The impact of glutathione metabolism in autism spectrum disorder.

This paper reviews the potential role of glutathione (GSH) in autism spectrum disorder (ASD). GSH plays a key role in the detoxification of xenobiotics and maintenance of balance in intracellular redox pathways. Recent data showed that imbalances in the GSH redox system are an important factor in the pathophysiology of ASD. Furthermore, ASD is accompanied by decreased concentrations of reduced GSH in part caused by oxidation of GSH into glutathione disulfide (GSSG). GSSG can react with protein sulfhydryl (SH) groups, thereby causing proteotoxic stress and other abnormalities in SH-containing enzymes in the brain and blood. Moreover, alterations in the GSH metabolism via its effects on redox-independent mechanisms are other processes associated with the pathophysiology of ASD. GSH-related regulation of glutamate receptors such as the N-methyl-D-aspartate receptor can contribute to glutamate excitotoxicity. Synergistic and antagonistic interactions between glutamate and GSH can result in neuronal dysfunction. These interactions can involve transcription factors of the immune pathway, such as activator protein 1 and nuclear factor (NF)-κB, thereby interacting with neuroinflammatory mechanisms, ultimately leading to neuronal damage. Neuronal apoptosis and mitochondrial dysfunction are recently outlined as significant factors linking GSH impairments with the pathophysiology of ASD. Moreover, GSH regulates the methylation of DNA and modulates epigenetics. Existing data support a protective role of the GSH system in ASD development. Future research should focus on the effects of GSH redox signaling in ASD and should explore new therapeutic approaches by targeting the GSH system.

Calanus oil in the treatment of obesity-related low-grade inflammation, insulin resistance, and atherosclerosis.

Calanus oil (COil) is a natural product extracted from marine zooplankton Calanus finmarchicus found in the North Atlantic Ocean. This oil is rich in wax esters of polyunsaturated fatty acids (PUFAs) and has been projected as the best alternative to fish oil because its production cannot keep pace with the demands from the growing markets. The COil is the only commercially available marine source of wax esters, whereas classic ω-3 PUFAs comes from triglycerides, ethyl esters, and phospholipids. It has, in recent decades, been seen that there is an unprecedented rise in the use of PUFA-rich oil in the aquaculture industry. A simultaneous rise in the demand of PUFAs is also observed in the health care industry, where PUFAs are suggested preventing various disorders related to lifestyles such as obesity, diabetes mellitus, chronic low-grade inflammation, atherosclerosis, and brain and cardiovascular disorders (CVDs). In this review, we will explore the metabolic aspects related to the use of COil as an antioxidant, anticholesterinemic, and anti-inflammatory dietary source and its impact on the prevention and therapy of obesity-related metabolic disorders.

COVID-19 Medical and Pharmacological Management in the European Countries Compared to Italy: An Overview.

(1) Background: Italy accounts for more than 150,000 deaths due to the COVID-19 pandemic, leading the top rank in SARS-CoV-2-caused deceases in Europe. A survey on the different ways by which the COVID-19 pandemic emergency was managed in the foreign European countries compared to Italy is the purpose of this paper. (2) Methods: A literature search and various mathematical algorithms to approach a rank scoring scale were used to describe in detail the different approaches used by European countries to manage the COVID-19 pandemic emergency. (3) Results: The study showed that Italy stands at the bottom ranking for COVID-19 management due to its high mortality rate. Possible causes of the observed huge numbers of hospitalization and deaths were (a) the demographic composition of the European country; (b) its decentralized healthcare system organization; (c) the role of correct pharmacology in the early stages before hospitalization. Post-mortem examinations were of paramount importance to elucidate the etiopathogenesis of COVID-19 and to tailor a suitable and proper therapy in the early symptomatic stages of COVID-19, preventing hospitalization. (4) Conclusions: Factors such as the significant impact on elderly people, the public health organization prevalently state-owned and represented mainly by hospitals, and criticism of the home therapy approach toward SARS-CoV-2-infected people, may have concurred in increasing the number of COVID-19 deaths in Italy.

Home pharmacological therapy in early COVID-19 to prevent hospitalization and reduce mortality: Time for a suitable proposal.

The COVID-19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post-mortem autopsy was performed on a very modest number of patients who died from COVID-19 infection, leading to a first confirmation of an immune-thrombosis of the lungs as the major COVID-19 pathogenesis, likewise for SARS. Since then (June-August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti-inflammatory, anti-platelet, anticoagulant and antibiotic therapy confirmed that COVID-19 was an endothelial inflammation with immuno-thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immune-thrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti-inflammatory therapy may treat endothelia inflammation and immune-thrombosis caused by COVID-19, by using drugs we are going to recommend in this paper.

Insights into the Effects of Dietary Omega-6/Omega-3 Polyunsaturated Fatty Acid (PUFA) Ratio on Oxidative Metabolic Pathways of Oncological Bone Disease and Global Health.

Various nutrients have been designated as antioxidants, with a possible effect on diseases like cancer. This is partly due to their effect on prostaglandins, thereby affecting local pathological metabolic acidosis. This paper aims to summarize the culprit pathophysiological mechanisms involved, with a focus on the bone microenvironment. The omega- 6/omega-3 PUFA ratio is particularly investigated for its antioxidative effects, countering these pathways to fight the disease. This feature is looked at concerning its impact on health in general, with a particular focus on malignant bone metastasis.

Relationship between gestational diabetes and serum trace element levels in pregnant women from Eastern Iran: a multivariate approach.

The prevalence of gestational diabetes mellitus (GDM) has increased over the recent decades. Exposure to environmental contaminants may be a risk factor for the development of GDM, but this is heavily dependent on particular circumstances. Studies on various areas linking various factors are therefore needed. We examined the associations between serum trace element levels and incidents of GDM among 102 pregnant women (diabetic n = 60 and healthy n = 42) living in Birjand (Iran). Blood serum samples were analyzed for concentrations of elements linked to particulate matter air pollution such as As, Cd, Cu, Hg, Mn, Ni, V, and Zn. Concentrations of As (8.58 vs. 3.15 µg/L), Cd (6.74 vs. 0.52 µg/L), and Hg (2.60 vs. 0.90 µg/L) were significantly higher in women with GDM. Risk difference (RD) estimation showed that As, 0.516 (0.355, 0.677); Cd, 0.719 (0.534, 0.904); and Hg, 0.505 (0.276, 0.735) increase GDM probability, while V lower that risk, -0.139 (-0.237, -0.042). With the principal component analysis, we were able to separate subjects according to their GDM status based on element levels. Such classification revealed very high efficiency with a true positive rate of 93%, according to linear discriminant analysis. GDM subjects presented higher levels of As, Cd, and Hg, indicating that these elements may disturb insulin metabolism and promote the development of GDM. Therefore, we conclude that systematic monitoring of trace elements followed by multivariate modeling in women planning pregnancy should be carried out to prevent the development of GDM.

GABA synaptopathy promotes the elevation of caspases 3 and 9 as pro-apoptotic markers in Egyptian patients with autism spectrum disorder.

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder characterized by reduced social communication as well as repetitive behaviors. Many studies have proved that defective synapses in ASD influence how neurons in the brain connect and communicate with each other. Synaptopathies arise from alterations that affecting the integrity and/or functionality of synapses and can contribute to synaptic pathologies. This study investigated the GABA levels in plasma being an inhibitory neurotransmitter, caspase 3 and 9 as pro-apoptotic proteins in 20 ASD children and 20 neurotypical controls using the ELISA technique. Analysis of receiver-operating characteristic (ROC) of the data that was obtained to evaluate the diagnostic value of the aforementioned evaluated biomarkers. Pearson's correlations and multiple regressions between the measured variables were also done. While GABA level was reduced in ASD patients, levels of caspases 3 and 9 were significantly higher when compared to neurotypical control participants. ROC and predictiveness curves showed that caspases 3, caspases 9, and GABA might be utilized as predictive markers in autism diagnosis. The present study indicates that the presence of GABAergic dysfunction promotes apoptosis in Egyptian ASD children. The obtained GABA synaptopathies and their connection with apoptosis can both relate to neuronal excitation, and imbalance of the inhibition system, which can be used as reliable predictive biomarkers for ASD.

Environmental, Neuro-immune, and Neuro-oxidative Stress Interactions in Chronic Fatigue Syndrome.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS) is a complex, multisystem disease that is characterized by long-term fatigue, exhaustion, disabilities, pain, neurocognitive impairments, gastrointestinal symptoms, and post-exertional malaise, as well as lowered occupational, educational, and social functions. The clinical and biomarker diagnosis of this disorder is hampered by the lack of validated diagnostic criteria and laboratory tests with adequate figures of merit, although there are now many disease biomarkers indicating the pathophysiology of CFS. Here, we review multiple factors, such as immunological and environmental factors, which are associated with CFS and evaluate current concepts on the involvement of immune and environmental factors in the pathophysiology of CFS. The most frequently reported immune dysregulations in CFS are modifications in immunoglobulin contents, changes in B and T cell phenotypes and cytokine profiles, and decreased cytotoxicity of natural killer cells. Some of these immune aberrations display a moderate diagnostic performance to externally validate the clinical diagnosis of CFS, including the expression of activation markers and protein kinase R (PKR) activity. Associated with the immune aberrations are activated nitro-oxidative pathways, which may explain the key symptoms of CFS. This review shows that viral and bacterial infections, as well as nutritional deficiencies, may further aggravate the immune-oxidative pathophysiology of CFS. Targeted treatments with antioxidants and lipid replacement treatments may have some clinical efficacy in CFS. We conclude that complex interactions between immune and nitro-oxidative pathways, infectious agents, environmental factors, and nutritional deficiencies play a role in the pathophysiology of CFS.

The Role of Zinc and Copper in Insulin Resistance and Diabetes Mellitus.

The prevalence of Type 2 Diabetes Mellitus (T2DM) is internationally ever-growing. Therefore, prevention, diagnostics, and control of insulin resistance and T2DM are of increasing importance. It has been suggested that mechanisms leading to insulin resistance and diabetes and its complications include high intake of refined and energy-rich food, which is presumed to be accompanied by suboptimal intake of trace elements, such as Zinc (Zn), Selenium (Se), Chromium (Cr), and Copper (Cu), which are essential and crucial for various biological processes. The purpose of this review is to highlight the role of Zn, Se, and Cu in T2DM. Diabetes seems prevalent when Zn, Se, and Cu are deficient, which may result from excessive intake of refined food. The literature search was conducted in PubMed and Scopus, supplemented with the reference lists of relevant articles and a Google Scholar search. We critically assessed all relevant citations, both review and research papers in English. The search terms that were used included Zn, Cu, diabetes, and diabetes mellitus. Research has shown that Zn, Se and Cu are involved in the pathogenesis of diabetes, but these trace elements can in excessive amounts be toxic. Zinc appears to activate key molecules that are involved in cell signaling, which maintain the homeostasis of glucose. Zinc also regulates insulin receptors, prolong the action of insulin, and promote healthy lipid profiles. Copper in excess can create oxidative stress, which is a factor in the onset and the progression of T2DM. Abnormal Zn and Cu metabolism appears to accompany and may also cause diabetes complications.

High Levels of Glycosaminoglycans in the Urines of Children with Attention-Deficit/Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral/neurodevelopmental disorder. Some early studies indicated that increased intake of added sugars might have a role in ADHD. In the present study, we tested this possibility by evaluating the urinary excretion of oligosaccharides and glycosaminoglycans (GAGs) in ADHD and control subjects. Forty ADHD subjects matched with 34 controls were enrolled in the study. The subjects underwent a standardized dietary regimen. The urine levels of oligosaccharides and GAGs were quantified biochemically, and their covariance and association were evaluated statistically. Fructose (21/40, 52.5%), maltose (26/40, 65%), galactose (30/40, 75%), and lactose (38/40, 95%) excretions were frequently found in the urine of ADHD subjects (p < 0.05), an excretion which does not occur normally. Furthermore, these subjects showed a pathologic tGAG (glycosaminoglycan) excretion (40/40, 100%). The present study supports the thesis that carbohydrate metabolism differs in ADHD subjects compared with control subjects.

Copper Concentrations in Breast Cancer: A Systematic Review and Meta-Analysis.

Breast cancer is the most common neoplasm, comprising 16% of all women's cancers worldwide. Research of Copper (Cu) concentrations in various body specimens have suggested an association between Cu levels and breast cancer risks. This systematic review and meta-analysis summarize the results of published studies and examine this association. We searched the databases PubMed, Scopus, Web of Science, and Google Scholar and the reference lists of relevant publications. The Standardized Mean Differences (SMDs) between Cu levels in cancer cases and controls and corresponding Confidence Intervals (CIs), as well as I2 statistics, were calculated to examine heterogeneity. Following the specimens used in the original studies, the Cu concentrations were examined in three subgroups: serum or plasma, breast tissue, and scalp hair. We identified 1711 relevant studies published from 1984 to 2017. There was no statistically significant difference between breast cancer cases and controls for Cu levels assayed in any studied specimen; the SMD (95% CI) was -0.01 (-1.06 - 1.03; P = 0.98) for blood or serum, 0.51 (-0.70 - 1.73; P = 0.41) for breast tissue, and -0.88 (-3.42 - 1.65; P = 0.50) for hair samples. However, the heterogeneity between studies was very high (P < 0.001) in all subgroups. We did not find evidence for publication bias (P = 0.91). The results of this meta-analysis do not support an association between Cu levels and breast cancer. However, due to high heterogeneity in the results of original studies, this conclusion needs to be confirmed by well-designed prospective studies.

Insights on Nutrients as Analgesics in Chronic Pain.

Many serious inflammatory disorders and nutrient deficiencies induce chronic pain, and anti-inflammatory diets have been applied successfully to modify the inflammatory symptoms causing chronic pain. Numerous scientific data and clinical investigations have demonstrated that long-term inflammation could lead to an inappropriate or exaggerated sensibility to pain. In addition, some Non-steroidal Anti-inflammatory Drugs (NSAID), which directly act on the many enzymes involved in pain and inflammation, including cyclooxygenases, are used to dampen the algesic signal to the central nervous system, reducing the responses of soft C-fibers to pain stimuli. On the other hand, there are a few reports from both health authorities and physicians, reporting that decreased transmission of pain signals can be achieved and improved, depending on the patient's dietary habit. Many nutrients, as well as a suitable level of exercise (resistance training), are the best methods for improving the total mitochondrial capacity in muscle cells, which can lead to a reduction in sensitivity to pain, particularly by lowering the inflammatory signaling to C-fibers. According to the current literature, it could be proposed that chronic pain results from the changed ratio of neuropeptides, hormones, and poor nutritional status, often related to an underlying inflammatory disorder. The current review also evaluates the effective role of nutrition-related interventions on the severity of chronic pain. This review pointed out that nutritional interventions can have a positive effect on pain experience through the indirect inhibitory effect on prostaglandin E2 and attenuation of mitochondrial dysfunction caused by ischemia/reperfusion in skeletal muscle, improving the intracellular antioxidant defense system. These data highlight the need for more nutrition studies where chronic pain is the primary outcome, using accurate interventions. To date, no nutritional recommendation for chronic pain has been officially proposed. Therefore, the goal of this article is to explore pain management and pain modulation, searching for a mode of nutrition efficient in reducing pain.

Zinc, copper, and oxysterol levels in patients with type 1 and type 2 diabetes mellitus.

BACKGROUND: The present study has the objective to assess the zinc (Zn), copper (Cu), and oxysterols plasma levels in type 1 (DM1) (n = 26) and type 2 (DM2) (n = 80) diabetes patients, as compared to healthy controls (n = 71), in order to testify whether metal levels may have a significant impact on the association between oxysterols and diabetes. METHODS: Plasma trace elements and plasma oxysterols were assessed using atomic absorption spectrometry and LC-MS/MS, respectively. Lifestyle, smoking status, alcohol intake, and drug usage, as well as microvascular complications, were also monitored and reported. RESULTS: The obtained data demonstrated that both DM1 and DM2 patients were characterized by significantly elevated HbA1c, FBG, TC, LDL-C, VLDL-C, and TG levels as compared to controls. Plasma Zn levels and Zn/Cu ratio in DM1 and DM2 patients were about 3- and 2-fold lower than controls. No significant differences in plasma Cu levels were reported. The 7-ketocholesterol (7-kchol) levels in DM1 and DM2 patients exceeded these values in healthy individuals by 2.5 and 5-fold, respectively. Similarly, cholestan-3ß, 5α, 6ß-triol (chol-triol) levels were more than 3- and 6-fold higher when compared to the respective values in non-diabetic controls. In regression models decreased plasma Zn and elevated oxysterol levels were significantly associated with HbA1c and fasting plasma glucose levels, after adjustment for anthropometric and clinical variables, as well as routine biochemical markers. CONCLUSIONS: Plasma Zn concentration is inversely associated with both 7-kchol and chol-triol levels. Assessment of Zn and oxysterol levels may be used both for risk assessment and as targets for the treatment of diabetes mellitus.

Iron Deficiency, Cognitive Functions, and Neurobehavioral Disorders in Children.

More than 25% of the world's population is affected by anemia, of which more than 50% suffers from iron deficiency anemia (IDA). Children below 7 years of age are the population group that is most vulnerable to iron deficiency. Iron is an essential element in brain metabolism. Iron deficiency can cause changes in neurotransmitter homeostasis, decrease myelin production, impair synaptogenesis, and decline the function of the basal ganglia. Therefore, IDA adversely affects cognitive functions and psychomotor development. Research has shown that iron deficiency is a frequent comorbidity in attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder. Iron deficiency may also induce or exacerbate deficiency of other essential nutrients, which may have a negative impact on the developing brain and other organs in infants. Many nations of the world have programs to control IDA based on the use of iron supplementation, intake of fortified food and drinks, improved food safety, and monitoring of dietary diversity. Based on the current recommendations of the World Health Organization on cost-effectiveness (WHO-CHOICE), iron fortification and iron supplementation programs can be considered cost-effective or even highly cost-effective in most countries of the world to averting cognitive impairment.

Does diet play a role in reducing nociception related to inflammation and chronic pain?

Dietary habits are fundamental issues to assess when modulating health and well-being; however, different nutritional panels may help individuals prevent acute and chronic pain. Many substances, known to be active antioxidants and anti-inflammatory compounds, should serve this fundamental task. Antinociceptive and analgesic natural compounds include flavonoids, terumbone from ginger root, curcuminoids, ω-3 polyunsaturated fatty acids, and taurine. Furthermore, correct intake of trace elements and minerals is strategic to reduce inflammation-related pain. This review addresses these items in an effort to suggest new criteria for proper dietary supplementation to prevent pain.

The role of zinc supplementation on the metallothionein system in children with autism spectrum disorder.

The present research was carried out to elucidate the role of zinc (Zn) supplementation on the plasma concentration and gene expression, as well as the effects on cognitive-motor performance, in a cohort of children with autism spectrum disorder (ASD). The study was performed on a cohort of 30 pediatric subjects with ASD, encompassing an age range of 3-8 years. The impact of Zn supplementation was investigated in 3 months (or 12 weeks) on the ASD children. Each daily dosage of Zn was calculated as being equal to the body weight in kg plus 15-20 mg. The effect of Zn was also evaluated on the serum level of metallothionein 1 (MT-1A), and the severity of autism via scores on the Childhood Autism Rating Scale. The effect of Zn was investigated on the gene expression of MT1-A before and after Zn supplementation. The data of the present study showed an increase in cognitive-motor performance and an increased serum metallothionein concentration, as well as a significant lowering in the circulating serum levels of copper (Cu) following Zn supplementation. In the cohort of ASD patients, the genetic expression of MT-1 was higher after Zn therapy than before the treatment. In conclusion, Zn supplementation might be an important factor in the treatment of children with ASD.

Influence of therapy with metformin on the concentration of certain divalent cations in patients with non-insulin-dependent diabetes mellitus.

Research was performed on a group of 30 patients with non-insulin-dependent diabetes mellitus (NIDDM), who never received antidiabetic medication before, and on a group of 17 healthy adults. The patients were administered treatment with metformin, 1,000 mg/day. Plasmatic and urinary concentration of magnesium have been measured, copper and zinc along with the concentrations of glucose, HDL, LDL, cholesterol, tryglicerides, HbA1c, and total erythrocyte magnesium, in advance and after 3 months of treatment. Data showed significant differences in the NIDDM group vs the control group: for plasma magnesium-1.95 ± 0.19 vs 2.20 ± 0.18 mg/dl, p < 0.001; urine magnesium-237.28 ± 34.51 vs 126.25 ± 38.22 mg/24 h, p < 0.001; erythrocyte magnesium-5.09 ± 0.63 vs 6.38 ± 0.75 mg/dl, p < 0.001; plasma zinc-67.56 ± 6.21 vs 98.41 ± 20.47 µg/dl, p < 0.001; urine zinc-1,347.54 ± 158.24 vs 851.65 ± 209.75 µg/24 h, p < 0.001; plasma copper-111.91 ± 20.98 vs 96.33 ± 8.56 µg/dl, p < 0.001; and urine copper-51.70 ± 23.79 vs 36.00 ± 11.70 µg/24 h, p < 0.05. Treatment with metformin for 3 months modified significant erythrocyte magnesium-5.75 ± 0.61 vs 5.09 ± 0.63 mg/dl, p < 0.001 and urine magnesium-198.27 ± 27.07 vs 237.28 ± 34.51 mg/24 h, p < 0.001, whereas it did not modify significant the plasmatic and urinary concentration of the other cations. The erythrocyte magnesium concentration was inversely correlated with HbA1c (r = -0.438, p = 0.015). The plasma level of copper was positively correlated with HbA1c (r = 0.517, p < 0.003), tryglicerides (r = 0.534, p < 0.003), and cholesterol (r = 0.440, p < 0.05), and the plasma level of zinc was inversely correlated with glycemia (r = -0.399, p = 0.029). Our data show a significant action of metformin therapy, by increasing the total intraerythrocyte magnesium concentration and decreasing the urinary magnesium elimination, positively correlated with the decrease of glycemia and HbA1c in NIDDM patients.