ABSTRACT
BACKGROUND: Irinotecan (IRI) is a common chemotherapeutic drug for colorectal cancer; however, the mechanism underlying its immunomodulatory effect remains unclear. Curcumin (CUR), an adjuvant drug with anti-inflammatory and antitumor effects, has been studied extensively, although its synergistic antitumor effect remains unclear. METHODS: The effects of CUR and IRI on oxidative stress and their antitumor effects were detected by flow cytometry. Endoplasmic reticulum stress-related proteins including CHOP and BiP, and immunogenic cell death (ICD) proteins including calreticulin (CALR) and high mobility group box 1 (HMGB1), were detected by Western blotting. IFN-γ and TNF-α levels in the serum of mice were detected by ELISA. RESULTS: IRI in combination with CUR had synergistic antitumor effects in CT-26 colon carcinoma cells. Combination treatment with IRI and CUR was more effective than IRI or CUR alone. IRI and CUR combination treatment significantly upregulated ICD-related proteins including CALR and HMGB1 and had a greater antitumor effect than IRI or CUR single treatment in vivo. CUR may synergistically improve the antitumor effect of IRI by promoting the ICD effect. CONCLUSION: Combination therapy with IRI and CUR may be an option for first-line chemotherapy in some patients with advanced colorectal cancer.
Subject(s)
Colonic Neoplasms , Curcumin , Immunogenic Cell Death , Irinotecan , Animals , Mice , Colonic Neoplasms/drug therapy , Curcumin/pharmacology , Curcumin/therapeutic use , HMGB1 Protein/metabolism , Irinotecan/therapeutic useABSTRACT
The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 µg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Curcumin/therapeutic use , Docetaxel/therapeutic use , Drug Carriers/chemistry , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Chitosan/analogs & derivatives , Chitosan/metabolism , Chitosan/pharmacokinetics , Chitosan/toxicity , Curcumin/chemistry , Curcumin/pharmacokinetics , Docetaxel/chemistry , Docetaxel/pharmacokinetics , Drug Carriers/metabolism , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Liberation , Humans , Hydrogen-Ion Concentration , Lung/pathology , Lung Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/drug effects , Macrophages/drug effects , Mice , Myeloid-Derived Suppressor Cells/drug effects , Nanoparticles/metabolism , Nanoparticles/toxicity , Reactive Oxygen Species/metabolism , T-Lymphocytes/drug effects , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To investigate the genetic crosstalk mechanisms that link periodontitis and Alzheimer's disease (AD). BACKGROUND: Periodontitis, a common oral infectious disease, is associated with Alzheimer's disease (AD) and considered a putative contributory factor to its progression. However, a comprehensive investigation of potential shared genetic mechanisms between these diseases has not yet been reported. METHODS: Gene expression datasets related to periodontitis were downloaded from the Gene Expression Omnibus (GEO) database, and differential expression analysis was performed to identify differentially expressed genes (DEGs). Genes associated with AD were downloaded from the DisGeNET database. Overlapping genes among the DEGs in periodontitis and the AD-related genes were defined as crosstalk genes between periodontitis and AD. The Boruta algorithm was applied to perform feature selection from these crosstalk genes, and representative crosstalk genes were thus obtained. In addition, a support vector machine (SVM) model was constructed by using the scikit-learn algorithm in Python. Next, the crosstalk gene-TF network and crosstalk gene-DEP (differentially expressed pathway) network were each constructed. As a final step, shared genes among the crosstalk genes and periodontitis-related genes in DisGeNET were identified and denoted as the core crosstalk genes. RESULTS: Four datasets (GSE23586, GSE16134, GSE10334, and GSE79705) pertaining to periodontitis were included in the analysis. A total of 48 representative crosstalk genes were identified by using the Boruta algorithm. Three TFs (FOS, MEF2C, and USF2) and several pathways (i.e., JAK-STAT, MAPK, NF-kappa B, and natural killer cell-mediated cytotoxicity) were identified as regulators of these crosstalk genes. Among these 48 crosstalk genes and the chronic periodontitis-related genes in DisGeNET, C4A, C4B, CXCL12, FCGR3A, IL1B, and MMP3 were shared and identified as the most pivotal candidate links between periodontitis and AD. CONCLUSIONS: Exploration of available transcriptomic datasets revealed C4A, C4B, CXCL12, FCGR3A, IL1B, and MMP3 as the top candidate molecular linkage genes between periodontitis and AD.
