Nutraceuticals as potential therapeutic agents for colon cancer: a review

Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.KEY WORDS: Colon cancer, Nutraceuticals, Therapeutics, Marine organisms, Plant derivativesAbbreviations: ACC, acetyl CoA carboxylase; ACF, aberrant crypt foci; ACL, ATP-citrate lyase; ASTX, astaxanthin; COX-2, cyclooxygenase 2; DHA, decahexaenoic acid; DMH, 1,2-dimethylhydrazine; DR, death receptor; EGCG, epigallocatechingallate; EPA, eicosapentaenoic acid; FAS, fatty acid synthase; 5-FU, 5-fluorouracil; GADD, growth arrest and DNA damage; HMG-CoA, 3-hydroxy-3-methyl-glutaryl CoA; HUVEC, human umbilical vein endothelial cell; IGF, insulin-like growth factor; IL, interleukin; LDH, lactate dehydrogenase; MMP, matrix metallo-proteins; NF-κB, nuclear factor-kappa B; PRAP, prolactin receptor associated protein; TCA, tricarboxylic acid cycle; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-induced ligand; VEGF, vascular endothelial growth factor     

The nutraceutical revolution: Emerging vision or broken dream? Understanding scientific and regulatory concerns

‘Nutraceuticals’ are a category of substances without a legal definition, often sold as dietary supplements or components of conventional foods. Nutraceuticals are considered to impart health benefits beyond ordinary nutrition; many nutraceuticals do improve health, but for others evidence is often equivocal or based on animal and/or in vitro data. Moreover, evidence that a component of a substance in a food has a beneficial effect often does not translate into benefits of a substance that has been isolated and consumed in greater quantities. Increasing regulatory requirements from multiple government agencies complicate the design, testing, and marketing of these substances. Dietary advice also is contradictory to much of the marketing of nutraceuticals as it emphasizes using whole foods and ensuring that the overall diet is adequate, rather than focusing on individual components. How the nutraceutical industry responds to these changing conditions will determine the health and growth of the industry over the coming decade(s).     

Tolerability and safety of commonly used dietary supplements and nutraceuticals with lipid-lowering effects

Introduction: Cardiovascular diseases are one of the highest causes of death and disability in industrialized countries, whereas a large portion of patients in primary prevention have cardiovascular disease risk factors that remain uncontrolled. Lifestyle interventions, including dietary supplementation with natural compounds possessing known lipid-lowering effects, are strongly supported by the international guidelines for cardiovascular disease prevention. Areas covered: This review provides insights on issues concerning the safety of the most commonly used dietary supplements and nutraceuticals with demonstrated lipid-lowering actions. Soluble fibers, phytosterols, soy proteins, omega 3 polyunsaturated fatty acids, monakolines, policosanols, berberine and garlic extracts are all discussed and a specific focus has been placed on their pharmacological interactions. Expert opinion: A relatively large amount of preclinical, epidemiological and clinical evidence has demonstrated the tolerability and safety of the most commonly used dietary supplements and nutraceuticals with demonstrated lipid-lowering action. However, for most supplements and nutraceuticals, no evidence is currently available from long-term trials on morbidity and mortality. Detailed knowledge of specific health risks and pharmacological interactions for each individual compound is needed for the management of frail patients, such as children, the elderly, patients with liver or renal failure, high-risk patients, and patients consuming numerous drugs.     

Tolerability and safety of commonly used dietary supplements and nutraceuticals with lipid-lowering effects

Introduction: Cardiovascular diseases are one of the highest causes of death and disability in industrialized countries, whereas a large portion of patients in primary prevention have cardiovascular disease risk factors that remain uncontrolled. Lifestyle interventions, including dietary supplementation with natural compounds possessing known lipid-lowering effects, are strongly supported by the international guidelines for cardiovascular disease prevention.

Areas covered: This review provides insights on issues concerning the safety of the most commonly used dietary supplements and nutraceuticals with demonstrated lipid-lowering actions. Soluble fibers, phytosterols, soy proteins, omega 3 polyunsaturated fatty acids, monakolines, policosanols, berberine and garlic extracts are all discussed and a specific focus has been placed on their pharmacological interactions.

Expert opinion: A relatively large amount of preclinical, epidemiological and clinical evidence has demonstrated the tolerability and safety of the most commonly used dietary supplements and nutraceuticals with demonstrated lipid-lowering action. However, for most supplements and nutraceuticals, no evidence is currently available from long-term trials on morbidity and mortality. Detailed knowledge of specific health risks and pharmacological interactions for each individual compound is needed for the management of frail patients, such as children, the elderly, patients with liver or renal failure, high-risk patients, and patients consuming numerous drugs.     

A decade of nutraceutical patents: where are we now in 2018?

ABSTRACT

Introduction: In the last 10 years, nutraceuticals have grown in interest to researchers, industry, and consumers and are now familiar in the collective imagination as a tool for preventing the onset of a disease. Often nutraceuticals are confused with biologically active phytochemicals/botanicals which can have health benefits. This is a misunderstanding however as the term nutraceutical refers to a product that must have a beneficial effect on health proven by clinical testing.

Areas covered: A search has been performed on both recent patents and the literature regarding nutraceuticals focusing on the beneficial and proven health effects on pathological conditions to give an overview of the state-of-the-art developments in this area. Patents and literature data addressing specific pathological conditions are discussed.

Expert opinion: Nutraceuticals represent a challenge for the future of drug-based pharmacotherapy, and, at the same time, are a powerful tool for the prevention of chronic disease. They are not proposed as an alternative to drugs, but instead, can be helpful to complement a pharmacological therapy and prevent the onset of chronic diseases in subjects who do not qualify for conventional pharmacological treatment.     

Carotenoids and human health.

Oxidative stress is an important contributor to the risk of chronic diseases. Dietary guidelines recommend increased consumption of fruits and vegetables to combat the incidence of human diseases such as cancer, cardiovascular disease, osteoporosis and diabetes. Fruits and vegetables are good sources of antioxidant phytochemicals that mitigate the damaging effect of oxidative stress. Carotenoids are a group of phytochemicals that are responsible for different colors of the foods. They are recognized as playing an important role in the prevention of human diseases and maintaining good health. In addition to being potent antioxidants some carotenoids also contribute to dietary vitamin A. There is scientific evidence in support of the beneficial role of phytochemicals in the prevention of several chronic diseases. Although the chemistry of carotenoids has been studied extensively, their bioavailability, metabolism and biological functions are only now beginning to be investigated. Recent interest in carotenoids has focused on the role of lycopene in human health. Unlike some other carotenoids, lycopene does not have pro-vitamin A properties. Because of the unsaturated nature of lycopene it is considered to be a potent antioxidant and a singlet oxygen quencher. This article will review carotenoids in general and lycopene in particular for their role in human health.     

Legislation relating to nutraceuticals in the European Union with a particular focus on botanical-sourced products

Nutraceuticals are food or food ingredients that have defined physiological effects. They do not easily fall into the legal categories of food or drug and often inhabit a grey area between the two. These products in general terms cover health promotion, "optimal nutrition" the concept of enhanced performance--both physically and mentally--and reduction of disease risk factors. In this paper the focus is mainly on legislation governing botanical-sourced nutraceuticals in the European Union (EU). Nutraceutical concept in general has been defined. Different pieces of legislation influencing botanical nutraceuticals are described. The issue of the borderline between food and drug is discussed. The regulatory status of botanical nutraceuticals as food supplement, food ingredient, functional and fortified food, novel foods and foods for particular nutritional use in the diversified, complex and ever-changing European regulatory environment is described. Botanical nutraceuticals present additional problems because of their complex nature and composition particularly with respect to the quality aspects, which in turn affect safety parameters and overall efficacy of the products. Quality issues relating to botanical sources, growth conditions, end products, their specifications and other technical criteria are highlighted. Guiding principles to be observed for conducting in vitro, in vivo studies in animals and their impact on clinical safety data are discussed. Finally, health claims, their types and criteria of substantiation in light of ongoing discussions with regard to the EU frame work of regulation on nutrition and health claims and role of process for the assessment of scientific support for claims (PASSCLAIM) initiative is discussed. The concept of grading of evidence to substantiate different claims and to establish standards, which should not be revoked or reversed by emerging science at a later stage has been considered. These issues are crucial and are being discussed at EU Parliament and Commission level during the development of the health claim regulations.     

The quality of commercially available nutraceutical supplements and food sources

Objectives Nutraceuticals are components of dietary origin, with claimed beneficial therapeutic activities. The quality of nutraceuticals is paramount for efficacy and safety, and it includes quality of raw materials, different available chemical forms, complex products, lack of substitution of inappropriate materials, and the absence of contaminants. The aim of this review is to investigate the extent of substandard formulated and raw material nutraceuticals, and to highlight any consequent health concern. Key findings Reports of the quality of raw materials have revealed wide variations, often as a result of lack of clear regulatory definitions with respect to size of polymeric entities and also presence of glycosidic and salt forms. Published evaluations of over 70 formulations of 25 different nutraceuticals revealed variable quality; no nutraceutical showed consistent high quality, but a number revealed consistent low quality, thereby making the case for closer regulation of manufacturers. Whole food sources have also been shown to be widely variable in constituent levels. The effect of different formulations requires consideration, as the different types have been shown to have marked effects on bioavailability. Summary The poor quality of commercially available nutraceuticals has been highlighted. In addition, incidences of side effects and drug interactions are increasing, as consumption of nutraceuticals rises. Pharmacists and health practitioners need to be aware of the scientific literature to advise accordingly.     

Protective effect of lycopene in cardiovascular disease

Coronary artery disease (CAD) represents the primary cause of death in Western Countries with an high incidence on human health and community social costs. Oxidative stress induced by reactive oxygen species (ROS) plays an important role in the aetiology of this disease. In particular, the LDL-oxidization has a key role in the pathogenesis of atherosclerosis and cardiovascular heart diseases through the initiation of plaque formation process. Dietary phytochemical products such antioxidant vitamins (A,C,E) and bioactive food components (alpha- and beta-carotene) have shown an antioxidant effect in reducing both oxidative markers stress and LDL-oxidization process. Scientifical evidences support the beneficial roles of phytochemicals in the prevention of some chronic diseases. Lycopene, an oxygenated carotenoid with great antioxidant properties, has shown both in epidemiological studies and supplementation human trials a reduction of cardiovascular risk. However, controlled clinical trials and dietary intervention studies using well-defined subjects population haven't been provided a clear evidence of lycopene in the prevention of cardiovascular diseases. The present short review aims to evaluate the beneficial effect of lycopene in the prevention of cardiovascular disease.     

Nutraceuticals use and type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a complicated metabolic disease and has become one of the significant medical problems worldwide. Researchers aim to provide fine-tuned treatment for T2DM with minimal exposed side effects. Nutraceuticals are compounds or materials and emerging evidence suggests that the use of nutraceuticals has recently been recognized as a promising option for the prevention and management of T2DM, such as probiotics and prebiotics, Vitamin D, n-3 long-chain polyunsaturated fatty acids, and Plant-derived nutraceuticals. This review attempts to show the most popular nutraceuticals and review their effects and possible mechanisms in the prevention or glycemic control of T2DM.     

Sex-gender differences in diabetes vascular complications and treatment

Diabetes mellitus and cardiovascular diseases act as two sides of the same coin: diabetes is an important risk factor for cardiovascular disease while patients with ischemic cardiovascular diseases often have diabetes or pre-diabetes. As firstly shown by Framingham study, diabetic women have an increased cardiovascular risk about 3.5 fold higher than non diabetic women, against an increase of "only" 2.1 fold found in male subjects. In view of the impact of sexual hormones on glucose homeostasis, the molecular pathways involved in insulin resistance suggest a sex-gender specificity mechanism in the development of diabetic complications leading to the unmet need of sex-gender therapeutic approaches. This has also been seen in other diabetic complications such as renal diseases, which seems to progress at a faster rate in females compared with males and women benefit less from treatment than do men. Of note, none of the trials done so far are primarily designed to assess sex-gender differences in the benefit from a specific intervention strategy, de facto excluding fertile women from experimentation. In order to provide a more evidence based medicine for women and to reach equity between men and women, sex-gender epidemiological reports, preclinical and clinical research are mandatory to evaluate the impact of gender on the outcomes and to improve sex-gender awareness and competency in the health care system. Future studies should consider sex-gender differences in the setting of randomized controlled trials with drugs.     

Nutrapharmacology of tocotrienols for metabolic syndrome

Metabolic syndrome is defined as a set of health risk factors that are associated with an increased chance of cardiovascular diseases and type 2 diabetes. These include abdominal obesity, hyperglycemia, impaired glucose tolerance, dyslipidemia, and hypertension. Interventions in metabolic syndrome include lifestyle interventions such as a healthy diet using functional foods together with increased physical activity to induce weight loss as the first aim of treatment. Nutraceuticals such as tocotrienols and tocopherols as members of the vitamin E family may be more targeted interventions. This review evaluates the effects of tocotrienols on the risk factors of metabolic syndrome using data from human, animal and in vitro studies. Tocotrienols improved lipid profiles and reduced atherosclerotic lesions, decreased blood glucose and glycated hemoglobin concentrations, normalized blood pressure, and inhibited adipogenesis. The differences in responses between tocopherols and tocotrienols in preventing obesity, diabetes, hypertension, atherosclerosis, ischemia, and inflammation suggest that different receptors or signaling mechanisms may be involved.     

Nutraceutical/drug/anti-terrorism safety assurance through traceability

Nutraceuticals are naturally occurring/derived bioactive compounds that are reported to have health benefits. The delivery systems for nutraceuticals are foods (functional foods), supplements, or both. Drugs are designed to have medicinal properties for the prevention and treatment of identified diseases or signs and symptoms of disease. Counterfeit drugs contain either placebo, materials not identified in the labeling or substandard or impure materials, which may produce untoward pharmacological or toxicological effects. In addition, the consumer has the right to microbiological safety and prevention from adverse exposure to hazardous chemical(s), and other adverse compounds. Nutraceutical/drug delivery systems are viewed as approaches to (1) enhanced consumer health, (2) decreased healthcare costs, and (3) enhanced economic development. Therefore, the nutra/pharma/ceutical industry is reliant upon a strong underpinning of diversified research that addresses safety and assures chemical and biological efficacy. Significant safety through traceability can be assured by the coupling of the technologies of (a) global positioning (GPS); (b) bar/chip coding; and (c) hazard analysis critical control point (HACCP) management, coupled to rapid nanotechnology marker assays now under development.     

Cardiovascular disease could be contained based on currently available data!

Largely due to better control of infectious diseases and significant advances in biomedical research, life expectancy worldwide has increased dramatically in the last three decades. However, as the average age of the population has risen, the incidence of chronic age-related diseases such as arthritis, Alzheimer's, Parkinson's, cardiovascular disease, cancer, osteoporosis, benign prostatic hyperplasia, and late-onset diabetes have increased and have become serious public health problem, as well. The etiology of these disorders is still incompletely understood, therefore, neither preventive strategies nor long-term effective treatment modalities are available for these disorders. In keeping with the aforementioned, the ultimate goal in cardiovascular research is to prevent the onset of cardiovascular episodes and thereby allow successful ageing without morbidity and cognitive decline. Herein, I argue that cardiovascular episodes could be contained with relatively simple approaches. Cardiovascular disorder is characterized by cellular and molecular changes that are commonplace in age-related diseases in other organ system, such alterations include increased level of oxidative stress, perturbed energy metabolism, and "horror autotoxicus" largely brought about by the perturbation of ubiquitin -proteasome system, and excessive oxidative stress damage to the cardiac muscle cells and tissues, and cross-reactions of specific antibodies against human heat shock protein 60 with that of mycobacterial heat shock protein 65. "Horror autotoxicus", a Latin expression, is a term coined by Paul Ehrlich at the turn of the last century to describe autoimmunity to self, or the attack of "self" by immune system, which ultimately results to autoimmune condition. Based on the currently available data, the risk of cardiovascular episodes and several other age-related disorders, including cancer, Alzheimer's disease and diabetes, is known to be influenced by the nature and level of food intake. Now, a wealth of scientific data from studies of rodents and monkeys has documented the significant beneficial effects of calorie restriction (CR) or dietary restriction (DR), and multiple antioxidant agents in extending life span and reducing the incidence of progeroid-related diseases. Reduced levels of cellular oxidative stress, protection of genome from deleterious damage, detoxification of toxic molecules, and enhancement of energy homeostasis, contribute to the beneficial effects of dietary restriction and multiple antioxidant agents. Recent findings suggest that employment of DR and multiple antioxidant agents (including, catalase, glutathione peroxidase, CuZn superoxide dismutase, and Mn superoxide dismutase = enzymes forming the primary defense against oxygen toxicity), and ozone therapy may mount an effective resistance to pathogenic factors relevant to the pathogenesis of cardiovascular episodes. Hence, while further studies will be needed to establish the extent to which CR and multiple antioxidant agents will reduce incidence of cardiovascular episodes in humans, it would seem prudent to recommend CR and multiple antioxidant agents as widely applicable preventive approach for cardiovascular disorders and other progeroid-related disorders.     

From pharmaceuticals to nutraceuticals: bridging disease prevention and management

Introduction: Nutraceuticals, up today, do not have a specific definition distinct from those of other food-derived categories, e.g. food supplements, herbal products, pre and probiotics, functional foods, etc. They have, however, a pharmacological beneficial effect on health. Many studies have been recently addressed to assess their safety, efficacy, and regulation since they are getting growing attention by market and research, with the aim to clear the difference between them and other market available food-derived products that claim beneficial effect on health.

Areas covered: The understanding of the potential mechanisms of action of pharmaceutically active substances contained in nutraceuticals that may improve health and reduce the risk of pathological conditions while enhancing overall well-being is the challenge for nutraceuticals to be considered as a preventive and therapeutic efficient tool in facing some diseases.

Expert commentary: It is of utmost importance to have a proper and unequivocal definition of nutraceuticals and a shared regulation. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and by efficacy in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed.     

Biomarkers for diet and cancer prevention research： potentials and challenges

As cancer incidence is projected to increase for decades there is a need for effective preventive strategies. Fortunately, evidence continues to mount that altering dietary habits is an effective and cost-efficient approach for reducing cancer risk and for modifying the biological behavior of tumors. Predictive, validated and sensitive biomarkers, including those that reliably evaluate ＂intake＂ or exposure to a specific food or bioactive component, that assess one or more specific biological ＂effects＂ that are linked to cancer, and that effectively predict individual ＂susceptibility＂ as a function of nutrient-nutrient interactions and genetics, are fundamental to evaluating who will benefit most from dietary interventions. These biomarkers must be readily accessible, easily and reliably assayed, and predictive of a key process（es） involved in cancer. The response to a food is determined not only by the effective concentration of the bioactive food component（s） reaching the target tissue, but also by the amount of the target requiring modification. Thus, this threshold response to foods and their components will vary from individual to individual. The key to understanding a personalized response is a greater knowledge of nutrigenomics, proteomics and metabolomics.     

Cost-effectiveness of stroke prevention

Stroke is a preventable disease and there are several interventions that might have an important role in reducing the burden of disease. Economic appraisal of these different interventions is essential as resources are scarce and it is logical to attempt to obtain the greatest reduction in disease for the lowest cost. Anticoagulation for non-rheumatic atrial fibrillation is highly effective, but is expensive and cost-effectiveness analyses show that use of aspirin alone would prevent almost as many strokes at much lower cost. Antiplatelet drugs are both effective and inexpensive and their use in secondary prevention would potentially save the NHS about 900 Pounds per life year gained. Carotid endarterectomy and the associated screening costs are poor value for money but recent attempts to use predictive models to determine which patients will benefit from surgery may improve its cost-effectiveness. Current evidence is dominated by pharmacological interventions and much less good evidence is available for life-style modifications such as dietary change and physical exercise. Modification of major cardiovascular risk factors (blood cholesterol, high blood pressure and smoking) is very cost-effective but needs to be better targeted if potential health gain is to be realised.     

Physical activity, obesity and cardiovascular diseases

Sedentary lifestyle and overweight are major public health, clinical, and economical problems in modern societies. The worldwide epidemic of excess weight is due to imbalance between physical activity and dietary energy intake. Sedentary lifestyle, unhealthy diet, and consequent overweight and obesity markedly increase the risk of cardiovascular diseases. Regular physical activity 45-60 min per day prevents unhealthy weight gain and obesity, whereas sedentary behaviors such as watching television promote them. Regular exercise can markedly reduce body weight and fat mass without dietary caloric restriction in overweight individuals. An increase in total energy expenditure appears to be the most important determinant of successful exercise-induced weight loss. The best long-term results may be achieved when physical activity produces an energy expenditure of at least 2,500 kcal/week. Yet, the optimal approach in weight reduction programs appears to be a combination of regular physical activity and caloric restriction. A minimum of 60 min, but most likely 80-90 min of moderate-intensity physical activity per day may be needed to avoid or limit weight regain in formerly overweight or obese individuals. Regular moderate intensity physical activity, a healthy diet, and avoiding unhealthy weight gain are effective and safe ways to prevent and treat cardiovascular diseases and to reduce premature mortality in all population groups. Although the efforts to promote cardiovascular health concern the whole population, particular attention should be paid to individuals who are physically inactive, have unhealthy diets or are prone to weight gain. They have the highest risk for worsening of the cardiovascular risk factor profile and for cardiovascular disease. To combat the epidemic of overweight and to improve cardiovascular health at a population level, it is important to develop strategies to increase habitual physical activity and to prevent overweight and obesity in collaboration with communities, families, schools, work sites, health care professionals, media and policymakers.     

HRT and its impact on the menopause,osteoporosis and breast cancer

Hormone replacement therapy (HRT) is a widely used treatment for vasomotor symptoms of the menopause. In this respect, there is a wealth of randomised evidence that it is an effective and cost-effective treatment, achieving substantial quality of life gains for relatively low cost. On the other hand, potentially major health benefits lie in the prevention of chronic diseases such as osteoporosis and cardiovascular disease. Observational data strongly support the role in HRT’s ability to prevent fractures; however, there is a suggestion that this antifracture benefit is only realised if treatment is taken soon after the menopause and is soon lost after cessation of treatment. HRT also increases the risk of breast cancer, which may negate much of its health benefit.     

Drugs for the treatment of hyperlipidemia

Hyperlipidemia is a major risk factor for the development of cardiovascular disease. Considerable evidence suggests that drugs with the ability to lower low density lipoprotein-cholesterol also lower cardiovascular deaths. This review will focus on new developments in the design of pharmacological agents and therapies that can favorably affect hyperlipidemia. A broad range of therapeutic agents will be discussed, including food additives, nutraceuticals, conventional pharmaceuticals as well as gene therapy. The potential adverse effects caused by these agents will also be discussed. Appetite suppressants, intestinal lipase inhibitors, inhibitors of dietary cholesterol absorption, inhibitors of chylomicron assembly, HMG CoA reductase inhibitors (statins) and adenovirus-mediated gene therapy are specifically discussed in detail. Treatments and issues specific to the elderly and to children are also described. The specific application of pharmacogenics to the problem of hyperlipidemia is presented as a likely direction for future research emphasis.