Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes?

The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes "(IRS-4 or IRS4)", or the combination of these terms with the word "(cancer)" or "(human)", for searches. Terms related to specific tumor pathologies ("breast", "ovary", "colon", "lung", "lymphoma", etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets.

Reduction of disease activity, corticosteroids use, and healthcare resource utilisation in patients with systemic lupus erythematosus treated with belimumab in clinical practice settings: OBSErve Spain multicentre study.

INTRODUCTION AND OBJECTIVES: This OBSErve Spain study, a part of the international OBSErve programme, evaluated belimumab real-world use and effectiveness following 6 months of treatment in patients with active systemic lupus erythematosus (SLE) in clinical practice in Spain. MATERIALS AND METHODS: In this retrospective, observational study (GSK Study 200883), eligible patients with SLE receiving intravenous belimumab (10mg/kg) had their disease activity (physician assessed), SELENA-SLEDAI scores, corticosteroid use, and healthcare resource utilisation (HCRU), assessed after 6 months of treatment versus index (belimumab initiation) or 6 months pre-index. RESULTS: Overall, 64 patients initiated belimumab, mainly due to ineffectiveness of previous treatments (78.1%) and to reduce corticosteroid use (57.8%). Following 6 months of treatment, 73.4% of patients achieved ≥20% overall clinical improvement, while only 3.1% of patients worsened. Mean (standard deviation, SD) SELENA-SLEDAI score decreased from 10.1 (6.2) at index to 4.5 (3.7) 6 months post-index. HCRU decreased from 6 months pre-index to 6 months post-index, with fewer hospitalisations (10.9% vs 4.7% patients) and ER visits (23.4% vs 9.4% patients). Mean (SD) corticosteroid dose decreased from 14.5 (12.5)mg/day at index to 6.4 (5.1)mg/day 6 months post-index. CONCLUSIONS: Patients with SLE receiving belimumab for 6 months in real-world clinical practice in Spain experienced clinical improvements and a reduction in HCRU and corticosteroid dose.

Development of a TaqMan qPCR assay for trypanosomatid multi-species detection and quantification in insects.

BACKGROUND: Trypanosomatid parasites are widely distributed in nature and can have a monoxenous or dixenous life-cycle. These parasites thrive in a wide number of insect orders, some of which have an important economic and environmental value, such as bees. The objective of this study was to develop a robust and sensitive real-time quantitative PCR (qPCR) assay for detecting trypanosomatid parasites in any type of parasitized insect sample. METHODS: A TaqMan qPCR assay based on a trypanosomatid-conserved region of the α-tubulin gene was standardized and evaluated. The limits of detection, sensitivity and versatility of the α-tubulin TaqMan assay were tested and validated using field samples of honeybee workers, wild bees, bumblebees and grasshoppers, as well as in the human infective trypanosomatid Leishmania major. RESULTS: The assay showed a detection limit of 1 parasite equivalent/µl and successfully detected trypanosomatids in 10 different hosts belonging to the insect orders Hymenoptera and Orthoptera. The methodology was also tested using honeybee samples from four apiaries (n = 224 worker honeybees) located in the Alpujarra region (Granada, Spain). Trypanosomatids were detected in 2.7% of the honeybees, with an intra-colony prevalence of 0% to 13%. Parasite loads in the four different classes of insects ranged from 40.6 up to 1.1 × 108 cell equivalents per host. CONCLUSIONS: These results show that the α-tubulin TaqMan qPCR assay described here is a versatile diagnostic tool for the accurate detection and quantification of trypanosomatids in a wide range of environmental settings.

Preventing organ damage in systemic lupus erythematosus: the impact of early biological treatment.

INTRODUCTION: One of the most important aims in the management of systemic lupus erythematosus (SLE) is to avoid or delay the accumulation of organ damage. The first five years after diagnosis are crucial for prognosis. AREAS COVERED: This manuscript reviews available data on organ damage accrual in SLE and early therapeutic intervention as a possible strategy to prevent its long-term accrual. EXPERT OPINION: Organ damage can be minimized by controlling disease activity and risk of flares, reducing the dose of glucocorticoids, and ensuring a proper therapeutic intervention with an early introduction of the right therapies. The current standard treatment cannot provide clinical remission in all patients with SLE. Therefore, there is a clinical need for introducing new therapeutic strategies able to achieve the main therapeutic objectives. The addition of biologic and other therapeutic agents to the standard of care is effective for controlling disease activity and for preventing severe flares, enabling a reduced use of glucocorticoids, and presumably reducing organ damage progression. Considering its efficacy and safety, early inclusion of biologic agents in the first lines of the treatment algorithm, at least in certain patients, could be considered as an innovative treatment approach to decrease disease burden in SLE patients.

Bee Products: An Emblematic Example of Underutilized Sources of Bioactive Compounds.

Beside honey, honeybees (Apis mellifera L.) are able to produce many byproducts, including bee pollen, propolis, bee bread, royal jelly, and beeswax. Even if the medicinal properties of these byproducts have been recognized for thousands of years by the ancient civilizations, in the modern era, they have a limited use, essentially as nutritional supplements or health products. However, these natural products are excellent sources of bioactive compounds, macro- and micronutrients, that, in a synergistic way, confer multiple biological activities to these byproducts, such as, for example, antimicrobial, antioxidant, and anti-inflammatory properties. This work aims to update the chemical and phytochemical composition of bee pollen, propolis, bee bread, royal jelly, and beeswax and to summarize the main effects exerted by these byproducts on human health, from the anticancer and immune-modulatory activities to the antidiabetic, hypolipidemic, hypotensive, and anti-allergic properties.

Industrial-Scale Decontamination Procedure Effects on the Content of Acaricides, Heavy Metals and Antioxidant Capacity of Beeswax.

Beeswax is useful for the beekeeping sector but also for the agro-food, pharmaceutical or cosmetics sectors. Frequently, this bee product is contaminated with pesticides reducing its utility and causing the decline in its market. This study aimed to prove the effectiveness of an industrial-scale decontamination method in removing acaricides from beeswax. Chlorfenvinphos and coumaphos decrease was higher than 90%, whereas tau fluvalinate decrease was only 30%. No changes were observed in the beeswax content of hydrocarbons and monoesters, whereas a decrease in the concentrations of Ca, Fe, Zn, Hg, Mn and P, and an increase in the concentrations of As and Si were found after the decontamination. Filtration reduced total phenolics, flavonoids and the antioxidant capacity of the lipophilic extract. These results demonstrate that the industrial method used was as effective as the method previously tested on a laboratory scale. The study also contributes to a better knowledge and characterization of beeswax, specially related to trace and ultra-trace elements and antioxidant capacity. Moreover, it offers the chance to further develop a method to effectively detect wax adulterations based on the chemical elements profile.

Beeswax by-Products Efficiently Counteract the Oxidative Damage Induced by an Oxidant Agent in Human Dermal Fibroblasts.

The antioxidant capacity and the phytochemical composition of two by-products from beeswax recycling processes were recently investigated. The aim of the present work was to evaluate the efficacy of one of these by-products, MUD1, against the oxidative stress induced by 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) in human dermal fibroblast (HDF) cells. After a preliminary viability assay, the protective effect of MUD1 was investigated through the measurement of apoptosis level, the reactive oxygen species (ROS) and nitrite (NO2-) production, the level of protein and lipid biomarkers (carbonyl groups, total glutathione and thiobarbituric acid-reactive substance) of oxidative damage, and the measurement of antioxidant enzymes activities (glutatione peroxidase, glutathione reductase, glutathione transferase, superoxide dismutase and catalase). The obtained results showed that MUD1 exerted protective effects on HDF, increasing cell viability and counteracted the oxidative stress promoted by AAPH-treatment, and improved mitochondria functionality and wound healing capacities. This work shows the antioxidant effects exerted by beeswax by-products, demonstrating for the first time their potential against oxidative stress in human dermal fibroblast cells; however, further research will be necessary to evaluate their potentiality for human health by more deeply in vitro and in vivo studies.

Histamine catabolism in Pseudomonas putida U: identification of the genes, catabolic enzymes and regulators.

In this study, the catabolic pathway required for the degradation of the biogenic amine histamine (Hin) was genetically and biochemically characterized in Pseudomonas putida U. The 11 proteins (HinABCDGHFLIJK) that participate in this pathway are encoded by genes belonging to three loci hin1, hin2 and hin3 and by the gene hinK. The enzymes HinABCD catalyze the transport and oxidative deamination of histamine to 4-imidazoleacetic acid (ImAA). This reaction is coupled to those of other well-known enzymatic systems (DadXAR and CoxBA-C) that ensure both the recovery of the pyruvate required for Hin deamination and the genesis of the energy needed for Hin uptake. The proteins HinGHFLKIJ catalyze the sequential transformation of ImAA to fumaric acid via N2 -formylisoasparagine, formylaspartic acid and aspartic acid. The identified Hin pathway encompasses all the genes and proteins (transporters, energizing systems, catabolic enzymes and regulators) needed for the biological degradation of Hin. Our work was facilitated by the design and isolation of genetically engineered strains that degrade Hin or ImAA and of mutants that accumulate Ala, Asp and Hin catabolites. The implications of this research with respect to potential biotechnological applications are discussed.

Are by-products from beeswax recycling process a new promising source of bioactive compounds with biomedical properties?

During the process of beeswax recycling, many industrial derivatives are obtained. These matrices may have an interesting healthy and commercial potential but to date they have not been properly studied. The aim of the present work was to evaluate the proximal and phytochemical composition, the antioxidant capacity and cytotoxic effects of two by-products from beeswax recycling process named MUD 1 and MUD 2 on liver hepatocellular carcinoma. Our results showed that MUD 1 presented the highest (P < .05) fiber, protein, carbohydrate, polyphenol and flavonoid concentration, as well as the highest (P < .05) total antioxidant capacity than the MUD 2 samples. MUD1 exerted also anticancer activity on HepG2 cells, by reducing cellular viability, increasing intracellular ROS levels and affecting mitochondrial functionality in a dose-dependent manner. We showed for the first time that by-products from beeswax recycling process can represent a rich source of phytochemicals with high total antioxidant capacity and anticancer activity; however, further researches are necessary to evaluate their potentiality for human health by in vivo studies.

Biomimetic oxidation of pyrene and related aromatic hydrocarbons. Unexpected electron accepting abilities of pyrenequinones.

We present a mild catalytic method to oxidize PAHs and, in particular, pyrene. The pyrenediones are much better electron acceptors than benzoquinone in the gas phase and present similar accepting abilities in solution.

Chemical and functional characterisation of propolis collected from East Andalusia (southern Spain).

INTRODUCTION: Propolis is a complex mixture of natural sticky, gummy and resinous components produced by honeybees (Apis mellifera L.) from plant materials. However, phytochemical data of the Andalusian (southern Spain) propolis are scant. OBJECTIVE: The primary objectives of this study were to chemically characterise the compounds and evaluate the anti-oxidant activity found in 28 Andalusian propolis samples. METHODS: Ethanol extracts of propolis (EEP) were prepared and examined for their anti-oxidant activity by 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) and 2,2-diphenyl-1-picrylhydrazyl assays. To characterise the phenolic composition, the presence of 11 compounds was identified by HPLC analysis with photodiode array and mass spectrometric detection. RESULTS: All propolis samples had strong anti-oxidant activity, accompanied by high total phenolic content. The most abundant compounds were flavonoids. Concerning the phenolic compounds content, our results showed that the 75% of the samples analysed contained at least 80 mg/g of flavonoids, primarily pinobanksin 3-acetate, pinocembrin, chrysin, galangin and pinobanksin. Caffeic acid phenethyl ester was detected in almost all EEP samples but in smaller proportions (mean 12.9 ± 2.8 mg/g). CONCLUSION: The present investigation constitutes the first comprehensive report on the phenolics identified in southern Spanish propolis. The results revealed that the samples tested showed a high scavenging activity and therefore indicate the possible use of Andalusian propolis as an important source of natural anti-oxidants.

The end-organ impairment in liver cirrhosis: appointments for critical care.

Liver cirrhosis (LC) can lead to a clinical state of liver failure, which can exacerbate through the course of the disease. New therapies aimed to control the diverse etiologies are now more effective, although the disease may result in advanced stages of liver failure, where liver transplantation (LT) remains the most effective treatment. The extended lifespan of these patients and the extended possibilities of liver support devices make their admission to an intensive care unit (ICU) more probable. In this paper the LC is approached from the point of view of the pathophysiological alterations present in LC patients previous to ICU admission, particularly cardiovascular, but also renal, coagulopathic, and encephalopathic. Infections and available liver detoxifications devices also deserve mentioning. We intend to contribute towards ICU physician readiness to the care for this particular type of patients, possibly in dedicated ICUs.

Evaluation of the performance of echocardiography in acute coronary syndrome patients during their stay in coronary units.

OBJECTIVES: To evaluate the frequency and the factors associated with performance of echocardiography in acute coronary syndrome (ACS) patients during their stay in intensive care units or coronary care units (ICU/CCU). METHODS: Retrospective cohort study including all patients diagnosed with acute coronary syndrome-unstable angina (UA), acute myocardial infarction (AMI)-included in the 'ARIAM' Spanish multi-centre register. The study period was from June 1996 to December 2005. The follow-up period is limited to the time of stay in the Intensive Care Units or Coronary Care Units (ICUs/CCUs). A univariate analysis was carried out on the patients with UA and AMI according to whether or not echocardiograms were performed during their stay in ICU/CCU. In addition the data was evaluated for any temporal variation in the performance of echocardiography, and two multivariate analyses were carried out to evaluate the factors associated with performance of echocardiography in UA and AMI patients. RESULTS: The study period included 45,688 AMI patients and 17,277 UA patients. Echocardiograms were performed in 26.87% AMI patients and 16.75% UA patients. In total, 15,172 echocardiograms were performed in ACS patients (23.6%). The multivariate analysis demonstrated that the variables associated with the performance of echocardiography in UA were: Killip and Kimball class, cigarette smoking, family history of cardiovascular events, cardiogenic shock, uncontrolled angina, mechanical ventilation and treatment with ACE inhibitors, while the presence of previous AMI was associated with fewer echocardiograms being performed. In AMI, the multivariate analysis showed the following variables to be associated with the performance of echocardiography: Killip and Kimball class, Q-AMI, right heart failure, the need for insertion of Swan-Ganz catheter, cardiogenic shock, high-degree AV block and the administration of ACE inhibitors, while age was associated with fewer being performed. Over the 10 years of the study period, there was a discrete but significant increase in the use of echocardiography in patients in ICU/CCU. CONCLUSIONS: Echocardiography is not commonly used in ACS patients while in ICU/CCU. UA and AMI patients who did have echocardiograms during their stay in ICU/CCU were chiefly those presenting heart failure and major complications, and represent a subpopulation with poor prognosis. The performance of echocardiography in ACS patients increased slightly over the length of their stay in ICU/CCU.

Echocardiographic hemodynamic monitoring in the critically ill patient.

Echocardiography has shown to be an essential diagnostic tool in the critically ill patient's assessment. In this scenario the initial fluid therapy, such as it is recommended in the actual clinical guidelines, not always provides the desired results and maintains a considerable incidence of cardiorrespiratory insufficiency. Echocardiography can council us on these patients' clinical handling, not only the initial fluid therapy but also on the best-suited election of the vasoactive/ inotropic treatment and the early detection of complications. It contributes as well to improving the etiological diagnosis, allowing one to know the heart performance with more precision. The objective of this manuscript is to review the more important parameters that can assist the intensivist in theragnosis of hemodynamically unstable patients.

Sepsis-induced cardiomyopathy.

Myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to 70%. During the sepsis-induced myocardial dysfunction, both ventricles can dilate and diminish its ejection fraction, having less response to fluid resuscitation and catecholamines, but typically is assumed to be reversible within 7-10 days. In the last 30 years, It's being subject of substantial research; however no explanation of its etiopathogenesis or effective treatment have been proved yet. The aim of this manuscript is to review on the most relevant aspects of the sepsis-induced myocardial dysfunction, discuss its clinical presentation, pathophysiology, etiopathogenesis, diagnostic tools and therapeutic strategies proposed in recent years.

Ti(III)-promoted radical cyclization of epoxy enones. Total synthesis of (+)-paeonisuffrone.

The total synthesis of (+)-paeonisuffrone starting from (+)-10-hydroxycarvone is described. The key step of our synthetic strategy is a titanium-catalyzed stereoselective cyclization initiated by epoxide opening through electron transfer. This reaction stereoselectively affords the highly oxygenated pinane skeleton present in the target molecule and opens a new and effective approach to the synthesis of the complex, biologically active terpenoids isolated from the roots of the Chinese paeony (Paeonia albiflora Pallas and Paeonia suffruticosa Andrews).