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Editor's Choice by Current Pharmaceutical Design

The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment... more The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment. In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slow— or even stop—irreversible structural changes. Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers. The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes. However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment. Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers. Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.

Hypothesis. The present study evaluates the hypothesis that sour cherry seed extract (SCSE) prote... more Hypothesis. The present study evaluates the hypothesis that sour cherry seed extract (SCSE) protects against cardiovascular disease and inflammation in hypercholesterolemic rabbits, and that this protection correlates with SCSE-induced activity of heme oxygenase- 1 (HO-1), a cytoprotective enzyme contributing to oxidative stress responses.

Methods: 18 New Zealand white rabbits were divided into three groups receiving: I. cholesterol-free rabbit chow; II. chow containing 2% cholesterol; or III. 2% cholesterol plus SCSE for 16 weeks. Heart functions were monitored by echocardiography 0, 4, and 16 weeks after the initiation of cholesterol-supplemented feeding. At the 16-week time-point, isolated hearts were subjected to ischemia-reperfusion (I/R), followed by measurement of heart rate (HR), aortic flow (AF), coronary flow (CF), aortic pressure (AoP), and left ventricular developed pressure (LVDP). Myocardial infarct size was determined using triphenyl tetrazolium chloride (TTC). Quantification of fatty streaks was assessed using Sudan-III staining. Western blot analysis was used to determine the content of cytochrome c oxidase III (COX III), vascular endothelial growth factor (VEGF), and HO-1 in the myocardium.

Results: Relative to cholesterol-treated animals not receiving SCSE, SCSE-treated animals exhibited significantly improved cardiac function and improved peak early diastolic velocity to peak atrial velocity ratio (E'/A'), along with decreased atherosclerotic plaque formation and infarct size. Increased HO-1 and COX III protein expression and COX activity were also noted in hearts from SCSE-treated rabbits.

Conclusions: This study demonstrates SCSE cardioprotective effects on hypercholesterolemic hearts. Correlation of these outcomes with HO-1 expression suggests that the effect may be mediated by activity of this enzyme. However, definitive proof of HO-1 dependence requires further investigation.

Bentham Science

Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinica... more Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinical perspective, neuroimaging plays a significant role, in diagnosis, treatment planning, and follow-up. To date MRI is considered the current clinical gold standard for imaging, however, despite providing superior structural detail it features poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. In the last years functional neuroimaging has become largely widespread thanks to the use of molecular tracers employed in cellular metabolism which has significantly improved the management of patients with brain tumors, especially in the post-treatment phase. Despite the considerable progress of molecular imaging in oncology its use in the diagnosis of brain tumors is still limited by a few wellknown technical problems. Because 18F-FDG, the most common radiotracer used in oncology, is avidly accumulated by normal cortex, the low tumor/background signal ratio makes it difficult to distinguish the tumor from normal surrounding tissues. By contrast, radiotracers with higher specificity for the tumor are labeled with a short half-life isotopes which restricts their use to those centers equipped with a cyclotron and radiopharmacy facility. 11C-Choline has been reported as a suitable tracer for neuroimaging application. The recent availability of choline labeled with a long half-life radioisotope as 18F increases the possibility of studying this tracer's potential role in the staging of brain tumors. The present review focuses on the possible clinical applications of PET/CT with choline tracers in malignant brain tumors and brain metastases,with a special focus on malignant gliomas.

Open Access by Current Pharmaceutical Design

Background: The present review article provides an overview of the published literature concernin... more Background: The present review article provides an overview of the published literature concerning microbial quality of medicinal plants and products and their decon-tamination methods. It is important to analyze different aspects regarding the cultivation, growing, harvesting, storage, manufacturing, and decontamination of medicinal plant products. Herbal medicinal plants bear a massive microbial load leading to contamination and mycotoxin, which needs to be considered, and properly controlled using suitable sterilization and decontamination methods. Methods: The main focus of this review is on the definition, advantages, disadvantages and applications of decontamination methods, particularly to show that one must consider the characteristics of the initial sample to be decontaminated. Results: The effects of various methods (ozone, plasma, irradiation) on medicinal herbs and products treated for microbiological decontamination are dependent on factors related to microbial load (i.e., nature and amount of initial contamination), herb/product matrix (i.e., complexity of chemical composition, physical state-solid or liquid) and treatment conditions (i.e., time, irradiation dose, absence or presence of oxygen). In addition, it is important to accept some loss of the chemical compounds , while decreasing microbial load to acceptable limits according to official herbal pharmacopoeias and literature, thus ensuring a final product with quality, safety and therapeutic efficacy. Conclusion: The conclusion, which comes from this contribution, is that herbal medicine has more contaminants than a chemically well-defined drug, thus, good manufacturing practices should be followed.

Adhesive mixtures for inhalation are the most widely used type of formulation in dry powder inhal... more Adhesive mixtures for inhalation are the most widely used type of formulation in dry powder inhalation products. Although they have been the subject of active research, the relationships between properties of the starting materials, the mixing and dispersion processes, and the dispersion performance of this type of formulation are generally poorly understood. Interactions between relevant variables have been mentioned as an important cause. By reviewing the effects on mixture dispersion performance of the most widely studied formulation variables we try to find out whether or not the understanding of adhesive mixtures has improved in recent years. We furthermore propose an approach that may potentially accelerate the process of understanding. General conclusions concerning the effects of the variables considered cannot be drawn, because inconsistent findings are reported throughout the literature for all of them. These inconsistencies are indeed largely the result of interactions between variables of the formulation and dispersion processes. Mechanisms for most of the observed effects and interactions have been proposed, but they often remain unproven and, therefore, speculative. We have attempted to condense the knowledge from the literature into a theoretical framework that is intended to help explain the interplay between variables. According to this framework, only few mixture properties are key to understanding the effects of and interactions between formulation variables. Therefore, we suggest that the development or optimisa-tion of techniques to accurately characterise these mixture properties could be an effective approach to further the fundamental understanding of adhesive mixtures for inhalation and enable their rational engineering.

The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also... more The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also central to many aspects of the malignant process. Genetic phenomena that lead to constitutive pathway activation are common in human cancer; the most relevant are mutations affecting the catalytic subunit of PI3K and loss of function of the PTEN tumor suppressor. These factors have made this important cascade attractive as a potential target for cancer therapeutics. A host of inhibitors are now in various stages of development that target key nodes within the PI3K pathway. To date, however, the efficacy of these agents has fallen short of expectation, with at least one possible explanation being the presence of feedback loops and cross-talk that exists within and between PI3K and other signaling pathways. Accordingly, enthusiasm is again high as strategies employing therapeutic combinations are gaining pace, with encouraging results documented in both preclinical studies and emerging clinical trials. Here, we review the agents that have reached evaluation in early phase clinical studies of human subjects with cancer, and discuss the rationale for and use of novel drug combinations.

The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous s... more The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

Drug discovery and development is a high-risk enterprise that requires significant investments in... more Drug discovery and development is a high-risk enterprise that requires significant investments in capital, time and scientific expertise. The studies of xenobiotic metabolism remain as one of the main topics in the research and development of drugs, cosmetics and nutritional supplements. Antihypertensive drugs are used for the treatment of high blood pressure, which is one the most frequent symptoms of the patients that undergo cardiovascular diseases such as myocardial infraction and strokes. In current cardiovascular disease pharmacology, four drug clusters-Angiotensin Converting Enzyme Inhibitors, Beta-Blockers, Calcium Channel Blockers and Diuretics-cover the major therapeutic characteristics of the most antihypertensive drugs. The pharmacokinetic and specifically the metabolic profile of the antihyperten-sive agents are intensively studied because of the broad inter-individual variability on plasma concentrations and the diversity on the efficacy response especially due to the P450 dependent metabolic status they present. Several computational methods have been developed with the aim to: (i) model and better understand the human drug metabolism; and (ii) enhance the experimental investigation of the metabolism of small xenobiotic molecules. The main predictive tools these methods employ are rule-based approaches, quantitative structure metabolism/activity relationships and docking approaches. This review paper provides detailed metabolic profiles of the major clusters of antihypertensive agents, including their metabolites and their metabolizing enzymes, and it also provides specific information concerning the computational approaches that have been used to predict the metabolic profile of several antihypertensive drugs.

The incidence of metabolic disorders is increasing all over the world and especially in technolog... more The incidence of metabolic disorders is increasing all over the world and especially in technologically advanced
countries due to numerous factors involved. Among them are environmental factors (like contaminants, pollution,
as well as climatic changes), antigenic pressure in particular from microbial infections, life style disorders like
alcohol, smoking or diet, as well as alteration of intestinal microbiota. All these factors seem to represent the major
etiopathogenic determinants for the development of metabolic disorders, which are in many cases systemic and
therefore are connected to such diseases, resulting in the contribution of pathology. Furthermore, several studies
show that most of these pathologies contribute towards further cardiovascular, hematological, gastrointestinal and
immune disorders, as well as cancer development.

Abnormal regulation of the ubiquitin-proteasome system (UPS) has been known to be involved in the... more Abnormal regulation of the ubiquitin-proteasome system (UPS) has been known to be involved in the pathogenesis of a variety of human diseases. A number of studies have focused on the identification of small modifiers for the UPS. Even though the proteasome inhibitor Bortezomib (Velcade ®) has been approved for the therapy of multiple myeloma and mantle cell lymphoma, there are still no DUB inhibitors endorsed for clinical usage. Since deubiquitinating enzymes (DUBs) are becoming as a new class of modifiers in the UPS, potential drugs that target specific DUBs have been investigated with the development of experimental technologies for screening small inhibitor molecules. However, the molecular mechanisms of these molecules are poorly understood. In order to design and develop specific small inhibitor molecules for specific DUBs, identification of specific substrates and molecular structures for each DUB is required. Here, we review structures, substrates, and small inhibitor molecules of DUBs identified up to date, providing a clear rationale for the development of novel small inhibitor molecules of DUBs for cancer.

Wnt/-catenin signaling is a branch of a functional network that dates back to the first metazoans... more Wnt/-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling,-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations , including the plasma membrane, where-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where-catenin levels are regulated and the nucleus where-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular-catenin levels. However,-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of-catenin at its various locations provides alternative points for therapeutic interventions.

Assessing whether a protein structure is a good target or not before actually doing structure-bas... more Assessing whether a protein structure is a good target or not before actually doing structure-based drug design on it is an important step to speed up the ligand discovery process. This is known as the " druggability " or " ligandability " assessment problem that has attracted increasing interest in recent years. The assessment typically includes the detection of ligand-binding sites on the protein surface and the prediction of their abilities to bind drug-like small molecules. A brief summary of the established methods of binding sites detection and druggability(ligandability) prediction, as well as a detailed description of the CAVITY approach developed in the authors' group was given. CAVITY showed good performance on ligand-binding site detection, and was successfully used to predict both the ligandabil-ities and druggabilities of the detected binding sites.

Several cellular signaling pathways are regulated by ADP-ribosylation, a posttranslational modifi... more Several cellular signaling pathways are regulated by ADP-ribosylation, a posttranslational modification catalyzed by members of the ARTD superfamily. Tankyrases are distinguishable from the rest of this family by their unique domain organization, notably the sterile alpha motif responsible for oligomerization and ankyrin repeats mediating protein-protein interactions. Tankyrases are involved in various cellular functions, such as telomere homeostasis, Wnt/-catenin signaling, glucose metabolism, and cell cycle progression. In these processes, Tankyrases regulate the interactions and stability of target proteins by poly (ADP-ribosyl)ation. Modified proteins are subsequently recognized by the E3 ubiquitin ligase RNF146, poly-ubiquitinated and predominantly guided to 26S proteasomal degradation. Several small molecule inhibitors have been described for Tankyrases; they compete with the co-substrate NAD+ for binding to the ARTD catalytic domain. The recent, highly potent and selective inhibitors possess several properties of lead compounds and can be used for proof-of-concept studies in cancer and other Tankyrase linked diseases.

The Culture-Repopulating Ability (CRA) assays is a method to measure in vitro the bone marrow-rep... more The Culture-Repopulating Ability (CRA) assays is a method to measure in vitro the bone marrow-repopulating potential of haematopoietic cells. The method was developed in our laboratory in the course of studies based on the use of growth factorsupplemented liquid cultures to study haematopoietic stem/progenitor cell resistance to, and selection at, low oxygen tensions in the incubation atmosphere. These studies led us to put forward the first hypothesis of the existence in vivo of haematopoietic stem cell niches where oxygen tension is physiologically lower than in other bone marrow areas. The CRA assays and incubation in low oxygen were later adapted to the study of leukaemias. Stabilized leukaemia cell lines, ensuring genetically homogeneous cells and enhancing repeatability of results, were found nevertheless phenotypically heterogeneous, comprising cell subsets exhibiting functional phenotypes of stem or progenitor cells. These subsets can be assayed separately, provided an experimental system capable to select one from another (such as different criteria for incubation in low oxygen) is established. On this basis, a two-step procedure was designed, including a primary culture of leukaemia cells in low oxygen for different times, where drug treatment is applied, followed by the transfer of residual cell population (CRA assay) to a drug-free secondary culture incubated at standard oxygen tension, where the expansion of population is allowed. The CRA assays, applied to cell lines first and then to primary cells, represent a simple and relatively rapid, yet accurate and reliable, method for the pre-screening of drugs potentially active on leukaemias which in our opinion could be adopted systematically before they are tested in vivo.

Mobilized, peripheral blood stem cells (PBSC) are increasingly used for both autologous and allog... more Mobilized, peripheral blood stem cells (PBSC) are increasingly used for both autologous and allogeneic transplants. Granulocyte-colony-stimulating
factor is the most widely used cytokine for mobilization. Several different mechanisms of stem cell mobilization
have been proposed including protease-dependent and non-protease- dependent mechanisms. In autologous transplants, the addition of
chemotherapy to mobilization can enhance the yield of PBSC collected but with substantial adverse effects, and not necessarily faster engraftment.
In allogeneic transplants, the use of mobilized PBSC is associated with faster engraftment and donor chimerism compared to
bone marrow. In the majority of studies, the rate of acute graft-versus-host disease (GVHD) has not been shown to be significantly higher
with PBSC, but the rate of chronic GVHD appears to be increased. Several different strategies have been proposed for patients and donors
who fail initial mobilization, including the use of novel agents. AMD3100 (Plerixafor) works by directly inhibiting the interaction
between stromal cell-derived factor-1 and its receptor CXCR4, and mobilizes hematopoietic stem cells within hours. It is being studied
alone or in conjunction with growth factors for PBSC mobilization in both autologous and allogeneic settings. Although the use of
growth factors after PBSC transplantation results in faster neutrophil engraftment its impact on treatment-related mortality and survival
does not appear significant. Here, we review the biology and methods of PBSC mobilization, the effect of growth factors on normal donors
and the controversies of growth factor use in the post-transplant setting. We also review the data on novel agents for mobilization of
stem cells.

This study was designed to evaluate the distribution of Tregs/Th17/Th1 cells in type 2 diabetic p... more This study was designed to evaluate the distribution of Tregs/Th17/Th1 cells in type 2 diabetic patients with foot disease before and after human umbilical cord blood mesenchymal stem cell (hUCB-MSCs) transplantation. Fifteen diabetic patients with foot disease under insulin therapy received hUCB-MSC transplantation. The hUCB-MSCs were directly injected into the quadriceps thigh muscles in patients with foot disease (cell quantity at 2􀀁106 per point). Physical attributes, blood cytokines, blood glucose and insulin dosage were evaluated before treatment and 1, 2, 4, 8, and 12 weeks thereafter. The ratios of Treg/Th17, Treg/Th1, and Th17/Th1 cells were measured using flow cytometry and their correlation with various cytokines (FoxP3, IL-17, INF-􀀃, C-RP, TNF-􀀂, and VEGF) was scrutinized. Levels of blood glucose and insulin dosage were significantly reduced in all 15 patients following hUCB-MSC transplantation. The ratios of CD4+CD25hiFoxP3+ Treg/Th17 and CD4+CD25hiFoxP3+ Treg/Th1 cells were significantly increased 4 weeks after transplantation (p < 0.01), while the ratio of Th17/Th1 cells remained unchanged. Serum levels of VEGF peaked at 4 weeks following transplantation. Levels of C-RP and TNF-􀀂 were significantly reduced 4 weeks after transplantation. Intriguingly, the ratios of Treg/Th17 were positively correlated with VEGF levels, and were inversely correlated with plasma IL-6 levels. Our data indicated that immune disorders are associated with the development of type 2 diabetes and its complications. Levels of blood glucose and required insulin dosage were reduced after hUCB-MSC transplantation accompanied with improved clinical profiles in diabetic patients. These data favor a role for Treg cells in the onset and progression of T2D

Platelet function testing was introduced more than a century ago with the invention of bleeding t... more Platelet function testing was introduced more than a century ago with the invention of bleeding time; a test which has now been replaced by more accurate methods. Light transmittance aggregometry is traditionally regarded as the gold standard for evaluating platelet function. However, lately the position of light transmittance aggregometry has been challenged by a panel of new instruments. Aspirin and P2Y12-inhibitors are antiplatelet drugs used for secondary prevention of cardiovascular disease. However, an increasing recognition of the fact that not all patients respond adequately to these agents has prompted a focus on individualising antiplatelet treatment. Platelet function testing enables the detection of patients with high on-treatment platelet reactivity and facilitates individually tailored antiplatelet therapy, yet platelet function tests have still not been adopted into routine clinical practice. The present review outlines key milestones of the development of platelet function testing and provides an up-to-date overview of currently available tests and important studies evaluating their strengths and limitations in a clinical context.

􀀁9-tetrahydrocannabinol (􀀁9-THC) is the main compound of the Cannabis Sativa responsible for most... more 􀀁9-tetrahydrocannabinol (􀀁9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of 􀀁9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of 􀀁9-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.

It is clear now that proteins lacking ordered structure, generally known as intrinsically disord... more It is clear now that proteins lacking ordered structure, generally known as intrinsically disordered proteins (IDPs), possess numerous biological functions that complement functional repertoires of ordered proteins. IDPs are common in nature, and abundantly found to be involved in the pathogenesis of various diseases. These proteins participate in various biological processes and play crucial roles in regulation of functions of their binding partners. Often, disorder-to-order transition induced by the IDP binding to a specific partner defines the low-affinity – high-specificity signaling interactions. Although many IDPs undergo a disorder-to-order transition upon binding, large fraction of IDPs can preserve significant amount of disorder even in their bound states. IDPs can participate in one-tomany and many-to-one interactions, where one intrinsically disordered protein region (IDPR) binds to multiple partners potentially gaining
very different structures in the bound state, or where multiple unrelated IDPs/IDPRs bind to one partner. Binding functions of IDPs and IDPRs are controlled by various means, such as numerous posttranslational modifications and alternative splicing. Some of the aspects of the intrinsic disorder-based protein interactions and modes of their regulation are considered in this review.

The term ribosome-inactivating protein (RIP) is used to denominate proteins mostly of plant origi... more The term ribosome-inactivating protein (RIP) is used to denominate proteins mostly of plant origin, which have N-glycosidase enzymatic activity leading to a complete destruction of the ribosomal function. The discovery of the RIPs was almost a century ago, but their usage has seen transition only in the last four decades. With the advent of antibody therapy, the RIPs have been a subject of extensive research especially in targeted tumor therapies, which is the primary focus of this review. In the present work we enumerate 250 RIPs, which have been identified so far. An attempt has been made to identify all the RIPs that have been used for the construction of immunotoxins, which are conjugates or fusion proteins of an antibody or ligand with a toxin. The data from 1960 onwards is reviewed in
this paper and an extensive list of more than 450 immunotoxins is reported. The clinical reach of tumor-targeted toxins has been identified and detailed in the work as well. While there is a lot of potential that RIPs embrace for targeted tumor therapies, the success in preclinical and clinical evaluations has been limited mainly because of their inability to escape the endo/lysosomal degradation. Various strategies that can increase the efficacy and lower the required dose for targeted toxins have been compiled in this article. It is plausible
that with the advancements in platform technologies or improved endosomal escape the usage of tumor targeted RIPs would see the daylight of clinical success.

Bentham Science

Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered t... more Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered to subjects carefully selected
according to their CVD risk. Usually, this risk is evaluated on the basis of the presence and severity of conventional vascular risk factors (VRFs); however, atherosclerosis, the main pathologic substrate of CVD, is not directly revealed by VRFs. The measurement of the arterial wall, using imaging techniques, has increased the early identification of individuals prone to develop atherosclerosis and to quantify its changes over time.
B-mode ultrasound is a technique which allows a non-invasive assessment of the arterial wall of peripheral arteries (e.g. extracranial carotid arteries), and provides measures of the intima-media thickness complex (C-IMT) and additional data on the occurrence, localization and morphology of plaques.
Being an independent predictor of vascular events, C-IMT has been considered as a tool to optimize the estimation of CVD risk but this application is still a matter of debate. Though the technique is innocuous, relatively inexpensive and repeatable, its use in the clinical practice is limited by the lack of standardized protocols and clear guidelines.
This review outlines the rationale for the potential use of C-IMT in the stratification of cardio- and cerebro-vascular risk and discusses several topics related to the measurement of this variable, which are still controversial among experts of the field.

Iron oxide (Fe3O4) nanoparticles (IONPs) have received much attention for their utility in biomed... more Iron oxide (Fe3O4) nanoparticles (IONPs) have received much attention for their utility in biomedical applications such as magnetic resonance imaging, drug delivery and hyperthermia. Recent studies reported that IONPs induced cytotoxicity in mammalian cells. However, little is known about the genotoxicity of IONPs following exposure to human cells. In this study, we investigated the cytotoxicity, oxidative stress and genotoxicity of IONPs in two human cell lines; skin epithelial A431 and lung epithelial A549. Prepared IONPs were polygonal in shape with a smooth surface and had an average diameter of 25 nm. IONPs (25-100 μg/ml) induced dose-dependent cytotoxicity in both types of cells, which was demonstrated by cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) and lactate dehydrogenase leakage assays. IONPs were also found to induce oxidative stress in a dose-dependent manner, evident by depletion of glutathione and induction of reactive oxygen species (ROS) and lipid peroxidation. Comet assay revealed that level of DNA damage was higher with concentration of IONPs in both types of cells. Quantitative real-time PCR analysis showed that following the exposure of cells to IONPs, the expression levels of mRNA of caspase-3 and caspase-9 genes were higher. We also observed the higher activity of caspase-3 and caspase-9 enzymes in IONPs treated cells. Moreover, western blot analysis showed that protein expression level of cleaved caspase-3 was up-regulated by IONPs in both types of cells. Taken together, our data demonstrates that IONPs have potential to induce genotoxicity in A431 and A549 cells, which is likely to be mediated through ROS generation and oxidative stress. This study suggests that genotoxic effects of IONPs should be further investigated at in vivo level.

Ghrelin is a gastric hormone that stimulates growth hormone (GH) secretion and food intake to reg... more Ghrelin is a gastric hormone that stimulates growth hormone (GH) secretion and food intake to regulate energy homeostasis and body weight by binding to its receptor, GH secretagogue receptor (GHSR1a), which is most highly expressed in the pituitary and hypothalamus. Nowadays there is considerable evidence showing that the GHSR1a is also expressed in numerous extra-hypothalamic neuronal populations and the physiological role of ghrelin is by far wider than considered before including learning and memory, anxiety, depression and neuroprotection. The present review attempts to provide a comprehensive picture of the role of ghrelin in the central nervous system and to highlight recent findings showing its potential as an innovative therapeutic agent in neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease.