When a nutrient must be consumed in the diet to maintain health and Cannot be made by the body it is considered to be?

Publisher Summary

Essential nutrients are ones that cannot be synthesized by the body and, therefore, must be supplied from foods. These nutrients are essential for normal body function and for growth. The body utilizes protein for the maintenance and repair of tissues for growth and energy. Protein is composed of 20 or more amino acids. The body cannot manufacture nine of these in adequate amounts. Complete proteins or the proteins of high biological value contain all of the essential amino acids. Examples include such foods as meat, eggs, milk, and soy­beans. Incomplete protein foods such as beans and peas do not contain all of the essential amino acids and must be combined in one meal with other foods or one another to supply all nine essential amino acids. Vitamins are organic compounds that cannot be synthesized by the organism and are needed in small amounts in the diet of animals to sustain metabolism and life. Vitamins are classified according to their solubility in fat or water. Solubility is important because this property determines the patterns of transport, excretion, and storage within the body. Vitamins can function in two ways—physiologically as vitamins and pharmacologically as drugs. The fat soluble vitamins are the regulators of specific metabolic activity. The water soluble vitamins function as coenzymes, small molecules that bind loosely to an enzyme protein, or apoenzyme to form a holoenzyme. The holoenzyme serves the catalytic function.

Mechanisms of antioxidant action

Metal ion chelation: The formation of ROS is effectively reduced by maintaining iron and copper in tightly bound form that cannot participate in Fenton-type reactions. The metal-chelating capacity of some food-derived compounds, such as flavonoids, may provide additional protection. The relevance of this effect at the cellular level remains unclear, however.

Enzyme-catalyzed reactions: The body has an elaborate system to protect against ROS. These systems tend to be most active at the sites of greatest ROS release. Catalase (EC1.11.1.6), which contains both heme and manganese, dissipates hydrogen peroxide in peroxisomes to oxygen and water. This enzyme with its high capacity and low affinity is best suited to detoxify overflow quantities and sudden bursts of hydrogen peroxide. Other enzymes with peroxidase activity have lower capacity, but their high substrate affinity keeps hydrogen peroxide concentrations very low. This group of high affinity peroxidases includes the peroxiredoxins (Prx), which are closely related heme enzymes.

Different superoxide dismutase (EC1.15.1.1) isoenzymes in cytosol and the extracellular space convert superoxide radicals to hydrogen peroxide (reaction equation 4). All isoenzymes contain copper and a second transition metal. The isoenzyme in mitochondria contains manganese, the ones in cytosol and extracellular fluids contain zinc or iron.

(reaction equation 4)2 O2−+2H+→O2+H2O2

Another high-capacity free radical scavenger in extracellular fluid is the copper-enzyme ferroxidase (ceruloplasmin, iron (II):oxygen oxidoreductase, EC1.16.3.1).

Thioredoxin reductase (EC1.6.4.5) is a ubiquitous NADPH-dependent selenoenzyme in cytosol that reduces both dehydroascorbate and the semidehydroascorbate radical to ascorbate (May et al., 1998).

A different protective strategy seeks to remedy the damage. Four different selenium-containing glutathione peroxidases (EC1.11.1.9) with distinct tissue distributions and activity profiles use glutathione (GSH) for the reduction of peroxides of free fatty acids and other lipids. Another example is the activity of arylesterase (paraoxonase 1, PON1, EC3.1.1.2) in high-density lipoprotein (HDL). This enzyme cleaves the fatty aldehydes from damaged phospholipids and releases them from the lipoprotein particle for further metabolic treatment in the liver and other tissues (Ahmed et al., 2001).

Antioxidants: The body uses both fat-soluble and water-soluble compounds to reach all cellular compartments.

The essential nutrient ascorbate is a particularly versatile antioxidant, because it can quench radicals that have one or two excess electrons. The systems for the regeneration of the oxidized forms include NADH-dependent monodehydroascorbate reductase (EC 1.6.5.4), thioredoxin reductase (EC 1.6.4.5), and an NADH-dependent dehydroascorbate-reducing transporter in erythrocytes (May el al., 1998). Thioredoxin is a small peptide with two redox-active cysteines that potently quenches singlet oxygen and hydroxyl radicals. The oxidation of its cysteines reduces oxidants or oxidized compounds. It also detoxifies hydrogen peroxide in conjunction with a group of enzymes, the peroxiredoxins. Thioredoxin reductase (EC 1.6.4.5) uses NADH to rapidly regenerate the oxidized thioredoxin. Lipoate, tetrahydrobiopterin, uric acid, phenols, flavonoids and isoflavones, additional protein disulfides, and possibly melatonin add to the mix of water-soluble antioxidants.

Table 9.2. Antioxidant enzymes

Table 9.3. Antioxidant compounds

Vitamin E is particularly important for antioxidant protection in lipoproteins, membranes, and other lipophilic environments. Since the interaction of ROS with vitamin E generates the tocopheroxyl radical, the net effectiveness depends on adequate availability of ascorbate and other co-antioxidants for regeneration (Terentis el al., 2002). Ubiquinone, and tetrahydrobiopterin, have considerable antioxidant potential unrelated to their function as enzyme cofactors. In addition to these endogenous metabolites, a wide range of food-derived compounds is known to provide additional protection. Hundreds of carotenoids from fruits and vegetables increase the resistance of tissues to the harmful effects of ROS.

Selenium

The essential nutrient selenium exerts potent antioxidant activity via its roles in the formation and function of selenium-dependent glutathione peroxidases. Selenoproteins serve as important regulators of tissue redox status, inflammation, and immune responses. Selenium deficiency has been linked to innate, humoral, and cell-mediated immunosuppression.69 Significantly reduced selenium levels have been found among patients with CHC, with greater deficiencies observed in cirrhotics compared to those with lesser fibrosis.70-73 Thus there is at least a theoretical role for supplemental selenium in limiting CHC-related disease progression, although efficacy has yet to be proven. Similarly, the potential role of selenium in HCC prevention among patients with chronic viral hepatitis remains uncertain. A large Taiwanese study conducted in the late 1980s and early 1990s examining selenium levels in 7342 men with chronic hepatitis B or C and development of HCC found selenium levels were lowest in men with CHC. Participants with the highest selenium levels were 38% less likely to develop HCC compared to participants with the lowest selenium levels.74 Another large-scale, contemporaneous Chinese study found a similar protective effect among patients with chronic hepatitis B infection.75 Subsequent studies, however, have failed to definitively demonstrate a chemoprotective effect associated with selenium supplementation and HCC risk.76,77

4.2 AMPK and mTOR

Two essential nutrient sensors in cells, AMPK and mTOR, facilitate coordination of the cellular response to metabolic stressors. AMPK is activated in response to oxidative stress and increased AMP:ADP and ADP:ATP ratios, which can be induced by glucose deprivation. The binding of AMP or ADP activates AMPK, as does phosphorylation by the serine/threonine liver-kinase-B1 (LKB1) kinase (Shaw et al., 2004). AMPK ultimately functions to restore ATP levels by inhibiting anabolic processes and promoting catabolic pathways in order to generate ATP (Garcia & Shaw, 2017). Activated AMPK is able to phosphorylate many downstream effectors involved in autophagy such as ULK1 (Egan et al., 2011), VPS34 (Kim et al., 2013), and Beclin-1 (Kim et al., 2013). The ability of AMPK to induce autophagy is also mediated by direct inhibition of mTORC1 activity. More specifically, AMPK is able to phosphorylate and activate TSC2 (Inoki et al., 2003) (a negative regulator of mTORC1) as well as phosphorylate and inhibit Raptor (Gwinn et al., 2008) (a component of the mTOR complex). In contrast to AMPK, mTOR suppresses autophagy by direct inhibitory phosphorylation of ULK1 as well as disrupting the ULK1 and AMPK interaction, during nutrient abundance and in response to growth factor signaling (Kim, Kundu, Viollet, & Guan, 2011).

As AMPK lies at the nexus of multiple nutrient sensing and stress pathways, it has been suggested to have multifaceted roles in both tumor progression and tumor suppression (Faubert, Vincent, Poffenberger, & Jones, 2015). Indirect AMPK agonists, such as metformin, were shown to suppress the growth of a p53 null, RAS-mutant, HCT116 CRC cell line (Buzzai et al., 2007). This observation was extended to RAS-mutant human LAC cell lines in which metformin treatment induced apoptosis and inhibited growth (Wu et al., 2011) as well as other tissue types (Kuznetsov, Leclerc, Leclerc, & Barredo, 2011). Supporting these findings, a direct agonist of AMPK (MT 63–78) exerts an anti-proliferative effect on prostate cancer through a lipogenesis-inhibitory mechanism (Zadra et al., 2014). Loss of AMPK activity can also have pro-tumorigenic consequences such as increased glycolytic flux (Faubert et al., 2015) and loss of mTORC1 regulation (Shaw et al., 2004). The role of AMPK as a tumor suppressor is likely due in part to the ability of this metabolic sensor to negatively regulate the Warburg effect (Faubert et al., 2013). However, the capability of AMPK to mitigate cellular stress can also aid in cancer cell growth and survival. In fact, AMPK has been shown to maintain NADPH levels as a stress response to the loss of acetyl CoA carboxylases (ACC1 or ACC2) ultimately resulting in cancer cell survival (Jeon, Chandel, & Hay, 2012). Similarly, it was demonstrated that AMPK protects leukemia-initiating cells from metabolic stress promoting development of more advanced disease, which could be abrogated with AMPK inhibition (Saito, Chapple, Lin, Kitano, & Nakada, 2015). The dual role of AMPK in tumor progression and tumor suppression, as well as a lack of specific and selective drugs, makes targeting AMPK a challenging task. There are clearly multiple roles AMPK can play in tumorigenesis, tumor maintenance, and cell survival following energetic stress. Further studies will be required to fully elucidate the tissue-specific role of AMPK and the potential therapeutic interventions (Eichner, Brun, Ross, Shaw, & Svensson, 2019).

Abstract

Vitamins are essential nutrients that are required in many areas of biochemical metabolism, including DNA synthesis, energy production, and biosynthetic pathways. The majority are obtained from the diet or synthetic preparations as the body cannot or does not make sufficient concentrations for optimal function. The water-soluble B vitamins include thiamine, riboflavin, niacin, pantothenic acid, pyridoxal phosphate, biotin, folic acid, and cobalamin. In the body, these vitamins function as activated carriers of molecule fragments or electrons, or as enzyme cofactors. Choline, while not a vitamin, is an essential micronutrient component of membrane lipids and is also an important neurotransmitter as acetylcholine.

Non-essential organic micronutrients

Some compounds can be synthesized by humans, but production may not always cover needs, especially at certain times in the life cycle. Thus, food sources have to augment endogenous synthesis of arginine, cysteine, taurine, and docosahexaenic acid (an omega-3 fatty acid) to meet the needs of very young infants. Severe injury, infections, chronic diseases or other temporary circumstances also may increase needs beyond the capacity of endogenous synthesis. On the other hand, dietary intakes of specific nonessential nutrients may become more important when genetic variants create a bottle-neck in the synthesis of a particular compound, such as carnitine. Vitamin D provides

Table 1.2. Essential nutrients

Table 1.3. Conditionally essential nutrients

Table 1.4. Non-essantial nutrients conferring health benfits

another illustration of an endogenously synthesized compound that can be conditionally essential. Humans can produce large amounts of cholecalciferol (vitamin D3) as long as their skin is exposed long enough to sufficiently intense sunlight. Only life at higher latitudes (especially during winter months) or indoors, or prevention of skin exposure to sun by clothing or sun-screen lotion makes any dietary intake of this misnamed nutrient (cholecalciferol is not even an amine, much less a vitamin) necessary. Decreased availability (for instance of lipoic acid), when production by intestinal bacteria is disturbed, should also be mentioned.

Undoubtedly, there are numerous further dietary compounds that promote health, sometimes to a very significant extent. Examples include a wide range of polysaccharides, flavonoids, phytosterols, saponins, and other constituents of plant-derived foods that have shown some promise for the prevention of atherosclerosis, cancer, or other debilitating disease. The real question about such nutrient-like compounds is how much can be safely consumed and whether higher than typical consumption with foods provides any worthwhile health benefit.

Lipids and Nutrition

Lipids are essential nutrients for healthy human nutrition. They possess the highest calorific value of the macronutrients at 9 kcal g−1 compared with about 4 kcal g−1 for carbohydrate and protein, hence they are a vital energy source, and were essential for the development and survival of early humans. They are also used in anabolic pathways to produce biologically important molecules such as polar lipids for the formation of membranes, which are ubiquitous throughout any living organism. Some dietary lipids have specific bioactivities, whether receptor or biochemically mediated, for example, the long chain omega-3 fatty acids (FAs) , docosahexaenoic acid, C22:6 (n-3)(DHA) and eicosapentaenoic acid, C20:5 (n-3)(EPA), from fish oils have been linked with reduced cardiovascular risk and reduced cognitive decline. Some FAs can promote release of gut hormones to control gut motility and appetite, and so, indirectly, can influence the absorption of other nutrients. In addition to the nutritional value of the lipids, they also act as the solvent for a wide range of fat soluble nutrients such as vitamins A, D, E, and K and a wide range of phytochemicals such as carotenoids, phytosterols, and tocopherols, which have a range of biological activities (Akoh and Min, 2008) including cholesterol lowering, cancer prevention, and macular degeneration.

Stoichiometry of Multiple Elements in Plants

All the essential nutrient elements have their specific functions in organisms, but stoichiometric studies have focused more on C, N, and P relationships in organisms because N and P are common limiting in terrestrial ecosystems (Ågren et al., 2012; Harpole et al., 2011; Sistla and Schimel, 2012). Recently, studies have begun to involve stoichiometric behaviors of other nutrients. For instance, Han et al. (2011) showed us a case study with stoichiometry of 11 elements (N, P, K, Ca, Mg, S, Si, Fe, Na, Mn, and Al) in leaves of 1900 plant species across China, showing that the concentrations of these elements display a significant variation along latitudinal and longitudinal gradients, with climate, soil, and plant functional type as driving forces. Among these environmental factors, precipitation explains more variation than temperature for all elements except P and Al. The 11 elements differentiate in relation to climate, soil, and functional type. For instance, with increasing MAP, Mn shows a negative relationship, but other elements show positive ones with diverse slopes (Han et al., 2011).

Sun et al. (2012) demonstrated stoichiometric traits of multiple elements in oak seeds at a regional scale and verified that plant seeds exhibit spatial patterns of variation in nutrients (e.g., Ca, Mg, K, and S:N ratio) with environmental variables. Thus, further studies are needed to draw a more general conclusion and to test the ‘stability of limiting elements’ hypothesis.

Publisher Summary

Primary metabolites as essential nutrients are being more intensively studied and their engineering has often been reviewed. Low molecular weight metabolites are important components of crop plants for both consumers and producers. Thus, this chapter first outlines the metabolic engineering of essential nutrients, such as essential amino acids, lipids, vitamins, and minerals, and then summarizes the recent advances in the modification of a more specific secondary metabolism for the improvement of quality traits. Essential amino acid biosynthesis is strictly regulated by some key enzymes, such as dihydrodipicolinate synthase (DHDPS) in lysine (Lys) biosynthesis and anthranilate synthase in tryptophan (Trp) synthesis. Folate has received considerable attention, since its deficiency induces neural tube defects during early pregnancy. Fatty acids are another target for nutritional improvement because some of them are critical in metabolism, cardiovascular health, inflammatory responses, and blood pressure regulation.

Bevacizumab and Angiogenesis

Angiogenesis delivers essential nutrients and oxygen for the sustained growth and metastasis in tumors and presents a rational target in cancer therapy.93 These tumor-induced blood vessels are often structurally and functionally abnormal, impairing the effective delivery of chemotherapeutic agents to the cancer.94 The abnormal process is thought to be driven by an imbalance of pro- and antiangiogenic factors, and disrupting the process by neutralizing vascular endothelial growth factor, a key ligand for angiogenesis, has been a focus in colorectal cancer therapy.95

Bevacizumab is a humanized recombinant monoclonal antibody that binds vascular endothelial growth factor and inhibits liganddependent angiogenesis. The drug's efficacy was demonstrated in two randomized controlled trials, which led to FDA approval for use with any intravenous 5-FU-containing regimen in first- or second-line metastatic colorectal cancer therapy.96 Several mechanisms have been speculated to explain the activity of bevacizumab and other antiangiogenic agents, including starving the tumor of essential nutrients and oxygen by inhibition of formation of tumor vasculature, and improving the delivery of chemotherapeutic agents by normalizing the tumor vasculature and decreasing interstitial pressures in tumors.

In a small randomized phase II trial, 104 patients were randomized to receive weekly bolus 5-FU and leucovorin (5-FU/LV) (control arm), bevacizumab 5 mg/kg or 10 mg/kg plus 5-FU/LV (low-dose and high-dose bevacizumab arms, respectively).97 Compared with those in the control arm, patients in both bevacizumab arms had better response rate (control 17%; low-dose 40%, high-dose 24%), longer median TTP (5.2, 9.0, and 7.2 months, respectively), and longer median survival (13.8, 21.5, and 16.1 months, respectively). It is interesting that the low-dose bevacizumab arm seemed to be superior to the high-dose arm and was partly attributed to some imbalance in randomization, resulting in more patients with poor prognostic factors in the latter group. The dose of 5 mg/kg for bevacizumab was thus chosen for the subsequent phase III trial. Bleeding (gastrointestinal and epistaxis), hypertension, thrombosis, and proteinuria were more common in the bevacizumab arms.

In the interim, irinotecan plus bolus 5-FU and leucovorin (IFL) became the standard first-line therapy for metastatic colorectal cancer in the United States (see earlier). As such, the subsequent phase III trial used IFL as the control regimen, and 813 patients with previously untreated metastatic colorectal cancer were randomized to IFL plus placebo, IFL plus bevacizumab 5 mg/kg, and 5-FU/LV plus bevacizumab 5 mg/kg.98 The 5-FU/LV/bevacizumab arm was discontinued during a planned interim analysis when the data monitoring committee found that the addition of bevacizumab to IFL had an acceptable safety profile. The intention-to-treat analysis showed a superior median survival for the IFL plus bevacizumab arm compared with the control arm (20.3 versus 15.6 months; P < .001) (Fig. 15-4). The study arm also had a better response rate (44.8% versus 34.8%; P = .004) and median duration of response (10.4 versus 7.1 months; P = .001). Reversible hypertension and proteinuria were more frequent in the study arm. Other rare but serious adverse events included thrombotic events, gastrointestinal perforation (1.5% of the patients in the bevacizumab arm) and wound dehiscence.

The role of bevacizumab with oxaliplatin-based regimen for second-line therapy for patients with metastatic colorectal cancer was studied in a randomized phase III study (E3200).99 In the study, previously treated patients were randomly assigned to FOLFOX4 alone or FOLFOX4 plus high-dose bevacizumab (10 mg/kg). Analysis of 829 patients showed superior median survival in the bevacizumab plus FOLFOX4 arm (12.9 versus 10.8 months; P = .001). Dose reduction of bevacizumab to 5 mg/kg was allowed in the study for hypertension, bleeding, thrombosis, proteinuria, and abnormal liver tests. About 56% of 240 patients in the FOLFOX4 plus bevacizumab had bevacizumab dose reduction, and the overall survival was not statistically different from the group without dose reduction.100

Despite the clear role of bevacizumab with intravenous 5-FU-based regimens in first- and second-line therapy for patients with metastatic colorectal cancer, more clinical questions still need to be clarified, such as efficacy of continuing bevacizumab into second-line therapy and synergism with oral fluoropyrimidines. Studies addressing the combination of bevacizumab and cetuximab are ongoing. In the BOND (Bowel Oncology with Cetuximab Antibody)-2 trial,101 patients with advanced colorectal cancer who had unsuccessful irinotecan-based therapy, more than 80% of whom had also been pretreated with oxaliplatin, were enrolled in a randomized phase II trial comparing cetuximab plus bevacizumab with cetuximab/bevacizumab plus irinotecan as salvage therapy. The primary objective of the trial was to document the feasibility of the dual-antibody combinations and to assess the response rate in both arms. In terms of the first objective, no unexpected adverse effects were encountered when cetuximab and bevacizumab were combined; the combination was feasible. Moreover, the addition of bevacizumab appeared to enhance the efficacy of cetuximab and cetuximab/irinotecan in terms of response rate, but more strikingly, in terms of time to tumor progression (TTP). This effect is even more noteworthy, since cetuximab monotherapy in BOND-1 was only associated with a rather disappointing median TTP of 1.5 months. Combining cetuximab with bevacizumab increased median TTP dramatically to 6.9 months. A similar effect was seen in the cetuximab + bevacizumab + irinotecan arm. Unfortunately, large clinical trials have indicated that “double biologic” strategies are harmful to patients.

With the latter data showing the feasibility of irinotecan with bevacizumab and cetuximab, several trials have investigated the combinations in first-line conventional chemotherapy and monoclonal antibodies.102–104 In a randomized phase III trial of chemotherapy/bevacizumab with or without panitumumab (PACCE Study), median PFS in the experimental arm with both the biologics was 10 versus 11.4 months in the experimental versus control arms, respectively, and overall survival was 19.4 versus 24.5 months, also favoring the control arm.102 The combination was inferior even in K-ras wild-type patients with more death rates and excess toxicity. The results are the same with another large study including cetuximab and bevacizumab (CAIRO 2 Study).103 In this study, the combination of capecitabine/oxaliplatin/bevacizumab chemotherapy, with or without cetuximab, was tested in 755 untreated metastatic colorectal cancer patients. The primary endpoint was PFS. The study demonstrated worsened PFS in the double biologic arm, 10.7 in the control arm, and 9.5 in the experimental arm (P = .01). The quality-of-life scores were worse and toxicities also more common in the experimental arm. In the subset analysis, even patients with wild-type K-ras also did not benefit.

Most double-biologic arms of ongoing studies were closed based on the latter results, and such combinations should not be used outside of a clinical trial. The CALGB/Southwest Oncology Group Intergroup 80405, a phase III intergroup trial comparing FOLFOX or FOLFIRI-based chemotherapy (investigators' choice) with bevacizumab, cetuximab or both was also evaluating the role of double biologics. This trial has been amended now to include patients with K-ras wild-type only.