1 J. Hortl. Sci. Vol. 17(1) : 01-05, 2022 This is an open access article d istributed under the terms of Creative Commons Attribution-NonCommer cial-ShareAl ike 4.0 International License, which permits unrestricted non-commercial use, d istribution, and reproduction in any med ium, provide d the original author and source are credited. Review Nutraceutical Horticulture : An overview of biochemical and molecular considerations Mohan Kumar G.N. Department of Horticulture, Washington State University, Pullman, WA 99163. USA Corresponding author Email: gnmkumar@wsu.edu T he ma jor c omp onent s of ou r diet , na mely, c a r b ohydr a t es , f a t s , pr ot eins , vit a mins , a nd minerals provide for the building blocks besides serving as metabolic fuel to fulfil the bioenergetic needs. Since they serve the basic cellular needs, they are considered as ‘primary metabolites’. The molecular and biochemical pathways modulated by the major food components of our diet are well- established. Many phytochemicals referred to as ‘secondary metabolites’ and not considered as an ‘essential part’ of our diet, also find their way into the digestive tr a ct a long with the major food components. Interest in the role played by the ‘non- essential’ or ‘minor ’ components of our diet in preventing the initiation or progression of metabolic disorders has gained momentum. The metabolic disor der s, by and large, ar e non-pathogenic in nature and originate as a consequence of derailed cellular metabolism. P la nt s p r odu c e over 5 0 , 00 0 p hyt oc hemic a ls b elonging t o t he ma jor gr oup s of s ec onda r y metabolites such as phenolics, alkaloids, saponins and terpenes. The secondary metabolites serve several functions in plants and tend to accumulate in various plant parts in response to biotic and/or a biotic inter a ctions. Ma ny of the seconda r y metabolites are used by the pharmaceutical industry either in the for mulation drugs dir ectly, or a s pr ecur s or s f or a ctive ingr edients in t he dr ug formulations. The secondary metabolites associated with our diet a re known to influence cellular function upon assimilation. Such dietary phytochemicals capable of sustaining normal cellular function and sustain health are known as ‘nutraceuticals’. Although phytochemicals of nutraceutical value occur widely, horticultural crops such as fruits, vegetables and spices are particularly rich in nutraceuticals. The interest in the nutraceuticals is on the increase as ca n be ascertained from number of books a nd jou r na ls f ea t u r ing r es ea r c h a r t ic les on nutraceuticals (Fig. 1, 2). This talk will focus on the role of dietar y nutra ceuticals derived fr om fruits, vegetables, and spices in sustaining health via their interaction with the biochemical/molecular components in our cells. C e llular c o mpo ne nt s int e r ac t ing w it h nutraceuticals The biochemical pathways modulated by the dietary nutraceuticals are many and complex. However, the major player interacting with nutraceuticals appears to be the nuclear transcription factor (NF- K B) . M a ny diet a r y nu t r a c eu t ic a ls ex hib it inhibitory effect on NF-kB (Fig. 3). In addition, nutr aceutica ls are capable of inhibiting NF-kB activation mediated by the tumor necrosis factor- alpha (TNF-), a cell-signaling molecule. T he activation of NF-kB transcribes genes that mediate the initiation and progression of several metabolic disorders. Transcription factors Transcription factors are proteins that bind to DNA to effect transcription. Over 1600 transcription fa ctor s exist in ma mma lia n cells. One su ch transcription factor of importance is NF-kB. As many as 133, 517 citations (Oct 2021; PubMed C ent r a l, N a t iona l C ent er f or Biot ec hnology Information, NCBI) exist on various aspects of NF- kB. It is a transcription factor of relevance to the initiation and progression of diseases. Therefore, inhib it ion of N F - kB a nd/ or it s endogenou s activators (see below) a re considered valuable targets for drug development. NF-kB was discovered in 1986 by Ranjan Sen and David Baltimore. It is ubiquitous to all mammalian cells a nd exists in the cytopla sm. NF-kB is expressed constitutively and remains inactive when 2 Mohan Kumar J. Hortl. Sci. Vol. 17(1) : 01-05, 2022 bound to its inhibitory peptide, IkB. The list of activators of NF-kB is large and include biotic as well as abiotic factors such as viral antigens, free- r a dic a ls ( F R s ) , c a r c inogens , en vir onment a l pollutants, alcohol, to name a few. In addition, a family of endogenous peptides known as tumor necrosis factors (TNFs), play a crucial role in the a c t iva t ion of N F - kB. Up on b ind ing t o it s a c tiva t or s, T N F p r omot es degr a da tion of its inhibitory peptide (IkB) resulting in the activation of N F-kB. T he a ctive NF- kB then enter s the nucleus and binds to the response elements (RE) of DNA to promote transcription. In fact, active NF- kB has potential to transcribe over 150 genes with a potential to deregulate cellular function. Tumor Necrosis Factor T NF is a tr ansmembr a ne protein that pla ys a crucial role in the activation of NF-kB. It was first isolated in 1984 and identified as an endogenous t u mor r egr e s s ion f a c t or. T her ef or e, it wa s designated as a tumor necrosis factor. However, over the years, the TNF was identified as a pro- inflammatory cytokine (cell-signaling peptide) with an ability to initiate several inflammation-induced metabolic disorders upon binding to its elicitors. Thus, TNF has a dual role in cell metabolism and often described as a ‘double-edged sword’. The loca liz ed a nd contr olled expr es sion of T N F- mediated inflammatory reaction has therapeutic significance. However, its uncontrolled expression lea ds to chr onic infla mma tion a nd contr ibute toward metabolic disorders. For example, in cancer cells, TNF is expressed constitutively. TNF plays a crucial role in pathogenesis of several diseases and hence has attracted a greater research interest. Several synthetic FDA approved drugs as inhibitors of TNF are currently available. The TNF inhibitor drug industry is expected to reach 42.1 billion US $ in the year 2025. Biochemical/molecular pathways modulated by the active TNF and NF-kB As described above, activation of TNF and NF-kB has potential to result in far-reaching consequences through their abilities in initiating transcriptions detrimental to the normal cellular function. Such transcriptional changes are significant to derail cells from their norma l function by activa ting pro- inflammatory pathways. Although localized and regulated inflammation is beneficial in containing the disea se pr ogr ession, chr onic infla mma tion contributes toward a number of diseases. In fact, most disea se na mes ending with suffix “ itis” ( b r onc hit is , hep a tit is , meningit is . . . ) s u gges t inflammatory origin (itis: inflammation). By inhibiting apoptosis (programmed cell death) and promoting angiogenesis (development of new blood vessels), NF-kB confirms immortality to abnormal cells. Fa ctors that inhibit a poptosis pr omote proliferation of cells with undesirable function. NF- kB also promotes development of new blood vessels (angiogenesis). Among several factors that promote angiogenesis, vesicular endothelial growth factor (VEGF) plays a major role in the development of blood vessels. Developing tumor cells promote angiogenesis mediated by VEGF. Inhibition of angiogenesis is therefore desirable for containing tumor growth. To date, over 14 FDA approved angiogenesis inhibitors are available. Inhibition of TNF, NF-kB and associated cellular events by nutraceuticals from fruits, vegetables, and spices By their ability to inhibit activation of TNF and NF- kB, nutraceuticals derived from fruits, vegetables, and spices modula te infla mma tion, a poptosis, a nd angiogenesis (Fig. 2, 3). These molecular/biochemical events promote metabolic disorders such as cancer. A significant body of knowledge exits pertaining to the potential and mode of action of nutraceuticals in containing diseases such as prostate, breast, colon cancer and Alzheimer’s disease. To date, information pertaining to the nutraceutical benefits of curcumin (turmeric), quercetin (onion), resveratrol (red grapes, peanut seed coat), sulforaphane (cole crops) and capsaicin (chilies) appear prominently (Fig. 4abc and 5ab). It is evident from the published literature that studies on the nutr a ceutica l benefits of other horticultural crops are actively pursued. An interdisciplinary course covering the nutraceutical aspects of horticultural crops will be a very useful addition to the undergraduate or graduate curriculum. Such a course deriving appropriate content from horticulture, biochemistry, molecular biology, food science, pharmacology, and human physiology will be valuable to advance awareness on the scientific basis for the health sustaining benefits of fruits, vegetables, and spices. 3 Nutraceutical Horticulture Fi g. 1 . N um be r of p ub lic at io ns p er ta in in g to t he n ut ra ce ut ic al p hy to ch em ic al s of s el ec te d fr ui ts , v eg et ab le s an d sp ic es c ap ab le m od ul at in g in fla m m at io n, a po pt os is ( pr og ra m m ed c el l d ea th ) an d an gi og en es is b y th ei r ab ili ty t o in hi bi t ac tiv at io n of T N F (t um or n ec ro si s fa ct or ) an d N F- kB (n uc le ar t ra ns cr ip tio n fa ct or ). So ur ce : N at io na l C en te r fo r B io te ch no lo gy I nf or m at io n, U SA . Snotaclbupforeb mun J. Hortl. Sci. Vol. 17(1) : 01-05, 2022 4 Mohan Kumar Fig. 2. Number of publications pertaining to the nutraceutical phytochemicals of selected fruits, vegetables, and spices capable of preventing or containing diseases such as prostate, breast and colon cancer and Alzheimer’s disease through their ability to inhibit activation of TNF (tumor necrosis factor) and NF-kB (nuclear transcription factor). Source: National Center for Biotechnology Information, USA. Fig. 3. Nutraceutical components of selected fruits, vegetables, and spices capable of inhibiting nuclear transcription factor and tumor necrosis factor (NF-kB/TNF). The activation of TNF/NF-kB has negative effects on cellular function. S no ta cl bu pf or eb m un J. Hortl. Sci. Vol. 17(1) : 01-05, 2022 5 Fig. 4. Simplified schematic presenting the mechanism of activation of tumor necrosis factor (TNF) and nuclear transcription factor (NF-kB). Nutraceuticals derived from fruits, vegetables and spices play a role in the inhibition of NF-kB and suppress cellular processes (inflammation, angiogenesis, and apoptosis) that lead to metabolic disorders (Bold faced TNF and NF-kB represent active forms). REFERENCES Anand, P., Kunnumakkara, A.B., Sundaram, C, Harikumar, K.B., Tharakan, S.T., Lai, O.S., Sung, B., Aggarwal, B.B. 2008. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res, 25:2097-116. Taniguchi, K., Karin, M. 2018. NF-κB, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol 18, 309–324. Liu, T., Zhang, L., Joo, D., Sun, S.C. 2017. NF-κB signaling in inflammation. Sig Transduct Target Ther 2, 17023 Holbrook, J. Lara-Reyna, S., Jarosz-Griffiths, H., McDermott, M. 2019. Tumour necrosis factor signaling in health and disease. F1000Res. 28: F1000 Fa culty Rev-111. doi:10. 12688/ f1000research. 17023.1. Nutraceutical Horticulture ACKNOWLEDGEMENT Thanks to Dr. TS Channesh, Director, Center for Public Understanding of Science (CPUS), Bangalore (https:/ /cfpus.org) for his constructive criticism. J. Hortl. Sci. Vol. 17(1) : 01-05, 2022