Peripheral targets in obesity treatment: a comprehensive update.

Obesity is a major epidemic of our time and is associated with diseases such as metabolic syndrome, type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Although weight loss drugs, when accompanied by diet and exercise, could be a very helpful medical tool in treating obese or overweight patients, their usefulness has been questioned due to the complexity of this type of medication, which regards a plethora of issues such as efficacy and safety of the drug and also risks and benefits among different patients. In general, obesity drugs that target peripheral pathophysiological mechanisms can be divided into two main categories. The first category includes anti-obesity agents able to reduce or limit energy absorption, such as pancreatic lipase and microsomal triglyceride transfer protein inhibitors. The second category consists of a heterogeneous group of compounds aiming to decrease fat mass by increasing energy expenditure or by redistributing adipose tissue. Angiogenesis inhibitors, beta-3 receptor agonists, sirtuin-I activators, diazoxide and other molecules belong to this group. The glucagon-like peptide-1 receptor agonists consist the third category of peripheral anti-obesity agents discussed therein. This review aims to provide a general overview of the molecules and substances that are already or could potentially be used as peripheral anti-obesity drugs, the molecular mechanisms by which they act, as well as their current stage of development, production and/or availability.

Flavonoids in atherosclerosis: an overview of their mechanisms of action.

Polyphenols are composed of a wide variety of molecules that are classified into several categories, according to their chemical type such as phenolic acids, flavonoids, stilbenes, and lignans. Many studies have proven the beneficial effects of flavonoids in atherosclerosis progression and cardiovascular disease. Dietary flavonoids reduce oxidative stress and exert anti-inflammatory actions. Moreover, flavonoids have the ability to avoid the thrombus formation, improve endothelial function, modify lipid levels and regulate glucose metabolism. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most important mechanisms of action of flavonoids in atherosclerosis progression.

Predictive value of biomarkers in patients with heart failure.

Heart failure (HF) is a complex syndrome with high morbidity and mortality while, myocardial injury, hemodynamic overload, genetic, neurohormonal, inflammatory and biochemical factors are implicated in the development and progression of the disease. Interestingly, despite the development of several diagnostic tests, HF diagnosis remains clinical, based on symptoms and signs, while there is a poor relationship between symptoms and the prognosis of HF. Several biomarkers have recently been examined for their efficacy to predict outcome and assess prognosis of HF patients. The best studied for its prognostic ability sub-group of biomarkers is the neurohormones including the natriuretic peptides, the components of the renin-angiotensin-aldosterone system and the catecholamines. Others sub-groups of biomarkers include inflammatory and oxidative stress markers, extracellular matrix remodeling markers and myocardial injury markers (such as troponins I and T). Nevertheless, it is difficult to access a single biomarker fulfilling our need to evaluate prognosis and guiding treatment in acute or chronic HF patients, thus the predictive ability of combined biomarkers is recently under research. Therefore, further studies are needed to elucidate the clinical significance of these biomarkers. In the present review, we will discuss the usefulness and significance of potentials or established biomarkers in HF patients focusing on their ability to predict adverse events, morbidity and mortality.

Biomarkers determining cardiovascular risk in patients with kidney disease.

Cardiovascular disease (CVD) remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of "classic" and "non-classic" cardiovascular risk factors is an important contributor in excessive and accelerated CVD in patients with CKD. Indeed, the imposing cardiovascular morbidity and mortality of CKD patients corresponds to a significant extent in endothelial dysfunction, inflammation, oxidative stress, vascular calcification and volume overload. In addition, the kidney's function decline is independently associated with CVD in patients with chronic kidney disease. Currently, there is a growing interest in the role of new biomarkers that are closely correlated with CVD in CKD population. In current review, we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors and new biomarkers of CVD in CKD patients, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population.

Adiponectin and cardiovascular disease: mechanisms and new therapeutic approaches.

Adiponectin is an abundant plasma protein secreted from adipocytes. Its role in energy homeostasis is well-known, including the regulation of hydrocarbons and lipids metabolism as well as the improvement of insulin resistance. It has been thought to be a key molecule in the development of type 2 diabetes mellitus and metabolic syndrome, which are epidemiological targets for preventing cardiovascular disease. In addition to beneficial metabolic effects, adiponectin seems to have anti-inflammatory, anti-atherosclerotic and vasoprotective actions. Furthermore, adiponectin affects signalling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia-reperfusion injury. The ability of adiponectin to reduce insulin resistance in conjunction with its antiinflammatory and cardioprotective properties makes this adipocytokine a promising therapeutic target. On clinical interest, agents that enhance endogenous adiponectin production or action have potential for the treatment of cardiovascular disease. Management strategies that increase adiponectin levels include weight reduction, Mediterranean diet, thiazolidinediones, antihypertensive and lipid lowering drugs. Current knowledge on the main actions of adiponectin and therapeutic approaches for cardiovascular disease is summarized in this review.

Novel biomarkers assessing the calcium deposition in coronary artery disease.

Coronary atherosclerosis is the pathophysiologic background of coronary artery disease. Vascular calcification is an actively regulated form of calcified tissue metabolism and a common feature of coronary atherosclerotic plaques. Interestingly, systematic research has revealed that vascular mineralization, is also a strong and independent predictor of cardiovascular morbidity and mortality. Recently, several biomarkers, including osteopontin, fetuin-A, matrix-carboxyglutamic acid protein, pyrophosphates, bone morphogenetic proteins, leptin, osteoprotegerin have emerged as surrogate markers of coronary calcification. Furthermore, biomarkers of vascular calcification can be used as prognostic markers of coronary artery disease and can predict future cardiovascular events and mortality. Nevertheless, there is little knowledge on the usefulness of these biomarkers in evaluating the results of treatments targeting coronary artery disease. Within this context, the present review sets out to discuss the role of new biomarkers assessing calcium deposition in coronary arteries and their role in the prognosis, progression, and treatment of cardiovascular disease.

DNA repair mechanisms in colorectal carcinogenesis.

Colon cancer is among the most common cancers and the third cause of cancer deaths worldwide. If detected at an early stage, treatment might often lead to cure. The present review adduces the so far studied alterations in the expression of genes, as well as polymorphisms of genes engaged in DNA repair systems, with particular emphasis on indirect ones that are correlated with colorectal cancer. Such aberrations could be linked to an increased risk for the development of colorectal cancer and might serve as potential targets in the areas of prevention and therapy.

Molecular pathogenesis of non muscle-invasive bladder cancer: implications for novel targeted therapies.

Approximately 70% to 80% of patients with urothelial carcinomas of the bladder are initially diagnosed with non-muscle invasive disease. Superficial, non-muscle invasive bladder cancers (NMIBCs) are managed with cystoscopic transurethral resection of all visible lesions followed by intravesical chemotherapy and/or immunotherapy. Despite this treatment, up to 70% of these tumors will recur within five years and 15% will ultimately progress to muscle-invasive disease, suggesting that novel therapeutic strategies are necessary. Recent studies have greatly advanced our understanding of urothelial carcinogenesis and have highlighted the distinct molecular pathogenesis of NMIBCs versus muscle-invasive bladder tumors. It is now clear that diverse genetic and epigenetic events are driving the oncogenesis of NMIBCs, thereby attesting to their potential as therapeutic targets for these tumors. This article reviews the molecular pathogenesis of NMIBCs, discusses recently completed and ongoing clinical trials and anticipates the future direction of molecular targeted agents in this disease.

ERp29 regulates response to doxorubicin by a PERK-mediated mechanism.

ERp29 is an endoplasmic reticulum (ER) luminal protein with a putative secretion factor/escort chaperone function. Accumulated evidence has implicated ERp29 in the thyroglobulin secretion, polyoma virus transport and recently in carcinogenesis. ERp29 levels were elevated in the tumors of various origins and under the conditions of genotoxic stress, such as ionizing radiation. Here we report the induction of ERp29 during the treatment of cells with doxorubicin, a commonly used antineoplastic agent. Experiments in the p53 -/- cells and p53 knockout mouse revealed that doxorubicin effect on ERp29 is p53 dependent. The increase of ERp29 level appears to activate a negative feedback loop where the elevated amounts of ERp29 augment cell viability as shown by a clonogenic cell survival assay. To elucidate the mechanisms behind the doxorubicin effects we have studied the impact of ERp29 on the interaction with the ER stress-activated eukaryotic translation initiation factor 2-alpha kinase 3 (PERK) that was shown to facilitate tumor cells' resistance to drug toxicity. Co-immunoprecipitation demonstrated physical interaction of ERp29 with PERK and moreover, overexpression of ERp29 enhanced endogenous levels of PERK. Our results identify ERp29 as a novel regulator of PERK and provide evidence for the role of ER resident factors in the regulation of chemotherapeutic efficacy. These findings show that PERK may represent a nodal point between ER stress and chemotherapeutic response.

Atypical induction of the unfolded protein response by mifepristone.

Mifepristone is a synthetic progesterone antagonist that is being used widely for the treatment of various conditions such as endometriosis, glaucoma, meningiomas, breast, ovarian and prostate cancer, as well as for research purposes, in the conditional induction of gene expression by using artificial plasmid-based systems. Here, we report that exposure of A549 human lung cancer cells to mifepristone caused an atypical induction of the cellular unfolded protein response, as evidenced by the time-dependent stimulation of RNA levels of the chaperone Grp94 and PDIa, as well as the endoplasmic reticulum stress-associated receptors ATF6, PERK and eIF2 but not of their downstream target, transcription factor ATF4. This profile was very different from that of progesterone, which at the same dose as mifepristone, failed to induce all of the ER-stress-related genes examined, apart from PERK. Furthermore, XBP1, a transcription factor that is regulated predominantly by alternative splicing by the IRE1 receptor, remains unspliced and therefore inactive either by mifepristone or progesterone treatment. Finally, the pro-apoptotic molecules CHOP and BIM are only induced in the presence of tunicamycin in the culture medium. Tunicamycin, the most commonly used pharmacologic inducer of ER stress that triggers the canonical ER stress response, was used for comparison purposes. Our results suggest that mifepristone can elicit an atypical ER stress response when used at different doses and for different time points. The subsequent induction of UPR should be taken into consideration when this agent is being used either for therapeutic or for experimental uses.

Circulating biomarkers for the diagnosis and prognosis of heart failure.

Despite substantial therapeutic advances, heart failure remains a syndrome associated with high morbidity and mortality. The management of heart failure remains challenging despite the recent different therapeutic advances. The emergence of cardiac biomarkers as increasingly effective clinical tools suggests the potential of a new approach to the management of patients with heart failure. A variety of circulating biomarkers of diagnostic and prognostic utility in heart failure is currently being studies in preclinical, observational and randomized prospective studies. Of the various candidate biomarkers, the greatest wealth of knowledge and clinical experience lies with the B-type naturetic peptides. However, because individual biomarkers may have limited sensitivity and specificity, a multi-marker approach, using combinations of different biomarkers that reflect different aspects of the pathophysiological milieu, would contribute to better risk stratification and optimization of therapy.

EGFR, HER-2 and COX-2 levels in colorectal cancer.

AIMS: Receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER-2 and cyclooxygenase-2 (COX-2) are promising molecular targets for cancer therapy and/or prevention. The aim was to evaluate EGFR, HER-2 and COX-2 mRNA and protein expression in colorectal cancer patients. METHODS AND RESULTS: EGFR, HER-2 and COX-2 protein levels were evaluated by immunohistochemistry in malignant tissue, dysplastic tissue and normal mucosa samples from 124 cases with primary colorectal carcinoma. Moreover, the corresponding mRNA levels were assessed by quantitative reverse transcriptase-polymerase chain reaction in 46 colorectal carcinomas. There was strong correlation between mRNA and protein expression for EGFR (P < 0.001), HER-2 (P < 0.004) and COX-2 (P < 0.007). EGFR levels did not correlate with stage of the disease or tumour differentiation. HER-2 and COX-2 levels increased in advanced stages and in differentiated carcinomas. Furthermore, a correlation between HER-2 and COX-2 expression was revealed in neoplastic tissue. CONCLUSIONS: EGFR as well as HER-2 and COX-2 overexpression represent important alterations that are related to the molecular pathways underpinning colorectal carcinogenesis. Further investigation is required to evaluate the impact of these markers on the management of patients with colorectal cancer.

Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study.

Common fragile sites (CFSs) are regions of the genome prone to breakage by replication inhibitors (extrinsic replication stress). Recently, we and others observed that oncogene-induced replication stress (RS) induces DNA damage from the earliest stages of cancer. Our aim was to perform a genome-wide analysis in precancerous and cancerous experimental models to examine whether allelic imbalance occurs within CFSs. Subsequently, CFSs sequence characteristics were assessed. We used a growth-factor-induced human skin hyperplasia and a H-ras-induced mouse hyperplastic urothelium as preneoplastic models, along with an inducible U2OS-CDT1(Tet-ON) cancer cell line model, all bearing established oncogene-induced RS stimuli. Human DNA was analysed with Affymetrix SNP microarrays, while mouse DNA was analysed with Nimblegen array CGH. We studied 56 aphidicolin-type CFSs and 1914 regions of control, nonfragile DNA. Our theoretical in silico analysis spanned 2.16 billion nonoverlapping bases on human chromosomes 1-22. Our results provide direct experimental evidence indicating that genomic alterations were more common within CFSs in epidermal and urothelial preneoplastic lesions as well as in cancer. CFSs were on average less flexible than nonfragile regions, contained more guanine-cytosine (GC) and Alu sequences. Importantly, regions with loss-of-heterozygosity were also less flexible and had a higher Alu percentage.

The MAPK-AP-1/-Runx2 signalling axes are implicated in chondrosarcoma pathobiology either independently or via up-regulation of VEGF.

AIMS: To investigate whether and how the JNK/ERK-AP-1/-Runx2 signalling pathways and vascular endothelial growth factor (VEGF) are engaged in the pathogenesis of cartilaginous tumours. Chondrosarcoma is the third most common primary skeletal malignancy. Nevertheless, the molecular events underlying its pathogenesis remain elusive. JNK/ERK MAPKs and their downstream effectors, c-Jun and c-Fos (AP-1), are involved in chondroblastic differention/proliferation. These proteins interact with the Runx2 transcription factor, which is also implicated in chondroblast biology. VEGF, a key angiogenic factor, is up-regulated in human chondrosarcomas. METHODS AND RESULTS: Normal cartilage and neoplastic cells from 45 chondrosarcomas and 21 enchondromas were investigated immunohistochemically. We evaluated the cellular levels of JNK2, p-JNK2 (phosphorylated/activated JNK2), its main substrate, c-Jun, pc-Jun (phosphorylated/activated c-Jun) and c-Fos. Moreover, the levels of p-ERK (phosphorylated/activated ERK), Runx2 and VEGF were assessed. Positive immunostaining for all proteins was observed in the majority of the examined chondrosarcomas and in a small fraction of enchondromas. The expression levels of all proteins were positively and significantly correlated with each other. These levels were substantially augmented in high-grade compared with low-grade chondrosarcomas and in low-grade tumours compared with benign enchondromas, implying a potential use as molecular markers for prediction of high-grade neoplasms. CONCLUSIONS: The JNK/ERK-AP-1/-Runx2 signal transduction 'network' is associated with chondroblastic malignant transformation and chondrosarcoma development, either separately or through coordinated induction of VEGF.

Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC).

Hormone-refractory prostate cancer (HRPC) is an inevitable evolution of prostate carcinogenesis, through which the normal dependence on hormones for growth and survival is bypassed. Although advances in terms of symptoms palliation and quality of life improvement have been addressed with current treatment options, innovative approaches are needed to improve survival rates. A thorough understanding of HRPC-associated molecular pathways and mechanisms of resistance are a prerequisite for novel potential therapeutic interventions. Preclinical and early clinical studies are ongoing to evaluate new therapies that target specific molecular entities. Agents under development include growth factor receptor inhibitors, small molecules targeting signal transduction pathways, apoptosis and cell-cycle regulators, angiogenesis and metastasis inhibitors, differentiation agents, telomerase inactivators, and epigenetic therapeutics. Incorporation of these agents into existing treatment regimens will guide us in the development of a multidisciplinary treatment strategy of HRPC. This article critically reviews published data on new biological agents that are being tested in HRPC clinical trials, highlights ongoing research and considers the future perspectives of this new class of agents.

Absence of association with cancer risk and low frequency of alterations at a p53 responsive PIG3 gene polymorphism in breast and lung carcinomas.

The mechanisms of p53-dependent apoptosis involve a set of genes that possess the ability to modulate oxidative stress. One of them PIG3, is induced by p53 through a microsatellite in its promoter region. This microsatellite was found to acquire its full structure and p53-functional dependence only in Hominoidea (apes and humans) and has been proposed to represent an evolutionary adaptation of tumor suppressor mechanisms. Microsatellite instability and genetic constitution, comprising the presence of the low repetition allele (10 TGYCC repeats), at this locus have been hypothesized to provide an increased risk for cancer development. Therefore, in the present analysis we examined this polymorphism in two common human cancers, lung and breast and compared it with corresponding control cases. Furthermore, for lung cancer we employed two different ethnic groups, Greek and British. Analysis of this locus in this types of tumors showed: (1) a very low frequency of microsatellite instability and loss of heterozygosity (1.4% and 4%, respectively) in the examined carcinomas, (2) the homozygous presence of the 10 repeats allele only in the control cases, and (3) a non-significant increase of the most frequent allele (15 repeats) in the cancer groups as compared to control ones. The last two observations were found in both Greek and British populations. Taken together, these data do not support the notion that this PIG3 polymorphism is associated with an increased risk for cancer susceptibility. Larger studies including other types of cancer should also be performed.