There must be something unique about a class of drugs (discovered and developed in the mid-1940s) where there are more than 130 ongoing clinical trials currently listed. Tetracyclines were developed as a result of the screening of soil samples for antibiotic organisms. The first of these compounds chlortetracycline was introduced in 1948. Soon after their development tetracyclines were found to be highly effective against various pathogens including rickettsiae, Gram-positive, and Gram-negative bacteria, thus, becoming a class of broad-spectrum antibiotics. The mechanism of action of tetracyclines is thought to be related to the inhibition of protein synthesis by binding to the 30S bacterial ribosome. Tetracyclines are also an effective anti-malarial drug. Over time, many other "protective" actions have been described for tetracyclines. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Its mechanism of action appears to relate to specific effects exerted on apoptosis signaling pathways. Another tetracycline, doxycycline is known to exert antiprotease activities. Doxycycline can inhibit matrix metalloproteinases, which contribute to tissue destruction activities in diseases such as gingivitis. A large body of literature has provided additional evidence for the "beneficial" actions of tetracyclines, including their ability to act as oxygen radical scavengers and anti-inflammatory agents. This increasing volume of published work and ongoing clinical trials supports the notion that a more systematic examination of their possible therapeutic uses is warranted. This review provides a summary of tetracycline's multiple mechanisms of action and while using the effects on the heart as an example, this review also notes their potential to benefit patients suffering from various pathologies such as cancer, Rosacea, and Parkinson's disease.

Non-technical summary During exercise, skeletal muscle performance depends in great part on the use of aerobic metabolism to supply the energetic demand of contractions. Endurance training increases the muscle aerobic capacity, which is not only associated with enhanced exercise performance, but also with a decreased risk of cardiovascular and metabolic diseases. Recently, it has been shown that regular use of small doses of dark chocolate may result in similar health benefits to exercise training. We show here that mice fed for 15 days with (-)-epicatechin (present in dark chocolate) had improved exercise performance accompanied by: (1) an increased number of capillaries in the hindlimb muscle; and (2) an increased amount of muscle mitochondria as well as signalling for mitochondrial biogenesis. These results suggest that (-)-epicatechin increases the capacity for muscle aerobic metabolism, thereby delaying the onset of fatigue. These findings may have potential application for clinical populations experiencing muscle fatigue. AbstractThe flavanol (-)-epicatechin, a component of cacao (cocoa), has been shown to have multiple health benefits in humans. Using 1-year-old male mice, we examined the effects of 15 days of (-)-epicatechin treatment and regular exercise on: (1) exercise performance, (2) muscle fatigue, (3) capillarity, and (4) mitochondrial biogenesis in mouse hindlimb and heart muscles. Twenty-five male mice (C57BL/6N) were randomized into four groups: (1) water, (2) water-exercise (W-Ex), (3) (-)-epicatechin ((-)-Epi), and (4) (-)-epicatechin-exercise ((-)-Epi-Ex). Animals received 1 mg kg −1 of (-)-epicatechin or water (vehicle) via oral gavage (twice daily). Exercise groups underwent 15 days of treadmill exercise. Significant increases in treadmill performance (∼50%) and enhanced in situ muscle fatigue resistance (∼30%) were observed with (-)-epicatechin. Components of oxidative phosphorylation complexes, mitofilin, porin, nNOS, p-nNOS, and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (-)-epicatechin treatment for hindlimb and cardiac muscles than exercise alone. In addition, there were significant increases in skeletal muscle capillarity. The combination of (-)-epicatechin and exercise resulted in further increases in oxidative phosphorylation-complex proteins, mitofilin, porin and capillarity than (-)-epicatechin alone. These findings indicate that (-)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles resulting in greater endurance capacity. These results, therefore, warrant the further evaluation of the underlying mechanism of action of (-)-epicatechin and its potential clinical application as an exercise mimetic.

Abstract-Recent reports indicate that (Ϫ)-epicatechin can exert cardioprotective actions, which may involve endothelial nitric oxide synthase (eNOS)-mediated nitric oxide production in endothelial cells. However, the mechanism by which (Ϫ)-epicatechin activates eNOS remains unclear. In this study, we proposed to identify the intracellular pathways involved in (Ϫ)-epicatechin-induced effects on eNOS, using human coronary artery endothelial cells in culture. Key Words: flavonoids Ⅲ ischemia Ⅲ polyphenols Ⅲ endothelial cells Ⅲ endothelial nitric oxide synthase C ardiovascular diseases (CVD) are is a leading cause of morbidity and mortality, affecting Western industrialized countries as well as developing countries. 1,2 CVD imposes major direct and indirect costs on health care systems, ranging from hospitalizations, drugs, and rehabilitation services to losses of productivity due to premature mortality and short-and long-term disability. 1 The incidence of CVD continues to increase; thus, it is important to identify potential therapeutic agents to prevent and treat CVD.CVD is importantly linked to endothelial cell dysfunction. Endothelial cell dysfunction is associated with conditions, such as obesity, smoking, diabetes, and hormonal changes. The vascular endothelium mediates many important physiological functions, such as responses to shear stress, angiogenesis, vascular remodeling, inflammation, and coagulation. It also participates in metabolic and synthetic processes. 3 A key modulator of endothelial cell activity is nitric oxide (NO), which under physiological conditions is mainly produced by the endothelial nitric oxide synthase (eNOS) isoform. NO regulates vascular tone, proliferation of vascular smooth muscle cells, and hemostasis, among other important functions. Disruptions in the physiological production of NO triggers endothelial cell dysfunction, resulting in an increased susceptibility to CVD. 4 Therefore, strategies aimed at "physiologically" increasing NO bioavailability are promising for the prevention and therapy of CVD.The induction of NO synthesis by flavonoid-containing compounds has received widespread attention, as their effects appear to positively impact CVD. Epidemiological studies indicate that the regular dietary intake of plant-derived foods and beverages high in flavonoids is inversely associated with the incidence of CVD. 5 Although these compounds are pleiotropic in nature, many of their effects may be explained by improving endothelial function. The regular consumption of cacao products high in flavonoid content has also been demonstrated to provide beneficial cardiovascular effects. 5 Natural cacao products are rich in monomeric and polymeric forms of the flavonoids (Ϫ)-epicatechin (EPI) and catechin (60/40 ratio) and can contain up to 10% flavonoids by weight. 6 The consumption of cacao products can ameliorate

Abstract(-)-Epicatechin (Epi), a fl avanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofi lin, nNOS, nitric oxide, cGMP, SIRT1, PGC1␣, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function.

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The first t of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the "beneficial" actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline's multiple mechanisms of action as a means to understand their beneficial effects.

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