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Indole-3-carbinol (I3C) is a bioactive phytochemical abundant in cruciferous vegetables. One of its main in vivo metabolites is 3,3′-diindolylmethane (DIM), formed by the condensation of two molecules of I3C. Both I3C and DIM alter multiple signaling pathways and related molecules controlling diverse cellular events, including oxidation, inflammation, proliferation, differentiation, apoptosis, angiogenesis, and immunity. There is a growing body of evidence from both in vitro and in vivo models that these compounds possess strong potential to prevent several forms of chronic disease such as inflammation, obesity, diabetes, cardiovascular disease, cancer, hypertension, neurodegenerative diseases, and osteoporosis. This article reviews current knowledge of the occurrence of I3C in nature and foods, along with the beneficial effects of I3C and DIM concerning prevention and treatment of human chronic diseases, focusing on preclinical studies and their mechanisms of action at cellular and molecular levels.

Sorghum is one of the most widely cultivated crops, and is used in foods, domestic animal feedstuffs, alcohol production, and biofuels. Recently, many research groups have demonstrated that sorghum contains various components that are strongly associated with the prevention of major human chronic diseases such as obesity, diabetes, atherosclerosis, cancer, and inflammation. However, to use sorghum more widely as a food for the potential prevention and treatment of human chronic diseases, more studies will be required to elucidate the biological mechanisms. In this review paper, we highlight multiple findings to propose a mechanistic link between sorghum consumption and reduced risk of chronic diseases. © 2020 Society of Chemical Industry.

Colorectal cancer is the third leading cause of cancer incidence and mortality in the United States. Cannabidiol (CBD), the second most abundant phytocannabinoid in Cannabis sativa, has potential use in cancer treatment on the basis of many studies showing its anti-cancer activity in diverse types of cancer, including colon cancer. However, its mechanism of action is not yet fully understood. In the current study, we observed CBD to repress viability of different human colorectal cancer cells in a dose-dependent manner. CBD treatment led to G1-phase cell cycle arrest and an increased sub-G1 population (apoptotic cells); it also downregulated protein expression of cyclin D1, cyclin D3, cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6. CBD further increased caspase 3/7 activity and cleaved poly(ADP-ribose) polymerase, and elevated expression of endoplasmic reticulum (ER) stress proteins including binding immunoglobulin protein (BiP), inositol-requiring enzyme 1α (IRE1α), phosphorylated eukaryotic initiation factor 2α (eIF2α), activating transcription factor 3 (ATF3), and ATF4. We found that CBD repressed cell viability and induced apoptotic cell death through a mechanism dependent on cannabinoid receptor type 2 (CB2), but not on CB1, transient receptor potential vanilloid, or peroxisome proliferator-activated receptor gamma. Anti-proliferative activity was also observed for other non-psychoactive cannabinoid derivatives including cannabidivarin (CBDV), cannabigerol (CBG), cannabicyclol (CBL), and cannabigerovarin (CBGV). Our data indicate that CBD and its derivatives could be promising agents for the prevention of human colorectal cancer.

Pendimethalin is globally registered for control of a wide range of weeds in agriculture and home landscaping. Human exposure to pendimethalin can occur by the oral route through food and other sources. Endothelial function is vital to numerous biological processes, and endothelial dysfunction and poor vascular health is associated with increased atherosclerotic events; however, no study has yet investigated the potential effect of pendimethalin on endothelial function and vasculature formation. The objective of the current study is to investigate if pendimethalin may affect the viability and function of vascular endothelial cells. We observed that pendimethalin significantly repressed viability of human endothelial cells, inducing G1 cell cycle arrest and apoptotic/necrotic cell death. Pendimethalin treatment also activated ER stress and autophagy, leading to loss of mitochondrial membrane potential. In addition, pendimethalin impaired the tube forming and migratory abilities of endothelial cells. This study provides previously unrecognized adverse effects of pendimethalin in vascular endothelial cells, mediated by ER stress-induced mitochondrial dysfunction.

Colon cancer (CC) is considered a high-risk cancer in developed countries. Its etiology is correlated with a high consumption of red meat and low consumption of plant-based foods, including whole grains. Sorghum bran is rich in polyphenols. This study aimed to determine whether different high-phenolic sorghum brans suppress tumor formation in a genetic CC rodent model and elucidate mechanisms. Tissue culture experiments used colorectal cancer cell lines SW480, HCT-116 and Caco-2 and measured protein expression, and protein activity. The animal model used in this study was APC Min+/mouse model combined with dextram sodium sulfate. High phenolic sorghum bran extract treatment resulted in the inhibition of proliferation and induced apoptosis in CC cell lines. Treatment with high phenolic sorghum bran extracts repressed TNF-α-stimulated NF-κB transactivation and IGF-1-stimulated PI3K/AKT pathway via the downregulation of β-catenin transactivation. Furthermore, high-phenolic sorghum bran extracts activated AMPK and autophagy. Feeding with high-phenolic sorghum bran for 6 weeks significantly suppressed tumor formation in an APC Min/+ dextran sodium sulfate promoted CC mouse model. Our data demonstrates the potential application of high-phenolic sorghum bran as a functional food for the prevention of CC.

OBJECTIVES: Environmental contamination by plastics has become a concern in a wide range of fields; in particular, alarm has risen concerning exposure of human tissues to microplastics (MPs). Despite the fact that MPs cross biological barriers and enter the circulation system, no research has yet explored whether MPs impact the normal function of endothelial cells. The objective is to investigate the adverse vascular events by polystyrene microplastics (PS-MPs), focusing on tube formation and viability, using human umbilical vein endothelial cells (HUVECs). METHODS: Tube formation (angiogenesis) was examined using an in vitro angiogenesis assay kit in HUVECs treated for 6 h with different doses of PS-MPs in a range of sizes (0.5, 1.0, 5 µm). Western blotting was performed to observe changes in protein expression of angiogenesis-regulating signaling components in HUVECs treated with 0, 40, and 80 µg/mL of 0.5 µm PS-MPs for 6 h. Next, we performed the MTT assay in the cells treated with different doses and sizes of PS-MPs to examine if long-term treatment with PS-MPs affects cell viability. We also examined if PS-MPs influence autophagy in HUVECs. RESULTS: Tube formation was inhibited by treatment with 0.5 µm PS-MPs in a dose-dependent manner and similar inhibitory activity was observed for both smaller particle sizes (0.5 and 1.0 µm) but not the large size (5 µm). The results of western blotting indicate suppression of cell migration- and angiogenesis-regulating signaling pathways (phosphorylation of p38, Smad2, Src, FAK, PLC1γ, ERK). For MTT assay, significant suppression of cell viability was observed in cells treated with 0.5 and 1 µm PS-MPs for two and three days. Regarding autophagy analysis, PS-MPs induced conversion of LC2-I to LC3-II in HUVECs treated with 0.5 µm PS-MPs. This data proposes autophagy as a possible cell death mechanism in HUVECs exposed to PS-MPs. CONCLUSIONS: Our data propose adverse effect of PS-MPs on the function of endothelial cells. FUNDING SOURCES: Cooperative Agreement from USDA-ARS to University of Maryland (S-HL).

Environmental contamination by microplastics (MPs) is an emerging concern in recent years due to associated adverse impacts of MPs on potential human health problems. Endothelial dysfunction is a condition in which the endothelial layer fails to form normally, and is associated with impaired vascular function. Despite the fact that MPs are known to enter the circulation system through intestinal epithelium, little has been known whether MPs impact the normal function of endothelial cells and the formation of vasculature. In the current study, we investigated the effect of polystyrene microplastics (PS-MPs) on tube formation and cytotoxicity in human umbilical vein endothelial cells (HUVECs). Our study showed that the treatment of HUVECs with PS-MPs significantly decreased cell viability, with intracellular accumulation occurring in a dose- and size-dependent manner. Moreover, significant dose-dependent inhibition of angiogenic tube formation was observed in HUVECs treated with 0.5 μm PS-MPs; this effect was accompanied by suppression of angiogenic signaling pathways and inhibitory activity against wound healing and cell migration. Regarding the mechanism of decreased viability, we observed increased autophagic and necrotic cell death. These results indicate that 6-h exposure of endothelial cells to PS-MPs represses tube-forming capacity, while 48-h exposure leads to autophagy and necrosis-mediated cytotoxicity.

OBJECTIVES: Colon cancer occupy third rank in the United States and its incidence is inversely associated with high consumption of plant-based diet including whole grains. Sorghum is one of broadly cultivated crops and the bran of sorghum contains high content of bioactive compounds including polyphenols. The current study was designed to examine if different type of high phenolic sorghum brans (PI570481, SC84 and Sumac) suppress tumor formation in genetic colon cancer mouse model and elucidate related biochemical and molecular mechanisms using human colon cancer cells. METHODS: Fifty-three Apc(Min/+) mice (4-week old male and female) were assigned and provided with one of following diets; 1) control (n = 11), 2) low dose of PI570481 (7.5% w/w) (n = 11), 3) high dose of PI570481 (15% w/w) (n = 11), 4) SC84 (15% w/w) (n = 10) and 5) Sumac (15% w/w) (n = 10) for 6 weeks. All mice were treated with 2% dextran sodium sulfate for one week in drinking water at 5 weeks of age. The number and size of tumor were measured from the large intestine. For in vitro study, human colon cancer cell lines were treated with different doses (0, 1.25 and 2.5 mg/mL) of high phenolic sorghum bran extracts (PI570481, SC84 and Sumac). Transcriptional activity of β-catenin was analyzed by measuring luciferase activity of reporter gene (Top and Fop flash). Gene expression was analyzed by Western blot using specific antibodies. RESULTS: Feeding three different types of high phenolic sorghum brans (PI570481, SC84 and Sumac) to Apc(Min/+) mice for 6 weeks did not change body weight and cause any toxicity. The tumor number and tumor load in the large intestine were significantly decreased in the mice treated with three types of high phenolic sorghum brans. Regarding mechanisms, treatment of high phenolic sorghum bran extracts repressed transcriptional activity of β-catenin and IGF-1-stimulated phosphorylation of Akt in human colon cancer cells. CONCLUSIONS: Our data propose a potential use of high phenolic sorghum brans as diets for the prevention of human colon cancer. FUNDING SOURCES: Cooperative Agreement from USDA-ARS to University of Maryland (S-HL).

Iron (Fe) biofortification of staple food crops is carried out through genetic selection and breeding. This study determined the genetic and environmental variation of total seed Fe concentration and food matrix factors (carotenoids, kestose, phytic acid, and phenolics) of field peas (Pisum sativum L.) grown in North Dakota, USA, and the genetic variation of seed Fe levels of commercial field pea cultivars grown under greenhouse conditions with different Fe fertilizer treatments. Total Fe and food matrix factors were measured using previously published methods, and data were presented as dry weight basis. The seed Fe concentration ranged between 45 and 53 mg/kg with a mean concentration of 49 mg/kg. Field peas contained significant concentrations of Fe promoters: xanthophyll (17 mg/100 g), canthaxanthin (68 mg/100 g), beta-carotene (680 μg/100 g), kestose (1433 mg/100 g), quercetin (51.7 mg/100 g), and ferulic acid (56.1 mg/100 g). The phytic acid concentration of field peas was naturally low (2.7–3.2 mg/g) and the phytic acid:Fe molar ratio ranged between 5.0 and 5.6. CDC Golden and DS Admiral would be suitable genotypes for future Fe biofortification studies. Overall, field pea is a good source of dietary Fe and future studies will address actual Fe bioavailability using animal/human models.

Inositol phosphates are the main form of phosphorous (P) storage in legume seeds. Mutants low in inositol hexaphosphate (IP6), also known as phytic acid (PA), have been developed to increase iron (Fe) bioavailability and reduce P waste to the environment. The objectives of this study were to determine 1) inositol-P form changes during germination, and 2) the effect of P fertilizer application on seed PA, total P, and Fe concentration of three field pea (Pisum sativum L.) cultivars and two low-PA lines grown under greenhouse conditions. Low-PA field pea lines clearly had lower PA (1.3 - 1.4 mg·g-1) than cultivars (3.1 - 3.7 mg·g-1). Phytic acid concentration in both cultivars and low-PA lines decreased during germination, but tended to increase seven days after germination. Levels of inositol-3-phosphate-phosphate (IP3-P; 0.6 mg·g-1) and inorganic P (1.8 - 2.0 mg·g-1) were higher in low-PA lines than in the field pea cultivars. Reduction of PA in low-PA line seeds may reduce seed Fe and total P concentrations, as levels in the low-PA lines (37 - 42 mg·kg-1 Fe; 4003 - 4473 mg·kg-1 total P) were typically less than in field pea cultivars (37 - 55 mg·kg-1 Fe; 3208 - 4985 mg·kg-1 total P) at different P fertilizer rates. Overall, IP3 is the major form of P present in low-PA field pea lines during germination; however IP6 is the major form of P present in field pea cultivars. Therefore, low-PA field pea lines could be a potential solution to increase Fe bioavailability, feed P utilization, and reduce P waste to the environment.

Biofortification of commonly eaten foods with iron (Fe) and zinc (Zn) might be a solution to global “hidden hunger”. This study was carried out to determine the micronutrient biofortification potential of US-grown field peas ( Pisum sativum L.). We analyzed seed Fe, Zn, calcium (Ca), magnesium (Mg), total phosphorus (P), and phytic acid (PA) concentrations of six commercial field pea genotypes grown at seven locations in North Dakota, USA. These US-grown field peas were naturally rich in Fe (46–54 mg kg –1 ), Zn (39–63 mg kg –1 ), and Mg (1350–1427 mg kg –1 ). A single serving of field pea could provide of 28–68% the recommended daily allowance (RDA) for Fe, 36–78% of the RDA for Zn, and 34–46% of the RDA for Mg. Field pea is not a good source of Ca (622–1219 mg kg –1 ; 6–12% of RDA). In addition, these field peas are naturally low in PA (4.9–7.1 mg g –1 of PA or 1.4–2 mg g –1 of phytic-P) despite very high total P concentrations (3.5–5 mg g –1 ). Overall, field pea is a good food source of Fe, Zn, and Mg, and selection of genetic material to enrich micronutrients in conjunction with growing location may further enhance mineral concentrations.

Cereals are the major energy source for humans throughout the world and hold a prominent position in a balanced diet to meet up carbohydrate demand of the body. Most of the cereals are deficient in micronutrient and vitamins and continuous dependency on cereal based diets resulted in human malnutrition. Biofortification is a novel concept defined as the enrichment of micronutrients through conventional plant breeding and modern biotechnology. In this post genomic era, an enormous amount of genetic information is available for staple food crops. This genetic information could be used to improve nutritional quality of the staple food crops to provide nutritional requirements. During last few decades, cereal biofortification research has been significantly contributed to reduce malnutrition around the world. Knowledge of precise phenotyping and genetics of the traits are prerequisite before starting of a genetic biofortification program. The inheritance of major micronutrients and vitamins in rice, wheat and maize were reported to be polygenic and in most of the cases the quantitative trait loci were mapped in the genome. A few commercial cereal cultivars are developed so far using genetic biofortification technique. The ongoing biofortification programs are more competitive as newer perspective of food matrix came into picture. In this article we reviewed an overview of current global cereal biofortification efforts, global malnutrition issues, and the promise of biotechnology techniques to improve cereals as a whole food solution to combat global malnutrition issues.