Bentham Briefs in Biomedicine and Pharmacotherapy Oxidative Stress and Natural Antioxidants

Molecular oxygen, a double-edged sword, is both a boon and a curse for the existence of life. Oxidative stress is the disequilibrium between reactive oxygen (ROS)-generation and elimination that inflicts cellular damage. Living cells can adapt to the ever-changing internal or external stresses. However, they gradually lose their radical-scavenging adaptability with persistent stress, which further increases during neoplasia. Cancer cells, well adapted in pro-oxidative milieu, drive metabolic and genomic reprogramming, which further escalates the oxidative load. This vicious cycle promotes further carcinogenic alterations. Contrastingly, the same ROS is essential for the oxidative-burst mediated anticancer host-defense. To sustain this redox pressure, cancer cells hijack the intracellular antioxidants. Therefore, redox reorientation towards enhanced responsiveness may selectively target malignant cells by ROS-enhancement beyond tolerance leading to mortality. Carcinogenesis, a multistep process, requires ROS during initiation, promotion and progression. However, supraphysiological ROS may induce apoptosis in unmanageable malignancies. Interestingly cells possess an evolutionary-conserved nature to get hormetically pre-conditioned by a transient ultralow exposure of a stressor, which in higher dose may show the opposite effect. Antioxidants are excellent chemopreventives and chemotherapeutics. Here, we have condensed the possible anticancer modulation of oxidative stress by phytochemicals, aiming at an insight for future strategies in cancer management.

Contaminants in the environment, such as oxidant fuels, chemical substances, particulate surfaces, cigarette smoke, toxins, metals, medicines, xenobiotics, or radiation, can trigger the generation of the reactive oxygen species (ROS) or the reactive nitrogen species (RNS), which can lead to oxidative stress. Many ROS-mediated mechanisms shield cells from oxidative damage and help them reclaim their redox homeostasis. The activation of metabolic or bioenergetics reaction processes mediated by thiol redox switches is one of the overt or indirect mechanisms of oxidative stress. Furthermore, toxic agents' oxidative stress can be exacerbated through metabolic processes in cells. Excess ROS is regulated by endogenous antioxidant protection mechanisms (both enzymatic and non-enzymatic), which help remove toxic oxygen molecules or scavenge ROS under normal conditions. To sustain redox homeostasis in the presence of environmental stress, the cells are fitted with several complementing energy-dependent structures. The cytochrome (CYP) enzymes are a monooxygenase superfamily that includes several enzymes involved in xenobiotic detoxification. As a result, it seems that the CYP families are the most prominent members. Heavy metal toxicity, such as zinc, arsenic, and cadmium, is believed to be caused by their interaction with sulfhydryl groups in biological systems. Many sulfhydryl residues in antioxidant proteins, including metallothionein and albumin, serve as a sink for heavy metal ions, saving important protein thiols in the process.

Reactive oxygen species are a result of normal oxygen metabolism, which even possess the ability to damage the cells; and thus, it becomes necessary to eliminate them. Redox homeostasis is a natural mechanism that detoxifies these ROS and involves many cellular processes in the detoxification. However, the production of ROS increases dramatically during environmental stress, which can result in the disruption of redox homeostasis. This disruption can lead to several complications that include the generation of tumour cells, ageing, diabetes and neurodegeneration. Antioxidants can prevent this disruption by reducing the propagation of free radicals and thus, they have an important role to play in the process of redox homeostasis. The chapter highlights the role of enzymatic and non-enzymatic antioxidants in redox homeostasis. Non-enzymatic antioxidants have been further divided into two categories namely, metabolic and nutritional antioxidants. The crucial role played by the antioxidants against ROS can be therefore used in therapeutics to treat the major diseases that are caused due to oxidative stress.

Antioxidants are used to inhibit the deterioration of a molecule and are used at a low concentration to slow or avoid the degradation of a molecule. They have the ability to chelate transition metals and work through a variety of synthetic processes like hydrogen atom transfer (HAT) and single electron transfer (SET). Understanding the biology of antioxidants, their possible applications, and their synthesis using different biotechnological methods are important aspects of antioxidant mechanisms. Antioxidant molecules can react in one of two ways: through multiple mechanisms or through a single mechanism. Understanding the antioxidant reaction process is possible due to the molecular structure of the antioxidant material. This chapter presents an overview of various antioxidants, their reaction mechanism against free radicals as well as the most utilized techniques to assess their different activities.

Abiotic stresses have contributed to the generation of reactive oxygen species called as free radicals which are highly toxic to the organism. Free radicals may be evaluated either explicitly or inadvertently after the production of oxidative byproducts of nucleic acids, proteins or lipids, a method also known as fingerprinting. Though the approaches for analyzing such reactive intermediates have been thoroughly studied; we concentrated primarily on recent implementations of these techniques to quantify free radicals and different candidate biomarkers of oxidative stress such as nitrotyrosine, isoprostane, etc. Further, the various biochemical approaches along with the conventional methods are also discussed for the evaluation of antioxidant activity of natural products.

The natural antioxidants are plant secondary metabolites that play a key role in preventing the development of various oxidative stress-induced degenerative and age-related disorders such as cardiovascular disease, cancer, etc. As a result, interest in these antioxidant compounds from natural sources has increased in recent years. For this reason, antioxidant substances in plants are extracted and presented to the market as a standardized solution. The first method of antioxidant extraction from plant sources is classical solvent extraction. Conventional solvent extraction takes place in two ways: liquid-liquid extraction and solid-liquid extraction. However, there are some disadvantages of using the classical extraction method to obtain antioxidants from plant sources. These methods use high amounts of solvents and require more time for extraction. Low selectivity, less efficiency, and environmental effects are some of the disadvantages. Therefore, the trend towards new extraction techniques has increased. Ultrasound-assisted, microwave-assisted, supercritical fluid, and accelerated extraction systems are very effective methods compared to conventional solvent extraction. These extraction procedures can be used in low temperatures and prevent the thermal degradation of antioxidants. In this study, the efficiency of new extraction methods and classical extraction methods are compared and the effect of extraction on antioxidant components has been compiled.

The growing interest in plant foods as a source of phytochemicals in general and antioxidants like polyphenols in particular continues to receive a great deal of attention of nutritionists, food scientists and consumers as well. Food is no more regarded as just a source of energy and nutrition but is gaining importance as a functional or nutraceutical diet ingredient. The functional compounds are the secondary metabolites (PSM), produced by the plants as a natural defense against insect pest damage or adverse environmental conditions and represents a large and diverse group of bioactive compounds. PSMs are strong antioxidants that complement or improve the functions of antioxidant vitamins and enzymes which have a protective role to play in the bodily system against reactive oxygen and nitrogen species, UV light exposure, attack of pathogens, parasites and predators. Antioxidants are prophylactic compounds that can possibly even be used to cure several prevailing human diseases by traditional medicinal and health care system. Antioxidants are very sensitive compounds and their bioavailability in food is subject to their occurrence in food and the food processing conditions. The complexity in structure, function and expression of different antioxidants coupled with their frequent occurrence in different herbals from negligible to significant amounts, extraction, identification and their analysis remain a challenging task as ever for the scientists and technologists, despite the recent advances in the analytical and the instrumentation procedures. Keeping in view the high health potential and the related concerns, the current contribution is focussed on extraction, profiling, characterization, biological activity and implications of antioxidant consumption on human health to diversify food applications.

Free radicals produced within the body as the inevitable side-effects of standard metabolic procedures of cells, or by exposure to poisons in nature. Excessive levels of free radicals trigger a disorder called oxidative stress, which can destroy cells and contribute to chronic diseases like atherosclerosis, diabetes, rheumatoid arthritis, ocular disease, Alzheimer's disease, deterioration in the immune system, and different kinds of cancer. Antioxidants are materials that counterbalanced free radicals and delay, hinder or remove harm brought about by free radicals. Nutritional antioxidants are commonly distributed in different food forms. Plant foods are major sources of antioxidants. They protect against oxidative stress and reduce the danger of numerous ailments by acting as oxygen and peroxyl radical scavengers. A diet that includes berries, fruits, vegetables, grains, tea, coffee, nuts, and healthy oils has an excellent antioxidant supplement. This combination of multiple detoxifying antioxidants can play a synergistic role in reducing the risk of ailments. Antioxidants including vitamins (A, E, and C), as well as carotenoids and other minerals (zinc, manganese, copper, and selenium) are important for antioxidant enzyme activities. Nutritional polyphenols and flavonoids are also powerful antioxidant compounds. In this chapter, we address the medicinal advantages of various antioxidants in reducing the risk of inflammatory ailments of skin, eye, neurodegenerative, cardiovascular, diabetes and liver diseases.

Cancer is a complex disease and is currently the leading cause of mortality and morbidity across the globe. Dysregulated bioenergetics is one of the hallmarks of cancer cells and is characterized by increased activity of several enzymes of metabolic pathways. Consequently, cancer cells produce higher levels of reactive oxygen species (ROS) which contribute to their enhanced proliferation and survival over normal cells. Elevated levels of ROS cause oxidative stress, redox imbalance, DNA damage, activation of oncogenes, chronic inflammation and eventually cancer. Additionally, ROS mediated oxidative stress activates several oncogenic signaling cascades including PI3K/Akt pathway, NF-κB pathway, cyclooxygenase pathway, JAK/STAT pathway, angiogenesis and metastasis. To maintain redox balance and neutralize the detrimental effects of ROS, normal cells exhibit an antioxidant defence system, comprising of both enzymatic and non-enzymatic division. Activation of Nrf2 signaling pathway is the key regulatory pathway that helps in restoring the cellular redox homeostasis. Extensive research in the past decades has witnessed the potential health benefits of dietary antioxidants alone or in combination in the prevention of several chronic diseases, including cancer. A number of antioxidants from dietary backgrounds such as epigallocatechin gallate, resveratrol, curcumin, phloretin, berberine and lycopene have shown appreciable potential as a chemopreventive agent without causing significant toxicity. This chapter presents an extensive analysis of existing knowledge on the protective effects of various dietary antioxidants against cancer with a focus on oxidative stress, redox homeostasis and dysregulated cellular signaling leading to cancer cell proliferation, survival and metastasis.

In the industrialized world, functional foods have become part of a diet that provide potential health benefits by curbing various diseases. Currently, the most commonly used functional foods are probiotics which reduce damages caused by oxidative stress and reactive oxygen species (ROS). Probiotics are live microbes used as a therapeutic food with fewer side effects in comparison to other therapeutic agents. The incorporation of probiotics in foods shows many medicinal properties by acting as antioxidant, anti-inflammatory, anti-bacterial and anti-cancer agents. As such probiotic foods (fermented dairy products, drinks, fruits, vegetables, etc.) can affect the individual by raising the existing gastrointestinal flora with live microbial nutritional supplements and improve the microbial balance of Lactobacillus, Bifidobacterium and several other microbial species in the gastrointestinal tract, which causes an alteration in carcinogen metabolism as well as regulation of the immune system. Accumulating evidence highlighted that probiotics have therapeutic effects with a reduction of invasion and metastasis in cancer cells by modulating key signaling pathways. Globally probiotics market extent was valued at $ 48.38 billion in 2018 and expanded at 6.9% annually which indicates the rising demand for probiotics worldwide. Hence, the chapter sheds light on the current state of probiotics and their potential applications for human health and in the development of modern therapeutic drugs for the treatment of diseases.

MicroRNAs (miRNAs) are short, non-coding and functional 18-22 nucleotide sequences, which bind to 3’ UTR region of the mRNA and modify mRNA expression by degrading them or modulating their translation process. Besides, miRNAs act as either suppressors or inducers of tumor depending upon binding with the target site. The action of miRNAs is reported for controlling the various important functions like metastasis, angiogenesis, apoptosis and tumor growth. They play an important role in suppressing cancer cell proliferation or invasion by targeting caspases and other factors involved in programmed cell death (apoptosis). So, the application of miRNA is proved to be a novel approach for cancer prevention. According to literature, numerous phytoconstituents isolated from medicinal plants or other botanicals modulate the functioning of different miRNAs which are involved in the pathology and biology of cancer. Therefore, the regulation of miRNA by botanicals or isolated compounds is a new model for researchers to develop/formulate a novel drug to combat this devastating disease. An attempt has been made in this chapter to explore the role of phytoconstituents to control the process of carcinogenesis targeting miRNAs.

Oxidative stress distorts the mitochondrial function and triggers deleterious effects in the cardiovascular system. Further, oxidative stress-induced overproduction of highly reactive oxygen/nitrogen species (RONS) is amplified in patients exposed to radiation, excessive consumption of alcohol and tobacco, environmental pollutants, exposure to agrochemicals like fertilizers, pesticides or endocrine disrupters. In modern times, oxidative stress-induced cardiovascular diseases (CVDs) have escalated globally. Synthetic medicines prescribed for the amelioration of CVDs are expensive and can cause life-time dependency in some patients, thus escalating the treatment cost. Sometimes, long-term use of synthetic medicines or drug polytherapy for co-morbid conditions can cause undesirable side-effects. Quite often, these therapeutic strategies do not succeed in attenuating the oxidative stress related CVDs. Therefore, researchers are exploring alternative and cost-effective phytobioactive therapies which have strong antioxidant and anti-inflammation properties, and can act as scavengers of RONS. Phytobioactive compounds, nutraceuticals and probiotics prepared from plant/animal origin are potential therapeutic substances for the promotion of health and well-being. Several plant-derived phytotherapies have demonstrated strong antioxidant, antiinflammatory, cardio-protective effects, inhibition of ischemic injury as well as alleviation in the pathological cardiac biomarkers and cardiac apoptotic proteins. In this review, we have described the therapeutic functions of various phytobioactive compounds and their purported mechanism of action at the genetic, epigenetic, cellular and molecular level with respect to their antioxidant and anti-inflammatory actions for the prevention and treatment of cardiovascular disorders.

Alzheimer’s disease (AD) is acknowledged as one of the most serious and progressive neurodegenerative disorder, and is the leading cause of dementia in late adult life having unknown etiological pathways. AD is characterized by the formation of intracellular neurofibrillary tangles leading to tau phosphorylation and extracellular amyloid deposits that develop into senile plaques. Amyloid beta (Aβ) plaques, the classic hallmarks of AD, in turn, cause the generation of free radical species of different metals (copper, iron) which modulate neuronal growth, differentiation, and progression of cell death through several signalling pathways. The conventional therapies recommended for the amelioration of AD are only restricted to treat the symptoms of AD and do not focus on the underlying causes of the disease. These allopathic medicines are non-economical and also have unwanted side-effects, which further decrease the quality of life (QOL) of the patients. Therefore, it is of utmost importance to explore alternatives to decrease the expression of neurodegeneration. Antioxidant and anti-inflammatory phytoconstituents play a crucial role in preventing the onset of neurodegenerative diseases and exert neuroprotection. Numerous antioxidant phytonutrients, herbal remedies, and food supplements have been reported for the prevention of cognitive decline and management of AD. The neuroprotective potential of phytotherapies has been demonstrated in numerous in vitro and in vivo studies. The purpose of this review is to describe phytoconstituents based on their therapeutic effects on etiological pathways (microglia, inflammasome, CB2, NLRP3 and NFKβ) of AD and their underlying molecular mechanisms of action involved in neuroprotection and prevention of AD.

In many countries, including Asian countries such as Japan, Singapore and Thailand, aging populations have been increasing, thus promoting a high risk for ageassociated chronic diseases. One of the devastating chronic diseases in people with old age known to greatly impact the patients’ quality of life is a group of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. It has been evident that neurotoxicity is a significant risk of neurodegenerative disorders. One of the crucial contributing factors leading to neurotoxicity in humans is glutamate, the excitatory neurotransmitter. If it is accumulated in the brain, this neurotransmitter can result in neurotoxicity via either glutamate-dependent pathway or glutamateindependent pathway. Glutamate neurotoxicity (GNT) is characterized by rising damage of cell components leading to cell death. In the death process due to oxidative stress, reactive oxygen species (ROS) are generated, thus impairing a vast array of cellular functions in many organelles such as mitochondria and endoplasmic reticulum. GNT has been clearly observed in the brain tissue because of the accumulation of glutamate, not only from the endogenous source, but also the exogenous source such as monosodium glutamate. Fortunately, numerous plant extracts and their chemical constituents, particularly the ones with high anti-oxidant activity, have been found to exhibit anti-GNT in both vitro and in vivo models. Herein, mechanisms of anti-GNT of botanicals and their chemical constituents are presented and discussed in detail. Their anti-GNT mechanisms elucidated could shed light on the discovery and application of neutraceuticals, and the cell defense mechanisms of natural neuroprotectants could certainly be beneficial to improve both healthspan and lifespan in humans.

Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one or 4’,5,7- trihydroxyisoflavone) can be found in various plants, though soy is especially rich in this compound. It has multiple biological activities, but one of its major features is its antioxidative function. Either genistein-rich extracts from plants or synthetic genistein have been used in studies on the potential treatment of various conditions and diseases. They are as different as neurodegenerative diseases (including Alzheimer's disease and various genetic diseases), cancer, cardiovascular disorders, liver dysfunctions, and many others. Although for the treatment of various diseases the major mechanisms of genistein action can be based on modulation of specific biochemical pathways, its antioxidative function may contribute significantly to its therapeutic potential. These aspects are discussed in the light of development of genistein-based therapies for a battery of different disorders.

The highly reactive free radical species generated through abiotic stress lead to the degradation of essential biomolecules like proteins, carbohydrates, lipids and nucleic acids, thus deregulating a series of cellular functions. Several pathological conditions like wrinkling of skin, ageing, asthma, arthritis, carcinogenesis, cardiovascular diseases, cataract, AIDS, autoimmune disorders, Parkinson’s dementia, Alzheimer’s disease, etc., are the manifestations of free radical toxicity. Apart from these clinical influences, free radicals are associated with spoilage of food resulting through oxidation of fats, oils and lipid content. Antioxidants have enormous potential to neutralize the effect of toxic moieties. Antioxidants can be natural or synthetic with the former taken directly from fruits, vegetables, herbs and spices. Synthetic antioxidants can also inhibit oxidation reactions but their use has been quoted as unsafe for humans. Therefore, expedition on innocuous antioxidants of natural origin has intensified in recent past. The scientific studies have demonstrated the potential of natural antioxidants as: (i) natural preservative for long term storage of ready to eat food products without compromising with their commercial and sensory values; (ii) an anti-ageing, anti-wrinkle agent in the cosmeceutical products; (iii) a medicinal ingredient preventing vesicular calcification and lipid peroxidation responsible for various diseases; (iv) a protective probe against several cardiovascular, neurodegenerative and autoimmune disorders. Owing to such a wide array of industrial applications, natural antioxidants are expected to capture the market in future generating high revenue of billions of dollars. Therefore, through this chapter we focus on bioprospecting diverse sources of natural antioxidant compounds and their industrial prospects.

Combination therapy, also known as polytherapy, is a form of treatment that involves the use of several drugs. In fact, the term applies to the use of various treatments to cure a particular illness, with pharmaceutical therapies being the most common. Non-medical treatment, such as the use of a mixture of medications and psychotherapy to relieve depression, may also be used. Polypharmacy, which applies to the usage of multiple medications, is also a related term. When referring to prescription combination treatment, the term polymedicine is also used. The antioxidant protection mechanism, which is responsible for reducing a wide variety of oxidants like reactive oxygen species (ROS), lipid peroxides, and metals, etc., maintains redox homeostasis. Antioxidants are used to guard against the harmful consequences of oxidation and as nutritional additives to counteract the negative effects of stress. Antioxidants are compounds that may prevent or delay cell damage induced by free radicals, which are reactive molecules produced by the body in response to external environmental and other stress. Free-radical scavengers is a term used to describe them. Antioxidants may come from either natural or synthetic sources. Many plant-based foods are thought to have high levels of antioxidants. Plant-based antioxidants are phytonutrients that contribute to disease prevention. These phytonutrients as single entity or in combination have demonstrated beneficial effects in several models and might protect against cancer.