The Relationship Between the Human Genome and Microbiome Comes into View.

The body's microbiome, composed of microbial cells that number in the trillions, is involved in human health and disease in ways that are just starting to emerge. The microbiome is assembled at birth, develops with its host, and is greatly influenced by environmental factors such as diet and other exposures. Recently, a role for human genetic variation has emerged as also influential in accounting for interpersonal differences in microbiomes. Thus, human genes may influence health directly or by promoting a beneficial microbiome. Studies of the heritability of gut microbiotas reveal a subset of microbes whose abundances are partly genetically determined by the host. However, the use of genome-wide association studies (GWASs) to identify human genetic variants associated with microbiome phenotypes has proven challenging. Studies to date are small by GWAS standards, and cross-study comparisons are hampered by differences in analytical approaches. Nevertheless, associations between microbes or microbial genes and human genes have emerged that are consistent between human populations. Most notably, higher levels of beneficial gut bacteria called Bifidobacteria are associated with the human lactase nonpersister genotype, which typically confers lactose intolerance, in several different human populations. It is time for the microbiome to be incorporated into studies that quantify interactions among genotype, environment, and the microbiome in order to predict human disease susceptibility.

Comparative efficacy of tocotrienol and tocopherol (vitamin E) on atherosclerotic cardiovascular diseases in humans.

Objective: To compare the efficacy of tocotrienol and tocopherol in the management of patients with atherosclerotic cardiovascular diseases. METHODS: The systematic review was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines 2020, and comprised literature search from 2002 till January 5, 2023, on PubMed, Google Scholar, Cochrane Library, Google, Wiley-Inter Science Library, Medline, SpringerLink, Taylor and Francis databases. The search was conducted using key words, such as: "tocopherol", "tocotrienol", "vitamin E", "dyslipidaemia", "cardiovascular diseases" "cardioprotective", "hypercholesterolemia" and "atherosclerosis" along with Boolean operators. Human clinical studies regarding the use of tocotrienol or tocopherol or comparison of its efficacy in patients having atherosclerosis, dyslipidaemia leading to cardiovascular diseases, and studies including details of efficacy of any of the four alpha, beta, gamma, delta isomers of tocopherol or tocotrienol were included. Pertinent data from the eligible studies was retrieved and reviewed. RESULTS: Of the 516 articles identified, 26 (5%) articles met eligibility criteria. Of them 5(19%) were subjected to detailed analysis. Tocotrienol showed significant anti-oxidant efficacy at (250 mg/d) by decreasing cholesterol and serum inflammatory biomarkers i.e C-reactive protein (40%), malondialdehyde (34%), gamma-glutamyl transferase (22%) (p<0.001). Total anti-oxidant status (TAS) levels raised 22% (p<0.001) and Inflammatory cytokines i.e resistin, interleukin (IL)-1, IL-12, Interferon-gamma were decreased 15-17% (p<0.05-0.01) respectively by tocotrienol. Several microRNA (miRNA-133a, miRNA-223, miRNA-214, miRNA-155) were modulated by δ-tocotrienol. Whereas, tocopherol showed heterogeneity of results by either decreasing or increasing the risk of mortality in atherosclerotic cardiovascular diseases. Conclusion: Compared to tocopherol, tocotrienol was found to be safe and potential candidate for improving cardiovascular health in the management of atherosclerotic cardiovascular diseases.

Tobacco smoking and vascular biology and function: evidence from human studies.

Tobacco cigarette smoking is among the most complex and least understood health risk factors. A deeper insight into the pathophysiological actions of smoking exposure is of special importance as smoking is a major cause of chronic non-communicable diseases, in particular of cardiovascular disease as well as risk factors such as atherosclerosis and arterial hypertension. It is well known that smoking exerts its negative effects on cardiovascular health through various interdependent pathophysiological actions including hemodynamic and autonomic alterations, oxidative stress, inflammation, endothelial dysfunction, thrombosis, and hyperlipidemia. Importantly, impaired vascular endothelial function is acknowledged as an early key event in the initiation and progression of smoking-induced atherosclerosis. Increasing evidence from human studies indicates that cigarette smoke exposure associates with a pathological state of the vascular endothelium mainly characterized by reduced vascular nitric oxide bioavailability due to increased vascular superoxide production. In the present overview, we provide compact evidence on the effects of tobacco cigarette smoke exposure on vascular biology and function in humans centered on main drivers of adverse cardiovascular effects including endothelial dysfunction, inflammation, and oxidative stress.

Psychological Stress and Gut Microbiota Composition: A Systematic Review of Human Studies.

INTRODUCTION: The associations between psychological stress and gut microbiota composition are not fully understood. This study investigated associations between psychological stress and gut microbiota composition and examined the potential modifying effects of age, sex, and ethnicity on such associations. METHODS: A systematic literature search was conducted using PubMed, Web of Science, PsycINFO, and Embase databases for studies published until November 2021 which examined associations between psychological stress and gut microbiota composition. RESULTS: During the search process, 10,790 studies were identified, and after screening, 13 met the eligibility criteria and were included. The median sample size was 70, and the median age of participants was 28.0 years. Most of the included studies did not report associations between measures of alpha- and beta diversity of the gut microbiota composition and psychological stress. A few studies reported that the Shannon index, Chao 1, Simpson index, and weighted UniFrac were negatively associated with psychological stress. Significant reductions in several taxa at the phyla-, family-, and genus-levels were observed in participants with higher psychological stress. At the phylum level, the abundance of Proteobacteria and Verrucomicrobia were negatively associated with psychological stress. At the family-level, no more than two studies reported associations of the same microbiota with psychological stress. At the genus level, the following results were found in more than two studies; psychological stress was negatively associated with the abundance of Lachnospira, Lachnospiraceae, Phascolarctobacterium, Sutterella, and Veillonella, and positively associated with the abundance of Methanobrevibacter, Rhodococcus, and Roseburia. However, it was not possible to determine the influence of age, sex, or ethnicity due to the limited studies included. CONCLUSION: Our findings provide evidence that psychological stress is associated with changes in the abundance of the gut microbiota. Larger sample longitudinal studies are needed to determine the causal relationship between psychological stress and the gut microbiota.

Short-chain fatty acids as a link between diet and cardiometabolic risk: a narrative review.

AIM: Diet has a profound impact on cardiometabolic health outcomes such as obesity, blood glucose, blood lipids and blood pressure. In recent years, the gut microbiota has emerged as one of several potential key players explaining dietary effects on these outcomes. In this review we aim to summarise current knowledge of interaction between diet and gut microbiota focusing on the gut-derived microbial metabolites short-chain fatty acids and their role in modulating cardiometabolic risk. FINDINGS: Many observational and interventional studies in humans have found that diets rich in fibre or supplemented with prebiotic fibres have a favourable effect on the gut microbiota composition, with increased diversity accompanied by enhancement in short-chain fatty acids and bacteria producing them. High-fat diets, particularly diets high in saturated fatty acids, have shown the opposite effect. Several recent studies indicate that the gut microbiota modulates metabolic responses to diet in, e.g., postprandial blood glucose and blood lipid levels. However, the metabolic responses to dietary interventions, seem to vary depending on individual traits such as age, sex, ethnicity, and existing gut microbiota, as well as genetics. Studies mainly in animal models and cell lines have shown possible pathways through which short-chain fatty acids may mediate these dietary effects on metabolic regulation. Human intervention studies appear to support the favourable effect of short-chain fatty acid in animal studies, but the effects may be modest and vary depending on which cofactors were taken into consideration. CONCLUSION: This is an expanding and active field of research that in the near future is likely to broaden our understanding of the role of the gut microbiota and short-chain fatty acids in modulating metabolic responses to diet. Nevertheless, the findings so far seem to support current dietary guidelines encouraging the intake of fibre rich plant-based foods and discouraging the intake of animal foods rich in saturated fatty acids.

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review.

According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have a phenethylamine related structure but also exhibit amphetamine-like stimulant effects. Illegal laboratories regularly develop new substances and place them on the market. For this reason, during the last decade this class of substances has presented a great challenge for public health and forensic toxicologists. Acting on different systems and with various mechanisms of action, the spectrum of side effects caused by the intake of these drugs of abuse is very broad. To date, most studies have focused on the substances' cardiac effects, and very few on their associated neurotoxicity. Specifically, synthetic cathinones appear to be involved in different neurological events, including increased alertness, mild agitation, severe psychosis, hyperthermia and death. A systematic literature search in PubMed and Scopus databases according to PRISMA guidelines was performed. A total of 515 studies published from 2005 to 2022 (350 articles from PubMed and 165 from Scopus) were initially screened for eligibility. The papers excluded, according to the criteria described in the Method Section (n = 401) and after full text analyses (n = 82), were 483 in total. The remaining 76 were included in the present review, as they met fully the inclusion criteria. The present work provides a comprehensive review on neurotoxic mechanisms of synthetic cathinones highlighting intoxication cases and fatalities in humans, as well as the toxic effects on animals (in particular rats, mice and zebrafish larvae). The reviewed studies showed brain-related adverse effects, including encephalopathy, coma and convulsions, and sympathomimetic and hallucinogenic toxidromes, together with the risk of developing excited/agitated delirium syndrome and serotonin syndrome.

Molecular Hydrogen Therapy-A Review on Clinical Studies and Outcomes.

With its antioxidant properties, hydrogen gas (H2) has been evaluated in vitro, in animal studies and in human studies for a broad range of therapeutic indications. A simple search of "hydrogen gas" in various medical databases resulted in more than 2000 publications related to hydrogen gas as a potential new drug substance. A parallel search in clinical trial registers also generated many hits, reflecting the diversity in ongoing clinical trials involving hydrogen therapy. This review aims to assess and discuss the current findings about hydrogen therapy in the 81 identified clinical trials and 64 scientific publications on human studies. Positive indications have been found in major disease areas including cardiovascular diseases, cancer, respiratory diseases, central nervous system disorders, infections and many more. The available administration methods, which can pose challenges due to hydrogens' explosive hazards and low solubility, as well as possible future innovative technologies to mitigate these challenges, have been reviewed. Finally, an elaboration to discuss the findings is included with the aim of addressing the following questions: will hydrogen gas be a new drug substance in future clinical practice? If so, what might be the administration form and the clinical indications?

The health effects of short fiber chrysotile and amphibole asbestos.

The potential toxic effects of short chrysotile and amphibole asbestos fibers with lengths <5 to ∼10 µm have been debated over the years. This stems from the large database of epidemiology, toxicology, and in-vitro studies, each of which often provides different information in understanding and differentiating the effects of short fibers. The epidemiology studies in which the cancer potency estimates were based upon relatively high exposure concentrations provide a conservative assessment that shorter fibers would have little if any effect, especially under controlled exposure or environmental conditions that may occur today. The QSAR models have shown that fiber aspect ratio and Mg content are excellent predictors of cancer potency and that short fibers/particles of amphibole would have no effect. The studies of motor vehicle mechanics and in particular workers who serviced chrysotile containing brakes with the majority of the fibers being short provides evidence that motor vehicle mechanics, including workers who were engaged in brake repair, are not at an increased risk of mesothelioma. Several inhalation toxicology studies clearly differentiated that short chrysotile and amphibole asbestos fibers did not produce a significant carcinogenic effect in the lung or pleural cavity. Because of dosing and lack of sensitivity to biosolubility, in vitro studies can be difficult to interpret; however, a number have differentiated short chrysotile and amphibole asbestos fibers from long fibers. Integral to understanding the importance of fiber length in determining possible health effects is an understanding of the biological and physiological function of the respiratory system. Short asbestos fibers, like innocuous dust, can be cleared through the tracheobronchial ciliated mucous transport, phagocytized by macrophages and cleared via the bronchial tree, and can also be removed through the lymphatic system. While the first two methods can remove them from the lung, with lymphatic transport through one-way valves, fibers are removed from the active area of the lung where the fiber-related disease has been shown to develop and can accumulate in lymphatic sumps and lymph nodes. While short asbestos fibers are present in most occupational or environmental exposures, the large body of studies strongly supports that they do not contribute to the health effects of asbestos exposure.

The glycocalyx as a permeability barrier: basic science and clinical evidence.

Preclinical studies in animals and human clinical trials question whether the endothelial glycocalyx layer is a clinically important permeability barrier. Glycocalyx breakdown products in plasma mostly originate from 99.6-99.8% of the endothelial surface not involved in transendothelial passage of water and proteins. Fragment concentrations correlate poorly with in vivo imaging of glycocalyx thickness, and calculations of expected glycocalyx resistance are incompatible with measured hydraulic conductivity values. Increases in plasma breakdown products in rats did not correlate with vascular permeability. Clinically, three studies in humans show inverse correlations between glycocalyx degradation products and the capillary leakage of albumin and fluid.

Endocrine disruptors: Challenges and future directions in epidemiologic research.

Public concern about the impact of endocrine disrupting chemicals (EDCs) on both humans and the environment is growing steadily. Epidemiologic research provides key information towards our understanding of the relationship between environmental exposures like EDCs and human health outcomes. Intended for researchers in disciplines complementary to epidemiology, this paper highlights the importance and challenges of epidemiologic research in order to present the key elements pertaining to the design and interpretation of an epidemiologic study on EDCs. The conduct of observational studies on EDCs derives from a thoughtful research question, which will help determine the subsequent methodological choices surrounding the careful selection of the study population (including the comparison group), the adequate ascertainment of exposure(s) and outcome(s) of interest, and the application of methodological and statistical concepts more specific to epidemiology. The interpretation of epidemiologic results may be arduous due to the latency occurring between EDC exposure and certain outcome(s), the complexity in capturing EDC exposure(s), and traditional methodological and statistical issues that also deserve consideration (e.g., confounding, effect modification, non-monotonic responses). Moving forward, we strongly advocate for an integrative approach of expertise in the fields of epidemiology, exposure science, risk assessment and toxicology to adequately study the health risks associated with EDCs while tackling their challenges.

Immunomodulation and exposure to per- and polyfluoroalkyl substances: an overview of the current evidence from animal and human studies.

Per- and polyfluoroalkyl substances (PFAS) have been widely used and represent a class of environmental persistent chemicals. An association of a reduction of vaccination efficacy with PFAS serum levels in humans was used by the European Food Safety Authority as a key effect for PFAS risk assessment. The data support for using this association is reviewed by a critical analysis of the respective human epidemiology and the available animal studies on the immunomodulation of PFAS. Based on an analysis of the available human epidemiology, the overall level of evidence regarding associations between PFAS serum levels and reduced antibody response remains weak. Absence of an association between an increase in clinical infections and PFAS serum levels and the limited understanding of the importance of antibody levels as an isolated data point further support this conclusion. Animal toxicity studies with PFAS focusing on immunomodulation also provide only limited support for immunomodulation as an important endpoint in PFAS toxicity. While immunomodulation is observed after PFAS administration, generally at blood concentrations several orders of magnitude above those seen in environmentally exposed humans, the relevance of these observation is hampered by the high doses required to influence immune endpoints, the limited number of endpoints assessed, and inconsistent results. The limitations of the current database on associations of human PFAS exposures outlined here indicate that more evidence is required to select immunomodulation as a critical endpoint for human PFAS risk assessment.

Prognosis in moderate-severe traumatic brain injury in a Swedish cohort and external validation of the IMPACT models.

BACKGROUND: A major challenge in management of traumatic brain injury (TBI) is to assess the heterogeneity of TBI pathology and outcome prediction. A reliable outcome prediction would have both great value for the healthcare provider, but also for the patients and their relatives. A well-known prediction model is the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic calculator. The aim of this study was to externally validate all three modules of the IMPACT calculator on TBI patients admitted to Uppsala University hospital (UUH). METHOD: TBI patients admitted to UUH are continuously enrolled into the Uppsala neurointensive care unit (NICU) TBI Uppsala Clinical Research (UCR) quality register. The register contains both clinical and demographic data, radiological evaluations, and outcome assessments based on the extended Glasgow outcome scale extended (GOSE) performed at 6 months to 1 year. In this study, we included 635 patients with severe TBI admitted during 2008-2020. We used IMPACT core parameters: age, motor score, and pupillary reaction. RESULTS: The patients had a median age of 56 (range 18-93), 142 female and 478 male. Using the IMPACT Core model to predict outcome resulted in an AUC of 0.85 for mortality and 0.79 for unfavorable outcome. The CT module did not increase AUC for mortality and slightly decreased AUC for unfavorable outcome to 0.78. However, the lab module increased AUC for mortality to 0.89 but slightly decreased for unfavorable outcome to 0.76. Comparing the predicted risk to actual outcomes, we found that all three models correctly predicted low risk of mortality in the surviving group of GOSE 2-8. However, it produced a greater variance of predicted risk in the GOSE 1 group, denoting general underprediction of risk. Regarding unfavorable outcome, all models once again underestimated the risk in the GOSE 3-4 groups, but correctly predicts low risk in GOSE 5-8. CONCLUSIONS: The results of our study are in line with previous findings from centers with modern TBI care using the IMPACT model, in that the model provides adequate prediction for mortality and unfavorable outcome. However, it should be noted that the prediction is limited to 6 months outcome and not longer time interval.

Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer's Disease Patients.

This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer's disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual's mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aß peptides brain catabolism and brain clearance.

On the causal relationships between hyperinsulinaemia, insulin resistance, obesity and dysglycaemia in type 2 diabetes.

Hundreds of millions of people are affected by hyperinsulinaemia, insulin resistance, obesity and the dysglycaemia that mark a common progression from metabolic health to type 2 diabetes. Although the relative contribution of these features and the order in which they appear may differ between individuals, the common clustering and seemingly progressive nature of type 2 diabetes aetiology has guided research and clinical practice in this area for decades. At the same time, lively debate around the causal relationships between these features has continued, as new data from human trials and highly controlled animal studies are presented. This 'For debate' article was prompted by the review in Diabetologia by Esser, Utzschneider and Kahn ( https://doi.org/10.1007/s00125-020-05245-x ), with the purpose of reviewing established and emerging data that provide insight into the relative contributions of hyperinsulinaemia and impaired glucose-stimulated insulin secretion in progressive stages between health, obesity and diabetes. It is concluded that these beta cell defects are not mutually exclusive and that they are both important, but at different stages.

The multi-faceted role of mitochondria in the pathology of Parkinson's disease.

Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity. These roles are especially important for neurons, which have higher energy demands and greater susceptibility to stress. Dysfunction of mitochondria has been associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, Glaucoma and Amyotrophic Lateral Sclerosis. The focus of this review is on how and why mitochondrial function is linked to the pathology of Parkinson's disease (PD). Many of the PD-linked genetic mutations which have been identified result in dysfunctional mitochondria, through a wide-spread number of mechanisms. In this review, we describe how susceptible neurons are predisposed to be vulnerable to the toxic events that occur during the neurodegenerative process of PD, and how mitochondria are central to these pathways. We also discuss ways in which proteins linked with familial PD control mitochondrial function, both physiologically and pathologically, along with their implications in genome-wide association studies and risk assessment. Finally, we review potential strategies for disease modification through mitochondrial enhancement. Ultimately, agents capable of both improving and/or restoring mitochondrial function, either alone, or in conjunction with other disease-modifying agents may halt or slow the progression of neurodegeneration in Parkinson's disease.

Effects of cannabis exposure in the prenatal and adolescent periods: Preclinical and clinical studies in both sexes.

Cannabis is the most commonly used illicit drug among adolescents and young adults, including pregnant women. There is substantial evidence for a significant association between prenatal cannabis exposure and lower birth weight in offspring, and mixed results regarding later behavioural outcomes in the offspring. Adolescent cannabis use, especially heavy use, has been associated with altered executive function, depression, psychosis and use of other drugs later in life. Human studies have limitations due to several confounding factors and have provided scarce information about sex differences. In general, animal studies support behavioural alterations reported in humans and have revealed diverse sex differences and potential underlying mechanisms (altered mesolimbic dopaminergic and hippocampal glutamatergic systems and interference with prefrontal cortex maturation). More studies are needed that analyse sex and gender influences on cannabis-induced effects with great clinical relevance such as psychosis, cannabis use disorder and associated comorbidities, to achieve more personalized and accurate treatments.

Antioxidant potential of family Cucurbitaceae with special emphasis on Cucurbita genus: A key to alleviate oxidative stress-mediated disorders.

Oxidative stress is the imbalance between reactive oxygen species (ROS) production, and accumulation and the ability of a biological system to clear these reactive products. This imbalance leads to cell and tissue damage causing several disorders in human body, such as neurodegeneration, metabolic problems, cardiovascular diseases, and cancer. Cucurbitaceae family consists of about 100 genera and 1,000 species of plants including mostly tropical, annual or perennial, monoecious, and dioecious herbs. The plants from Cucurbita species are rich sources of phytochemicals and act as a rich source of antioxidants. The most important phytochemicals present in the cucurbits are cucurbitacins, saponins, carotenoids, phytosterols, and polyphenols. These bioactive phyto-constituents are responsible for the pharmacological effects including antioxidant, antitumor, antidiabetic, hepatoprotective, antimicrobial, anti-obesity, diuretic, anti-ulcer activity, and antigenotoxic. A wide number of in vitro and in vivo studies have ascribed these health-promoting effects of Cucurbita genus. Results of clinical trials suggest that Cucurbita provides health benefits for diabetic patients, patients with benign prostate hyperplasia, infertile women, postmenopausal women, and stress urinary incontinence in women. The intend of the present review is to focus on the protective role of Cucurbita spp. phytochemicals on oxidative stress-related disorders on the basis of preclinical and human studies. The review will also give insights on the in vitro and in vivo antioxidant potential of the Cucurbitaceae family as a whole.

Erythrocyte Deformability and Na,K-ATPase Activity in Various Pathophysiological Situations and Their Protection by Selected Nutritional Antioxidants in Humans.

The physicochemical and functional properties of erythrocytes are worsened in a variety of diseases. Erythrocyte deformability refers to their ability to adjust their shape according to external forces exerted against them in the circulation. It is influenced by the functionality of the Na,K-ATPase enzyme, which is localized in their membranes. The proposed review is focused on knowledge regarding changes in erythrocyte Na,K-ATPase activity, and their impact on erythrocyte deformability in various pathophysiological situations observed exclusively in human studies, as well as on the potential erytroprotective effects of selected natural nutritional antioxidants. A clear link between the erythrocyte properties and the parameters of oxidative stress was observed. The undesirable consequences of oxidative stress on erythrocyte quality and hemorheology could be at least partially prevented by intake of diverse antioxidants occurring naturally in foodstuffs. Despite intensive research concerning the effect of antioxidants, only a small number of investigations on erythrocyte properties in humans is available in databases. It is worth shifting attention from animal and in vitro experiments and focusing more on antioxidant administration in human studies in order to establish what type of antioxidant, in what concentration, and in which individuals it may provide a beneficial effect on the human organism, by protecting erythrocyte properties.

DUSP4 appears to be a highly localized endogenous inhibitor of epileptic signaling in human neocortex.

BACKGROUND: We previously identified the Mitogen Activated Protein Kinase (MAPK) pathway as focally upregulated in brain regions with high epileptic activity and showed that inhibition of MAPK signaling reduces epileptic spiking in an animal model. Here we examined how activators and inhibitors of the MAPK pathway are expressed in human epileptic cortex and how these could contribute to the localization of epileptic signaling. METHODS: We localized gene and protein expression in human epileptic neocortical tissues based on epileptic activities from 20 patients based on long-term intracranial recordings. Follow-up mechanistic studies by depolarization of human Sh-SY5Y cell line were used to model epileptic activity in the human brain. RESULTS: A clustering algorithm of differentially expressed genes identified a unique gene expression cluster distinct from other MAPK genes. Within this cluster was dual specificity phosphatase 4 (DUSP4), a potent MAPK inhibitor. In situ hybridization studies revealed focal patches of DUSP4 mRNA in layer 2/3 brain regions associated with a dramatic reduction in MAPK signaling genes. In vitro depolarization led to the rapid and transient induction of DUSP4 protein, which, in turn, reduced MAPK activity. Activity-dependent induction of DUSP4 protein was transient and required MAPK signaling. Human epileptic brain regions with lower epileptic activity had lower MAPK activity and higher DUSP4 protein levels. DISCUSSION: DUSP4 is a highly localized, endogenous feedback inhibitor of pro-epileptogenic MAPK signaling in the human epileptic brain. Increasing DUSP4 expression could therefore be a novel therapeutic approach to prevent the development and spread of epileptic circuits. SIGNIFICANCE STATEMENT: Epilepsy is a chronic debilitating disease. Once it develops, epileptic circuits often persist throughout life. Fortunately, in focal forms of epilepsy, these circuits can remain highly localized and are amenable to surgical resections, suggesting that endogenous mechanisms restrict their spread to other brain regions. Using a high-throughput genomic analysis of human epileptic brain regions, we identified DUSP4 as an activity-dependent inhibitor of MAPK signaling expressed in focal patches surrounding human neocortical epileptic brain regions. Our results suggest that DUSP4, through local inhibition of MAPK signaling, acts as an endogenous, spatially segregated safety mechanism to prevent the spread of epileptic activity. Augmenting DUSP4 expression could be a novel disease-modifying approach to prevent or treat human epilepsy.

Considerations for the design and conduct of human gut microbiota intervention studies relating to foods.

With the growing appreciation for the influence of the intestinal microbiota on human health, there is increasing motivation to design and refine interventions to promote favorable shifts in the microbiota and their interactions with the host. Technological advances have improved our understanding and ability to measure this indigenous population and the impact of such interventions. However, the rapid growth and evolution of the field, as well as the diversity of methods used, parameters measured and populations studied, make it difficult to interpret the significance of the findings and translate their outcomes to the wider population. This can prevent comparisons across studies and hinder the drawing of appropriate conclusions. This review outlines considerations to facilitate the design, implementation and interpretation of human gut microbiota intervention studies relating to foods based upon our current understanding of the intestinal microbiota, its functionality and interactions with the human host. This includes parameters associated with study design, eligibility criteria, statistical considerations, characterization of products and the measurement of compliance. Methodologies and markers to assess compositional and functional changes in the microbiota, following interventions are discussed in addition to approaches to assess changes in microbiota-host interactions and host responses. Last, EU legislative aspects in relation to foods and health claims are presented. While it is appreciated that the field of gastrointestinal microbiology is rapidly evolving, such guidance will assist in the design and interpretation of human gut microbiota interventional studies relating to foods.