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BACKGROUND: Emodin is a chemical compound found in traditional Chinese herbs. It possesses anti-inflammatory and many other pharmacological effects. Our previous study showed that emodin significantly alleviates the inflammation effect of severe acute pancreatitis (SAP). However, its poor solubility, high toxicity and limited pancreas retention time hinder its clinical application. PURPOSE: We aimed to prepare emodin nanocapsules with improved bioavailability to achieve the controlled release of emodin by targeting macrophages. Further, the mechanism of mannose-conjugated chitosan-coated lipid nanocapsules loaded with emodin (M-CS-E-LNC) in the treatment of SAP was explored. METHODS: M-CS-E-LNC were prepared by the phase inversion method with slight modification. The expression of inflammation mediators and the anti-inflammation efficacy of M-CS-E-LNC were examined by ELISA, IHC and IF in macrophage cells and LPS-induced SAP mice. IVIS spectrum imaging and HPLC were applied to explore the controlled release of M-CS-E-LNC in the pancreas. LC-MS/MS was performed for lipidomics analysis of macrophages. Moreover, a vector-based short hairpin RNA (shRNA) method was used to silence CTP1 gene expression in macrophage cells. RESULTS: The levels of inflammatory mediators in macrophages were markedly decreased after treatment with M-CS-E-LNC. The same anti-inflammation effects were detected in SAP mouse through the analysis of serum levels of amylase, TNF-α and IL-6. Importantly, M-CS-E-LNC allowed the emodin to selectively accumulate at pancreas and gastrointestinal tissues, thus exhibiting a targeted release. Mechanistically, the M-CS-E-LNC treatment group showed up-regulated expression of the carnitine palmitoyltransferase 1 (CPT1) protein which promoted intracellular long-chain fatty acid transport, thereby promoting the M2 phenotype polarization of macrophages. CONCLUSION: M-CS-E-LNC exhibited significantly improved bioavailability and water solubility, which translated to greater therapeutic effects on macrophage polarization. Our findings also demonstrate, for the first time, that CPT1 may be a new therapeutic target for SAP treatment.
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Emodina , Metabolismo dos Lipídeos , Macrófagos , Nanocápsulas , Pancreatite , Animais , Emodina/farmacologia , Camundongos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pancreatite/tratamento farmacológico , Células RAW 264.7 , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Anti-Inflamatórios/farmacologia , Quitosana/farmacologia , Quitosana/química , Camundongos Endogâmicos C57BL , Lipopolissacarídeos , Reprogramação MetabólicaRESUMO
PURPOSE: Targeting inflammatory crosstalk between tumors and their microenvironment has emerged as a crucial method for suppressing pancreatic adenocarcinoma (PAAD) progression. Berberine (BBR) is a natural pentacyclic isoquinoline alkaloid known for its anti-inflammatory and antitumor pharmacological effects; however, the mechanism underlying PAAD suppression remains unclear. We aim to investigate the effects of BBR on PAAD progression and their underlying mechanisms. METHODS: The prognostic value of inflammation-related genes in PAAD was assessed using bioinformatics analyses, then the pharmacological effects and potential mechanisms of BBR on PAAD will be investigated in silico, in vitro, and in vivo. RESULTS: Fifty-eight prognostic inflammation-related genes were identified in PAAD, which were shown to have good sensitivity and specificity using a novel inflammation-related gene risk-prognosis prediction model. Among these, four candidate genes (CAPS3, PTGS2, ICAM1, and CXCR4) were predicted as targets of BBR in PAAD in silico. Molecular docking simulations showed that the four key targets docked well with BBR. Further BBR treatment suppressed cell proliferation, colony formation, and induced cell cycle arrest in vitro. Moreover, BBR exhibited a significant tumor-suppressive effect in murine subcutaneous xenografts without macroscopic hepatic and renal toxicities. In addition, BBR downregulated CAPS3, PTGS2, ICAM1, and CXCR4 protein expression. CONCLUSION: This study not only elucidated the prognostic value of inflammation-related genes in PAAD but also demonstrated the potential of BBR to inhibit PAAD by targeting these genes.
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BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor in urgent need of novel diagnostics, prognostic markers, and treatments. Eukaryotic translation initiation factor 2 subunits (EIF2Ss), comprising Eukaryotic translation initiation factor 2 subunit alpha (EIF2S1), Eukaryotic translation initiation factor 2 subunit beta (EIF2S2), and Eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), is a family of eukaryotic initiation factors that participate in early protein synthesis and are crucial for tumor initiation and progression. However, the role of EIF2Ss in PAAD has yet to be reported. The aim of this study was therefore to analyze EIF2Ss in relation to the diagnosis, prognosis, and treatment of PAAD. METHODS: The cancer genome atlas (TCGA) database was used to investigate gene expression and patient survival. Gene alterations, immune cell infiltration, and immune checkpoints in PAAD were also evaluated. Univariate and multivariate analysis, nomograms, calibration curves, and Decision Curve Analysis (DCA) diagrams were used to develop and evaluate a prediction model for patient outcome. Single-cell RNA-seq (scRNA) analysis, functional enrichment, co-IP assay, mass spectrometry, and western blot were used to study the relationship between EIF2Ss and c-myc in PAAD. RESULTS: EIF2Ss are over-expressed in PAAD tissue and are associated with poor prognosis. The frequency of EIF2S1, EIF2S2, and EIF2S3 gene alteration in PAAD was 0.2%, 0.4%, and 0.2%, respectively. High EIF2Ss expression was associated with Th2 cell infiltration, whereas low expression was associated with pDC infiltration. Moreover, EIF2Ss expression was positively correlated with the expression of the NT5E, ULBP1, PVR, CD44, IL10RB, and CD276 checkpoints. A prediction model developed using EIF2Ss and important clinicopathologic features showed good predictive value for the overall survival of PAAD patients. ScRNA-Seq data showed that EIF2Ss was associated with enrichment for endothelial cells, fibroblasts, malignant cells, and ductal cells. EIF2Ss expression was also correlated with adipogenesis, interferon-alpha response, epithelial-mesenchymal transition, myc targets, G2M checkpoint, oxidative phosphorylation, and hypoxia. Functional enrichment analysis of EIF2Ss showed a close correlation with the myc pathway, and interactions between EIF2Ss and c-myc were confirmed by co-IP assay and mass spectrometry. Importantly, knockdown of c-myc decreased the expression of EIF2S1, EIF2S2, and EIF2S3 in PAAD cells. CONCLUSIONS: EIF2Ss were found to have significant clinical implications for the prognosis and treatment of PAAD. Inhibition of c-myc caused the downregulation of EIF2S1, EIF2S2, and EIF2S3 expression.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Células Endoteliais , Fator de Iniciação 2 em Procariotos , Neoplasias Pancreáticas/genética , Genes myc/genética , Regulação Neoplásica da Expressão Gênica , Antígenos B7RESUMO
BACKGROUND: The DIAPHs (DIAPH1, DIAPH2, and DIAPH3) are members of the diaphanous subfamily of the formin family. KIF20B and MET, hub genes of DIAPHs, play crucial roles in cytoskeletal remodeling, cell migration, and adhesion. However, their combined prognostic and treatment value in pancreatic adenocarcinoma (PC) warrants further investigation. METHODS: Multiomics analysis tools were used to comprehensively assess the genomic expression and prognostic value of KIF20B and MET in PC. Immune cell infiltration, functional enrichment, single-cell RNA-seq (scRNA) analysis, potential therapeutic drugs, and nomograms were established and analyzed. CCK-8 levels, transwell assay, Co-IP assay, mass spectrometry, and western blotting were performed to assess the role of KIF20B and MET as modulators of ß-catenin and Lactate Dehydrogenase A (LDHA) in vitro. Xenograft tumor models were used to evaluate the anti-tumor effects in vivo. RESULTS: DIAPHs, KIF20B, and MET were overexpressed and functioned as poor prognostic markers of PC. Immunoinfiltration analysis revealed that pDC and NK cells were enriched with low expression levels of KIF20B and MET, whereas Th2 cells were enriched with high expression levels of these two genes. The copy number variations (CNVs) in KIF20B and MET were positively correlated with B cell and CD4 + T cell infiltration. Immunological checkpoints NT5E and CD44 were positively correlated with KIF20B and MET expression. Moreover, the nomogram constructed based on KIF20B and MET demonstrated predictive value for overall survival. scRNA-Seq analysis indicated that KIF20B and MET were enriched in endothelial, malignant, B, T, and CD8 + T cells, which correlated with glycolysis and the epithelial-mesenchymal transition (EMT). The interactions of KIF20B and MET with ß-catenin and LDHA were verified by Co-IP assay and mass spectrometry. Knockdown of KIF20B and MET downregulates ß-catenin and LDHA in vitro. Furthermore, dual knockdown of KIF20B and MET exhibited a synergistic suppressive effect on PC progression in vitro and in vivo. CONCLUSION: DIAPHs, KIF20B, and MET are promising candidates for the prognosis and treatment of PC. More importantly, downregulation of KIF20B and MET inhibited pancreatic cancer progression by regulating LDHA and EMT.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , beta Catenina/metabolismo , Adenocarcinoma/genética , Variações do Número de Cópias de DNA , Linhagem Celular Tumoral , Processos Neoplásicos , Prognóstico , Regulação Neoplásica da Expressão Gênica , Forminas/genética , Forminas/metabolismo , Cinesinas/genética , Cinesinas/metabolismoRESUMO
BACKGROUND: Protein kinases play a pivotal role in the malignant evolution of pancreatic cancer (PC) through mediating phosphorylation. Many kinase inhibitors have been developed and translated into clinical use, while the complex pathology of PC confounds their clinical efficacy and warrants the discovery of more effective therapeutic targets. METHODS: Here, we used the Gene Expression Omnibus (GEO) database and protein kinase datasets to map the PC-related protein kinase-encoding genes. Then, applying Gene Expression and Profiling Interactive Analysis (GEPIA), GEO and Human Protein Atlas, we evaluated gene correlation, gene expression at protein and mRNA levels, as well as survival significance. In addition, we performed protein kinase RIPK2 knockout and overexpression to observe effects of its expression on PC cell proliferation, migration and invasion in vitro, as well as cell apoptosis, reactive oxygen species (ROS) production and autophagy. We established PC subcutaneous xenograft and liver metastasis models to investigate the effects of RIPK2 knockout on PC growth and metastasis. Co-immunoprecipitation and immunofluorescence were utilized to explore the interaction between protein kinases RIPK2 and PRKCI. Polymerase chain reaction and immunoblotting were used to evaluate gene expression and protein phosphorylation level. RESULTS: We found fourteen kinases aberrantly expressed in human PC and nine kinases with prognosis significance. Among them, RIPK2 with both serine/threonine and tyrosine activities were validated to promote PC cells proliferation, migration and invasion. RIPK2 knockout could inhibit subcutaneous tumor growth and liver metastasis of PC. In addition, RIPK2 knockout suppressed autophagosome formation, increased ROS production and PC cell apoptosis. Importantly, another oncogenic kinase PRKCI could interact with RIPK2 to enhance the phosphorylation of downstream NF-κB, JNK and ERK. CONCLUSION: Paired protein kinases PRKCI-RIPK2 with multiple phosphorylation activities represent a new pathological mechanism in PC and could provide potential targets for PC therapy.
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Neoplasias Hepáticas , Neoplasias Pancreáticas , Proteína Quinase C , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Humanos , Linhagem Celular Tumoral , Neoplasias Hepáticas/secundário , NF-kappa B/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Quinase C/genética , Animais , Neoplasias PancreáticasRESUMO
Methionine adenosyltransferases (MATs) synthesize S-adenosylmethionine (SAM) from methionine, which provides methyl groups for DNA, RNA, protein, and lipid methylation. MATs play a critical role in cellular processes, including growth, proliferation, and differentiation, and have been implicated in tumour development and progression. The expression of MATs is altered in hepatobiliary and pancreatic (HBP) cancers, which serves as a rare biomarker for early diagnosis and prognosis prediction of HBP cancers. Independent of SAM depletion in cells, MATs are often dysregulated at the transcriptional, post-transcriptional, and post-translational levels. Dysregulation of MATs is involved in carcinogenesis, chemotherapy resistance, T cell exhaustion, activation of tumour-associated macrophages, cancer stemness, and activation of tumourigenic pathways. Targeting MATs both directly and indirectly is a potential therapeutic strategy. This review summarizes the dysregulations of MATs, their proposed mechanism, diagnostic and prognostic roles, and potential therapeutic effects in context of HBP cancers.
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Neoplasias Gastrointestinais , Neoplasias Pancreáticas , Humanos , Lipídeos , Metionina , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , RNA , S-Adenosilmetionina/metabolismo , S-Adenosilmetionina/uso terapêuticoRESUMO
Background: Damp-heat syndrome is one of the most important syndrome types in the traditional Chinese medicine (TCM) syndrome differentiation and treatment system, as well as the core pathogenesis of pancreatic cancer (PC) which remains a challenge to medical researchers due to its insidious onset and poor prognosis. Great attention has been given to the impact of damp-heat syndrome on tumorigenesis and progression, but less attention has been given to damp-heat modeling per se. Studying PC in a proper damp-heat syndrome animal model can recapitulate the actual pathological process and contribute to treatment strategy improvement. Methods: Here, an optimized damp-heat syndrome mouse model was established based on our prior experience. The Fibonacci method was applied to determine the maximum tolerated dosage of alcohol for mice. Damp-heat syndrome modeling with the old and new methods was performed in parallel of comparative study about general appearance, food intake, water consumption and survival. Major organs, including the liver, kidneys, lungs, pancreas, spleen, intestines and testes, were collected for histological evaluation. Complete blood counts and biochemical tests were conducted to characterize changes in blood circulation. PC cells were subcutaneously inoculated into mice with damp-heat syndrome to explore the impact of damp-heat syndrome on PC growth. Hematoxylin-eosin staining, Masson staining and immunohistochemistry were performed for pathological evaluation. A chemokine microarray was applied to screen the cytokines mediating the proliferation-promoting effects of damp-heat syndrome, and quantitative polymerase chain reaction and Western blotting were conducted for results validation. Results: The new modeling method has the advantages of mouse-friendly features, easily accessible materials, simple operation, and good stability. More importantly, a set of systematic indicators was proposed for model evaluation. The new modeling method verified the pancreatic tumor-promoting role of damp-heat syndrome. Damp-heat syndrome induced the proliferation of cancer-associated fibroblasts and promoted desmoplasia. In addition, circulating and tumor-located chemokine levels were altered by damp-heat syndrome, characterized by tumor promotion and immune suppression. Conclusions: This study established a stable and reproducible murine model of damp-heat syndrome in TCM with systematic evaluation methods. Cancer associated fibroblast-mediated desmoplasia and chemokine production contribute to the tumor-promoting effect of damp-heat syndrome on PC.
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ETHNOPHARMACOLOGICAL RELEVANCE: Xiang-lian pill, consisting of Coptis chinensis Franch. coprocessed with Tetradium ruticarpum (A.Juss.) T.G.Hartley (Yu-huang-lian) and Aucklandia lappa DC. (Mu-xiang), is traditionally used to relieve fever, abdominal pain, and gastrointestinal inflammatory symptoms observed in patients with malignancies of the gastrointestinal tract. Each of the three herbs contained in Xiang-lian pill has been indicated to have anticancer effects on a variety of cancers, but its effects on pancreatic cancer remain unexplored. The main extracts of these herbs have anti-pancreatic cancer effects, but the comprehensive mechanism of this compound prescription of Xiang-lian pill in pancreatic cancer remains to be revealed. AIM OF THE STUDY: To explore the main active ingredients, potential anti-pancreatic cancer targets, and related mechanisms of the Xiang-lian pill and to determine its therapeutic value in vivo. MATERIALS AND METHODS: Network pharmacology and bioinformatics analysis were applied to screen the potential effective ingredients and key targets. Liquid/gas-mass spectrometry was performed for ingredients validation. Molecular docking and the cellular thermal shift assay were performed to test the binding efficiency between ingredients and targets. A murine pancreatic cancer model was established and administered different doses of the Xiang-lian pill. Hematoxylin-eosin staining was used for histopathological observation. Immunohistochemistry and immunoblotting were conducted for target validation. In vitro studies (cell viability and clonogenicity assays) were conducted to investigate the impact of three main ingredients in Xiang-lian pill on pancreatic cancer cells. PTGS2 overexpression was performed to reversely confirm the antitumor mechanisms of rutaecarpine as a specific PTGS2 inhibitor. RESULTS: Xiang-lian pill suppressed pancreatic cancer growth in the dose range of 0.78-2.34g/kg with no significant toxicity. Sixteen potentially active ingredients and 26 corresponding therapeutic targets for pancreatic cancer were identified. PTGS2, PTGS1, KCNH2, PRSS1, and HSP90AA1 were the top 5 significant genes targeted by the Xiang-lian pill. Evodiamine, rutaecarpine and stigmasterol bound to PTGS2 and PTGS1 with different affinities and inhibited pancreatic cancer cell proliferation. The PTGS2-associated metabolic pathway MEK/ERK was downregulated by rutaecarpine in vitro and the Xiang-lian pill in vivo. CONCLUSIONS: Xiang-lian pill mainly regulates inflammation, apoptosis, metastasis, and metabolism to exert an antitumor effect. The main active ingredients in Xiang-lian pill exhibit antitumor roles through directly binding to key targets in pancreatic cancer. PTGS2 mediated MEK/ERK inhibition by rutaecarpine represents a key therapeutic mechanism of Xiang-lian pill.
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Medicamentos de Ervas Chinesas , Neoplasias Pancreáticas , Animais , Ciclo-Oxigenase 2 , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias PancreáticasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The Qingyihuaji decoction (QYHJ) is composed of seven herbs: Scutellaria barbata D.Don (Banzhilian, HSB), Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan, GP), Oldenlandia diffusa (Willd.) Roxb. (Baihuasheshecao, HDH), Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi, GL), Myristica fragrans Houtt. (Doukou, AK), and Amorphophallus kiusianus (Makino) Makino (Sheliugu, RA), and Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf (Yiyiren, CL). QYHJ has been reported to exhibit clinical efficacy in the treatment of pancreatic adenocarcinoma (PAAD). However, the molecular mechanism remains unclear. AIM OF THE STUDY: This study explores the therapeutic mechanism of QYHJ in the treatment of PAAD using network pharmacology to identify related targets and pathways in vivo and in vitro. MATERIALS AND METHODS: The bioactive compounds of QYHJ were retrieved and screened using the ADME network pharmacology approach, followed by compound-target prediction and overlapping genes between PAAD oncogenes and QYHJ target genes. The compound-target-pathway network was established using The KEGG pathway, GO analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis to identify potential action pathways. The effects of QYHJ on PAAD were evaluated in vivo and in vitro, and the predicted targets and potential pathways related to QYHJ in PAAD treatment were evaluated using qRT-PCR and immunoblotting. RESULTS: A total of 68 bioactive compounds of QYHJ fulfilled the ADME screening criterion, and their respective 242 target genes were retrieved. The compound-target-disease network identified 11 possible target genes. The KEGG pathway analysis showed significant enrichment of pathways in cancers, involving regulating cancer-related pathways of inflammation, oxidative stress, and apoptosis. Furthermore, QYHJ inhibited PAAD growth in vivo; suppressed cell proliferation, invasion, and migration of PAAD; and induced cellular apoptosis in vitro. The qRT-PCR results showed that QYHJ suppressed the mRNA expression of ICAM1, VCAM1, and Bcl2, and increased that of HMOX1 and NQO1. Immunoblotting revealed changes in the PI3K/AKT/mTOR, Keap1/Nrf2/HO-1/NQO1, and Bcl2/Bax pathways upon QYHJ treatment. CONCLUSIONS: QYHJ can suppress PAAD growth and progression through various mechanisms, including anti-inflammation and apoptosis-induction.
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Adenocarcinoma , Medicamentos de Ervas Chinesas , Neoplasias Pancreáticas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Farmacologia em Rede , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias PancreáticasRESUMO
Cancer is one of the deadliest diseases affecting the health of human beings. With limited therapeutic options available, complementary and alternative medicine has been widely adopted in cancer management and is increasingly becoming accepted by both patients and healthcare workers alike. Chinese medicine characterized by its unique diagnostic and treatment system is the most widely applied complementary and alternative medicine. It emphasizes symptoms and ZHENG (syndrome)-based treatment combined with contemporary disease diagnosis and further stratifies patients into individualized medicine subgroups. As a representative cancer with the highest degree of malignancy, pancreatic cancer is traditionally classified into the "amassment and accumulation". Emerging perspectives define the core pathogenesis of pancreatic cancer as "dampness-heat" and the respective treatment "clearing heat and resolving dampness" has been demonstrated to prolong survival in pancreatic cancer patients, as has been observed in many other cancers. This clinical advantage encourages an exploration of the essence of dampness-heat ZHENG (DHZ) in cancer and investigation into underlying mechanisms of action of herbal formulations against dampness-heat. However, at present, there is a lack of understanding of the molecular characteristics of DHZ in cancer and no standardized and widely accepted animal model to study this core syndrome in vivo. The shortage of animal models limits the ability to uncover the antitumor mechanisms of herbal medicines and to assess the safety profile of the natural products derived from them. This review summarizes the current research on DHZ in cancer in terms of the clinical aspects, molecular landscape, and animal models. This study aims to provide comprehensive insight that can be used for the establishment of a future standardized ZHENG-based cancer animal model.
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ETHNOPHARMACOLOGICAL RELEVANCE: Matrine injection is a complex mixture of plant bioactive substances extracted from Sophora flavescens Aiton and Smilax glabra Roxb. Since its approval by the Chinese Food and Drug Administration (CFDA) in 1995, Matrine injection has been clinically used as a complementary and alternative treatment for various cancers; however, the underlying mechanism of pancreatic cancer treatment is yet to be elucidated. AIM OF THE STUDY: The present study explores the potential mechanism of matrine injection on pancreatic cancer through network pharmacology technique and in vitro experimental validation. MATERIALS AND METHODS: Genes differentially expressed in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database (GSE101448). The potential active components of matrine injection were selected following a literature search, and target prediction was performed by the SwissTarget Prediction database. Overlapping genes associated with survival were screened by the Gene Expression Profiling Interactive Analysis (GEPIA) database. In vitro experimental validation was performed with cell counting kit-8 (CCK-8) assay, apoptosis detection, cell cycle analysis, immunoblotting, and co-immunoprecipitation of the identified proteins. RESULTS: One thousand seven hundred genes differentially expressed among pancreatic tumor and non-tumor tissues were screened out. Sixteen active components and 226 predicted target genes were identified in matrine injection. A total of 25 potential target genes of matrine injection for the treatment of pancreatic cancer were obtained. Among them, the prognostic target genes carbonic anhydrase 9 (CA9) and carbonic anhydrase 12 (CA12) based on the GEPIA database are differently expressed in tumors compared to adjacent normal tissue. In vitro experiments, the results of CCK-8 assay, apoptosis and cell cycle analysis, immunoblotting, and co-immunoprecipitation showed that matrine injection inhibited Capan-1 and Mia paca-2 proliferation, arrested the cell cycle at the S phase, and induced apoptosis through up-regulated CA12 and down-regulated CA9. CONCLUSIONS: In this study, bioinformatics and network pharmacology were applied to explore the treatment mechanism on pancreatic cancer with matrine injection. This study demonstrated that matrine injection inhibited proliferation, arrested the cell cycle, and induced apoptosis of pancreatic cancer cells. The mechanism may be related to the induction of CA12 over-expression, and CA9 reduced expression. As novel targets for pancreatic cancer treatment, Carbonic anhydrases require further study.
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Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Anidrases Carbônicas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Quinolizinas/farmacologia , Sophora/química , Alcaloides/isolamento & purificação , Antígenos de Neoplasias/genética , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Anidrase Carbônica IX/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Farmacologia em Rede , Neoplasias Pancreáticas/genética , Quinolizinas/isolamento & purificação , Regulação para Cima/efeitos dos fármacos , MatrinasRESUMO
BACKGROUND: SMARCAs, belonged to SWI/SNF2 subfamilies, are critical to cellular processes due to their modulation of chromatin remodeling processes. Although SMARCAs are implicated in the tumor progression of various cancer types, our understanding of how those members affect pancreatic carcinogenesis is quite limited and improving this requires bioinformatics analysis and biology approaches. METHODS: To address this issue, we investigated the transcriptional and survival data of SMARCAs in patients with pancreatic cancer using ONCOMINE, GEPIA, Human Protein Atlas, and Kaplan-Meier plotter. We further verified the effect of significant biomarker on pancreatic cancer in vitro through functional experiment. RESULTS: The Kaplan-Meier curve and log-rank test analyses showed a positive correlation between SMARCA1/2/3/SMARCAD1 and patients' overall survival (OS). On the other hand, mRNA expression of SMARCA6 (also known as HELLS) showed a negative correlation with OS. Meanwhile, no significant correlation was found between SMARCA4/5/SMARCAL1 and tumor stages and OS. The knockdown of HELLS impaired the colony formation ability, and inhibited pancreatic cancer cell proliferation by arresting cells at S phase. CONCLUSIONS: Data mining analysis and cell function research demonstrated that HELLS played oncogenic roles in the development and progression of pancreatic cancer, and serve as a poor prognostic biomarker for pancreatic cancer. Our work laid a foundation for further clinical applications of HELLS in pancreatic cancer.
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Neoplasias Pancreáticas , Neoplasias PancreáticasRESUMO
Macrophages play a crucial role in the pathogenesis of pancreatitis that is a common gastrointestinal disease. Particularly, macrophages differentiate into different phenotypes and exert diverse functions in acute pancreatitis (AP) and chronic pancreatitis (CP), respectively. In AP, macrophages in the pancreas and other related organs are mainly activated and differentiated into a pro-inflammatory M1 phenotype, and furthermore secrete inflammatory cytokines and mediators, causing local inflammation of the pancreas, and even intractable systemic inflammatory response or multiple organ failure. In CP, macrophages often exhibit a M2 polarisation and interact with pancreatic stellate cells (PSCs) in an autocrine and paracrine cytokine-dependent manner to promote the progression of pancreatic fibrosis. As the severity of pancreatic fibrosis aggravates, the proportion of M2/M1 macrophage cytokines in the pancreas increases. The discovery of macrophages in the pathogenesis of pancreatitis has promoted the research of targeted drugs, which provides great potential for the effective treatment of pancreatitis. This paper provides an overview of the roles of various macrophages in the pathogenesis of pancreatitis and the current research status of pancreatitis immunotherapy targeting macrophages. The findings addressed in this review are of considerable significance for understanding the pivotal role of macrophages in pancreatitis.