Metal Dyshomeostasis Research Articles

Study on Multi-Target Synergistic Treatment of Alzheimer's Disease Based on Metal Chelators.

Alzheimer's disease (AD) has become the fourth leading cause of death in the world. Due to its complex pathogenesis, there is still a lack of effective drug treatments. Studies have found that the metal dyshomeostasis is closely related to other pathogeneses of AD such as oxidative stress, β-amyloid protein deposits, etc. Therefore, it becomes an important target to find the appropriate metal chelating agents to regulate the metal homeostasis. At the same time, because of the complex pathogenesis, single target drugs cannot achieve good effects. Therefore, current studies are mainly focused on exploring multi-target therapy for AD. In this work, the multi-target studies based on metal chelators and other targets with synergistic anti-AD activities were reviewed. The structural characteristics of different chelating agents were summarized and the structure-activity relationship was analyzed, which provided some valuable clues for the subsequent development of anti-AD multi-target drugs based on metal chelating agents.

Tacrine-Based Hybrids: Past, Present, and Future.

Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the "one drug-multiple targets" strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.

Metallomics in pulmonary arterial hypertension patients.

Pulmonary arterial hypertension (PAH) prevalence is increasing worldwide, and the prognosis is poor with 5-year survival < 50% in high risk patients. The relationship between metal exposure/essential metal dyshomeostasis and PAH/right ventricular dysfunction is less investigated. The aim of this study is to investigate vegetable consumptions and metal levels between PAH patients and controls. This was a prospective, single center pilot study. Questionnaires were completed by all study subjects (20 PAH patients and 10 healthy controls) on smoking, metal exposure risks, metal supplements, and vegetable consumptions. Blood and urine samples were collected to measure 25 metal levels in blood, plasma, and urine using an X Series II quadrupole inductively coupled plasma mass spectrometry. Statistical analysis was conducted using SAS 9.5 and results with p value < 0.05 were considered significant. Vegetables consumptions (broccoli risk ratio[RR] = 0.4, CI = (0.2, 0.9)], cabbage [RR = 0.2, CI = (0.1, 0.8)], and brussel sprouts [RR = 0.2, CI = (0.1, 0.5)]) are associated with less risks of PAH. In the plasma samples, silver (p < 0.001), and copper (p = 0.002) levels were significantly higher in PAH patients. There was significant positive correlation between cardiac output and cardiac index with plasma levels of silver (r = 0.665, p = 0.001 and r = 0.678 p = 0.001), respectively. There was significant correlation between mixed venous saturation, 6-min walk distance, and last BNP with plasma levels of chromium (r = -0.520, p = 0.022; r = -0.55, p = 0.014; r = 0.463, p = 0.039), respectively. In conclusion, there are significant differences between PAH and control groups in terms of vegetable consumptions and metal concentrations. Silver and chromium levels are correlated with clinical indicators of PAH severities.

Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti-AD Lead Compound.

Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins were chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1-3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, βamyloid (Aβ) aggregation, and metal dyshomeostasis were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico. Results showed that 1-3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aβ aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC50 =11.15 μM). Compound 1-3 could also selectively chelate with Cu2+ and Al3+ to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1-3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1-3 could be promising MTDLs applied as anti-AD candidate drugs.

Neonatal exposure to ultrafine iron but not combined iron and sulfur aerosols recapitulates air pollution-induced impulsivity in mice

Air pollution (AP) is becoming recognized as a major threat to neurological health across the lifespan with increased risk of both neurodevelopmental and neurodegenerative disorders. AP is a complex mixture of gases and particulate matter, with adsorbed contaminants including metals and trace elements, which may differentially contribute to its neurodevelopmental impacts. Iron (Fe) is one of the most abundant metals found in AP, and Fe concentrations may drive some behavioral deficits observed in children. Furthermore, brains of neonate mice exposed to concentrated ambient ultrafine particulate matter (UFP) show significant brain accumulation of Fe and sulfur (S) supporting the hypothesis that AP exposure may lead to brain metal dyshomeostasis. The current study determined the extent to which behavioral effects of UFP, namely memory deficits and impulsive-like behavior, could be recapitulated with exposure to Fe aerosols with or without concomitant SO2. Male and female neonate mice were either exposed to filtered air or spark discharge-generated ultrafine Fe particles with or without SO2 gas (n = 12/exposure/sex). Inhalation exposures occurred from postnatal day (PND) 4–7 and 10–13 for 4 hr/day, mirroring our previous UFP exposures. Mice were aged to adulthood prior to behavioral testing. While Fe or Fe + SO2 exposure did not affect gross locomotor behavior, Fe + SO2-exposed females displayed consistent thigmotaxis during locomotor testing. Neither exposure affected novel object memory. Fe or Fe + SO2 exposure produced differential outcomes on a fixed-interval reinforcement schedule with males showing higher (Fe-only) or lower (Fe + SO2) response rates and postreinforcement pauses (PRP) and females showing higher (Fe-only) PRP. Lastly, Fe-exposed, but not Fe + SO2-exposed, males showed increased impulsive-like behavior in tasks requiring response inhibition with no such effects in female mice. These findings suggest that: 1) exposure to realistic concentrations of Fe aerosols can recapitulate behavioral effects of UFP exposure, 2) the presence of SO2 can modulate behavioral effects of Fe inhalation, and 3) brain metal dyshomeostasis may be an important factor in AP neurotoxicity.

Characterization of the spatial distribution of metals and profile of metalloprotein complexes in a mouse model of repetitive mild traumatic brain injury.

Metal dyshomeostasis is a well-established consequence of neurodegenerative diseases and traumatic brain injury. While the significance of metals continues to be uncovered in many neurological disorders, their implication in repetitive mild traumatic brain injury remains uncharted. To address this gap, we characterized the spatial distribution of metal levels (iron, zinc, and copper) using laser ablation-inductively coupled plasma-mass spectrometry, the profile of metal-binding proteins via size exclusion chromatography-inductively coupled plasma-mass spectrometry and the expression of the major iron storing protein ferritin via western blotting. Using a mouse model of repetitive mild traumatic brain injury, 3-month-old male and female C57Bl6 mice received one or five impacts (48h apart). At 1 month following 5× TBI (traumatic brain injury), iron and ferritin levels were significantly elevated in the contralateral cortex. There was a trend toward increased iron levels in the entire contralateral hemisphere and a reduction in contralateral cortical iron-binding proteins following 1× TBI. No major changes in zinc levels were seen in both hemispheres following 5× or 1× TBI, although there was a reduction in ipsilateral zinc-binding proteins following 5× TBI and a contralateral increase in zinc-binding proteins following 1× TBI. Copper levels were significantly increased in both hemispheres following 5× TBI, without changes in copper-binding proteins. This study shows for the first time that repetitive mild TBI (r-mTBI) leads to metal dyshomeostasis, highlighting its potential involvement in promoting neurodegeneration, which provides a rationale for examining the benefit of metal-targeting drugs, which have shown promising results in neurodegenerative conditions and single TBI, but have yet to be tested following r-mTBI.

Ultrathin Zinc Selenide Nanoplatelets Boosting Photoacoustic Imaging of In Situ Copper Exchange in Alzheimer's Disease Mice.

The critical role of transition metal dyshomeostasis in Alzheimer's disease (AD) pathology poses demands of in vivo imaging for brain copper levels. Nanostructured probes afford prolonged retention time, increased accumulation, and enhanced photostability; however, their development for activatable photoacoustic (PA) imaging remains largely unexplored. We develop a principle of concept for activable PA imaging using in situ cation exchange of ultrathin zinc selenide (ZnSe) nanoplatelets for monitoring brain copper levels in AD mice. We start from quantitative modeling of optical absorption, time-resolved temperature field, and thermal expansion of copper selenide (CuSe) nanocrystals of different morphologies and reveal that ultrathin nanoplatelets afford substantial enhancement of near-infrared (NIR) absorption and PA pressures as compared to nanodots and nanoparticles. By tethering with a blood-brain barrier (BBB)-targeting peptide ligand, the ultrathin ZnSe nanoplatelet probe efficiently transports across the BBB and rapidly exchanges with endogenous copper ions, boosting activatable PA imaging of brain copper levels. We also demonstrate that the efficient exchange of ZnSe nanoplatelets with copper ions can reduce oxidative stress of neurons and protect neuronal cells from apoptosis. The nanoplatelet probe provides a paradigm for activatable PA imaging of brain copper levels, highlighting its potential for pathophysiologic study of AD.

ATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism

Hyposmia is a prevalent prodromal feature of Parkinson’s disease (PD), though the neuropathology that underlies this symptom is poorly understood. Unlike the substantia nigra, the status of metal homeostasis in the olfactory bulbs has not been characterized in PD. Given the increasing interest in metal modulation as a therapeutic avenue in PD, we sought to investigate bulbar metals and the effect of AT434 (formerly PBT434) an orally bioavailable, small molecule modulator of metal homeostasis on hyposmia in a mouse model of parkinsonism (the tau knockout (tau−/−) mouse). 5.5 (pre-hyposmia) and 13.5-month-old (pre-motor) mice were dosed with ATH434 (30 mg/kg/day, oral gavage) for 6 weeks. Animals then underwent behavioral analysis for olfactory and motor phenotypes. The olfactory bulbs and the substantia nigra were then collected and analyzed for metal content, synaptic markers, and dopaminergic cell number. ATH434 was able to prevent the development of hyposmia in young tau−/− mice, which coincided with a reduction in bulbar iron and copper levels, an increase in synaptophysin, and a reduction in soluble α-synuclein. ATH434 was able to prevent the development of motor impairment in aged tau−/− mice, which coincided with a reduction in iron levels and reduced neurodegeneration in the substantia nigra. These data implicate metal dyshomeostasis in parkinsonian olfactory deficits, and champion a potential clinical benefit of ATH434 in both prodromal and clinical stages of PD.

Redox stress and metal dys-homeostasis appear as hallmarks of early prion disease pathogenesis in mice

Neurodegenerative diseases are associated with a multitude of dysfunctional cellular pathways. One major contributory factor is a redox stress challenge during the development of several protein misfolding conditions including Alzheimer's (AD), Parkinson's disease (PD), and less common conditions such as Creutzfeldt Jakob disease (CJD). CJD is caused by misfolding of the neuronal prion protein and is characterised by a neurotoxic unfolded protein response involving chronic endoplasmic reticulum stress, reduced protein translation and spongiosis leading subsequently to synaptic and neuronal loss. Here we have characterised prion disease in mice to assess redox stress components including nitrergic and oxidative markers associated with neuroinflammatory activation. Aberrant regulation of the homeostasis of several redox metals contributes to the overall cellular redox stress and we have identified altered levels of iron, copper, zinc, and manganese in the hippocampus of prion diseased mice. Our data show that early in disease, there is evidence for oxidative stress in conjunction with reduced antioxidant superoxide dismutase mRNA and protein expression. Moreover, expression of divalent metal transporter proteins was reduced for Atp7b, Atox1, Slc11a2, Slc39a14 at 6–7 weeks but increased for Slc39a14 and Mt1 at 10 weeks of disease. Our data present evidence for a strong pro-oxidant environment and altered redox metal homeostasis in early disease pathology which both may be contributory factors to aggravating this protein misfolding disease.

Air Pollution-Related Neurotoxicity Across the Life Span.

Air pollution is a complex mixture of gases and particulate matter, with adsorbed organic and inorganic contaminants, to which exposure is lifelong. Epidemiological studies increasingly associate air pollution with multiple neurodevelopmental disorders and neurodegenerative diseases, findings supported by experimental animal models. This breadth of neurotoxicity across these central nervous system diseases and disorders likely reflects shared vulnerability of their inflammatory and oxidative stress-based mechanisms and a corresponding ability to produce brain metal dyshomeo-stasis. Future research to define the responsible contaminants of air pollution underlying this neurotoxicity is critical to understanding mechanisms of these diseases and disorders and protecting public health.

The potential involvement of inhaled iron (Fe) in the neurotoxic effects of ultrafine particulate matter air pollution exposure on brain development in mice

BackgroundAir pollution has been associated with neurodevelopmental disorders in epidemiological studies. In our studies in mice, developmental exposures to ambient ultrafine particulate (UFP) matter either postnatally or gestationally results in neurotoxic consequences that include brain metal dyshomeostasis, including significant increases in brain Fe. Since Fe is redox active and neurotoxic to brain in excess, this study examined the extent to which postnatal Fe inhalation exposure, might contribute to the observed neurotoxicity of UFPs. Mice were exposed to 1 µg/m3 Fe oxide nanoparticles alone, or in conjunction with sulfur dioxide (Fe (1 µg/m3) + SO2 (SO2 at 1.31 mg/m3, 500 ppb) from postnatal days 4–7 and 10–13 for 4 h/day.ResultsOverarching results included the observations that Fe + SO2 produced greater neurotoxicity than did Fe alone, that females appeared to show greater vulnerability to these exposures than did males, and that profiles of effects differed by sex. Consistent with metal dyshomeostasis, both Fe only and Fe + SO2 exposures altered correlations of Fe and of sulfur (S) with other metals in a sex and tissue-specific manner. Specifically, altered metal levels in lung, but particularly in frontal cortex were found, with reductions produced by Fe in females, but increases produced by Fe + SO2 in males. At PND14, marked changes in brain frontal cortex and striatal neurotransmitter systems were observed, particularly in response to combined Fe + SO2 as compared to Fe only, in glutamatergic and dopaminergic functions that were of opposite directions by sex. Changes in markers of trans-sulfuration in frontal cortex likewise differed in females as compared to males. Residual neurotransmitter changes were limited at PND60. Increases in serum glutathione and Il-1a were female-specific effects of combined Fe + SO2.ConclusionsCollectively, these findings suggest a role for the Fe contamination in air pollution in the observed neurotoxicity of ambient UFPs and that such involvement may be different by chemical mixture. Translation of such results to humans requires verification, and, if found, would suggest a need for regulation of Fe in air for public health protection.

Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer's Disease?

In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic Aβ assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer’s Disease (AD). However, the course of cognitive decline and AD development better correlates with tau accumulation rather than amyloid peptide deposition. Moreover, all clinical trials of amyloid-targeting drug candidates have been unsuccessful, implicitly suggesting that the amyloid hypothesis needs significant amendments. Accumulating evidence supports the existence of a series of potentially dangerous relationships between Aβ oligomeric species and tau protein in AD. However, the molecular determinants underlying pathogenic Aβ/tau cross interactions are not fully understood. Here, we discuss the common features of Aβ and tau molecules, with special emphasis on: (i) the critical role played by metal dyshomeostasis in promoting both Aβ and tau aggregation and oxidative stress, in AD; (ii) the effects of lipid membranes on Aβ and tau (co)-aggregation at the membrane interface; (iii) the potential of small peptide-based inhibitors of Aβ and tau misfolding as therapeutic tools in AD. Although the molecular mechanism underlying the direct Aβ/tau interaction remains largely unknown, the arguments discussed in this review may help reinforcing the current view of a synergistic Aβ/tau molecular crosstalk in AD and stimulate further research to mechanism elucidation and next-generation AD therapeutics.

Cadmium Through Disturbing MTF1-Mediated Metal Response Induced Cerebellar Injury.

Cadmium (Cd) is a toxic environmental contaminant, which bio-accumulate in animals through the food chain. Cerebellum is one of the primary target organs for Cd exposure. In this study, we established a chronic Cd exposure model; 60 chickens were treated with Cd (0 mg/kg, 35 mg/kg, 70 mg/kg) for 90 days. Clinical manifestations indicated that the chicken was depressed and has unstable gait under Cd exposure. Histopathological results indicated that Cd induced neuronal shrunken and indistinct nucleoli, and the number of Purkinje cells decreased significantly. Cerebellar metal contents were analyzed by ICP-MS. We found that Cd caused Cd and Cu accumulation and decreased the content of Se, Fe, and Zn, suggesting that Cd disturbed metal homeostasis. Besides, Cd treatment group also showed high levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) content and inhibited selenoprotein transcriptome, suggesting that Cd exposure resulted in oxidative stress. Notably, low-dose Cd exposure activated MTF1 mRNA and protein expression and its target metal-responsive genes, including MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B which indicate cellular adaptive response against Cd-induced damage. On the other hand, 70 mg/kg Cd downregulated MTF1-mediated metal response, which was involved in Cd-induced cerebellar injury in chicken. In conclusion, our data demonstrated that molecular mechanisms are associated with Cd-induced cerebellar injury due to disturbing MTF1-mediated metal response.Graphical abstractThis study indicated that the cerebellum is one of the target organs of Cd-induced toxicity. Additionally, Cd exposure induced metal dyshomeostasis in chicken’s cerebellum, whereas this study found that lower level of Cd dose triggered the activation of the cytoprotective mechanism through activating the expression of MTF1 which regulate MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B expressions in cerebellum. However, MTF1-mediated metal response was inhibited under the exposure of high dose of Cd, which ultimately caused cerebellar injury. The present study provides a new insight that Cd through disturbed MTF1-mediated metal response disrupts metal homeostasis that induced cerebellar injury. Supplementary InformationThe online version contains supplementary material available at 10.1007/s12640-022-00474-x.

Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis.

Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in post-mortem VaD brain tissue (n = 10) and age-/sex-matched controls (n = 10) from seven brain regions. We found novel evidence for elevated wet-weight cerebral sodium levels in VaD brain tissue in six out of the seven regions analyzed. Decreased cerebral-potassium levels as well as increased Na/K ratios (consistent with high tissue sodium and low potassium levels) were also observed in several brain regions. These data suggest that reduced Na+/K+-exchanging ATPase (EC 7.2.2.13) activity could contribute to the contrasting changes in sodium and potassium measured here.

Pharmacological Exploration of Triazole-based Therapeutics for Alzheimer’s Disease: An Overview

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder that may account for approximately 60-70% of cases of dementia worldwide. AD is characterized by impaired behavioural and cognitive functions, including memory, language, conception, attentiveness, judgment, and reasoning problems. The two important hallmarks of AD are the appearance of plaques and tangles of amyloid-beta (Aβ) and tau proteins, respectively, in the brain based on the etiology of the disease, including cholinergic impairment, metal dyshomeostasis, oxidative stress, and degradation of neurotransmitters. Currently, the used medication only provides alleviation of symptoms but is not effective in curing the disease, which creates the need to develop new molecules to treat AD. Heterocyclic compounds have proven their ability to be developed as drugs for the treatment of various diseases. The five-membered heterocyclic compound triazole has received foremost fascination for the discovery of new drugs due to the possibility of structural variation. Moreover, it has proved its significance in various drug categories. This review mainly summarizes the recent advancements in the development of novel 1,2,3-triazole and 1,2,4-triazole-based molecules in the drug discovery process for targeting various AD targets such as phosphodiesterase 1 (PDE1) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, somatostatin receptor subtype-4 (SSTR4) agonist, several other druggable targets, molecular modelling studies, as well as various methodologies for the synthesis of triazoles containing molecules such as click reaction, Pellizzari reaction, and Einhorn- Brunner reaction.

Recent advances in the application of metallomics in diagnosis and prognosis of human cancer.

Metals play a critical role in human health and diseases. In recent years, metallomics has been introduced and extensively applied to investigate the distribution, regulation, function, and crosstalk of metal(loid) ions in various physiological and pathological processes. Based on high-throughput multielemental analytical techniques and bioinformatics methods, it is possible to elucidate the correlation between the metabolism and homeostasis of diverse metals and complex diseases, in particular for cancer. This review aims to provide an overview of recent progress made in the application of metallomics in cancer research. We mainly focuses on the studies about metallomic profiling of different human biological samples for several major types of cancer, which reveal distinct and dynamic patterns of metal ion contents and the potential benefits of using such information in the detection and prognosis of these malignancies. Elevated levels of copper appear to be a significant risk factor for various cancers, and each type of cancer has a unique distribution of metals in biofluids, hair/nails, and tumor-affected tissues. Furthermore, associations between genetic variations in representative metalloprotein genes and cancer susceptibility have also been demonstrated. Overall, metallomics not only offers a better understanding of the relationship between metal dyshomeostasis and the development of cancer but also facilitates the discovery of new diagnostic and prognostic markers for cancer translational medicine.

The Relationships Among Metal Homeostasis, Mitochondria, and Locus Coeruleus in Psychiatric and Neurodegenerative Disorders: Potential Pathogenetic Mechanism and Therapeutic Implications.

While alterations in the locus coeruleus-noradrenergic system are present during early stages of neuropsychiatric disorders, it is unclear what causes these changes and how they contribute to other pathologies in these conditions. Data suggest that the onset of major depressive disorder and schizophrenia is associated with metal dyshomeostasis that causes glial cell mitochondrial dysfunction and hyperactivation in the locus coeruleus. The effect of the overactive locus coeruleus on the hippocampus, amygdala, thalamus, and prefrontal cortex can be responsible for some of the psychiatric symptoms. Although locus coeruleus overactivation may diminish over time, neuroinflammation-induced alterations are presumably ongoing due to continued metal dyshomeostasis and mitochondrial dysfunction. In early Alzheimer's and Parkinson's diseases, metal dyshomeostasis and mitochondrial dysfunction likely induce locus coeruleus hyperactivation, pathological tau or α-synuclein formation, and neurodegeneration, while reduction of glymphatic and cerebrospinal fluid flow might be responsible for β-amyloid aggregation in the olfactory regions before the onset of dementia. It is possible that the overactive noradrenergic system stimulates the apoptosis signaling pathway and pathogenic protein formation, leading to further pathological changes which can occur in the presence or absence of locus coeruleus hypoactivation. Data are presented in this review indicating that although locus coeruleus hyperactivation is involved in pathological changes at prodromal and early stages of these neuropsychiatric disorders, metal dyshomeostasis and mitochondrial dysfunction are critical factors in maintaining ongoing neuropathology throughout the course of these conditions. The proposed mechanistic model includes multiple pharmacological sites that may be targeted for the treatment of neuropsychiatric disorders commonly.

Tau Pathology, Metal Dyshomeostasis and Repetitive Mild Traumatic Brain Injury: An Unexplored Link Paving the Way for Neurodegeneration.

Repetitive mild traumatic brain injury (r-mTBI), commonly experienced by athletes and military personnel, causes changes in multiple intracellular pathways, one of which involves the tau protein. Tau phosphorylation plays a role in several neurodegenerative conditions including chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder linked to repeated head trauma. There is now mounting evidence suggesting that tau phosphorylation may be regulated by metal ions (such as iron, zinc and copper), which themselves are implicated in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Recent work has also shown that a single TBI can result in age-dependent and region-specific modulation of metal ions. As such, this review explores the linkage among TBI, CTE, aging, and neurodegeneration, with a specific focus on the involvement of (and interaction between) tau pathology and metal dyshomeostasis. The authors highlight that metal dyshomeostasis has yet to be investigated in the context of repeat head trauma or CTE. Given the evidence that metal dyshomeostasis contributes to the onset and/or progression of neurodegeneration, and that CTE itself is a neurodegenerative condition, this brings to light an uncharted link that should be explored. The development of adequate models of r-mTBI and/or CTE will be crucial in deepening our understanding of the pathological mechanisms that drive the clinical manifestations in these conditions and also in the development of effective therapeutics targeted toward slowing progressive neurodegenerative disorders.

Total plasma magnesium, zinc, copper and selenium concentrations in obese patients before and after bariatric surgery

Obesity enhances the risk of type-2 diabetes, cardiovascular disease and inflammatory conditions and often leads to metal dyshomeostasis, which contributes to the negative health aspects associated with the disease. In severe cases, bariatric surgery can be recommended to achieve sustained weight loss and improvement in health. Here, magnesium, zinc, copper and selenium concentrations were examined in 24 obese patients (7 males; 17 females) before and 9 months after undergoing Roux-en-Y gastric bypass surgery. All patients lost weight over this period, with the mean BMI reducing from 51.2±7.1 kg/m2 to 37.2±5.5 kg/m2. Moreover, whole-blood glycated haemoglobin (HbA1c), as a marker of average glycaemia, was also measured and a correlative analysis of this parameter with metal concentrations performed. Significant alterations in the plasma concentrations of magnesium, zinc (both increased by 13.2% and 25.2% respectively) and copper (decreased by 7.9%) were observed over this period (plasma selenium concentration was unchanged), with BMI values correlating with plasma magnesium (p = 0.004) and zinc (p = 0.022) concentrations. At 9 months post-surgery, an increase in mean zinc/copper ratio was observed (0.86±0.29 compared to 0.63±0.14 pre-surgery). Comparison of whole-blood HbA1c concentrations pre- and post-surgery revealed a reduction from 6.50±1.28% pre-surgery to 5.51±0.49% post-surgery. Differences in plasma HbA1c and magnesium at either pre- and post-surgery correlated significantly, as did HbA1c and magnesium levels when pre- and post-surgery values were analysed together. Collectively, this work reveals that bariatric surgery, in conjunction with lifestyle/dietary changes, lead to improvements in the nutritional status of magnesium, zinc and copper. Furthermore, the observed improvements in magnesium and zinc were associated with weight loss and in the case of magnesium, to better glycaemic control.

Nutrient-sensing amyloid metastasis.

Amyloids are organized suprastructural polypeptide arrangements. The prevalence of amyloid-related processes of pathophysiological relevance has been linked to aging-related degenerative diseases. Besides the role of genetic polymorphisms on the relative risk of amyloid diseases, the contributions of nongenetic ontogenic cluster of factors remain elusive. In recent decades, mounting evidences have been suggesting the role of essential micronutrients, in particular transition metals, in the regulation of amyloidogenic processes, both directly (such as binding to amyloid proteins) or indirectly (such as regulating regulatory partners, processing enzymes, and membrane transporters). The features of transition metals as regulatory cofactors of amyloid proteins and the consequences of metal dyshomeostasis in triggering amyloidogenic processes, as well as the evidences showing amelioration of symptoms by dietary supplementation, suggest an exaptative role of metals in regulating amyloid pathways. The self- and cross-talk replicative nature of these amyloid processes along with their systemic distribution support the concept of their metastatic nature. The role of amyloidosis as nutrient sensors would act as intra- and transgenerational epigenetic metabolic programming factors determining health span and life span, viability, which could participate as an evolutive selective pressure.