Zinc Deficiency

Zinc is an essential trace element for humans and plays a critical role both as a structural component of proteins and as a cofactor in about 300 enzymes. Zinc deficiency was, for example, reported to affect the immune response and the endocrine system and to induce and modify brain disorders. Besides hereditary zinc deficiency, zinc deficiency – at least in mild forms – is nowadays a very abundant health issue. Today, an estimated 20% of the population worldwide is at risk of developing zinc deficiency with a high number also in industrialized countries. The major risk factors to develop zinc deficiency in industrialized nations are aging and pregnancy. Mechanistic and behavioral studies on the effects of zinc deficiency have mainly been performed using animal models. However, in combination with the few studies on human subjects, a picture emerges that shows importance of adequate nutritional zinc supply for many processes in the body. Especially the immune system and brain development and function seem to be highly sensitive to zinc deficiency. Here, we provide an overview on the effects of zinc deficiency on different organ systems, biological processes, and the associations of zinc deficiency with pathologies observed in humans and animal models

Standardization of research methods employed in assessing the interaction metallic-based nanoparticles and the blood-brain barrier: present and future perspectives

peer-reviewedThe full text of this article will not be available until the embargo expires on the 18/01/2020.Treating diseases of the central nervous system (CNS) is complicated by the presence of the blood-brain barrier (BBB), a semipermeable boundary layer protecting the CNS from toxins and homeostatic disruptions. However, this layer also excludes almost 100% of therapeutics, impeding the treatment of CNS diseases. The advent of nanoparticles, in particular metallic-based nanoparticles, presents the potential to overcome this barrier and transport drugs into the CNS. Recent interest in metallic-based nanoparticles has generated an immense array of information pertaining to nanoparticles of different materials, sizes, morphologies, and surface properties. Nanoparticles with different physico-chemical properties lead to distinct nanoparticle-host interactions; yet, comprehensive characterization is often not completed. Similarly, in vivo testing has involved a mixed evaluation of parameters, including: BBB permeability, integrity, biodistribution, and toxicity. The methods applied to assess these parameters are inconsistent; this complicates the comparison of different nanoparticle-host system responses. A systematic review was conducted to investigate the methods by which metallic-based nanoparticles are characterized and assessed in vivo. The introduction of a standardized approach to nanoparticle characterization and in vivo testing is crucial if research is to transition to a clinical setting. The approach suggested, herein, is based on equipment and techniques that are accessible and informative to facilitate the routine incorporation of this standardized, informative approach into different research settings. Thorough characterization could lead to improved interpretation of in vivo responses, which could clarify nanoparticle properties that result in favorable in vivo outcomes whilst exposing nanoparticle-specific weaknesses. Only then will researchers successfully identify nanoparticles capable of delivering life-saving therapeutics across the blood-brain barrier

Nanoparticle transport across the blood brain barrier

ABSTRACT: While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes

Development of Novel Zn2+ Loaded Nanoparticles Designed for Cell-Type Targeted Drug Release in CNS Neurons: In Vitro Evidences

Intact synaptic function and plasticity are fundamental prerequisites to a healthy brain. Therefore, synaptic proteins are one of the major targets for drugs used as neuro-chemical therapeutics. Unfortunately, the majority of drugs is not able to cross the blood–brain barrier (BBB) and is therefore distributed within the CNS parenchyma. Here, we report the development of novel biodegradable Nanoparticles (NPs), made of poly-lactide-co-glycolide (PLGA) conjugated with glycopeptides that are able to cross the BBB and deliver for example Zn2+ ions. We also provide a thorough characterization of loaded and unloaded NPs for their stability, cellular uptake, release properties, toxicity, and impact on cell trafficking. Our data reveal that these NPs are biocompatible, and can be used to elevate intracellular levels of Zn2+. Importantly, by engineering the surface of NPs with antibodies against NCAM1 and CD44, we were able to selectively target neurons or glial cells, respectively. Our results indicate that these biodegradable NPs provide a potential new venue for the delivery Zn2+ to the CNS and thus a means to explore the influence of altered zinc levels linked to neuropsychological disorders such as depression

Sperm selection by rheotaxis improves sperm quality and early embryo development

peer-reviewedThe objective of this work was to elucidate whether a sperm selection method that combines rheotaxis and microfluidics can improve the selection of spermatozoa over density gradient and swim-up. For this purpose human sperm selected by rheotaxis were compared against density gradient, swim-up and a control group of non-selected spermatozoa in split frozen-thawed (FT) and fresh (F) semen samples. Sperm quality was assessed in terms of motility, morphology, DNA fragmentation index (DFI), viability, acrosome integrity and membrane fluidity. Using a mouse model, we compared fertilisation and embryo development rates after performing ICSI with spermatozoa, sorted using rheotaxis or swim-up. Selection by rheotaxis yielded a sperm population with reduced DFI than the control (P < 0.05), improved normal morphology (P < 0.001) and higher total motility (TM; P < 0.001) than the other techniques studied in F and FT samples. Swim-up increased TM compared to density gradient and control in FT or F samples (P < 0.001), and yielded lower DFI than the control with F samples (P < 0.05). In FT samples, selection by rheotaxis yielded sperm with higher viability than control, density gradient and swim-up (P < 0.01) while acrosomal integrity and membrane fluidity were maintained. When mouse spermatozoa were selected for ICSI using rheotaxis compared to swim-up, there was an increase in fertilisation (P < 0.01), implantation (P < 0.001) and foetal development rates (P < 0.05). These results suggest that, in the absence of non-destructive DNA testing, the positive rheotaxis can be used to select a population of low DNA fragmentation spermatozoa with high motility, morphology and viability, leading to improved embryo developmental rates

Consensus recommendations on organization of care for individuals with Phelan-McDermid syndrome

The manifestations of Phelan-McDermid syndrome (PMS) are complex, warranting expert and multidisciplinary care in all life stages. In the present paper we propose consensus recommendations on the organization of care for individuals with PMS. We indicate that care should consider all life domains, which can be done within the framework of the International Classification of Functioning, Disability and Health (ICF). This framework assesses disability and functioning as the outcome of the individual's interactions with other factors. The different roles within care, such as performed by a centre of expertise, by regional health care providers and by a coordinating physician are addressed. A surveillance scheme and emergency card is provided and disciplines participating in a multidisciplinary team for PMS are described. Additionally, recommendations are provided for transition from paediatric to adult care. This care proposition may also be useful for individuals with other rare genetic neurodevelopmental disorders.</p

Object phobia and altered RhoA signaling in amygdala of mice lacking RICH2

RICH2 knockout (RICH2 KO) mice exhibit neophobia in the novel object test. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests to elucidate whether the behavioral abnormality in these mice is a consequence of reduced exploratory motivation, and whether the neophobia is linked specifically to objects or also present for other modalities. RICH2 KO mice engage in normal exploration in a novel environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Increased fear response was not observed using novel olfactory cues, but restricted to objects. Given that the amygdala is an important brain region mediating anxiety-related behaviors and a prime target for anxiety-related therapeutics, and RICH2 is a Rho-GAP protein regulating synaptic spine plasticity via small GTPases, we analyzed spine formation, morphology and receptor composition in amygdala. We found disinhibition of RhoA in the amygdala of RICH2 KO mice, along with a decreased ability for actin polymerization and a reduction in mature spines. However, we detected increased neuronal activation in the amygdala evidenced by c-fos labeling. Thus, we conclude that despite unaltered baseline activity, RICH2 KO mice show heightened amygdala response after exposure to objects, which, however, does not result in homeostatic strengthening of excitatory synapes

Brain Lateralization in Mice Is Associated with Zinc Signaling and Altered in Prenatal Zinc Deficient Mice That Display Features of Autism Spectrum Disorder

A number of studies have reported changes in the hemispheric dominance in autism spectrum disorder (ASD) patients on functional, biochemical, and morphological level. Since asymmetry of the brain is also found in many vertebrates, we analyzed whether prenatal zinc deficient (PZD) mice, a mouse model with ASD like behavior, show alterations regarding brain lateralization on molecular and behavioral level. Our results show that hemisphere-specific expression of marker genes is abolished in PZD mice on mRNA and protein level. Using magnetic resonance imaging, we found an increased striatal volume in PZD mice with no change in total brain volume. Moreover, behavioral patterns associated with striatal lateralization are altered and the lateralized expression of dopamine receptor 1 (DR1) in the striatum of PZD mice was changed. We conclude that zinc signaling during brain development has a critical role in the establishment of brain lateralization in mice