Insights into the Sex-Related Effects of Dietary Polyphenols and Metabolic Disruptors on Inflammatory and (Neuro) Endocrine Pathways in Obesity: The HEAL Project.

Background: this study was performed under the umbrella of the Health Extended Alliance for Innovative Therapies, Advanced Lab Research, and Integrated Approaches of Precision Medicine (HEAL ITALIA) partnership and funded under the National Recovery and Resilience Plan, Mission 4 Component 2 Investment 1.3, and by the European Union.

Objectives: the overall objective of the HEAL project is to identify innovative and effective therapeutic approaches to reduce disease burden.

Western diet-induced cognitive and metabolic dysfunctions in aged mice are prevented by rosmarinic acid in a sex-dependent fashion.

Background & Aims: Unhealthy lifestyles, such as chronic consumption of a Western Diet (WD), have been associated with increased systemic inflammation and oxidative stress (OS), a condition that may favour cognitive dysfunctions during aging. Polyphenols, such as rosmarinic acid (RA) may buffer low-grade inflammation and OS, characterizing the aging brain that is sustained by WD, promoting healthspan. The aim of this study was to evaluate the ability of RA to prevent cognitive decline in a mouse model of WD-driven unhealthy aging and to gain knowledge on the specific molecular pathways modulated within the brain.

Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose.

Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis.

Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity.

Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal.

The predictive role of proinflammatory and neuroendocrine factors in the acute phases of bipolar disorder: study protocol of a longitudinal controlled trial.

Introduction And Aims: Bipolar disorder (BD) is a severe and recurring mental illness associated with a significant personal and social burden. It has been recently hypothesized that increased levels of pro-inflammatory cytokines and cortisol, which is also associated with a reduced expression of the brain-derived neurotrophic factor (BDNF), may influence affective recurrences in BD. Our study aims to: 1) assess changes in the levels of peripheral cytokines, BDNF and salivary cortisol during acute and euthymic phases of bipolar disorder, compared to that of a sample oh healthy controls; 2) evaluate whether these changes represent a biosignature for the different phases of the illness.

Rosmarinic Acid Improves Cognitive Abilities and Glucose Metabolism in Aged C57Bl/6N Mice While Disrupting Lipid Profile in Young Adults in a Sex-Dependent Fashion.

A growing body of evidence suggests that regular consumption of natural products might promote healthy aging; however, their mechanisms of action are still unclear. Rosmarinic acid (RA) is a polyphenol holding anti-inflammatory, antioxidant and neuroprotective properties. The aim of this study was to characterise the efficacy of an oral administration of RA in promoting healthspan in a mouse model of physiological aging.

Inflammatory Signatures of Maternal Obesity as Risk Factors for Neurodevelopmental Disorders: Role of Maternal Microbiota and Nutritional Intervention Strategies.

Obesity is a main risk factor for the onset and the precipitation of many non-communicable diseases. This condition, which is associated with low-grade chronic systemic inflammation, is of main concern during pregnancy leading to very serious consequences for the new generations. In addition to the prominent role played by the adipose tissue, dysbiosis of the maternal gut may also sustain the obesity-related inflammatory milieu contributing to create an overall suboptimal intrauterine environment.

Ion-Pairing Chromatography and Amine Derivatization Provide Complementary Approaches for the Targeted LC-MS Analysis of the Polar Metabolome.

Liquid chromatography coupled to mass spectrometry is a key metabolomics/metabonomics technology. Reversed-phase liquid chromatography (RPLC) is very widely used as a separation step, but typically has poor retention of highly polar metabolites. Here, we evaluated the combination of two alternative methods for improving retention of polar metabolites based on 6-aminoquinoloyl--hydroxysuccinidimyl carbamate derivatization for amine groups, and ion-pairing chromatography (IPC) using tributylamine as an ion-pairing agent to retain acids.

Prenatal psychological or metabolic stress increases the risk for psychiatric disorders: the "funnel effect" model.

Adverse stressful experiences in utero can redirect fetal brain development, ultimately leading to increased risk for psychiatric disorders. Obesity during pregnancy can have similar effects as maternal stress, affecting mental health in the offspring. In order to explain how similar outcomes may originate from different prenatal conditions, we propose a "funnel effect" model whereby maternal psychological or metabolic stress triggers the same evolutionarily conserved response pathways, increasing vulnerability for psychopathology.

Chronic Isolation Stress Affects Central Neuroendocrine Signaling Leading to a Metabolically Active Microenvironment in a Mouse Model of Breast Cancer.

Social isolation is a powerful stressor capable of affecting brain plasticity and function. In the case of breast cancer, previous data indicate that stressful experiences may contribute to a worse prognosis, activating neuroendocrine and metabolism pathways, although the mechanisms underlying these effects are still poorly understood. In this study, we tested the hypothesis that chronic isolation stress (IS) may boost hypothalamic-pituitary-adrenal (HPA) axis activity, leading to changes in the hypothalamic expression of genes modulating both mood and metabolism in an animal model of breast cancer.

, the "Golden Spice" to Counteract Neuroinflammaging and Cognitive Decline-What Have We Learned and What Needs to Be Done.

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways.

High-fat diet during adulthood interacts with prenatal stress, affecting both brain inflammatory and neuroendocrine markers in male rats.

Prenatal stress (PNS) affects foetal programming and, through an interaction with subsequent challenges, can increase vulnerability to mood and metabolic disorders. We have previously shown that, following PNS, adult male rats are characterized by increased vulnerability to a metabolic stressor experienced at adulthood (8-week-high-fat diet-HFD). In this study, we specifically assessed whether PNS might interact with an adult metabolic challenge to induce an inflammatory phenotype.

Health and longevity studies in C. elegans: the "healthy worm database" reveals strengths, weaknesses and gaps of test compound-based studies.

Several biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the "Healthy Worm Database" ( http://healthy-worm-database.

Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability.

Exposure to early life stress can interfere with neurodevelopmental trajectories to increase the vulnerability for psychiatric disorders later in life. With this respect, epigenetic mechanisms play a key role for the long-lasting changes in brain functions that may elicit and sustain psychopathologic outcomes. Here, we investigated DNA methylation changes as possible epigenetic mechanism mediating the effect of prenatal stress (PNS), an experimental paradigm associated with behavioral and molecular alterations relevant for psychiatric disorders.

Natural products improve healthspan in aged mice and rats: A systematic review and meta-analysis.

Over the last decades a decrease in mortality has paved the way for late onset pathologies such as cardiovascular, metabolic or neurodegenerative diseases. This evidence has led many researchers to shift their focus from researching ways to extend lifespan to finding ways to increase the number of years spent in good health; "healthspan" is indeed the emerging concept of such quest for ageing without chronic or disabling diseases and dysfunctions. Regular consumption of natural products might improve healthspan, although the mechanisms of action are still poorly understood.

Healthspan pathway maps in and humans highlight transcription, proliferation/biosynthesis and lipids.

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. Here, we define health based on the absence of diseases and dysfunctions.

Maternal Obesity as a Risk Factor for Brain Development and Mental Health in the Offspring.

Maternal obesity plays a key role in the health trajectory of the offspring. Although research on this topic has largely focused on the potential of this condition to increase the risk for child obesity, it is becoming more and more evident that it can also significantly impact cognitive function and mental health. The mechanisms underlying these effects are starting to be elucidated and point to the placenta as a critical organ that may mediate changes in the response to stress, immune function and oxidative stress.

Trehalose administration in C57BL/6N old mice affects healthspan improving motor learning and brain anti-oxidant defences in a sex-dependent fashion: a pilot study.

Aim of this study was to characterize the effects of oral trehalose administration (2%w/v) on healthspan in old mice. Trehalose was administered in drinking water for 1 month to male and female C57BL/6N mice aged 25-months. After behavioral phenotyping (grip strength, beam walking and rotarod tests), autophagy (LC3-II/actin) and oxidative stress were tested in the cerebral cortex and gastrocnemius muscle.

Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways.

Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one's health, there is an urgent need to find a broadly acceptable and useful definition of health, based on a list of (molecular) features; to operationalize features of health so that it can be measured; to identify predictive biomarkers and (molecular) pathways of health; and to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define as a state of an individual characterized by the of physiological, cognitive, physical and reproductive function, and a lack of disease.

Administration of the Antioxidant N-Acetyl-Cysteine in Pregnant Mice Has Long-Term Positive Effects on Metabolic and Behavioral Endpoints of Male and Female Offspring Prenatally Exposed to a High-Fat Diet.

A growing body of evidence suggests the consumption of high-fat diet (HFD) during pregnancy to model maternal obesity and the associated increase in oxidative stress (OS), might act as powerful prenatal stressors, leading to adult stress-related metabolic or behavioral disorders. We hypothesized that administration of antioxidants throughout gestation might counteract the negative effects of prenatal exposure to metabolic challenges (maternal HFD feeding during pregnancy) on the developing fetus. In this study, female C57BL/6J mice were fed HFD for 13 weeks (from 5-weeks of age until delivery) and were exposed to the N-acetyl-cysteine (NAC) antioxidant from 10-weeks of age until right before delivery.

Dynamic changes in p66Shc mRNA expression in peripheral blood mononuclear cells following resistance training intervention in old frail women born to obese mothers: a pilot study.

The p66Shc gerontogene may affect healthspan by promoting fat accumulation. We assessed changes of p66Shc-mRNA in peripheral tissues in relation to maternal obesity and the moderating effects of resistance-training (RT) exercise in elderly frail women. Thirty-seven women participated in a 4-month RT program.

Long-Term Sex-Dependent Vulnerability to Metabolic challenges in Prenatally Stressed Rats.

Prenatal stress (PNS) might affect the developmental programming of adult chronic diseases such as metabolic and mood disorders. The molecular mechanisms underlying such regulations may rely upon long-term changes in stress-responsive effectors such as Brain-Derived Neurotrophic Factor (BDNF) that can affect neuronal plasticity underlying mood disorders and may also play a role in metabolic regulation. Based upon previous data, we hypothesized that PNS might lead to greater vulnerability to an obesogenic challenge experienced at adulthood.

Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte.

The metabolic syndrome (MetS) is defined as a cluster of 3 or more metabolic and cardiovascular risk factors and represents a serious problem for public health. Altered function of adipose tissue has a significant impact on whole-body metabolism and represents a key driver for the development of these metabolic derangements, collectively referred as to MetS. In particular, increased visceral and ectopic fat deposition play a major role in the development of insulin resistance and MetS.

Anti-GAPDH Autoantibodies as a Pathogenic Determinant and Potential Biomarker of Neuropsychiatric Diseases.

Objective: To investigate the potential role of circulating autoantibodies specific to neuronal cell surface antigens in the pathophysiology of neuropsychiatric disorders.

Methods: Two different kinds of immunoscreening approaches were used to identify autoantigens associated with neuropsychiatric disorders in the serum of patients with schizophrenia. The presence of autoantibodies specific to the identified autoantigens was then tested in patients with various psychiatric disorders and in patients with systemic lupus erythematosus (SLE) and concomitant neuropsychiatric manifestations.