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World Journal of Clinical Oncology Apr 2024Britanin is a bioactive sesquiterpene lactone known for its potent anti-inflammatory and anti-oxidant properties. It also exhibits significant anti-tumor activity,... (Review)
Review
Britanin is a bioactive sesquiterpene lactone known for its potent anti-inflammatory and anti-oxidant properties. It also exhibits significant anti-tumor activity, suppressing tumor growth and . The current body of research on Britanin includes thirty papers predominantly related to neoplasms, the majority of which are gastrointestinal tumors that have not been summarized before. To drive academic debate, the present paper reviews the available research on Britanin in gastrointestinal tumors. It also outlines novel research directions using data not directly concerned with the digestive system, but which could be adopted in future gastrointestinal research. Britanin was found to counteract liver, colorectal, pancreatic, and gastric tumors, by regulating proliferation, apoptosis, autophagy, immune response, migration, and angiogenesis. As confirmed in pancreatic, gastric, and liver cancer, its most commonly noted molecular effects include nuclear factor kappa B and B-cell lymphoma 2 downregulation, as well as Bcl-2-associated X protein upregulation. Moreover, it has been found to induce the Akt kinase and Forkhead box O1 axis, activate the AMP-activated protein kinase pathway, elevate interleukin-2 and peroxisome proliferator-activated receptor-γ levels, reduce interleukin-10, as well as downregulate matrix metalloproteinase-9, Twist family bHLH transcription factor 1, and cyclooxygenase-2. It also inhibits Myc-HIF1α interaction and programmed death ligand 1 transcription by interrupting the Ras/ RAF/MEK/ERK pathway and mTOR/P70S6K/4EBP1 signaling. Future research should aim to unravel the link between Britanin and acetylcholinesterase, mast cells, osteolysis, and ischemia, as compelling data have been provided by studies outside the gastrointestinal context. Since the cytotoxicity of Britanin on noncancerous cells is significantly lower than that on tumor cells, while still being effective against the latter, further in-depth studies with the use of animal models are merited. The compound exhibits pleiotropic biological activity and offers considerable promise as an anti-cancer agent, which may address the current paucity of treatment options and high mortality rate among patients with gastrointestinal tumors.
PubMed: 38689621
DOI: 10.5306/wjco.v15.i4.523 -
Poultry Science Jul 2024Goose astrovirus genotype 2 (GAstV-2) mainly causes gout in goslings; therefore, it is a major pathogen threatening to goose flocks. However, the mechanisms underlying...
Goose astrovirus genotype 2 (GAstV-2) mainly causes gout in goslings; therefore, it is a major pathogen threatening to goose flocks. However, the mechanisms underlying host-GAstV-2 interactions remain unclear because host cells suitable for GAstV-2 replication have been unavailable. We previously noted that GAstV-2 is primarily located in goose renal epithelial cells, where it causes kidney damage. Therefore, here, we derived goose primary renal tubular epithelial (RTE) cells (GRTE cells) from the kidneys of goose embryos after collagenase I digestion. After culture in Dulbecco's modified Eagle medium/Nutrient mixture F-12 with 10% fetal bovine serum (FBS), the isolated cells had polygonal with roadstone-like morphology; they were identified to be epithelial cells based on the presence of cytokeratin 18 expression detected through immunofluorescence assay (IFA). GAstV-2 infection in GRTE cells led to no obvious cytopathic effects; the maximum amounts of infectious virions were observed 48 h post infection through IFA and quantitative PCR. Next, RNA-seq was performed to identify and map post-GAstV-2 infection differentially expressed genes. The downregulated pathways were mainly related to metabolism, including tryptophan metabolism, drug metabolism by cytochrome P450, xenobiotic metabolism by cytochrome P450, retinol metabolism, butanoate metabolism, starch and sucrose metabolism, ascorbate and aldarate metabolism, and drug metabolism by other enzymes and peroxisome. In contrast, the upregulated pathways were mostly related to the host cell defense and proliferation, including extracellular matrix-receptor interaction, complement and coagulation cascades, phagosome, PI3K-Akt signaling pathway, human T-lymphotropic virus 1 infection, lysosome, and tumor necrosis factor signaling pathway. In conclusion, we developed a GRTE cell line for GAstV-2 replication and analyzed the potential host-GAstV-2 interactions through RNA-seq; our results may aid in further investigating the pathogenic mechanisms underlying GAstV-2 infection and provide strategies for its prevention and control.
Topics: Animals; Geese; Epithelial Cells; Poultry Diseases; Genotype; Astroviridae Infections; Sequence Analysis, RNA; Kidney Tubules; Avastrovirus; Cells, Cultured
PubMed: 38669820
DOI: 10.1016/j.psj.2024.103774 -
Nature May 2024Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer....
Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE), a known negative regulator of immune response in the tumour microenvironment, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 TILs via the PGE receptors EP2 and EP4. Mechanistically, PGE inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ chain, resulting in defective assembly of IL-2Rβ-IL2Rγ membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Proliferation; Dinoprostone; Down-Regulation; Ferroptosis; Interleukin Receptor Common gamma Subunit; Interleukin-2; Interleukin-2 Receptor beta Subunit; Lymphocytes, Tumor-Infiltrating; Mitochondria; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 38658764
DOI: 10.1038/s41586-024-07352-w -
American Journal of Respiratory Cell... Apr 2024Idiopathic pulmonary fibrosis (IPF) is an aging-associated interstitial lung disease resulting from repeated epithelial injury and inadequate epithelial repair. Alveolar...
Idiopathic pulmonary fibrosis (IPF) is an aging-associated interstitial lung disease resulting from repeated epithelial injury and inadequate epithelial repair. Alveolar type II cells (AEC2) are progenitor cells that maintain epithelial homeostasis and repair the lung after injury. In the current study, we assessed lipid metabolism in AEC2s from human lungs of IPF patients and healthy donors, as well as AEC2s from bleomycin-injured young and old mice. Through single cell RNA sequencing (scRNA-seq), we observed that lipid metabolism-related genes were downregulated in IPF AEC2s and bleomycin-injured mouse AEC2s. Aging aggravated this decrease and hindered recovery of lipid metabolism gene expression in AEC2s after bleomycin injury. Pathway analyses revealed down-regulation of genes related to lipid biosynthesis and fatty acid -oxidation in AEC2s from IPF lungs and bleomycin-injured, aged mouse lungs compared to the respective controls. We confirmed decreased cellular lipid content in AEC2s from IPF lungs and bleomycin-injured, aged mouse lungs using immunofluorescence staining and flow cytometry. We further show that lipid metabolism was associated with AEC2 progenitor function. Lipid supplementation and peroxisome proliferator activated receptor gamma (PPARγ) activation promoted progenitor renewal capacity of both human and mouse AEC2s in 3D organoid cultures. Lipid supplementation also increased AEC2 proliferation and expression of in AEC2s. In summary, we identified a lipid metabolism deficiency in AEC2s from lungs of patients with IPF and bleomycin-injured aged mice. Restoration of lipid metabolism homeostasis in AEC2s might promote AEC2 progenitor function and offer new opportunities for therapeutic approaches to IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
PubMed: 38657143
DOI: 10.1165/rcmb.2023-0290OC -
Inflammopharmacology Jun 2024Gastric ulcer (GU) is one of the most common diseases of the upper gastrointestinal tract that affects millions of people worldwide. This study aimed to investigate the...
Gastric ulcer (GU) is one of the most common diseases of the upper gastrointestinal tract that affects millions of people worldwide. This study aimed to investigate the possible alleviating effect of a combined treatment of pantoprazole (PANTO) and adipose tissue-derived mesenchymal stem cells (ADSCs) in comparison with each treatment alone on the healing process of the experimentally induced GU in rats, and to uncover the involved pathways. Rats were divided into five groups: (1) Control, (2) GU, (3) PANTO, (4) ADSCs and (5) ADSCs + PANTO. Markers of oxidative stress, inflammation and apoptosis were assessed. The current data indicated that PANTO-, ADSCs- and ADSCs + PANTO-treated groups showed significant drop (p < 0.05) in serum advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEPs) along with significant elevation (p < 0.05) in serum TAC versus the untreated GU group. Moreover, the treated groups (PANTO, ADSCs and ADSCs + PANTO) displayed significant down-regulation (p < 0.05) in gastric nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), matrix metallopeptidase 9 (MMP-9) and caspase-3 along with significant up-regulation (p < 0.05) in vascular endothelial growth factor (VEGF) and peroxisome proliferator-activated receptor gamma (PPARγ) genes expression compared to the untreated GU group. Immunohistochemical examination of gastric tissue for transforming growth factor β1 (TGF-β1), epidermal growth factor (EGF) and proliferating cell nuclear antigen (PCNA) showed moderate to mild and weak immune reactions, respectively in the PANTO-, ADSCs- and ADSCs + PANTO-treated rat. Histopathological investigation of gastric tissue revealed moderate to slight histopathological alterations and almost normal histological features of the epithelial cells, gastric mucosal layer, muscularis mucosa and submucosa in PANTO-, ADSCs- and ADSCs + PANTO-treated rats, respectively. Conclusively, the co-treatment with ADSCs and PANTO evidenced sententious physiological protection against GU by suppressing oxidative stress, inhibiting inflammation and reducing apoptosis with consequent acceleration of gastric tissue healing process.
Topics: Animals; Oxidative Stress; Stomach Ulcer; Rats; Apoptosis; Pantoprazole; Inflammation; Mesenchymal Stem Cells; Male; Mesenchymal Stem Cell Transplantation; Rats, Wistar; Anti-Ulcer Agents; Adipose Tissue; Combined Modality Therapy
PubMed: 38652367
DOI: 10.1007/s10787-024-01469-0 -
Clinics and Research in Hepatology and... Jun 2024Various liver diseases pose great threats to humans. Although the etiologies of these liver diseases are quite diverse, they share similar pathologic phenotypes and... (Review)
Review
Various liver diseases pose great threats to humans. Although the etiologies of these liver diseases are quite diverse, they share similar pathologic phenotypes and molecular mechanisms such as oxidative stress, lipid and glucose metabolism disturbance, hepatic Kupffer cell (KC) proinflammatory polarization and inflammation, insulin resistance, and hepatic stellate cell (HSC) activation and proliferation. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is expressed in various types of liver cells with relatively higher expression in KCs and HSCs. Accumulating evidence has revealed the versatile functions of PPARβ/δ such as controlling lipid homeostasis, inhibiting inflammation, regulating glucose metabolism, and restoring insulin sensitivity, suggesting that PPARβ/δ may serve as a potential molecular drug target for various liver diseases. This article aims to provide a concise review of the structure, expression pattern and biological functions of PPARβ/δ in the liver and its roles in various liver diseases, and to discuss potential future research perspectives.
Topics: Humans; PPAR-beta; PPAR delta; Liver Diseases; Molecular Targeted Therapy; Insulin Resistance
PubMed: 38641250
DOI: 10.1016/j.clinre.2024.102343 -
Heliyon Apr 2024To investigate the biological effects and putative biological mechanism of G protein-coupled receptor kinase 4 (GRK4) on HepG2 cells.
BACKGROUND AND AIM
To investigate the biological effects and putative biological mechanism of G protein-coupled receptor kinase 4 (GRK4) on HepG2 cells.
MATERIALS AND METHODS
Cell proliferation, cycle, and apoptosis were evaluated by Cell Counting Kit-8 and flow cytometry (FCM) in HepG2 cells infected with either the GRK4-overexpressing lentivirus vector (OE) or the negative control lentivirus vector (NC). The protein profiles and differentially expressed proteins (DEPs) of the OE and NC cells were analyzed and compared using the quantitative proteomics technique, and their function, expression, and probable mechanism were investigated using bioinformatic assays and parallel reaction monitoring (PRM).
RESULTS
HepG2 cells that received the OE grew more slowly than those that received the NC. FCM revealed that, when compared to the NC cells, the OE cells had undergone S-phase cycle arrest, and neither the OE nor NC cells underwent apoptosis. Among the 7006 proteins that were identified by quantitative proteomics, 403 DEPs were examined based on the filtering parameters, with the expressions of 135 being downregulated and 268 being upregulated. In addition to being involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, the DEPs were implicated in the biological processes of cell proliferation, cycle, and metabolism. PRM verified the expressions of DEPs that were connected to the PPAR pathway.
CONCLUSIONS
This study shows that GRK4 prevents HepG2 cells from proliferating and causes cell cycle arrest in the S-phase, while the PPAR pathway is involved in the regulation of HepG2 cells via GRK4.
PubMed: 38638965
DOI: 10.1016/j.heliyon.2024.e29514 -
Experimental and Therapeutic Medicine Jun 2024The present study aimed to investigate the effect and mechanism of Pulsatilla compounds on lung adenocarcinoma. The representative drug chosen was the compound 23-HBA....
The present study aimed to investigate the effect and mechanism of Pulsatilla compounds on lung adenocarcinoma. The representative drug chosen was the compound 23-HBA. GeneCards, Swiss target prediction, DisGeNET and TCMSP were used to screen out related genes, and MTT and flow cytometry assays were used to verify the inhibitory effect of Pulsatilla compounds on the proliferation of lung adenocarcinoma cells. Subsequently, the optimal target, peroxisome proliferator-activated receptor (PPAR)-γ, was selected using bioinformatics analysis, and its properties of low expression in lung adenocarcinoma cells and its role as a tumor suppressor gene were verified by western blot assay. The pathways related to immunity and inflammation, vascular function, cell proliferation, differentiation, development and apoptosis with the highest degree of enrichment and the mechanisms were explored through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Finally, the clinical prognosis in terms of the survival rate of patients in whom the drug is acting on the target was analyzed using the GEPIA database. The results indicated that Pulsatilla compounds can inhibit the proliferation of lung adenocarcinoma cells by blocking the cell cycle at the G phase. Subsequently, the related PPAR-γ gene was verified as a tumor suppressor gene. Further analysis demonstrated that this finding was related to the PPAR signaling pathway and mitochondrial reactive oxygen species (ROS) production. Finally, the clinical prognosis was found to be improved, as the survival rate of patients was increased. In conclusion, Pulsatilla compounds were indicated to inhibit the viability and proliferation of lung adenocarcinoma H1299 cells, and the mechanism of action was related to PPAR-γ, the PPAR signaling pathway and mitochondrial ROS. The present study provides novel insight to further explore the treatment of lung adenocarcinoma.
PubMed: 38633355
DOI: 10.3892/etm.2024.12527 -
Oncology Reports Mar 2024Prostate cancer (PCa) is one the most common malignancies in men. The high incidence of bone metastasis years after primary therapy suggests that disseminated tumor...
Prostate cancer (PCa) is one the most common malignancies in men. The high incidence of bone metastasis years after primary therapy suggests that disseminated tumor cells must become dormant, but maintain their ability to proliferate in the bone marrow. Abscisic acid (ABA) is a stress response molecule best known for its regulation of seed germination, stomal opening, root shoot growth and other stress responses in plants. ABA is also synthesized by mammalian cells and has been linked to human disease. The aim of the present study was to examine the role of ABA in regulating tumor dormancy via signaling through lanthionine synthetase C‑like protein 2 (LANCL2) and peroxisome proliferator activated receptor γ (PPARγ) receptors. ABA signaling in human PCa cell lines was studied using targeted gene knockdown (KD), western blotting, quantitative PCR, cell proliferation, migration, invasion and soft agar assays, as well as co‑culture assays with bone marrow stromal cells. The data demonstrated that ABA signaling increased the expression of p21, p27 and p16, while inhibiting viability, migration, invasion and colony size in a reversable manner without toxicity. ABA also induced p38MAPK activation and NR2F1 signaling. Targeted gene KD of LANCL2 and PPARγ abrogated the cellular responses to ABA. Taken together, these data demonstrate that ABA may induce dormancy in PCa cell lines through LANCL2 and PPARγ signaling, and suggest novel targets to manage metastatic PCa growth.
Topics: Humans; Male; Abscisic Acid; Cell Line, Tumor; Membrane Proteins; Phosphate-Binding Proteins; PPAR gamma; Prostatic Neoplasms; Seeds; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 38624012
DOI: 10.3892/or.2024.8698 -
Medical Oncology (Northwood, London,... Apr 2024As one of the peroxisome-proliferator-activated receptors (PPARs) members, PPARγ is a ligand binding and activated nuclear hormone receptor, which is an important... (Review)
Review
As one of the peroxisome-proliferator-activated receptors (PPARs) members, PPARγ is a ligand binding and activated nuclear hormone receptor, which is an important regulator in metabolism, proliferation, tumor progression, and immune response. Increased evidence suggests that activation of PPARγ in response to ligands inhibits multiple types of cancer proliferation, metastasis, and tumor growth and induces cell apoptosis including breast cancer, colon cancer, lung cancer, and bladder cancer. Conversely, some reports suggest that activation of PPARγ is associated with tumor growth. In addition to regulating tumor progression, PPARγ could promote or inhibit tumor immunotherapy by affecting macrophage differentiation or T cell activity. These controversial findings may be derived from cancer cell types, conditions, and ligands, since some ligands are independent of PPARγ activity. Therefore, this review discussed the dual role of PPARγ on tumor progression and immunotherapy.
Topics: Female; Humans; Breast Neoplasms; Colonic Neoplasms; Immunotherapy; Ligands; PPAR gamma
PubMed: 38619661
DOI: 10.1007/s12032-024-02363-z