Silencing Signal Transducer and Activator of Transcription 3 (STAT3) and Use of Anti-Programmed Cell Death-Ligand 1 (PD-L1) Antibody Induces Immune Response and Anti-Tumor Activity

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

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Myocardial Damage by SARS-CoV-2: Emerging Mechanisms and Therapies

Viruses ◽

10.3390/v13091880 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1880

Author(s):

Huyen Tran Ho ◽

Stefan Peischard ◽

Nathalie Strutz-Seebohm ◽

Karin Klingel ◽

Guiscard Seebohm

Keyword(s):

Immune Response ◽

Cell Death ◽

Energy Metabolism ◽

Programmed Cell Death ◽

Viral Replication ◽

Ion Homeostasis ◽

Membrane Vesicles ◽

Cardiac Cells ◽

The Body ◽

Double Membrane

Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.

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Combination of DNA demethylation and chemotherapy to trigger cell pyroptosis for inhalation treatment of lung cancer

Nanoscale ◽

10.1039/d1nr05001j ◽

2021 ◽

Author(s):

Beibei Xie ◽

Tingting Liu ◽

Shuang Chen ◽

Yan Zhang ◽

Dongxian He ◽

...

Keyword(s):

Lung Cancer ◽

Immune Response ◽

Cell Death ◽

Programmed Cell Death ◽

Effective Means ◽

Dna Demethylation ◽

Local Immune Response ◽

Anticancer Efficacy

Pyroptosis is an inflammation-dependent and self-cascade amplifying type of programmed cell death, serving as an effective means for activating the local immune response and improving the anticancer efficacy. As the...

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Programmed cell death-ligand 2: A neglected but important target in the immune response to cancer?

Translational Oncology ◽

10.1016/j.tranon.2020.100811 ◽

2020 ◽

Vol 13 (10) ◽

pp. 100811 ◽

Cited By ~ 2

Author(s):

Cinzia Solinas ◽

Marco Aiello ◽

Esdy Rozali ◽

Matteo Lambertini ◽

Karen Willard-Gallo ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Programmed Cell Death ◽

Important Target ◽

Immune Response To Cancer

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Maprotiline Prompt the Anti-tumor Effect by Inhibiting the PD-L1 in Mice Burdened Melanoma

10.21203/rs.3.rs-1172486/v1 ◽

2021 ◽

Author(s):

Tiesuo Zhao ◽

Yang Li ◽

Miaomiao Liu ◽

Lin Zhou ◽

Zunge Wu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Tumor Tissues ◽

Programmed Cell Death 1 ◽

Tetracyclic Antidepressant ◽

And Migration ◽

Cell Death Protein

Abstract Programmed cell death 1 ligand 1(PD-L1) binds with programmed cell death protein 1 (PD-1) to inhibit the responses of T cells. PD-L1 is significantly upregulated on tumor cells and blocking the PD-L1/PD-1 signal has become an important target of immunotherapy in clinic. At present, some old drugs of non-antitumor have been found that could play the effect of anti-tumor. Maprotiline, as a tetracyclic antidepressant, has been widely used for treating mental depression. Here, we study the anti-tumor effect of maprotiline by strengthening the immune response of mice. In vitro, treatment with maprotiline inhibits the proliferation and migration of B16 cells, increases the cell apoptosis. Importantly, treatment with maprotiline reduces the expression of PD-L1 in tumor tissue, prompts the ratios of CD4+ T cells, CD8+ T cells and NK cells in spleens, increases the infiltration of CD4+ and CD8+ T cells in tumor-tissues. In brief, we determine that maprotiline could prompt the anti-tumor immune response by inhibiting the PD-L1 in mice. This study may find a new inhibitor of PD-L1, which provides a new drug treated tumor in clinical.

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CRISPR knock out of programmed cell death protein 1 enhances anti-tumor activity of cytotoxic T lymphocytes

Oncotarget ◽

10.18632/oncotarget.23730 ◽

2017 ◽

Vol 9 (4) ◽

pp. 5208-5215 ◽

Cited By ~ 24

Author(s):

Zhilong Zhao ◽

Long Shi ◽

Wei Zhang ◽

Jinsheng Han ◽

Shaohui Zhang ◽

...

Keyword(s):

Cell Death ◽

T Lymphocytes ◽

Programmed Cell Death ◽

Cytotoxic T Lymphocytes ◽

Knock Out ◽

Anti Tumor Activity ◽

Cell Death Protein

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Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell–derived Neurons

Anesthesiology ◽

10.1097/aln.0000000000000345 ◽

2014 ◽

Vol 121 (4) ◽

pp. 786-800 ◽

Cited By ~ 55

Author(s):

Danielle M. Twaroski ◽

Yasheng Yan ◽

Jessica M. Olson ◽

Zeljko J. Bosnjak ◽

Xiaowen Bai

Keyword(s):

Cell Death ◽

Stem Cell ◽

Embryonic Stem Cell ◽

Human Embryonic Stem Cell ◽

Embryonic Stem ◽

Terminal Deoxynucleotidyl Transferase ◽

Signal Transducer ◽

Deoxyuridine Triphosphate ◽

Transcription 3

Abstract Background: Recent studies in various animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. These studies have raised significant safety concerns regarding the use of anesthetics in the pediatric population and highlight the need for a better model to study anesthetic-induced neurotoxicity in humans. Human embryonic stem cells are capable of differentiating into any cell type and represent a promising model to study mechanisms governing anesthetic-induced neurotoxicity. Methods: Cell death in human embryonic stem cell–derived neurons was assessed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling staining, and microRNA expression was assessed using quantitative reverse transcription polymerase chain reaction. miR-21 was overexpressed and knocked down using an miR-21 mimic and antagomir, respectively. Sprouty 2 was knocked down using a small interfering RNA, and the expression of the miR-21 targets of interest was assessed by Western blot. Results: Propofol dose and exposure time dependently induced significant cell death (n = 3) in the neurons and down-regulated several microRNAs, including miR-21. Overexpression of miR-21 and knockdown of Sprouty 2 attenuated the increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling–positive cells following propofol exposure. In addition, miR-21 knockdown increased the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling–positive cells by 30% (n = 5). Finally, activated signal transducer and activator of transcription 3 and protein kinase B (Akt) were down-regulated, and Sprouty 2 was up-regulated following propofol exposure (n = 3). Conclusions: These data suggest that (1) human embryonic stem cell–derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in human embryonic stem cell–derived neurons, and (3) the propofol-induced cell death may occur via a signal transducer and activator of transcription 3/miR-21/Sprouty 2–dependent mechanism.

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