A Review of the Potential of Nuclear Factor [Erythroid-Derived 2]-like 2 Activation in Autoimmune Diseases.

An autoimmune disease is the consequence of the immune system attacking healthy cells, tissues, and organs by mistake instead of protecting them. Inflammation and oxidative stress (OS) are well-recognized processes occurring in association with acute or chronic impairment of cell homeostasis. The transcription factor Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is of major importance as the defense instrument against OS and alters anti-inflammatory activities related to different pathological states. Researchers have described Nrf2 as a significant regulator of innate immunity. Growing indications suggest that the Nrf2 signaling pathway is deregulated in numerous diseases, including autoimmune disorders. The advantageous outcome of the pharmacological activation of Nrf2 is an essential part of Nrf2-based chemoprevention and intervention in other chronic illnesses, such as neurodegeneration, cardiovascular disease, autoimmune diseases, and chronic kidney and liver disease. Nevertheless, a growing number of investigations have indicated that Nrf2 is already elevated in specific cancer and disease steps, suggesting that the pharmacological agents developed to mitigate the potentially destructive or transformative results associated with the protracted activation of Nrf2 should also be evaluated. The activators of Nrf2 have revealed an improvement in the progress of OS-associated diseases, resulting in immunoregulatory and anti-inflammatory activities; by contrast, the depletion of Nrf2 worsens disease progression. These data strengthen the growing attention to the biological properties of Nrf2 and its possible healing power on diseases. The evidence supporting a correlation between Nrf2 signaling and the most common autoimmune diseases is reviewed here. We focus on the aspects related to the possible effect of Nrf2 activation in ameliorating pathologic conditions based on the role of this regulator of antioxidant genes in the control of inflammation and OS, which are processes related to the progression of autoimmune diseases. Finally, the possibility of Nrf2 activation as a new drug development strategy to target pathogenesis is proposed.

Short overview on the relevance of microRNA-reactive oxygen species (ROS) interactions and lipid peroxidation for modulation of oxidative stress-mediated signalling pathways in cancer treatment.

OBJECTIVES: Modulation of oxidative stress-mediated signalling pathways is constantly getting more attention as a valuable therapeutic strategy in cancer treatment. Although complexity of redox signalling pathways might represent a major hurdle, the development of advanced -omics technologies allow thorough studies on cancer-specific biology, which is essential to elucidate the impact of these signalling pathways in cancer cells. The scope of our review is to provide updated information about recent developments in cancer treatment. KEY FINDINGS: In recent years identifying oxidative stress-mediated signalling pathways is a major goal of cancer research assuming it may provide novel therapeutic approaches through the development of agents that may have better tissue penetration and therefore affect specific redox signalling pathways. In this review, we discuss some recent studies focussed on the modulation of oxidative stress-related signalling pathways as a novel anti-cancer treatment, with a particular emphasis on the induction of lipid peroxidation. CONCLUSIONS: Characterization and modulation of oxidative stress-mediated signalling pathways and lipid peroxidation products will continue to foster novel interest and further investigations, which may pave the way for more effective, selective, and personalized integrative biomedicine treatment strategies.

Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer.

Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the world. Thus, there is an urgent need for novel therapies targeting major cancer-related pathways. Nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative modulator Kelch-like ECH-associated protein 1 (KEAP1) are main players of the cellular defense mechanisms against internal and external cell stressors. However, NRF2/KEAP1 signaling pathway is dysregulated in various cancers, thus promoting tumor cell survival and metastasis. In the present review, we discuss the mechanisms of normal and deregulated NRF2 signaling pathway focusing on its cancer-related functions. We further explore activators and inhibitors of this pathway as cancer targeting drug candidates in order to provide an extensive background on the subject.

New indole-7-aldehyde derivatives as melatonin analogues; synthesis and screening their antioxidant and anticancer potential.

Over the last decade, there has been substantial interest in the use of melatonin (MLT) and MLT-like compounds in the treatment of several diseases. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. Our ongoing study relies on changing the groups in the different modifiable sites of the indole ring to increase the antioxidant activity. In this study a new approach for substitution of indole ring as indole based MLT analogue was proposed. We report the synthesis and characterization of a series of new indole-7-aldehyde hydrazide/hydrazone derivatives as indole-based MLT analogues. Anticancer potential of the compounds were evaluated both by their antioxidant and CYP1 inhibitory activities. In vitro antioxidant capacity of the compounds was investigated both in a cell-based (DCFH assay) and a cell-free (DPPH assay) assay. Potential inhibitory effects of the compounds on CYP1 catalytic activity were investigated via EROD assay. Cytotoxic activity of the compounds was further evaluated by the MTT assay in CHO-K1 cells. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any cytotoxic effect. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant agents.

The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives.

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review.

Potential Applications of NRF2 Modulators in Cancer Therapy.

The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

Bioisosteric modification on melatonin: synthesis of new naphthalene derivatives, in vitro antioxidant activity and cytotoxicity studies

Melatonin (MLT) is a strong free radical scavenger that protects the body from the deleterious effects of excess oxidants. Synthesis of MLT analogue compounds with antioxidant potency has recently attracted the interest of researchers. In general, the strategy consists of modifying the groups in the different sites of the indole ring or replacing the indole ring with an analogue. As part of our ongoing research, the antioxidant capacity and cytotoxicity of newly synthesized MLT analogue naphthalene derivatives were evaluated. The radical scavenging activity was tested by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Most of the synthesized compounds showed significant antioxidant activity in comparison to MLT. The structure-activity relationship was identified. The in vitro cytotoxic effects of the synthesized compounds were also investigated in CHO-K1 cells using the MTT assay.

Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs.

Oxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed.

Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity studies.

A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use. In the present study aromatase inhibiting potential of 2-methyl indole hydrazones are investigated, and compared with melatonin, by two in vitro models; a cell-free assay using a fluorescence substrate and a cell-based assay where cell proliferation was determined in ER + human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone. Aromatase inhibitory effect is also explored by molecular modelling studies. In biological activity assays monochloro substituted indole hydrazones were found to have stronger aromatase inhibitory activity among all tested derivatives and were more active than melatonin. This finding is further confirmed by molecular modelling. These results may be useful in the design and synthesis of novel melatonin analogues with higher inhibitory potency against aromatase.

The Role of Oxidative Stress Modulators in Breast Cancer.

BACKGROUND: Latest data from International Agency for Cancer Research shows that breast cancer is the leading cancer site in women and is the leading cause of death among female cancers. Induction of reactive oxygen species (ROS) and oxidative stress as a consequence of impaired balance between prooxidants and antioxidants are suggested to be involved in induction and progression of breast cancer. Cancer cells are found to exhibit higher levels of ROS compared to normal cells. However increased antioxidant defence which balances the oxidative status within the cancer cells suggests that high ROS levels may prevent tumorigenesis via various mechanisms. These contradictory roles of ROS and oxidative stress in breast cancer let scientists investigate potential oxidative stress modulators as anticancer strategies. CONCLUSIONS: In the present review we address the mechanisms of ROS production in breast cancer cells, the role of impaired oxidative status as well as the benefits of introducing oxidative stress modulators in therapeutic strategies in breast cancer. This review is focusing more on melatonin which we have been working on during the last decade. Our data, in accordance with the literature, suggest an important role for melatonin in breast cancer prevention and adjuvant therapy.

Novel indole-based melatonin analogues: Evaluation of antioxidant activity and protective effect against amyloid ß-induced damage.

Oxidative stress has been recognized as a contributing factor in ageing and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid ß-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid ß was tested. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any membrane-damaging effect. Moreover, derivatives having o-halogenated and dihalogenated aromatic side chain significantly protected neuronal cells at concentrations of 10 and 100 µM. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant and neuroprotective agents.

Novel indole-based melatonin analogues substituted with triazole, thiadiazole and carbothioamides: studies on their antioxidant, chemopreventive and cytotoxic activities.

Melatonin (MLT) is a well-known free-radical scavenger, involving in the prevention of cellular damage that can lead to cancer, ageing and a variety of neurodegenerative diseases. Research on MLT-related compounds has been required to optimise the maximum pharmaceutical activity with the lowest side effects. In our ongoing research, we have synthesized new indole-based MLT analogues as potential antioxidant agents by modifying the MLT molecule. In this study, we build on previous findings, through the synthesis, characterization and in vitro antioxidant profiling of a series of new indole-based MLT analogues which possess triazole, thiadiazole and carbothioamides on the third position on the indole ring. In vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe and their radical scavenging activity was assessed via the DPPH assay. In addition, in vitro cytotoxic effects of newly synthesized compounds were investigated in CHO-K1 cells using the MTT assay.

Antioxidant properties of melatonin and its potential action in diseases.

In recent years, relationship between free radicals and oxidative stress with aging, cancer, atherosclerosis, neurodegenerative disorders, diabetes, and inflammatory diseases became increasingly clear. Confirming the role of oxidants in numerous pathological conditions such as cancer, the antioxidants developed as therapeutics have been proven ineffective. It is well established that melatonin (MLT) and its metabolites are able to function as endogenous free-radical scavengers and broadspectrum antioxidants. Numerous studies also proved the role of MLT and its derivatives in many physiological processes and therapeutic functions, such as the regulation of circadian rhythm and immune functions. The aim of this review is to arouse attention to MLT as a potentially valuable agent in the prevention and/or treatment of some diseases.

Melatonin, its metabolites and its synthetic analogs as multi-faceted compounds: antioxidant, prooxidant and inhibitor of bioactivation reactions.

It is known that melatonin (MLT) and some of its metabolites act as antioxidants by scavenging free radicals as well as increasing the activity of antioxidant enzymes in the body. MLT is suggested to exert beneficial effects via various mechanisms in the treatment of many diseases, such as cancer, neurodegenerative diseases, epilepsy, diabetes mellitus and obesity. People working in nightshift exhibit decreased MLT levels that are suggested to be related with increased risk of hormone-related diseases. Similarly blind people were found to have increased MLT levels protecting against many diseases. This review briefly summarizes the published reports supporting these beneficial effects of MLT. Furthermore the present review involves recent developments related to the antioxidant effect of remarkable and multi-faceted molecule MLT as well as its metabolites and its synthesized analogues. The role of MLT as an inhibitor of bioactivation reactions is also discussed.

Oxidative stress in carcinogenesis: new synthetic compounds with dual effects upon free radicals and cancer.

DNA mutation is a very important step in carcinogenesis and elevated levels of oxidative DNA damage have been monitored in a variety of tumors. The discovery of the role of free radicals in cancer has led to a new medical approach. Minimizing oxidative damage may be a significant advance in the prevention or treatment of these diseases, since antioxidants are able to stop the free-radical formation and prevent oxidizing chain reactions. These findings have generated great interest in therapeutic antioxidant-based cancer drug development. The design and development of synthetic compounds, able to scavenge free radicals, could present a significant therapeutic advance, in particular for treating pathological conditions such as cancer. This article will outline the state of the research on the relationship between antioxidant therapy and cancer, describing the new synthetic antioxidant molecules that have anticancer activities. Investigations and association between dietary antioxidants, oxidative stress, and cancer will be also discussed.

Synthesis and antioxidant properties of substituted 2-phenyl-1H-indoles.

In this study, we report the design, synthesis and antioxidant activity of a series of substituted 2-(4-aminophenyl)-1H-indoles and 2-(methoxyphenyl)-1H-indoles. The new compounds are structurally related to the known indole-based antioxidant lead compound melatonin (MLT), and the antitumour 2-(4-aminophenyl)benzothiazole and 2-(3,4-dimethoxyphenyl)benzothiazole series. Efficient access to the target 2-phenylindoles was achieved via Fischer indole synthesis between substituted phenylhydrazines and acetophenones. 2-(4-Aminophenyl)indoles (such as the 6-fluoro analogue 3b) in particular showed potent antioxidant activity in the DPPH and superoxide radical scavenging assays (80% and 81% inhibition at 1mM concentration of 3b, respectively), at a level comparable with the reference standard MLT (98% and 75% at 1 mM).

Melatonin and synthetic analogs as antioxidants.

Recent studies suggest that overproduction of reactive oxygen and nitrogen species (ROS/RNS), lowered antioxidant defense of the body. Oxidative stress is damaging to DNA, lipids, proteins and many more vital macromolecules. Consequences of oxidative stress thought to contribute to the development of a wide range of diseases including Alzheimer's disease, Parkinson's disease, diabetes, rheumatoid arthritis, neurodegeneration in motor neuron diseases and many cancer types. Melatonin (MLT) is a powerful antioxidant with a particular role in the protection of nuclear and mitochondrial DNA. To find an improved antioxidant activity, developments of novel synthetic analogues are under investigation. These studies may offer a new progress and approach in antioxidant drug development as well as antioxidant chemistry. Therefore, we have been synthesizing novel MLT derivatives and investigating their antioxidant capacities. This review gives a brief knowledge about the MLT based analogue indole derivatives as potential antioxidants.

Osteopoikilosis associated with fibromyalgia and active myofascial trigger point in upper trapezius muscles.

Osteopoikilosis is a sclerosing bone dysplasia, characterized by multiple oval spots of radiodensities within the trabecular bone. It occurs equally common among men and women. Prevalence is estimated to be as high as 1:50,000. Most reported cases have been found incidentally on roentgenograms taken for other purposes. We present a 58-year-old woman with OPK associated with fibromyalgia and active myofascial trigger point in upper trapezius muscles.

Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: discussion on possible antioxidant mechanisms and comparison with melatonin.

Oxidative stress has been implicated in the development of many neurodegenerative diseases and also responsible from aging and some cancer types. Indolic compounds are a broad family of substances present in microorganisms, plants and animals. They are mainly related to tryptophan metabolism, and present particular properties that depend on their respective chemical structures. Due to free radical scavenger and antioxidant properties of indolic derivatives such as indolinic nitroxides and melatonin, a series of 2-phenyl indole derivatives were prepared and their in vitro effects on rat liver lipid peroxidation levels, superoxide formation and DPPH stable radical scavenging activities were determined against melatonin, BHT and alpha-tocopherol. The compounds significantly inhibited (72-98%) lipid peroxidation at 10(-3) M. These values were similar to that observed with BHT (88%). Possible structure-activity relationships of the compounds were discussed.