The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention

Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment

Redox regulation in cancer: A double-edged sword with therapeutic potential

Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and cell’s own antioxidant defenses. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Ultraviolet (UV) exposures, γ-radiation and other environmental carcinogens generate ROS in the cells, which can exert apoptosis in the tumors, thereby killing the malignant cells or induce the progression of the cancer growth by blocking cellular defense system. Cancer stem cells take the advantage of the aberrant redox system and spontaneously proliferate. Oxidative stress and gene-environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Prolonged lifetime exposure to estrogen is associated with several kinds of DNA damage. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. BRCA1, a tumor suppressor against hormone responsive cancers such as breast and prostate cancer, plays a significant role in inhibiting ROS and estrogen mediated DNA damage; thereby regulate the redox homeostasis of the cells. Several transcription factors and tumor suppressors are involved during stress response such as Nrf2, NFκB and BRCA1. A promising strategy for targeting redox status of the cells is to use readily available natural substances from vegetables, fruits, herbs and spices. Many of the phytochemicals have already been identified to have chemopreventive potential, capable of intervening in carcinogenesis

Funktionelle Charakterisierung des Interaktoms des Guanin-rich Sequence binding Factor 1 und dessen Beteiligung an der Regulation der Redoxhomöostase

Die Regulation der Genexpression findet auf transkriptioneller, posttranskriptioneller, translationaler und posttranslationaler Ebene statt und befähigt eukaryotische Zellen dazu, sich an verändernde Umweltbedingungen anzupassen. Sie erfordert das Zusammenspiel einer Vielzahl von regulatorischen Proteinen, wie dem RNA-bindenden Protein Guanin-rich Sequence binding factor 1 (GRSF1). Dieses Protein bindet Guanin-reiche Sequenzen in seinen RNA-Substraten und spielt beispielsweise, durch die positive Regulation der Translation der Glutathionperoxidase 4 (GPx4), eine wichtige Rolle in der murinen Embryonalentwicklung. Bislang konnten nur wenige RNA-Substrate von GRSF1 entdeckt werden. Ebenso wenig ist über die Proteininteraktionspartner von GRSF1 bekannt. Im ersten Teil meiner Arbeit wurde mittels eines Hefe-Zwei-Hybrid Screens nach neuen, mit GRSF1 interagierenden Proteinen, gesucht. Zwei dieser im Hefemodell entdeckten Interaktionspartner, das Cytochrom C1 (CYC1) und das COMM domain containing protein 1 (COMMD1), binden in Säugetierzellen an die Alanin-reiche, N-terminalen Domäne von GRSF1. Es folgte eine funktionelle Charakterisierung der Interaktion von GRSF1 mit COMMD1, bei der sich zeigte, dass COMMD1 über einen unbekannten Mechanismus die mitochondriale Lokalisation verhindert bzw. die mitochondriale Translokation von GRSF1 blockiert. Die zelluläre Redoxhomöostase beschreibt die Balance prooxidativer Vorgängen und effektiver antioxidativer Antworten. Durch ihre Fähigkeiten komplexe Hydroxyperoxylipide zu reduzieren, spielt die GPx4 eine wichtige Rolle beim antioxidativen Schutz von Zellen, sodass GRSF1 als positiver Regulator dieses Enzyms eine wichtige Rolle in der Redoxhomöostase zukommt. Wenig ist über die Beteiligung von GRSF1 an der Regulation der Redoxhomöostase bekannt, sodass hier durch Etablierung eines GRSF1 knockout Systems in humanen Caco-2 Zellen die Rolle von GRSF1 beleuchtet werden konnte. Dabei zeigte sich, dass in Abwesenheit von GRSF1 eine erniedrigte Konzentration an intrazellulären reaktiven Sauerstoffspezies (ROS) gebildet wurde. ROS entstehen vor allem in der Atmungskette (Mitochondrium) oder als Nebenprodukte enzymatischer Oxidationsreaktionen und aktivieren als second messenger zum Beispiel die c-Jun N-terminale Kinase (JNK). Dessen Aktivität war in Abwesenheit von GRSF1 vermindert, sodass durch Analyse der RNA-Level wichtiger pro- und antioxidativer Proteine eine Ursache für die erniedrigte Konzentration an ROS gefunden werden sollte. Dabei zeigte sich eine signifikante Verringerung der zellulären RNA-Konzentrationen der Cyclooxygenase 2.The regulation of gene expression takes place on transcriptional, posttranscriptional, translational and posttranslational levels and allows eukaryotic cells to adapt to changes in their environments. It requires the concerted activity of many different regulatory proteins such as the RNA binding protein Guanin-rich Sequence binding factor 1 (GRSF1). This protein binds to guanin-rich sequences in its RNA substrates and plays an important role in murine embryo development via its regulatory interaction with the mRNA encoding for glutathione peroxidase 4 (GPx4). So far, only a few RNA substrates of GRSF1 have been discovered and little is also known about the cellular interactome of GRSF1. We employed the Yeast Two-Hybrid system to search for GRSF1 interacting proteins. Two of these proteins [the COMM domain containing protein 1 (COMMD1) and Cytochrome C1 (CYC1)] interacted with the Ala-rich N-terminal domain of GRSF1. Next, we explored the molecular mechanism of COMMD1-GRSF1 interaction and found that COMMD1 hinders the mitochondrial translocation of GRSF1 through an unknown mechanism. The cellular redox homoeostasis is characterized by a balance between pro-oxidative events and effective anti-oxidative responses. GPx4 is an anti-oxidative enzyme capable of reducing complex hydroperoxy lipids to the corresponding alcohols. Grsf1 regulates GPx4 expression and thus, impacts the cellular redox homeostasis. Unfortunately, little is currently known about the role of Grsf1 in intracellular redox regulation. To shed light on this topic we established a cellular GRSF1 knockout system and explored the functional consequences of this genetic manipulation. We found that in the absence of GRSF1 decreased levels of reactive oxygen species (ROS) were detected. ROS are predominantly generated as side-products of the respiratory chain in the mitochondria but they are also formed in other enzymatic oxidation reactions. They function as second messengers and activate for instance c-Jun N-terminal Kinase (JNK). We found that JNK’s activity was decreased in GRSF1 deficient cells and that the intracellular mRNA concentrations of cyclooxygenase 2 were significantly reduced in the absence of GRSF1

Mode of action of non-genotoxic carcinogens

Das hepatozelluläre Karzinom (HCC), als besonders aggressiver Tumor, führt zu über einer halben Million Todesfälle pro Jahr. Es ist daher von Bedeutung, die potentiellen Risikofaktoren auszuschalten und die Entstehung dieser Krankheit besser zu verstehen. Viele, an Millionen von Menschen weltweit, verschriebene Medikamente zählen zu der Gruppe von nicht gentoxischen Kanzerogenen (NGC), das heißt sie sind nicht gentoxisch, erzeugen aber Tumore in Ratten in Langzeit „Bioassays“. Die Bedeutung dieser Ergebnisse für den humanen Leberkrebs ist nicht eindeutig. Das Ziel dieser Diplomarbeit war die Erforschung der Wirkungsweise von prototypischen NGC (Phenobarbital, PB; Cyproterone Acetat, CPA und Wyeth, WY), um das Risiko für die Gesundheit des Menschen besser einschätzen zu können. Bislang lag der Schwerpunkt der Forschung auf Hepatozyten (HC) als direkte Zielzellen von NGC. Da es Hinweise gibt, dass NGC auch auf nicht parenchymale Zellen der Leber (NPC) wirken, wurden die Experimente in der Weise aufgebaut, dass die Effekte von NGC gesondert für HC und NPC untersucht werden konnten. Die Versuche basierten darauf, dass die Ratten entweder einmalig oder für einen längeren Zeitraum mit PB oder CPA behandelt wurden. Die Zellen wurden mittels Kollagenase Perfusion aus der Rattenleber isoliert, mittels Percoll Gradienten Zentrifugation in HC und NPC aufgetrennt, auf Kulturplatten ausgesät und mit PB, CPA, oder WY für bis zu 24 Stunden behandelt. Die Analyse von veränderten Genexpressionsmustern erfolgte mit Hilfe der Polymerase-Ketten-Reaktion (PCR), quantitativer Real-Time PCR (qrt-PCR), sowie DNA Chip Analyse des gesamten Transkriptoms. Des Weiteren wurde die Phosphorylierung der „extracellular-signal regulated kinase“ (ERK1/2) Proteine untersucht, die in vitro mit PB oder CPA behandelt worden waren. Die Auswirkung der Zellüberstände von unbehandelten oder PB behandelten NPC auf den pro-entzündlichen Status von HC wurde erforscht. Das Gleiche wurde mit NPC, welche den Zellüberständen von unbehandelten oder PB behandelten HC ausgesetzt wurden, durchgeführt. Die Veränderung der mRNA Level von pro-entzündlichen Genen, wie zum Beispiel des Tumornekrosefaktors (TNFα) oder Interleukin-6 (IL-6), diente als Endpunkt. Es stellte sich heraus, dass HC hauptsächlich die Nuklearen Rezeptoren (NR) PXR und PPARα und im geringeren Ausmaß CAR und ERα exprimieren. Im Vergleich zu HC waren die Expressionslevel der NR in Endothelzellen und Kupfferzellen geringer oder sogar vernachlässigbar. Es zeigte sich, dass HC in Primärkulturen in der Lage sind auf NGC in Form von erhöhter mRNA der Zytochrom-P450 Isoenzyme (Cyp1a1, Cyp2b1 und Cyp2c12) zu reagieren, wohingegen der Effekt von NGC auf mesenchymale Zellen teilweise geringer ausfiel. Das Gleiche galt für die Phosphorylierung der ERK1/2 Proteine in PB behandelten HC. Zusätzlich ergab die Gene Chip Analyse von HC, welche aus CPA behandelten Tieren isoliert worden waren, eine Hochregulierung von Genen des ERK Signalweges. Infolgedessen könnte dieser Signalweg bei der Wirkungsweise von NGC eine Rolle spielen. In Bezug auf die epithelialen-mesenchymalen Wechselwirkungen löste das Sekretom aus unbehandelten NPC eine pro-entzündliche Reaktion in HC aus. Diese wurde verschärft, wenn NPC eingesetzt wurden, die aus PB behandelten Tieren stammten. Im Gegensatz dazu führten die Überstände aus unbehandelten HC zu einer Unterdrückung der Transkriptionslevel von pro-entzündlichen Genen in NPC. Dieser Effekt wurde durch den Einsatz von Überständen aus PB behandelten HC noch verstärkt. Die Ergebnisse deuten auf einen fundierten epithelialen-mesenchymalen Dialog hin, welcher zur Feinabstimmung der Expressionslevel in Leberzelltypen dienen könnte. Es wäre denkbar, dass NGC in diese Interaktionen eingreifen. Zusammenfassend erlangte diese Arbeit Hinweise darauf, dass NGC möglicherweise die Leberkrebsentstehung durch Beeinflussung von Signalwegen und Veränderungen des pro-entzündlichen Status in mesenchymalen und parenchymalen Leberzellen fördern könnte.As particularly aggressive cancer entity, hepatocellular carcinoma (HCC) causes about half a million deaths per year. Therefore, it is important to eliminate putative cancer risk factors and to understand the mechanisms underlying the pathogenesis of this tumor. Many drugs prescribed to millions of people worldwide belong to the class of non-genotoxic hepatocarcinogens (NGC), i.e. they do not feature genotoxicity but produce tumors in long-term rodent bioassays. The significance of these findings for human liver cancer risk is not clear. This thesis aimed to study the mode of action of prototypical NGC (phenobarbital, PB; cyproterone acetate, CPA; and Wyeth, WY) in order to better estimate whether NGC may pose a risk to human health. Hitherto, research has been focusing on hepatocytes (HC) as direct target cells of NGC. Since there is evidence that NGC are able to act also on non-parenchymal liver cells (NPC), the present study was designed to investigate the effects of NGC, separately for HC and NPC. As main experimental approaches, rats were treated with PB or CPA either once or for a prolonged period of time. The cells were isolated from rat liver by collagenase perfusion, were separated into HC and NPC by percoll gradient centrifugation, were seeded to culture plates and were treated with PB, CPA, or WY for up to 24 hours. Analysis of altered gene expression patterns was performed via conventional polymerase chain reaction (PCR), quantitative Real-Time PCR (qrt-PCR) as well as by Gene Chip analysis of the whole transcriptome. Furthermore, the phosphorylation of extracellular signal-regulated kinase (ERK1/2) proteins was analysed in HC and NPC exposed to PB and CPA in vitro. The impact of the secretome of untreated or PB treated NPC on the pro-inflammatory state of HC was investigated. The same was done with NPC exposed to supernatants derived from untreated or PB treated HC. Changes in mRNA level of pro-inflammatory genes, such as the tumor necrosis factor-alpha (TNFα) or interleukin-6 (IL-6), served as end point. HC were found to express considerably the nuclear receptors (NR) PXR and PPARα and to lower extent CAR and ERα. Compared to HC, the expression levels of NR in EC and KC were lower or even negligible. In primary culture, HC are able to respond to NGC as indicated by elevated mRNAs of cytochrome P450 enzymes (Cyp1a1, Cyp2b1 and Cyp2c12) while the effect on mesenchymal cells was partially weaker. This was similar with the phosphorylation of ERK1/2 proteins in PB-treated cultured HC. Furthermore, Gene Chip analysis revealed the upregulation of components of the ERK pathway in HC exposed to CPA in vivo. As a consequence, NGC action may involve this signalling pathway. With regard to epithelial-mesenchymal interactions, the secretome from untreated NPC triggered a pro-inflammatory response in HC which was aggravated when NPC had been exposed to PB in vivo. In contrast, supernatants of untreated HC suppressed transcription levels of pro-inflammatory genes in NPC which became more pronounced when supernatant of PB-exposed HC was applied. The results indicate a profound epithelial-mesenchymal dialogue for the fine tuning of expression levels in liver cell types and that NGC may interfere with these interactions. In summary, the present work could gain evidence that NGC may promote hepatocarcinogenesis by affecting signalling pathways and altering the pro-inflammatory state in both, mesenchymal and parenchymal liver cells

The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis.

The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels

IDENTIFICATION AND CHARACTERIZATION OF KINASE REGULATORS IN KEAP1/NRF2 SIGNALING

The cellular environment is compartmentalized to maximize peak performance while minimizing extreme damage to biomolecules such as DNA, protein, and lipids. In the event of damage to biomolecules, the cell either triggers stress response or undergoes cell death in case of unresolved damage. Oxidative stress causes these types of cellular damage, and arises from changes in the oxidative-reductive (Redox) balance. Throughout a cells’ lifetime, exposure to oxidants from both exogenous and endogenous sources is unavoidable. Highly reactive molecules have a common outcome of producing free radical Oxygen, Nitrogen, and Sulfur species among others as a byproduct of redox reactions that occur in nature. As a result, cells have developed waste elimination processes such as antioxidant response, efflux pumps, electrophile detoxification enzymes, and Glutathione (GSH) metabolism to name a few. Cellular redox homeostasis is achieved in a state of flux as the environments is bombarded by different reactive molecules, where oxidative stress response pathways tend to work towards a thermodynamically stable environment to reach steady state. Oxidative stress response is a tightly regulated process that engages various cell signaling pathways that yield a balance in overall cellular health. One of the key regulatory nodes of cellular protection is the presence of transcriptionally inducible electrophilic/antioxidant response elements (Ep/AREs) on target genes that are involved in these waste elimination processes. AREs are 41 base pair cis –regulatory enhancer regions found in the promoter of detoxifying enzymes induced in response to treatment with planar aromatic and phenolic compounds. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) was identified as a key regulator of transcriptional activity at AREs. NRF2 protein level is regulated by ubiquitin-mediated proteasomal degradation via the cysteine rich E3 ubiquitin ligase adaptor kelch like ECH-associated protein 1 (KEAP1). The KEAP1/NRF2 field has been linked to various human health and diseases that rely on balanced oxidative stress signaling. As the cells primary source of defense, KEAP1/NRF2 signaling receives input from various pathways throughout the cell such as kinases. Kinases are key enzymes required for cellular signal transduction that promotes cell proliferation and survival. Kinases relay signal via phosphorylation of their substrates. Studies on the extent to which kinases modulate KEAP1/NRF2 signaling is an active area of research, yet there has not be an exhaustive study of the intricate cross-talk between kinase signaling and antioxidant response. Additionally, NRF2 level is perturbed in various diseases, thus finding targetable nodes for future therapeutic approaches is of paramount importance. Here, we leverage gain-of-function and small molecule inhibitor screen to identify additional regulators of the KEAP1/NRF2 pathway. We identified several kinases that inhibit (HIPK4, BRD3, BRSK2) or Activate (MAP3K8, MOS, MAP3K7) NRF2 signaling. Furthermore, we show that kinase inhibitors targeting MEK5/ERK5 pathway activates NRF2 signaling while PLK1 and PI3K inhibitors downregulate NRF2 signaling. In a focused study, we report Brain Specific Kinase 2/1 (BRSK2/1) as novel repressors of NRF2 signaling. BRSK2/1 downregulate NRF2 signaling by depleting protein levels, and we propose that the mechanism of action is through MTOR-mediated protein translation Block. We believe that this has application in tissues where BRSK2 is highly active, the brain and pancreas. Specifically, there are potential application of BRSK2/1-NRF2 cross-talk in neurodegenerative disorders and diabetes. Overall, we show potential targetable nodes that influence KEAP1/NRF2 signaling.Doctor of Philosoph

Polyphenols for Cancer Treatment or Prevention

Polyphenols are commonly found in fruits and vegetables, and have been suggested to have protective effects against chronic diseases, such as cancers. They are a diverse group of molecules, many of which possess antioxidant, anti-inflammatory, epigenetic, drug sensitization, and/or modulation of xenobiotic metabolizing enzyme properties. However, there is mixed evidence regarding their protective effects with respect to various cancers. Some of this controversy may be due to the combination of polyphenols administered, synergistic effects of accompanying compounds, bio-accessibility, bioavailability, effect of gut microbiota, and the type of cancer investigated. The purpose of this Special Issue is to present the recent evidence for the effect of polyphenol intake on cancer, as well as mechanisms of action. This Special Issue, entitled "Polyphenols for Cancer Treatment or Prevention", welcomes manuscript submissions of original research, meta-analyses, or reviews of the scientific literature. Authors should focus their manuscripts on polyphenol bioactives or dietary patterns naturally rich in polyphenols that have been identified and used for the prevention and or treatment of cancer

Υποδοχείς Farnesoid X Reseptors (FXRs) και καρκίνος προστάτη

Σκοπός της παρούσας βιβλιογραφικής ανασκόπησης ήταν η μελέτη του παρόντος δημοσιευμένου υλικού επάνω στη συσχέτιση του πυρηνικού υποδοχέα χολικών οξέων FXR με τη δημιουργία και εξέλιξη του καρκίνου του προστάτη. Ο διαρκώς αυξανόμενος όγκος ερευνών τονίζει τη σημασία του εν λόγω υποδοχέα στο μεταβολισμό και συγκεκριμένα στη διαχείριση των λιπιδίων σε συνδυασμό με τον παγιωμένο ρόλο των ανδρογόνων και των υποδοχέων τους στην ογκογένεση του καρκίνου του προστάτη, αλλά και η ήδη εξακριβωμένη εμπλοκή του με κακοήθεις νεοπλασίες άλλων οργάνων, όπως του μαστού, τον καθιστούν ως ελκυστικό πεδίο έρευνας και στόχο ανάπτυξης νέων φαρμάκων και θεραπευτικών επιλογών. Η ανασκόπηση έφτασε στο συμπέρασμα ότι, παρά τα πολύ υποσχόμενα υπάρχοντα δεδομένα, δυστυχώς, δεν υπάρχουν επαρκή στοιχεία ακόμα για ασφαλή συμπεράσματα. Επομένως, καθίσταται υψίστης σημασίας ο σχεδιασμός περισσότερων ερευνών οι οποίες να περιλαμβάνουν και ζωικά μοντέλα για τη διεξαγωγή ασφαλέστερων συμπερασμάτων σχετικά με αυτό το πολλά υποσχόμενο αντικείμενο.The purpose of this literature review was to investigate current published scientific data on the relation of bile acid nuclear receptor FXR and prostate cancer development and evolution. Constantly announced evidence on the importance of FXR on metabolism and especially on lipid control combined with the certain role of androgens and their receptors on prostate tumourigenesis, as well as already known involution of FXR and other cancers like breast, provide an appealing research field and a promising pharmacological target and therapeutic option. This review concluded that, unfortunately, there is not enough evidence yet on this matter, although the first results are very encouraging, rendering further research publications, including animal models, of paramount significance

Identification of novel and potent Nrf2 activators from medicinal plants

Oxidative stress has been implicated in the pathogenesis of various age-related chronic diseases (cancer, cardiovascular disease, chronic obstructive pulmonary disease and neurodegenerative disease). The antioxidant response pathway, which is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), shields cells from oxidative stress by enhancing the expression of cytoprotective genes and enzymes. Transcriptional regulator Nrf2 induces the expression of detoxification enzymes (Phase II detoxifying and antioxidant enzymes) such as glutathione S-transferase (GST) and metabolic pathway enzymes for glutathione synthesis. Antioxidant therapy with the Nrf2 activation is a strategy to prevent cells from exposure to the oxidants and correct cellular redox homeostasis. Plant-derived Nrf2 activators might be used to stimulate the body's antidefense mechanisms. Our study was focused on the discovery of novel Nrf2 activators as therapeutic agents from medicinal plants. A variety of commercially available ethanolic extracts were screened for Nrf2 activity using an Nrf2-luciferase reporter cell line (AREc32), and Valeriana officinalis (root), Cynara scolymus (leaves) and Salix alba (bark) were identified to be part of the most potent samples. Sequential extraction and bioassay-guided fractionation of these plants led to the isolation of compounds identified as Nrf2 activators. NMR and LC/HRMS analysis confirmed the structures. As GST is among the Nrf2 upregulated genes, changes in GST activity upon incubation with the isolated Nrf2 activators were determined in a HepG2 cell line resulted in an increased GST activity. These compounds augmented the intracellular glutathione (GSH) and cysteinylglycine (CysGly) levels by promoting the nuclear translocation of Nrf2 that was determined by the HPLC fluorescence detection method. This thesis describes the screening of ethanolic extracts of 91 medicinal herbal samples from Integria Health care, Ballina, NSW, Australia. This study led to the isolation of 8 pure compounds that are known, but the Nrf2-ARE related pharmacological activity is reported first time with the sequential extraction of these plants. Natural products undoubtedly fulfill irreplaceable drug discovery roles and are an invaluable source for drug candidates and leads. The Nrf2-activity of these compounds has demonstrated their potential as a therapeutic agent against oxidative stress-related diseases (e.g., COPD, diabetes, cardiovascular diseases). These Nrf2 activators have been shown to activate the Nrf2-ARE pathway and its regulated genes and enzymes to protect the cells from oxidative damage. Future directions call for a further biological evaluation to illustrate the detailed mechanisms by which these Nrf2 active compounds activate the Nrf2-ARE pathway and a sufficient pharmacological investigation in vivo to confirm the prevention of oxidative stress-induced diseases