, which will provide a new perspective for the diagnosis, treatment and management of IBD patients.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Humanos , Qualidade de Vida , Doenças Inflamatórias Intestinais/genética , Marcadores Genéticos , Perfilação da Expressão Gênica , Quimiocinas/genética
9.
Aging (Albany NY) ; 15(24): 14830-14844, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38097358

RESUMO

Coronary artery disease (CAD) is the most common aging-related disease in adults. We used bioinformatics analysis to study genes associated with aging in patients with CAD. The microarray data of the GSE12288 dataset were downloaded from the Gene Expression Omnibus database to obtain 934 CAD-associated differentially expressed genes. By overlaying them with aging-related genes in the Aging Atlas database, 33 differentially expressed aging-related genes (DEARGs) were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the 33 DEARGs were mainly enriched in cell adhesion and activation, Th17 and Th1/Th2 cell differentiation, and longevity regulation pathways. Hub genes were further screened using multiple algorithms of Cytoscape software and validation set GSE71226. Clinical samples were then collected, and the expression of hub genes in whole blood was detected by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and western blot at the transcription and translation levels. Finally, HSP90AA1 and CEBPA were identified as hub genes. The results of this study suggest that HSP90AA1 and CEBPA are closely related to CAD. These findings provide a theoretical basis for the association between aging effectors and CAD, and indicate that these genes may be promising biomarkers for the diagnosis and treatment of CAD.


Assuntos
Doença da Artéria Coronariana , Perfilação da Expressão Gênica , Humanos , Perfilação da Expressão Gênica/métodos , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Biomarcadores , Biologia Computacional/métodos , Envelhecimento/genética
10.
Ibrain ; 9(2): 133-147, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37786553

RESUMO

Due to the existence of the blood-brain barrier in glioma, traditional drug therapy has a poor therapeutic outcome. Emerging immunotherapy has been shown to have satisfactory therapeutic effects in solid tumors, and it is clinically instructive to explore the possibility of immunotherapy in glioma. We performed a retrospective analysis of RNA-seq data and clinical information in 1027 glioma patients, utilizing machine learning to explore the relationship between tyrosine metabolizing enzymes and clinical characteristics. In addition, we also assessed the role of tyrosine metabolizing enzymes in the immune microenvironment including immune infiltration and immune evasion. Highly expressed tyrosine metabolizing enzymes 4-hydroxyphenylpyruvate dioxygenase, homogentisate 1,2-dioxygenase, and fumarylacetoacetate hydrolase not only promote the malignant phenotype of glioma but are also closely related to poor prognosis. The expression of tyrosine metabolizing enzymes could distinguish the malignancy degree of glioma. More importantly, tyrosine metabolizing enzymes regulate the adaptive immune process in glioma. Mechanistically, multiple metabolic enzymes remodel fumarate metabolism, promote α-ketoglutarate production, induce programmed death-ligand 1 expression, and help glioma evade immune surveillance. Our data suggest that the metabolic subclass driven by tyrosine metabolism provides promising targets for the immunotherapy of glioma.

11.
Expert Opin Ther Targets ; 27(8): 733-743, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37571851

RESUMO

INTRODUCTION: Ovarian cancer (OC) is a gynecological tumor disease, which is usually diagnosed at an advanced stage and has a poor prognosis. It has been established that the glucose metabolism rate of cancer cells is significantly higher than that of normal cells, and the pentose phosphate pathway (PPP) is an important branch pathway for glucose metabolism. Glucose-6-phosphate dehydrogenase (G6PD) is the key rate-limiting enzyme in the PPP, which plays an important role in the initiation and development of cancer (such as OC), and has been considered as a promisinganti-cancer target. AREAS COVERED: In this review, based on the structure and biological function of G6PD, recent research on the roles of G6PD in the progression, metastasis, and chemoresistance of OC are summarized and accompanied by proposed molecular mechanisms, which may provide a systematic understanding of targeting G6PD for the treatment of patients with OC. EXPERT OPINION: Accumulating evidence demonstrates that G6PD is a promising target of cancer. The development of G6PD inhibitors for cancer treatment merits broad application prospects.


Assuntos
Glucosefosfato Desidrogenase , Neoplasias Ovarianas , Humanos , Feminino , Glucosefosfato Desidrogenase/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Via de Pentose Fosfato , Glucose/metabolismo
13.
Front Immunol ; 14: 1164183, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37435082

RESUMO

Objective: Endomyocardial biopsy is the gold standard method for the diagnosis of cardiac allograft rejection. However, it causes damage to the heart. In this study, we developed a noninvasive method for quantification of granzyme B (GzB) in vivo by targeted ultrasound imaging, which detects and provides quantitative information for specific molecules, for acute rejection assessment in a murine cardiac transplantation model. Methods: Microbubbles bearing anti-GzB antibodies (MBGzb) or isotype antibodies (MBcon) were prepared. Hearts were transplanted from C57BL/6J (allogeneic) or C3H (syngeneic) donors to C3H recipients. Target ultrasound imaging was performed on Days 2 and 5 post-transplantations. A pathologic assessment was performed. The expression of granzyme B and IL-6 in the heart was detected by Western blotting. Results: After MB injection, we observed and collected data at 3 and 6 min before and after the flash pulse. Quantitative analysis revealed that the reduction in peak intensity was significantly higher in the allogeneic MBGzb group than in the allogeneic MBcon group and the isogeneic MBcon group at PODs 2 and 5. In the allogeneic groups, granzyme B and IL-6 expression levels were higher than those in the isogeneic group. In addition, more CD8 T cells and neutrophils were observed in the allogeneic groups. Conclusion: Ultrasound molecular imaging of granzyme B can be used as a noninvasive method for acute rejection detection after cardiac transplantation.


Assuntos
Diagnóstico por Imagem , Interleucina-6 , Animais , Camundongos , Granzimas , Ultrassonografia , Aloenxertos
14.
Environ Monit Assess ; 195(7): 912, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37392290

RESUMO

Ecological environment is the essential material basis of human survival and connects regional economy with socially sustainable development. However, climate changes characterized by global climate warming have caused a series of ecological environmental problems in recent years. Few studies have discussed various climate factors affecting the ecological environment, and the spatial non-stationary effects of different climate factors on the ecological environment are still unclear. Dynamically monitoring ecological environment changes in fragile areas and identifying its climate-driving mechanism are essential for ecological protection and environmental repair. Taking Zoige Plateau as a case, this paper simulated the eco-environmental quality during 1987-2020 using remote sensing data, utilized Geodetector method to identify the contributions of various climate drivers to ecological environment quality, and then adopted the Geographically Weighted Regression model to explore the spatial non-stationary impacts of climate factors on ecological environment quality. The results showed that the ecological quality in the middle regions of the Zoige Plateau was slightly better than in the surrounding marginal areas. For the whole area of Zoige Plateau, the average ecological environment quality index was 54.92, 53.99, 56.17, 57.88, 63.44, 56.93, 59.43, and 59.76 in 1987, 1992, 1997, 2001, 2006, 2013, 2016 and 2020, respectively, which indicated that eco-environmental quality witnessed several fluctuations during the study period but showed a generally increasing trend. Among five climate factors, the temperature was the dominant climate factor affecting the ecological environment quality (q value: 0.11-0.19), sunshine duration (0.03-0.17), wind speed (0.03-0.11), and precipitation (0.03-0.08) were the main climate drivers, while the explanatory power of relative humidity to ecological environment quality was relatively small. Such various climate factors impacting the ecological environment quality demonstrated distinct spatial non-stationary and the range of driving impact varied with time. Temperature, sunshine duration, wind speed, and relative humidity promoted ecological environment quality in most regions (regression coefficients > 0), while precipitation mainly had a negative inhibitory impact (regression coefficients < 0). Meanwhile, the greater impacts of these five climate factors were concentrated in high-elevation regions of the south and west or the northern areas. The appropriate enhancement of climate warming and air humidity was beneficial to the improvement of the ecological environment, but the excessive precipitation would result in landslides and exhibit inhibition of vegetation growth. Therefore, selecting cold-tolerant herbs and shrubs, and strengthening climate monitoring and early warning systems (such as drought and excessive precipitation) are essential for ecological restoration.


Assuntos
Mudança Climática , Monitoramento Ambiental , Humanos , Umidade , Temperatura Baixa , Secas
15.
Int J Biol Macromol ; 243: 125196, 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37285890

RESUMO

The cells are like a highly industrialized and urbanized city, filled with numerous biological macromolecules and metabolites, forming a crowded environment. While, the cells have compartmentalized organelles to complete different biological processes efficiently and orderly. However, membraneless organelles are more dynamic and adaptable for transient events including signal transduction and molecular interactions. Liquid-liquid phase separation (LLPS) is a mechanism that is widespread in which macromolecules form condensates without membranes to exert biological functions in crowded environments. Due to the lack of deep understanding of phase-separated proteins, platforms exploring phase-separated proteins by high-throughput methods is lacking. Bioinformatics has its unique properties and has proven to be a great impetus in multiple fields. Here, We integrated the amino acid sequence, protein structure, and cellular localization, then developed a workflow for screening phase-separated proteins and identified a novel cell cycle-related phase separation protein, serine/arginine-rich splicing factor 2 (SRSF2). In conclusion, we developed a workflow as a useful resource for predicting phase-separated proteins based on multi-prediction tool, which has an important contribution to the further identification of phase-separated proteins and the development strategies for treating disease.


Assuntos
Proteínas Intrinsicamente Desordenadas , Sequência de Aminoácidos , Proteínas Intrinsicamente Desordenadas/química , Organelas/metabolismo
16.
MedComm (2020) ; 4(2): e245, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36999124

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is a major type II enzyme responsible for symmetric dimethylation of arginine (SDMA), and plays predominantly roles in human cancers, including in ovarian cancer. However, the exactly roles and underlying mechanisms of PRMT5 contributing to the progression of ovarian cancer mediated by reprogramming cell metabolism remain largely elusive. Here, we report that PRMT5 is highly expressed and correlates with poor survival in ovarian cancer. Knockdown or pharmaceutical inhibition of PRMT5 is sufficient to decrease glycolysis flux, attenuate tumor growth, and enhance the antitumor effect of Taxol. Mechanistically, we find that PRMT5 symmetrically dimethylates alpha-enolase (ENO1) at arginine 9 to promotes active ENO1 dimer formation, which increases glycolysis flux and accelerates tumor growth. Moreover, PRMT5 signals high glucose to increase the methylation modification of ENO1. Together, our data reveal a novel role of PRMT5 in promoting ovarian cancer growth by controlling glycolysis flux mediated by methylating ENO1, and highlights that PRMT5 may represent a promising therapeutic target for treating ovarian cancer.

17.
Acta Pharm Sin B ; 13(1): 157-173, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36815049

RESUMO

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

18.
Cell Mol Biol Lett ; 28(1): 4, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658472

RESUMO

BACKGROUND: Ischemia-reperfusion injury (IRI) is an inevitable process in renal transplantation that significantly increases the risk of delayed graft function, acute rejection, and even graft loss. Formyl peptide receptor 2 (FPR2) is an important receptor in multiple septic and aseptic injuries, but its functions in kidney IRI are still unclear. This study was designed to reveal the pathological role of FPR2 in kidney IRI and its functional mechanisms. METHODS: To explore the mechanism of FPR2 in kidney IRI, the model rats were sacrificed after IRI surgery. Immunofluorescence, enzyme-linked immunosorbent assays, and western blotting were used to detect differences in the expression of FPR2 and its ligands between the IRI and control groups. WRW4 (WRWWWW-NH2), a specific antagonist of FPR2, was administered to kidney IRI rats. Kidney function and pathological damage were detected to assess kidney injury and recovery. Flow cytometry was used to quantitatively compare neutrophil infiltration among the experimental groups. Mitochondrial formyl peptides (mtFPs) were synthesized and administered to primary rat neutrophils together with the specific FPR family antagonist WRW4 to verify our hypothesis in vitro. Western blotting and cell function assays were used to examine the functions and signaling pathways that FPR2 mediates in neutrophils. RESULTS: FPR2 was activated mainly by mtFPs during the acute phase of IRI, mediating neutrophil migration and reactive oxygen species production in the rat kidney through the ERK1/2 pathway. FPR2 blockade in the early phase protected rat kidneys from IRI. CONCLUSIONS: mtFPs activated FPR2 during the acute phase of IRI and mediated rat kidney injury by activating the migration and reactive oxygen species generation of neutrophils through the ERK1/2 pathway.


Assuntos
Neutrófilos , Receptores de Formil Peptídeo , Traumatismo por Reperfusão , Animais , Ratos , Sistema de Sinalização das MAP Quinases , Neutrófilos/metabolismo , Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Formil Peptídeo/metabolismo , Traumatismo por Reperfusão/metabolismo
19.
Cell Tissue Res ; 390(3): 465-489, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36098854

RESUMO

Overexposure to transforming growth factor b1 (TGF-ß1) induces myofibroblastic differentiation of mesenchymal stem cells (MSCs), which could be attenuated by myeloid-derived suppressor cell (MDSC) supernatant. However, the promyofibroblastic effects of TGF-ß1 and the antimyofibroblastic effects of MDSC supernatant in MSCs have not been fully elucidated. To further clarify the latent mechanism and identify underlying therapeutic targets, we used an integrative strategy combining transcriptomics and metabolomics. Bone marrow MSCs were collected 24 h following TGF-ß1 and MDSC supernatant treatment for RNA sequencing and untargeted metabolomic analysis. The integrated data were then analyzed to identify significant gene-metabolite correlations. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) were assessed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for exploring the mechanisms of myofibroblastic differentiation of MSCs. The integration of transcriptomic and metabolomic data highlighted significantly coordinated changes in glycolysis/gluconeogenesis and purine metabolism following TGF-ß1 and MDSC supernatant treatment. By combining transcriptomic and metabolomic analyses, this study showed that glycolysis/gluconeogenesis and purine metabolism were essential for the myofibroblastic differentiation of MSCs and may serve as promising targets for mechanistic research and clinical practice in the treatment of fibrosis by MDSC supernatant.


Assuntos
Células-Tronco Mesenquimais , Células Supressoras Mieloides , Miofibroblastos , Diferenciação Celular , Células Supressoras Mieloides/metabolismo , Purinas/metabolismo , Purinas/farmacologia , Transcriptoma/genética , Fator de Crescimento Transformador beta1/metabolismo , Fatores de Crescimento Transformadores/genética , Fatores de Crescimento Transformadores/metabolismo , Fatores de Crescimento Transformadores/farmacologia , Miofibroblastos/citologia
20.
Front Pharmacol ; 13: 934729, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814224

RESUMO

Network pharmacology, as a novel way using bioinformatics to explore drug targets and interactions in cancer, broadens our understanding of drug action, thereby facilitating drug discovery. Here, we utilized network pharmacology to explore the role and mechanism by which cinobufotalin functions in colon adenocarcinoma (COAD). We found that cinobufotalin represses the growth and proliferation of colon cancer cells, and integrated public databases for targets reported to be associated with COAD, together with those predicted to be targets of cinobufotalin. Targets overlapped between COAD-associated proteins and cinobufotalin target proteins were used to filter candidate targets of cinobufotalin in COAD. The following proteins were thought to occupy a key position in COAD-cinobufotalin target networks: SRC, PIK3R1, MAPK1, PIK3CA, HSP90AA1, CTNNB1, GRB2, RHO1, PTPN11, and EGFR. The networks regulated by cinobufotalin were involved mainly in extracellular signal stimulation and transduction, including MAPK signaling pathway, PI3K-AKT signaling pathway, and JAK-STAT signaling pathway. Besides, transcriptome sequencing results also indicated that cinobufotalin inhibits the response of colon cancer cells to extracellular stimulation and promotes cell apoptosis. Molecular docking results showed that cinobufotalin matches in the pocket of the top candidate cinobufotalin target proteins (SRC, PIK3R1, MAPK1 and PIK3CA). These findings demonstrate cinobufotalin can be developed as potential anti-cancer therapeutics.

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