scholarly journals Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 349
Author(s):  
Sepideh Mirzaei ◽  
Ali Zarrabi ◽  
Farid Hashemi ◽  
Amirhossein Zabolian ◽  
Hossein Saleki ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Adverse Effects ◽  
Cancer Progression ◽  
Related Factor ◽  
Pharmacological Agents ◽  
Nrf2 Signaling Pathway ◽  
High Concentrations ◽  
Genetic Interventions ◽  
Underlying Mechanisms ◽  
In Cells

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

scholarly journals Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xuling Su ◽  
Xin Jiang ◽  
Lingbin Meng ◽  
Xiaoming Dong ◽  
Yanjun Shen ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Antioxidant Activities ◽  
Epigenetic Modification ◽  
Dna Methyltransferases ◽  
Related Factor ◽  
Epigenetic Alterations ◽  
Anticancer Activities ◽  
Anticancer Effects ◽  
Nrf2 Signaling Pathway ◽  
Inhibition Of Angiogenesis

Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects, has been extensively studied due to its numerous bioactivities, such as anticancer and antioxidant activities. SFN exerts its anticancer effects by modulating key signaling pathways and genes involved in the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. SFN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress; Nrf2 activation is also involved in the cancer-preventive effects of SFN. Accumulating evidence supports that epigenetic modification is an important factor in carcinogenesis and cancer progression, as epigenetic alterations often contribute to the inhibition of tumor-suppressor genes and the activation of oncogenes, which enables cells to acquire cancer-promoting properties. Studies on the mechanisms underlying the anticancer effects of SFN have shown that SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs), and noncoding RNAs. Therefore, in this review, we will discuss the anticancer activities of SFN and its mechanisms, with a particular emphasis on epigenetic modifications, including epigenetic reactivation of Nrf2.

scholarly journals Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Siying Li ◽  
Wenjuan Wang ◽  
Ting Niu ◽  
Hui Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adverse Effects ◽  
Cardiac Dysfunction ◽  
Protein Aggregates ◽  
Autophagic Flux ◽  
Related Factor ◽  
Causative Role ◽  
Myocardial Oxidative Stress ◽  
Underlying Mechanisms

The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.

scholarly journals Targeting Tumor Endothelial Cells with Nanoparticles

2019 ◽  
Vol 20 (23) ◽  
pp. 5819 ◽  
Author(s):  
Sakurai ◽  
Akita ◽  
Harashima
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Cancer Therapy ◽  
Adverse Effects ◽  
Cancer Progression ◽  
Drug Delivery Systems ◽  
Major Contributor ◽  
Angiogenic Therapy ◽  
Current State ◽  
Tumor Endothelial Cells

Because angiogenesis is a major contributor to cancer progression and metastasis, it is an attractive target for cancer therapy. Although a diverse number of small compounds for anti-angiogenic therapy have been developed, severe adverse effects commonly occur, since small compounds can affect not only tumor endothelial cells (TECs), but also normal endothelial cells. This low selectivity for TECs has motivated researchers to develop alternate types of drug delivery systems (DDSs). In this review, we summarize the current state of knowledge concerning the delivery of nano DDSs to TECs. Their payloads range from small compounds to nucleic acids. Perspectives regarding new therapeutic targets are also mentioned.

scholarly journals Baicalein Alleviates Liver Oxidative Stress and Apoptosis Induced by High-Level Glucose through the Activation of the PERK/Nrf2 Signaling Pathway

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 599
Author(s):  
Yuesheng Dong ◽  
Yan Xing ◽  
Jin Sun ◽  
Wenlong Sun ◽  
Yongbin Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Diabetic Mice ◽  
Protein Kinase R ◽  
Nrf2 Pathway ◽  
Nrf2 Signaling Pathway ◽  
Underlying Mechanisms ◽  
High Level ◽  
Liver Tissues

Baicalein, a widely-distributed natural flavonoid, exhibits antioxidative activity in mice with type-2 diabetes. However, the underlying mechanisms remain partially elucidated. In this study, we investigated the effect of baicalein on protein kinase R-like ER kinase (PERK)/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway for the alleviation of oxidative stress and apoptosis. Human liver HL-7702 cells were stimulated with 60.5 mM of glucose to induce oxidative stress and treated with baicalein. The apoptosis was determined by fluorescence microscopy and flow cytometry. The regulation of the PERK/Nrf2 pathway by baicalein was determined by immunoblotting in both HL-7702 cells and liver tissues from diabetic mice. We found that baicalein significantly alleviated the oxidative stress and apoptosis in HL-7702 cells stimulated with glucose. Mechanistic studies showed that baicalein downregulated PERK and upregulated Nrf2, two key proteins involved in endoplasmic reticulum stress, in both HL-7702 cells and liver tissues from diabetic mice receiving baicalein treatment. Furthermore, the subcellular localization of Nrf2 and the regulation of downstream proteins including heme oxygenase-1 and CCAAT-enhancer-binding protein homologous protein (CHOP) by baicalein were also investigated. Our results suggest that the regulation of the PERK/Nrf2 pathway is one of the mechanisms contributing to the bioactivities of baicalein to improve diabetes-associated complications.

scholarly journals Phloretin suppresses neuroinflammation by autophagy-mediated Nrf2 activation in macrophages

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tess Dierckx ◽  
Mansour Haidar ◽  
Elien Grajchen ◽  
Elien Wouters ◽  
Sam Vanherle ◽  
...  
Keyword(s):  
Mouse Bone Marrow ◽  
Related Factor ◽  
Nrf2 Activation ◽  
Nrf2 Signaling Pathway ◽  
Inflammatory Phenotype ◽  
Transcriptional Changes ◽  
Nrf2 Knockout ◽  
Underlying Mechanisms ◽  
The Impact

Abstract Background Macrophages play a dual role in neuroinflammatory disorders such as multiple sclerosis (MS). They are involved in lesion onset and progression but can also promote the resolution of inflammation and repair of damaged tissue. In this study, we investigate if and how phloretin, a flavonoid abundantly present in apples and strawberries, lowers the inflammatory phenotype of macrophages and suppresses neuroinflammation. Methods Transcriptional changes in mouse bone marrow-derived macrophages upon phloretin exposure were assessed by bulk RNA sequencing. Underlying pathways related to inflammation, oxidative stress response and autophagy were validated by quantitative PCR, fluorescent and absorbance assays, nuclear factor erythroid 2–related factor 2 (Nrf2) knockout mice, western blot, and immunofluorescence. The experimental autoimmune encephalomyelitis (EAE) model was used to study the impact of phloretin on neuroinflammation in vivo and confirm underlying mechanisms. Results We show that phloretin reduces the inflammatory phenotype of macrophages and markedly suppresses neuroinflammation in EAE. Phloretin mediates its effect by activating the Nrf2 signaling pathway. Nrf2 activation was attributed to 5′ AMP-activated protein kinase (AMPK)-dependent activation of autophagy and subsequent kelch-like ECH-associated protein 1 (Keap1) degradation. Conclusions This study opens future perspectives for phloretin as a therapeutic strategy for neuroinflammatory disorders such as MS. Trial registration Not applicable.

Targeting Tumour Metastasis: The Emerging Role of Nanotechnology

2020 ◽  
Vol 27 (8) ◽  
pp. 1367-1381 ◽  
Author(s):  
Sarah Visentin ◽  
Mirela Sedić ◽  
Sandra Kraljević Pavelić ◽  
Krešimir Pavelić
Keyword(s):  
Cancer Progression ◽  
Metastatic Cancer ◽  
Treatment Strategies ◽  
Metastatic Progression ◽  
Therapeutic Concept ◽  
Molecular Alterations ◽  
Tumour Metastasis ◽  
Metastatic Cells ◽  
Metastatic Process ◽  
Underlying Mechanisms

The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.

The Effects of Butyric Acid on the Differentiation, Proliferation, Apoptosis, and Autophagy of IPEC-J2 Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 307-317
Author(s):  
Yuan Yang ◽  
Jin Huang ◽  
Jianzhong Li ◽  
Huansheng Yang ◽  
Yulong Yin
Keyword(s):  
Cell Viability ◽  
P38 Mapk ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Mapk Pathway ◽  
Mrna Level ◽  
Dependent Manner ◽  
M Phase ◽  
High Concentrations ◽  
Underlying Mechanisms

Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated. Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high concentrations.

Lipid-based Nanoplatforms in Cancer Therapy: Recent Advances and Applications

2020 ◽  
Vol 20 (4) ◽  
pp. 271-287 ◽  
Author(s):  
Kuldeep Rajpoot
Keyword(s):  
Drug Delivery ◽  
Cancer Therapy ◽  
Adverse Effects ◽  
Targeted Drug Delivery ◽  
Tumor Therapy ◽  
Cancer Therapies ◽  
Medication Delivery ◽  
Lipid Nanocarriers ◽  
Targeted Drug ◽  
Drug Nanocarriers

Though modern available cancer therapies are effective, they possess major adverse effects, causing non-compliance to patients. Furthermore, the majority of the polymeric-based medication platforms are certainly not universally acceptable, due to their several restrictions. With this juxtaposition, lipid-based medication delivery systems have appeared as promising drug nanocarriers to replace the majority of the polymer-based products because they are in a position to reverse polymer as well as, drug-associated restrictions. Furthermore, the amalgamation of the basic principle of nanotechnology in designing lipid nanocarriers, which are the latest form of lipid carriers, has tremendous chemotherapeutic possibilities as tumor-targeted drug-delivery pertaining to tumor therapy. Apart from this, it is reported that nearly 40% of the modern medication entities are lipophilic. Moreover, research continues to be efficient in attaining a significant understanding of the absorption and bioavailability of the developed lipids systems.

Exploring PLAC1 Structure and Underlying Mechanisms to Design a Derivative Vaccine Against Breast Cancer Progression; In-Silico Study

2020 ◽  
Vol 17 (5) ◽  
pp. 379-391
Author(s):  
Farzaneh Afzali ◽  
Parisa Ghahremanifard ◽  
Mohammad Mehdi Ranjbar ◽  
Mahdieh Salimi
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
In Silico ◽  
Tertiary Structure ◽  
Specific Antigen ◽  
Docking Simulation ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Underlying Mechanisms

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

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