Pancreatic Cancer and Cachexia-Metabolic Mechanisms and Novel Insights.

Cachexia is a major characteristic of multiple non-malignant diseases, advanced and metastatic cancers and it is highly prevalent in pancreatic cancer, affecting almost 70-80% of the patients. Cancer cachexia is a multifactorial condition accompanied by compromised appetite and changes in body composition, i.e., loss of fat. It is associated with lower effectiveness of treatment, compromised quality of life, and higher mortality. Understanding the complex pathways underlying the pathophysiology of cancer cachexia, new therapeutic targets will be unraveled. The interplay between tumor and host factors, such as cytokines, holds a central role in cachexia pathophysiology. Cytokines are possibly responsible for anorexia, hypermetabolism, muscle proteolysis, and apoptosis. In particular, cachexia in pancreatic cancer might be the result of the surgical removal of pancreas parts. In recent years, many studies have been carried out to identify an effective treatment algorithm for cachexia. Choosing the most appropriate treatment, the clinical effect and the risk of adverse effects should be taken under consideration. The purpose of this review is to highlight the pathophysiological mechanisms as well as the current ways of cachexia treatment in the pharmaceutical and the nutrition field.

Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia.

Derangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=-0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in ßTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.

Androgen Receptor in Breast Cancer-Clinical and Preclinical Research Insights.

The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The concordance of more than 70% of AR expression in primary and metastatic breast tumors implies that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. AR exhibits different behavior depending on the breast cancer subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since the prognostic and predictive value of AR positivity remains uncertain, it is difficult to identify and stratify patients that would benefit from AR-targeted therapies. Herein, through a review of preclinical studies, clinical studies, and clinical trials, we summarize the biology of AR, its prognostic and predictive value, as well as its therapeutic implications by breast cancer molecular subtype.

The Impact of Omega 3 Fatty Acids in Atherosclerosis and Arterial Stiffness: An Overview of their Actions.

BACKGROUND: Fatty acids are common dietary nutrients particularly in economically developed countries. Research has revealed that omega-3fatty acids exert beneficial effects in the progression of atherosclerosis and cardiovascular disease. Moreover, eicosapentaenoic acid and docosahexaenoic acid possess a number of biological actions which improve cardio-metabolic health. Omega-3 fatty acids display remarkable anti-oxidant, anti-inflammatory, anti-thrombotic and anti-arrhythmogenic actions. Furthermore, they improve the levels of triglycerides, glucose metabolism and endothelial function. METHODS: The aim of this review article is to present physical, biochemical and biological properties of omega-3 fatty acids and summarize the most important mechanisms of action on arterial wall properties and arterial stiffness in atherosclerosis. RESULTS: Omega-3 fatty acids may prevent the progression of atherosclerosis. Endothelial dysfunction and arterial stiffness can be regulated by the supplementation of omega-3 fatty acids. CONCLUSION: The mechanisms of action of omega-3 fatty acids on cardiovascular health and arterial stiffening have been established. However, further research is needed in order to translate the conflicting results among the studies and improve the therapeutic options of cardiovascular disease.

The impact of dietary flavonoid supplementation on smoking-induced inflammatory process and fibrinolytic impairment.

BACKGROUND AND AIMS: Smoking is associated with increased inflammatory process and impairment of fibrinolytic status. Concord grape juice (CGJ), a rich source of flavonoids, can modify cardiovascular risk factors. We aimed to evaluate the impact of CGJ on smoking-induced impairment of inflammatory and fibrinolytic status in healthy smokers. METHODS: We studied the effect of a 2-week oral treatment with CGJ in 26 healthy smokers on three occasions (day 0: baseline, day 7 and day 14) in a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm) and 20 min after (Sm20) cigarette smoking. Serum levels of intercellular adhesion molecule-1 (sICAM-1) and plasminogen activator inhibitor 1 (PAI-1) were measured as markers of inflammatory and fibrinolytic status, respectively. RESULTS: Treatment with CGJ reduced pSm sICAM-1 levels (p < 0.001), while placebo had no impact on ICAM-1 levels (p = 0.31). Moreover, treatment with CGJ decreased pSm values of PAI-1 (p < 0.001) while placebo had no impact on PAI-1 levels (p = 0.89). Smoking induced an elevation in PAI-1 levels after smoking compared to pro-smoking levels in all study days and in both arms (CGJ and placebo) of the study (p < 0.001 for all). Interestingly, CGJ compared to placebo, attenuated the acute smoking increase in sICAM-1 and PAI-1 levels (p < 0.001 and p = 0.005 respectively). CONCLUSIONS: CGJ consumption improved inflammatory and fibrinolytic status in healthy smokers and attenuated acute smoking induced increase in ICAM-1 and PAI-1 levels. These findings shed further light on the favorable effects of flavonoids in cardiovascular health.

Vitamin D interferes with glucocorticoid responsiveness in human peripheral blood mononuclear target cells.

Glucocorticoids (GCs) are widely used in the treatment of inflammatory and autoimmune diseases; however, patients are often resistant to GC effects. Current studies indicate that vitamin D reduces the risk or modifies the course of autoimmune diseases posing vitamin D supplementation as a prevention or therapeutic option. Herein, we investigated whether vitamin D can modify the response to GCs at the molecular level. To this end, peripheral blood mononuclear cells (PBMCs) were isolated from healthy vitamin D-deficient women and incubated with either the active metabolite 1,25(OH)2D3 (VitD) for 11 days or dexamethasone (Dex) for the last 2 days in the presence or absence of VitD. Ex vivo GC sensitivity was assessed by the expression of the glucocorticoid receptor (GR) responsive gene GILZ with RT-PCR. Long-term incubation of PBMCs with VitD significantly decreased the Dex-induced augmentation of GILZ expression. Since the intracellular concentration of GR and the GR nuclear translocation are critical determinants of GC sensitivity, we next evaluated the effect of VitD on these factors. RT-PCR and western-blot analysis revealed that VitD reduced the expression of GR. This effect was abolished by the HDAC-specific inhibitor trichostatin A, implying that HDAC was implicated in this effect. Moreover, NCoR1 mRNA was significantly decreased upon treatment with VitD either alone or as pre-treatment to Dex, suggesting that a possible increase in expression of this co-repressor was not involved. In addition, immunofluorescence analysis showed that VitD hindered the Dex-induced GRα nuclear translocation, an effect verified by subcellular fractionation and western-blot experiments. To further explore the underpinning mechanism, we examined the potential of VitD to: (1) strengthen the FK506-binding protein 5 (FKBP5) negative feedback loop and (2) modify the phosphorylation status of GR. Remarkably, VitD decreased FKBP5 expression and decreased phosphorylation at Ser211, while enhancing phosphorylation of GR at Ser203. Overall, VitD decreases the ex vivo GC sensitivity and this effect is, at least in part, attributed both to decrease of GR expression owing to a mechanism that engages HDAC and inhibition of GR translocation to nucleus via differential modulation of the phosphorylation state of GR. Our study provides, for the first time, evidence that long-term action of VitD induces GC resistance in PBMCs from healthy volunteers and offers a possible mechanistic basis for VitD-triggered attenuation of GC effects.

Impact of androgen and dietary advanced glycation end products on female rat liver.

BACKGROUND/AIMS: Advanced glycation end products (AGEs) have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS). The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. METHODS: The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30) and adult rats (Group B, n=20) that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30). All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. RESULTS: Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (x03B3;GT) (p≤0.0002) and indices of AGE immunostaining in liver tissue (p<0.01) when compared to the respective low-AGE group, while aspartate aminotransferase (AST) levels were affected only in non-androgenized animals (p=0.0002). Androgenization per se constitutes an aggravating factor as demonstrated by the elevated x03B3;GT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002) and by the elevated AST and alanine aminotransferase (ALT) levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002) followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007). CONCLUSION: The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions.

Dietary glycotoxins induce RAGE and VEGF up-regulation in the retina of normal rats.

Exogenous intake of glycotoxins present in western diet accelerates the accumulation of advanced glycation end products (AGEs) in multiple organs leading to potential tissue damage. Advanced ageing and diabetic conditions have been associated with AGEs deposition in multiple eye compartments including Bruch's membrane, optic nerve, lens and cornea. However, the impact of dietary AGEs in ocular physiology has not been extensively studied. The present study investigates the direct effects of a high AGE content diet in the ocular tissues of normal rats of different age. Two groups of baby (4 weeks of age) and adult (12 weeks of age) female Wistar rats (n = 73) were allocated to high- or low-AGE diet for 3 months. Upon completion of experimental protocol, somatometric, hormonal and biochemical parameters were evaluated in all groups. Circulating and tissue AGE levels were estimated along with their signaling receptor (receptor for AGEs, RAGE) and vascular endothelial growth factor A (VEGF-A) expression in ocular tissues of the different subgroups. High AGE intake was associated with elevated serum AGEs (p = 0.0001), fructosamine (p = 0.0004) and CRP levels (p = 0.0001) compared to low AGE. High peripheral AGE levels were positively correlated with significant increased tissue immunoreactivity of AGEs and RAGE in retinal and uveal tissues as well as retinal VEGF-A expression. Up-regulation of RAGE and VEGF-A expression was observed in the ocular tissue of both baby and adult animals fed with high-AGE diet. Co-localization of AGEs and RAGE staining was observed mainly in the inner retinal layers and the retinal pigment epithelium (RPE) of all groups. VEGF-A expression was elevated in the RPE, the inner nuclear layer and the retinal ganglion cell layer of the animals exposed to high-AGE diet. In conclusion, dietary AGEs intake affects the physiology of ocular tissues by up-regulating RAGE and VEGF-A expression contributing to enhanced inflammatory responses and pathologic neovascularization in normal organisms independent of ageing.

Consumption of a boiled Greek type of coffee is associated with improved endothelial function: the Ikaria study.

OBJECTIVE: The association of coffee consumption with cardiovascular disease remains controversial. Endothelial function is associated with cardiovascular risk. We examined the association between chronic coffee consumption and endothelium function in elderly inhabitants of the island of Ikaria. METHODS: The analysis was conducted on 142 elderly subjects (aged 66-91 years) of the Ikaria Study. Endothelial function was evaluated by ultrasound measurement of flow-mediated dilation (FMD). Coffee consumption was evaluated based on a food frequency questionnaire and was categorized as 'low' (< 200 ml/day), 'moderate' (200-450 ml/day), or 'high' (> 450 ml/day). RESULTS: From the subjects included in the study, 87% consumed a boiled Greek type of coffee. Moreover, 40% had a 'low', 48% a 'moderate' and 13% a 'high' daily coffee consumption. There was a linear increase in FMD according to coffee consumption ('low': 4.33 ± 2.51% vs 'moderate': 5.39 ± 3.09% vs 'high': 6.47 ± 2.72%; p = 0.032). Moreover, subjects consuming mainly a boiled Greek type of coffee had a significantly higher FMD compared with those consuming other types of coffee beverages (p = 0.035). CONCLUSIONS: Chronic coffee consumption is associated with improved endothelial function in elderly subjects, providing a new connection between nutrition and vascular health.

Effects of Ω-3 fatty acids on endothelial function, arterial wall properties, inflammatory and fibrinolytic status in smokers: a cross over study.

BACKGROUND: Smoking is associated with endothelial dysfunction and arterial stiffness. Supplementation of Ω-3 PUFAs is associated with better prognosis. Aim of this study was to evaluate the effects of Ω-3 polyunsaturated fatty acids (PUFAs) supplementation on smoking-induced impairment of arterial function. METHODS: We studied the effect of a 12 weeks oral treatment with 2gr/day of Ω-3 PUFAs in 20 healthy smokers on three occasions (day 0:baseline, day 28 and day 84). The study was carried out on two separate arms (Ω-3 fatty acids and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm), immediately and 20min after cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Circulating levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) were measured. RESULTS: Compared with placebo, Ω-3 PUFAs treatment resulted in a significant improvement in pSm values of FMD (p<0.05), AIx (p<0.001) and PWV (p<0.01). Although, acute cigarette smoking decreased FMD and caused an increase in AIx and PWV, Ω-3 PUFAs treatment blunted the acute smoking-induced impairment of FMD (p<0.001), AIx (p<0.05) and PWV (p<0.05) and significantly decreased levels of TNFα (p<0.05) and IL-6 (p=0.01) and increased levels of PAI-1 (p=0.05). CONCLUSIONS: Ω-3 PUFAs improved endothelial function and the elastic properties of the arterial tree in healthy smokers, with a parallel anti-inflammatory effect.

Molecular mechanisms regulating matrix metalloproteinases.

The family of matrix metalloproteinases (MMPs) comprises 24 multidomain enzymes with a zinc-dependent activity. Their structural diversity over the archetypal domain organization confers variable biological function to these molecules ranging from cellular homeostasis and control of tissue turnover to implication in multiple pathological conditions such as inflammation, arthritis, cardiovascular disease and cancer. MMP expression and activity exhibits high tissue-species- and signal-specificity and involves multiple regulatory mechanisms that co-ordinate zymogen activation, endogenous inhibition and gene transcription. In this article, we provide an overview of the molecular mechanisms that regulate MMPs gene expression at transcriptional and post-transcriptional level through integration of signals from multiple pathways to cis-acting elements present in MMP promoters, epigenetic modifications, mRNA stability mechanisms and microRNA modulation. Loss of MMP activity through mutations and single nucleotide polymorphisms is further discussed in the context of disease susceptibility.

The impact of oral L-arginine supplementation on acute smoking-induced endothelial injury and arterial performance.

BACKGROUND: Smoking is associated with endothelial dysfunction and increased inflammatory status. The amino acid L-arginine, improves endothelial function in patients with cardiovascular risk factors. We investigated the effect of L-arginine on vascular function and inflammatory process in healthy smokers at rest and after acute smoking. METHODS: We studied the effect of L-arginine and/or placebo in 12 healthy young smokers on three occasions (day 0, day 1, and day 3). The study was carried out on two separate arms, one with L-arginine (3 x 7 g/day) and one with placebo, according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before, immediately after, and 20 min after cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) and as a measure of arterial wave reflections. Serum soluble intercellular adhesion molecule-1 (sICAM-1) was measured. RESULTS: Compared to placebo, L-arginine improved FMD (P < 0.01 at day 1 and P < 0.05 at day 3). L-Arginine reduced PWV and AIx at both days 1 and 3 (P < 0.05 vs. baseline). L-Arginine blunted the acute smoking-induced increase of AIx at both day 1 (P < 0.05) and day 3 (P < 0.01), and prevented the smoking-induced elevation of PWV at day 3 (P < 0.05). Importantly, L-arginine reduced sICAM-1 at days 1 and 3 (P < 0.05 for both vs. baseline). CONCLUSIONS: Oral L-arginine improves endothelial function and vascular elastic properties of the arterial tree during the acute phase of smoking, an effect accompanied by reduced sICAM-1 levels in these subjects.

Educational and social-ethical issues in the pursuit of molecular medicine.

Molecular medicine is transforming everyday clinical practice from an empirical art to a rational ortho-molecular science. The prevailing concept in this emerging framework of molecular medicine is a personalized approach to disease prevention, diagnosis, prognosis, and treatment. In this mini-review, we discuss the educational and social-ethical issues raised by the advances of biomedical research as related to medical practice; outline the implications of molecular medicine for patients, physicians, and researchers; and underline the responsibilities of academia and the pharmaceutical industry to translate the scientific knowledge to a meaningful improvement of the quality of life across all members of society.