Toxic Metal -Mediated Neurodegradation: A Focus on Glutathione and GST Gene Variants.

Increasing pieces of evidence have supported those chemicals from industrial, agricultural wastes and organoleptic activities play important role in the development of neurological disorders. The frequency of neurological disorders is increased to a much extent in recent years with the advancements in science and technology. Google Scholar, PubMed, and Scopus databases were selected to search the relevant information by using keywords including "Heavy metals", "Neurotoxicity", "Glutathione", "Glutathione AND Neurodegenerative disorders" etc. Heavy metals are particularly recognized as a major resource of toxicities during the stage of early pregnancy where a fetus gets exposed to them from maternal activities and circulation. As infants have a weak immune system and cannot respond to the specific challenge as faced by the body during mercury, zinc, iron, and cadmium exposure. Daily diet and drinking habits in addition to industrial activities also form a major field of study under investigation. This study aims to investigate the role of these metals in the accumulation of pollutants in the brain, liver, and kidneys hence leading to serious consequences. Moreover, their prevalence in teenagers that are under the age of ten years is being observed that leads them to learn, writing, and intellectual abilities. Males are more affected due to their hormonal differences. The role of the GST gene in the development of cognitive conditions and its phenotypes has been discussed thoroughly in this review. The mutations of GST lead to the accumulation of peroxides and superoxides which exacerbate oxidative damage to cells. Binding of toxic metals to GSH genes and the role of glutathione transferase genes is was demonstrated in this review.

Toxic Metals Exposure and APOE4 Gene Variant in Cognitive Decline Disorders.

Neurodegenerative disorders are those which affect cognitive functions. Misfolding of proteins especially apolipoprotein E is a key genetic factor involved in several cognitive impairments. Increasing evidence also described the toxic effects of metals, generated by both nature and humans, on the development of neurological disorders. Understanding of interaction between toxic metals and apolipoprotein E protein in cognitive decline diosrders would provide alternative treatment options. Google Scholar and PubMed database were used to search the articles using different search terms like 'toxic metals', 'cognitive decline', 'Apolipoprotein E', "neurodegenerative disorders" and "metals neurotoxicity". Only those papers were included that discussed the metal exposure-apolipoprotein association in the development of cognitive decline disorders. Heavy metals are particularly recognized as a major source of neurotoxicity. These toxic metals can interact with genetic factors and play important role in disease etiology. Understanding the underlying mechanism of this interaction could provide tremendous benefits to treat cognitive decline disorders. In this study, the role of the apolipoprotein E4 gene in the development of cognitive disease conditions and their phenotypes has been discussed thoroughly which leads to the accumulation of amyloid-beta fibrils. This exploratory study revealed novel hypothetical findings which might contribute to the understanding of the neurotoxic effects of chronic toxic metals exposure and possibly improve our knowledge on the molecular mechanisms linking metal exposure to cognitive decline disorder risk.

Increasing Efficacy of Covid-19 Vaccines by Lifestyle Interventions.

COVID-19 caused a serious threat to the world population as it spread worldwide rapidly. Existing medicines and vaccines could not cure and control this deadly disease. In this regard, several vaccines have been proposed and designed to control this infection's spread effectively. Along with these vaccines, the general population should adopt specific lifestyle interventions to strengthen their immune system and combat deadly viruses. We used Google Scholar and PubMed databases to find the related information using key terms such as 'COVID-19', 'COVID-19 AND Vaccine efficacy', 'Lifestyle intervention AND COVID-19', and "Lifestyle intervention AND Vaccines," etc. Only articles that discussed the interactions between lifestyle intervention and the efficacy of COVID-19 vaccines were selected for this study. Several previous clinical trials and scientific observations with influenza, polio, and other viral vaccines have demonstrated that vaccine response varies across individuals for antibody titer, independent of vaccine antigenicity. This different vaccine response observed among individuals is attributed to several factors such as dietary and nutritional habits, physical activity, stress and sleep deprivation, deficiency of micronutrients (minerals, vitamins), gut microbiota composition, immunosenescence, smoking, and drinking habits. Although there is not much information about COVID-19 vaccine efficacy and lifestyle interventions, experience with other vaccines can undoubtedly be used to suggest lifestyle interventions to improve COVID-19 vaccine efficacy. These lifestyle interventions may boost antibody responses against COVID-19 vaccines, leading to higher protection from the disease, especially among elderly and immunocompromised people. In conclusion, the present review attempts to understand the role of various nutritional and psychological factors that lead to poor vaccine response and suggests specific nutritional and psychological interventions that can enhance vaccine efficacy and improve immune response against COVID-19 vaccines.

A Review on Metabolic Paradoxes and their Impact on Metabolism.

The current review paper portrays the important link of different nutrients like trace elements, proteins, fatty acids, vitamins, and amino acids with the immune system as well as information related to metabolic paradoxes. Optimum working of the metabolic system is essential because it gives various types of supplements to the human body and aid in chemical pathways. Here related data have been retrieved from two databases i.e., PubMed and Google scholar to grasp detailed knowledge about micronutrients and nutrients as well as their association in the metabolic system. Like protein play important role in the normal development of different immune components, amino acids including alanine, Arginine, and glutamic acid properly control the movement of neutrophils, macrophages, and cytokines. While fatty acids act as an anti-inflammatory agent because they possess the ability to inhibit the expression of the MHC class. Apart from these, many essential molecules like uric acid, proteins, calcium, lanolin are also obtained as end products after catabolic and anabolic reactions, and it was found that the uric acid paradox has a cancer inhibitory role. Additionally, TGF and IL-6 paradoxes have a role in the development of tumors, the onset of diabetes, and low-grade inflammatory disorders respectively. However, the entire functioning of metabolic processes depends upon daily diet because humans get the important nutrient from the diet which further vital role in the immune system. Moreover, it was also observed that calcium paradox is related to heart disorders because high calcium accumulation leads to cardiac disorders. Thus, the complete knowledge about these essential components as well as metabolic paradoxes is very important due to their antagonistic role to plan better and improved therapeutic strategies for various diseases.

Nutrients Interaction with the Immune System.

This study described the interactions of different nutritional components with the immune system. A detailed search was carried out on Google Scholar and PubMed databases to find out the relevant research studies using different keywords, such as "Nutrients", "Micronutrients", and "Immune system and micronutrients". Only those papers that discussed the interactions between nutrients and the components of the immune system were included in the study. This research outlined the impact of different vitamins, trace elements or metals, amino acids, and fatty acids on different immune system components. It was found that vitamins, such as vitamin A, D, and C, tend to help immune cell differentiation and enhance the expression of different cytokines. Vitamins also contribute to the proliferation of T and B cells and impact the production of white blood cells. Similarly, trace elements or metals act as enzyme cofactors and control different immune response cycles by controlling the expression of cytokines, chemokines, and other signaling molecules. Moreover, different essential and non-essential amino acids play important roles in immune system development as they are primarily involved in protein synthesis. Amino acids, such as arginine, glutamine, and alanine, modulate the expression of cytokines and also control the migration and transmigration capabilities of macrophages. They also enhance the phagocytic properties of macrophages and neutrophils. In a similar way, fatty acids act as anti-inflammatory agents since they can decrease the expression of major histocompatibility complex class I (MHC-I) and MHC-II. Furthermore, they inhibit the secretion of different inflammatory cytokines. In conclusion, all the components of our daily diet are associated with the development of the immune system, and understanding their interactions is important for future immune therapies and drug development.

Lifestyle Genetics-Based Reports in the Treatment of Obesity.

Obesity becomes a chronic disease due to the increasing number of mortality and morbidity cases around the world. In most regions, chronic illnesses, such as obesity, are important sources of morbidity and mortality. Due to a lack of effective strategies for prevention and management, the adverse effects of obesity and related diseases on health continue to be a serious problem. Relevant information was searched from Google Scholar, Scopus, and PubMed using such different terms as "Obesity", "Obesity Management", "Obesity AND Physical activity", "Obesity AND Genetics", "Obesity AND Diet", and "Obesity AND Nutrigenomics". Obesity is characterized by a complex interaction of hereditary and lifestyle factors, which includes food. Diet is an environmental element that plays an important and considerable role in the management of health and reduces the risk of obesity and its comorbidities. Changes in lifestyle patterns not only help burn extra calories but also prevent the development of obesity via its modulating effect on genetic factors. Different people respond differently to an obesogenic environment. The notion of nutrigenetics emerged as a result of various genetic variations that may explain this heterogeneity. Nutritional genomics, also known as nutrigenetics, is the study that investigates and analyses gene variations linked to varied responses to certain foods; moreover, it links this variation to diseases, such as obesity. As a result, tailored nutrition advice based on a person's genetic profile may improve the outcomes of a specific dietary strategy and offer a novel dietary strategy to improve life quality and preventing obesity. This study concluded that physical activity and dietary interventions play an effective role in the management of obesity. Moreover, understanding of the function of the most prominent obesity-related genes, as well as the interaction between nutrition and gene expression, will help researchers design personalized treatment strategies for humans.

Association between Siesta (Daytime Sleep), Dietary Patterns and the Presence of Metabolic Syndrome in Elderly Living in Mediterranean Area (Medis Study): The Moderating Effect of Gender.

OBJECTIVES: Several lifestyle parameters including diet, physical activity and sleep were associated in isolation with the presence of Metabolic Syndrome (MetS) in adults, to date there is a paucity of studies which evaluated their combined role aging populations and especially with respect to gender. Therefore, the aim of the present study was to provide a global consideration of the lifestyle factors associated with MetS among elderly individuals. DESIGN: Cross-sectional observational study. SETTING: 21 Mediterranean islands and the rural Mani region (Peloponnesus) of Greece. PARTICIPANTS: during 2005-2015, 2749 older (aged 65-100 years) from were voluntarily enrolled in the study. MEASUREMENTS: Dietary habits, energy intake, physical activity status, socio-demographic characteristics, lifestyle parameters (sleeping and smoking habits) and clinical profile aspects were derived through standard procedures. The presence of MetS was defined using the definition provided by NCEP ATP III (revised) and cluster analysis was used to identify overall dietary habit patterns. RESULTS: The overall prevalence of MetS in the study sample was 36.2%, but occurred more frequently in females (40.0% vs. 31.8%, respectively, p=0.03). Individuals with MetS were more likely to sleep during the day (89.4% vs. 76.8% respectively, p=0.039) and frequent 'siesta' was positively linked to the odds of MetS presence in females (Odds Ratio (OR) =3.43, 95% Confidence Intervals (CI): 1.08-10.9), but not for men (p=0.999). The lower carbohydrate (i.e., 45.2% of total daily energy, 120±16gr/day) dietary cluster was inversely associated with the odds for MetS presence, but only for men (OR=0.094, 95%CI: 0.010-0.883). CONCLUSIONS: Lifestyle parameters including sleep and diet quality are strongly associated with the presence of MetS in elderly cohort, but different their level of influence appears to be different, depending on gender. Further research is needed to better consider the role of lifestyle characteristics in the management of MetS in clinical practice.

Med Diet 4.0: the Mediterranean diet with four sustainable benefits.

OBJECTIVE: To characterize the multiple dimensions and benefits of the Mediterranean diet as a sustainable diet, in order to revitalize this intangible food heritage at the country level; and to develop a multidimensional framework - the Med Diet 4.0 - in which four sustainability benefits of the Mediterranean diet are presented in parallel: major health and nutrition benefits, low environmental impacts and richness in biodiversity, high sociocultural food values, and positive local economic returns. DESIGN: A narrative review was applied at the country level to highlight the multiple sustainable benefits of the Mediterranean diet into a single multidimensional framework: the Med Diet 4.0. Setting/subjects We included studies published in English in peer-reviewed journals that contained data on the characterization of sustainable diets and of the Mediterranean diet. The methodological framework approach was finalized through a series of meetings, workshops and conferences where the framework was presented, discussed and ultimately refined. RESULTS: The Med Diet 4.0 provides a conceptual multidimensional framework to characterize the Mediterranean diet as a sustainable diet model, by applying principles of sustainability to the Mediterranean diet. CONCLUSIONS: By providing a broader understanding of the many sustainable benefits of the Mediterranean diet, the Med Diet 4.0 can contribute to the revitalization of the Mediterranean diet by improving its current perception not only as a healthy diet but also a sustainable lifestyle model, with country-specific and culturally appropriate variations. It also takes into account the identity and diversity of food cultures and systems, expressed within the notion of the Mediterranean diet, across the Mediterranean region and in other parts of the world. Further multidisciplinary studies are needed for the assessment of the sustainability of the Mediterranean diet to include these new dimensions.

Developmental changes in cognitive and behavioural functioning of adolescents with fragile-X syndrome.

BACKGROUND: Individuals with fragile-X syndrome exhibit developmental delay, hyperexcitation and social anxiety; they also show lack of attention and hyperactivity. Few studies have investigated whether levels of functioning change with increasing age. Here, we explored developmental changes across adolescence in the cognitive and behavioural profile of individuals with fragile-X syndrome. To this scope, we assessed intellectual functioning, adaptive behaviour, autistic symptomatology, behavioural problems (e.g. hyperactivity/lack of attention) and strengths (prosocial behaviours). METHOD: Thirty-six participants underwent standardised outcome measures (i.e. the Wechsler Intelligence Scales-Revised, the Childhood Autism Rating Scale, the Vineland Adaptive Behavior Scales, and the Strengths and Difficulty Questionnaire) in three time points (Time 1: 9-11; Time 2: 11-13, and Time 3: 13-15 years). RESULTS: Verbal IQ improved across time, whereas Nonverbal IQ declined and Full Scale IQ was quite unchanged. Autism ratings decreased; communication and social aspects of adaptive behaviour also enhanced. Finally, elevated levels of hyperactivity/lack of attention at Time 1 significantly improved across the three time points, whereas emotional symptoms, behavioural difficulties, problems with peers and prosocial behaviours remained stable over time. CONCLUSION: These findings revealed specific developmental changes in cognitive and behavioural functioning of individuals with fragile-X syndrome, likely related to a progressive maturation of brain systems devoted to attentional control.

Modulation of an AMPA-like glutamate receptor (SqGluR) gating by L- and D-aspartic acids.

L- and D-aspartic acids (L-Asp and D-Asp) are present in the majority of nervous systems. In phylogeny, significant levels have been reported in mollusc brains, particularly cephalopods. To examine the role of L- and D-Asp on a cephalopod receptor, we studied ligand gating of a squid glutamate receptor (SqGluR) expressed in HEK 239 (human embryonic kidney) cells. Under voltage clamp, application of L-glutamate (L-Glu; 1-30 mM), but not D-glutamate (D-Glu), or L- or D-Asp, evoked an inward current of 0.1 nA. L- or D-Asp (200 microM) applied with 20 mM L-Glu, slowed the time course of activation and inactivation of the L-Glu gated current (time constant increased from 1 s (L-Glu alone) to 3 s (D-Asp and L-Glu) and to 19 s (L-Asp and L-Glu)). Our results suggest that in molluscan systems, aspartic acid could act as a neuromodulator during glutamatergic transmission and could significantly alter synaptic integration by slowing glutamate receptor gating.

Trains of sleep sequences are indices of learning capacity in rats.

In previous work dealing with the identification of four sleep sequences (SS-->W, SS-->PS, SS-->TS-->W and SS-->TS-->PS) in the baseline session of adult male Wistar rats [Mandile P, Vescia S, Montagnese P, Romano F, Giuditta A. Characterization of transition sleep episodes in baseline EEG recordings of adults rats, Physiol Behav 1996;60:1435-1439], we have shown that those containing an intervening episode of transition sleep (TS) strongly correlate with the number of avoidances scored the following day [Vescia S, Mandile P, Montagnese P, Romano F, Cataldo G, Cotugno M, Giuditta A. Baseline transition sleep and associated sleep episodes are related to the learning ability of rats, Physiol Behav 1996;60:1513-152]. More recently, clusters of sleep sequences (trains) separated by waking intervals longer than 60 s have been identified in the baseline session of the same rats [Piscopo S, Mandile P, Montagnese P, Cotugno M, Giuditta A, Vescia S. Identification of trains of sleep sequences in adult rats, Behav Brain Res, this volume], and distinguished in homogeneous or mixed trains according to the presence of a single sleep sequence or more than one sequence. Mixed trains have been further separated into trains containing the SS-->TS-->W sequence (+TSW trains) and trains lacking it (-TSW trains). Analysis of the distribution of variables of baseline trains (and of their sleep sequences and components) among fast learning (FL), slow learning (SL), or non-learning (NL) rats, indicates that variables of +TSW trains prevail in FL rats, while variables of -TSW trains prevail in NL rats. In addition, variables of +TSW trains correlate with the number of avoidances of the training session, while variables of -TSW trains do not significantly correlate, or show inverse correlations. Interestingly, sleep sequences such as SS-->W or SS-->TS-->W show direct or inverse correlations with avoidances depending on whether they are included in +TSW trains or in -TSW trains. The data are interpreted to suggest that the outcome of brain operations performed during a sleep sequence may selectively condition the appearance of later sequences within a time interval shorter than a given threshold. An analogous mechanism may be responsible for the aggregation of sleep components in sleep sequences.

Identification of trains of sleep sequences in adult rats.

In previous studies based on high resolution EEG analyses of the 7 h baseline session of 18 adult male Wistar rats [6,14], we have identified four sleep sequences initiating with slow wave sleep (SS) and terminating with waking (W) or paradoxical sleep (PS). Two of these sequences contained an intervening episode of transition sleep (TS). Several variables of these sequences (SS-->W, SS-->TS-->W, SS-->TS-->PS, and SS-->PS) were selectively correlated with the capacity of rats to learn a two-way active avoidance task the following day, and were differently distributed in fast learning, slow learning and non learning rats [21]. The temporal organization of different sleep components in sequences suggested that a comparable temporal organization might concern the different sleep sequences, albeit on a longer time scale. We have now used waking periods longer than 60 s to separate clusters of baseline sleep sequences (trains) in the same rats. Trains containing the same sleep sequence (homogeneous trains) have been distinguished from trains containing different sleep sequences (mixed trains). In addition, mixed trains including the SS-->TS-->W sequence (+TSW trains) have been separated from mixed trains lacking that sequence (-TSW trains). Mixed trains of the +TSW type were longest and most numerous, while homogeneous trains were shortest and least abundant. Mixed trains of the -TSW type displayed intermediate values. Several variables of sleep sequences and sleep components differed within mixed trains and among mixed and homogeneous trains. The data indicate that baseline sleep sequences aggregate in relatively long strings in a non random fashion. The mechanism of this association is discussed.

Post-trial sleep sequences including transition sleep are involved in avoidance learning of adult rats.

High resolution computerized EEG analyses, and behavioral observations were used to identify slow wave sleep (SS), paradoxical sleep (PS) and transition sleep (TS) in adult male Wistar rats exposed to a session of two-way active avoidance training. Of the four sleep sequences that could be identified, two included TS (SS-->TS-->W and SS-->TS-->PS), while the other two did not (SS-->W and SS-->PS). Comparison of post-trial sleep variables between fast learning rats (FL, reaching criterion in the training session), slow learning rats (SL, reaching criterion in the retention session the following day), and non learning rats (NL, failing to reach criterion) indicated that the total amounts of SS, TS and PS of the SS-->TS-->PS sequence was markedly higher in FL rats than in SL rats. In addition, in comparison with the corresponding baseline period, the average duration and total amount of SS and TS episodes of the SS-->TS-->PS sequence increased in FL rats, while the number of SS-->TS-->W sequences decreased. On the other hand, the average duration of SS episodes increased in the SS-->TS-->W and SS-->W sequences of SL rats, and in the SS-->W and SS-->TS-->PS sequences of NL rats. Correlative analyses between number of avoidances and post-trial sleep variables demonstrated that avoidances were directly correlated with the duration of SS episodes of the SS-->TS-->PS sequence and with the duration of TS episodes of the SS-->TS-->W sequence, but inversely correlated with the number and amount of SS episodes of the SS-->W sequence and with the duration and amount of SS episodes of the SS-->PS sequence. On the whole, the data supported the view that TS-containing sleep sequences are involved in long-term storage of novel adaptive behavior, while sleep sequences lacking TS are involved in the maintenance of innate behavioral responses.

Comparison of effects of albendazole sulfoxide on in vitro produced bovine embryos and rat embryos.

OBJECTIVE: To evaluate and compare effects of albendazole sulfoxide (ABZSO) on rat embryos and bovine embryos produced in vitro. ANIMALS: In vitro produced bovine embryos. Rat embryos recovered from naturally bred Sprague-Dawley rats. PROCEDURE: 4- and 8-cell bovine embryos were randomly allocated to ABZSO or vehicle control groups. After 48 hours, embryos were evaluated for cell number and blastomere morphology. Rat embryos of similar stages, flushed from the uterine tube on gestational day 2-5, were randomly allocated to treatment or control groups. After 24 hours, embryos were evaluated as described previously. RESULTS: 44% of control bovine embryos divided in culture (> or = 16-cell stage). Fifteen percent of the controls had morphologic abnormalities, including disparity in blastomere size and cytoplasmic vacuoles and stippling. Treated (> or = 1 microgram of ABZSO/ml) bovine embryos differed (P < 0.0001) from controls, with 4% development and 93% abnormal morphology. Forty-five percent of control rat embryos divided in culture. Treated (> or = 500 ng of ABZSO/ml) rat embryos differed (P < 0.0003) from controls with regard to ability to divide. There were no consistent morphologic abnormalities in rat embryos. CONCLUSIONS: In vitro produced bovine embryos were susceptible to ABZSO at a concentration > or = 1 microgram/ ml, resulting in decreased ability to divide and presence of gross morphologic abnormalities. Rat embryos produced in vivo and exposed in vitro to ABZSO at a concentration > or = 500 ng/ml had decreased ability to divide in culture. CLINICAL RELEVANCE: Despite severe effects of ABZSO (> or = 1 microgram/ml) on bovine embryo development in vitro, it is beyond the scope of this study to speculate whether a therapeutic dosage of albendazole (10 mg/kg of body weight) would result in necessary concentrations of ABZSO in vivo to disrupt embryogenesis.

Determination of concentration of albendazole sulfoxide in plasma and uterine fluid of heifers.

OBJECTIVES: To determine time and concentration of peak plasma and uterine fluid concentrations of albendazole (ABZ) sulfoxide (ABZSO) in heifers after oral administration of ABZ. SAMPLE POPULATION: 25 young Angus and Simmental heifers maintained on pasture with ad libitum access to hay and water. PROCEDURE: Heifers were assigned at random to ABZ or control (water) groups, and were drenched with ABZ suspension at a dosage of 15, 30, 60, or 120 mg/kg of body weight, or with water. Plasma was collected hourly, from 14 to 25 hours after administration of ABZ or water. After a drug-withdrawal period, heifers were synchronized for estrus and drenched with 60 mg of ABZ/kg, or water (50 ml). Each uterine horn was flushed. All samples were extracted and subjected to high-performance liquid chromatography analysis. RESULTS: For all groups, highest mean +/- SEM plasma concentration of ABZSO was observed between 15 and 16 hours after ABZ administration, at 2.0 +/- 0.4 micrograms/ml (15 mg/kg), 5.3 +/- 1.0 micrograms/ml (30 mg/kg), 7.4 +/- 1.5 micrograms/ml (60 mg/kg), and 11.1 +/- 2.7 micrograms/ml (120 mg/kg). Mean concentration for all uterine horn fluid samples was 265 +/- 25 ng/ml/horn; range was 79 to 546 ng/ml/horn. The only significant (P = 0.0006) source of variation was the technician performing the flush. Mean concentration for each technician was 184 +/- 24 ng/ml/horn and 345 +/- 35 ng/ml/horn. CLINICAL RELEVANCE: Teratogenic and embryotoxic effects of ABZSO differ for ewes and heifers. Albendazole sulfoxide is detectable in the uterus of heifers; however, ABZSO peaks in heifer plasma earlier and at a lower concentration than that reported for ewes, perhaps contribution to differences in susceptibility at similar dosages.