Discovery of Alpha-Tocopheryl Succinate as a Cancer Treatment Agent Led to the Development of Methods to Potentially Improve the Efficacy of Cancer Therapy.

The discovery of alpha-tocopheryl succinate (alpha-TS) as a cancer therapeutic agent markedly stimulated research with or without tumor therapeutic agents on cancer cells and normal cells. Results showed that alpha-TS treatment induced apoptosis in cancer cells and enhanced the apoptotic effects of tumor therapeutic agents on tumor cells in a synergistic manner without affecting the growth of normal cells. Liposomal alpha-TS was more effective than alpha-TS. Some tumors are difficult to treat with chemotherapeutic agents while some become resistant of such treatment. Using a nanotechnology technique, it was demonstrated that alpha-TS conjugated with a chemotherapeutic agent enhanced the levels of apoptosis and restored the sensitivity of tumor cells to that chemotherapeutic agent. The mechanisms of action of alpha-TS alone or in combination with therapeutic agents include the following: (a) inhibition of the expression of oncogenes C-myc and H-ras; (b) alterations in the levels of expression of numerous genes; (c) activation of caspases; (d) inhibition of angiogenesis; (e) destabilization of mitochondria and lysosomes; (f) inhibition of production of production of prostaglandin E2 (PGE2) and PGE2-mediated pro-inflammatory responses; (g) reduction of survivin signaling pathway; and (h) reduction of CD47 expression on the tumor cell surface causing enhancement of phagocytic activity of macrophages leading to engulfment of tumor cells. Despite impressive results in cell culture and in animal models, no studies with alpha-TS alone or in combination with cancer therapeutic agents in human cancer resistant to these therapies have been performed.

Alpha-TS inhibited the growth of cancer cells without affecting normal cells.Alpha-TS enhanced the effects of therapeutic agents on tumor cells but not on normal cells.Liposomal alpha-TS was more effective than alpha-TS.Using a nanotechnology technique, alpha-TS conjugated with a chemotherapeutic agent produced synergistic growth inhibition in cancer cells but not in normal cells.

A micronutrient mixture with collagen peptides, probiotics, cannabidiol, and diet may reduce aging, and development and progression of age-related alzheimer's disease, and improve its treatment.

Human aging involves gradual decline in organ functions leading to organ specific age-related chronic diseases such as Alzheimer's disease (AD). Although advances in the development of new drugs, novel surgical procedures, improved diet and lifestyle, have resulted in doubling of lifespan of humans, the quality of life in many cases remains poor because of increased incidence of age-related chronic diseases. Using experimental models of accelerated aging, several cellular defects associated with aging and AD have been identified. Some cellular defects due to increased oxidative stress, chronic inflammation, autophagy defects, mitochondrial dysfunction, and imbalances in the composition probiotics in favor of harmful bacteria over beneficial bacteria are common to both aging and AD, while others such as telomere attrition, loss of collagen, elastin, and hyaluronic acid, failure of DNA repair system, and impaired immune function are unique to aging; and some such as increased production of beta-amyloids, hyperphosphorylation of tau protein, and abnormal behaviors are unique to AD. It is suggested that supplementation with a micronutrient mixture, probiotics, collagen peptides, CBD, and modifications in the diet and lifestyle may reduce the aging processes, and the development, progression of AD, and improve the treatments of this disease.

Can a Micronutrient Mixture Delay the Onset and Progression of Symptoms of Single-Point Mutation Diseases?

Single-point mutation diseases in which substitution of one nucleotide with another in a gene occurs include familial Alzheimer's disease (fAD), familial Parkinson's disease (fPD), and familial Creutzfeldt-Jacob disease (fCJD) as well as Huntington's disease (HD), sickle cell anemia, and hemophilia. Inevitability of occurrence of these diseases is certain. However, the time of appearance of symptoms could be influenced by the diet, environment, and possibly other genetic factors. There are no effective approaches to delay the onset or progression of symptoms of these diseases. The fact that increased oxidative stress and inflammation significantly contribute to the initiation and progression of these point mutation diseases shows that antioxidants could be useful. The major objectives are (a) to present evidence that increased oxidative stress and chronic inflammation are associated with selected single-point mutation diseases, such as fAD, fPD, and fCJD, HD, sickle cell anemia, and hemophilia; (b) to describe limited studies on the role of individual antioxidants in experimental models of some of these diseases; and (c) to discuss a rationale for utilizing a comprehensive mixture of micronutrients, which may delay the development and progression of symptoms of above diseases by simultaneously reducing oxidative and inflammatory damages.Key teaching pointsSelected single-point mutation diseases and their pattern of inheritanceCharacteristics of each selected single-point mutation diseaseEvidence for increased oxidative stress and inflammation in each diseasePotential reasons for failure of single antioxidants in human studiesRationale for using a comprehensive mixture of micronutrients in delaying the onset and progression of single-point mutation diseases.

Electronic cigarette aerosol increases the risk of organ dysfunction by enhancing oxidative stress and inflammation.

An electronic cigarette is a rechargeable device that produces an inhaled aerosol containing varying levels of nicotine, and inorganic and organic toxicants and carcinogenic compounds. The aerosol is generated by heating a solution of propylene glycol and glycerin with nicotine and flavoring ingredients at a high temperature. The e-cigarette was developed and marketed as a safer alternative to the regular cigarette which is known to be injurious to human health. However, published studies suggest that the aerosol of e-cigarette can also have adverse health effects. The main objective of this review is to briefly describe some consequences of e-cigarette smoking, and to present data showing that the resulting increased oxidative stress and inflammation are likely to be involved in effecting to lung damage. Other organs are also likely to be affected. The aerosol contains varying amounts of organic and inorganic toxicants as well as carcinogens, which might serve as the source of such deleterious events. In addition, the aerosol also contains nicotine, which is known to be addictive. E-cigarette smoking releases these toxicants into the air leading to inhalation by nonsmokers in residential or work place areas. Unlike regular tobacco smoke, the long-term consequences of direct and secondhand exposure to e-cigarette aerosol have not been extensively studied but based on available data, e-cigarette aerosol should be considered harmful to human health.

Attenuation of acute and chronic inflammation using compounds derived from plants.

The appearance of excessive inflammatory activity is associated with onset of many disease states. Such non-productive responses are often the basis of the mortality consequent to incurring numerous disorders. The current outbreak of coronavirus disease 2019 caused by the virus "severe acute respiratory syndrome coronavirus 2" is a striking reflection of the inadequacy of current medical science to adequately address this issue. The usefulness of a range of materials of botanical origin in the attenuation of both chronic and acute inflammatory responses to various disease stressors is described. The properties of preparations of plant-based origin often parallel those of synthesized pharmacologics, but differ from them in some key respects. These differences can lead to more traditional preparations having distinct therapeutic advantages but also a number of specific shortcomings. The strengths and weaknesses of these materials are objectively contrasted with that of a more orthodox pharmacological approach. Each of these emphases in style has specific advantages and they should not be considered as competitors, but rather as accomplices in combating adverse states involving derangement of immune function.

Alternatives to Insulin for the Regulation of Blood Sugar Levels in Type 2 Diabetes.

This short overview focuses on the causation and treatment of type 2 diabetes (T2D). Emphasis is given to the historical basis of understanding this disease and the background leading to emergence of the central role of insulin. The strengths of insulin administration in the treatment of diabetes are profound, but these need to be balanced against several serious shortcomings of its extended use. Some alternative approaches to T2D management are considered. Insulin is no longer considered as the first choice for type 2 diabetes, and an expanding range of new therapeutic possibilities is emerging. While these may lack the potency of insulin, at a minimum, they allow a major reduction in the intensity of insulin use. In view of the rising worldwide incidence of this disease, it is imperative to develop safe and inexpensive means of limiting its potential for impairment of normal functioning.

Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?

Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the ß-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate the conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redoxsensitive metals Cu and Fe with PrPsc inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be an important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease.

Dietary Fibers and Their Fermented Short-Chain Fatty Acids in Prevention of Human Diseases.

Many studies show that daily consumption of high-fiber diet is associated with a reduced risk of developing kidney stones, inflammatory disease, colon cancer and other malignancies, obesity, type II diabetes, and cardiovascular disease. Dietary fibers are non-digestible polysaccharides that are composed of complex carbohydrates. Based on their relative solubility in water, dietary fibers can be divided into insoluble and soluble forms. An important property of insoluble fibers is their ability to bind with carcinogens, mutagens, and other toxic chemicals that are formed during digestion of food and eliminate them through the feces. Soluble fibers can often be degraded to short-chain fatty acids, such as butyrate, propionate, and acetate by microbial fermentation. This review discusses mechanisms of action of fibers and their beneficial effects on the GI tract as well as on other organs. Among short-chain fatty acids, butyrate has been most extensively studied and the effects of sodium butyrate on cell culture and animal models are discussed in order to emphasize its potential value in prevention of certain diseases.

MicroRNAs in Hearing Disorders: Their Regulation by Oxidative Stress, Inflammation and Antioxidants.

MicroRNAs (miRs) are small non-coding single-stranded RNAs that bind to their complimentary sequences in the 3'-untranslated regions (3'-UTRs) of the target mRNAs that prevent their translation into the corresponding proteins. Since miRs are strongly expressed in cells of inner ear and play a role in regulating their differentiation, survival and function, alterations in their expression may be involved in the pathogenesis of hearing disorders. Although increased oxidative stress and inflammation are involved in initiation and progression of hearing disorders, it is unknown whether the mechanisms of damage produced by these biochemical events on inner ear cells are mediated by altering the expression of miRs. In neurons and non-neuronal cells, reactive oxygen species (ROS) and pro-inflammatory cytokines mediate their damaging effects by altering the expression of miRs. Preliminary data indicate that a similar mechanism of damage on hair cells produced by oxidative stress may exist in this disease. Antioxidants protect against hearing disorders induced by ototoxic agents or adverse health conditions; however, it is unknown whether the protective effects of antioxidants in hearing disorders are mediated by changing the expression of miRs. Antioxidants protect mammalian cells against oxidative damage by changing the expression of miRs. Therefore, it is proposed that a similar mechanism of protection by antioxidants against stress may be found in hearing disorders. This review article discusses novel concepts: (a) alterations in the expression of miRs may be involved in the pathogenesis of hearing disorders; (b) presents evidence from neurons and glia cells to show that oxidative stress and pro-inflammatory cytokines mediate their damaging effects by altering the expression of miRs; and proposes that a similar mechanism of damage by these biochemical events may be found in hearing loss; and (c) present data to show that antioxidants protect mammalian cells against oxidative by altering the expression of miRs. A similar role of antioxidants in protecting against hearing disorders is put forward. New studies are proposed to fill the gaps in the areas listed above.

Telomere shortening during aging: Attenuation by antioxidants and anti-inflammatory agents.

Telomeres are a repeated sequence -of bases found at the ends of chromosomes. In humans, this sequence is TTAGGG, which is repeated over 2000 times. Telomeres protect the ends chromosomes from fusion with nearby chromosomes, and allow effective replication of DNA. Each time a cell divides, 25-200 base pairs are lost from the terminal sequence of chromosomes. By becoming truncated during cell division, telomeres protect essential genes from being shortened and thus inactivated. In addition, telomeres are sensitive to inflammation and oxidative stress, which can further promote telomere shortening. Reduction in the length of telomeres leads to the cessation of cell division and thus cellular senescence and apoptosis. This review discusses evidence for the role of oxidative stress and inflammation in regulating the length of telomeres in mammalian cells during senescence. Evidence is presented suggesting that antioxidants and anti-inflammatories can reduce the pace of shortening of telomere length during aging. The distinctive properties of transformed cells suggest that treatment with such materials will have a deleterious rather than a protective effect on such abnormal cells.

Oxidative Stress, Pro-Inflammatory Cytokines, and Antioxidants Regulate Expression Levels of MicroRNAs in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a slow progressive neurodegenerative disease associated with abnormal function of extrapyramidal system. Although several biochemical and genetic defects are identified, increased oxidative stress and chronic inflammation are one of the earliest events that initiate and promote PD. Oxidative stress also participates in impaired nonmotor symptoms. The levels of microRNAs that are evolutionarily conserved single-stranded noncoding RNAs of approximately 22 nucleotide in length may have a role in PD. METHOD: Published studies on changes in the levels of microRNAs in PD were critically reviewed, and the role of Reactive Oxygen Species (ROS), pro-inflammatory cytokines, and antioxidants in regulating the levels of microRNAs was evaluated. RESULTS: MicroRNAs levels were altered in PD. Downregulated microRNAs cause neurodegeneration by decreasing the levels of Nrf2 (nuclear transcriptional factor-2), mTOR (mammalian target of rapamycin), and DJ-1 and Parkin genes; and by increasing the levels of alpha-synuclein, RelA, Bim and Calpain-1, and A2AR (adenosine A2A receptor). Upregulated microRNAs cause degeneration of nerve cells by decreasing the levels of IGF-1 (Insulin Growth Factor-1), GRP78 (glucose regulated protein 78), DJ-1, and Hsc-70 (Heat- Shock Protein-70) that enhanced alpha-synuclein levels. ROS and pro-inflammatory cytokines cause neurodegeneration by altering the levels of microRNAs. Antioxidants that protect neurons by reducing oxidative stress and chronic inflammation altered the levels of microRNAs. CONCLUSION: Increased oxidative stress and chronic inflammation may cause neurodegeneration in PD by altering the levels of microRNAs and their target proteins. Antioxidants may provide neuroprotection by changing the levels of microRNAs and their target proteins.

Oxidative stress and pro-inflammatory cytokines may act as one of the signals for regulating microRNAs expression in Alzheimer's disease.

Oxidative stress and chronic inflammation are one of the earliest defects that initiate and promote Alzheimer's disease (AD). Studies showed that expressions of microRNAs were upregulated or downregulated in AD. Therefore, these biochemical defects may influence the levels of microRNAs. The up-regulated microRNAs cause neurodegeneration by: (a) decreasing the levels of a nuclear transcriptional factor-2 (Nrf2), (b) reducing the levels of α-secretase ADM10; and (c) reducing the levels of phosphatases. The down-regulated microRNAs cause neurodegeneration by: (a) increasing the levels of ß-secretase, (b) increasing the levels of tau kinase; (c) elevating the levels of tau proteins; (d) increasing the levels of APP; and (e) increasing the levels of nuclear factor-kappaB (NF-kB). Antioxidants protect neurons by reducing oxidative stress and chronic inflammation. Therefore, they may also influence the levels of microRNAs. This review briefly describes the studies on changes in the expressions of microRNAs in the pathogenesis of AD. It proposes a hypothesis that free radicals and pro-inflammatory cytokines act as one of the signals that upregulate or downregulate the levels of microRNAs by influencing their transcription, processing or stability leading to neurodegeneration in AD. Antioxidants that reduce oxidative stress and pro-inflammatory cytokines also regulate the levels of microRNAs.

Oxidative Damage and Inflammation Biomarkers: Strategy in Hearing Disorders.

IMPORTANCE: Excess free radical-induced oxidative stress and inflammatory processes are increasingly recognized as causative factors in hearing and balance disorders. Antioxidant micronutrients neutralize free radicals and, at adequate doses, reduce inflammation and demonstrate benefits in animal models and human trials. Therefore, it is reasonable to expect that biomarkers of oxidative damage and inflammation are appropriate correlative biological outcome parameters in clinical hearing intervention studies. OBJECTIVE: To provide the otology investigator a selected panel of biomarkers from the large universe of available tests that can be used as reasonable secondary endpoints in hearing and balance research. BACKGROUND SETTING: The tenets of antioxidant science dictate that there are a great variety of free radicals and that they impact different cellular targets. They also demonstrate varying functions in different cellular environments. In addition, oxidative stress and inflammation may cause direct injury to tissues, cell membrane lipids, proteins and mitochondrial, and nuclear DNA. To accommodate these many pathways, the useful categories of potential biomarkers become extensive. The degree of injury is also reflected by separate markers of inflammation and measures of antioxidant levels. Therefore, to provide a reliable indication of oxidative damage, inflammation and antioxidant level, it is necessary to determine a broad spectrum of lipid peroxidation markers, adducts of DNA, oxidation levels of proteins and pro-inflammatory cytokines. CONCLUSION: This report highlights some of the most clinically relevant and well-studied biomarkers in each category of tissue damage. It also includes those markers with which the authors have had direct positive clinical experience. The outcome from these studies is intended to provide a list of adjunctive measures that can be recommended as a relevant biomarker panel in hearing disorder clinical trials.

Simultaneous activation of Nrf2 and elevation of antioxidant compounds for reducing oxidative stress and chronic inflammation in human Alzheimer's disease.

Despite extensive research, neither the incidence nor the rate of progression of Alzheimer's disease (AD) has significantly changed. Some biochemical and genetic defects that initiate and promote AD include: (a) increased oxidative stress, (b) chronic inflammation (c) mitochondrial dysfunction, (d) Aß1-42 peptides generated from the amyloid precursor protein (APP), (e) proteasome inhibition, and (f) mutations in APP, presenilin-1 and presenilin-2 genes. Increased oxidative stress appears to precede other biochemical and genetic defects. Oxidative damage induces chronic inflammation. Therefore, reducing these defects simultaneously may reduce the development and progression of AD. Previous studies with individual antioxidants produced consistent benefits in animal models of AD; however, a similar approach produced inconsistent results in human AD. This review proposes a hypothesis that simultaneous elevation of the levels of antioxidant enzymes and antioxidant compounds is necessary for optimally reducing oxidative stress and chronic inflammation in human AD. Supplementation can enhance the levels of antioxidant compounds; but elevation of antioxidant enzymes requires activation of Nrf2. This review discusses activation and regulation of Nrf2. The need for multi- antioxidants that can affect multi-targets has been proposed without specific recommendations. This review proposes a micronutrient mixture that would simultaneously enhance the levels of antioxidant enzymes and antioxidant compounds in human AD.

Simultaneous Activation of Nrf2 and Elevation of Dietary and Endogenous Antioxidant Chemicals for Cancer Prevention in Humans.

Despite extensive studies in cancer prevention, the incidence of cancer is increasing. We review studies that have identified several biochemical and genetic defects as well as potential carcinogens in the diet, environmental factors, and lifestyle-related habits. Two of the biochemical abnormalities increased oxidative stress and chronic inflammation, and chronic exposure to carcinogens and mutagens play a significant role in the initiation of multistage carcinogenesis. Therefore, attenuation of these biochemical defects may be useful in reducing the incidence of cancer. Activation of the transcriptional factor called nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which enhances the levels of antioxidant enzymes and phase-2-detoxifying enzymes by complex mechanisms, may be one of the ways to reduce oxidative stress and chronic inflammation. Antioxidant enzymes destroy free radicals by catalysis, whereas phase-2-detoxifying enzymes remove potential carcinogens by converting them to harmless compounds for elimination from the body. However, increasing the levels of antioxidant enzymes by activating Nrf2 may not be sufficient to decrease oxidative stress and chronic inflammation optimally, because antioxidant chemicals, which are decreased in a high oxidative environment, must also be elevated. This review discusses the regulation of activation of Nrf2 and proposes a hypothesis that an elevation of the levels of antioxidant enzymes and dietary and endogenous antioxidant chemicals simultaneously may reduce the incidence of cancer by decreasing oxidative stress and chronic inflammation. The levels of antioxidant chemicals can be increased by supplementation, but increasing the levels of antioxidant enzymes requires activation of Nrf2 by reactive oxygen species (ROS)-dependent and-independent mechanisms. Several phytochemicals and antioxidant chemicals that activate Nrf2 have been identified. This review also describes clinical studies on antioxidants in cancer prevention that have produced inconsistent results. It discusses the possible reasons for the inconsistent results and proposes criteria that should be included in the experimental designs of future clinical studies to obtain consistent results. KEY TEACHING POINTS: • Reducing oxidative stress and chronic inflammation optimally requires an elevation of the levels of antioxidant enzymes and phase-2-detoxifying enzymes as well as dietary and endogenous antioxidant chemicals. • How the levels of antioxidant enzymes and phase-2-detoxifying enzymes are regulated by a nuclear transcriptional factor Nrf2. • How the activation and transcription of Nrf2 is regulated. • Identification of antioxidants that activate Nrf2 by ROS-dependent and-independent mechanisms, those that destroy free radicals by scavenging, and those that exhibit both functions. • Possible reasons for the inconsistent results produced by the previous clinical studies on antioxidants in cancer prevention. • The criteria that should be included in the experimental designs of future clinical studies on antioxidants in cancer prevention in high-risk populations to obtain consistent results.

Inhibition of Early Biochemical Defects in Prodromal Huntington's Disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients.

Huntington's disease (HD) is a progressive fatal dominant hereditary neurodegenerative disease of the brain, which primarily affects the cortex and the striatum. The disorder is typified by an expansion of more than 35 repeats of the nucleotide triplet cytosine- adenine-guanosine (CAG) which codes for the amino acid glutamine in the huntingtin gene. Despite studies of several decades, there are no effective means to block or postpone the appearance of symptoms of HD. Analysis of these studies led us to propose that increased oxidative stress and chronic inflammation are earliest events in the pathogenesis of HD, and together with excessive glutamate release, participate in the progression of the disease. This review briefly describes evidence for the involvement of oxidative stress, chronic inflammation and glutamate in the pathogenesis of HD. It is proposed that attenuation of these biochemical abnormalities together, may delay the appearance of symptoms of HD. In order to achieve this goal, the simultaneous activation of the nuclear transcriptional factor-2/antioxidant response elements (Nrf2/ARE) pathway that would enhance the transcription of target genes coding for antioxidant enzymes and phase-2-detoxifying enzymes, and an elevation of the levels of antioxidant compounds by supplementation may be needed. Normal mechanisms of activation of Nrf2 requiring reactive oxygen species (ROS) may be impaired in HD, but certain antioxidant compounds can activate Nrf2 without ROS. Use of a combination of micronutrients that can activate the Nrf2/ARE pathway and enhance the levels of antioxidant compounds is suggested.

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI.

Post-traumatic stress disorder (PTSD) is a complex mental disorder with psychological and emotional components, caused by exposure to single or repeated extreme traumatic events found in war, terrorist attacks, natural or man-caused disasters, and by violent personal assaults and accidents. Mild traumatic brain injury (TBI) occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck as in contact sports, or when in close proximity to a blast pressure wave following detonation of explosives in the battlefield. Penetrating TBI occurs when an object penetrates the skull and damages the brain, and is caused by vehicle crashes, gunshot wound to the head, and exposure to solid fragments in the proximity of explosions, and other combat-related head injuries. Despite clinical studies and improved understanding of the mechanisms of cellular damage, prevention and treatment strategies for patients with PTSD and TBI remain unsatisfactory. To develop an improved plan for treating and impeding progression of PTSD and TBI, it is important to identify underlying biochemical changes that may play key role in the initiation and progression of these disorders. This review identifies three common biochemical events, namely oxidative stress, chronic inflammation and excitotoxicity that participate in the initiation and progression of these conditions. While these features are separately discussed, in many instances, they overlap. This review also addresses the goal of developing novel treatments and drug regimens, aimed at combating this triad of events common to, and underlying, injury to the brain.

Inhibition of early upstream events in prodromal Alzheimer's disease by use of targeted antioxidants.

A link between Alzheimer's disease (AD) and an excess presence of oxidant free radicals in the brain has frequently been reported. It is generally assumed that such oxidative stress and related cellular damage is caused by inflammatory changes in the brain and is consequent to amyloid deposition. This review makes the argument that elevated oxidative stress in AD is an early causal event in the initiation and advancement of this disease. Oxidative stress can be decreased by enhancing antioxidant enzymes through activation of the cytoplasmic transcriptional factor (Nrf2)/ARE (antioxidant response element) pathway, and by dietary and endogenous antioxidant chemicals. Reduction in the binding ability of Nrf2 to ARE lowers antioxidant enzyme levels. Decreased levels of Nrf2 and augmentation of oxidative stress in AD suggest that the ROS-dependent mechanism of activating the Nrf2/ARE pathway has become unresponsive. A combination of agents that can either activate the Nrf2-ARE pathway by ROS-independent mechanisms, or by acting directly as antioxidant chemicals, may be necessary to reduce oxidative stress in AD. Earlier shortcomings of using individual antioxidants may be due to consideration of antioxidants as pharmacological agents, ignoring the fact that individual antioxidants can be transmuted in the highly oxidant milieu that is present in AD. Interactions between various cellular compartments may require simultaneous examination of more than one agent. The clinical utility of such a more integrative method can reveal interactive effects such as those found in nutritional research and this can compensate for any mechanistic shortcomings of simultaneous testing of more than a single agent.

Evaluation of role of oxidative stress on aging in Caenorhabditis elegans: a brief review.

Recently the relationship between oxidative stress and aging has been brought into question. It has been suggested that while oxidative events may play a role in the progression of age-related pathologies, it is not relevant to aging processes not involving specific diseases associated with senescence. The evidence in support of this concept is largely based on studies with the roundworm, Caenorhabditis elegans (C. elegans) that has been extensively used as a model system to study aging. This commentary evaluates data derived from C. elegans and documents that the preponderance of evidence from this species supports the role of pro-oxidant events as being a significant contributor to normal aging. Possible reasons for some anomalous findings conflicting with this concept, are discussed.

Antioxidant micronutrient impact on hearing disorders: concept, rationale, and evidence.

PURPOSE: Although auditory disorders are complex conditions, device-related modalities dominate current treatment. However, dysfunction from the central cortex to the inner ear apparatus is increasingly thought to be related to biochemical pathway abnormalities and to free radical-induced oxidative damage and chronic inflammation. Therefore, considering appropriate biologic therapy as an adjunct to standard care against these damaging factors may provide rational expansion of treatment options for otolaryngologists and audiologists. METHODS: This review outlines the biologic concepts related to some auditory and vestibular conditions and details the current rationale for utilizing antioxidants for a spectrum of hearing disorders. The strategy is based on the authors' collective experience in antioxidant science and supported with published research, pilot animal data and preliminary clinical observations. RESULTS: A comprehensive micronutrient approach was developed to exploit these pathways, and demonstrated safety and efficacy against oxidative damage and inflammation and clinically relevant neuroprotection. Cooperative research with Department of Defense institutions used prospective, randomized designs to show (1) reduction in oxidative damage measured in plasma and urine over six months, (2) protection against oxidative damage during 12 weeks of intense military training, (3) protection against inflammation after total body blast exposure (rodents), (4) strong neuroprotection against chemically-induced Parkinson's disease (rodents), (5) nerve VIII function improvement after concussive head injury in military personnel, and (6) tinnitus improvement in majority of patients after 90-day evaluation. CONCLUSION: This systematic review of biologic strategies against hearing disorders combined with new animal and human observations may provide a rational basis for expanding current practice paradigms.