Additionally, clinical studies are needed, since in vitro and animal studies, while potentially relevant as preclinical models, do not directly assess outcomes such as the vascular effects in humans. Clinical and mechanistic data on the biological effects of polyphenols derived from dates are limited . Such evidence is crucial for agriculture, health professionals and consumers, particularly as the concept of personalized nutrition grows more popular. In addition to randomized clinical trials on the fruit in general, more data is needed to identify which polyphenols are the most vasculoprotective and then determine how best to cultivate, harvest and process the fruit for maximum bio-activity. The efficacy of date consumption also needs further interrogation in various at-risk groups such as those with lipid disorders, hypertension, obesity or diabetes. Since all fruits are not equal in composition, identification of unique bio-active compounds or fractions in dates would help define benefits that may not be obtained from other fruits or plant-based foods. Beyond polyphenols, dates contain cardiovascular-protective nutrients including potassium, magnesium, folate, selenium, fiber, and vitamin C . Most date varieties are rich in potassium and low in sodium, both of which are important dietary factors that help maintain blood pressure in the normal range.Dates contain folic acid and vitamin C. Folic acid is required to metabolize homocysteine to methionine. Elevated levels of serum homocysteine have been associated with increased risk for CVD . Although the mechanisms by which increased homocysteine promotes CVD are incompletely defined,blueberry packaging box suggested alterations include impaired vascular tone due to decreases in NO bio-availability and increases in ET-1, promotion of damaging ROS, and endothelial inflammation and the activation of the coagulation cascade.
The vitamin C in dates, while modest in amount compared to most citrus fruits, can nonetheless help to scavenge free radicals via enzymatic and non-enzymatic activities, and help protect lipoproteins from oxidative damage. In addition, vitamin C can improve measures such as arterial stiffness and endothelial function, and low serum concentrations of vitamin C have been linked to increased CVD risk and mortality. Some of the cardioprotective effects of dates have been ascribed to dietary fibers, which have a well-established lipid-lowering effect. Serum triacylglycerol, total cholesterol, and LDL-C levels were significantly lowered in rats given 100 g/kg of date dietary fibers. Most of the fibers in dates are insoluble. These fibers can bind to cholesterol and triacylglycerols in the intestine and facilitate their excretion, which helps lower circulating cholesterol levels. As a result, less lipoprotein is also susceptible to oxidation, thus reducing the impact on atherogenesis. Further, fiber-rich foods can promote production of beneficial commensal bacteria while limiting the growth of known opportunistic pathogens. A high-fiber diet was reported to increase acetateproducing micro-biota, lower blood pressure and decrease cardiac hypertrophy and fibrosis in hypertensive mice. Bacterial fermentation of prebiotic soluble fiber generates short chain fatty acids, which are thought to exert several beneficial effects including differentiation of immune regulatory T cells, and decreasing the expression and activation of peroxisome proliferator-activated receptor-γ . Downregulation of PPAR-γ activates a mitochondrial uncoupling protein 2 and an AMP-activated protein kinase network, shifting metabolism in adipose and liver tissue from lipogenesis to fatty acid oxidation. Conversely, activation of PPAR-γ has been shown to have anti-inflammatory effects, promote the expression of genes for fatty acid oxidation, and decrease lipotoxicity in macrophages .
The gut micro-biota are critical for enhanced bio availability and activity of ingested polyphenols, as most parent compounds are not well absorbed in the small intestine. Following the ingestion of polyphenols, typically in their glycosylated forms, bacteria in the gastrointesti-nal tract metabolize these molecules to low-molecular-weight phenolic compounds that are then absorbed by intestinal epithelial cells. Polyphenols have been shown to undergo a variety of enzymatic processes by bacterial populations in the gastrointestinal tract, including the hydrolysis of glycosylated flavonoids, acylation of flavanol-3-ols and esterification of hydroxycinnamic acids . A detailed description of these mechanisms can be found elsewhere. While the health promoting cardiovascular benefits of a number of fruits, nuts and berries rich in select polyphenols have been characterized through animal and human studies, no such data exists for dates to our knowledge. Given the polyphenol and fiber content of dates, vascular function and gut micro-biome studies would be useful. Vascular function is commonly assessed by two noninvasive techniques: flow-mediated dilation of the brachial artery and peripheral arterial tonometry in the fingertip. Both methods have demonstrated prognostic value for the assessment of cardiovascular risk factor burden. High dietary intakes of select polyphenols, such as the flavanols and PACs found in berries, tea, red grapes, and cocoa have been reported to significantly improve FMD and PAT in various population groups. Importantly, no data exists with respect to the impact of date products and their polyphenols on vascular dysfunction via measurement of FMD and PAT. An inherent challenge with most nutrition studies is the identification of suitable controls. This is particularly difficult when examining the potential health effects of whole foods that contain a multitude of compounds that are bio-active either separately or through their interaction with other constituents in the food matrix.
One model for testing foods or extracts is to use a control product that is closely matched in calories, macro- and micronutrients, taste, and color, but devoid of the test fraction or compound. This model has been used successfully in studies that assess the effects of a dietary strawberry powder and a flavanol-rich cocoa drink . Another model is to employ a no-intervention control group, although operationally, this may skew the results since a number of those assigned to the control group may withdraw from the study prior to its completion, and those remaining may not fully represent the population initially enrolled. Future human research on dates must select the study population carefully, and focus mainly on groups at risk for CVD. Accordingly, hormonal status, age and sex are factors that can produce significant interindividual variability in cardiometabolic responses to phenolic compounds and must be considered. Factors such as microbial metabolism and genetic polymorphisms may be other contributors to outcome variability. Recent attention has also emphasized the challenge of reproducibility and accuracy in human nutrition research. As noted above, more complete compositional profiles of dates are needed rather than simply recognizing the total amount of GAEs, a gross index of flavonoid content. A more detailed characterization of products, reagents, and model systems used, as well as better rigor and reporting of experimental designs, protocols, and data analysis, will help achieve this goal. Worthy of note, many of these elements were limiting factors in the in vitro and in vivo animal reports discussed above. While dates have positive biological effects, concerns have been raised about their potential concentrations of heavy metals. Exposure to heavy metals can result in cardiovascular diseases, encephalopathy, renal dysfunction, dementia, and certain cancers. A recent study of seven date varieties collected from different locations in Saudi Arabia noted that aluminum, chromium, and antimony were within a safe range based on the maximum allowable levels set by the World Health Organization, while arsenic, lead, and cadmium exceeded the upper limit in some of the date cultivars. Numerous environmental factors can increase concentrations of heavy metals such as mining, fertilizer applications and industrial emissions,blueberry packaging containers as well as naturally occurring amounts normally found in some soils. An increasing body of evidence suggests that the gut micro-biota has a profound impact on human health. While the micro-biome of a healthy individual is relatively stable, gut microbial dynamics can be influenced by host lifestyle and dietary choices. An acute change in dietary pattern from animal-based to plant-based diet alters gut microbial populations within 24 h and then reverts to baseline within 48 h of returning to the baseline dietary pattern. Studies that involve intake of a specific dietary component demonstrate how certain micro-biota tend to respond to nutrient-specific challenges. Protein, fats, digestible and non-digestible carbohydrates, probiotics, and dietary polyphenols all induce shifts in the micro-biome with secondary effects on host immunological and metabolic markers. An emerging and rapidly growing scientific literature is implicating the micro-biome in a number of conditions and disorders including inflammatory bowel disease, obesity, type 2 diabetes mellitus, cardiovascular disease, cancer, autism, mood and neurodegenerative disorders. The consumption of polyphenol-rich foods, including fruits and vegetables, has been reported to reduce pathogenic Clostridia and to enrich beneficial bacteria such as Bifidobacterium and Lactobacillus species in human studies. In conjunction with these changes, reductions in plasma triglycerides and C-reactive protein have been noted. Dietary polyphenols have been shown to help maintain intestinal health by preserving the gut microbial balance through the stimulation of the growth of beneficial bacteria and the inhibition of pathogenic bacteria, exerting prebiotic-like effects.
We have previously demonstrated the effect of water extract of culinary spices, including cinnamon, Mediterranean oregano, ginger, rosemary, black and cayenne pepper, on the growth of 33 Bifidobaterium and Latobacillus spp., and its antimicrobial activity against 88 intestinal, pathogenic, and toxigenic bacterial strains in an in vitro model. These spices promoted the growth of Bifidobaterium and Latobacillus spp. Cinnamon, ginger, oregano, black pepper, and cayenne pepper showed activity against several pathogenic Fusobaterium and Ruminococcus spp. and selected Clostridium difficile strains. The present pilot study was designed to investigate the effects of mixed spices at culinary doses consumed over 2 weeks in a standardized 5 g capsule on the production of gut micro-biota and short-chain fatty acids in healthy subjects compared to a placebo maltodextrin capsule in a parallel randomized controlled clinical trial. The pilot study was conducted in accordance with the guidelines of the Office of the Human Research Protection Programs of the University of California, Los Angeles. The clinical protocol was approved by the UCLA Internal Review Board and the study was registered at the NIH Clinical Trial Registry . A total of 66 healthy women and men aged 18 to 65 were screened in 2017 through local advertisement. Participants with a history of gastrointestinal surgery, diabetes mellitus, or other serious medical conditions such as chronic hepatic or renal disease, bleeding disorder, congestive heart disease, chronic diarrhea, myocardial infarction, coronary artery bypass graft, angioplasty within 6 months prior to screening, current diagnosis of uncontrolled hypertension or chronic gastrointestinal disorders, bulimia, anorexia, laxative abuse, or endocrine disorders were excluded. Participants who were consuming a high-fiber/polyphenol diet; taking any medication or dietary supplement interfering with the absorption of polyphenols; pregnant or breastfeeding; frequently using prebiotics, probiotics, yogurt, or fiber supplements; taking antibiotics or laxatives within the previous 3 months; or currently using tobacco products were also excluded. Thirty-one subjects meeting enrollment criteria were recruited and provided written informed consent before the study began. A randomized, placebo-controlled, double-blind pilot study was conducted. Subjects were randomized according to an algorithm modified from a previous publication. The study was divided into two periods: an initial run-in period of 1 week and an intervention period of 2 weeks. After the run-in period, 31 subjects were randomly allocated to consume either 5 g capsules of spice mixture containing 1 g cinnamon, 1.5 g oregano, 1.5 g ginger, 0.85 g black pepper, and 0.15 g cayenne pepper, or 5 g capsules containing maltodextrin daily for 2 weeks. The individual spices were purchased from local grocery stores. At the start of study, participants received a diet instructional handout and were counseled by a registered dietitian on compliance. During the run-in and intervention period, all participants consumed a beige diet . The beige diet handout advised participants to eat foods beige in color and rich in simple carbohydrates like white breads/bagels, crackers, granola bars, rice, macaroni/pasta, yogurt, dairy, poultry, cereal, and bananas and to avoid foods high in polyphenols and/or fiber. Participants were also provided with weekly checklists to track their fruit and vegetable intake throughout the study with a limit of three servings per day. This checklist included a list of higher fiber/polyphenol foods to avoid as well as a list of lower fiber/polyphenol fruits and vegetables theycould consume as a part of their three servings per day, with a serving size estimation tool included. At the baseline and final visits, participants also completed and returned 3-day food records that were evaluated by the dietitian for compliance with the beige diet.