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Nicotinamide adenine dinucleotide (NAD+) is an evolutionarily highly conserved coenzyme with multi-faceted cell functions, including energy metabolism, molecular signaling processes, epigenetic regulation, and DNA repair. Since the discovery that lower NAD+ levels are a shared characteristic of various diseases and aging per se, several NAD+-boosting strategies have emerged. Other than pharmacological and nutritional approaches, exercise is thought to restore NAD+ homeostasis through metabolic adaption to chronically recurring states of increased energy demand. In this review we discuss the impact of acute exercise and exercise training on tissue-specific NAD+ metabolism of rodents and humans to highlight the potential value as NAD+-boosting strategy. By interconnecting results from different investigations, we aim to draw attention to tissue-specific alterations in NAD+ metabolism and the associated implications for whole-body NAD+ homeostasis. Acute exercise led to profound alterations of intracellular NAD+ metabolism in various investigations, with the magnitude and direction of changes being strongly dependent on the applied exercise modality, cell type, and investigated animal model or human population. Exercise training elevated NAD+ levels and NAD+ metabolism enzymes in various tissues. Based on these results, we discuss molecular mechanisms that might connect acute exercise-induced disruptions of NAD+/NADH homeostasis to chronic exercise adaptions in NAD+ metabolism. Taking this hypothesis-driven approach, we hope to inspire future research on the molecular mechanisms of exercise as NAD+-modifying lifestyle intervention, thereby elucidating the potential therapeutic value in NAD+-related pathologies.

Human-induced pluripotent stem cell derived brain organoids provide models to study the human brain and its diseases. The neuronal activities of these organoids are recorded over time by Multi-electrode Arrays, calling for approaches to analyze their longitudinal variations to study the organoids’ electrophysiological maturation. We introduce a pipeline (Il-Vis) that incrementally learns and visualizes a progression trajectory representing the organoids’ electrophysiological properties. Unlike a static model that runs at the end of the experiment, Il-Vis generates a progression trajectory thus far at each sampling timepoint. Results on simulated data, for which the true progression trajectories are known, verified Il-Vis’s ability to capture and visualize the trajectories accurately and relative to each other. Results on brain organoid data revealed useful insights about organoids’ electrophysiological maturation stages and response patterns when exposed to Quinolinic Acid (and its blocking antibody), a metabolite contributing to many neuroinflammatory diseases including Alzheimer’s.

Nicotinamide adenine dinucleotide (NAD

Neuroinflammation is one of the most frequently studied topics of neurosciences as it is a common feature in almost all neurological disorders. Although the primary function of neuroinflammation is to protect the nervous system from an insult, the complex and sequential response of activated glial cells can lead to neurological damage. Depending on the type of insults and the time post-insult, the inflammatory response can be neuroprotective, neurotoxic, or, depending on the glial cell types, both. There are multiple pathways activated and many bioactive intermediates are released during neuroinflammation. One of the most common one is the kynurenine pathway, catabolizing tryptophan, which is involved in immune regulation, neuroprotection, and neurotoxicity. Different models have been used to study the kynurenine pathway metabolites to understand their involvements in the development and maintenance of the inflammatory processes triggered by infections. Among them, the parasitic infection

This expert opinion focuses on the impact of global warming and climate change on the spread and distribution of Australian ticks and the prevalence and intensity of associated human diseases.

In the central nervous system, astrocytes and microglia contribute to homeostasis, regulating the immune response to infectious agents. Neospora caninum is an obligate intracellular protozoan that infects different animal species and it is encysted in their nervous tissue while triggering an immune response modulated by glia. This study aimed to evaluate the infection of primary cultures of rat glial cells by N. caninum through the catabolites of tryptophan, the expression of inflammatory mediators and the integrity of neural tissue. Infection with this coccidium resulted in morphological and functional changes, particularly astrogliosis and microgliosis, and increased the expression of the inflammatory mediators TNF, IL1β, IL-10, and arginase, as well as mRNA for CCL5 and CCL2, molecules involved in the CNS chemotaxis. The infection with N. caninum in glial cells also triggered the activation of the tryptophan pathway, characterized by increased kynurenine 2,3 monooxygenase (KMO) mRNA expression, and by the production of the excitotoxin quinolinic acid (QUIN). Moreover, glia-neuron co-cultures, when exposed to the secretome derived from N. caninum infected glial cells, presented greater neurons distribution and formation of neurite extensions, associated to morphological changes in astrocytes compatible with neuro-preservation. Considering that the tryptophan catabolism is associated to immune response, these findings suggest that glial activation in N. caninum infection should be responsible for modulating the inflammatory status in an attempt to restore the nervous system homeostasis, since excessive inflammatory response can cause irreversible damage to tissue preservation.

In addition to the degradation of homologous RNAs through the RNA interference (RNAi) pathway, small interfering RNAs (siRNAs) can in some systems induce cytosine methylation and transcriptional silencing of homologous promoters. Targeting of HIV-1 by RNAi results in transient suppression of the virus through degradation of viral transcripts. In an effort to prolong the suppressive effect of siRNAs on productive HIV-1 infection, we targeted conserved tandem NF-kappaB binding motifs in the viral LTR. A 21-nucleotide-RNA duplex induced marked and durable (at least 30 days) suppression of productive HIV-1 infection in chronically infected Magic-5 cells. This suppression is associated with CpG methylation within the 5'LTR and marked reduction of HIV-1 transcription in nuclear run-on assays. We then assessed three additional siRNAs targeting other sites within the HIV-1 promoter region. These siRNAs suppressed HIV-1 infection to different extents and the degree of suppression correlated with the extent of de novo methylation of CpG motifs within the HIV-1 promoter region. These findings indicate that HIV-1 can be silenced by an RNA-directed mechanism that suppresses transcription and induces CpG methylation. In addition to providing evidence that this RNA-directed DNA methylation is active in mammalian cells, this is the first report of prolonged suppression of HIV-1 infection induced by siRNA.

Cerebrovascular disorders are common diseases and stroke constitutes the third cause of death following myocardial infarction and cancer as well as the first cause of disability across the globe worldwide. Although several studies have demonstrated the beneficial effects of herbal preparations on stroke, this study was designed to classify and analyze the results of these studies. For this purpose, electronic databases were searched including Cochrane, ISI, PubMed, and Scopus to 15 January 2018 for English language human studies. Only randomized controlled trials (CRTs) were involved and case studies were excluded from this review. Finally, four randomized controlled trials were included in this systematic review which four medicinal plants were assessed in four articles. Inclusion and exclusion criteria, and also outcome measures varied between different articles. The results of these studies indicated that these special medicinal plants may be effective in the management of ischemic stroke and No severe reactions were described during the administration of herbal remedies. However, the efficacy of herbal medicines on Ischemic stroke needs to be further proven through future additional studies