ABSTRACT
Type 2 diabetes mellitus (T2DM) is a metabolic disease. Diabetes increases the risk of benign prostatic hyperplasia (BPH). Capsaicin is extracted from chili peppers and possesses many pharmacological properties, including anti-diabetic, pain-relieving, and anti-cancer properties. This study aimed to investigate the effects of capsaicin on glucose metabolism and prostate growth in T2DM mice and uncover the related mechanisms. Mice model of diabetes was established by administering a high-fat diet and streptozotocin. Oral administration of capsaicin for 2 weeks inhibited prostate growth in testosterone propionate (TP)-treated mice. Furthermore, oral administration of capsaicin (5 mg/kg) for 2 weeks decreased fasting blood glucose, prostate weight, and prostate index in diabetic and TP-DM mice. Histopathological alterations were measured using hematoxylin & eosin (H&E) staining. The protein expression of 5α-reductase type II, androgen receptor (AR), and prostate-specific antigen (PSA) were upregulated in diabetic and TP-DM mice, but capsaicin reversed these effects. Capsaicin decreased the protein expression of p-AKT, insulin-like growth factor-1 (IGF-1), IGF-1R, and the receptor for advanced glycation end products (RAGE) in diabetic and TP-DM mice. Capsaicin also regulated epithelial-mesenchymal transition (EMT) and modulated the expression of fibrosis-related proteins, including E-cadherin, N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-ß1, and p-Smad in TP-DM mice. In this study, capsaicin alleviated diabetic prostate growth by attenuating EMT. Mechanistically, capsaicin affected EMT by regulating RAGE/IGF-1/AKT, AR, and TGF-ß/Smad signalling pathways. These results provide with new therapeutic approach for treating T2DM or T2DM-induced prostate growth.
ABSTRACT
Despite being a minor futures category, Polyvinyl chloride (PVC) futures have emerging as a vital element in energy and chemical futures domain. Employing three benchmark models component share (CS), information share (IS), and information leadership share (ILS), this study explores the price discovery function of Chinese PVC futures and spot markets. It assesses whether PVC futures have matured into an effective hedging tool and reference point for spot markets, and also examines the impact of the COVID-19 pandemic on this price discovery relationship. Empirical analysis reveals that the futures market has become the primary site for price discovery in the Chinese PVC market. All the models consistently demonstrate a mature price discovery function in PVC futures, providing risk mitigation tools for industry players. However, post-pandemic dynamics indicate that price discovery in PVC markets primarily occurs within the spot market. This suggests that compared to the futures market, the PVC spot market is able to respond more quickly to the strong signals of industrial recovery after the end of the pandemic. The feedback and pricing efficiency of the PVC futures market in response to new market information are also influenced. Furthermore, our study offers better anticipation of future market prices.
ABSTRACT
Riemerella anatipestifer (RA) causes epizootic infectious polyserositis in ducks with high mortality and leads to huge economic losses worldwide. Bacterial resistance poses a challenge for the control of the disease, vaccines failed to provide ideal cross-protection. Thus, the preparation of vaccines based on popular serotypes is important. In this study, we collected 700 brain and liver tissues of dead ducks from 8 provinces in southern China from 2016 to 2022 and obtained 195 RA isolates with serotypes 1, 2, 7, and 10. Serotypes 1 and 2 were the most prevalent (82%). A novel bivalent inactivated vaccine WZX-XT5 containing propolis adjuvant was prepared, we chose XT5 (serotype 1) and WZX (serotype 2) as vaccine strains and evaluated WZX-XT5-induced immune response and protective efficacy in ducks. Results showed that the XT5 (LD50, 3.5 × 103 CFU) exhibited high virulence and provided better protection against RA compared with ZXP, DCR and LCF1 (LD50, 108 CFU). Notably, the dose of 109 CFU provided ideal protection compared with 108 CFU, propolis and oil emulsion adjuvants induced stronger protective efficacy compared with aluminum hydroxide adjuvant. Importantly, WZX-XT5 immunization induced high levels of RA-specific IgY, IFN-γ, IL-2, and IL-4 in serum and offered over 90% protection against RA with ultra-high lethal dose in ducks. Additionally, no clinical signs of RA infection or obvious pathological damage in tissues were observed in protected ducks. Overall, this study first reports the identification, serotyping and virulence of RA in ducks of southern China and the preparation of a novel bivalent inactivated vaccine, providing useful scientific information to prevent and control RA infection.
Subject(s)
Flavobacteriaceae Infections , Poultry Diseases , Propolis , Riemerella , Animals , Ducks/microbiology , Serogroup , Poultry Diseases/microbiology , Flavobacteriaceae Infections/prevention & control , Flavobacteriaceae Infections/veterinary , Vaccines, Combined , Chickens , Adjuvants, Immunologic/pharmacology , Vaccines, InactivatedABSTRACT
BACKGROUND: Cotransplantation of adipose-derived stem cells (ASCs) and endothelial progenitor cells has shown superior angiogenic effects compared with ASCs alone in recent animal studies. However, endothelial progenitor cells could only be collected from blood vessels or bone marrow. Thus, the authors have established a method for purifying adipose-derived endothelial progenitor cells (AEPCs). The authors hypothesized that AEPCs would enhance the therapeutic effect of ASCs on radiation ulcers. METHODS: Seven-week-old male nude mice (BALB/cAJcl-nu/nu) were irradiated on the dorsal skin (total 40 Gy); 12 weeks later, 6-mm-diameter wounds were created. The mice were then treated with subcutaneous injection of human ASCs [1 × 10 5 ( n = 4)], human AEPCs [2 × 10 5 or 5 × 10 5 ( n = 5)], combinations of those [ASCs 1 × 10 5 plus AEPCs 2 × 10 5 ( n = 4) or 5 × 10 5 ( n = 5)], or only vehicle ( n = 7). The nonirradiated group was also prepared as a control ( n = 6). The days required for macroscopic epithelialization was compared, and immunostaining for human-derived cells and vascular endothelial cells was performed at day 28. RESULTS: AEPC-ASC combination-treated groups healed faster than the ASC-treated group (14 ± 0 days versus 17 ± 2 days; P < 0.01). Engraftment of the injected cells could not be confirmed. Only the nonirradiated mice had significantly higher vascular density (0.988 ± 0.183 × 10 -5 /µm -2 versus 0.474 ± 0.092 × 10 -5 /µm 2 ; P = 0.02). CONCLUSION: The results suggested therapeutic potentials of AEPCs and an enhanced effect of combination with ASCs. This study is a xenogenic transplantation model, and further validation in an autologous transplantation model is needed. CLINICAL RELEVANCE STATEMENT: Human AEPCs and their combination with ASCs accelerated epithelialization of radiation ulcers in nude mice. The authors suggest that administration of humoral factors secreted from AEPCs (eg, treatment with culture-conditioned media) could be used for the same purpose.
Subject(s)
Endothelial Progenitor Cells , Humans , Male , Mice , Animals , Mice, Nude , Ulcer , Adipocytes , Culture Media, Conditioned , Adipose Tissue , Stem Cell Transplantation/methodsABSTRACT
BACKGROUND: Radiation therapies are often associated with permanent devitalization in the surrounding tissue. We hypothesized that stem cells are damaged depending on each irradiation dose and frequency of fractionated radiotherapies, which results in impaired tissue function including wound healing capacity. METHODS: To test the hypothesis, susceptibility of human adipose-derived stem cells (ASCs) to a single irradiation (0-10 Gy) was assessed in vitro. In vivo chronic radiation effects were also assessed on the mouse dorsal skin (N=4-5) for 6 months after a total of 40 Gy irradiation (0 Gy as control) using one of three fractionated protocols (2 Gy daily for 20 days, 10 Gy weekly for 4 weeks, or 10 Gy monthly for 4 months). Oxygen partial pressure, oxygen saturation of hemoglobin, and dorsal skin viscoelasticity were periodically measured, and wound healing and tissue immunohistology were compared at 6 months. RESULTS: A single irradiation of cultured human ASCs resulted in a dose-dependent increase in cell death up to 2 Gy but with no further increases between 2 and 10 Gy. Most of the apoptotic ASCs were in the proliferation phase. Among the three in vivo irradiation protocols, the 2 Gy×20 group had the most severe chronic tissue damage (i.e., skin dysfunction, subcutaneous atrophy, and depletion of CD34+ stem cells) 6 months after the irradiation. Wound healing was also impaired most significantly in the 2 Gy×20 group. CONCLUSIONS: These results have important clinical implications for surgeons and radiotherapists such as the timing of surgical interventions and the optimization of fractionation protocols.Clinical Relevance Statement: Irradiation damages stem cells depending on the radiation dose and frequency. Using the ultimately optimized protocol, we can minimize the long-term functional deficits of radiated tissue without losing anti-cancer efficacy of radiation therapy.
ABSTRACT
Increasing evidence showed that the substance P (SP)/neurokinin1 receptor (NK1R) complex is involved in the development of several cancers. However, little is known about the mechanisms by which SP/NK1R complex plays a role in esophageal squamous cell carcinoma (ESCC) progression. RTqPCR, CCK8, Transwell, western blotting, immunohistochemical, immunofluorescence, ELISA and analysis of apoptosis were employed in the present study. It was aimed to investigate the function and therapeutic potential of the SP/trNK1R system in human ESCC progression. The results revealed that both SP and trNK1R were highly expressed in ESCC cell lines and specimens. In ESCC tissues, SP was mainly derived from ESCC cells and M2 macrophages. The NK1R antagonist aprepitant inhibited the SPinduced proliferation of human ESCC cell lines. Aprepitant inhibited cell migration and invasion and induced apoptosis of ESCC cells by downregulating the PI3K/AKT/mTOR signaling pathways. Animal experiments revealed that aprepitant inhibited tumor progression of ESCC in xenograft mice. In conclusion, high expression of SP plus trNK1R indicated poor prognosis in ESCC, suggesting that aprepitant has a potential application in ESCC. To the best of our knowledge, high SP and trNK1R expression in ESCC cell lines was reported for the first time in the present study. These findings provided evidence for a novel therapeutic strategy for patients with ESCC.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Animals , Mice , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/metabolism , Receptors, Neurokinin-1/genetics , Receptors, Neurokinin-1/metabolism , Aprepitant/pharmacology , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Movement , Gene Expression Regulation, NeoplasticABSTRACT
Acute Stanford type A aortic dissection (ATAAD) with sudden onset and high mortality requiries a standard Bentall operation and a accurate prognosis in common, together with alteration of CO2 combining power (CO2CP) and serum sodium rase concern, hence, we evaluated the prognostic value of CO2CP combined with serum sodium in ATAAD patients. This retrospective study included 183 patients who underwent Bentall operation for ATAAD from 2015 to 2021 in the Fourth Hospital of Hebei Medical University, subsequently followed grouping by the levels of CO2CP and serum sodium. The study endpoint was 30-day all-cause mortality, and the prognostic value of CO2CP combined with serum sodium levels in ATAAD patients were evaluated with multivariate logistic regression method. The postoperative incidence of in-hospital death and adverse events in patients with ATAAD were 18% and 25.7%, respectively. Combination of CO2CP and serum sodium for predicting ATAAD death and adverse events presented a higher predictive value than each single indicator with ROC curve analysis (the AUC of CO2CP combined with serum sodium was 0.786, 95% CI 0.706-0.869, P < 0.001), along with CO2CP < 22.5 mmol/L + serum sodium > 138.5 mmol/L group had the worst prognostic. Multivariate regression analyse showed that CO2CP < 22.5 mmol/L combined with serum sodium > 138.5 mmol/L preferably predicted the prognosis of ATAAD (OR =6.073, 95% CI 2.557-14.425, P < 0.001). Consistently, the cumulative 30-day survival after surgery in ATAAD patients with the low CO2CP and high serum sodium simultaneously was the worst (log-rank P < 0.05). The combination of CO2CP and serum sodium increases the predictive value of prognosis, which is conducive to risk stratification of patients with ATAAD.
Subject(s)
Aortic Dissection , Carbon Dioxide , Humans , Retrospective Studies , Hospital Mortality , Aortic Dissection/surgery , Prognosis , SodiumABSTRACT
Human adipose tissue is a rich source of adipose-derived stem cells (ASCs) and vascular endothelial progenitor cells (EPCs). However, no standardized method has been established for the isolation and purification of adipose-derived EPCs (AEPCs). The aim of this study was to establish a method for the isolation and purification of AEPCs. The stromal vascular fraction (SVF) was extracted from human lipoaspirates, and the CD45-CD31+ fraction of the SVF was collected by magnetic-activated cell sorting (MACS). The CD45-CD31+ fraction was cultured for 4.5 days, followed by a second MACS separation to collect the CD31+ fraction. Purified AEPCs were expanded without being overwhelmed by proliferating ASCs, indicating that a high level (> 95%) of AEPC purification is a key factor for their successful isolation and expansion. AEPCs exhibited typical endothelial markers, including CD31, von Willebrand factor, and the isolectin-B4 binding capacity. AEPCs formed colonies, comparable to cultured human umbilical vein endothelial cells (HUVECs). Both AEPCs and HUVECs formed capillary-like networks in the tube formation assay, with no significant difference in network lengths. We are the first to establish a purification and expansion method to isolate these cells. Because adipose tissue is a clinically accessible and abundant tissue, AEPCs may have potential advantages as a therapeutic tool for regenerative medicine.
Subject(s)
Adipose Tissue/cytology , Biomarkers/metabolism , Endothelial Progenitor Cells/cytology , Regenerative Medicine , Stromal Cells/cytology , Adipose Tissue/metabolism , Adult , Cells, Cultured , Endothelial Progenitor Cells/metabolism , Female , Humans , Male , Middle Aged , Stromal Cells/metabolismABSTRACT
Adipose-derived stem cells (ASCs) have been growing in popularity for their potential in wound healing and tissue engineering. Stem cell therapies are limited in application, with the need to maintain cell viability and function as well as safety concerns. It has been increasingly reported that the effects of ASCs are predominantly attributable to the paracrine effects of the secreted factors, which can be collected in conditioned medium (CM). The goal of this systematic review was to investigate the effects on wound healing of CM collected from ASC culture. Original articles relevant to ASC-CM and wound healing (in vitro: dermal fibroblast, epidermal keratinocytes, and their equivalent cell lines; in vivo: full-thickness wound models) were included. The agreement level of selections between two investigators was calculated by the kappa scores. And the information concerning to the publications, CM preparation, and its application and effects was extracted and reported in a systematic way and summarized in tables. In total, 121 publications were initially identified through a search of the PubMed/MEDLINE database with a specific search algorithm, and 36 articles were ultimately included after 2 screenings. Nineteen were in vitro studies that met the search criteria and 17 were in vivo studies with or without in vitro data. In summary, based on the included articles, treatment with ASC-CM, to a large extent, resulted in positive effects on wound healing in vitro and in vivo. Modulation of the culture conditions of ASCs producing the CM, including hypoxic conditions, alternative substrates, medium supplementation, as well as genetic modification of cells, favorably promoted the effects of ASC-CM. Finally, a discussion of the future perspectives and therapeutic potential of ASC-CM, which also addresses the limitations of the field, is presented. A limitation of the evidence is the inconsistency in CM preparation methods among included articles. In conclusion, ASC-CM is a promising novel cell-free therapy for wound healing in regenerative medicine and warrants further exploration. Impact Statement This systematic review researched in vitro and in vivo studies regarding therapeutic effects of adipose-derived stem cell (ASC) conditioned medium (CM) on wound healing, generally indicating favorable effects. ASC-CM can avoid safety concerns accompanying stem cell therapies and reduce the cost of treatment. Modulation in the process of ASC culture and CM preparation may promote its therapeutic potential. The limitation and future perspectives of the field of ASC-CM therapy were also presented. ASC-CM may be useful to its future application for a wide range of clinical targets including inflammatory and ischemic diseases.
Subject(s)
Stem Cells , Wound Healing , Adipocytes/metabolism , Adipose Tissue , Culture Media, Conditioned/metabolism , Culture Media, Conditioned/pharmacology , HumansABSTRACT
Cisplatin (CDDP) is widely used for chemotherapy of esophageal squamous cell carcinoma (ESCC) but the drug resistance limits its therapeutic benefit. Heterogeneous nuclear ribonucleoprotein U-like 1 (HNRNPUL1) belongs to the family of RNA-binding proteins (RBPs) and is involved in DNA damage repair. To investigate whether and how HNRNPUL1 affects CDDP resistance of ESCC, we evaluated the expression of HNRNPUL1 and found that it was associated with recurrence in ESCC patients receiving postoperative platinum-based chemotherapy and was an independent prognostic factor for disease-free survival (DFS). Besides, we showed that the reduced expression of HNRNPUL1 enhanced the CDDP sensitivity of ESCC cells. Furthermore, RNA immunoprecipitation coupled with high-throughput sequencing (RIP-seq) were performed and a range of HNRNPUL1-binding RNAs influenced by CDDP treatment were identified followed by bioinformatics analysis. In terms of mechanism, we found that HNRNPUL1 inhibited CDDP sensitivity of ESCC cells by regulating the CDDP sensitivity-inhibited circular RNA (circRNA) MAN1A2 formation. Taken together, our results first demonstrated the role of HNRNPUL1 in CDDP resistance of ESCC and suggested that HNRNPUL1 may be a potential target of ESCC chemotherapy.
Subject(s)
Cisplatin/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/genetics , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Nuclear Proteins/genetics , RNA, Circular/genetics , Transcription Factors/genetics , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle AgedABSTRACT
The regulation of anions and cations at the atomic scale is of great significance in membrane-based separation technologies. Ionic transport regulation techniques could also play a crucial role in developing high-performance alkali metal batteries such as alkali metal-sulfur and alkali metal-selenium batteries, which suffer from the non-uniform transport of alkali metal ions (e.g., Li+ or Na+) and detrimental shuttling effect of polysulfide/polyselenide anions. These drawbacks could cause unfavourable growth of alkali metal depositions at the metal electrode and irreversible consumption of cathode active materials, leading to capacity decay and short cycling life. Herein, we propose the use of a polypropylene separator coated with negatively charged Ti0.87O2 nanosheets with Ti atomic vacancies to tackle these issues. In particular, we demonstrate that the electrostatic interactions between the negatively charged Ti0.87O2 nanosheets and polysulfide/polyselenide anions reduce the shuttling effect. Moreover, the Ti0.87O2-coated separator regulates the migration of alkali ions ensuring a homogeneous ion flux and the Ti vacancies, acting as sub-nanometric pores, promote fast alkali-ion diffusion.
ABSTRACT
Graphitic carbon nitride (g-C3N4)-based photocatalysts have shown great potential in the splitting of water. However, the intrinsic drawbacks of g-C3N4, such as low surface area, poor diffusion, and charge separation efficiency, remain as the bottleneck to achieve highly efficient hydrogen evolution. Here, a hollow oxygen-incorporated g-C3N4 nanosheet (OCN) with an improved surface area of 148.5 m2 g-1 is fabricated by the multiple thermal treatments under the N2/O2 atmosphere, wherein the C-O bonds are formed through two ways of physical adsorption and doping. The physical characterization and theoretical calculation indicate that the O-adsorption can promote the generation of defects, leading to the formation of hollow morphology, while the O-doping results in reduced band gap of g-C3N4. The optimized OCN shows an excellent photocatalytic hydrogen evolution activity of 3519.6 µmol g-1 h-1 for ~ 20 h, which is over four times higher than that of g-C3N4 (850.1 µmol g-1 h-1) and outperforms most of the reported g-C3N4 catalysts.
ABSTRACT
Filler injection demand is increasing worldwide, but no ideal filler with safety and longevity currently exists. Sodium alginate (SA) is the sodium salt of alginic acid, which is a polymeric polysaccharide obtained by linear polymerization of two types of uronic acid, d-mannuronic acid (M) and l-guluronic acid (G). This study aimed to evaluate the therapeutic value of SA. Nine SA types with different M/G ratios and viscosities were tested and compared with a commercially available sodium hyaluronate (SH) filler. Three injection modes (onto the periosteum, intradermally, or subcutaneously) were used in six rats for each substance, and the animals were sacrificed at 4 or 24 weeks. Changes in the diameter and volume were measured macroscopically and by computed tomography, and histopathological evaluations were performed. SA with a low M/G ratio generally maintained skin uplift. The bulge gradually decreased over time but slightly increased at 4 weeks in some samples. No capsule formation was observed around SA. However, granulomatous reactions, including macrophage recruitment, were observed 4 weeks after SA implantation, although fewer macrophages and granulomatous reactions were observed at 24 weeks. The long-term volumizing effects and degree of granulomatous reactions differed depending on the M/G ratio and viscosity. By contrast, SH showed capsule formation but with minimal granulomatous reactions. The beneficial and adverse effects of SA as a filler differed according to the viscosity or M/G ratio, suggesting a better long-term volumizing effect than SH with relatively low immunogenicity.
Subject(s)
Alginates/adverse effects , Alginates/pharmacology , Dermal Fillers/adverse effects , Dermal Fillers/pharmacology , Alginates/administration & dosage , Animals , Collagen/metabolism , Dermal Fillers/administration & dosage , Hexuronic Acids/chemistry , Hyaluronic Acid/administration & dosage , Hyaluronic Acid/adverse effects , Hyaluronic Acid/pharmacology , Injections, Intradermal , Injections, Subcutaneous , Macrophages/metabolism , Male , Periosteum/drug effects , Rats, Wistar , Skin/pathology , ViscosityABSTRACT
Solar energy-driven photoreduction of CO2 to energy-rich chemicals is of significance for sustainable development but challenging. Herein, quinacridone (QA)/nBiVO4 (n=0.2-20, in which n stands for the mass ratio of BiVO4 to QA) nanocomposites were developed for photoreduction of CO2 . Characterization of the materials with Fourier-transform (FT)IR spectroscopy and X-ray photoelectron spectroscopy (XPS) pointed to QA/nBiVO4 preparation via hydrogen-bonding-directed self-assembly of QA on BiVO4 nanosheets. Using triethanolamine (TEOA) as a sacrifice reagent, QA/10BiVO4 showed the best performance, affording CO with a production rate of 407â µmol g-1 h-1 , 24 times higher than those of pure QA. It was indicated that the Z-scheme charge-transfer mechanism of QA/nBiVO4 could significantly improve the separation and transmission efficiency of photo-generated electrons and holes. This novel approach provides new insight for fabricating the composite photocatalytic materials of small molecule organic semiconductors and inorganic semiconductors with high efficiency for photocatalytic of reduction CO2 .
ABSTRACT
Breast cancer is the leading cause of cancer-associated deaths in women. Combination immunotherapy attracts great interest as a treatment for breast cancer. However, there are no studies on the use of cytotoxic Tlymphocyte antigen 4 (CTLA4) monoclonal antibody in combination with the melanomaassociated antigen A family (MAGEAs) coantigen peptide (p248V9) for treating breast cancer, which should be explored. To this aim, in the present study, the samples of 115 patients with breast cancer were collected, and MAGEAs and CTLA4 levels in breast cancer and adjacent normal tissues were assessed by immunohistochemical staining. The effect of 5aza2'deoxycytidine (5DC) on the expression of MAGEAs in breast cancer cell lines was assessed by reverse transcriptionquantitative PCR and western blot assay. Cytotoxic T cells (CTLs) were induced by MAGEAs coantigen peptide. The specific lytic rate and IFNγ level were examined by CCK8 assay and ELISA, respectively. It was found that MAGEAs were highly expressed in breast cancer tissues. 5DC treatment promoted the expression of MAGEAs in breast cancer cells. The upregulation of the expression of MAGEAs specifically enhanced the ability of CTLs to kill breast cancer cells. CTLA4 was highly expressed in breast cancer tissues and cells, and patients with breast cancer exhibiting high expression of CTLA4 had low overall survival. CTLA4 promoted the lytic efficiency of CTLs in breast cancer cells, and the combination of an antiCTLA4 antibody and 10 µM 5DC exhibited the highest cell lysis ability of CTLs. The present study demonstrated that MAGEAs coantigen peptidespecific CTLs in combination with an antiCTLA4 monoclonal antibody and 5DC, have potent tumor cellkilling effects. It provides a novel theory for the development of breast cancer therapies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , CTLA-4 Antigen/antagonists & inhibitors , Carcinoma, Ductal, Breast/drug therapy , Melanoma-Specific Antigens/metabolism , T-Lymphocytes, Cytotoxic/immunology , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , CTLA-4 Antigen/immunology , Carcinoma, Ductal, Breast/immunology , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Cell Line, Tumor , Decitabine/administration & dosage , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , MCF-7 Cells , Melanoma-Specific Antigens/genetics , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Survival Rate , T-Lymphocytes, Cytotoxic/drug effectsABSTRACT
Cancer testis antigens (CTAs) are promising targets for T cell-based immunotherapy and studies have shown that certain CT genes are epigenetically depressed in cancer cells through DNA demethylation. Melanoma-associated antigen A11 (MAGE-A11) is a CTA that is frequently expressed in esophageal cancer and is correlated with a poor esophageal cancer prognosis. Consequently, MAGE-A11 is a potential immunotherapy target. In this study, we evaluated MAGE-A11 expression in esophageal cancer cells and found that it was downregulated in several tumor cell lines, which restricted the effect of immunotherapy. Additionally, the specific recognition and lytic potential of cytotoxic T lymphocytes (CTLs) derived from the MAGE-A11 was determined. Specific CTLs could kill esophageal cancer cells expressing MAGE-A11 but rarely lysed MAGE-A11-negative tumor cells. Therefore, induction of MAGE-A11 expression is critical for CTLs recognition and lysis of esophageal cancer cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased MAGE-A11 expression in esophageal cancer cells and subsequently enhanced the cytotoxicity of MAGE-A11-specific CD8+T cells against cancer cell lines. Furthermore, we found that PD-L1 expression in esophageal cancer cells affected the antitumor function of CTLs. programmed death-1 (PD-1)/PD-L1 blockade could increase the specific CTL-induced lysis of HLA-A2+/MAGE-A11+ tumor cell lines treated with 5-aza-2'-deoxycytidine. These findings indicate that the treatment of tumor cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine augments MAGE-A11 expression in esophageal cancer cells. The combination of epigenetic modulation by 5-aza-2'-deoxycytidine and PD-1/PD-L1 blockade may be useful for T cell-based immunotherapy against esophageal cancer.
Subject(s)
Antigens, Neoplasm/genetics , B7-H1 Antigen/genetics , Carcinoma/therapy , Esophageal Neoplasms/therapy , Neoplasm Proteins/genetics , Programmed Cell Death 1 Receptor/genetics , Antigens, Neoplasm/immunology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes , Carcinoma/genetics , Carcinoma/immunology , Carcinoma/pathology , Cell Line, Tumor , Decitabine/pharmacology , Epigenesis, Genetic/immunology , Esophageal Neoplasms/genetics , Esophageal Neoplasms/immunology , Esophageal Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Immunotherapy , Neoplasm Proteins/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunologyABSTRACT
Qigesan (QGS) has been used to effectively treat esophageal cancer (EC) for decades in China, but the mechanism by which it suppresses EC metastasis remains unknown. In this study, we examined the effects of QGS on EC cell mobility. Using immunohistochemistry and immunofluorescence, expression of Gas6 and Axl, which promote tumor cell migration and invasion, was examined in carcinoma tissues and adjacent normal tissues from EC patients. Levels of Gas6, Axl, and the Gas6/Axl complex were also examined in ECA109 and TE13 EC cells treated with QGS. In addition, immunofluorescent staining and quantitative protein analysis were used to examine E-cadherin, N-cadherin, and Snail levels in ECA109 and TE13 EC cells after QSG administration, and cell mobility was assessed. The results demonstrated that levels of Gas6 and Axl expression are higher in EC tissues than in adjacent normal tissues. Moreover, QGS decreased Gas6/Axl levels, increased E-cadherin expression, decreased Snail and N-cadherin expression, and inhibited epithelial-mesenchymal transition (EMT) in EC cells. QGS thus suppresses EMT in EC by inhibiting Gas6/Axl binding.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Movement/drug effects , Drugs, Chinese Herbal/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Esophageal Neoplasms/drug therapy , Cell Line, Tumor , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Neoplasm Invasiveness , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Axl Receptor Tyrosine KinaseABSTRACT
O-heterocycles have wide applications, and their efficient and green synthesis is very interesting. Herein, we report hydrogen-bonding catalyzed ring-closing metathesis of aliphatic ethers to O-heterocycles over ionic liquid (IL) catalyst under metal- and solvent-free conditions. The IL 1-butylsulfonate-3-methylimidazolium trifluoromethanesulfonate ([SO3 H-BMIm][OTf]) is discovered to show outstanding performance, better than the reported catalysts. An interface effect plays an important role in mediating the reaction rate due to the immiscibility between the products and the IL catalyst, and the products can be spontaneously separated. NMR analysis and DFT calculation suggest that a pair of cation and anion of [SO3 H-BMIm][OTf] could form three strong H-bonds with an ether molecule, which catalyze the ether transformation via a cyclic oxonium intermediate. A series of O-heterocycles including tetrahydrofurans, tetrahydropyrans, morpholines and dioxane can be obtained from their corresponding ethers in excellent yields (e.g., >99 %). This work opens an efficient and metal-free way to produce O-heterocycles from aliphatic ethers.