Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action

Although resveratrol has been proven to possess diverse health benefits, several recent reports have demonstrated conflicting results on some aspects of its effects, including its anti-aging properties. Considerable debate appears to exist on the dose and bioavailability of resveratrol, leading to the controversies on its effectiveness. To resolve the problem, we designed a study with a resveratrol formulation that contained resveratrol supplemented with 5% quercetin and 5% rice bran phytate (commercially known as Longevinex). These ingredients were micronized to increase the bioavailability. Sprague-Dawley rats were gavaged with either Longevinex or vehicle (5% quercetin plus 5% rice bran phytate), and rats were sacrificed after 1 or 3 months, when isolated working hearts were subjected to 30 min ischemia followed by 2 h of reperfusion. Longevinex-treated hearts, irrespective of the duration of treatments, revealed superior cardiac performance, reduced infarct size, and induction of survival signals as evidenced by increased Bcl2/Bax ratio and enhanced Akt phosphorylation. In contrast, LC3-II and Beclin were enhanced significantly after 3 months of Longevinex treatment, suggesting that autophagy occurred only after feeding Longevinex to rats for a prolonged period of time. Corroborating with the results of autophagy, Sirt1 and Sirt3 increased significantly only after 3 months of Longevinex treatment, suggesting that enhanced expression of Sirts correlated with induction of autophagy. In concert, Longevinex caused phosphorylation and nuclear translocation of FoxO1, FoxO3a, and FoxO4, indicating involvement of FoxOs with autophagy. Since Sirts and FoxOs are reliable markers of longevity, the results appear to suggest that Longevinex induces longevity after prolonged feeding via induction of autophagy, while it converts death signals into survival signals and provides cardioprotection within a relatively shorter period of time.     

Chronic crude garlic-feeding modified adult male rat testicular markers: mechanisms of action

Background  

Garlic or Allium sativum (As) shows therapeutic effects such as reduction of blood pressure or hypercholesterolemia but side-effects on reproductive functions remain poorly investigated. Because of garlic's chemical complexity, the processing methods and yield in preparations differ in efficacy and safety. In this context, we clarify the mechanisms of action of crushed crude garlic on testicular markers.     

Ton-dependent colicins and microcins: modular design and evolution

Ton-dependent colicins and microcins are actively taken up into sensitive cells at the expense of energy which is provided by the proton motive force of the cytoplasmic membrane. The Ton system consisting of the proteins TonB, ExbB and ExbD is required for colicin and microcin import. Colicins as well as the outer membrane transport proteins contain proximal to the N-terminus a short sequence, called TonB box, which interacts with TonB and in which point mutants impair uptake. No TonB box is found in microcins. Colicins are composed of functional modules which during evolution have been interchanged resulting in new colicins. The modules define sites of interaction with the outer membrane transport genes, TonB, the immunity proteins, and the activity regions. Six TonB-dependent microcins with different primary structures are processed and exported by highly homologous proteins. Three of these microcins are modified in an unknown way and they have in common specificity for catecholate siderophore receptors.     

Lantibiotics and microcins: polypeptides with unusual chemical diversity

Bacterial-derived antimicrobial polypeptides enjoy a large degree of structural and chemical diversity. Two well-studied examples of such polypeptides are the lanthionine-containing lantibiotics produced by a variety of Gram-positive bacteria, and their Gram-negative counterparts, the microcins. Both groups are produced as gene-encoded precursor peptides and undergo post-translational modification to generate the active moieties. Structure elucidation of novel lantibiotics and microcins has recently uncovered further novel structural and chemical features and, combined with the generation of analogue peptides by genetic manipulation, new insights into structure-function relationships have been gained. Furthermore, study of the mode of action of the lantibiotics nisin and mersacidin has revealed their use of a 'docking molecule' in the target cell to facilitate their biological activities. Meanwhile, in vitro studies with microcin B17 have helped to uncover the molecular mechanisms by which post-translational modification results in the formation of heterocyclic oxazole and thiazole rings. From a practical standpoint, both groups of polypeptides represent new lead structures for future development of antimicrobial agents, whilst the identification of the 'docking molecules' represents a step forward in the search for novel targets for future antibiosis.     

Antifungal agents: mechanisms of action

Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides--a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.     

Biocides: mechanisms of action and microbial resistance

World Journal of Microbiology and Biotechnology -     

Isoflavonoids and chronic disease: mechanisms of action

Soy and its isoflavones are associated with a reduced risk of chronic disease. The mechanisms of action of isoflavones include their roles as weak estrogens, inhibitors of tyrosine kinase-dependent signal transduction processes and as cellular antioxidants. Although estrogen receptor beta binds genistein with an affinity close to that of 17beta-estradiol, it remains to be determined whether it is a mediator of genistein's activity in vivo. Genistein's inhibition of protein tyrosine kinases is not limited to direct effect on these kinases, but may result from alteration in kinase expression. Genistein is not a particularly good scavanger of cellular oxidants; however, it reacts vigorously with the prooxidant hypochlorous acid, produced by neutrophils as part of the inflammatory response. The chlorinated isoflavones may have altered biochemical and biological effects compared to their parent compounds and may provide increased protection against inflammatory disease.     

Keratinocyte growth factor: effects on keratinocytes and mechanisms of action

Keratinocyte growth factor (KGF) is a potent and specific mitogen for different types of epithelial cells, and it can protect these cells from various insults. Due to these properties, it is of particular importance for the repair of injured epithelial tissues, and it is currently therapeutically explored for the treatment of radiation- and chemotherapy-induced mucosal epithelial damage in cancer patients. In this review we summarize the current knowledge on the role of KGF in tissue repair and cytoprotection, and we report on its mechanisms of action in keratinocytes.     

Aldosterone: the mechanisms of molecular action

Aldosterone: a steroid hormone of adrenal cortex, has recently attracted much interest not only due to its great importance in regulation of salt and water balance, but also because of its key role in therapy of cardiovascular and renal pathology. The classical genomic mechanism of molecular action of aldosterone is mediated through interaction with mineral-corticoid receptors. Fast nongenomic pathway of cell signal transduction begins with interaction with hypothetic membrane receptors and includes activation of different kinase cascades. Interference of these two pathways of signal transduction assures abroad spectrum of aldosterone effects depending on the cell type, and also secures multycomponent regulation depending on the need of specific functional and stress situation. This review is dedicated to modern views of mechanisms of aldosterone molecular action, mostly of the level of aldosterone-sensitive segment of kidney nephron.     

Phospholipid phase transitions: kinetics and structural mechanisms

A brief review is given on the principles and methods used to investigate structural phase transitions in phospholipid supramolecular structures. The conceptual differences of approaches close to and far from equilibrium are addressed, and the consequences in terms of the limits of interpretation for different types of methods, in particular referring to jump-relaxation and steady-state techniques, are surveyed. With the emphasis on connecting dynamic and structural information, the results obtained so far from different techniques are reviewed, and the open questions addressed. The more recent advances by millisecond time-resolved X-ray diffraction with synchrotron radiation and their main results obtained for transitions triggered by IR-laser temperature jumps are summarized. As a major novel aspect in the field, the necessity of considering martensitic, diffusionless transformation mechanisms and the occurrence of intermediate structures is highlighted.     

Neuroinflammation: modulation by flavonoids and mechanisms of action

Neuroinflammatory processes are known to contribute to the cascade of events culminating in the neuronal damage that underpins neurodegenerative disorders such as Parkinson's and Alzheimer's disease. Recently, there has been much interest in the potential neuroprotective effects of flavonoids, a group of plant secondary metabolites known to have diverse biological activity in vivo. With respect to the brain, flavonoids, such as those found in cocoa, tea, berries and citrus, have been shown to be highly effective in preventing age-related cognitive decline and neurodegeneration in both animals and humans. Evidence suggests that flavonoids may express such ability through a multitude of physiological functions, including an ability to modulate the brains immune system. This review will highlight the evidence for their potential to inhibit neuroinflammation through an attenuation of microglial activation and associated cytokine release, iNOS expression, nitric oxide production and NADPH oxidase activity. We will also detail the current evidence indicting that their regulation of these immune events appear to be mediated by their actions on intracellular signaling pathways, including the nuclear factor-κB (NF-κB) cascade and mitogen-activated protein kinase (MAPK) pathway. As such, flavonoids represent important precursor molecules in the quest to develop of a new generation of drugs capable of counteracting neuroinflammation and neurodegenerative disease.     

Neuroendocrine mechanisms of stress ulceration: Focus on thyrotropin-releasing hormone (TRH)

It is generally accepted that stress ulceration, a multifactorial or pluricausal gastrointestinal disorder, may be the result of mechanistic interrelationships between mucosal, vascular, hormonal and neurogenic factors. The relative importance of each of these independent mechanisms remains unclear. This minireview represents an attempt to interpret many recent studies on certain neurogenic mechanisms and to integrate these observations into the existing body of knowledge. A variety of in vitro techniques and animal models to manipulate actual structures, organ systems, and certain well-defined hormonal influences have been utilized. The peripheral studies have followed, for the most part, the established observation that the stomach is under reciprocal control by sympathetic inhibitory and parasympathetic excitatory autonomic fibers. As a result, several autonomic adrenergic neurotransmitter substances have been found to promote mucosal resistance. Some of these include dopamine, epinephrine, and norepinephrine. Others in contrast, appear to promote vulnerability of the mucosa, and of these, the most well-studied include acetylcholine and histamine.     

Artemisinin: mechanisms of action,resistance and toxicity

Artemisinin and its derivatives are widely used throughout the world. The mechanism of action of these compounds appears to involve the heme-mediated decomposition of the endoperoxide bridge to produce carbon-centred free radicals. The involvement of heme explains why the drugs are selectively toxic to malaria parasites. The resulting carbon-centred free radicals are alkylate heme and proteins, one of which is the translationally controlled tumour protein. Clinically relevant artemisinin resistance has not been demonstrated, but it is likely to occur since artemisinin resistance has been obtained in laboratory models. At high doses, artemisinin can be neurotoxic but toxicity has not been found in clinical studies. The mechanism of neurotoxicity may be similar to the mechanism of action.     

Bacterial endotoxins: biological properties and mechanisms of action

Endotoxins (lipopolysaccharides, LPS) are agents of pathogenicity of Gram-negative bacteria, implicated in the development of Gram-negative shock. Endotoxin reacts with lipopolysaccharide-sensitive cells producing endogenous mediators such as tumour necrosis factor alpha (TNFalpha). Macrophages are cells mediating the toxic activities of LPS and TNFalpha is the primary mediator of the lethal action of endotoxin. This review article discusses the various mechanisms by which endotoxin hypersensitivity in bacteria-sensitized animals develops. The paper concludes with a discussion on the possible protective effect of carnitine congeners against the lethal action of LPS.