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Journal of Controlled Release :... Mar 2024Triple-negative breast cancer (TNBC) is characterized by complex heterogeneity, high recurrence and metastasis rates, and short overall survival, owing to the lack of...
Triple-negative breast cancer (TNBC) is characterized by complex heterogeneity, high recurrence and metastasis rates, and short overall survival, owing to the lack of endocrine and targeted receptors, which necessitates chemotherapy as the major treatment regimen. Exosome-like nanovesicles derived from medicinal plants have shown great potential as novel biotherapeutics for cancer therapy by delivering their incorporated nucleic acids, especially microRNAs (miRNAs), to mammalian cells. In this study, we isolated exosome-like nanovesicles derived from B. javanica (BF-Exos) and investigated their influence and underlying molecular mechanisms in TNBC. We found that BF-Exos delivered 10 functional miRNAs to 4T1 cells, significantly retarding the growth and metastasis of 4T1 cells by regulating the PI3K/Akt/mTOR signaling pathway and promoting ROS/caspase-mediated apoptosis. Moreover, BF-Exos were shown to inhibit the secretion of vascular endothelial growth factor, contributing to anti-angiogenesis in the tumor microenvironment. In vivo, BF-Exos inhibited tumor growth, metastasis, and angiogenesis in breast tumor mouse models, while maintaining high biosafety. Overall, BF-Exos are considered promising nanoplatforms for the delivery of medicinal plant-derived nucleic acids, with great potential to be developed into novel biotherapeutics for the treatment of TNBC.
Topics: Humans; Mice; Animals; MicroRNAs; Brucea javanica; Phosphatidylinositol 3-Kinases; Exosomes; Vascular Endothelial Growth Factor A; Triple Negative Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Mammals; Tumor Microenvironment
PubMed: 38295998
DOI: 10.1016/j.jconrel.2024.01.060 -
Advanced Science (Weinheim,... Aug 2023Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program invoked by cancer cells to drive cancer progression. Transcription factor ZEB1 is a...
Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program invoked by cancer cells to drive cancer progression. Transcription factor ZEB1 is a master regulator of EMT, driving disease recurrence in poor-outcome triple negative breast cancers (TNBCs). Here, this work silences ZEB1 in TNBC models by CRISPR/dCas9-mediated epigenetic editing, resulting in highly-specific and nearly complete suppression of ZEB1 in vivo, accompanied by long-lasting tumor inhibition. Integrated "omic" changes promoted by dCas9 linked to the KRAB domain (dCas9-KRAB) enabled the discovery of a ZEB1-dependent-signature of 26 genes differentially-expressed and -methylated, including the reactivation and enhanced chromatin accessibility in cell adhesion loci, outlining epigenetic reprogramming toward a more epithelial state. In the ZEB1 locus transcriptional silencing is associated with induction of locally-spread heterochromatin, significant changes in DNA methylation at specific CpGs, gain of H3K9me3, and a near complete erasure of H3K4me3 in the ZEB1 promoter. Epigenetic shifts induced by ZEB1-silencing are enriched in a subset of human breast tumors, illuminating a clinically-relevant hybrid-like state. Thus, the synthetic epi-silencing of ZEB1 induces stable "lock-in" epigenetic reprogramming of mesenchymal tumors associated with a distinct and stable epigenetic landscape. This work outlines epigenome-engineering approaches for reversing EMT and customizable precision molecular oncology approaches for targeting poor outcome breast cancers.
Topics: Humans; Triple Negative Breast Neoplasms; Clustered Regularly Interspaced Short Palindromic Repeats; Neoplasm Recurrence, Local; Transcription Factors; Epigenesis, Genetic
PubMed: 37217832
DOI: 10.1002/advs.202301802 -
European Journal of Pharmacology Jul 2023Non-coding RNA transcripts are RNA molecules that have mainly regulatory functions and they do not encode proteins. microRNAs (miRNAs), lncRNAs and circRNAs are major... (Review)
Review
Non-coding RNA transcripts are RNA molecules that have mainly regulatory functions and they do not encode proteins. microRNAs (miRNAs), lncRNAs and circRNAs are major types of this family and these epigenetic factors participate in disease pathogenesis, especially cancer that their abnormal expression may lead to cancer progression. miRNAs and lncRNAs possess a linear structure, whereas circRNAs possess ring structures and high stability. Wnt/β-catenin is an important factor in cancer with oncogenic function and it can increase growth, invasion and therapy resistance in tumors. Wnt upregulation occurs upon transfer of β-catenin to nucleus. Interaction of ncRNAs with Wnt/β-catenin signaling can determine tumorigenesis. Wnt upregulation is observed in cancers and miRNAs are able to bind to 3'-UTR of Wnt to reduce its level. LncRNAs can directly/indirectly regulate Wnt and in indirect manner, lncRNAs sponge miRNAs. CircRNAs are new emerging regulators of Wnt and by its stimulation, they increase tumor progression. CircRNA/miRNA axis can affect Wnt and carcinogenesis. Overall, interaction of ncRNAs with Wnt can determine proliferation rate, migration ability and therapy response of cancers. Furthermore, ncRNA/Wnt/β-catenin axis can be utilized as biomarker in cancer and for prognostic applications in patients.
Topics: Humans; RNA, Long Noncoding; RNA, Circular; beta Catenin; RNA, Untranslated; MicroRNAs; Neoplasms; Wnt Signaling Pathway; Carcinogenesis; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Cell Proliferation
PubMed: 37179043
DOI: 10.1016/j.ejphar.2023.175781 -
Journal of Ethnopharmacology Jan 2024Moringa oleifera Lam. (M. oleifera) is a perennial deciduous tree with considerable agricultural and pharmacological value. Nearly all parts of the tree are edible, and...
ETHNOPHARMACOLOGICAL RELEVANCE
Moringa oleifera Lam. (M. oleifera) is a perennial deciduous tree with considerable agricultural and pharmacological value. Nearly all parts of the tree are edible, and nearly all parts are used in traditional medicine. Leaves of M. oleifera have the functions of hypoglycemic (antidiabetic), anti-cancer and anti-oxidant stress, but less research pay attention to the anti-inflammatory effect of M. oleifera leaves.
AIM OF THE STUDY
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut with no ideal medication. Here, we investigated the anti-inflammatory effects of aqueous extract of M. oleifera leaves.
MATERIALS AND METHODS
Intestinal organoids and mice as in vitro and in vivo models to investigate the effects of aqueous extract of M. oleifera leaves on inflammation induced by TNF-α and dextran sulfate sodium (DSS) respectively. The expression of inflammatory cytokines and proliferation-related genes were evaluated by RT-qPCR, respectively. The compounds in the leaf extract were determined by LC/MS, and network pharmacology approach was employed to predict 54 anti-IBD potential targets of quercetin-3-galactoside (QG) and isoquercitrin (IS).
RESULTS
We found that the extract protected against damage to intestinal organoids caused by tumor necrosis factor (TNF-α), and significantly down-regulated the expression of inflammatory cytokines. The extract also suppressed the TNF-α-induced expression of Pcna, c-Myc, and c-Jun. Additionally, oral administration of the extract also ameliorated DSS-induced colon damage (colonic shortening, loss of goblet cells and overall abnormal cellularity), and inhibited the expression of inflammatory cytokines and proliferation-related genes in colitis. By LC/MS we identified nearly 2000 of the compounds in the leaf extract, of the flavonoids identified, QG and IS made up the largest percentage; both have been shown to have anti-inflammatory properties. Moreover, network pharmacology approach was employed to predict 54 anti-IBD potential targets of QG and IS. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the overlapping targets participated in response to oxidative stress and PI3K-Akt signaling pathway respectively.
CONCLUSIONS
The present study demonstrated the anti-inflammatory capability, in vitro and in vivo, of the aqueous extract of M. oleifera leaves and suggests its potential phytotherapeutic treatment for IBD.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Phosphatidylinositol 3-Kinases; Colitis; Inflammation; Colon; Anti-Inflammatory Agents; Cytokines; Plant Extracts; Inflammatory Bowel Diseases; Dextran Sulfate; Mice, Inbred C57BL
PubMed: 37480965
DOI: 10.1016/j.jep.2023.116929 -
Non-coding RNA Research Jun 2024The brain tumors and especially glioblastoma, are affecting life of many people worldwide and due to their high mortality and morbidity, their treatment is of importance... (Review)
Review
The brain tumors and especially glioblastoma, are affecting life of many people worldwide and due to their high mortality and morbidity, their treatment is of importance and has gained attention in recent years. The abnormal expression of genes is commonly observed in GBM and long non-coding RNAs (lncRNAs) have demonstrated dysregulation in this tumor. LncRNAs have length more than 200 nucleotides and they have been located in cytoplasm and nucleus. The current review focuses on the role of lncRNAs in GBM. There two types of lncRNAs in GBM including tumor-promoting and tumor-suppressor lncRNAs and overexpression of oncogenic lncRNAs increases progression of GBM. LncRNAs can regulate proliferation, cell cycle arrest and metastasis of GBM cells. Wnt, STAT3 and EZH2 are among the molecular pathways affected by lncRNAs in GBM and for regulating metastasis of GBM cells, these RNA molecules mainly affect EMT mechanism. LncRNAs are involved in drug resistance and can induce resistance of GBM cells to temozolomide chemotherapy. Furthermore, lncRNAs stimulate radio-resistance in GBM cells. LncRNAs increase PD-1 expression to mediate immune evasion. LncRNAs can be considered as diagnostic and prognostic tools in GBM and researchers have developed signature from lncRNAs in GBM.
PubMed: 38511060
DOI: 10.1016/j.ncrna.2024.02.002 -
Journal of Ethnopharmacology Dec 2023Sophora davidii (Franch.) Skeels Flower (SDF) is a characteristic folk medicine in Yunnan and Guizhou, which can be used to prevent the occurrence of tumors. The extract...
ETHNOPHARMACOLOGICAL RELEVANCE
Sophora davidii (Franch.) Skeels Flower (SDF) is a characteristic folk medicine in Yunnan and Guizhou, which can be used to prevent the occurrence of tumors. The extract of SDF (SDFE) is confirmed to be antitumor by pre-experiment. However, effective components and anticancer mechanisms of SDFE are still unclear.
AIM OF THE STUDY
The purpose of this study was to explore the material basis and action mechanisms of SDFE in the treatment of non-small cell carcinoma (NSCLC).
MATERIALS AND METHODS
UHPLC-Q-Exactive-Orbitrap-MS/MS was used to identify the chemical components of SDFE. The network pharmacology was applied to screen out the main active components, core genes and related signaling pathways of SDFE in treatment of NSCLC. Molecular docking was used to predict the affinity of major components and core targets. The database was applied to predict the mRNA and protein expression levels of core targets in NSCLC. Finally, the experiments in vitro were performed by CCK-8, flow cytometry and western blot (WB).
RESULTS
In this study, 98 chemical components were identified by UHPLC-Q-Exactive- Orbitrap-MS/MS. 5 main active components (namely quercetin, genistein, luteolin, kaempferol, isorhamnetin), 10 core genes (namely TP53, AKT1, STAT3, SRC, MAPK3, EGFR, JUN, EP300, TNF, PIK3R1) and 20 pathways were screened out through network pharmacology. The 5 active ingredients were molecularly docked with the core genes, and most the LibDockScore values were higher than 100. The data collected from the database indicated that TP53, AKT1 and PIK3R1 were closely related to the occurrence of NSCLC. The results of experiment in vitro showed that SDFE promoted NSCLC cells apoptosis by down-regulating the phosphorylation of PI3K, AKT and MDM2, up-regulating the phosphorylation of P53, inhibiting the expression of Bcl-2 and up-regulating the expression of Bax.
CONCLUSION
The combination of network pharmacology, molecular docking, database validation, and in vitro experimental validation effectively demonstrates that SDFE can promote cell apoptosis by regulating PI3K-AKT/MDM2-P53 signaling pathway, so as to treat NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Sophora; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Tandem Mass Spectrometry; Tumor Suppressor Protein p53; Lung Neoplasms; China; Carcinoma; Transcription Factors; Plant Extracts; Drugs, Chinese Herbal
PubMed: 37400006
DOI: 10.1016/j.jep.2023.116815 -
Nutrients Mar 2024As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer... (Review)
Review
As one of the malignant diseases globally, cancer seriously endangers human physical and mental health because of its high morbidity and mortality. Conventional cancer treatment strategies, such as surgical resection and chemoradiotherapy, are effective at the early stage of cancer but have limited efficacy for advanced cancer. Along with cancer progress and treatment, resistance develops gradually within the population of tumor cells. As a consequence, drug resistance become the major cause that leads to disease progression and poor clinical prognosis in some patients. The mechanisms of cancer drug resistance are quite complex and involve various molecular and cellular mechanisms. Therefore, exploring the mechanisms and finding specific targets are becoming imperative to overcome drug resistance. In recent years, plant-derived natural products have been evaluated as potential therapeutic candidates against cancer with drug resistance due to low side effects and high anticancer efficacy. A growing number of studies have shown that natural products can achieve superior antitumor effects through multiple signaling pathways. The mechanisms include regulation of multiple drug resistance (MDR)-related genes, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, induction of autophagy, and blockade of the cell cycle. This paper reviews the molecular and cellular mechanisms of cancer drug resistance, as well as the therapeutic effects and mechanisms of plant-derived natural products against cancer drug resistance. It provides references for developing therapeutic medication for drug-resistant cancer treatment with high efficacy and low side effects.
Topics: Humans; Phosphatidylinositol 3-Kinases; Biological Products; Neoplasms; Proto-Oncogene Proteins c-akt; Drug Resistance, Neoplasm; Signal Transduction; Cell Line, Tumor
PubMed: 38542707
DOI: 10.3390/nu16060797 -
Chemical Biology & Drug Design Dec 2023Targeted therapy has attracted more and more attention in cancer treatment in recent years. However, due to the diversity of tumor types and the mutation of target sites...
Targeted therapy has attracted more and more attention in cancer treatment in recent years. However, due to the diversity of tumor types and the mutation of target sites on the tumor surface, some existing targets are no longer suitable for tumor therapy. In addition, the long-term administration of a single targeted drug can also lead to drug resistance and attenuate drug potency, so it is important to develop new targets for tumor therapy. The expression of Type III transforming growth factor β receptor (TGFBR3) is upregulated in colon, breast, and prostate cancer cells, and plays an important role in the occurrence and development of these cancers, so TGFBR3 may be developed as a novel target for tumor therapy, but so far there is no report on this research. In this study, the structure of bone morphogenetic protein 4 (BMP4), one of the ligands of TGFBR3 was analyzed through the docking analysis with TGFBR3 and sequence charge characteristic analysis, and a functional tumor-targeting penetrating peptide T3BP was identified. The results of fluorescent labeling experiments showed that T3BP could target and efficiently enter tumor cells with high expression of TGFBR3, especially A549 cells. When the expression of TGFBR3 on the surface of tumor cells (HeLa) was knocked down by RNA interference, the high delivery efficiency of T3BP was correspondingly reduced by 40%, indicating that the delivery was TGFBR3-dependent. Trichosanthin (TCS, a plant-derived ribosome inactivating protein) fused with T3BP can enhance the inhibitory activity of the fusion protein on A549 cells by more than 200 times that of TCS alone. These results indicated that T3BP, as a novel targeting peptide that can efficiently bind TGFBR3 and be used for targeted therapy of tumors with high expression of TGFBR3. This study enriches the supply of tumor-targeting peptides and provides a new potential application option for the treatment of tumors with high expression of TGFBR3.
Topics: Male; Humans; Cell-Penetrating Peptides; Drug Delivery Systems; Receptors, Transforming Growth Factor beta; Proteoglycans; Cell Line, Tumor
PubMed: 37620132
DOI: 10.1111/cbdd.14333 -
Pathology, Research and Practice Jan 2024Gastrointestinal (GI) cancers continue to be a major cause of mortality and morbidity globally. Understanding the molecular pathways associated with cancer progression... (Review)
Review
Gastrointestinal (GI) cancers continue to be a major cause of mortality and morbidity globally. Understanding the molecular pathways associated with cancer progression and severity is essential for creating effective cancer treatments. In cancer research, there is a notable emphasis on Enhancer of zeste homolog 2 (EZH2), a key player in gene expression influenced by its irregular expression and capacity to attach to promoters and alter methylation status. This review explores the impact of EZH2 signaling on various GI cancers, such as colorectal, gastric, pancreatic, hepatocellular, esophageal, and cholangiocarcinoma. The primary function of EZH2 signaling is to facilitate the accelerated progression of cancer cells. Additionally, EZH2 has the capacity to modulate the reaction of GI cancers to chemotherapy and radiotherapy. Numerous pathways, including long non-coding RNAs and microRNAs, serve as upstream regulators of EZH2 in these types of cancer. EZH2's enzymatic activity enables it to attach to target gene promoters, resulting in methylation that modifies their expression. EZH2 could be considered as an independent prognostic factor, with increased expression correlating with a worse disease prognosis. Additionally, a range of gene therapies including small interfering RNA, and anti-tumor agents are being explored to target EZH2 for cancer treatment. This comprehensive review underscores the current insights into EZH2 signaling in gastrointestinal cancers and examines the prospect of therapies targeting EZH2 to enhance patient outcomes.
Topics: Humans; Enhancer of Zeste Homolog 2 Protein; Polycomb Repressive Complex 2; Gastrointestinal Neoplasms; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 38118215
DOI: 10.1016/j.prp.2023.154988 -
Chinese Journal of Integrative Medicine Nov 2023Immunotherapy targeting immune checkpoint molecules has emerged as a key approach in cancer treatment, representing the forefront of antitumor research. However, studies... (Review)
Review
Immunotherapy targeting immune checkpoint molecules has emerged as a key approach in cancer treatment, representing the forefront of antitumor research. However, studies on immune checkpoint molecules have mainly focused on targeted therapies. Chinese medicine (CM) research as a complementary medicine has revealed that immune checkpoint molecules also undergo disease-specific changes in the context of autoimmune diseases. This review article presents a comprehensive analysis of CM studies on immune checkpoint molecules in the last 5 years, with a focus on their role in different diseases and treatment modalities. CM research predominantly utilizes oral administration of herbal plant extracts or acupuncture techniques, which stimulate the immune system by activating specific acupoints through temperature and needling. In this study, we analyzed the modulation and mechanisms of immune checkpoint molecules associated with different coinhibitory and costimulatory molecules, and reviewed the immune functions of related molecules and CM studies in treating autoimmune diseases and tumors. By summarizing the characteristics and research value of CM in regulating immune checkpoint molecules, this review aims to provide a useful reference for future studies in this field.
Topics: Humans; Medicine, Chinese Traditional; Immune Checkpoint Proteins; Acupuncture Therapy; Neoplasms; Autoimmune Diseases
PubMed: 37580466
DOI: 10.1007/s11655-023-3743-8