Mini Reviews in Medicinal Chemistry - Volume 4, Issue 8, 2004

A large variety of peptides are generated in the gut lumen during normal digestion of dietary proteins. Large quantities of small peptides (ie. dipeptides and tripeptides) are absorbed through the gut mucosa and represent the primary mechanism for absorption of dietary nitrogen. However, larger peptide fragments are also absorbed with absorption decreasing with increasing chain length. Many of these dietary peptides have been shown to have biologic activity and many are active in microgram quantities. These peptides may modulate neural, endocrine, and immune function. In this report, we review normal protein digestion and absorption. We then discuss the biological actions of the amino acids arginine and glutamine and the biologic actions of a variety of dietary derived peptides. We concentrate on the immune effects of these peptides. We illustrate the potency of dietary peptides with a discussion of the cardiovascular effects of carnosine. We also review biologic effects of different protein sources, which generate different peptide profiles during digestion. The implications of dietary peptides for modulation of disease are discussed.

Arginine is a semi-essential amino acid that is required during periods of maximal growth, severe stress, and injury. Arginine is a substrate for protein synthesis but also modulates cellular biochemical functions via conversion to a number of biologically active compounds. Arginine is utilized by a vast variety of metabolic pathways that produce a variety of biologically active compounds such as nitric oxide, creatine phosphate, agmatine, polyamines, ornithine, and citrulline. Arginine supply is primarily regulated by two enzyme systems: arginase (part of the urea cycle) and nitric oxide synthase. Arginine has many effects in the body that include modulation of immune function, wound healing, hormone secretion, vascular tone, insulin sensitivity, and endothelial function. Arginine mediates its effects via nitric oxide independent and dependent pathways. Nitric oxide modulates many cellular functions that include vascular tone, expression of adhesion molecules, leukocyte adhesion, and platelet aggregation. Arginine modulates the development of atherosclerotic cardiovascular disease, improves immune function in healthy and ill patients, stimulates wound healing in healthy and ill patients, and modulates carcinogenesis and tumor growth. Thus, arginine is a biologically active dietary compound with numerous physiologic and pharmacological activities.

Glutamine is the most abundant amino acid in humans and possesses many functions in the body. It is the major transporter of amino-nitrogen between cells and an important fuel source for rapidly dividing cells such as cells of the immune and gastrointestinal systems. It is important in the synthesis of nucleic acids, glutathione, citrulline, arginine, gamma aminobutyric acid, and glucose. It is important for growth, gastrointestinal integrity, acid-base homeostasis, and optimal immune function. The regulation of glutamine levels in cells via glutaminase and glutamine synthetase is discussed. The cellular and physiologic effects of glutamine upon the central nervous system, gastrointestinal function, during metabolic support, and following tissue injury and critical illness is also discussed.

Short chain fatty acids (SCFA) have multiple in vivo and in vitro effects including cell cycle arrest and induction of protein synthesis, differentiation, and apoptosis. Butyrate or derivatives have promise for treating inflammatory bowel disease and colon cancer. Genomic and proteomic analysis have generated new knowledge on function and applications for SCFA.

From a nutritional standpoint, saturated triglycerides with a medium (6 to 12) carbon chain length (MCT) have traditionally been regarded as biologically inert substances, merely serving as a source of fuel calories that is relatively easily accessible for metabolic breakdown compared with long chain triglycerides (LCT). This quality of MCT has been shown to offer both benefits and risks depending on the clinical situation, with potential positive effects on protein metabolism in some studies on one side, and an increased risk for ketogenesis and metabolic acidosis on the other. At another level, studies regarding lipid effects of MCT on the immune system, as with LCT, so far have yielded equivocal results, although there is a recent experimental evidence to suggest that MCT posses immune modulating properties and should in fact be regarded as bioactive mediators. Most of this information comes from studies where effects of MCT have been compared with those of LCT in lipid emulsions, as part of parenteral (intravenous) nutrition formulations. Unfortunately, the relevance of these observations for clinical practice remains largely unclear because adequately powered trials that clearly point out the position of MCT in relation to structurally different lipids have not been performed. In the present paper we review the experimental and clinical evidence for cellular and physiological effects of nutritional MCT. In addition, studies describing possible mechanisms behind the observed effects of MCT will be discussed.

Epidemiological evidence has established that ingestion of long-chain polyunsaturated omega-3 fatty acids (ω-3 PUFAs), abundant in fish oils, have profound effects on many human disorders and diseases, including cardiovascular disease and cancer. Here we briefly review the dietary recommendations and the food sources that are naturally enriched by these fatty acids. There are also a number of products including eggs, bread, and cereals available to supplement ω-3 fatty acid dietary intake. Some of these supplements are proposed to aid different pathological conditions. While the beneficial effects of omega-3 fatty acids can no longer be doubted, their molecular mechanism of action remains elusive. Without question, the action of omega-3 fatty acids is complex and involves a number of integrated signaling pathways. This review focuses on one of the possible cellular mechanisms by which the ω-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may function. Studies with cancer cells suggest that DHA induces cell cycle arrest and apoptosis by activating protein phosphatases, leading to dephosphorylation of retinoblastoma protein (pRB). Protein phosphatases are also involved with the protein Bcl2, which regulates the release of cytochrome c from mitochondria, and eventually, activation of the apoptotic enzyme caspase 3.

In Asia, a variety of dietary products have been used for centuries as popular remedies to prevent or treat different diseases. A large number of herbs and extracts from medicinal mushrooms are used for the treatment of diseases. Mushrooms such as Ganoderma lucidum (Reishi), Lentinus edodes (Shiitake), Grifola frondosa (Maitake), Hericium erinaceum (Yamabushitake), and Inonotus obliquus (Chaga) have been collected and consumed in China, Korea, and Japan for centuries. Until recently, these mushrooms were largely unknown in the West and were considered “fungi” without any nutritional value. However, most mushrooms are rich in vitamins, fiber, and amino acids and low in fat, cholesterol, and calories. These mushrooms contain a large variety of biologically active polysaccharides with immunostimulatory properties, which contribute to their anticancer effects. Furthermore, other bioactive substances, including triterpenes, proteins, lipids, cerebrosides, and phenols, have been identified and characterized in medicinal mushrooms. This review summarizes the biological effects of Ganoderma lucidum upon specific signaling molecules and pathways, which are responsible for its therapeutic effects.

Recent experimental and epidemiological studies have provided convincing evidence for a variety of health benefits derived from the consumption of soy and soy food products. For example, soy isoflavones are felt to protect against different cancers, cardiovascular disease, and bone loss. Many studies have demonstrated the effect of soy isoflavones on specific target molecules and signaling pathways, including but not limited to, cell proliferation and differentiation, cell cycle regulation, apoptosis, angiogenesis, cell adhesion and migration, metastasis, and activity of different enzymes. Isoflavones also share structural homologies with estrogens and are therefore classified as phytoestrogens with weak estrogenic properties. Since isoflavones bind to estrogen receptors (ERα and ERβ), they are considered to be possible estrogen receptor modulators. However, isoflavones can also exert biological effects independent of their phytoestrogenic activities. Recent studies suggest beneficial health effects of soy and recommend increasing the intake of isoflavone-rich soy protein to the level of intake commonly used in Asian countries.

We review the present knowledge on the biological mechanisms of action of probiotics and prebiotics. They include direct effects in the intestinal lumen or on intestinal or immune cells, and indirect mechanisms through modulation of the endogenous microflora (composition or functions such as butyrate production) or of the immune system.

Excessive hepatic glucose production is thought to be a major contributor to the type 2 diabetic state. Drug discovery efforts have yielded small synthetic inhibitors for gluconeogenic and glycogenic regulators of this pathway. The most advanced targets are outlined in this mini-review and include: the glucocorticoid receptor, 11β-hydroxysteroid dehydrogenase type 1, fructose 1,6-bisphosphatase, the glucagon receptor, glycogen phosphorylase, glycogen synthase kinase-3, and glucose-6-phosphatase.

Changes in the biochemical integrity and function of the GABAA-benzodiazepine receptor (BZR) complex have been implicated in various neurological and psychiatric disorders. The development of specific radioligands for the GABAA-BZR have not only contributed to the elucidation of the receptor's biochemical functions, but also provided a means by which these changes are correlated to disease states when studied with the functional imaging modalities of positron emission tomography (PET) and single photon emission computed tomography (SPECT).