Research

-Food as Medicine-

Dr. Sang’s lab studies food as medicine through an integrated program, both independently and in collaboration with others, to conduct the following research: 1) purify and identify bioactive components from functional foods and herbal medicine; 2) determine the biotransformation and bioavailability of these bioactive food components in rodents and humans; 3) use targeted and untargeted metabolomic approaches to study dietary and disease biomarkers; and 4) investigate the in vivo efficacy and underlying molecular mechanisms of bioactive food components, with a focus on gut health and metabolic diseases.

Carbonyl stress arises from the abnormal accumulation of carbonyl metabolites that can modify proteins, lipids, and DNA to form advanced glycation end products (AGEs), contributing to cell and tissue dysfunction seen in aging and metabolic diseases, such as diabetes and cardiovascular disease. This stress results from an imbalance in the formation and metabolism of carbonyl metabolites, as well as increased exposure to exogenous carbonyl species.

Key reactive carbonyl metabolites implicated in carbonyl stress include methylglyoxal (MGO), glyoxal (GO), 3-deoxyglucosone (3-DG), acrolein (ACR), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE). Supported by grants from USDA/AFRI, Qatar National Research Fund, US Apple Association, and NIH, our research focuses on how dietary polyphenols, particularly flavonoids, interact with reactive carbonyl species (RCS). We have demonstrated that flavonoids and their metabolites can trap RCS, forming RCS conjugates, and inhibit AGE formation in various systems, including food matrices, in vitro, and in animal and human models.

Our lab was the first to show that flavonoids and their metabolites trap RCS to form conjugates and prevent AGE formation in vivo. We are now investigating whether dietary flavonoids, along with their RCS conjugates and oxidized metabolites, can serve as biomarkers for flavonoid intake, reflect individual differences, and have an inverse association with the risk of carbonyl and oxidative stress-related metabolic diseases.

2. Biomarkers and Health Benefits of Whole Grain Intake

Cereal-based food products have been a staple of the human diet for centuries, with cereals typically contributing about 50% of dietary fiber intake in Western countries. Increased consumption of whole grains (WGs) is generally associated with a lower risk of developing diet-related disorders, including diabetes, cancer, and coronary heart disease (CHD). However, many epidemiological studies have failed to produce consistent results regarding this relationship, primarily due to the limitations of current dietary assessment tools and the variability in WG bioactive components.

Traditional methods like food frequency questionnaires and 24-hour food recalls have inherent weaknesses in accurately assessing dietary intake. Additionally, factors such as food variety, processing, and storage can affect the levels of bioactive components, and inter-individual genetic differences further complicate the relationship between WG intake and chronic disease risk.

To address these challenges, we are focusing on identifying biomarkers for WG exposure and effects. Our lab is building an in-house dietary compound library and employing both targeted and untargeted metabolomic approaches to study WG biomarkers. We have extensively researched the chemistry, metabolism, bioavailability, and bioactivities of WG wheat and oat. Notably, we identified a panel of WG wheat metabolites as novel biomarkers for WG wheat/rye intake. Additionally, we reported for the first time that avenanthramides (AVAs)—unique compounds in oats—and their microbial metabolites, as well as avenacosides, another group of unique compounds in oats, could serve as potential biomarkers for WG oat intake.

Our ongoing research aims to extend these findings by studying biomarkers for WG barley, rice, and corn. We are examining the inter-relationships between objective biomarkers of intake for six major WGs (wheat, rye, oat, barley, rice, and corn), dietary measures of WG intake, and the risk of metabolic diseases in epidemiological settings. Additionally, we are exploring the interactions and potential additive and synergistic effects among prebiotics, probiotics, and WG phytochemicals in the context of gut health and metabolic disease prevention. 

3. Fecal Metabolome as Indicators of Dietary and Health Status

Our microbiome research focuses on using the fecal metabolome as indicators of an individual’s dietary and health status. Key areas of focus include: 1) utilizing a precision nutrition approach to identify unique microbial metabolites of dietary compounds as exposure biomarkers for specific foods and to reflect inter-individual variations (metabotypes); 2) identifying novel bioactive microbial metabolites, such as metabolites of bilirubin and amino acid-conjugated short-chain fatty acids, and the bacteria that produce them, which are associated with chronic diseases, with the goal of establishing them as disease biomarkers; and 3) building an in-house library of microbial metabolites and using both targeted and untargeted metabolomic approaches to study the fecal metabolome. 4) isolate and characterize the specific functional bacteria from human fecal slurry and research their relation with health

4. Precision Research on Ginger for Chronic Disease Prevention 

Ginger (Zingiber officinale Rosc.) is a widely consumed spice with numerous pharmacological properties. However, studies on its efficacy in humans have yielded inconsistent results. Various confounding factors must be considered when assessing ginger’s health effects against chronic diseases, particularly the levels of bioactive components in ginger formulations used in human trials. Gingerols, the primary compounds in fresh ginger, tend to dehydrate and convert into shogaols, the main compounds in dried ginger, due to the instability of the β-hydroxyl ketone when exposed to heat and acidic conditions. Consequently, concentrations of gingerols and shogaols in ginger products can vary significantly depending on heating and processing methods.

Our research has focused on investigating the compositional differences between fresh and dried ginger, along with their bioactivities, molecular targets, and metabolic pathways. These findings indicate that a "one-size-fits-all" approach may not apply to ginger, and that precision research should be considered for ginger and other foods. We have developed methods to purify the major gingerols and shogaols from ginger and explored their anti-inflammatory, anti-diabetic, and anti-cancer activities. Supported by an R21 grant from the National Cancer Institute (NCI/NIH), we have extensively studied the bioavailability and metabolism of gingerols and shogaols in cancer cells, mice, and humans. We also synthesized the major ginger metabolites and found that these metabolites remain bioactive.

Using microarray and metabolomic approaches, we discovered that both 6-shogaol and its cysteine-conjugated metabolite act as Nrf2 activators, enhancing the expression of antioxidative enzymes and phase II detoxification enzymes in cancer cells and mice. We also examined the impact of gut microbiota on the metabolism and anti-inflammatory effects of gingerols and shogaols. Supported by the Qatar National Research Fund, we studied the effects of gingerols and shogaols on diabetes-related oxidative and carbonyl stress.

In collaboration with Dr. Charles Emala at Columbia University, we received an R61 grant to study the therapeutic effects of ginger for asthma, and an R01 grant to investigate the molecular mechanisms of shogaol metabolites and novel derivatives in asthma using rodent models. Our long-term goal is to define the optimal formulation and dosing strategy for oral ginger dietary supplements that offer resilience against inflammatory diseases, such as asthma, inflammatory bowel disease (IBD), and colon cancer, and metabolic diseases.

5. Novel Prodrugs of Food Bioactive Compounds and Aspirin for Disease Prevention and Treatment

Aspirin is widely used to reduce pain and inflammation, and low-dose aspirin is commonly employed for cardiovascular disease prevention. Recent large-scale human studies also suggest that low-dose aspirin can help prevent colorectal cancer. However, long-term aspirin use, even at low doses, can lead to gastrointestinal complications, such as gastric ulcers and bleeding. This highlights the urgent need to develop safer and more effective aspirin derivatives for patients managing cardiovascular diseases, colon cancer, or chronic pain and inflammation.

Using a prodrug approach, we have synthesized several novel aspirin derivatives by conjugating aspirin with bioactive phytochemicals, including gingerols and shogaols from ginger, resveratrol from grapes, and pterostilbene from blueberries. Our work has led to the issuance of three patents titled "Aspirin Derivatives and Uses Thereof" (Sang, Shengmin, United States Patent Numbers: 9,187,402 B2, November 17, 2015; 9,745,248, August 29, 2017; and 9,850,195, December 26, 2017).

Both aspirin and these phytochemicals possess multiple bioactivities. We have demonstrated that these novel aspirin derivatives exhibit no gastrointestinal toxicity and are more effective than aspirin alone. This suggests that patients may be able to experience the benefits of aspirin without the associated adverse side effects by using these novel aspirin prodrugs.

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