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Background: Microglia are associated with neuroinflammation, which play a key role in the pathogenesis of neurodegenerative diseases. It has been reported that some quinazolines and quinazolinones possess anti-inflammatory properties. However, the pharmacological properties of certain quinazoline derivatives are still unknown., Objective: The antioxidant, cytotoxic, and protective effects of a series of synthesized 2- trifluoromethylquinazolines (2, 4, and 5) and quinazolinones (6-8) in lipopolysaccharide (LPS)- murine microglia (BV2) and hydrogen peroxide (H 2 O 2 )-mouse neuroblastoma-2a (N2a) cells were investigated., Method: The antioxidant activity of synthesized compounds was evaluated with ABTS and DPPH assays. The cytotoxic activities were determined by MTS assay in BV2 and N2a cells. The production of nitric oxide (NO) in LPS-induced BV2 microglia cells was quantified., Results: The highest ABTS and DPPH scavenging activities were observed for compound 8 with 87.7% of ABTS scavenge percentage and 54.2% DPPH inhibition. All compounds were noncytotoxic in BV2 and N2a cells at 5 and 50 μg/mL. The compounds which showed the highest protective effects in LPS-induced BV2 and H 2 O 2 -induced N2a cells were 5 and 7. All tested compounds, except 4, also reduced NO production at concentrations of 50 μg/mL. The quinazolinone series 6-8 exhibited the highest percentage of NO reduction, ranging from 38 to 60%. Compounds 5 and 8 possess balanced antioxidant and protective properties against LPS- and H 2 O 2 -induced cell death, thus showing great potential to be developed into anti-inflammatory and neuroprotective agents., Conclusion: Compounds 5 and 7 were able to protect the BV2 and N2a cells against LPS and H 2 O 2 toxicity, respectively, at a low concentration (5 μg/mL). Compounds 6-8 showed potent reduction of NO production in BV2 cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Obesity is a major health concern for a growing fraction of the population, as its prevalence and related metabolic disorders are not fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue leads to the pathogenesis of obesity- related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. On the whole, the collected data suggest that there are both natural and synthetic compounds that show beneficial and promising activity as PPAR agonists in chronic diseases related to obesity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: A convenient approach to modulation of the inflammation has an influence on the production of inflammatory mediators - icosanoids, generated in arachidonic acid (AA) metabolism. The common therapeutic activity of non-steroidal anti-inflammatory drugs (NSAID), such as aspirin, includes inhibition of two crucial enzymes of AA metabolism - cyclooxygenase- 1 and -2 (COX-1/2), with certain risk for gastrointestinal and renal intolerance. Ever since the enrolment of COX-2, particularly overabundance of its main products prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in numerous pathological processes was recognized, it became a significant therapeutic target., Objective: The aim of this study was to examine the effects of synthesized organo-fluorine compounds on PGE2 and TXA2 production in the inflammation process., Methods: Trifluoromethyl compounds were synthesized from N-benzyl trifluoromethyl aldimine, commercially available 2-methyl or 2-phenyl α-bromo esters (β-lactams trans-1 and trans-2 and trifluoromethyl β-amino ester, respectively) and methyl 2-isocyanoacetate (2-imidazoline trans-4). The reactions proceeded with high geometric selectivity, furnishing the desired products in good yields. The influence of newly synthesized compounds on PGE2 and TXA2 production in human leukemic U937 macrophages on both enzyme activity and gene expression levels was observed., Results: Among the tested trifluoromethyl compounds, methyl trans-1-benzyl-5-(trifluoromethyl)- 4,5-dihydro-1H-imidazole-4-carboxylate (trans-4) can be distinguished as the most powerful antiinflammatory agent, probably due to its trifluoromethyl-imidazoline moiety., Conclusion: Some further structural modifications in tested compounds and particularly in the synthesis of different trifluoromethyl imidazolines could contribute to the development of new COX-2 inhibitors and potent anti-inflammatory agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) is a unique enzyme that, besides its main function in glycolysis (catalysis of glyceraldehyde-3-phosphate oxidation), possesses a number of non-glycolytic activities. The present review summarizes information on the role of oxidative stress in the regulation of the enzymatic activity as well as non-glycolytic functions of GAPDH., Methods: Based on the analysis of literature data and the results obtained in our research group, mechanisms of the regulation of GAPDH functions through the oxidation of the sulfhydryl groups in the active site of the enzyme have been suggested., Results: Mechanism of GAPDH oxidation includes consecutive oxidation of the catalytic Cysteine (Cys150) into sulfenic, sulfinic, and sulfonic acid derivatives, resulting in the complete inactivation of the enzyme. The cysteine sulfenic acid reacts with reduced glutathione (GSH) to form a mixed disulfide (S-glutathionylated GAPDH) that further reacts with Cys154 yielding the disulfide bond in the active site of the enzyme. In contrast to the sulfinic and sulfonic acids, the mixed disulfide and the intramolecular disulfide bond are reversible oxidation products that can be reduced in the presence of GSH or thioredoxin., Conclusion: Oxidation of sulfhydryl groups in the active site of GAPDH is unavoidable due to the enhanced reactivity of Cys150. The irreversible oxidation of Cys150 is prevented by Sglutathionylation and disulfide bonding with Cys154. The oxidation/reduction of the sulfhydryl groups in the active site of GAPDH can be used for regulation of glycolysis and numerous side activities of this enzyme including the induction of apoptosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug- Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein- Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with a suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Currently, used oral antiplatelet drugs are both limited and associated with the risk of treatment failure/resistance. Research in this area is hence highly desired. A series of xanthene-3-ones derivatives, we had synthesized, showed us that these derivatives had antiplatelet activity. As far as we know, no research on the effects of xanthen-3-ones in this area has been done., Objective: The aim was to study the antiplatelet potential of a series of synthesised 9-phenylxanthene- 3-ones and to find the ideal structural feature(s) for antiplatelet potential and determine the mechanism of action., Methods: The compounds were synthesized from 1,2,4-triacetoxybenzene and various benzaldehydes. The reaction proceeded smoothly under acidic alcoholic conditions, furnishing the desired products in good yields. The compounds were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action., Results: Initial screening showed that a majority of the synthesized derivatives had substantial antiplatelet potential. None of the compounds were able to block cyclooxygenase 1 or thromboxane synthase. The mechanism appeared to be based on antagonism of thromboxane effects. The most potent compound 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one had better potential to block collagen induced platelet aggregation than clinically used acetylsalicylic acid., Conclusion: The last mentioned derivative is promising for further in vivo testing., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: It is known that an increased oxidative stress is present in a wide range of diseases and, given the vulnerability of the central nervous system, its involvement has been in particular investigated in neurological and psychiatric diseases, including anxiety disorders., Objective: In this review, we analyse the studies that have been conducted on the effects of oxidative stress modulators in anxiety, focusing on their possible clinical use., Discussion and Conclusion: While preclinical studies have shown a clear anxiolytic-like effect of different oxidative stress modulators, less significant results have been obtained from clinical studies. After having reviewed the possible reasons for the discrepancy between preclinical and clinical data, we encourage further studies aimed at better investigating the utility of the modulation of oxidative stress in humans, as an adjunctive therapy of the traditional integrated psychotherapeutic and pharmacological approach., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oxidative stress is a pathological feature common to a multitude of neurological diseases. The production of reactive oxygen species (ROS) is the main mechanism underlying this cellular redox imbalance. Antioxidants protect biological targets against ROS, therefore, they have been considered as attractive potential therapeutic agents to counteract ROS-mediated neuronal damage. However, despite encouraging in vitro and preclinical in vivo data, the clinical efficacy of antioxidant treatment strategies is marginal and most clinical trials using antioxidants as therapeutic agents in neurodegenerative diseases have yielded disappointing outcomes. This might in part be due to the need of adjustment in concentrations and time parameters between preclinical studies and clinical settings. Moreover new efficient delivery methods need to be investigated, particularly taking into account that a successful therapeutic agent for neurological diseases should readily cross the blood-brain barrier (BBB). In that sense, the use of compounds that cross the BBB and boost the endogenous antioxidant defense machinery, by activating for instance the Nrf2 pathway, or compounds that are able to modulate ROS production, such as NOX enzyme inhibitors, seems to represent a more promising approach to combat oxidative stress in the central nervous system (CNS). Here we present a brief overview of the main players in oxidative stress and outline evidences of their involvement in Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis. Finally, we review and critically discuss the potential of antioxidants as therapeutics for central nervous system disorders with a special focus on emerging novel therapeutic strategies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The potential role of polyphenolic acetate (PA) in causing diverse biological and pharmacological actions has been well studied in our laboratory. Our investigations, for the first time, established the role of calreticulin transacetylase (CRTAase) in catalyzing the acetylation of nitric oxide synthase (NOS) by Pas leading to robust activation of NOS. 7, 8- Diacetoxy-4-methylcoumarin (DAMC) and other acetoxycoumarins augmented the expression of thioredoxin (TRX) and vascular endothelial growth factor (VEGF) in human peripheral blood mononuclear cells (PBMCs). These findings substantiated our earlier observations that DAMC was a superb inducer of angiogenesis. The enhanced expression of thioredoxin reductase (TRXR) and diminished expression of thioredoxin interacting protein (TRXIP) leading to increased expression and activity of TRX in PBMCs due to the action of DAMC was revealed by real time RT-PCR analysis. The possible activation of TRX due to acetylation was confirmed by the fact that TRX activity of PBMCs was enhanced by various acetoxycoumarins in tune with their affinities to CRTAase as substrates. DAMC caused enhanced production of NO by way of acetylation of NOS as mentioned above and thereby acted as an inducer of VEGF. Real time RT-PCR and VEGF ELISA results also revealed the overexpression of TRX. DAMC and other PAs were found to reduce the oxidative stress in cells as proved by significant reduction of intracellular ROS levels. Thus, the crucial role of TRX in DAMC-induced angiogenesis with the involvement of VEGF was established.

Neurodegeneration is the hallmark of many chronic progressive neurogical disorders characterized by specific clinical, morphological and biochemical features. Central nervous system is very sensitive to oxidative stress, which is considered as a key factor of neurodegenerative disorders. Therefore, many therapeutical strategies are focused on molecules with redox activity to re-establish the equilibrium between pro and antioxidants. Due to the fact that melatonin readily crosses the blood- brain-barrier, concomitant with its safety profile at the highest dosages makes this dietary supplement very useful in possible clinical application in neurodegeneration. Melatonin is currently marketed in several countries as a dietary supplement with no prescription. Clinical trials have shown different effectiveness of melatonin supplementation in several disorders, including neurodegenerative disorders. Melatonin has unique biochemical properties such as scavenging of hydroxyl, carbonate, alkoxyl, peroxyl and aryl cation radicals and stimulation of activities main antioxidative enzymes (glutathione peroxidase, superoxide dismutase etc.). Moreover, it can suppress nitric oxide synthase. The present paper highlighted the potential clinical role of melatonin in main neurodegenerative diseases including Alzheimer disease, Parkinson disease, amylotrophic lateral sclerosis and multiple sclerosis. Moreover, in this review the main molecular aspects of melatonin in brain cell protection and survival mechanisms were discussed. Therefore, melatonin is regarded as a potential therapeutical agent in clinical application in neurodegenerative disorders, but this findings needs to be confirmed by the larger, more well-designed clinical trials.

The development of inflammatory immune response is related to an activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The intracellular molecules from this pathway are sensitive to the alterations in the microenvironment. The changes in cellular redox state, proliferation, gene expression pattern and genomic stability during inflammation induce the activation of non-canonical and atypical NK-κB signaling increasing the crosstalk with molecules involved in neddylation, cell cycle checkpoints regulation and DNA repair. This review article describes the reactive oxygen species (ROS)-sensitive kinases from the NF-κB pathway and presents the effects of their suppression by small kinase inhibitors. It illustrates that selective targeting of the redox sensor molecules from the inflammatory NK- κB cascades can influence cell survival and metabolism as well. We think that this issue is important when evaluating the drug efficacy in clinical studies and their side effects.

Cardiovascular diseases (CVDs) are the major health concern and the leading cause of death. Imbalance between free radicals and anti-oxidant defence is associated with cellular dysfunctions leading to the pathophysiology of various diseases including cardiac and vascular diseases. The stress responsive transcription factor NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) regulates the expression of many detoxifying genes. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important regulator of vascular function. Involvement of NO in modulating Nrf2 signaling is well established. Thus, it is apparent that increasing NO bioavailability and antioxidant status in vascular and myocardial tissue can be considered as a potential strategy to prevent the onset of vascular dysfunction and CVDs and is therefore of therapeutical interest. Based on the marked protective effect of Nrf2/ARE signalling and intriguing links between antioxidant mechanism and endothelial derived NO, the aim of the present review is to compile conclusive evidence for the involvement of NO-Nrf2/ARE axis in the regulation of cardiovascular function. This review also discusses on improving eNOS and Nrf2 signalling by Nrf2 activators which holds promise for countering cardiac and vascular disorders.

Neurodegeneration is the hallmark of many chronic progressive neurogical disorders characterized by specific clinical, morphological and biochemical features. Central nervous system is very sensitive to oxidative stress, which is considered as a key factor of neurodegenerative disorders. Therefore, many therapeutical strategies are focused on molecules with redox activity to re-establish the equilibrium between pro and antioxidants. Due to the fact that melatonin readily crosses the blood- brain-barrier, concomitant with its safety profile at the highest dosages makes this dietary supplement very useful in possible clinical application in neurodegeneration. Melatonin is currently marketed in several countries as a dietary supplement with no prescription. Clinical trials have shown different effectiveness of melatonin supplementation in several disorders, including neurodegenerative disorders. Melatonin has unique biochemical properties such as scavenging of hydroxyl, carbonate, alkoxyl, peroxyl and aryl cation radicals and stimulation of activities main antioxidative enzymes (glutathione peroxidase, superoxide dismutase etc.). Moreover, it can suppress nitric oxide synthase. The present paper highlighted the potential clinical role of melatonin in main neurodegenerative diseases including Alzheimer disease, Parkinson disease, amylotrophic lateral sclerosis and multiple sclerosis. Moreover, in this review the main molecular aspects of melatonin in brain cell protection and survival mechanisms were discussed. Therefore, melatonin is regarded as a potential therapeutical agent in clinical application in neurodegenerative disorders, but this findings needs to be confirmed by the larger, more well-designed clinical trials.

The potential role of polyphenolic acetate (PA) in causing diverse biological and pharmacological actions has been well studied in our laboratory. Our investigations, for the first time, established the role of calreticulin transacetylase (CRTAase) in catalyzing the acetylation of nitric oxide synthase (NOS) by Pas leading to robust activation of NOS. 7, 8-Diacetoxy-4-methylcoumarin (DAMC) and other acetoxycoumarins augmented the expression of thioredoxin (TRX) and vascular endothelial growth factor (VEGF) in human peripheral blood mononuclear cells (PBMCs). These findings substantiated our earlier observations that DAMC was a superb inducer of angiogenesis. The enhanced expression of thioredoxin reductase (TRXR) and diminished expression of thioredoxin interacting protein (TRXIP) leading to increased expression and activity of TRX in PBMCs due to the action of DAMC was revealed by real time RT-PCR analysis. The possible activation of TRX due to acetylation was confirmed by the fact that TRX activity of PBMCs was enhanced by variousacetoxycoumarins in tune with their affinities to CRTAase as substrates. DAMC caused enhanced production of NO by way of acetylation of NOS as mentioned above and thereby acted as an inducer of VEGF. Real time RT-PCR and VEGF ELISA results also revealed the overexpression of TRX. DAMC and other PAs were found to reduce the oxidative stress in cells as proved by significant reduction of intracellular ROS levels. Thus, the crucial role of TRX in DAMC-induced angiogenesis with the involvement of VEGF was established.

Cardiovascular diseases, which are the leading cause of mortality in the Western World, are closely associated with atherosclerosis development. Atherosclerosis is a chronic multifactorial disease of the arterial wall characterized by endothelial dysfunction, inflammation and oxidative stress. Oxidative stress is an alteration of the balance between pro-oxidant and antioxidant mechanisms which promotes vascular complications and represents a valid therapeutic target to prevent or treat cardiovascular diseases. Statins are enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that have been included in the therapeutic regimen of cardiovascular diseases due to their lipid-lowering activity. Experimental and clinical data demonstrated that the antiatherogenic effects of these drugs are also related to other pleiotropic activities, particularly to their anti-inflammatory, anti-thrombotic and antioxidant effects. This review summarizes experimental and clinical studies demonstrating the impact of statins on atherosclerotic disease with a focus on the antioxidant activity of atorvastatin. Atorvastatin is a synthetic statin characterized by a high efficacy, in part due to its longer half-life compared to other molecules of the same group. It also exerts high antioxidant effects, independent from its hypolipidemic activity, beneficial for the prevention and therapy of atherosclerosis.

There are numerous reports on the role of oxidative stress in the origin of some neurodegenerative (Alzheimer's and Parkinson's) diseases; however, the information concerning molecular mechanisms of the observed effects is rather contradictory. This paper summarizes the review of our own works in this field and new experimental observations on the antioxidant action of some hydrophobic plant compounds. We discuss our hypothesis on the role of misfolded proteins in the regulation of the chaperone system involved in the genesis of amyloid neurodegenerative (prion and Alzheimer's) diseases, briefly describe the role of modification of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in the inhibition of glycolysis and induction of the apoptosis of nerve cells, and suggest possible ways of the use of hydrophobic plant antioxidants for the prevention of amyloid transformation of proteins and other neurodegenerative processes.

Lanthanides are group of rare-earth elements with growing applications both in the industry and healthcare. Their unique properties impose various possibilities for involvement in electron transfer reactions essential for the cellular survival and health on general. The intensified contact of people with lanthanides and the expanding medicinal applications of their compounds insist more profound knowledge on the involvement in biologically relevant electron transfer reactions. It is well known that the balance between formation and elimination of free radicals in a living body is essential for its health and survival. Any internal or environmental factor that alters this balance alters the homeostasis and this way altering the health status. In the present review, the possibilities of changing the balance between formation and elimination of free radicals, due to introduction of different lanthanides and their complexes with organic ligands, were explored, based on the available information in the literature. It was observed that lanthanides may act either as antioxidants or pro-oxidants, depending on the environment, the nature of the bonding in their compounds, and concentration in the tissues. The opportunities for their application in medicine were related with the abilities to control over their involvement in the overall oxidative status of the body.

Acetylation of proteins with the addition of an acetyl group on the lysine residue is one of the vital posttranslational modifications that regulate protein stability, function and intracellular compartmentalization. Like other posttranslational modifications, protein acetylation influences many if not all vital functions of the cell. Protein acetylation has been originally associated with histone acetylation regulated by Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) and was mainly considered to be involved in epigenetic regulation through chromatin remodelling. It is now widely referred to as lysine acetylation orchestrated by lysine acetyl transferase (KAT) and lysine deacetylase (KDAC) and influences many cellular functions. Protein acetylation fine tunes the redox balance and cell signalling in the context of cancer by exerting its control on expression of two very important redox sensors viz. Nrf2 and NF-κB. Accumulating evidences show that inhibitors of deacetylase (KDACi), responsible for cytotoxic effects in cancer cells, mediate their actions by inhibiting the deacetylases, thereby simulating an hyperacetylation state of histone as well as non-histone proteins, similar to the one created by KATs. Emergence of calreticulin (CRT) mediated protein acetylation system using polyphenolic acetates as donors coupled with over expression of CRT has opened new avenues for targeting protein acetylation for improving cancer therapy. Modifiers of protein acetylation are therefore, emerging as a class of anticancer therapeutics and adjuvant as they inhibit growth, induce differentiation and death (apoptosis) differentially in cancer cells and also exhibit chemo-radiation sensitizing potential. Although pre-clinical investigations with many natural and synthetic KDAC inhibitors have been very promising, their clinical utility has so far been limited to certain types of cancers of the hematopoietic system. The future of protein acetylation modifiers appears to depend on the development of newer engineered molecules and their rational combinations that can exploit the differences in the regulation of protein acetylation between tumor and normal cells/tissues.

Oxidative stress is linked with many pathologies ranging from cancer to neurodegenerative disorders and antioxidants have presumably therapeutic value in such diseases. In this review, we categorize different direct and indirect mechanisms by which antioxidants exert their action. These include scavenging and metal chelating effects, mimicking the antioxidant enzymes or upregulation of their expression, activation of nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the activity of sirtuins and inhibition of pro-oxidant enzymes among others. Recent findings on the most frequently investigated antioxidants including polyphenolics, thiolics, spin trapping agents, SOD mimetics, inducers of heme oxygenase-1 and nitric oxide synthase, activators of Nrf2, NADPH oxidase inhibitors and herbal supplements are summarized. Furthermore, the antioxidant effects of drugs that are clinically used for other pharmacological purposes including ACE inhibitors and statins are discussed. Cost-effectiveness and adverse effects of antioxidants are also evaluated. Since antioxidant therapy has failed in many instances, we have classified the reasons that may explain these shortcomings in different categories. Novel approaches to antioxidant therapy, that include mitochondria-targeting drugs, antioxidant gene therapy and approaches for improvement of cell uptake and alteration of subcellular compartment localization are also described. In the end, "shadows" that are shortcomings of antioxidant therapy as well as "lights" that include positive outcomes are addressed. It is concluded that if we learn from failures, invest on agents with higher potential and take advantage of novel emerging approaches, antioxidants could be an asset for the management of certain carefully chosen oxidative stress-related diseases.

Oxidative stress is implicated in the pathogenesis of different human diseases: Alzheimer, Parkinson, Huntington, amyotrophic lateral sclerosis (Lou Gehrig's disease), Down's syndrome, atherosclerosis, vascular disease, cancer, diabetes mellitus type 1 and type 2, age - related macular degeneration, psoriatic arthritis. The aim of current study is to summarize the scientific evidences for the antioxidant and neuroprotective activity of Galantamine and some of its derivatives. Galantamine is a scavenger of reactive oxygen species and causes neuroprotective effect by lowering the oxidative neuronal damage, through the following pathways: 1) prevention of the activation of P2X7 receptors; 2) protection of mitochondrial membrane potential; 3) pre - vention of the membrane fluidity disturbances. Another mechanism is the decreasing of the overproduction of reactive oxygen species, a result from the increasing of acetylcholine level due to: 1) acethylcholinesterase inhibition; 2) allosteric potentiation of α7 - subtype of nicotinic acetylcholine receptors. A close relationship between acethylcholinesterase inhibition and reduced oxidative injury is observed. Through allosteric potentiation of the α7 - subtype of nicotinic acetylcholine receptors, the drug leads to induction of phosphorylation of serine - threonine protein kinase, stimulates phosphoinositide 3 - kinase and elevates the expression of protective protein Bcl - 2. By activation of these important neuroprotective cascades, Galantamine exerts neuroprotection against a variety of cytotoxic agents (β- amyloid peptide, glutamate, hydrogen peroxide, oxygen and glucose deprivation). The new trend in therapy of Alzheimer's disease will be the investigation and application of compounds such as Galantamine derivatives, which possess acethylcholinesterase and γ- secretase inhibitory activity and antioxidant properties.

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by endothelial dysfunction, and in which innate and adaptive immune responses have a crucial role. Autoimmune reactions against several self molecules and modified self molecules have been identified in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients is the major event causing protein structural modifications, thus inducing the appearance of neo/cryptic epitopes. Following intraplaque haemorrhage large amounts of cell-free haemoglobin (Hb) accumulate within atheroma, due to its impaired clearance by the haptoglobin-CD163 scavenging system. The pro-oxidative intraplaque microenvironment may induce Hb structural changes, thus generating neo/cryptic autoantigenic epitopes and rendering the oxidized self molecule as a dangerous signal for both immune and endothelial cells. In this review, we will present the most relevant information on Hb as a candidate self antigen involved in the pathogenesis of atherosclerotic disease and on its ability to trigger signals that drive endothelial dysfunction and immune cell activation. On these grounds, we will also discuss how these new paradigms may lead to novel therapeutic targets for cardiovascular diseases.

The search for metal-derived antioxidants has received much attention and effort in order to identify the compounds having high capacity in scavenging free radicals related to various disorders and diseases associated with oxidative damage, caused by reactive oxygen species (ROS). Presently, synthetic antioxidants are widely used because they are effective and cheaper than natural antioxidants. Currently a number of Schiff-base metal complexes have been investigated as effective scavengers of ROS, acting as antioxidants. The aim of this review is to highlight specific characteristics of Schiff-based compounds capable of chelating metal ions and their antioxidant activity. Schiff bases form an important class of organic compounds with a wide variety of biological properties. Schiff bases have often been used as chelating ligands in the field of coordination chemistry, and their metal complexes have been of great interest to researchers for many years. The activity is usually increased by complexation therefore to understand the properties of both ligands and metal can lead to the synthesis of highly active compounds. The influence of certain metals on the biological activity of these compounds and their intrinsic chemical interest as multidentate ligands has prompted a considerable increase in the study of their coordination behavior. Development of a new chemotherapeutic Schiff bases and their metal complexes is now attracting the attention of medicinal chemists.

The distinct biochemical function of endoplasmic reticulum (ER) protein Calreticulin (CR) catalyzing the transfer of acyl group from acyloxycoumarin to a receptor protein was termed calreticulin transacylase (CRTAase). The present study, unlike the previous reports of others utilizing CR-deficient cells alone, dealt with the recombinant CR domains of Heamonchus contortus (rhCRTAase) in order to examine their CRTAase activity. P-domain of rhCR unlike N- and C-domains was found to be endowed with CRTAase function. We have also observed for the first time acetyl CoA, as a substrate for rhCRTAase/P-domain mediated acetylation of recombinant Schistosoma japonicum glutathione S-transferase (rGST). rhCRTAase/P-domain were also found to undergo autoacylation by acyloxycoumarins. Also, the isolated autoacylated rhCRTAase/P-domain in non-denatured form alone exhibited the ability to transfer acyl group to rGST indicating the stable intermediate nature of acylated CR. P-domain catalyzed acetylation of rGST by 7,8-Diacetoxy-4-methylcoumarin or acetyl CoA resulted in the modification of several lysine residues in common was evidenced by LC-MS/MS analysis. The putative site of the binding of acyloxycoumarins with CR was predicted by computational blind docking studies. The results showed the involvement of two lysine residues Lys-173 and Lys-174 present in P-domain for binding acyloxycoumarins and acetyl CoA thus highlighting that the active site for the CRTAase activity would reside in the P-domain of CR. Certain ER proteins are known to undergo acetylation under the physiological conditions involving acetyl CoA. These results demonstrating CRTAase mediated protein acetylation by acetyl CoA may hint at CR as the possible protein acetyltransferase of the ER lumen.

Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.

Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.