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1.
Int J Biol Sci ; 20(7): 2388-2402, 2024.
Article in English | MEDLINE | ID: mdl-38725844

ABSTRACT

Metastasis is the leading cause of death in colorectal cancer (CRC) patients. By mediating intercellular communication, exosomes exhibit considerable value in regulating tumor metastasis. Long non-coding RNAs (lncRNAs) are abundant in exosomes and participate in regulating tumor progression. However, it is poorly understood how the cancer-secreted exosomal lncRNAs affect CRC proliferation and metastasis. Here, by analyzing the public databases we identified a lncRNA SNHG3 and demonstrated that SNHG3 was delivered through CRC cells-derived exosomes to promote metastasis in CRC. Mechanistically, exosomal SNHG3 was internalized by CRC cells and afterward upregulated the expression of ß-catenin by facilitating the intranuclear transport of hnRNPC. Consequently, the RNA stability of ß-catenin was enhanced which led to the activation of EMT and metastasis of CRC cells. Our findings expand the oncogenic mechanisms of exosomal SNHG3 and identify it as a diagnostic marker for CRC.


Subject(s)
Colorectal Neoplasms , Exosomes , RNA, Long Noncoding , beta Catenin , Humans , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , RNA, Long Noncoding/metabolism , RNA, Long Noncoding/genetics , beta Catenin/metabolism , Exosomes/metabolism , Cell Line, Tumor , RNA Stability/genetics , Gene Expression Regulation, Neoplastic , Neoplasm Metastasis , Animals , Mice , Cell Proliferation/genetics , Mice, Nude
2.
Cell Rep Med ; 5(5): 101536, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38697103

ABSTRACT

Spatial transcriptomics (ST) provides insights into the tumor microenvironment (TME), which is closely associated with cancer prognosis, but ST has limited clinical availability. In this study, we provide a powerful deep learning system to augment TME information based on histological images for patients without ST data, thereby empowering precise cancer prognosis. The system provides two connections to bridge existing gaps. The first is the integrated graph and image deep learning (IGI-DL) model, which predicts ST expression based on histological images with a 0.171 increase in mean correlation across three cancer types compared with five existing methods. The second connection is the cancer prognosis prediction model, based on TME depicted by spatial gene expression. Our survival model, using graphs with predicted ST features, achieves superior accuracy with a concordance index of 0.747 and 0.725 for The Cancer Genome Atlas breast cancer and colorectal cancer cohorts, outperforming other survival models. For the external Molecular and Cellular Oncology colorectal cancer cohort, our survival model maintains a stable advantage.


Subject(s)
Deep Learning , Neoplasms , Tumor Microenvironment , Humans , Prognosis , Neoplasms/pathology , Neoplasms/genetics , Neoplasms/diagnosis , Transcriptome/genetics , Gene Expression Regulation, Neoplastic , Female , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/diagnosis
3.
Genomics ; 116(2): 110821, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38447684

ABSTRACT

Prefoldin Subunit 5 (PFDN5) plays a critical role as a member of the prefoldins (PFDNs) in maintaining a finely tuned equilibrium between protein production and degradation. However, there has been no comprehensive analysis specifically focused on PFDN5 thus far. Here, a comprehensive multi-omics (transcriptomics, genomics, and proteomics) analysis, systematic molecular biology experiments (in vitro and in vivo), transcriptome sequencing and PCR Array were performed for identifying the value of PFDN5 in pan-cancer, especially in Gastric Cancer (GC). We found PFDN5 had the potential to serve as a prognostic and therapeutic biomarker in GC. And PFDN5 could promote the proliferation of GC cells, primarily by affecting the cell cycle, cell death and immune process etc. These findings provide novel insights into the molecular mechanisms and precise treatments of in GC.


Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Prognosis , Multiomics , Genomics , Biomarkers
4.
Int J Med Inform ; 185: 105402, 2024 May.
Article in English | MEDLINE | ID: mdl-38467099

ABSTRACT

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in the world, posing a serious threat to human health. Currently, gastric cancer treatment strategies emphasize a multidisciplinary team (MDT) consultation approach. However, there are numerous treatment guidelines and insights from clinical trials. The application of AI-based Clinical Decision Support System (CDSS) in tumor diagnosis and screening is increasing rapidly. OBJECTIVE: The purpose of this study is to (1) summarize the treatment decision process for GC according to the treatment guidelines in China, and then create a knowledge graph (KG) for GC, (2) based on aforementioned KG, built a CDSS and conducted an initial feasibility evaluation for the current system. METHODS: Firstly, we summarized the decision-making process for treatment of GC. Then, we extracted relevant decision nodes and relationships and utilized Neo4j to create the KG. After obtaining the initial node features for building the graph embedding model, graph embedding algorithm, such as Node2Vec and GraphSAGE, were used to construct the GC-CDSS. At last, a retrospective cohort study was used to compare the consistency between GC-CDSS and MDT in treatment decision making. RESULTS: In current study, we introduce a GC-CDSS, which is constructed based on Chinese GC treatment guidelines knowledge graph (KG). In the KG, we define four types of nodes and four types of relationships, and it comprise a total of 207 nodes and 300 relationships. Regarding GC-CDSS, the system is capable of providing dynamic and personalized diagnostic and treatment recommendations based on the patient's condition. Furthermore, a retrospective cohort study is conducted to compare GC-CDSS recommendations with those of the MDT group, the overall consistency rate of treatment recommendations between the auxiliary decision system and MDT team is 92.96%. CONCLUSIONS: We construct a GC treatment support system, GC-CDSS, based on KG. The GC-CDSS may help oncologists make treatment decisions more efficient and promote standardization in primary healthcare settings.


Subject(s)
Decision Support Systems, Clinical , Stomach Neoplasms , Humans , Stomach Neoplasms/diagnosis , Stomach Neoplasms/therapy , Retrospective Studies , Pattern Recognition, Automated , Algorithms
5.
BMC Cancer ; 24(1): 312, 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38448878

ABSTRACT

BACKGROUND: There are differences in the pharmacoeconomics of Immune checkpoint blocking (ICB) therapies for the treatment of lung squamous cell carcinoma (LSCC). However, no corresponding review studies have fully discussed the cost-effectiveness of ICBs in treating LSCC. The aim of this paper is to systematically review and evaluate all available pharmacoeconomic studies of ICBs for LSCC. METHOD: The inclusion criteria were based on the population, intervention, comparator, outcomes, and study designs. An electronic search was conducted by June 2023, and the following databases were used: PubMed, EMBASE, Cochrane Library, and Web of Science. Search keywords included 'Carcinoma', Non-Small-Cell Lung', 'Immunotherapy', and 'Economics, Medical'. The primary outcome was the cost-effectiveness analysis of ICB therapy in LSCC patients. Drummond Checklist was used to assess quality problems and possible bias in the study design of included pharmacoeconomic studies. RESULTS: This review searched 15 articles on the economic evaluation of ICB treatment for LSCC. After a qualitative review of 15 studies, we concluded that nivolumab is more cost-effective as a monotherapy than chemotherapy alone. In the combination regimen, pembrolizumab combined with chemotherapy appears to be the most cost-effective option at present, but for Chinese payers with LSCC, locally developed treatments such as sintilimab or toripalimab in combination with chemotherapy are more cost-effective. DISCUSSION: The inclusion of economic evaluation has heterogeneity in research design and outcomes, which can only support qualitative synthesis. Therefore, The results of this paper need to be treated with caution. For the Chinese market, instead of imported drugs, the possible cost-effectiveness of locally developed ICB therapies should be the focus of future research.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Cost-Benefit Analysis , Cost-Effectiveness Analysis , Lung Neoplasms/drug therapy , Carcinoma, Squamous Cell/drug therapy , Immunotherapy
6.
BMC Geriatr ; 23(1): 849, 2023 12 13.
Article in English | MEDLINE | ID: mdl-38093184

ABSTRACT

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China. METHODS: With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0. RESULTS: A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist's intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models. CONCLUSION: DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Renal Insufficiency, Chronic , Humans , Drug-Related Side Effects and Adverse Reactions/epidemiology , Pharmacists , Prospective Studies , Logistic Models , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/epidemiology
7.
Medicine (Baltimore) ; 102(50): e36379, 2023 Dec 15.
Article in English | MEDLINE | ID: mdl-38115308

ABSTRACT

INTRODUCTION: This paper presents a case of a Chinese patient with advanced colon cancer who developed drug-induced interstitial lung disease while undergoing treatment with cetuximab combined with XELOX. PATIENT CONCERNS: A 75-year-old man with a history of colon cancer, had metastases in the liver, peritoneum, and lungs, which were initially treated with XELOX and cetuximab (0.4 g) in 2019. However, the lung metastases progressed, and the cetuximab dosage was adjusted to 0.9 g and then readjusted to 0.4 g. DIAGNOSIS: In January 2021, computed tomography revealed developed interstitial lung disease, leading to the discontinuation of chemotherapy and cetuximab. INTERVENTIONS: Receiving methylprednisolone pulse therapy. OUTCOMES: The patient experienced respiratory failure and passed away. The Naranjo Algorithm Assessment score indicated a probable relationship between cetuximab and the adverse event. CONCLUSION: This case highlights the need for regular pulmonary imaging examinations during cetuximab therapy, as drug-induced interstitial lung disease may be associated with the dose and duration of treatment.


Subject(s)
Colonic Neoplasms , Lung Diseases, Interstitial , Lung Neoplasms , Male , Humans , Aged , Cetuximab/adverse effects , Colonic Neoplasms/drug therapy , Colonic Neoplasms/etiology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Lung Neoplasms/etiology , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/drug therapy
8.
Turk J Gastroenterol ; 34(12): 1197-1205, 2023 12.
Article in English | MEDLINE | ID: mdl-37823316

ABSTRACT

BACKGROUND/AIMS: Gastric cancer is a prevalent malignancy with unfavorable prognosis partially resulting from its high metastasis rate. Clarifying the molecular mechanism of gastric cancer occurrence and progression for improvement of therapeutic efficacy and prognosis is needed. The study tended to delineate the role and regulatory mechanism of aldo-keto reductase 1B10 (AKR1B10) in gastric cancer progression. MATERIALS AND METHODS: The relationship of AKR1B10 expression with survival rate in gastric cancer was analyzed through Kaplan-Meier analysis. The mRNA levels of AKR1B10 and integrin subunit alpha 5 (ITGA5) in gastric cancer tissues and cell lines were measured by real-time quantitative polymerase chain reaction. Protein levels of AKR1B10 and integrin subunit alpha 5 were assayed via western blot. The molecular relationship between AKR1B10 and ITGA5 was analyzed by co-immunoprecipitation assay. Cell viability was assayed through Cell Counting Kit-8, invasion and migration of tumor cells was assessed through wound healing and transwell assays. Transwell assay was utilized to detect invasion. The adhesion of gastric cancer cells was detected using cell adhesion assays. RESULTS: The results unveiled that integrin subunit alpha 5 was upregulated, while AKR1B10 was downregulated in gastric cancer tissues and cells. Overexpressing AKR1B10 hindered gastric cancer cell proliferation, migration, invasion and adhesion. It was striking that we certified the inhibitory effect of AKR1B10 on integrin subunit alpha 5 expression and their (AKR1B10 and ITGA5)) negative relationship via bioinformatics method, real-time quantitative polymerase chain reaction, and co-immunoprecipitation assays. Via rescue experiments, it was concluded that AKR1B10 served as tumor suppressor potentially by ITGA5 expression in gastric cancer. CONCLUSION: Our results indicated that AKR1B10 inhibited migration, invasion, and adhesion of gastric cancer cells via modulation of ITGA5.


Subject(s)
Aldo-Keto Reductases , Integrins , Stomach Neoplasms , Humans , Aldehyde Reductase/genetics , Aldehyde Reductase/metabolism , Aldo-Keto Reductases/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Stomach Neoplasms/pathology
9.
Comput Struct Biotechnol J ; 21: 3383-3403, 2023.
Article in English | MEDLINE | ID: mdl-37389187

ABSTRACT

Background: Cuproptosis, a novel identified cell death form induced by copper, is characterized by aggregation of lipoylated mitochondrial enzymes and the destabilization of Fe-S cluster proteins. However, the function and potential clinical value of cuproptosis and cuproptosis-related biomarkers in colorectal cancer (CRC) remain largely unknown. Methods: A comprehensive multi-omics (transcriptomics, genomics, and single-cell transcriptome) analysis was performed for identifying the influence of 16 cuproptosis-related markers on clinical status, molecular functions and tumor microenvironment (TME) in CRC. A novel cuproptosis-related scoring system (CuproScore) based on cuproptosis-related markers was also constructed to predict the prognosis of CRC individuals, TME and the response to immunotherapy. In addition, our transcriptome cohort of 15 paired CRC tissue, tissue-array, and various assays in 4 kinds of CRC cell lines in vitro were applied for verification. Results: Cuproptosis-related markers were closely associated with both clinical prognosis and molecular functions. And the cuproptosis-related molecular phenotypes and scoring system (CuproScore) could distinguish and predict the prognosis of CRC patients, TME, and the response to immunotherapy in both public and our transcriptome cohorts. Besides, the expression, function and clinical significance of these markers were also checked and analyzed in CRC cell lines and CRC tissues in our own cohorts. Conclusions: In conclusion, we indicated that cuproptosis and CPRMs played a significant role in CRC progression and in modeling the TME. Inducing cuproptosis may be a useful tool for tumor therapy in the future.

10.
Ann Hepatol ; 28(4): 101099, 2023.
Article in English | MEDLINE | ID: mdl-37030571

ABSTRACT

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) may be diagnosed using the GAAP and ASAP models; our goal was to verify and evaluate their diagnostic effectiveness compared to alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and AFP & DCP for both HCC and HCC caused by the hepatitis B virus (HBV). PATIENTS AND METHODS: GAAP and ASAP models were validated and compared using a retrospective investigation of 938 patients from our hospital between July 2020 and July 2021. RESULTS: Both the GAAP and ASAP models had better diagnostic efficacy than AFP, DCP, AFP & DCP. The GAAP model achieved better performance in section A for the detection of HCC and in section C for the detection of HBV-HCC than the ASAP model. The Hosmer-Lemeshow test showed that the GAAP and ASAP models were well-calibrated for the diagnoses of these two groups. To be more specific, the area under curve (AUC) of the GAAP model for HCC detection in section A was 0.862 [95% confidence interval (CI): 0.838-0.883], and that of the ASAP model was 0.850 [95% CI: 0.826-0.872]. The AUC of the GAAP model for HBV-HCC detection in section C was 0.897 [95% CI: 0.872-0.918], and that of the ASAP model was 0.878 [95% CI: 0.852-0.902]. CONCLUSIONS: The GAAP model was more accurate and reliable than the AFP, DCP, AFP and DCP, as well as the ASAP model in section A for the detection of HCC and in section C for the detection of HBV-HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , alpha-Fetoproteins , Retrospective Studies , Liver Neoplasms/pathology , Biomarkers, Tumor , Biomarkers , Protein Precursors , Prothrombin , Hepatitis B virus
11.
Adv Sci (Weinh) ; 10(14): e2206139, 2023 05.
Article in English | MEDLINE | ID: mdl-36919784

ABSTRACT

Endothelial dysfunction is considered a predominant driver for pulmonary vascular remodeling in pulmonary hypertension (PH). SOX17, a key regulator of vascular homoeostasis, has been found to harbor mutations in PH patients, which are associated with PH susceptibility. Here, this study explores whether SOX17 mediates the autocrine activity of pulmonary artery ECs to maintain endothelial function and vascular homeostasis in PH and its underlying mechanism. It is found that SOX17 expression is downregulated in the endothelium of remodeled pulmonary arteries in IPH patients and SU5416/hypoxia (Su/hypo)-induced PH mice as well as dysfunctional HPAECs. Endothelial knockdown of SOX17 accelerates the progression of Su/hypo-induced PH in mice. SOX17 overexpression in the pulmonary endothelium of mice attenuates Su/hypo-induced PH. SOX17-associated exosomes block the proliferation, apoptosis, and inflammation of HPAECs, preventing pulmonary arterial remodeling and Su/hypo-induced PH. Mechanistic analyses demonstrates that overexpressing SOX17 promotes the exosome-mediated release of miR-224-5p and miR-361-3p, which are internalized by injured HPAECs in an autocrine manner, ultimately repressing the upregulation of NR4A3 and PCSK9 genes and improving endothelial function. These results suggest that SOX17 is a key gene in maintaining endothelial function and vascular homeostasis in PH through regulating exosomal miRNAs in an autocrine manner.


Subject(s)
Exosomes , Hypertension, Pulmonary , MicroRNAs , Animals , Humans , Mice , Endothelial Cells/metabolism , Endothelium/metabolism , Exosomes/metabolism , HMGB Proteins/genetics , HMGB Proteins/metabolism , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Hypoxia/metabolism , MicroRNAs/genetics , Proprotein Convertase 9/metabolism , SOXF Transcription Factors/genetics , SOXF Transcription Factors/metabolism
12.
Heliyon ; 9(2): e13317, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36825174

ABSTRACT

Objective: To explore the effectiveness, feasibility, and training effect of a highly simulated and adaptable laparoscopic training system in the advanced integrated two-stage laparoscopic simulation training course for surgical residents. Methods: This study prospectively took the surgical residents who received the advanced integrated two-stage laparoscopic simulation training course in our hospital from December 2019 to December 2021 as the research objects. In the stage one course, the trainees are randomly distributed into the dry simulation system group and Darwin laparoscopic training system group. The subjective assessment results of the trainees from the two groups are collected by questionnaires, and the simulation assessment results of the two groups are evaluated in a unified, objective, and standardized assessment form. The pre-course and post-course questionnaires were used to evaluate the feasibility and effectiveness of the Darwin system in the stage two course. Results: A total of 62 trainees completed the stage one and stage two courses. In the stage one course, the trainees were randomly distributed into the dry simulation trainer group (N = 19) and the Darwin group (N = 43). The results of the subjective assessment questionnaire showed that compared with the dry simulator group, the students in the Darwin group had higher subjective scores (P < 0.05). The objective assessment results for the 3 modules of "One Track Transfer", "One Tunnel Pass" and "High and Low Pillars" in the Darwin group were significantly better than those in the dry simulator group (P < 0.05). The trainees who received the stage two course completed the questionnaires before and after the course. The results showed that compared with pre-course evaluation, "basic theoretical knowledge of laparoscopy", "basic skills of laparoscopy", "laparoscopic suture technique" and "camera-holding technique" were significantly improved after training (P < 0.05). Conclusion: The highly simulated and adaptable laparoscopic training system is effective and feasible in the advanced integrated two-stage laparoscopic simulation training course for surgical residents.

13.
Front Oncol ; 13: 1026561, 2023.
Article in English | MEDLINE | ID: mdl-36816970

ABSTRACT

Objective: Colorectal cancer (CRC) is the third cause of expected cancer deaths both in men and women in the U.S. and the third most commonly diagnosed cancer in China Targeted therapy has been proven to improve overall survival for unresectable metastatic CRC. But the location of the primary tumor or the presence of various core driver gene mutations that confer resistance may limit the utility of targeted therapy. Therefore, it is of great significance to further elucidate novel mechanisms of invasion and metastasis of CRC and find potential novel therapeutic targets. Protein Kinase C Delta (PKCδ) plays an important role in various diseases, including tumors. In CRC, the function of PKCδ on proliferation and differentiation is mostly studied but various research results were reported. Therefore, the role of PKCδ in CRC needs to be further studied, especially in tumor invasion and metastasis in CRC which few studies have looked into. Methods: The expression of PRKCD was analyzed by the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases and Immunohistochemical (IHC). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis were used to explore the biological functions and pathways related to PRKCD. Lentivirus transfection was used to construct CRC cell lines with overexpression and knock-down of PKCδ or N-myc Downstream Regulated Gene 1 (NDRG1). Cell invasion and migration assay, wound healing assay were used to detect the function of PKCδ and NDRG1 in the invasion and migration of cells. Flow cytometry analysis was used to detect the influence of PKCδ on the CRC cell cycles .Immunofluorescence histochemistry ,Immunoprecipitation Assay and qPCR were used to detect the relationship of PKCδ and NDRG1. Xenograft model was used to verify the role of PKCδ in vivo. Results: PKCδ is overexpressed in CRC and could promote Epithelial-Mesenchymal Transition (EMT) and the invasion and migration of CRC in vitro. We confirmed that PKCδ and the tumor suppressor factor NDRG1 had a co-localization relationship in CRC. PKCδ inhibited NDRG1 transcription and protein expression. Overexpressing NDRG1 could inhibit the function of PKCδ in promoting tumor invasion and migration. PKCδ could regulate c-Myc, one transcription factor of NDRG1, to down-regulate NDRG1. In vivo, overexpressing PKCδ could promote xenograft growth and volume. Thus, our results showed that PKCδ reduced the expression of NDRG1 through c-Myc, promoting the invasion and migration of CRC through promoting EMT. Conclusion: The increased expression of PKCδ in CRC tumor tissue could promote the invasion and migration of tumor cells, and one of the mechanisms may be regulating c-Myc to inhibit the expression of NDRG1 and promote EMT.

14.
Acta Pharmacol Sin ; 44(7): 1442-1454, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36658427

ABSTRACT

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 µM) and kaempferol (10 µM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.


Subject(s)
Acute Kidney Injury , Cisplatin , Mice , Animals , Cisplatin/pharmacology , Kaempferols/pharmacology , Kaempferols/therapeutic use , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Acute Kidney Injury/pathology , Oxidative Stress , Autophagy , Apoptosis , Mice, Inbred C57BL
15.
Cell Mol Life Sci ; 80(1): 5, 2022 Dec 08.
Article in English | MEDLINE | ID: mdl-36477655

ABSTRACT

It has been established that long noncoding RNAs (lncRNAs) play a crucial role in various cancer types, and there are vast numbers of long noncoding RNA transcripts that have been identified by high-throughput methods. However, the biological function of many novel aberrantly expressed lncRNAs remains poorly elucidated, especially in gastric cancer (GC). Here, we first identified a novel lncRNA termed LENGA (Low Expression Noncoding RNA in Gastric Adenocarcinoma), which was significantly downregulated in GC tissues compared to adjacent normal tissues. Next, we found that reduced expression of LENGA in GC was also associated with a shorter life expectancy. The proliferation, migration, and invasion of GC cells were increased after LENGA knockdown but restrained after LENGA overexpression in vitro and in vivo. It was further demonstrated that LENGA physically binds to BRD7 (bromodomain-containing 7) in the bromodomain domain and acts as a scaffold that enhances the interaction between BRD7 and TP53 (tumor protein p53), regulating the expression of a subset of genes in the p53 pathway, including CDKN1A (cyclin-dependent kinase inhibitor 1A) and PCDH7 (protocadherin 7), at the transcriptional level. Consistently, the expression of CDKN1A has a positive correlation with LENGA in GC patients. Taken together, this study uncovers a novel tumor suppressor lncRNA, LENGA, and describes its biological function, molecular mechanism, and clinical significance. This highlights the potential importance of targeting the LENGA/BRD7/TP53 axis in GC treatment.


Subject(s)
RNA, Long Noncoding , Stomach Neoplasms , Humans , RNA, Long Noncoding/genetics , Stomach Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Chromosomal Proteins, Non-Histone
16.
Front Pharmacol ; 13: 1057571, 2022.
Article in English | MEDLINE | ID: mdl-36506511

ABSTRACT

Malignant tumors are the second leading cause of death worldwide. This is a public health concern that negatively impacts human health and poses a threat to the safety of life. Although there are several treatment approaches for malignant tumors, surgical resection remains the primary and direct treatment for malignant solid tumors. Anesthesia is an integral part of the operation process. Different anesthesia techniques and drugs have different effects on the operation and the postoperative prognosis. Propofol is an intravenous anesthetic that is commonly used in surgery. A substantial number of studies have shown that propofol participates in the pathophysiological process related to malignant tumors and affects the occurrence and development of malignant tumors, including anti-tumor effect, pro-tumor effect, and regulation of drug resistance. Propofol can also reshape the tumor microenvironment, including anti-angiogenesis, regulation of immunity, reduction of inflammation and remodeling of the extracellular matrix. Furthermore, most clinical studies have also indicated that propofol may contribute to a better postoperative outcome in some malignant tumor surgeries. Therefore, the author reviewed the chemical properties, pharmacokinetics, clinical application and limitations, mechanism of influencing the biological characteristics of malignant tumors and reshaping the tumor microenvironment, studies of propofol in animal tumor models and its relationship with postoperative prognosis of propofol in combination with the relevant literature in recent years, to lay a foundation for further study on the correlation between propofol and malignant tumor and provide theoretical guidance for the selection of anesthetics in malignant tumor surgery.

17.
Front Pharmacol ; 13: 1000639, 2022.
Article in English | MEDLINE | ID: mdl-36313338

ABSTRACT

Objective: Erchen Decoction (ECD), a well-known traditional Chinese medicine, exerts metabolism-regulatory, immunoregulation, and anti-tumor effects. However, the action and pharmacological mechanism of ECD remain largely unclear. In the present study, we explored the effects and mechanisms of ECD in the treatment of CRC using network pharmacology, molecular docking, and systematic experimental validation. Methods: The active components of ECD were obtained from the TCMSP database and the potential targets of them were annotated by the STRING database. The CRC-related targets were identified from different databases (OMIM, DisGeNet, GeneCards, and DrugBank). The interactive targets of ECD and CRC were screened and the protein-protein interaction (PPI) networks were constructed. Then, the hub interactive targets were calculated and visualized from the PPI network using the Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. In addition, the molecular docking was performed. Finally, systematic in vitro, in vivo and molecular biology experiments were performed to further explore the anti-tumor effects and underlying mechanisms of ECD in CRC. Results: A total of 116 active components and 246 targets of ECD were predicted based on the component-target network analysis. 2406 CRC-related targets were obtained from different databases and 140 intersective targets were identified between ECD and CRC. 12 hub molecules (STAT3, JUN, MAPK3, TP53, MAPK1, RELA, FOS, ESR1, IL6, MAPK14, MYC, and CDKN1A) were finally screened from PPI network. GO and KEGG pathway enrichment analyses demonstrated that the biological discrepancy was mainly focused on the tumorigenesis-, immune-, and mechanism-related pathways. Based on the experimental validation, ECD could suppress the proliferation of CRC cells by inhibiting cell cycle and promoting cell apoptosis. In addition, ECD could inhibit tumor growth in mice. Finally, the results of molecular biology experiments suggested ECD could regulate the transcriptional levels of several hub molecules during the development of CRC, including MAPKs, PPARs, TP53, and STATs. Conclusion: This study revealed the potential pharmacodynamic material basis and underlying molecular mechanisms of ECD in the treatment of CRC, providing a novel insight for us to find more effective anti-CRC drugs.

18.
Acta Biochim Biophys Sin (Shanghai) ; 54(11): 1671-1683, 2022 Sep 25.
Article in English | MEDLINE | ID: mdl-36111743

ABSTRACT

Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.


Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Humans , Cetuximab/pharmacology , Cetuximab/therapeutic use , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Biomarkers , Fatty Acids , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology
19.
BMC Genomics ; 23(1): 630, 2022 Sep 02.
Article in English | MEDLINE | ID: mdl-36056316

ABSTRACT

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is a common and organ-specific autoimmune disease. Early diagnosis and novel treatments are essential to improve the prognosis of TAO patients. Therefore, the current work was performed to identify the key genes and pathways for the biological and clinical implications of TAO through comprehensive bioinformatics analysis and a series of clinical validations. METHODS: GSE105149 and GSE185952 were obtained from the Gene Expression Omnibus (GEO) database for analysis. The data were normalized to identify the common differentially expressed genes (DEGs) between the two datasets, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to assess key pathways in TAO. Protein-protein interaction (PPI) networks and hub genes among the common DEGs were identified. Furthermore, we collected the general information and blood samples from 50 TAO patients and 20 healthy controls (HCs), and the expression levels of the proteins encoded by hub genes in serum were detected by enzyme-linked immunosorbent assay (ELISA). Then we further assessed the relationship between the ELISA data and the TAO development. RESULTS: Several common pathways, including neuroactive ligand-receptor interaction, the IL-17 signaling pathway, and the TNF signaling pathway, were identified in both datasets. In parallel, 52 common DEGs were identified. The KEGG analysis showed that these common DEGs are mainly enriched in long-term depression, the VEGF signaling pathway, the IL-17 signaling pathway, the TNF signaling pathway, and cytokine-cytokine receptor interactions. The key hub genes PRKCG, OSM, DPP4, LRRTM1, CXCL6, and CSF3R were screened out through the PPI network. As confirmation, the ELISA results indicated that protein expression levels of PRKCG, OSM, CSF3R, and DPP4 were significantly upregulated in TAO patients compared with HCs. In addition, PRKCG and DPP4 were verified to show value in diagnosing TAO, and CSF3R was found to be a valuable diagnostic marker in distinguishing active TAO from inactive TAO. CONCLUSIONS: Inflammation- and neuromodulation-related pathways might be closely associated with TAO. Based on the clinical verification, OSM, CSF3R, CXCL6, DPP4, and PRKCG may serve as inflammation- or neuromodulation-related biomarkers for TAO, providing novel insights for the diagnosis and treatment of TAO.


Subject(s)
Gene Expression Profiling , Graves Ophthalmopathy , Computational Biology/methods , Dipeptidyl Peptidase 4 , Gene Expression Profiling/methods , Gene Regulatory Networks , Graves Ophthalmopathy/genetics , Humans , Inflammation , Interleukin-17 , Protein Interaction Maps
20.
Front Genet ; 13: 962575, 2022.
Article in English | MEDLINE | ID: mdl-36092924

ABSTRACT

Colorectal cancer (CRC) is one of the most common malignant tumors with a high incidence rate and mortality. LncRNA is an important regulator of the immune system. It is of great significance to study immune-related lncRNAs (IR-lncRNAs) for CRC. In this study, we screened IR-lncRNAs differentially expressed in normal and CRC tissues, and Univariate Cox regression and the Least Absolute Shrinkage and Selection Operator were applied to construct IR-lncRNA prognostic signature in TCGA training dataset, and its predictive capability for the prognosis of CRC patients was verified in GSE39582 validation dataset. The novel signature was identified as an independent predictor of prognosis in CRC patients. In addition, the signature could accurately predict the feature of the immune microenvironment and therapeutic response in CRC patients. The CMap database was adopted to screen for small molecule candidate drugs that can reverse and treat high-risk CRC patients. Finally, the expression of six IR-lncRNAs were verified by qRT-PCR in clinical specimens from our patient cohort. In conclusion, we construct an IR-lncRNA prognostic signature, which is a powerful biomarker of CRC and can accurately predict the prognosis, immune microenvironment feature, and therapeutic response of CRC patients.

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