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OPEN ACCESS PLUS
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Contents
5(3): Pp. 163 - 175
Patricia Grasso
[Open Access Plus] |
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Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptins role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to a number of hypothalamic-pituitaryendocrine axes, including adrenal, gonadal, growth hormone, pancreatic islets, and thyroid. The pleiotropic nature of leptin has been confirmed by demonstration of a role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, reproduction, and wound healing. Unfortunately, the results of the majority of clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only to the management of those rare forms of human obesity caused by mutation in the ob gene. Failure of leptin in the clinic, and withdrawal of phentermine from Europe, and fenfluramine and sibutrimine from clinical use in the United States, have stimulated new approaches in the development of anti-obesity and anti-diabetes pharmacophores. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics. This review summarizes patents on leptin-related peptide analogs, antagonists and mimetics.
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5(2): Pp. 80 - 90
Daniel P. Cardinali, Analia M. Furio and Luis I. Brusco
[Open Access Plus] |
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Treatment of circadian rhythm disorders, whether precipitated by intrinsic factors (e.g., sleep disorders, blindness, mental disorders, aging) or by extrinsic factors (e.g., shift work, jet-lag) has led to the development of a new type of agents called “chronobiotics”. The term “chronobiotic” defines a substance displaying the therapeutic activity of shifting the phase or increasing the amplitude of the circadian rhythms. The prototype of this therapeutic group is melatonin, whose administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from circadian rhythm sleep disorders, like delayed sleep phase syndrome, jet lag or shift-work. Daily melatonin production decreases with age, and in several pathologies, attaining its lowest values in Alzheimers disease (AD) patients. About half of dementia patients have severe disruptions in their sleep-wakefulness cycle. Melatonin replacement is effective to treat sundowning and other sleep wake disorders in fully developed AD, although controversial data on this point exist. Indeed, large interindividual differences between patients suffering from AD exist and can explain these erratic results. Theoretically the effect of melatonin could be more consistent at an earlier stage of the disease, i.e., mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. PubMed was searched using Entrez for articles including clinical trials. Search terms were “Alzheimer” “mild cognitive impairment” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. Five double blind, randomized placebo-controlled trials and 1 open-label retrospective study (N = 651) all agree in indicating that treatment with daily evening melatonin improves sleep quality and cognitive performance in MCI. The analysis of published evidence and patents indicates that melatonin can be a useful ad-on therapeutic tool in the early phases of AD.
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1(2): Pp. 166 - 175
Agnes Ribeiro, Amena Archer, Johanne Le Beyec, Anne-Laure Cattin, Susan Saint-Just, Martine Pinçon-Raymond, Jean Chambaz, Michel Lacasa and Philippe Cardot
[Open Access Plus] |
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Hepatic nuclear factor-4 (HNF-4) is a transcription factor and a member of the large family of nuclear receptors. It was first cloned from liver but is expressed also in kidney, pancreas and intestine. Three genes encoding three isoforms have been identified, HNF- 4α and γ, in mammals, drosophila and xenopus and HNF-4β, exclusively in xenopus. HNF-4α is the best studied isoform, especially in liver. Such studies put HNF-4α at the crossroads between architecture and function of epithelia, as it induces expression of cell/cell junction proteins while it also controls glucido-lipidic metabolism and drug metabolizing enzyme genes. Furthermore, mutations in the HNF-4α gene lead to a metabolic disease in humans, Maturity Onset Diabetes of the Young-1 (MODY-1). The existence of a “true ligand” is not clearly established but a “structural” fatty acid is present in the ligand binding pocket of HNF-4α and γ. Consequently, activity of HNF-4 can be modulated by the interaction with co-regulators or by post-translational modifications. Then, HNF-4 is a potential direct or indirect target for pharmacologic drugs, with a special interest for the intestinal epithelium which is the primary site of metabolic control, due to its roles in nutrient absorption and in sensing energy. The patents related to the HNF-4α gene are also discussed in this article.
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