Current Medicinal Chemistry (v.19, #32)

Since its discovery in 1995 adiponectin has garnered considerable interest from the academic, clinical and biotech communities due to its proposed salutary anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. As a result our appreciation of adiponectin's structure and the importance of post-translational modifications (PTMs) in adiponectin production are now relatively advanced. So too, following the identification of a variety of adiponectin receptors, binding proteins and downstream signalling networks, is our understanding of adiponectin's intracellular signalling pathways that are implicated in mediating adiponectin's pleiotropic effects. Adiponectin's ability to moderate inflammation, which is recognised as a key protagonist in many modern diseases, may be the key to many of its beneficial effects. Recent insights indicate that adiponectin modulates cellular inflammation by affecting sphingolipid metabolism, with the adiponectin receptors displaying intrinsic ceramidase activity. In the current review we will summarise the molecular details of adiponectin, discuss key players and recent insights into adiponectin signalling and consider the physiologic role(s) of adiponectin. We will also review studies into the effects of diet or exercise on circulating adiponectin levels focusing largely on reports from human trials.

Adiponectin in Pregnancy: Implications for Health and Disease by A. Retnakaran, R. Retnakaran (5444-5450).
Pregnancy is a unique physiologic state that is associated with profound alterations in maternal metabolic, endocrine, and vascular function, designed to ensure the delivery of appropriate energy and nutrition to the developing fetus. In this context, the role of the fat-derived hormone adiponectin is of interest, particularly in light of emerging recognition of the broad array of physiologic processes upon which this adipokine impacts. Indeed, adiponectin has pleiotropic effects on the regulation of energy homeostasis, systemic inflammation, vascular function, cell growth, and even bone metabolism. Thus, in this review, we consider existing evidence for the physiologic role of adiponectin in human gestation and how this protein may be relevant to two major medical disorders of pregnancy: gestational diabetes mellitus and preeclampsia. While studies to date have yielded many conflicting findings pertaining to adiponectin in pregnancy, further investigation in this area is essential. Ultimately, elucidation of adiponectin physiology in the setting of both normal pregnancy and its pathologic conditions may provide unique insight into fundamental processes that are relevant to health and disease in mother and child.

Adiponectin in Diabetes Mellitus by N. Xita, A. Tsatsoulis (5451-5458).
Adiponectin represents one of the most abundant and well-studied adipokines that has been implicated as a major protective factor against the adverse metabolic and cardiovascular consequences of obesity. The main insulin-sensitizing action of adiponectin results from decrease in hepatic gluconeogenesis and increase in muscle glucose transport and, secondly from enhancement of energy consumption and fatty acid oxidation in peripheral tissues with the aim of increasing ATP production. Besides these effects, the potential role of adiponectin on insulin secretion, as well as on energy expenditure, through central action, has also been investigated. Accumulating evidence from clinical, experimental animal and genetic studies support a close association between hypoadiponectinemia and insulin resistance/ type 2 diabetes. The question that arises is whether hypoadiponectinemia is the result of insulin resistance/type 2 diabetes or the cause of this disorder. Based on the observation that various drug classes exert beneficial effects on insulin resistance partly by increasing plasma adiponectin levels, it could hypothesized that substances that enhance or mimic adiponectin to activate its receptors and/or postreceptor signaling pathway may be a promising therapeutic strategy in the prevention and treatment of diabetes. However, many questions need to be addressed before adiponectin can be used as a potent therapeutic target.

Protective Role of Adiponectin in Cardiovascular Disease by R. Shibata, T. Murohara, N. Ouchi (5459-5466).
This review focuses on the recent findings that adiponectin plays a significant role of in cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting adipocytokines that can directly affect nearby or remote organs. Adiponectin is an adipocytokine whose concentration is down-regulated in subjects with obesity-related disorders. Low levels of circulating adiponectin appear to associate with the increased prevalence of obesity-linked diseases including atherosclerosis and ischemic heart disease. A number of experimental studies have shown that adiponectin exerts beneficial effects on the cardiovascular system by directly acting on the component cells in the heart and blood vessels. The cardiovascular protection by adiponectin is mediated through its ability to attenuate inflammatory responses and apoptotic activities in the target organs. Thus, adiponectin could represent a therapeutic target molecule for prevention or treatment of cardiovascular diseases.

Adiponectin: Key Player in the Adipose Tissue-Liver Crosstalk by A. R. Moschen, V. Wieser, H. Tilg (5467-5473).
The adipose tissue has recently emerged as an important endocrine organ releasing numerous mediators including adipocytokines, classical cytokines and others. Adiponectin, one of the major products of adipocytes, is a prototypic anti-diabetic adipocytokine, the actions of which are mainly exerted by the activation of AMP-activated kinase and peroxisome proliferator-activated receptor alpha. This adipocytokine is one of the most abundant circulating (adipo)cytokines in health. Non-alcoholic fatty liver disease (NAFLD), the major reason for abnormal liver functions in the western world, is commonly associated with obesity, insulin resistance and decreased adiponectin serum levels. Adiponectin has many anti-inflammatory activities and suppresses tumour necrosis factor-alpha (TNF), a cytokine of key importance in NAFLD. The anti-inflammatory effects of adiponectin are also exerted by induction of the anti-inflammatory cytokines interleukin-10 (IL-10) or IL-1 receptor antagonist and up-regulation of heme-oxygenase-1. Whereas the liver probably is not a relevant source of circulating adiponectin, it is a major target organ for many adiponectin effects. Adiponectin is able to regulate steatosis, insulin resistance, inflammation and fibrosis. NAFLD is also associated with decreased liver expression of the two adiponectin receptors (AdipoR1 and 2) thereby contributing to a state of hepatic adiponectin resistance. In contrast, most other liver diseases especially in advanced disease states exhibit increased adiponectin serum levels with highest levels observed in cirrhosis. Targeting adiponectin could evolve as a major treatment concept especially for fatty liver diseases in the future.

Adiponectin in Autoimmune Diseases by E. Toussirot, D. Binda, C. Gueugnon, G. Dumoulin (5474-5480).
Adiponectin is the most abundant adipokine circulating in the organism. Different molecular forms of adiponectin exist: low, middle and high molecular isoforms, as well as globular adiponectin, all of which have different biological properties. Adiponectin is considered a key adipokine in metabolic diseases such as type 2 diabetes, metabolic syndrome and related complications, especially cardiovascular diseases. In these metabolic conditions, circulating adiponectin is reduced. It is now well known that adiponectin has beneficial effects on endothelial cells and endothelial function and is also cardioprotective. Unlike metabolic diseases, systemic autoimmune and chronic inflammatory joint diseases are characterized by increased production of adiponectin. There is evidence to suggest that adiponectin may be related to disease activity and/or severity in different conditions such as rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis. Since adiponectin has been found to display both pro and anti-inflammatory activities, controversial findings have been observed on the role of total adiponectin in systemic autoimmune and inflammatory joint diseases. Thus, the relative contribution of each adiponectin isoform to the inflammatory response and joint and/or tissue damage requires further study.

Adiponectin in Metabolic Bone Disease by I. Kanazawa (5481-5492).
Adiponectin has attracted widespread attention because of its pivotal role in glucose metabolism and energy homeostasis. Adiponectin and its receptor are shown to be expressed in osteoblasts, suggesting that adiponectin might affect bone metabolism. A number of clinical studies have shown that serum adiponectin is negatively associated with bone mineral density (BMD) and positively with biochemical markers of bone turnover, suggesting that adiponectin may be a negative regulator of bone mass. However, most in vitro studies demonstrate that adiponectin stimulates the differentiation and mineralization of osteoblasts as well as the expression of osteocalcin. Adiponectin indirectly stimulates osteoclast differentiation via receptor activator for nuclear factor B ligand and osteoprotegerin expression in osteoblasts, while adiponectin directly inhibits osteoclast activity and bone resorption. These in vitro findings suggest that adiponectin stimulates bone formation and remodeling as well as inhibits bone resorption. In contrast, previous in vivo studies using overexpression and knockout mice of adiponectin have produced controversial results. On the other hand, recent studies have shown that osteocalcin derived form osteoblasts acts as a hormone regulating glucose metabolism and fat mass. Osteocalcin could decrease fat pads and stimulate the expression of adiponectin in adipocytes, suggesting that bone metabolism is associated with fat metabolism through adiponectin and osteocalcin. In this review, I summarize the effect of adiponectin on osteoblasts and osteoclasts in vitro and in vivo, the association of adiponectin with BMD and bone markers in humans, and the role of adiponectin in the endocrine loop between bone and fat metabolism.

Adiponectin is a predominantly anti-inflammatory protein produced by adipose tissue with possible signalling activity in the lung. It is increasingly associated with inflammatory pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and in critical illness. Although mouse studies indicate causative associations between adiponectin and asthma and COPD, the human literature in this regard is inconclusive. Some, but not all, studies demonstrate that serum adiponectin concentrations are inversely associated with asthma prevalence among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are associated with lower asthma severity among boys but greater severity among men. Further, case-control studies demonstrate higher systemic and airway adiponectin concentrations in primarily male COPD patients than controls. Systemic adiponectin is positively associated with lung function in healthy adults but inversely associated in studies of male subjects with COPD. Murine and human studies further show contradictory associations of systemic adiponectin with critical illness. Higher premorbid systemic adiponectin concentrations are associated with improved survival from sepsis in mice. On the other hand, higher systemic adiponectin concentrations on day 1 of critical illness are associated with lower survival in critically ill patients with respiratory failure. In the absence of adequate longitudinal data, it is not possible to determine whether the adiponectin derangements are the consequence or the cause of the disease studied. Future research will determine whether modulation of adiponectin, independent of BMI, may be helpful in the prevention or treatment of asthma, COPD or critical illness.

Adiponectin is an adipose tissue-derived hormone, expressed almost exclusively in adipose tissue, with significant antidiabetic, anti-atherosclerotic, anti-inflammatory and anti-proliferative properties. The anti-carcinogenic effects of adiponectin result from two main mechanisms: a modulation in the signaling pathways involved in proliferation process and a subtle regulation of the apoptotic response. In this review, we present recent findings on the association of adiponectin with the risk of several malignancies (breast, colorectal, liver and prostate cancers), as well as data on underlying molecular mechanisms by which adiponectin plays a substantial role in cancer pathogenesis.

Therapeutic Perspectives for Adiponectin: an Update by F. Y.L. Li, K. S.L. Lam, A. Xu (5513-5523).
In obesity, the expansion of dysfunctional adipose tissue leads to augmented production of pro-inflammatory adipokines that mediate metabolic changes through their paracrine and/or endocrine actions. By contrast, the secretion and plasma concentration of adiponectin, an adipokine with cardiovascular protective, anti-diabetic and anti-inflammatory properties, are markedly decreased in obesity and its related pathologies. Epidemiological studies on different ethnic groups have identified hypoadiponectinemia as an independent risk factor for type 2 diabetes, hypertension, coronary heart disease and several types of cancers. In animals, replenishment of recombinant adiponectin or transgenic expression of adiponectin can reverse these obesity-related pathological conditions. Although there is currently no direct clinical evidence demonstrating that adiponectin is effective in treating obesity-related cardiometabolic diseases, therapeutic benefits of several anti-diabetic and cardiovascular drugs, such as the agonists of peroxisome proliferator-activated receptor (PPAR) and PPAR and statins, are associated with increased plasma adiponectin in humans. In addition, a number of medicinal herbs and natural compounds with beneficial effects on cardiometabolic diseases, have been shown to increase adiponectin secretion in adipocytes. This review highlights recent advances on multiple beneficial effects of adiponectin and discusses the potential therapeutic interventions for obesity-related cardiometabolic syndromes by targeting adiponectin.

Bone Metastases and Non-Small Cell Lung Cancer: From Bisphosfonates to Targeted Therapy by A. Rossi, C. Gridelli, S. Ricciardi, F. de Marinis (5524-5535).
About 30-40% of patients affected by non-small cell lung cancer (NSCLC) develop, during the course of their disease, bone metastases. The prognosis of these patients is poor with a median survival of less than 1 year. The therapeutic approach includes: palliative radiotherapy, and systemic therapy. In clinical practice, zoledronate is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events in patients with metastatic NSCLC. However, an Italian Association of Thoracic Oncology (AIOT) survey, conducted to evaluate how bisphosphonates were used in clinical practice for the treatment of lung cancer bone metastases in Italy, showed that the bisphosphonates treatment is still not routine and varies in duration. Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor kappa-B (RANK)-Ligand inhibiting the maturation of pre-osteoclasts into osteoclasts and is the first example of targeted therapy for bone metastases. An exploratory analysis showed that denosumab was associated with improved overall survival compared with zoledronate in patients with bone metastases from lung cancer. Biochemical markers of bone turnover to predict what patients are at greatest risk of developing skeletal-related events, and to direct treatment of bone metastases with either bisphosphonates or denosumab, are under investigation. This review is focused on the systemic management of bone metastases from NSCLC.

Raltegravir, the only drug targeting the integration step in HIV-1 life cycle, makes β-ketoenol integrase (IN) strand transfer inhibitor (STI) gain a definitive place in the treatment of HIV-1 infection. However, the emergence of viral strains resistant to β-ketoenol STI demands a continued effort toward the discovery of novel IN inhibitors interfering with HIV-1 IN in a mechanistically different manner. Polyphenols, among the most developed IN inhibitors, exhibit a different mechanism of action compared with β-ketoenol STI. Some of them exhibit strong IN inhibitory activity and anti-viral activity at nanomolar level and 1,5-DCQA has been in phase II clinical trial in China. It is undoubted that this kind of compounds are attractive candidates for future inhibitor design, as they should be effective against STI resistant viral strains and display synergistic effect when combined with the current existing STI. However, almost all reviews about IN inhibitors have been focused on β-ketoenol STI, while the thorough evolution and general structure-activity relationship (SAR) summaries of polyphenols as IN inhibitors had never been specially discussed. In this review, we provide a comprehensive report of the nearly twenty years development of polyphenols as IN inhibitors: summarizing general SAR and suggesting the orientation for further research. Compilation of such data will prove beneficial in developing a novel generation of IN inhibitors.

Virtual Screening Methods as Tools for Drug Lead Discovery from Large Chemical Libraries by X. H. Ma, F. Zhu, X. Liu, Z. Shi, J. X. Zhang, S. Y. Yang, Y. Q. Wei, Y. Z. Chen (5562-5571).
Virtual screening methods have been developed and explored as useful tools for searching drug lead compounds from chemical libraries, including large libraries that have become publically available. In this review, we discussed the new developments in exploring virtual screening methods for enhanced performance in searching large chemical libraries, their applications in screening libraries of ~ 1 million or more compounds in the last five years, the difficulties in their applications, and the strategies for further improving these methods.

Non-Viral Engineering of Skin Precursor-Derived Schwann Cells for Enhanced NT-3 Production in Adherent and Microcarrier Culture by A. Shakhbazau, D. Shcharbin, M. Bryszewska, R. Kumar, H. M. Wobma, M. S. Kallos, N. Goncharova, I. Seviaryn, S. Kosmacheva, M. Potapnev, R. Midha (5572-5579).
Genetic engineering of stem cells and their derivatives has the potential to enhance their regenerative capabilities. Here, dendrimer- and lipofection-based approaches were used for non-viral neurotrophin-3 (NT-3) over-expression in Schwann cells differentiated from skin precursors (SKP-SCs). A variety of dendrimers were first tested for transfection efficiency on HEK 293T cells, with PAMAMNH2 G4 found most effective and used subsequently for SKP-SCs transfection. Plasmid-based expression resulted in increased NT-3 release from SKP-SCs in both adherent and microcarrier-based culture. In a proof-of-concept study, the microcarrier/SKP-SCs were implanted into the injured nerve, and transfected cells were shown to detach, integrate into the nerve tissue and associate with regenerating axons. Virus-free systems for transient neurotrophin expression are a feasible and biologically safe option to increase the therapeutic value of stem cells and stem cell-derived cells in nerve repair strategies. Further work to develop bioprocesses for expansion of SKP-SCs on microcarriers in bioreactors is still needed.

Photodynamic Molecular Beacons Triggered by MMP-2 and MMP-9: Influence of the Distance Between Photosensitizer and Quencher onto Photophysical Properties and Enzymatic Activation by M. Verhille, H. Benachour, A. Ibrahim, M. Achard, P. Arnoux, M. Barberi-Heyob, J.-C. Andre, X. Allonas, F. Baros, R. Vanderesse, C. Frochot (5580-5594).
Angiogenesis is a key step in the tumoral progression process. It is characterized by an over-expression of a number of matrix metalloproteinases (MMP). Among these MMPs, gelatinases (MMP-2 and MMP-9) are known to play a critical role in tumor angiogenesis and the growth of many cancers. Photodynamic Molecular Beacons (PMB) can be designed for cancer treatment by associating a chlorin-like photosensitizer and a black hole quencher linked by a gelatinase substrate peptide with the aim of silencing photosensitizer toxicity in non-targeted cells and restore its toxicity only in surrounding gelatinases. This article provides a report on the synthesis and photophysical and biochemical studies of new families of PMB, using tetraphenylchlorin and a black hole quencher as a donor-acceptor pair, and MMP specific sequence (H-Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln-Lys-OH or H-Pro-Leu-Gly-Leu-OH) to keep them in close proximity. Different spacers were used to evaluate the influence of the distance between the photosensitizer and the quencher on the photophysical properties and enzymatic activation of the PMB. Time-resolved quenching experiments were performed and FRET energy transfer could be observed. Photosensitizers’ triplet state band in transient absorption disappears in PMB. However, even if both MMP-2 and MMP-9 were found to efficiently cleave the peptide alone, no cleavage was observed for all PMB. Further studies would be required to assess the ability of the PMB constructs to retain the sensitivity of the peptide linker to be cleaved by matrix metalloproteinases.