ABSTRACT
Sepsis is a life-threatening multi-organ dysfunction syndrome caused by an abnormal host response to infection. Regulated cell death is essential for maintaining tissue homeostasis and eliminating damaged, infected, or aging cells in multicellular organisms. Gasdermin D, as a member of the gasdermin family, plays a crucial role in the formation of cytoplasmic membrane pores. Research has found that GSDMD plays important roles in various forms of regulated cell death such as pyroptosis, NETosis, and necroptosis. Therefore, through mediating regulated cell death, GSDMD regulates different stages of disease pathophysiology. This article mainly summarizes the concept of GSDMD, its role in regulated cell death, its involvement in organ damage associated with sepsis-related injuries mediated by regulated cell death via GSDMD activation and introduces potential drugs targeting GSDMD that may provide more effective treatment options for sepsis patients through drug modification.
Subject(s)
Intracellular Signaling Peptides and Proteins , Phosphate-Binding Proteins , Sepsis , Humans , Sepsis/drug therapy , Sepsis/immunology , Phosphate-Binding Proteins/metabolism , Animals , Intracellular Signaling Peptides and Proteins/metabolism , Regulated Cell Death/drug effects , Pyroptosis/drug effects , GasderminsABSTRACT
Given that currently used classical chemotherapeutic drugs lack the ideal therapeutic effect and produce severe side effects, platinum nanomaterials (Pt-NMs) have gradually gained attention, and their antitumor effect has been initially explored. However, the specific mechanisms underlying the action of Pt-NMs in non-small cell lung cancer (NSCLC) cells remain unclear. Moreover, the interaction between Pt-NMs and autophagy in inducing apoptosis of NSCLC cells remains unexplored. In this study, we explored the anti-NSCLC effect of amine-caged Pt nanoclusters (Nano-Pt) using cell cycle, migration, proliferation, apoptosis, and autophagy assays. We found that Nano-Pt significantly inhibited cell viability, reduced migration ability, caused DNA damage, induced S phase (period of DNA synthesis in the cell cycle) arrest, and promoted apoptosis in NSCLC cells. Nano-Pt also reduced mitochondrial membrane potential (MMP), increased permeability transition, and promoted apoptosis by upregulating Bax and PARP expression. Nano-Pt-induced apoptosis was accompanied by protective autophagy, which could be enhanced by autophagy inhibitors. Our findings on the biological behavior and the interaction between autophagy and apoptosis can provide the clear anti-NSCLC molecular mechanism of Nano-Pt, which have a promising potential for the development of novel Pt-based antitumor chemotherapy drugs with excellent curative efficacy and fewer side effects.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/pathology , Cell Line, Tumor , Apoptosis , Antineoplastic Agents/therapeutic use , Autophagy , Mitochondria , Platinum/pharmacology , Cell ProliferationABSTRACT
Lung cancer remains the most common fatal malignant disease, and the 5-year survival rate of patients with metastasis is merely 6%. In this research, the platinum nanocluster (short for nano-Pt) was used for optical imaging without the help of other fluorescent probes and possess targeted antitumor activity as well as low systemic toxicity. The endocytic pathway and distribution of nano-Pt in non-small cell lung cancer NSCLC H1299 cells was explored by the means of quantitative and qualitative tests. Furthermore, the targeting capability and antitumor efficiency of nano-Pt was detected by intravital imaging experiment and antitumor experiment. The research implies that nano-Pt entered H1299 cells dominatingly through macropinocytosis and clathrin-dependent endocytosis pathway, and has significant antitumor efficiency, targeting properties and reliable safety for mouse tumor, indicating this nano-Pt has great potential for clinical diagnosis and therapy of NSCLC H1299 cells.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Endocytosis , Humans , Lung Neoplasms/pathology , Mice , PlatinumABSTRACT
In recent years, multifunctional platinum nanoclusters (Pt-NCs) as new Pt-based anti-cancer drugs exhibit a promising therapeutic efficiency for several cancer diseases, especially for human pulmonary carcinoma. However, the endocytosis behaviors (like uptake pathway, etc.) and induced apoptosis mechanism of Pt-NCs for drug-resistant non-small cell lung cancer (NSCLC), are still inconclusive. In this research, we explored the endocytic pathway of Pt-NCs in both typical NSCLC A549 cells and cisplatin-resistant A549/Cis cells through qualitative confocal laser scanning microscope (CLSM) measurement and quantitative flow cytometry (FCM) and inductive coupled plasma-optical emission spectroscopy (ICP-OES) analysis, by the means of introducing the specific inhibitors which impede the classical ways of endocytosis. It was found that Pt-NCs dominatingly entered A549 cells via caveolin-mediated endocytosis as well as A549/Cis cells through micropinocytosis approach. Pt-NCs possessed an excellent inhibitory effect on the cell proliferation, migration and invasion, which the cell activity of A549 cells reduced to 14% and that of A549/Cis cells went down about four fifths. Moreover, Pt-NCs treatment increased caspase-3 protein levels and downregulated the expression of c-Myc and Bcl-2, proving the Pt-NCs-induced apoptosis of NSCLC cells was related to c-Myc/p53 and Bcl-2/caspase-3 signal pathways. These results demonstrate the explicit uptake pathway and apoptotic signaling pathway of Pt-NCs for NSCLC, which provides an in-depth and reasonable theoretical basis for the development of new Pt-NCs-based chemotherapeutics in future clinical practice.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caspase 3/drug effects , Endocytosis/drug effects , Platinum Compounds/pharmacology , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-myc/drug effects , Signal Transduction/drug effects , Tumor Suppressor Protein p53/drug effects , A549 Cells , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Movement/drug effects , Drug Resistance, Neoplasm , Humans , Nanostructures , Platinum Compounds/administration & dosage , Tumor Stem Cell AssayABSTRACT
OBJECTIVE: Immune checkpoint inhibitors (ICI) has achieved remarkable clinical benefit in advanced lung adenocarcinoma (LUAD). However, effective clinical use of ICI agents is encumbered by the high rate of innate resistance. The aim of our research is to identify significant gene mutations which can predict clinical benefit of immune checkpoint inhibitors in LUAD. METHODS: The "mafComapre" function of "MafTools" package was used to screen the differentially mutated genes between durable clinical benefit (DCB) group and no durable clinical benefit (NDB) group based on the somatic mutation data from NSCLc_PD1_mSK_2018. Machine learning was performed to select significantly mutated genes to accurately classify patients into DCB group and NDB group. A nomogram model was constructed based on the significantly mutated genes to predict the susceptibility of patients to ICI. Finally, we explored the correlation between two classifications of immune cell infiltration, PD-1 and PD-L1 expression, tumor mutational burden (TMB) and prognosis. RESULTS: Through utilize machine learning, 6 significantly mutated genes were obtained from 8 differentially mutated genes and used to accurately classify patients into DCB group and NDB group. The DCA curve and clinical impact curve revealed that the patients can benefit from the decisions made based on the nomogram model. Patients highly sensitive to ICI have elevated immune activity, higher expression of PD-1 and PD-L1, increased TMB, and well prognosis if they accept ICI treatment. CONCLUSIONS: Our research selected 6 significantly mutated genes that can predict clinical benefit of ICI in LUAD patients.
ABSTRACT
[This corrects the article DOI: 10.3892/ol.2019.10834.].
ABSTRACT
The present study aimed to investigate the association between microRNA-152 and cisplatin resistance in non-small cell lung cancer. A549 and cisplatin-resistant A549 cells (A549/cis) were maintained in vitro. Reverse transcription-quantitative PCR (RT-qPCR) was performed to analyze differences in microRNA-152 levels between A549 and A549/cis cells, and changes in Bcl-2 and NF-κB expression levels were analyzed via RT-qPCR and western blot analyses. MicroRNA-152 was overexpressed in A549/cis cells via transfection of a microRNA-152 mimic. Upon treating transfected or untransfected A549/cis cells with 2 µg/l cisplatin for 24 h, a Cell Counting Kit-8 assay, morphological analysis and flow cytometry analysis were performed to evaluate the effect of microRNA-152 on the inhibition of cell proliferation and induction of apoptosis. Furthermore, changes in Bcl-2 and NF-κB expression levels in microRNA-152-overexpressing A549/cis cells were also analyzed. MicroRNA-152 was significantly downregulated and Bcl-2 and NF-κB were significantly upregulated in A549/cis cells (P<0.05). MicroRNA-152 upregulation enhanced the inhibitory effect of cisplatin on A549/cis cells. These results suggest that microRNA-152 downregulates Bcl-2 and NF-κB. MicroRNA-152 downregulation may induce cisplatin resistance in non-small cell lung cancer cells, whereas microRNA-152 upregulation may improve cisplatin sensitivity among A549/cis cells via downregulation of Bcl-2 and NF-κB.