Neurogenerative Diseases Research Articles

Extracellular CIRP Induces Calpain Activation in Neurons via PLC-IP3-Dependent Calcium Pathway.

Abnormal calcium homeostasis, activation of protease calpain, generation of p25 and hyperactivation of cyclin-dependent kinase 5 (Cdk5) have all been implicated in the pathogenesis of neurogenerative diseases including Alzheimer's disease. We have recently shown that extracellular cold-inducible RNA-binding protein (eCIRP) induces Cdk5 activation via p25. However, the precise molecular mechanism by which eCIRP regulates calcium signaling and calpain remains to be addressed. We hypothesized that eCIRP regulates p25 via Ca2+-dependent calpain activation. eCIRP increased calpain activity and decreased the endogenous calpain inhibitor calpastatin in Neuro 2a (N2a) cells. Calpain inhibition with calpeptin attenuated eCIRP-induced calpain activity and p25. eCIRP specifically upregulated cytosolic calpain 1, and calpain 1 silencing attenuated the eCIRP-induced increase in p25. eCIRP stimulation increased cytosolic free Ca2+, especially in hippocampal neuronal HT22 cells, which was attenuated by the eCIRP inhibitor Compound 23 (C23). Endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor (IP3R) inhibition using 2-aminoethoxy-diphenyl-borate or xestospongin-C (X-C), interleukin-6 receptor alpha (IL-6Rα)-neutralization, and phospholipase C (PLC) inhibition with U73122 attenuated eCIRP-induced Ca2+ increase, while Ca2+ influx across the plasma membrane remained unaffected by eCIRP. Finally, C23, IL-6Rα antibody, U73122 and X-C attenuated eCIRP-induced p25 in HT-22 cells. In conclusion, the current study uncovers eCIRP-triggered Ca2+ release from ER stores in an IL-6Rα/PLC/IP3-dependent manner as a novel molecular mechanism underlying eCIRP's induction of Cdk5 activity and potential involvement in neurodegeneration.

The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling.

The posttranslational proteolytic cleavage is a unique and irreversible process that governs the function and half-life of numerous proteins. Thereby the role of the family of A disintegrin and metalloproteases (ADAMs) plays a leading part. A member of this family, ADAM8, has gained attention in regulating disorders, such as neurogenerative diseases, immune function and cancer, by attenuating the function of proteins nearby the extracellular membrane leaflet. This process of "ectodomain shedding" can alter the turnover rate of a number of transmembrane proteins that function in cell adhesion and receptor signal transduction. In the past, the major focus of research about ADAMs have been on neurogenerative diseases, such as Alzheimer, however, there seems to be evidence for a connection between ADAM8 and cancer. The role of ADAMs in the field of cancer research has gained recent attention, but it has been not yet been extensively addressed. Thus, this review article highlights the various roles of ADAM8 with particular emphasis on pathological conditions, such as cancer and malignant cancer progression. Here, the shedding function, direct and indirect matrix degradation, effects on cancer cell mobility and transmigration, and the interplay of ADAM8 with matrix-embedded neighboring cells are presented and discussed. Moreover, the most probable mechanical impact of ADAM8 on cancer cells and their matrix environment is addressed and debated. In summary, this review presents recent advances in substrates/ligands and functions of ADAM8 in its new role in cancer and its potential link to cell mechanical properties and discusses matrix mechanics modifying properties. A deeper comprehension of the regulatory mechanisms governing the expression, subcellular localization, and activity of ADAM8 is expected to reveal appropriate drug targets that will permit a more tailored and fine-tuned modification of its proteolytic activity in cancer development and metastasis.

Antioxidant Activity of Panax ginseng to Regulate ROS in Various Chronic Diseases

Reactive oxygen species (ROS)-the byproduct of regular cell activity formed by various cellular components—play a significant role in pathological and physiological conditions. Alternatively, antioxidants are compounds that reduce or scavenge reactive species in cells. An asymmetry between the antioxidant defense system and ROS from intracellular and extracellular sources cause chronic diseases such as cancer, inflammation, tumorigenesis, cardiovascular and neurogenerative diseases. However, Panax ginseng and its secondary metabolites (known as ginsenosides, phenolic compounds, peptides, acid polysaccharides, polyacetylene, and alkaloids) are well-recognized as antioxidants in many in vitro and in vivo experiments which show beneficial activity in regulating ROS in these diseases. There are extensive evidences that P. ginseng can destroy cancer cells specifically by increasing oxidative stress through ROS generation without significantly harming normal cells. Additionally, numerous studies have examined the antioxidant activity of ginseng and its derivatives on ROS-mediated signaling pathways which are discussed herein. This review summarizes the potential antioxidant activity of P. ginseng in several chronic diseases, and gives updated research evidence with related mechanisms and the future possibilities of nano-formulated compounds of P. ginseng and other polyphenols.

Evidence of Flavonoids on Disease Prevention

A growing body of evidence highlights the properties of flavonoids in natural foods for disease prevention. Due to their antioxidative, anti-inflammatory, and anti-carcinogenic activities, flavonoids have been revealed to benefit skeletal muscle, liver, pancreas, adipocytes, and neural cells. In this review, we introduced the basic classification, natural sources, and biochemical properties of flavonoids, then summarize the experimental results and underlying molecular mechanisms concerning the effects of flavonoid consumption on obesity, cancers, and neurogenerative diseases that greatly threaten public health. Especially, the dosage and duration of flavonoids intervening in these diseases are discussed, which might guide healthy dietary habits for people of different physical status.

Conformational and functional interrelation between mitochondrial carrier proteins: UCP4, ANT, PiT.

Mitochondrial uncoupling proteins (UCPs) attenuate proton motive force across the inner membrane of mitochondria (IMM) by transporting protons from the intermembrane space into matrix, thus reducing the ATP synthesis rate. UCPs together with adenine nucleotide translocase (ANT) and inorganic phosphate translocase (PiT) create a subgroup of carriers directly linked to mitochondrial energetics. While its potential role in neuroprotection of neurogenerative diseases has been speculated, the brain specific neuronal UCP4 is among the least investigated UCPs. This integrative study will focus on the structural features and functional interrelation of UCP4, ANT and PiT. We designed recombinant versions of these proteins that, using a modified autoinduction method, were overexpressed in the membrane of Escherichia coli, extracted with mild detergents, and purified as monomers. Purified proteins, embedded in a shell of bacterial membrane lipids, were then reconstituted in IMM-mimicking phospholipid vesicles for biophysical studies using circular dichroism (CD) and fluorescence spectroscopies. Native-like helical conformations of proteins in the mild detergent octyl glycoside (OG) and phospholipid membranes were confirmed by CD spectroscopy. Interestingly, in agreement with our previous studies, monomeric UCP4 spontaneously self-associated to form tetramers in lipid vesicles. Conversely, ANT and PiT maintained their molecular forms in both detergent and liposome milieus. Reconstituted proteins in lipid membranes exhibited different levels of proton transport activity in the presence of fatty acids and decreased with the addition of ATP. UCP4 showed significantly higher proton transport rates compared to ANT and PiT. Research on the functional interrelation between these three carrier proteins, as well as the effect of mitochondrial lipid cardiolipin on their conformational stability and proton transport activity, is in progress in our laboratory.

Effect of cooking time on the nutritional and anti-nutritional properties of red and black beans of Phaseolus lunatus (L.) consumed in south and east of Côte d’Ivoire

Legume seeds, particularly those of the Phaseolus lunatus (L.), are an important source of vegetable protein, fiber and micronutrients in the diet of the Ivorian population. However, these seeds contain anti-nutritive factors that limit their use. This study allowed us to evaluate the effect of cooking time on the nutritional and anti-nutritional parameters of Phaseolus lunatus (L.) bean seeds for a better utilization of these seeds. Red and black seeds harvested at stage 4 (52 days) of Phaseolus lunatus (L.) bean were cooked at 100 °C for 45, 60 and 75 minutes. The nutritional and anti-nutrional composition was determined on uncooked (control) and cooked samples. The results obtained showed an increase in carbohydrate (64.16 to 71.56%), energy value (29.68 to 36.27%) and fiber (4.62 to 6.05%) followed by a reduction in protein (4.62 to 6.05%), ash (4.62 to 6.05%) and fat (4.62 to 6.05%). The same cooking also caused a reduction in total phenols (59.18 to 72.49%), phytates (33.32 to 39.18%), oxalates (64.64 to 68.91%), tannins (62.07 to 67.59%), cyanidric acid (58.18 to 61.38%) and antioxidant activity (53.71 to 63.94%). The analysis of the seeds cooked at different times (45, 60 and 75 minutes) also shows us that the B vitamins and minerals decrease during cooking. The consumption of Phaseolus lunatus bean seeds cooked at 45 minutes could be recommended in human diet due to the decrease of oxalates and phytates to prevent and treat some diseases such as cancer, inflammatory diseases, cardiovascular diseases and neurogenerative diseases.

F4-neuroprostanes and F2-dihomo-isoprostanes: biomarkers and bioactive oxylipins

Under condition of oxidative stress, free radical-catalyzed peroxidation of docosahexaenoic acid (DHA) and adrenic acid (AdA) generates in vivo neuroprostanes (NeuroPs) and dihomo-isoprostanes (dihomo-IsoPs), among a large number of key products participating in many pathophysiological processes. These non-enzymatic oxygenated metabolites display a wide range of biological actions (especially DHA-metabolites), and some of them are now considered as the most reliable indicators of oxidative stress in neurogenerative, neurodevelopmental or cardiovascular diseases. In this review, we will present an overview regarding neuroprostanes and dihomo-isoprostanes and discuss about their biological interests.

The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation.

Patients with the fatal disorder Transthyretin Amyloidosis (ATTR) experience polyneuropathy through the progressive destruction of peripheral nervous tissue. In these patients, the transthyretin (TTR) protein dissociates from its functional tetrameric structure, misfolds, and aggregates into extracellular amyloid deposits that are associated with disease progression. These aggregates form large fibrillar structures as well as shorter oligomeric aggregates that are suspected to be cytotoxic. Several studies have shown that these extracellular TTR aggregates enter the cell and accumulate intracellularly, which is associated with increased proteostasis response. However, there are limited experimental models to study how proteostasis influences internalized TTR aggregates. Here, we use a humanized yeast system to recapitulate intracellular TTR aggregating protein in vivo. The yeast molecular chaperone Hsp104 is a disaggregase that has been shown to fragment amyloidogenic aggregates associated with certain yeast prions and reduce protein aggregation associated with human neurogenerative diseases. In yeast, we found that TTR forms both SDS-resistant oligomers and SDS-sensitive large molecular weight complexes. In actively dividing cultures, Hsp104 has no impact on oligomeric or large aggregate populations, yet overexpression of Hsp104 is loosely associated with an increase in overall aggregate size. Interestingly, a potentiating mutation in the middle domain of Hsp104 consistently results in an increase in overall TTR aggregate size. These data suggest a novel approach to aggregate management, where the Hsp104 variant shifts aggregate populations away from toxic oligomeric species to more inert larger aggregates. In aged cultures Hsp104 overexpression has no impact on TTR aggregation profiles suggesting that these chaperone approaches to shift aggregate populations are not effective with age, possibly due to proteostasis decline.

The role of magnetic resonance imaging in the diagnosis and prognosis of dementia.

Dementia is a syndrome characterized by multidomain acquired chronic cognitive impairment that has a profound impact on daily life. Neurogenerative diseases such as Alzheimer's disease or nondegenerative diseases such as vascular dementia are considered to cause dementia. The need for further diagnostic improvement originates from the prevalence of these conditions, especially in developed countries with a predominance of the elderly population. Today, the diagnosis and follow-up of all neurodegenerative diseases cannot be performed without radiological imaging, primarily magnetic resonance imaging (MRI). The introduction of 3T MRI and its modern techniques, such as arterial spin labeling, has enabled better visualization of morphologic changes in dementia. For better diagnosis and follow-up in patients with dementia, various semiquantitative scales have been designed to improve the accuracy of assessment and decrease interobserver variability. Moreover, there is a growing need for MRI in the assessment of novel therapies and their side effects. To better apply MRI findings in the diagnosis of both already developed dementia and its early stages, the aim of this paper is to review the available literature and summarize the specific MRI changes.

Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease.

Organisms are continually exposed to exogenous and endogenous sources of reactive oxygen species (ROS) and other oxidants that have both beneficial and deleterious effects on the cell. ROS have important roles in a wide range of physiological processes; however, high ROS levels are associated with oxidative stress and disease progression. Oxidative stress has been implicated in nearly all major human diseases, from neurogenerative diseases and neuropsychiatric disorders to cardiovascular disease, diabetes, and cancer. Antioxidant defence systems have evolved as a means of protection against oxidative stress, with the transcription factor Nrf2 as the key regulator. Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress and has been extensively studied in the disease contexts. This review aims to provide the reader with a general overview of oxidative stress and Nrf2, including basic mechanisms of Nrf2 activation and regulation, and implications in various major human diseases.

Multicomponent System of Single‐Walled Carbon Nanotubes Functionalized with a Melanin‐Inspired Material for Optical Detection and Scavenging of Metals

AbstractThe accumulation of metal ions in organisms and the presence of heavy metals in water cause adverse effects on ecosystems and results in numerous human health issues such as cancer and neurogenerative diseases. Therefore, the development of novel platforms for metal‐scavenging and rapid metal detection for in situ applications are of high importance. Here, this challenge is tackled by taking advantage of the metal chelation ability of a melanin‐inspired material in combination with the near‐infrared (NIR) fluorescence response of single‐walled carbon nanotubes (SWCNTs) to surface binding. SWCNTs are functionalized by a melanin‐like substance, obtained by enzymatic oxidative polymerization of a fluorenylmethyloxycarbonyl‐tyrosine (FmocY) precursor. The resulting multicomponent system (SWCNT‐FmocYOx) serves as a metal‐ion scavenging platform that concurrently reports on metal binding with optical signal transduction. Upon binding of a library of mostly divalent transition metal‐ions, the fluorescence emission of the functionalized SWCNTs is modulated, showing a concentration‐dependent response with a limit of detection in the nanomolar range. Metal‐binding and removal from water of up to 98% is further shown via inductively coupled plasma mass spectrometry. The SWCNT‐FmocYOx hybrid system presents a novel platform with NIR optical signal for real‐time feedback on metal‐ion scavenging.

An Insight into Animal Glutamate Receptors Homolog of Arabidopsis thaliana and Their Potential Applications-A Review.

Most excitatory impulses received by neurons are mediated by ionotropic glutamate receptors (iGluRs). These receptors are located at the apex and play an important role in memory, neuronal development, and synaptic plasticity. These receptors are ligand-dependent ion channels that allow a wide range of cations to pass through. Glutamate, a neurotransmitter, activates three central ionotropic receptors: N-methyl-D-aspartic acid (NMDA), -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainic acid (KA). According to the available research, excessive glutamate release causes neuronal cell death and promotes neurodegenerative disorders. Arabidopsis thaliana contains 20 glutamate receptor genes (AtGluR) comparable to the human ionotropic glutamate (iGluRs) receptor. Many studies have proved that AtGL-rec genes are involved in a number of plant growth and physiological activities, such as in the germination of seeds, roots, abiotic and biotic stress, and cell signaling, which clarify the place of these genes in plant biology. In spite of these, the iGluRs, Arabidopsis glutamate receptors (AtGluR), is associated with the ligand binding activity, which confirms the evolutionary relationship between animal and plant glutamate receptors. Along with the above activities, the impact of mammalian agonists and antagonists on Arabidopsis suggests a correlation between plant and animal glutamate receptors. In addition, these glutamate receptors (plant/animal) are being utilized for the early detection of neurogenerative diseases using the fluorescence resonance energy transfer (FRET) approach. However, a number of scientific laboratories and institutes are consistently working on glutamate receptors with different aspects. Currently, we are also focusing on Arabidopsis glutamate receptors. The current review is focused on updating knowledge on AtGluR genes, their evolution, functions, and expression, and as well as in comparison with iGluRs. Furthermore, a high throughput approach based on FRET nanosensors developed for understanding neurotransmitter signaling in animals and plants via glutamate receptors has been discussed. The updated information will aid in the future comprehension of the complex molecular dynamics of glutamate receptors and the exploration of new facts in plant/animal biology.

Coronarin D attenuates MPTP-induced Parkinson’s disease in mice by inhibition of oxidative stress and apoptosis

Parkinson’s disease (PD) is a brain-related disease condition, globally it is the second most common neurodegenerative disease that mostly disturbs the brain motor control and action of the aged populations. It involves a tiny, dark portion of the brain denoted as substantia nigra. Dopamine is produced in the substantia nigra for the usage of the brain. This dopamine communicates messages among nerves and controls muscle movements. Coronarin D is a diterpenoid with exclusive pharmacological possessions and its effectiveness over a few neurogenerative diseases exposed to some intense properties. The present study was intended to exhibit the neuroprotective efficacy of Coronarin D over MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced animals. Oral management of Coronarin D (10 and 20 mg/kg body wt.) protects the MPTP-induced nigrostriatal dopamine (DA) depletion and its intermediate substances. Behavioral studies like narrow beam walk test, open field test and hang test were conducted to study the movement and actions of Coronarin D treated MPTP induced experimental animals, in which Coronarin D treated group III & IV animals showed better behavioral alterations. Our compound as well attenuated MPTP persuaded oxidative pressure in experimental animals. Apoptotic marker studies displayed that management with Coronarin D upturned MPTP induced programmed cell death, which might be its anti-apoptotic properties. Ultimately to conclude, Coronarin D recovered oxidative pressure, neurochemical alterations, apoptosis, and functional irregularities in investigational mice and propose a potential approach to disease management of neurodegenerative and its related disease.

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

The Antimicrobial Properties of Cannabis and Cannabis-Derived Compounds and Relevance to CB2-Targeted Neurodegenerative Therapeutics.

Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP–microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed.

Discovering Semantic Relations between Neurodegenerative Diseases and Artistic Behaviors

This paper aims to introduce the value of semantics for representing knowledge related to patients with brain neurodegenerative diseases (Parkinson’s, Alzheimer’s, and dementia) or behavioral disorders (i.e., schizophrenia) and artistic behavior. The ultimate goal is to facilitate an effective and efficient study of neurological and behavioral changes of patients, analyzing semantically interlinked data related to neurological/behavioral conditions and artistic behaviors. By mapping the neurologically affected areas of the brain in healthy and unhealthy individuals, and by modeling their particular characteristics at the level of both behavioral and neurological expressions, it may be possible to identify semantic similarities in high-level behavioral and brain characteristics that justify correlation and causation between diseases/disorders and artistic behaviors. In this concept paper, we present our view on two key points related to proposed research on a novel framework that will (a) verify if early biomarkers of the neurogenerative diseases can be identified via artistic behavior observations, and (b) correlate patients with delayed onset of the diseases/disorders with artists, at the molecular level, or at the level of brain regions. The proposed framework is evaluated with the development of a proof-of-concept expert system based on the representation of the relevant knowledge.

Type-I Interferons in Alzheimer's Disease and Other Tauopathies.

The detection of pathogen-associated molecular patterns can elicit the production of type-I interferons (IFNs), soluble cytokines that induce a transcriptional state inhibitory to viral replication. Signatures of type-I IFN-driven gene expression, and type-I IFNs themselves, are observed in the central nervous system during neurodegenerative diseases including Alzheimer's disease and other tauopathies, the umbrella term for diseases that feature aggregation of the cytosolic protein tau. The contribution of the type-I IFN response to pathological progression of these diseases, however, is not well-understood. The wholesale transcriptional changes that ensue from type-I IFN production can both promote protective effects and lead to damage dependent on the context and duration of the response. The type-I IFN system therefore represents a signaling pathway with a potential disease-modifying role in the progression of neurodegenerative disease. In this review we summarize the evidence for a type-I IFN signature in AD and other tauopathies and examine the role of aggregated proteins as inflammatory stimuli. We explore both the protective role of IFN against protein pathologies as well as their downstream toxic consequences, which include the exacerbation of protein pathology as a potentially destructive feed-forward loop. Given the involvement of type-I IFNs in other neurogenerative diseases, we draw comparisons with other categories of homotypic protein aggregation. Understanding how type-I IFN influences progression of AD and other tauopathies may yield important insight to neurodegeneration and identify new targets in an area currently lacking disease-modifying therapies.

Central nervous system cholesterol metabolism in health and disease.

Cholesterol is a ubiquitous and essential component of cellular membranes, as it regulates membrane structure and fluidity. Furthermore, cholesterol serves as a precursor for steroid hormones, oxysterol, and bile acids, that are essential for maintaining many of the body's metabolic processes. The biosynthesis and excretion of cholesterol is tightly regulated in order to maintain homeostasis. Although virtually all cells have the capacity to make cholesterol, the liver and brain are the two main organs producing cholesterol in mammals. Once produced, cholesterol is transported in the form of lipoprotein particles to other cell types and tissues. Upon formation of the blood-brain barrier (BBB) during embryonic development, lipoproteins cannot move between the central nervous system (CNS) and the rest of the body. As such, cholesterol biosynthesis and metabolism in the CNS operate autonomously without input from the circulation system in normal physiological conditions. Nevertheless, similar regulatory mechanisms for maintaining cholesterol homeostasis are utilized in both the CNS and peripheral systems. Here, we discuss the functions and metabolism of cholesterol in the CNS. We further focus on how different CNS cell types contribute to cholesterol metabolism, and how ApoE, the major CNS apolipoprotein, is involved in normal and pathophysiological functions. Understanding these basic mechanisms will aid our ability to elucidate how CNS cholesterol dysmetabolism contributes to neurogenerative diseases.

Whole-Genome Sequencing and Genomic Variant Analysis of Kazakh Individuals.

Kazakhstan, the ninth-largest country in the world, is located along the Great Silk Road and connects Europe with Asia. Historically, its territory has been inhabited by nomadic tribes, and modern-day Kazakhstan is a multiethnic country with a dominant Kazakh population. We sequenced and analyzed the genomes of five ethnic Kazakhs at high coverage using the Illumina HiSeq2000 next-generation sequencing platform. The five Kazakhs yielded a total number of base pairs ranging from 87,308,581,400 to 107,526,741,301. On average, 99.06% were properly mapped. Based on the Het/Hom and Ti/Tv ratios, the quality of the genomic data ranged from 1.35 to 1.49 and from 2.07 to 2.08, respectively. Genetic variants were identified and annotated. Functional analysis of the genetic variants identified several variants that were associated with higher risks of metabolic and neurogenerative diseases. The present study showed high levels of genetic admixture of Kazakhs that were comparable to those of other Central Asians. These whole-genome sequence data of healthy Kazakhs could contribute significantly to biomedical studies of common diseases as their findings could allow better insight into the genotype–phenotype relations at the population level.

Overnutrition Induced Cognitive Impairment: Insulin Resistance, Gut-Brain Axis, and Neuroinflammation.

Overnutrition-related obesity has become a worldwide epidemic, and its prevalence is expected to steadily rise in the future. It is widely recognized that obesity exerts negative impacts on metabolic disorders such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases. However, relatively fewer reports exist on the impairment of brain structure and function, in the form of memory and executive dysfunction, as well as neurogenerative diseases. Emerging evidence indicates that besides obesity, overnutrition diets independently induce cognitive impairments via multiple mechanisms. In this study, we reviewed the clinical and preclinical literature about the detrimental effects of obesity or high-nutrition diets on cognitive performance and cerebral structure. We mainly focused on the role of brain insulin resistance (IR), microbiota-gut-brain axis, and neuroinflammation. We concluded that before the onset of obesity, short-term exposure to high-nutrition diets already blunted central responses to insulin, altered gut microbiome composition, and activated inflammatory mediators. Overnutrition is linked with the changes in protein expression in brain insulin signaling, leading to pathological features in the brain. Microbiome alteration, bacterial endotoxin release, and gut barrier hyperpermeability also occur to trigger mental and neuronal diseases. In addition, obesity or high-nutrition diets cause chronic and low-grade systematic inflammation, which eventually spreads from the peripheral tissue to the central nervous system (CNS). Altogether, a large number of unknown but potential routes interact and contribute to obesity or diet-induced cognitive impairment. The challenge for future research is to identify effective interventions involving dietary shifts and personalized therapy targeting the underlying mechanisms to prevent and improve cognition deficits.