Many of these factors are not accounted for via statistical modeling or adjustment

Familial CRC cases reporting regular wine consumption were noted to have earlier stage at presentation, and the major OS benefit from regular wine consumption was observed for local stage cases . However, this survival improvement for regular wine consumption among familial CRC cases was independent of stage, age, and other clinical variables in an adjusted analysis as shown in Table 4. Local and regional stage CRC patients represent those with potentially curable disease after surgical resection and adjuvant chemotherapy. The cause of death analysis reveals that most CRC cases died from their cancer among familial and sporadic CRC cases. Thus, any protective benefit of wine consumption among familial CRC cases is not likely to be due to a specific decreased mortality risk from death by other causes when compared to sporadic CRC cases. It is not known whether the cases in our study continued with the same wine consumption habits after their diagnosis compared to before diagnosis, which remains a limitation of this study. Nonetheless, potentially operative gene-environment survival effects among wine-consuming early stage, familial CRC cases could be investigated further. Among the numerous compounds found in wine, resveratrol and anthocyanin have been reported to have anticancer activity in vitro. Experimental studies suggest that resveratrol, a naturally occurring compound found in grape skin and wine , has been shown to inhibit tumor initiation, promotion, and progression and is reported to have anti-proliferative effects in colon cancer cells and in experimental murine models . Several mechanisms of action have been proposed for the antitumorigenic effects of resveratrol including inhibition of polyamine synthesis, cyclooxegenase inhibition,round plastic planter and inhibition of NF-kappa-B signaling, among others. Abnormalities in the control of polyamine metabolism result in increased polyamine levels that can promote tumorigenesis .

Resveratrol has been shown to inhibit ornithine decarboxylase , which is the rate-limiting step in polyamine biosynthesis . The polyamine catabolic enzyme spermine spermidine acetyltranferase is upregulated by resveratrol in colon cancer cell lines , promoting polyamine efflux. Thus, resveratrol, through its interactions with ODC and SSAT, affects both the biosynthetic and catabolic pathways involved in polyamine regulation to decrease polyamine levels. Resveratrol was reported to inhibit cyclooxegenase-1 and tumor initiation . Additionally, resveratrol has been shown to inhibit cyclooxygenase-2 and I-kappa-B, thereby inhibiting NF-kappa-B dependent signaling . Preliminary data from our laboratory indicate that resveratrol down regulates signaling through the Wnt pathway , a pathway that is activated in over 85% of CRC cases . Recently, it was demonstrated that resveratrol improves health and survival in obese mice that had been fed a high-caloric diet—although the amounts of resveratrol used in that study were far beyond what could be obtained through wine consumption in humans . The flavonoid extract anthocyanin from red wine showed a suppressive effect on human colon and gastric cancer cells in vitro . White wine was not found to have anthocyanins, and yet the nonanthocyanic extractions from red wine and white wine still suppressed cell growth in the aforementioned study but at a reduced rate compared to anthocyanin . Phenolic acid and anthocyanin extracts from certain blueberries and grapes have been shown to inhibit viability of colon cancer cells, with increased apoptosis noted after anthocyanin treatment. Thus, a variety of compounds in wine may contribute to the observed survival benefit noted in our study through effects on multiple signaling pathways. The observed survival differences for familial CRC cases in our study may reflect other unique differences between regular wine consumers and infrequent wine users. For example, Johansen et al. conducted a cross-sectional study of dietary habits among wine drinkers and beer drinkers and found that people who purchase wine at grocery stores in Denmark also have a healthier selection of other foods.

Wine buyers purchased more olives, chicken, fruits, vegetables, milk, and meat than beer buyers in that study. People buying beer purchased more ready cooked dishes, sugar, chips, and sausages than wine buyers. Although dietary fiber, total daily energy intake, fruit and vegetable consumption, and BMI were not associated with survival in this study, it should be recognized that other dietary factors, lifestyle factors, or habits may contribute to the observed survival effects of wine consumption among familial CRC cases. Importantly, wine consumption has been associated with higher SES compared to beer drinkers , but SES was not a major determinant of survival in our epidemiologic study. This is consistent with other studies on CRC cases that have shown no effect of SES on survival . In contrast, higher SES has been associated with a higher incidence of breast cancer , among others, and has been associated with improved survival in aggregate data for all U.S. cancer patients . High SES is generally associated with improved access to care and insurance coverage—factors that affect screening practices and thus stage at presentation. In our study, there was an association with wine consumption and SES; however, there was not a statistically significant association with SES and stage at presentation among familial or sporadic CRC cases. Larger epidemiologic studies are needed to investigate SES as a potential confounder of the effects of wine consumption on stage at diagnosis among familial CRC cases. It is important to note that the proportion of cases reporting regular wine consumption in this study is low compared to what has been reported in other major studies on alcohol consumption and mortality or risk of CRC . Even among the regular wine consumers in this study, reported consumption appeared quite moderate . This may reflect population differences between otherwise “healthy” cohort study subjects and our population, which was comprised purely of CRC cases. This epidemiologic study provides important hypothesisgenerating results related to wine consumption among familial CRC cases. Some of the genes and gene variants involved in multi-factorial inherited susceptibility to colorectal adenomas have now been described .

However, currently, there is an incomplete understanding of the genes involved, and even less is known about how these genes interact with environmental exposures to affect survival. Notwithstanding available investigations of wine consumption on CRC incidence, this study represents the first large, population based study addressing outcomes for CRC patients based on reported wine consumption. Further investigations aimed at elucidating the mechanisms for the observed benefits of wine consumption in familial CRC patients are needed.Survival of humans will depend on increased agricultural productivity. Agricultural productivity is not only more yield per area, but also higher nutritional content, less dependence on fertilizers, and more resilience against environmental hazards. All of these traits impinge upon plant metabolism. Plants carry out a myriad of metabolic reactions that are intricately connected into complex networks. To understand and engineer plant metabolism, it is important that metabolic complements of plant genomes are accurately and consistently annotated across species. To provide the research community with comprehensive information about plant small-molecule metabolism, we previously introduced the Plant Metabolic Network , a plant-specific online resource of metabolic databases . PMN consists of PlantCyc, a database of all experimentally-supported information found in the literature from any plant species, as well as 22 single-species databases with a mix of experimentally-supported and computationally-predicted information,round plastic plant pot which allow researchers to explore each species’ unique metabolism. Here we describe the substantial expansion of PMN in both quantity and quality, which includes 126 single-species databases. We demonstrate the utility of the PMN resource by applying recently published omics data to gain insights into plant physiology and cellular level metabolism. Additionally, we systematically compare 126 species in the context of metabolism to identify metabolic domains and pathways that distinguish plant families. Finally, we present new website tools for viewing and analyzing metabolic data including a CoExpression Viewer and subcellular boundaries for metabolic pathways.PMN is a compendium of databases for plant metabolism with a substantial amount of experimentally supported information. The latest release contains 126 databases of organism-specific genome-scale information of small-molecule metabolism alongside the pan-plant reference database PlantCyc . Together, these databases include 1,280 pathways, of which 1,163 have direct experimental evidence of presence in at least one plant species. In addition, PMN 15 includes 1,167,691 proteins encoding metabolic enzymes and transporters where 3,436 have direct experimental evidence for at least one assigned enzymatic function. There are 9,129 reactions , and 7,316 compounds. Compared to the PMN 10 release described in Schläpfer et al. , PMN 15 increases the number of species 4.7-fold and proteins 8-fold, and adds 2,929 more reactions, 2,178 more compounds, 66 more pathways, and 3,229 more references . Data in the PMN databases are represented using structured ontologies consisting of hierarchical classes to which pathways and compounds are assigned by PMN curators, which makes statistical enrichment analyses possible. The pathway and compound ontology classes, alongside the phylogeny of the included species, illustrate the breadth of metabolic information and species included in the database . Prominent specialized metabolism classes such as terpenoids and phenylpropanoids are highly represented in the databases. This large volume of metabolic information makes PMN a unique resource for plant metabolism. The reference database, PlantCyc, is a comprehensive plant metabolic pathway database. PlantCyc 15.0.1 contains experimentally supported metabolic information from 515 species. Most of the data come from a few model and crop species .

For example, Arabidopsis thaliana contributes to 43.4% of experimentally supported enzyme information in PlantCyc, followed by 7.46% from Chlamydomonas reinhardtii and 3.37% from Zea mays. Compared to other metabolic pathway databases such as KEGG and Plant Reactome , PlantCychas substantially higher numbers of experimentally supported reaction and pathway data . PlantCyc 15 includes 3,077 experimentally validated reactions with at least one curated enzyme and 1,163 curated pathways . Plant Reactome includes 1,887 and 320 curated reactions and pathways, with 677 reactions and 266 pathways predicted to occur in A. thaliana , while KEGG includes 543 experimentally supported pathways as of February, 2021, with 136 occurring in A. thaliana. Data on the number of reactions in KEGG that were experimentally validated were not available at the time of publication. The reference information in PlantCyc is incorporated into MetaCyc, which also includes experimentally supported metabolic information from non-plant organisms and is used to predict species-specific pathway databases . In addition to the reference database PlantCyc, PMN 15 contains 126 organism-specific metabolism databases . These databases range widely in the plant lineage including several green algae and nonvascular plants. The majority of the plants are angiosperms with the Poaceae family most highly represented with 25 organisms. There are also 8 pairs of wild and domesticated plants, including rice, wheat, tomato, switch grass, millet, rose, cabbage, and banana, alongside their wild relatives . Finally, PMN 15 includes 6 medicinal plants : Camptotheca acuminata, Cannabis sativa, Catharanthus roseus, Ginkgo biloba, Salvia miltiorrhiza, and Senna tora. The newest addition to the list of the medicinal plants is Senna tora, which is a rich source for anthraquinones and whose recent genome sequencing and metabolic complement annotation helped discover the first plant gene encoding a type III polyketide synthase catalyzing the first committed step in anthraquinone biosynthesis . This rich collection of species-specific metabolic pathway databases enables a wide range of analyses and comparisons. To promote interoperability and cross-referencing with other databases, PMN databases contain links to several compound databases such as ChEBI , PubChem , and KNApSAcK . PubChem containins over 270 million chemical entries as of March 2021, and 95% of PMN compounds link to it. ChEBI release 197 has 58,829 entries and serves as a primary source of compound structural information during curation into PMN databases. Within PMN, 65% of compounds link to ChEBI. Examining 50 randomly chosen compounds that are not mapped to ChEBI suggest that the majority of the remaining 35% compounds do not yet exist in ChEBI . KNApSAcK links are comparatively rare, as only 1.7% of compounds have had a KNApSAcK link added by curators. Linking to these chemical databases provides a more in-depth source of information on the compounds and their physical and chemical properties. In summary, PMN is a broad resource for plant metabolism and continues to be under active development and expansion. The single-species databases were created using a computational pipeline and Methods. The large number of predicted databases in PMN 15 allows us to evaluate the quality of the predictions quantitatively.