Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 8, Issue 2, 2008

Type 2 diabetes, obesity, metabolic syndrome, and their cardiovascular complications represent a major public health problem around the world. Strategies for effective prevention and treatment for these devastating diseases are of great interest to the general public, government organization, and the healthcare industry. Dietary interventions are a popular approach used frequently by the general public in the fight against these diseases. In particular, dietary supplementation is a major part of diet intervention. Botanical products as an important category of supplementation are common components in dietary interventions. The most popular botanicals include herbs, tea, and polyphenols. Botanicals represent a potentially rich source of remedies for type 2 diabetes [1, 2]. In the past ten year, botanical research and usage were enhanced significantly in many countries around the world. In the USA, the National Center for Complementary and Alternative Medicine (NCCAM) was established in 1998 [3]. One of the main tasks of NCCAM is to support botanical research. NCCAM is one of the 27 institutes and centers that comprise the NIH. In June 2004, the US Food and Drug Administration (FDA) issued new guidelines accelerating approval of herbal mixtures with evidence of safety and effectiveness, even if the active constituents are not known. In China, a new 15-year plan was established in 2007 to enhance research in Traditional Chinese Medicine with an investment of 1 billion yuan (US$130 million) [4]. This is 5 - 6 times as much as the previous investment. In the past few years, India developed a huge electronic database known as the Traditional Knowledge Digital Library to enhance botanical research [5]. In this special issue, five review articles provide current information on botanicals relevant to the management of Type 2 diabetes, obesity, and metabolic syndrome. The first review is prepared for safety and efficacy of botanicals in the clinical management of glucose homeostasis. The reviews 2-4 discuss bioactivities, active components, and mechanisms of action for specific botanicals. Herbs, tea, and phenolic compounds are discussed in these three articles for management of Type 2 diabetes, obesity and metabolic syndrome. Herbs provide fertile ground for modern drug development [6-8]. However, the process of developing a drug from herbs is complicated [9]. The fifth review documents standard procedures and key points in preparation of botanicals. This special issue devoted to “Botanical Treatments for Diabetes and Obesity” is a timely and helpful reference of this important emerging area of research. REFERENCE [1] Dey, L.; Attele, A.S.; Yuan, C.S. (2002) Altern. Med. Rev., 7, 45-58. [2] Yeh, G.Y.; Eisenberg, D.M.; Kaptchuk, T.J.; Phillips, R.S. (2003) Diabetes Care, 26, 1277-1294. [3] Richardson, M.A. (2001) J. Nutr., 131, 3037S-3040S. [4] Qiu, J. (2007) Nature, 446, 590-591. [5] Jayaraman, K.S. (2006) Nature, 442, 342-343. [6] Towie, N. (2006) Nature, 440, 852-853. [7] Qiu, J. (2007) Nature, 448, 126-128. [8] Corson, T.W.; Crews, C.M. (2007) Cell, 130, 769-774. [9] Editorial, N. (2007) Nature, 448, 105-106.

Botanical products are widely used in nutritional supplementation for promotion of health or prevention of diseases. With the high prevalence of obesity and type 2 diabetes, abnormalities in carbohydrate metabolism are common in the general population and obtaining glycemic control is important in reducing the complications of diabetes. If shown to be effective, botanical products have a unique position in potentially aiding the general public in regard to obesity and diabetes. They can be obtained “over-the-counter” and may have less side effects compared to many synthetic drugs. Although most of the popular botanicals have a long history in folk medicine, there is paucity of data regarding their efficacy and safety, particularly as it relates to human studies. In this review, we discuss the data that was available in the literature for nine botanicals that are frequently promoted to help manage blood glucose. They are Bitter Melon (Momordica charantia), Fenugreek (trigonella foenum graecum), Gymnema Sylvestre, Ivy Gourd (Coccinia indica), Nopal or Prickly Pear Cactus (Opuntia streptacantha), Ginseng, Aloe Vera, Russian Tarragon (Artemisia dracunculus), and Garlic (Allium sativum). The discussion is emphasized on the clinical aspect of these botanicals. Due to the lack of sufficient evidence from clinical studies for any of the botanicals reviewed, it is premature to actively recommend use of any particular herb to treat either glucose or other risk factors. Thus, well defined randomized clinical trials are warranted in this area.

Tea is a popular beverage with a number of putative beneficial health effects. A recent large epidemiological study in Japan demonstrates that increased tea consumption is associated with decreased cardiovascular mortality (but not cancer mortality) in a dose-dependent manner. The polyphenol epigallocatechin-3-gallate (EGCG) is the most abundant tea catechin. Beneficial effects of EGCG therapy have been reported in a number of human and animal studies. Emerging evidence suggests that EGCG may improve endothelial function, hypertension, coronary heart disease, obesity, insulin resistance, as well as glucose and lipid metabolism. Studies in cultured cells and animal models suggest molecular mechanisms for EGCG to activate specific cellular signaling pathways that may play major roles in prevention and amelioration of cardiovascular and metabolic diseases. In this review, the beneficial health effects of tea and molecular mechanisms of EGCG related to cardiovascular and metabolic diseases will be discussed.

The metabolic syndrome (MetS) encompasses a constellation of cardio-metabolic abnormalities associated with a high risk of developing type 2 diabetes and cardiovascular disease (CVD), the top killer in the ageing population. Recent studies have demonstrated multiple beneficial effects of moderate wine consumption in the protection against development of the MetS and its related medical complications. The association of moderate wine consumption with lower incidence of the MetS and atherosclerotic heart disease has been repeatedly documented in numerous epidemiological studies on diverse ethnic groups. In addition to the favorable effects of moderate ethanol intake on lipid profiles, polyphenols enriched in red wine possess multiple benefits on the MetS beyond alcohol through their anti-oxidant, anti-inflammatory, vascular-protective and insulin-sensitizing properties. Notable among these red wine polypheolic compounds is resveratrol, a phytoalexin that has recently attracted great attention due to its role in mimicking calorie restriction. This compound can act as a potent activator of the NAD+-dependent deacetylases sirtuins to expand the life span and to prevent the deleterious effects of excess intake on insulin resistance and metabolic derangement. In addition, resveratrol exerts its multiple protective effects against the MetS through stimulating AMP-activated protein kinase and promoting mitochondria biogenesis. In this review, we highlight the recent epidemiological and experimental evidences supporting the protective effects of moderate wine intake against the MetS and its associated cardio-metabolic complications, and discuss the molecular mechanisms underlying the multiple beneficial actions of red wine polyphenols with the focus on resveratrol.

In management of metabolic syndrome, the traditional Chinese medicine (TCM) is an excellent representative in alternative and complementary medicines with a complete theory system and substantial herb remedies. In this article, basic principle of TCM is introduced and 25 traditional Chinese herbs are reviewed for their potential activities in the treatment of metabolic syndrome. Three herbs, ginseng, rhizoma coptidis (berberine, the major active compound) and bitter melon, were discussed in detail on their therapeutic potentials. Ginseng extracts made from root, rootlet, berry and leaf of Panax quinquefolium (American ginseng) and Panax ginseng (Asian ginseng), are proved for anti-hyperglycemia, insulin sensitization, islet protection, anti-obesity and anti-oxidation in many model systems. Energy expenditure is enhanced by ginseng through thermogenesis. Ginseng-specific saponins (ginsenosides) are considered as the major bioactive compounds for the metabolic activities of ginseng. Berberine from rhizoma coptidis is an oral hypoglycemic agent. It also has anti-obesity and anti-dyslipidemia activities. The action mechanism is related to inhibition of mitochondrial function, stimulation of glycolysis, activation of AMPK pathway, suppression of adipogenesis and induction of low-density lipoprotein (LDL) receptor expression. Bitter melon or bitter gourd (Momordica charantia) is able to reduce blood glucose and lipids in both normal and diabetic animals. It may also protect β cells, enhance insulin sensitivity and reduce oxidative stress. Although evidence from animals and humans supports the therapeutic activities of ginseng, berberine and bitter melon, multi-center large-scale clinical trials have not been conducted to evaluate the efficacy and safety of these herbal medicines.

Plants are chemical storehouses, a fact which has driven countless multidisciplinary quests for bioactive compounds. As the very first step of botanical research, the whole desire is to find “hit” plants with specific bioactivities. It is logical to use some strategies that can maximize the chances of finding these “hits” with limited time and resources. In addition to selecting the right plants for screening, how the plant extracts are prepared can also influence the bioactivity screening outcomes. An extract from the same plant material can be quite different in chemical composition having different preparations. Because of the complex mixture nature of plant extracts, it is possible artifact activities may be observed. Thus confirmatory activity tests are often necessary to warrant the next laborious isolation step. A bioassay directed isolation approach may be the most efficient in identifying the bioactive compounds because of the narrowed focus at each isolation step, but a phytochemistry isolation approach is appropriate to characterize a purified bioactive extract. In fact, these two approaches can be taken intermittently whenever efficiency can be improved. Finally, use of the identified active compounds is now broader. In addition to determining a lead compound to continue a drug development path, there is an increasing interest in support for the use of botanical extracts as botanical drugs. Instead of dropping the extract after extracting the lead compound, the natural analogues representing the purified extract now have a chance to become leading compounds in the pursuit of novel therapies for metabolic syndrome and other diseases.

The contraceptive options available to men have not changed in several decades and are still limited to the nonsurgical methods of the use of a condom, a timely withdrawal, or a surgical procedure that removes a segment of the vas deferens (vasectomy). The first two approaches have relatively higher failure rates whereas the last approach is largely irreversible and may not be suitable for younger men. Thus, providing a safe, effective and readily available contraception for men has remained an unfulfilled goal. In this article, we intend to review the current status of the research and development on male contraceptives. It is apparent that the scientific community in the past few decades has witnessed impressive progress in understanding the basics of male physiology, the knowledge necessary for developing new contraceptive methods for men. We will highlight various new and improved strategies for the regulation of fertility in males. The diverse approaches that are at various stages of development and/or in clinical trials include: 1) administration of hormones, herbal extracts or chemicals to suppress/arrest sperm production in the testes (spermatogenesis); 2) interference with the delivery of spermatozoa during ejaculation by targeted blockage of vas deferens with plugs or chemicals (polymers) that prevent flow of sperm through the vas duct; 3) active or passive immunization of males with well characterized antigens/ antibodies which are intended to block sperm function; and 4) administration of site-directed antagonists to block specific sperm function(s) necessary for normal fertilization. All these approaches do not involve surgery and are reversible. Our intention is to discuss the current status of various approaches which show promising results in clinical trials, particularly in China and India, the world's most populous nations.

The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to Acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants such as glutathione, and chelates zinc, copper and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. By acting as an insulin mimetic agent, LA stimulates glucose uptake in many different cell types and can also modulate insulin signaling. The p38 and ERK MAP kinase pathways, AKT and NFκB are all regulated by LA. In addition, LA activates the prostaglandin EP2 and EP4 receptors to stimulate the production of the small molecule cyclic adenosine 5' monophosphate (cAMP). These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress associated diseases. This review discusses the known biochemical properties of LA, its antioxidant properties, its ability to modulate signal transduction pathways, and the recent progress made in the utilization of LA as a therapeutic alternative for multiple sclerosis, Alzheimer's disease and diabetic neuropathy.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment with insidious onset. Neuropathological analysis of AD-affected brains reveals extensive atrophy and an accumulation of neurofibrillary tangles. Taken together, the neurochemical changes in the brain in patients with AD indicate multiple disturbances, and it seems likely that the changes are secondary to more fundamental changes in the brain. The IGF-I is a potent neurotrophic as well as a neuroprotective factor found in the brain, with a wide range of actions in both the central and the peripheral nervous systems. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor- I (IGF-I) axis with ageing, and the possibility that the GH/IGF-I axis is involved in cognitive deficits has been recognized for several years. IGF-I is a critical promoter of brain development and neuronal survival, and plays a role in neuronal rescue during degenerative diseases. The investigations of GH-releasing stimulation tests, and especially of GHRH in AD, are equivocal and in some cases contradictory. The results of several studies addressing this point show varied results: superimposable response of GH to GHRH than response of GH to GHRH in controls; blunted GH to GHRH response in AD patients; higher GH concentrations in the morning; greater increase of GH to GHRH in AD patients than in controls. When an acetylcholinesterase inhibitor, such as rivastigmine, a drug for AD, is acutely administered, the area under the curve of the GH response to GHRH doubles, showing that rivastigmine is a powerful drug in the enhancement of GH release. Consequently, an emerging clinical target for improving the clinical manifestations of AD may be the activation of GH/IGF-I, which rejuvenates the axis, so resulting in an overall physiological benefit.