Biomarkers to Be Used for Decision of Treatment of Hypogonadal Men with or without Insulin Resistance.

Male hypogonadism is a result of low testosterone levels, but patients could be insulin-sensitive (IS) or insulin-resistant (IR), showing different impaired metabolic pathways. Thus, testosterone coadministration, which is commonly used to reestablish testosterone levels in hypogonadism, must take into account whether or not insulin is still active. By comparing metabolic cycles recorded in IS and IR plasma before and after testosterone therapy (TRT), it is possible to know what metabolic pathways can be reactivated in the two different groups upon testosterone recovery, and it is possible to understand if antagonism or synergy exists between these two hormones.

Extracellular serine empowers epidermal proliferation and psoriasis-like symptoms.

The contribution of nutrient availability to control epidermal cell proliferation, inflammation, and hyperproliferative diseases remains unknown. Here, we studied extracellular serine and serine/glycine metabolism using human keratinocytes, human skin biopsies, and a mouse model of psoriasis-like disease. We focused on a metabolic enzyme, serine hydroxymethyltransferase (SHMT), that converts serine into glycine and tetrahydrofolate-bound one‑carbon units to support cell growth.

On the Need to Distinguish between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy.

Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids.

Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment.

Hypogonadic subjects with insulin resistance (IR) showed different metabonomic profiles compared to normo-insulinemic subjects (IS). Testosterone replacement therapy (TRT) may have a different impact on the metabolisms of those with the presence or absence of insulin resistance. We evaluated the changes in the metabolism of IR hypogonadic patients before and after 60 days of TRT.

Plasma Metabolomics Profile of "Insulin Sensitive" Male Hypogonadism after Testosterone Replacement Therapy.

Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.

Anti-Inflammatory Potential of Cow, Donkey and Goat Milk Extracellular Vesicles as Revealed by Metabolomic Profile.

In recent years, extracellular vesicles (EVs), cell-derived micro and nano-sized structures enclosed in a double-layer membrane, have been in the spotlight for their high potential in diagnostic and therapeutic applications. Indeed, they act as signal mediators between cells and/or tissues through different mechanisms involving their complex cargo and exert a number of biological effects depending upon EVs subtype and cell source. Being produced by almost all cell types, they are found in every biological fluid including milk.

A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children.

Since recently metabolic abnormalities in autistic children have been associated with ASD disturbs, the aim of this study is to determine the neurotransmitter levels in urine samples of autistic children and to analyse the altered metabolic pathway involved in their production. Thus, ASD-specific urinary metabolomic patterns were explored in 40 ASD children and 40 matched controls using untargeted metabolomics through UHPLC-mass spectrometry (Q-exactive analyser), and by using XCMS Metlin software for data interpretation. Through this new advanced technique, a more considerable number of urinary altered metabolites were recorded in autistic children, than in the previous investigations, which allowed us to collect metabolites involved in neurotransmitter production.

Testosterone replacement therapy in insulin-sensitive hypogonadal men restores phosphatidylcholine levels by regulation of arachidonic acid metabolism.

Male hypogonadism is notoriously associated with altered lipid metabolism. In this study, we performed an untargeted mass spectrometry-based profiling of plasma lipids from twenty healthy and twenty hypogonadal men before and after testosterone replacement therapy (TRT) for 60 days. Results demonstrated that hypogonadism was associated with a significant increase in sphingomyelin (SM), whereas phosphatidylcholine (PC) was mainly cleaved by activated phospholipase-A2 into lysophosphatidylcholine (LPC).

ALS skin fibroblasts reveal oxidative stress and ERK1/2-mediated cytoplasmic localization of TDP-43.

The main hallmark of many forms of familiar and sporadic amyotrophic lateral sclerosis (ALS) is a reduction in nuclear TDP-43 protein and its inclusion in cytoplasmic aggregates in motor neurons. In order to understand which cellular and molecular mechanisms underlie the mislocalization of TDP-43, we examined human skin fibroblasts from two individuals with familial ALS, both with mutations in TDP-43, and two individuals with sporadic ALS, both without TDP-43 mutations or mutations in other ALS related genes. We found that all ALS fibroblasts had a partially cytoplasmic localization of TDP-43 and had reduced cell metabolism as compared to fibroblasts from apparently healthy individuals.

Brain protein changes in Mecp2 mouse mutant models: Effects on disease progression of Mecp2 brain specific gene reactivation.

Rett syndrome (RTT) is a leading cause of severe intellectual disability in females, caused by de novo loss-of function mutations in the X-linked methyl-CpG binding protein 2 (MECP2). To better investigate RTT disease progression/pathogenesis animal models of Mecp2 deficiency have been developed. Here, Mecp2 mouse models are employed to investigate the role of protein patterns in RTT.

Lymphatic Cannulation for Lymph Sampling and Molecular Delivery.

Unlike the blood, the interstitial fluid and the deriving lymph are directly bathing the cellular layer of each organ. As such, composition analysis of the lymphatic fluid can provide more precise biochemical and cellular information on an organ's health and be a valuable resource for biomarker discovery. In this study, we describe a protocol for cannulation of mouse and rat lymphatic collectors that is suitable for the following: the "omic" sampling of pre- and postnodal lymph, collected from different anatomical districts; the phenotyping of immune cells circulating between parenchymal organs and draining lymph nodes; injection of known amounts of molecules for quantitative immunological studies of nodal trafficking and/or clearance; and monitoring an organ's biochemical omic changes in pathological conditions.

A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells.

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies.

A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors.

Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells.

Multi-omics profiling of calcium-induced human keratinocytes differentiation reveals modulation of unfolded protein response signaling pathways.

By proteomic, metabolomic and transcriptomic approaches we shed light on the molecular mechanism by which human keratinocytes undergo to terminal differentiation upon in vitro calcium treatment. Proteomic analysis revealed a selective induction of the ribosomal proteins RSSA, an inhibitor of cell proliferation and inducer of differentiation, HSP 60, a protein folding chaperone and GRP78, an unfolding protein response signal. Additionally, we observed an induction of EF1D, a transcription factor for genes that contain heat-shock responsive elements.

The concomitant lower concentrations of vitamins B6, B9 and B12 may cause methylation deficiency in autistic children.

Autism spectrum disorder (ASD) is characterized by severe and persistent difficulties in social communication and social interaction at multiple levels. Recently, metabolic disorders have been associated with most cases of patients with ASD. The aim of this study was to investigate, through a new and more sophisticated mass technique, such as UHPLC-mass spectrometry (Q-exactive analyzer), alteration in metabolisms analyzing ASD children urine samples from children showing simultaneous vitamin B6, B9 and B12 deficiencies.

Untargeted Metabolomics of Plant Leaf Tissues.

Untargeted metabolomics is a useful approach for the simultaneous analysis of a vast array of compounds from a single extract. Metabolomic profiling is the relative multi-parallel quantification of a mixture of low molecular weight compounds, or classes of compounds, and it is most often performed by using ultra performance liquid chromatography (UPLC) coupled with mass spectrometry (MS). Being an extension of the classical targeted methods, this approach allows a broader view of the main biochemical events within a particular sample.

Urinary Metabolic Signature of Primary Aldosteronism: Gender and Subtype-Specific Alterations.

Purpose: The current clinical investigation for primary aldosteronism (PA) diagnosis requires complex expensive tests from the initial suspicion to the final subtype classification, including invasive approaches; therefore, appropriate markers for subtype definition are greatly desirable. The present study performs a metabolomics analysis to further examine specific molecular signatures of PA urines EXPERIMENTAL DESIGN: The study considered PA subtype and gender-related differences using two orthogonal advanced UHPLC-MS metabolomics approaches. Patients with essential hypertension (n = 36) and PA (n = 50) who were referred to the outpatient hypertension clinic and matched healthy subjects (n = 10) are investigated.

Deoxynivalenol Detoxification in Transgenic Wheat Confers Resistance to Fusarium Head Blight and Crown Rot Diseases.

diseases, including Fusarium head blight (FHB) and Fusarium crown rot (FCR), reduce crop yield and grain quality and are major agricultural problems worldwide. These diseases also affect food safety through fungal production of hazardous mycotoxins. Among these, deoxynivalenol (DON) acts as a virulence factor during pathogenesis on wheat.

Ribosomal RACK1 promotes proliferation of neuroblastoma cells independently of global translation upregulation.

Neuroblastoma is the most frequent solid tumor among those diagnosed during infancy and like most tumors, it is characterized by elevated rates of cell proliferation, migration and invasion. RACK1 is among the top 10 genes identified for unfavorable prognosis at 5 years in neuroblastoma cases and its depletion negatively affects proliferation, invasion and migration. Here, we show that the ribosomal localization of RACK1 modulates the proliferation of SH-SY5Y neuroblastoma cells by regulating the expression of cell cycle genes, such as Cyclin D1, D3 and B1 independently of global translation increase.

Metabolic patterns in insulin-resistant male hypogonadism.

Male hypogonadism associated with insulin resistance (IR) very often leads to metabolic syndrome, at variance with hypogonadism in its first stadium of insulin sensitivity (IS). A plasma metabolomic investigation of these patients can provide useful information in comparison with the values of IS patients. To this aim plasma from insulin-resistant males with hypogonadism were analysed by using ultra high-performance liquid chromatography (UHPLC) and high-resolution mass spectrometry (HRMS).

Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress.

The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity.

Metabolic patterns in insulin-sensitive male hypogonadism.

Male hypogonadism is a disorder characterised by low levels of the hormone testosterone. At beginning subjects with low levels of testosterone do not show insulin resistance (insulin-sensitive patients), which develops over time (insulin-resistance patients). To analyse the metabolic alterations mainly related to decreased testosterone, we performed metabolomics investigations on the plasma of males with hypogonadism who showed normal insulin levels.

Simulated microgravity induces a cellular regression of the mature phenotype in primary osteoblasts.

Decreased mechanical loading on bones, such as prolonged bed rest and microgravity during space flights, leads to the development of an osteoporotic-like phenotype. Although osteoblast hypo-functionality is reported to be involved in the progression of bone pathological conditions, the cellular mechanisms of this process remain largely unknown. The combined application of mass spectrometry "-omics" and histochemical and ultrastructural approaches have been employed to investigate the effects of the gravitational unloading on bone-cell biology.

Metabolomics and proteomics reveal drought-stress responses of leaf tissues from spring-wheat.

To reveal the integrative biochemical networks of wheat leaves in response to water deficient conditions, proteomics and metabolomics were applied to two spring-wheat cultivars (Bahar, drought-susceptible; Kavir, drought-tolerant). Drought stress induced detrimental effects on Bahar leaf proteome, resulting in a severe decrease of total protein content, with impairments mainly in photosynthetic proteins and in enzymes involved in sugar and nitrogen metabolism, as well as in the capacity of detoxifying harmful molecules. On the contrary, only minor perturbations were observed at the protein level in Kavir stressed leaves.

Redox Status, Procoagulant Activity, and Metabolome of Fresh Frozen Plasma in Glucose 6-Phosphate Dehydrogenase Deficiency.

Objective: Transfusion of fresh frozen plasma (FFP) helps in maintaining the coagulation parameters in patients with acquired multiple coagulation factor deficiencies and severe bleeding. However, along with coagulation factors and procoagulant extracellular vesicles (EVs), numerous bioactive and probably donor-related factors (metabolites, oxidized components, etc.) are also carried to the recipient.