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The study had the objective of evaluating the effects of a lupin protein concentrate on plasma lipids and other cardiovascular risk factors, e.g. blood pressure and insulin resistance, compared to a skimmed milk powder. Fifty subjects followed a randomised, parallel, double-blind, single-centre study, consisting in a 12-week intervention: half of the participants consumed a lupin protein concentrate (30 g/day of protein), the other half a lactose-free skimmed milk powder (30 g/day of protein), both integrated into a mixed low-lipid diet. At the end of intervention, both groups showed similar reductions of total cholesterol concentrations versus baseline (−6.7%, and −7.2%, respectively), but the reductions of LDL-cholesterol (−8.0%), non-HDL-cholesterol (−7.5%), and proprotein convertase subtilisin/kexin type 9 (PCSK9) (−12.7%) levels were statistically significant only after the lupin diet. A significant reduction of HDL-cholesterol concentration was observed only after the milk diet. The differences between the two groups, however, were not statistically significant. [ABSTRACT FROM AUTHOR]

• Ecological Quality Status (EQS) assessed in a Mediterranean transitional system. • Biological traits analysis used in combination with diversity and biotic indices. • Functional diversity correlated significantly with taxonomic diversity and M−AMBI. • The joint use of taxonomic and functional metrics enhances the EQS assessment of coastal lagoons. In the present study, we tested the effectiveness of biological trait analysis (BTA) as an ecological indicator in support of the assessment of the Ecological Quality Status (EQS) of a Mediterranean transitional system by commonly used macrobenthic assemblage diversity (e.g. H' and Margalef) and biotic (BENTIX, M−AMBI and M−bAMBI) indices. Ten biological traits describing morphological, behavioral and life history characteristics were considered for the analysis of the functional structure of macrobenthos. As a test study, a historical dataset obtained from the Cabras lagoon (Sardinia, Italy) comprising a riverine site, the lagoonal main body, a confined pond, a seaward creek and a marine channel connected to the Gulf of Oristano was analyzed. Our results showed clear spatial changes in macrobenthic density, number of species and diversity indices along the riverine-lagoon-sea gradient, which were well reflected in the EQS values based on M−AMBI and to a lesser extent on M−bAMBI. The abundance-based functional diversity was significantly related to the structure and taxonomic diversity of the benthic community. Similarly, the Community-level Weighted Mean test computed with abundance data, rather than with biomass data, supported major evidence for differences in the ecological conditions of the different study sites. In particular, all riverine, lagoonal and confined stations had poor or bad EQS, indicating unstable and warning conditions in this Mediterranean transitional water body. Overall, the BTA approach appeared to be a very promising method in reporting the expected environmental and biotic variability in the Cabras lagoon system and in supporting the EQS assessment by M−AMBI. We conclude that an in-depth knowledge of the benthic communities in terms of both taxonomic and functional aspects is an indispensable basic tool for understanding the variability of the brackish-water systems and for properly assessing their environmental quality. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the proprotein convertase family. Several studies have demonstrated its involvement in the regulation of low-density lipoprotein (LDL) cholesterol levels by inducing the degradation of the LDL receptor (LDLR). However, experimental, epidemiologic, and pharmacologic data provide important evidence on the role of PCSK9 also on high-density lipoproteins (HDLs). In mice, PCSK9 regulates the HDL cholesterol (HDL-C) levels by the degradation of hepatic LDLR, thus inhibiting the uptake of apolipoprotein (Apo)E-containing HDLs. Several epidemiologic and genetic studies reported positive relationship between PCSK9 and HDL-C levels, likely by reducing the uptake of the ApoE-containing HDL particles. PCSK9 enhances also the degradation of LDLR's closest family members, ApoE receptor 2, very low-density lipoprotein receptor, and LDLR-related protein 1. This feature provides a molecular mechanism by which PCSK9 may affect HDL metabolism. Experimental studies demonstrated that PCSK9 directly interacts with HDL by modulating PCSK9 self-assembly and its binding to the LDLR. Finally, the inhibition of PCSK9 by means of monoclonal antibodies directed to PCSK9 (ie, evolocumab and alirocumab) determines an increase of HDL-C fraction by 7% and 4.2%, respectively. Thus, the understanding of the role of PCSK9 on HDL metabolism needs to be elucidated with a particular focus on the effect of PCSK9 on HDL-mediated reverse cholesterol transport. [ABSTRACT FROM AUTHOR]

In coastal lagoons, many studies indicated that macrozoobenthic assemblages undergo marked temporal fluctuations as related to the strong environmental variability of these systems. However, most of these studies have not assessed the seasonal patterns of these fluctuations and none of them has investigated the consistency of this variation in different areas within the same lagoon system. In this study, we assessed patterns of variation at multiple temporal (date, season and year) scales in two different areas in the coastal lagoon of Mellah (northeast Algeria). These areas (hereafter Shore and Center ) are representative of two different environments typically found in coastal lagoons. The Shore (water depth of about 1.5–2 m) is characterized by relatively higher hydrodynamics, sand to silty-sand sediments and the presence of vegetation ( Ruppia maritima ), the Center (water depth of about 3–3.5 m) is characterized by mud to sandy-mud, organic-enriched sediments due to fine particle accumulation. Results showed two distinct patterns of seasonal variation in Shore and Center assemblages for two consecutive years. In Shore , species richness ( S ), total abundance ( N ) and the abundance of several dominant taxa were highest in summer and/or autumn. This pattern can be related to the local environmental conditions maintaining relatively well oxidized conditions, while increasing food availability, and favoring the recruitment of species and individuals in summer/autumn. On the contrary in Center , S was lowest in summer and autumn, and N and the abundance of fewer dominant taxa were lowest in summer. In Center , the bivalve Loripes lucinalis showed a 10-fold increase from summer to autumn in both years, likely related to the lagoon's hydrodynamics favoring larval transport and settlement in the central sector of the lagoon. Overall, the seasonal variation found in Center followed a regression/recovery pattern typical of opportunistic assemblages occurring in confined organic-enriched environments. In conclusion, our results provide new insight into the patterns of seasonal variation in lagoon soft-sediment benthos and highlight the importance of local environmental conditions on this variation. This study provides a valuable tool for adopting appropriate monitoring strategies in these systems, with special reference to Southern-Eastern Mediterranean lagoons which are expected to suffer from increasing coastal development and human pressure in the near future. [ABSTRACT FROM AUTHOR]

The use of statins for cardiovascular disease prevention is clearly supported by clinical evidence. However, in January 2014 the U.S. Food and Drug Administration released an advice on statin risk reporting that “statin benefit is indisputable, but they need to be taken with care and knowledge of their side effects”. Among them the by far most common complication is myopathy, ranging from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. This class side effect appears to be dose dependent, with more lipophilic statin ( i.e. , simvastatin) carrying a higher overall risk. Hence, to minimize statin-associated myopathy, clinicians should take into consideration a series of factors that potentially increase this risk ( i.e. , drug–drug interactions, female gender, advanced age, diabetes mellitus, hypothyroidism and vitamin D deficiency). Whenever it is appropriate to stop statin treatment, the recommendations are to stay off statin until resolution of symptoms or normalization of creatine kinase values. Afterwards, clinicians have several options to treat dyslipidemia, including the use of a lower dose of the same statin, intermittent non-daily dosing of statin, initiation of a different statin, alone or in combination with nonstatin lipid-lowering agents, and substitution with red yeast rice. [ABSTRACT FROM AUTHOR]

Background Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings. Objective To evaluate gender-related differences in statin responses. Methods Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women). Results In this series of patients, a significantly attenuated reduction of total cholesterol and low-density lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: −28.5 ± 11.8% in men vs −22.7 ± 11.8% in women; P < .001). Conclusions The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Primary cardiovascular prevention may be achieved by lifestyle/nutrition improvements and specific drugs, although a relevant role is now emerging for specific functional foods and nutraceuticals. Objectives: The aim of this study was to evaluate the usefulness of a nutraceutical multitarget approach in subjects with moderate cardiovascular risk and to compare it with pravastatin treatment. Subjects: Thirty patients with moderate dyslipidemia and metabolic syndrome (according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults) were included in an 8-week randomized, double-blind crossover study and took either placebo or a nutraceutical combination that contained red yeast rice extract, berberine, policosanol, astaxanthin, coenzyme Q10, and folic acid (Armolipid Plus). Subsequently, they were subjected to another 8-week treatment with pravastatin 10 mg/d. This dosage was selected on the basis of its expected −20% efficacy in reducing low-density lipoprotein-cholesterol. Results: Treatment with Armolipid Plus led to a significant reduction of total cholesterol (−12.8%) and low-density lipoprotein-cholesterol (−21.1%), similar to pravastatin (−16% and −22.6%, respectively), and an increase of high-density lipoprotein-cholesterol (4.8%). Armolipid Plus improved the leptin-to-adiponectin ratio, whereas adiponectin levels were unchanged. Conclusions: These results indicate that this nutraceutical approach shows a lipid-lowering activity comparable to pravastatin treatment. Hence, it may be a safe and useful option, especially in conditions of moderate cardiovascular risk, in which a pharmacologic intervention may not be appropriate. [Copyright &y& Elsevier]

Dyslipidemias and atherosclerosis play a pivotal role in cardiovascular risk and disease. Although some pathophysiological mechanisms underlying these conditions have been unveiled, several knowledge gaps still remain. Experimental models, both in vitro and in vivo , have been instrumental to our better understanding of such complex processes. The latter have often been based on rodent species, either wild-type or, in several instances, genetically modified. In this context, the zebrafish may represent an additional very useful in vivo experimental model for dyslipidemia and atherosclerosis. Interestingly, the lipid metabolism of zebrafish shares several features with that present in humans, recapitulating some molecular features and pathophysiological aspects in a better way than that of rodents. The zebrafish model may be of help to address questions related to exposome factors as well as to genetic features, aiming to dissect selected aspects of the more complex scenario observed in humans. Indeed, exposome-related dyslipidemia/atherosclerosis research in zebrafish may target different scientific questions, related to nutrition, microbiota, temperature, light exposure at the larval stage, exposure to chemicals and epigenetic consequences of such external factors. Addressing genetic features related to dyslipidemia/atherosclerosis using the zebrafish model is already a reality and active research is now ongoing in this promising area. Novel technologies (gene and genome editing) may help to identify new candidate genes involved in dyslipidemia and dyslipidemia-related diseases. Based on these considerations, the zebrafish experimental model appears highly suitable for the study of exposome factors, genes and molecules involved in the development of atherosclerosis-related disease as well as for the validation of novel potential treatment options. • Experimental models to study dyslipidemias and atherosclerosis are relevant tools • Rodent species (wild-type/genetically modified) have been used over time • Zebrafish represents another very useful recently-developed experimental model • Lipid metabolism of zebrafish shares several features with that present in humans • Gene/genome editing in zebrafish may help to identify new candidate genes associated to dyslipidemia-related diseases [ABSTRACT FROM AUTHOR]

Abstract: This paper presents TGI-Simulator, a software tool designed to show, through a 2-D graphical animation, the simulated time effect of an anticancer drug on a tumor mass by exploiting the well-known Tumor Growth Inhibition (TGI) model published by Simeoni et al. . Simeoni TGI model is a mathematical model routinely used by pharma companies and researchers during the drug development process. The application is based on a Java graphical user interface (GUI) including a self installing differential equation solver implemented in Matlab together with an optimization algorithm that performs model identification via Weighted Least Squares (WLS). However, it can graphically show also the simulation results obtained within other scientific software tools, if they are preventively stored into a suitable ASCII file. The tool would be a valid support also for researchers with no specific skills in scientific calculations and in pharmacokinetic and pharmacodynamic modeling but daily involved in pharma companies drug development processes at different levels. The availability of a movie with a temporal varying 2-D iconographic representation is an original instrument to communicate results and learn Simeoni TGI model and its potential application in preclinical studies. [Copyright &y& Elsevier]

Summary: Throughout evolution, organisms have devised strategies to limit fertility in case of prolonged starvation. In mammals, the liver plays a central role in the orchestration of mechanisms allowing for the maintenance of energy homeostasis. We here demonstrate that dietary amino acids regulate the transcriptional activity of hepatic estrogen receptor alpha (ERα) through an mTOR-dependent mechanism. As a result of ERα activation, hepatic IGF-1 mRNA and blood IGF-1 are increased. Conversely, calorie restriction or selective ablation of ERα in the liver decrease blood IGF-1 to levels inadequate for the correct proliferation of the lumen epithelium in the uterus and the progression of the estrous cycle. We propose that the liver acts as critical mediator of energetic and reproductive functions responsible for the blockade of the estrous cycle in case of protein scarcity. Our findings may provide novel insights to understand the cause of selected forms of infertility and metabolic alterations in women after menopause. [ABSTRACT FROM AUTHOR]

Abstract: The Water Framework Directive (WFD) and the Marine Strategy Framework Directive (MSFD) are the European umbrella regulations for water systems. It is a challenge for the scientific community to translate the principles of these directives into realistic and accurate approaches. The aim of this paper, conducted by the Benthos Ecology Working Group of ICES, is to describe how the principles have been translated, which were the challenges and best way forward. We have tackled the following principles: the ecosystem-based approach, the development of benthic indicators, the definition of ‘pristine’ or sustainable conditions, the detection of pressures and the development of monitoring programs. We concluded that testing and integrating the different approaches was facilitated during the WFD process, which led to further insights and improvements, which the MSFD can rely upon. Expert involvement in the entire implementation process proved to be of vital importance. [ABSTRACT FROM AUTHOR]

• We show how data availability affects the predictive performance of PBPK models for ethambutol. • Urinary excretion data were crucial for accurate predictions for ethambutol. • Prediction accuracy highly depends on intestinal permeability value for ethambutol. • Caution is recommended for PBPK use if key in vivo data/parameters are unavailable. Whole-body physiologically based pharmacokinetic (WB-PBPK) models have become an important tool in drug development, as they enable characterization of pharmacokinetic profiles across different organs based on physiological (systems-specific) and physicochemical (drug-specific) properties. However, it remains unclear which data are needed for accurate predictions when applying the approach to novel candidate molecules progressing into the clinic. In this work, as case study, we investigated the predictive performance of WB-PBPK models both for prospective and retrospective evaluation of the pharmacokinetics of ethambutol, considering scenarios that reflect different stages of development, including settings in which the data are limited to in vitro experiments, in vivo preclinical data, and when some clinical data are available. Overall, the accuracy of PBPK model-predicted systemic and tissue exposure was heavily dependant on prior knowledge about the eliminating organs. Whilst these findings may be specific to ethambutol, the challenges and potential limitations identified here may be relevant to a variety of drugs, raising questions about (1) the minimum requirements for prospective use of WB-PBPK models during the characterization of drug disposition and (2) implication of uncertainty for dose selection in humans. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Multiomics approaches are pivotal in understanding atherosclerotic cardiovascular disease (ASCVD) and offer promising preventive and therapeutic strategies beyond traditional risk factors. Integrating genomics, epigenomics, transcriptomics, proteomics, and metabolomics data enhances risk stratification quality. Artificial intelligence (AI) and machine learning (ML) models provide advanced tools for accurate ASCVD risk prediction by integrating multiomics and clinical data. Large-scale collaborative efforts are essential for gathering comprehensive data sets to train AI/ML models effectively. Standardized data, interdisciplinary collaboration, and regulatory approval are crucial for successful implementation. Multiomics studies offer accurate preventive and therapeutic strategies for atherosclerotic cardiovascular disease (ASCVD) beyond traditional risk factors. By using artificial intelligence (AI) and machine learning (ML) approaches, it is possible to integrate multiple 'omics and clinical data sets into tools that can be utilized for the development of personalized diagnostic and therapeutic approaches. However, currently multiple challenges in data quality, integration, and privacy still need to be addressed. In this opinion, we emphasize that joined efforts, exemplified by the AtheroNET COST Action, have a pivotal role in overcoming the challenges to advance multiomics approaches in ASCVD research, with the aim to foster more precise and effective patient care. [ABSTRACT FROM AUTHOR]

Xenograft models are commonly used in oncology drug development. Although there are discussions about their ability to generate meaningful data for the translation from animal to humans, it appears that better data quality and better design of the preclinical experiments, together with appropriate data analysis approaches could make these data more informative for clinical development. An approach based on mathematical modeling is necessary to derive experiment-independent parameters which can be linked with clinically relevant endpoints. Moreover, the inclusion of biomarkers as predictors of efficacy is a key step towards a more general mechanism-based strategy. [Copyright &y& Elsevier]

Abstract: Objectives: The purpose of the paper is to propose a methodology for learning gene regulatory networks from DNA microarray data based on the integration of different data and knowledge sources. We applied our method to Saccharomyces cerevisiae experiments, focusing our attention on cell cycle regulatory mechanisms. We exploited data from deletion mutant experiments (static data), gene expression time series (dynamic data) and the knowledge encoded in the Gene Ontology. Methods: The proposed method is based on four phases. An initial gene network was derived from static data by means of a simple statistical approach. Then, the genes classified in the Gene Ontology as being involved in the cell cycle were selected. As a third step, the network structure was used to initialize a linear dynamic model of gene expression profiles. Finally, a genetic algorithm was applied to update the gene network exploiting data coming from an experiment on the yeast cell cycle. Results: We compared the network models provided by our approach with those obtained with a fully data-driven approach, by looking at their AIC scores and at the percentage of preserved connections in the best solutions. The results show that several nearly equivalent solutions, in terms of AIC scores, can be found. This problem is greatly mitigated by following our approach, which is able to find more robust models by fixing a portion of the network structure on the basis of prior knowledge. The best network structure was biologically evaluated on a set of 22 known cell cycle genes against independent knowledge sources. Conclusions: An approach able to integrate several sources of information is needed to infer gene regulatory networks, as a fully data-driven search is in general prone to overfitting and to unidentifiability problems. The learned networks encode hypotheses on regulatory relationships that need to be verified by means of wet-lab experiments. [Copyright &y& Elsevier]

Abstract: Peptidomimetics containing the spiroazepinoindolinone scaffold were designed and synthesized in order to ascertain their antiproliferative activity on the DU-145 human prostatic carcinoma cell line. Ethyl 2′-oxa-1,2,3,5,6,7-hexahydrospiro[4H-azepine-4,3′-3H-indole]-1′-carboxylate scaffold was functionalized at nitrogen azepino ring with Aib-(l/d)Trp-OH dipeptides. Combining the different stereochemistries of the scaffold and the tryptophan, diastereoisomeric peptidomimetics were prepared and tested. Their biological activity was evaluated by proliferation studies proving that the isomer containing S spiroazepino-indolinone scaffold and l tryptophan is the most active compound. Docking studies confirmed that the active peptidomimetic could bind the GHSR-1a receptor with docking scores comparable with those of well-known agonists even though with a somewhat different binding mode. [Copyright &y& Elsevier]

Studies focusing on patterns of spatial variation in marine soft-bottom assemblages suggest that variability is mainly concentrated at small spatial scale (from tens of centimeters to few meters), but there is still a lack of knowledge about the consistency of this spatial pattern across habitats and seasons. To address this issue, we quantified the variability in the structure of macrozoobenthic assemblages and in the abundance of dominant macroinvertebrate species in the Mellah Lagoon (Algeria) at three spatial scales, i.e., Plot (meters apart), Station (10's m apart) and Site (kms apart) scale, in Ruppia maritima (Ruppia) beds and unvegetated sediments (Unvegetated), and in two dates in winter and two dates in summer 2016. Spatial variability of the most dominant bivalve Mytilaster marioni varied significantly between habitats, but consistent across the two seasons, with a more heterogeneous distribution in Ruppia than in Unvegetated at the Station scale. Furthermore, a second-order interaction among the hierarchical nature of spatial variability, season and habitat emerged for the assemblage structure. Spatial variability between habitats varied significantly in winter, with the largest variation at the Plot scale in Unvegetated and more heterogenous assemblages at the Plot and Site scales than at the Station scale in Ruppia , but did not vary in summer when most of the variance was at the Site scale. We demonstrate that the scales of influence of the processes operating in the Mellah Lagoon are contingent on the specific habitat and/or period of the year at which the study was conducted, highlighting the importance of examining all these sources of variation simultaneously to increase the accuracy of explanatory models derived from the observed patterns in sedimentary environments. • The spatial variability of soft-bottom macrobenthos was analyzed across 3 spatial scales ranging from meters to kilometers in a Mediterranean lagoon. • The consistency of patterns of variation was tested between Ruppia and unvegetated habitats and between winter and summer. • Between-habitats and seasonal shifts on the relevant scales of variation were shown by distinct components of the assemblage. • Complex interactions among environmental conditions, biotic factors and plant's meadows emerged. • Examining simultaneously all these sources of variation increases the accuracy of ecological explanations in soft-bottoms. [ABSTRACT FROM AUTHOR]

The characterisation of pharmacokinetics, pharmacodynamics and dose-exposure-response relationships requires data arising from well-designed study protocols and a relatively large sample from the target patient population. Such a prerequisite is unrealistic for paediatric rare diseases, where the patient population is often vulnerable and very small. In such cases, different sources of data and knowledge need to be considered to ensure trial designs are truly informative and oncoming data can be analysed efficiently. Here, we use clinical trial simulations to assess the contribution of historical data for (1) the analysis of sparse samples from a limited number of children and (2) the optimisation of study design when an increase in the number of subjects is not feasible. The evaluation of the pharmacokinetics of deferasirox in paediatric patients affected by haemoglobinopathies was used as case study. Our investigation shows that the incorporation of prior knowledge increases parameter precision and probability of successful convergence from only 12% with no priors to 56% and 75% for weakly and highly informative priors, respectively. In addition, results suggest that even when only one sample is collected per subject, as implemented in the original trial and in many other examples in clinical research, there is a 60% probability of biased parameter estimates (>25%). In conjunction with adult prior information and optimisation techniques, the probability of bias could be limited to <20% by increasing the number of samples/subject from 1 to 3. The methodology described here can be easily applied to other studies in small populations. Unlabelled Image [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT , ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma. [ABSTRACT FROM AUTHOR]

Introduction Iron overload leads to multiple organ damage including endocrine organ dysfunctions. Hypogonadism is the most common non-diabetic endocrinopathy in primary and secondary iron overload syndromes. Aim To explore the molecular determinants of iron overload-induced hypogonadism with specific focus on hypothalamic derangements. A dysmetabolic male murine model fed iron-enriched diet (IED) and cell-based models of gonadotropin-releasing hormone (GnRH) neurons were used. Results Mice fed IED showed severe hypogonadism with a significant reduction of serum levels of testosterone (−83%) and of luteinizing hormone (−86%), as well as reduced body weight gain, body fat and plasma leptin. IED mice had a significant increment in iron concentration in testes and in the pituitary. Even if iron challenge of in vitro neuronal models (GN-11 and GT1-7 GnRH cells) resulted in 10- and 5-fold iron content increments, respectively, no iron content changes were found in vivo in hypothalamus of IED mice. Conversely, mice placed on IED showed a significant increment in hypothalamic GnRH gene expression (+34%) and in the intensity of GnRH-neuron innervation of the median eminence (+1.5-fold); similar changes were found in the murine model HFE −/− , resembling human hemochromatosis. Conclusions IED-fed adult male mice show severe impairment of hypothalamus-pituitary-gonadal axis without a relevant contribution of the hypothalamic compartment, which thus appears sufficiently protected from systemic iron overload. [ABSTRACT FROM AUTHOR]

The suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway activated by pro-inflammatory cytokines, including the tumor necrosis factor-α (TNF-α). SOCS3 is also implicated in hypertriglyceridemia associated to insulin resistance. Proprotein convertase subtilisin kexin type 9 (PCSK9) levels are frequently found to be positively correlated to insulin resistance and plasma very low density lipoprotein (VLDL) triglycerides concentrations. The present study aimed to investigate the possible role of TNF-α and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. TNF-α induced both SOCS3 and PCSK9 in a concentration-dependent manner. This effect was inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Retroviral overexpression of SOCS3 inHepG2 cells (HepG2SOCS3) strongly inhibited STAT3 phosphorylation and induced PCSK9 mRNA and protein, with no effect on its promoter activity and mRNA stability. Consistently, siRNA anti-SOCS3 reduced PCSK9 mRNA levels, whereas an opposite effect was observed with siRNA anti-STAT3. In addition, HepG2SOCS3 express higher mRNA levels of key enzymes involved in the de novo lipogenesis, such as fatty-acid synthase, stearoyl-CoA desaturase (SCD)-1, and apoB. These responses were associated with a significant increase of SCD-1 protein, activation of sterol regulatory element-binding protein-1c (SREBP-1), accumulation of cellular triglycerides, and secretion of apoB. HepG2SOCS3 show lower phosphorylation levels of insulin receptor substrate 1 (IRS-1) Tyr896 and Akt Ser473 in response to insulin. Finally, insulin stimulation produced an additive effect with SOCS3 overexpression, further inducing PCSK9, SREBP-1, fatty acid synthase, and apoB mRNA. In conclusion, our data candidate PCSK9 as a gene involved in lipid metabolism regulated by proinflammatory cytokine TNF-α in a SOCS3-dependent manner. [ABSTRACT FROM AUTHOR]

Background Increased levels of adiponectin, a major adipokine with insulin sensitizing properties showing a strong sexual dimorphism, have been reported in individuals with chronic HCV infection (CHC), but data are limited by small samples and lack of control for the genetic background and hepatic fibrosis. The aim of this study was to compare adiponectin levels between CHC patients and accurately matched controls. Methods We considered 184 CHC patients, matched (1:1) for age, gender, body mass index, and Adiponectin genotype ( ADIPOQ ) with healthy individuals. To control for the severity of liver disease, a second control group consisting of 95 patients with histological nonalcoholic fatty liver disease (NAFLD) further matched (1:1) for severe fibrosis was exploited. ADIPOQ genotype was evaluated by Taqman assays, serum adiponectin measured by ELISA. Results Serum adiponectin was higher in CHC patients than in healthy individuals (9.0 ± 5.0 μg/ml vs. 7.3 ± 4.0 μg/ml; p = 0.001; adjusted estimate + 1.8, 1.7–2.9; p = 0.001), and than in NAFLD patients (8.3 ± 4.5 μg/ml vs. 6.0 ± 4.2 μg/ml; p < 0.001; adjusted estimate + 0.8, 0.2–1.4, p = 0.006). After stratification for sex, serum adiponectin was higher in males with CHC than in healthy individuals and NAFLD patients (p < 0.005 for both), whereas the difference was not significant in females. Conclusions CHC is associated with increased serum adiponectin independently of age, body mass, diabetes, ADIPOQ genotype, and of severe liver fibrosis, particularly in men. [ABSTRACT FROM AUTHOR]

Abstract: The use of statins for cardiovascular disease (CVD) prevention is clearly supported by clinical evidence. Although statin therapy is rather well tolerated, recent data from prospective and retrospective clinical trials and related meta-analyses suggest an increased incidence of new-onset type 2 diabetes mellitus (T2DM) in association with such treatment. The incidence of this adverse effect is not negligible, especially for specific subsets of patients, such as women, elderly, presence of familial history of T2DM and Asian ethnicity. Statin-driven T2DM appears to be a medication class-effect, mostly not related to potency nor to individual statin, as well as to be independent of previous history of CVD. Therefore, implementation of strategies for identification of patients using statins and at specific risk of incident T2DM, as well as of different therapeutic options is important and is discussed in this article. As most authors emphasized that benefits of CVD reduction by statin therapy seem to far exceed the risk of T2DM development itself, these medications remain the cornerstone for primary and secondary CVD prevention, although a specific attention to glucose metabolism and metabolic syndrome features should be payed before and during statin treatment, especially in cohorts at greater risk. [Copyright &y& Elsevier]

Abstract: Copaiba is the oleoresin (OR) obtained from Copaifera (Fabaceae), a neotropical tree which grows in Amazon regions. The balsam, constituted by an essential oil and a resinous fraction is used as folkloristic remedy in the treatment of several inflammatory diseases and for its antioxidant and antibacterial properties. Aim of this work was (a) to carry out a characterization by GC–MS of the volatile and nonvolatile constituents of Copaifera langsdorffii Desf. oleoresin (OR); (b) to investigate the mechanism of its anti-inflammatory activity; (c) to evaluate its antipsoriatic effect after oral intake/topical application. The volatile fraction (yield: 22.51%, w/w) shows: α-bergamotene (48.38%), α-himachalene (11.17%), β-selinene (5.00%) and β-caryophyllene (5.47%). The OR residue (77.49%, w/w), after derivatization, showed as main constituents the following compounds: copalic, abietic, daniellic, lambertinic, labd-7-en-15-oic, pimaric, isopimaric acids and kaur16-en18-oic acid. Preincubation of LPS-stimulated human THP-1 monocytes with increasing concentrations of the OR purified fraction (OR-PF), containing diterpene acids, diterpenes and sesquiterpenes, reduced the release of pro-inflammatory cytokines (IL-1β, IL-6, TNFα) in a dose-range of 0.1–10μM. In addition, in cell culture system of human THP-1 monocytes, 1μM OR-PF counteracts LPS-driven NF-κB nuclear translocation. In a preliminary clinical trial three patients affected by chronic psoriasis, treated with oral intake or topical application of the OR, exhibited a significant improvement of the typical signs of this disease, i.e. erythema, skin thickness, and scaliness. In conclusion, the results of this work, beside an extensive analytical characterization of the OR chemical composition, provide strong evidences that its anti-inflammatory activity is related to the inhibition of the NF-κB nuclear translocation, and consequently of proinflammatory cytokines secretion. [Copyright &y& Elsevier]

Abstract: Eco-physiology studies, performed in laboratory under controlled conditions, provide an essential tool for quantifying the impact of environmental changes on the metabolism and behaviour of individual fish. One way of quantifying such impact is by measuring the Metabolic Scope (MS) of a fish and how it is affected by environmental factors. Laboratory experiments were performed to calculate the empirical mathematical equations describing the variation of the MS of flathead grey mullet, Mugil cephalus, under different environmental conditions (water temperature and water oxygen concentration). The equation obtained was introduced into a coupled hydrodynamic–ecological numerical model able to reproduce the variability of the water temperature, salinity, dissolved oxygen, and of the main dissolved nutrients and chlorophyll-a. The coupled empirical–numerical model was used to reproduce the temporal and spatial variation in MS of a M. cephalus fish population in the Oristano gulf and the Cabras lagoon system (Italy), a typical Mediterranean shallow water environment. Results from numerical simulations show that during the spring and the beginning of summer period, Cabras lagoon provides a higher MS for M. cephalus than the Oristano gulf. During the rest of the year, apart from some transitional phases, the gulf provides more suitable conditions (higher MS) for M. cephalus. The obtained results are in general accordance with fisheries data, showing that M. cephalus catches are highest during the end-July to August period, as they migrate out of the lagoon. This approach, combined with observation on the temporal and spatial distribution of fishes, can allow predictions of fish productivity in non-limiting conditions. [Copyright &y& Elsevier]

Abstract: Unlike normal cells, tumor cells survive in a specific redox environment where the elevated reactive oxygen species contribute to enhance cell proliferation and to suppress apoptosis. Alpha-lipoic acid, a naturally occurring reactive oxygen species scavenger, has been shown to possess anticancer activity, due to its ability to suppress proliferation and to induce apoptosis in different cancer cell lines. Since at the moment little information is available regarding the potential effects of alpha-lipoic acid on breast cancer, in the present study we addressed the question whether alpha-lipoic acid induces cell cycle arrest and apoptosis in the human breast cancer cell line MCF-7. Moreover, we investigated some molecular mechanisms which mediate alpha-lipoic acid actions, focusing on the role of the PI3-K/Akt signalling pathway. We observed that alpha-lipoic acid is able to scavenge reactive oxygen species in MCF-7 cells and that the reduction of reactive oxygen species is followed by cell growth arrest in the G1 phase of the cell cycle, via the specific inhibition of Akt pathway and the up-regulation of the cyclin-dependent kinase inhibitor p27kip1, and by apoptosis, via changes of the ratio of the apoptotic-related protein Bax/Bcl-2. Thus, the anti-tumor activity of alpha-lipoic acid observed in MCF-7 cells further stresses the role of redox state in regulating cancer initiation and progression. [Copyright &y& Elsevier]

The study investigated the effects of the dopamine-somatostatin chimeric compound BIM-23A760 on cell proliferation and apoptosis in cultured cells from human non-functioning pituitary tumors (NFPTs). Both BIM-23A760 and the dopaminergic agonist BIM-53097 induced a significant inhibition of cell proliferation associated with increased p27 expression, together with a significant increase in caspase-3 activity. Conversely, null or marginal effects were elicited by somatostatin analogs. Moreover, BIM-23A760 and BIM-53097 induced ERK1/2 and p38 phosphorylation and the blockade of these pathways prevented both the antiproliferative and the pro-apoptotic effects of these drugs. In conclusions the chimeric compound BIM-23A760 is able to exert cytostatic and cytotoxic effects in NFPTs, these phenomena being mainly mediated by DR2D and involving ERK1/2 and p38 pathways activation. [ABSTRACT FROM AUTHOR]

Abstract: Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonists, the available data in prostate cancer (PCa) model systems and clinical studies are few, conflicting and not conclusive. This study investigated the effects of lanreotide and new mono- and bi-specific SRIF agonists on proliferation, ligand-driven SRIF receptor (sst) dimerization and secretory pattern of the IGF system in LNCaP cells, a model of androgen-dependent PCa. LNCaP expressed all ssts, but sst4. Among them, sst1 and sst3 were inversely regulated by serum concentration. sst1/sst2 and sst2/sst5 dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst1/sst2) and BIM-23244 (sst2/sst5), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst2) and BIM-23206 (sst5) alone or in combination. Treatment with BIM-23296 (sst1) markedly reduced cell proliferation, whereas exposure to BIM-23704 resulted in a lower cell growth inhibition. The antiproliferative effects of BIM-23244, lanreotide and BIM-23704 were unchanged, reduced and abolished by the sst2 antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27KipI and p21 and down-regulation of protein expression of cyclin E, as well as reduced IGF-I and IGF-II secretion. In particular, the administration of exogenous IGF-I, at variance to IGF-II, counteracted the inhibitory effect on cell proliferation of these compounds. Moreover, SRIF agonists reduced endogenous IGFBP-3 proteolysis. These results show that, in LNCaP cells, activation of sst1 and sst2/sst5 results in relevant antiproliferative/antisecretive actions. [Copyright &y& Elsevier]

Abstract: The biosynthesis and release of neuropeptide Y (NPY) is regulated by several factors. Here, the effect of the muscarinic agonist carbachol on NPY biosynthesis and release was analyzed utilizing the SH-SY5Y human neuroblastoma cell line. We observed that: (a) carbachol moderately increased the post-translational cleavage of proNPY to NPY; (b) carbachol treatment stimulated NPY accumulation into the medium in a time- and dose-related manner; (c) protein kinase C activation is involved in carbachol-mediated NPY synthesis/release (>6h). In conclusion, the present observations support the hypothesis that muscarinic receptor activation regulates the biosynthesis and secretion of NPY. [Copyright &y& Elsevier]

Abstract: The neuropeptide Y (NPY) family of peptides, in addition to its many physiological actions, has also been involved in the modulation of tumor progression, with specific reference to endocrine-related cancers such as neuroendocrine tumors, breast and prostate cancers. These have been found either to express NPY receptors, or to secrete NPY-related peptides, or both. The study of the role of the NPY family of peptides in the biology of endocrine-related tumors, specifically concerning cell proliferation, angiogenesis, invasion and metastatization, may help to clarify some aspects of tumor pathophysiology, as well as to indicate novel diagnostic markers and therapeutical approaches. [Copyright &y& Elsevier]