Imbalance of Essential Metals in Traumatic Brain Injury and Its Possible Link with Disorders of Consciousness.

Dysfunction of the complex cerebral networks underlying wakefulness and awareness is responsible for Disorders of Consciousness (DoC). Traumatic Brain Injury (TBI) is a common cause of DoC, and it is responsible for a multi-dimensional pathological cascade that affects the proper functioning of the brainstem and brain consciousness pathways. Iron (Fe), Zinc (Zn), and Copper (Cu) have a role in the neurophysiology of both the ascending reticular activating system, a multi-neurotransmitter network located in the brainstem that is crucial for consciousness, and several brain regions. We aimed to summarize the role of these essential metals in TBI and its possible link with consciousness alterations. We found that TBI alters many neuronal molecular mechanisms involving essential metals, causing neurodegeneration, neural apoptosis, synaptic dysfunction, oxidative stress, and inflammation. This final pattern resembles that described for Alzheimer's disease (AD) and other neurological and psychiatric diseases. Furthermore, we found that amantadine, zolpidem, and transcranial direct current stimulation (tDCS)-the most used treatments for DoC recovery-seem to have an effect on essential metals-related pathways and that Zn might be a promising new therapeutic approach. This review summarizes the neurophysiology of essential metals in the brain structures of consciousness and focuses on the mechanisms underlying their imbalance following TBI, suggesting their possible role in DoC. The scenario supports further studies aimed at getting a deeper insight into metals' role in DoC, in order to evaluate metal-based drugs, such as metal complexes and metal chelating agents, as potential therapeutic options.

Non-Ceruloplasmin Copper Identifies a Subtype of Alzheimer's Disease (CuAD): Characterization of the Cognitive Profile and Case of a CuAD Patient Carrying an RGS7 Stop-Loss Variant.

Alzheimer's disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin Cu (non-Cp Cu) levels were increased in serum/plasma samples. Non-Cp Cu was advocated as a stratification add-on biomarker of a Cu subtype of AD (CuAD subtype). To further circumstantiate this concept, we evaluated non-Cp Cu reliability in classifying subtypes of AD based on the characterization of the cognitive profile. The stratification of the AD patients into normal AD (non-Cp Cu ≤ 1.6 µmol/L) and CuAD (non-Cp Cu > 1.6 µmol/L) showed a significant difference in executive function outcomes, even though patients did not differ in disease duration and severity. Among the Cu-AD patients, a 76-year-old woman showed significantly abnormal levels in the Cu panel and underwent whole exome sequencing. The CuAD patient was detected with possessing the homozygous (c.1486T > C; p.(Ter496Argext*19) stop-loss variant in the RGS7 gene (MIM*602517), which encodes for Regulator of G Protein Signaling 7. Non-Cp Cu as an add-on test in the AD diagnostic pathway can provide relevant information about the underlying pathological processes in subtypes of AD and suggest specific therapeutic options.

Regulatory miRNAs in Cardiovascular and Alzheimer's Disease: A Focus on Copper.

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs' functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer's disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs.

Plastic and Placenta: Identification of Polyethylene Glycol (PEG) Compounds in the Human Placenta by HPLC-MS/MS System.

The placenta is a crucial interface between the fetus and the maternal environment. It allows for nutrient absorption, thermal regulation, waste elimination, and gas exchange through the mother's blood supply. Furthermore, the placenta determines important adjustments and epigenetic modifications that can change the phenotypic expression of the individual even long after birth. Polyethylene glycol (PEG) is a polyether compound derived from petroleum with many applications, from medicine to industrial manufacturing. In this study, for the first time, an integration of ultra-high-performance liquid chromatography (UHPLC) coupled with mass spectrometry (MS) was used to detect suites of PEG compounds in human placenta samples, collected from 12 placentas, originating from physiological pregnancy. In 10 placentas, we identified fragments of PEG in both chorioamniotic membranes and placental cotyledons, for a total of 36 samples.

GSTA1*-69C/T and GSTO2*N142D as asthma- and allergy-related risk factors in Italian adult patients.

1. Asthma and allergies are characterized by variable and subjective symptoms influenced by many genes, molecular mechanisms and environmental factors. The presence of inflammation and oxidative stress in the airways are important biochemical features of asthma and respiratory allergies. Glutathione S-transferase (GSTs) enzymes play an important role in cellular protection against inflammation, and functional genetic polymorphisms in GST genes show a significant association with asthma and allergy risk. Specifically, our previous study on asthmatic children highlighted GSTA1 and GSTO2 as novel susceptibility loci for asthma. 2. In the present study we focused our attention on GSTA1*-69C/T (rs3957357) and GSTO2*N142D (rs156697) polymorphisms to confirm our previous results in an independent adult study population and to clarify whether GSTA1 and GSTO2 gene polymorphisms are involved in a non-discriminative pathway towards asthma and respiratory allergy. 3. To accomplish this, we recruited 103 patients with respiratory allergies, 199 patients with asthma and 200 healthy controls. Genomic DNA extracted from buccal cells was screened for GSTA1*-69C/T and GSTO2*N142D single nucleotide polymorphisms. 4. The GSTA1*-69T and GSTO2*D142 variants are both associated with a significantly increased risk of asthma, whereas only GSTA1*-69C/T is significantly associated with allergies. These outcomes confirm the involvement of GSTO2 loci in asthma and suggest that GSTA1 is a common risk factor for asthma and allergies.

Copper excess in psychiatric disorders: a focus on mood spectrum disorders and sex.

BACKGROUND: Meta-analyses show increased copper (Cu) levels in major depression disorder. However, the association of Cu biomarkers with clinical classification in other mental health disorders has not been fully explored. METHODS: To this aim, we compared an extensive panel of Cu biomarkers, composed of Cu, ceruloplasmin (Cp) Cp activity, Cp specific activity, Cu not bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in 171 consecutive patients affected by psychiatric disorders and in 61 healthy controls (HC) using MANOVA adjusting for the effect of sex and age, and studied their association with the clinical scale outcomes at psychiatric examination, namely Global Assessment of Functioning, Clinical Global Impression, and Brief Psychiatric Rating Scale. RESULTS: individuals with psychiatric disorders were classified as 109 patients affected by mood spectrum disorders (MSD), 20 patients with schizophrenia spectrum disorders (SSD), and 42 with personality disorders (PD). Cu and non-Cp Cu were increased in psychiatric individuals than in HC, which also differed among the patients stratified per the clinical classification, being higher in the MSD individuals. The analysis stratified for sex revealed that women from the patient group, and specifically from the MSD group, had increased levels of Cu and non-Cp Cu than healthy women, while no difference was revealed in men. A logistic regression model considering the effect of sex and age revealed that non-Cp Cu could explain 26 % increased odds of having MSD per µmol/L unit increase (OR = 1.26; p = 0.0008; 95 % CI 1.099-1.436), that reached 40 % when considering only women. This result was driven by non-Cp Cu that correctly classified 64.1 % MSD (70 % in women) individuals vs. HC in a decision tree model, with values higher than 2.1 µmol/L which could distinguish the majority of MSD patients (86.3 % MSD vs. 13.7 % HC in women). None of the biological variables under study correlated with outcomes of the clinical scales, substances, or alcohol abuse. CONCLUSION: Current results suggest mild Cu toxicity in women with MSD, as revealed by a value of non-Cp Cu higher than 2.1 µmol/L, which can be further investigated to assess its potential diagnostic accuracy in bigger and longitudinal cohorts.

The Debated Issue on Tissue Copper Levels in Colorectal Cancer Patients: A Meta-analysis and Replication Study.

Colorectal cancer (CRC) is a growing public health problem. Several clinical studies have shown a potentially oncogenic role of copper in CRC progression, but the reports are inconsistent. To examine published evidence on the association between tissue copper status and CRC, we carried out a systematic review and meta-analysis, searching Cochrane Library, EBSCOhost, Embase, ProQuest, PubMed/Medline, Scopus, and Web of Science for studies reporting colon tumor and matched non-cancerous tissue copper concentrations in CRC patients for articles published till June 2023. Based on a random effects model, standardized mean differences (SMD) were assessed. We also completed a replication study on 17 CRC patients that analyzed copper levels in both cancer tissue specimens and healthy mucosa dissected from the same patient. Thirteen studies investigating copper levels (including the replication study) in colorectal specimens from a pooled total of 312 CRC and 298 healthy mucosa were selected. Our meta-analysis estimated a high between-study heterogeneity (I2 = 96%) and lower levels of copper in CRC tissue cancer specimens than in matched healthy mucosa: the decrease was equal to - 0.74 (95% CI, - 2.18; 0.71) but was not significant. The replication study showed a significant decrease in tissue cancer specimens. Sensitivity analyses of the meta-analysis revealed that pre-analytical methodology for tissue preparation significantly reduced the between-study heterogeneity strongly influencing copper levels (p < 0.01), indicating a copper decrease in the cytoplasmic copper pool of the tumor tissue suggesting a rapid turnover of the metal in cancer cells.

Serum copper status of patients with colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and a public health problem. Several clinical studies have shown that copper (Cu) is involved in carcinogenesis, possibly via cuproptosis, a new form of programmed cell death, but the conclusions from published reports are inconsistent. This study aimed at evaluating the potential of Cu dysregulation as a CRC susceptibility factor. METHODS: In this systematic review and meta-analysis, we searched Cochrane Library, EBSCOhost, EMBASE, ProQuest, PubMed/MEDLINE, Scopus, and Web of Science for studies reporting serum Cu concentrations in CRC patients and controls from articles published till June 2023. The studies included reported measurements of serum/plasma/blood Cu levels. Meta-analyses were performed as well as study quality, heterogeneity, and small study effects were assessed. Based on a random effects model, summary standardized mean differences (SMDs) and the corresponding 95% confidence intervals (95% CIs) were applied to compare the levels of Cu between CRC patients and controls. RESULTS: 26 studies with a pooled total of9628 participants and 2578 CRC cases were included. The pooled SMD was equal to 0.85 (95% CIs -0.44; 2.14) showing that the CRC patients had higher mean Cu levels than the control subjects, but the difference was not significant (p = 0.185) and the heterogeneity was very high, I2 = 97.9% (95% CIs: 97.5-98.3%; p < 0.001). CONCLUSION: The pooled results were inconclusive, likely due to discordant results and inaccuracy in reporting data of some studies; further research is needed to establish whether Cu dysregulation might contribute to the CRC risk and whether it might reflect different CRC grades.

Selenium levels in colorectal cancer: A systematic review and meta-analysis of serum, plasma, and colorectal specimens.

BACKGROUND: Colorectal cancer (CRC) is a growing public health problem. Several clinical studies have shown a potentially protective effect of selenium (Se), but the reports are inconsistent. The objective of the study was to examine the evidence for relation between serum/tissue Se status and CRC. METHOD AND MATERIALS: In this Systematic Review and Meta-Analysis, we searched Cochrane Library, EBSCOhost, EMBASE, ProQuest, PubMed/MEDLINE, Scopus, and Web of Science for studies reporting serum/plasma/whole blood/tissue Se concentrations in CRC patients and controls for articles published till August 2023. Meta-analysis was performed, and study quality, heterogeneity, and small study effects were assessed. Based on a random effects model, summary mean differences in serum levels of Se between CRC patients and healthy controls, and Se levels between malignant and matched non-malignant tissue specimens were assessed. RESULTS: After initial screening, a total of 24 studies (18 serum and 6 tissue studies) with a pooled total of 2640 participants were included in the meta-analysis. CRC patients had significantly lower serum Se levels than healthy controls, being the difference between the two equal to 3.73 µg/dl (95% CI: 6.85-0.61). However, the heterogeneity was very high, I2= 99% (p < 0.01). Our meta-analysis showed higher Se levels in CRC cancerous specimens than in matched healthy colon tissue: the increase was equal to 0.07 µg/g wet tissue weight (95% CI: 0.06-0.09; p= 0.02). CONCLUSIONS: CRC patients have lower serum and higher colon cancerous tissue Se levels. Some factors, such as Se levels in different tumor grades of CRC need to be further considered for a more conclusive association between Se levels and risk of CRC.

Might Diet, APOE-APOA1 Axis, and Iron Metabolism Provide Clues About the Discrepancy in Alzheimer's Disease Occurrence Between Humans and Chimpanzees? A Bioinformatics-Based Re-Analysis of Gene Expression Data on Mice Fed with Human and Chimpanzee Diets.

The emergence of conflicting reports on the natural occurrence of Alzheimer's disease (AD) in non-human primates has prompted research on the comparison of the role of diet-associated changes in gene expression between humans and non-human primates. This article analyzes the effects of different human and chimpanzee diets and their link with apolipoproteins, lipid, and iron (Fe) metabolism, starting from available data, to find out any gap in the existing knowledge. By using a system biology approach, we have re-analyzed the liver and brain RNA seq data of mice fed with either human or chimpanzee diet for 2 weeks to look for genetic differences that may explain the differences in AD occurrence between those two classes. In liver samples of mice fed with the chimpanzee diet in comparison to the human diet, apolipoprotein A-1, ceruloplasmin, and 10 other genes were upregulated while 21 genes were downregulated. However, brain apolipoprotein E4 gene expression was not changed upon diet. Genetic, structural, and functional differences in apolipoprotein E protein, along with differences in Fe metabolisms and a longer lifespan of humans during evolution may account for the observed disparity.

Iron in Alzheimer's Disease: From Physiology to Disease Disabilities.

Reactive oxygen species (ROS) play a key role in the neurodegeneration processes. Increased oxidative stress damages lipids, proteins, and nucleic acids in brain tissue, and it is tied to the loss of biometal homeostasis. For this reason, attention has been focused on transition metals involved in several biochemical reactions producing ROS. Even though a bulk of evidence has uncovered the role of metals in the generation of the toxic pathways at the base of Alzheimer's disease (AD), this matter has been sidelined by the advent of the Amyloid Cascade Hypothesis. However, the link between metals and AD has been investigated in the last two decades, focusing on their local accumulation in brain areas known to be critical for AD. Recent evidence revealed a relation between iron and AD, particularly in relation to its capacity to increase the risk of the disease through ferroptosis. In this review, we briefly summarize the major points characterizing the function of iron in our body and highlight why, even though it is essential for our life, we have to monitor its dysfunction, particularly if we want to control our risk of AD.

Evaluation of zinc, copper, and Cu:Zn ratio in serum, and their implications in the course of COVID-19.

BACKGROUND: The dynamics of essential metals such as Copper (Cu) and Zinc (Zn) may be associated with the novel coronavirus disease 2019 (COVID-19) that has spread across the globe. OBJECTIVES: The aim of this study is to investigate the relationship between serum levels of Cu and Zn, as well as the Cu:Zn ratio in the acute phase of COVID-19 along with the assessment of their connection to other laboratory parameters (hematological, biochemical, hemostatic). METHODS: Serum levels of Cu and Zn were measured by atomic absorption spectrometry in 75 patients in the acute COVID-19 phase and were compared with those of 22 COVID-19 patients evaluated three months after the acute phase of the disease ('non-acute' group) and with those of 68 healthy individuals. RESULTS: In comparison with both the non-acute patients and the healthy controls, the acute patients had lower levels of hemoglobulin and albumin, and higher levels of glucose, creatinine, liver transaminases, C-reactive protein (CRP), and higher values of the neutrophils to lymphocytes ratio (NLR) at the hospital admission. They also exhibited increased levels of Cu and decreased of Zn, well represented by the Cu:Zn ratio which was higher in the acute patients than in both non-acute patients (p = 0.001) and healthy controls (p < 0.001), with no statistical difference between the last two groups. The Cu:Zn ratio (log scale) positively correlated with CRP (log scale; r = 0.581, p < 0.001) and NLR (r = 0.436, p = 0.003). CONCLUSION: Current results demonstrate that abnormal dynamics of Cu and Zn levels in serum occur early during the course of COVID-19 disease, and are mainly associated with the inflammation response.

Copper in tumors and the use of copper-based compounds in cancer treatment.

Copper homeostasis is strictly regulated by protein transporters and chaperones, to allow its correct distribution and avoid uncontrolled redox reactions. Several studies address copper as involved in cancer development and spreading (epithelial to mesenchymal transition, angiogenesis). However, being endogenous and displaying a tremendous potential to generate free radicals, copper is a perfect candidate, once opportunely complexed, to be used as a drug in cancer therapy with low adverse effects. Copper ions can be modulated by the organic counterpart, after complexed to their metalcore, either in redox potential or geometry and consequently reactivity. During the last four decades, many copper complexes were studied regarding their reactivity toward cancer cells, and many of them could be a drug choice for phase II and III in cancer therapy. Also, there is promising evidence of using 64Cu in nanoparticles as radiopharmaceuticals for both positron emission tomography (PET) imaging and treatment of hypoxic tumors. However, few compounds have gone beyond testing in animal models, and none of them got the status of a drug for cancer chemotherapy. The main challenge is their solubility in physiological buffers and their different and non-predictable mechanism of action. Moreover, it is difficult to rationalize a structure-based activity for drug design and delivery. In this review, we describe the role of copper in cancer, the effects of copper-complexes on tumor cell death mechanisms, and point to the new copper complexes applicable as drugs, suggesting that they may represent at least one component of a multi-action combination in cancer therapy.

Deeply in Plasticenta: Presence of Microplastics in the Intracellular Compartment of Human Placentas.

Microplastics (MPs) are defined as plastic particles smaller than 5 mm. They have been found almost everywhere they have been searched for and recent discoveries have also demonstrated their presence in human placenta, blood, meconium, and breastmilk, but their location and toxicity to humans have not been reported to date. The aim of this study was twofold: 1. To locate MPs within the intra/extracellular compartment in human placenta. 2. To understand whether their presence and location are associated with possible structural changes of cell organelles. Using variable pressure scanning electron microscopy and transmission electron microscopy, MPs have been localized in ten human placentas. In this study, we demonstrated for the first time the presence and localization in the cellular compartment of fragments compatible with MPs in the human placenta and we hypothesized a possible correlation between their presence and important ultrastructural alterations of some intracytoplasmic organelles (mitochondria and endoplasmic reticulum). These alterations have never been reported in normal healthy term pregnancies until today. They could be the result of a prolonged attempt to remove and destroy the plastic particles inside the placental tissue. The presence of virtually indestructible particles in term human placenta could contribute to the activation of pathological traits, such as oxidative stress, apoptosis, and inflammation, characteristic of metabolic disorders underlying obesity, diabetes, and metabolic syndrome and partially accounting for the recent epidemic of non-communicable diseases.

Microglia and Astrocytes in Alzheimer's Disease in the Context of the Aberrant Copper Homeostasis Hypothesis.

Evidence of copper's (Cu) involvement in Alzheimer's disease (AD) is available, but information on Cu involvement in microglia and astrocytes during the course of AD has yet to be structurally discussed. This review deals with this matter in an attempt to provide an updated discussion on the role of reactive glia challenged by excess labile Cu in a wide picture that embraces all the major processes identified as playing a role in toxicity induced by an imbalance of Cu in AD.

Non-Ceruloplasmin Copper as a Stratification Biomarker of Alzheimer's Disease Patients: How to Measure and Use It.

Alzheimer's Disease (AD) is a type of dementia very common in the elderly. A growing body of recent evidence has linked AD pathogenesis to Copper (Cu) dysmetabolism in the body. In fact, a subset of patients affected either by AD or by its prodromal form known as Mild Cognitive Impairment (MCI) have been observed to be unable to maintain a proper balance of Cu metabolism and distribution and are characterized by the presence in their serum of increased levels of Cu not bound to ceruloplasmin (non-ceruloplasmin Cu). Since serum non-ceruloplasmin Cu is a biomarker of Wilson's Disease (WD), a well-known condition of Cu-driven toxicosis, in this review, we propose that in close analogy with WD, the assessment of non-ceruloplasmin Cu levels can be exploited as a cost-effective stratification and susceptibility/risk biomarker for the identification of some AD/MCI individuals. The approach can also be used as an eligibility criterion for clinical trials aiming at investigating Cu-related interventions against AD/MCI.

Zinc and COVID-19: Basis of Current Clinical Trials.

Coronavirus disease-2019 (COVID-19) pandemic continues to threaten patients, societies, and economic and healthcare systems around the world. Like many other diseases, the host immune system determines the progress of COVID-19 and fatality. Modulation of inflammatory response and cytokine production using immunonutrition is a novel concept that has been applied to other diseases as well. Zinc, one of the anti-inflammatory and antioxidant micronutrient found in food with well-established role in immunity, is currently being used in some clinical trials against COVID-19. This review integrates the contemporary studies of role of zinc in antiviral immunity along with discussing its potential role against COVID-19, and ongoing COVID-19 clinical trials using zinc.

Copper Imbalance in Alzheimer's Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants.

Evidence indicates that patients with Alzheimer's dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

Plasticenta: First evidence of microplastics in human placenta.

Microplastics are particles smaller than five millimeters deriving from the degradation of plastic objects present in the environment. Microplastics can move from the environment to living organisms, including mammals. In this study, six human placentas, collected from consenting women with physiological pregnancies, were analyzed by Raman Microspectroscopy to evaluate the presence of microplastics. In total, 12 microplastic fragments (ranging from 5 to 10 µm in size), with spheric or irregular shape were found in 4 placentas (5 in the fetal side, 4 in the maternal side and 3 in the chorioamniotic membranes); all microplastics particles were characterized in terms of morphology and chemical composition. All of them were pigmented; three were identified as stained polypropylene a thermoplastic polymer, while for the other nine it was possible to identify only the pigments, which were all used for man-made coatings, paints, adhesives, plasters, finger paints, polymers and cosmetics and personal care products.