- Hormones, Metabolism and the Benefits of Exercise: Tryptophan-Kynurenine Metabolites in Exercise and Mental Health [BOOK]
- BOOKSpringer: Chamcham
- In our efforts to identify molecular mediators of the benefits of exercise to human health, we have uncovered a biochemical pathway in skeletal muscle that positively impacts mental health. This mech…
In our efforts to identify molecular mediators of the benefits of exercise to human health, we have uncovered a biochemical pathway in skeletal muscle that positively impacts mental health. This mechanism is activated by endurance training and controlled by the transcriptional coactivator PGC-1α1, which induces transcription of several kynurenine aminotransferase (KAT) genes in muscle. KAT enzymes catabolize the neuroinflammatory tryptophan metabolite kynurenine, which can accumulate in the brain and lead to alterations associated with stress-induced depression (among other psychiatric diseases). Here, we discuss our findings in the context of what is known about the kynurenine pathway of tryptophan degradation and how its many metabolites can directly affect the brain. These findings provide a mechanism for how physical exercise can improve mental health and offers potential therapeutic targets for future antidepressant medications.
- Hormones, Metabolism and the Benefits of Exercise: Sending the Signal: Muscle Glycogen Availability as a Regulator of Training Adaptation [BOOK]
- BOOKSpringer: Chamcham
- Exercise training-induced adaptations in human skeletal muscle are largely determined by the mode, volume, intensity and frequency of the training stimulus. However, a growing body of evidence demons…
Exercise training-induced adaptations in human skeletal muscle are largely determined by the mode, volume, intensity and frequency of the training stimulus. However, a growing body of evidence demonstrates that the availability of endogenous and exogenous macronutrients can modify multiple intramuscular responses to both endurance- and resistance-based exercise. Acutely manipulating substrate availability (by altering diet composition and/or timing of meals) rapidly alters the concentration of blood-borne substrates and hormones that modulate several receptor-mediated signaling pathways. The release of cytokines and growth factors from contracting skeletal muscle also stimulates cell surface receptors and activates many intracellular signaling cascades. These local and systemic factors cause marked perturbations in the storage profile of skeletal muscle (and other insulin-sensitive tissues) that, in turn, exert pronounced effects on resting fuel metabolism and patterns of fuel utilization during exercise. When repeated over weeks and months, such nutrient-exercise interactions have the potential to alter numerous adaptive processes in skeletal muscle that ultimately drive the phenotype-specific variability observed between individuals. One strategy that augments endurance-training adaptation is commencing exercise with low muscle glycogen concentration (“train-low”). The amplified training response observed with low endogenous carbohydrate availability is likely regulated by enhanced activation of key cell signalling kinases (e.g., AMPK, p38MAPK), transcription factors (e.g., p53, PPARδ) and transcriptional co-activators (e.g., PGC-1α), such that a coordinated up-regulation of both the nuclear and mitochondrial genomes occurs. This chapter provides a contemporary perspective of our understanding of the molecular and cellular events that take place in skeletal muscle in response to exercise commenced after alterations in nutrient availability and discusses how the ensuing hormonal milieu interacts with specific contractile stimulus to modulate many of the acute responses to exercise, thereby potentially promoting or inhibiting subsequent training adaptation.
- Genome Editing in Neurosciences: In Vitro Modeling of Complex Neurological Diseases [BOOK]
- BOOKSpringer: Cham (CH)
- A major reason for the lack of effective therapeutics and a deep biological understanding of complex diseases, which are thought to result from a complex interaction between genetic and environmental…
A major reason for the lack of effective therapeutics and a deep biological understanding of complex diseases, which are thought to result from a complex interaction between genetic and environmental risk factors, is the paucity of relevant experimental models. This review describes a novel experimental approach that allows the study of the functional effects of disease-associated risk in complex disease by combining genome wide association studies (GWAS) and genome–scale epigenetic data to prioritize disease-associated risk variants with efficient gene editing technologies in human pluripotent stem cells (hPSCs). As a proof of principle, we recently used such a genetically precisely controlled experimental system to identify a common Parkinson’s disease-associated risk variant in a non-coding distal enhancer element that alters the binding of transcription factors and regulates the expression of α-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson’s disease.
- Genome Editing in Neurosciences: Using Genome Engineering to Understand Huntington’s Disease [BOOK]
- BOOKSpringer: Cham (CH)
- Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the Huntingtin (HTT) gene, leading to an expanded polyglutamine (polyQ…
Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the Huntingtin (HTT) gene, leading to an expanded polyglutamine (polyQ) region in the encoded protein HTT. We have used homologous recombination (HR) to genetically correct HD patient-derived induced pluripotent stem cells (iPSCs) and found that this reversed HD disease phenotypes. We have utilized exploited genome editing tools including TALENs (Transcription like activator effectors) and CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats)/Cas9 technology to carry out genetic correction or expansion, and we were able to detect HR without selection in human cells. The overall goal is to use this technology to model HD-relevant cell types and better understand disease progression by leveraging system biology approaches. To understand the disease progression, isogenic iPSC lines were created. We found that the disease phenotypes only manifested in the differentiated neural stem cell (NSC) stage, not in iPSCs. Transcriptomic analysis of HD iPSCs and HD NSCs compared to isogenic controls was utilized to understand the molecular basis for the CAG repeat expansion-dependent disease phenotypes in NSCs. Differential gene expression and pathway analysis identified transforming growth factor β (TGF-β) signaling, netrin-1 signaling and medium spiny neuron (MSNs) maturation and maintenance as the top dysregulated pathways in HD NSCs. The ability to create additional isogenic cell lines through CRISPR-mediated HR will further enhance our understanding of HD progression. These lines can be manipulated with CRISPR to understand the effects of common SNPs (single nucleotide polymorphism) that modulate disease onset in HD, allowing the identification of new pathways and helping to elucidate potential therapeutic targets for HD. Beyond drug discovery, the CRISPR system could eventually be optimized to use in vivo, correcting a patient’s disease-causing mutation, in the asymptomatic stages of HD.
- Efficient Human Cytomegalovirus Replication in Primary Endothelial Cells Is SOCS3 Dependent. [Journal Article]
- IIntervirology 2019 Jul 17; :1-10
- CONCLUSIONS: These findings indicate the implication of SOCS3 in the mechanism of HCMV-mediated control of cellular immune responses.
- Global Analysis of Intercellular Homeodomain Protein Transfer. [Journal Article]
- CRCell Rep 2019 Jul 16; 28(3):712-722.e3
- The homeodomain is found in hundreds of transcription factors that play roles in fate determination via cell-autonomous regulation of gene expression. However, some homeodomain-containing proteins (H…
The homeodomain is found in hundreds of transcription factors that play roles in fate determination via cell-autonomous regulation of gene expression. However, some homeodomain-containing proteins (HPs) are thought to be secreted and penetrate neighboring cells to affect the recipient cell fate. To determine whether this is a general characteristic of HPs, we carried out a large-scale validation for intercellular transfer of HPs. Our screening reveals that intercellular transfer is a general feature of HPs, but it occurs in a cell-context-sensitive manner. We also found the secretion is not solely a function of the homeodomain, but it is supported by external motifs containing hydrophobic residues. Thus, mutations of hydrophobic residues of HPs abrogate secretion and consequently interfere with HP function in recipient cells. Collectively, our study proposes that HP transfer is an intercellular communication method that couples the functions of interacting cells.
- Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons. [Journal Article]
- CRCell Rep 2019 Jul 16; 28(3):682-697.e7
- Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to co…
Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons. Here, we show that seven transcription factors (TFs) (Ascl1, Phox2b, AP-2α, Gata3, Hand2, Nurr1, and Phox2a) are able to convert astrocytes and fibroblasts into induced NA (iNA) neurons. These iNA neurons express the genes required for the biosynthesis, release, and re-uptake of noradrenaline. Moreover, iNA neurons fire action potentials, receive synaptic inputs, and control the beating rate of co-cultured ventricular myocytes. Furthermore, iNA neurons survive and integrate into neural circuits after transplantation. Last, human fibroblasts can be converted into functional iNA neurons as well. Together, iNA neurons are generated by direct reprogramming, and they could be potentially useful for disease modeling and cell-based therapies.
- Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease. [Journal Article]
- CRCell Rep 2019 Jul 16; 28(3):655-669.e5
- BDNF/TrkB neurotrophic signaling regulates neuronal development, differentiation, and survival, and deficient BDNF/TrkB activity underlies neurodegeneration in Alzheimer's disease (AD). However, exac…
BDNF/TrkB neurotrophic signaling regulates neuronal development, differentiation, and survival, and deficient BDNF/TrkB activity underlies neurodegeneration in Alzheimer's disease (AD). However, exactly how BDNF/TrkB participates in AD pathology remains unclear. Here, we show that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of transcription factor C/EBPβ. This, in turn, results in increased expression of δ-secretase, leading to both APP and Tau fragmentation by δ-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBPβ, or the δ-secretase enzymatic-dead C189S mutant. Inhibition of this pathological cascade can also rescue impaired synaptic plasticity and cognitive dysfunctions. Importantly, reduction in BDNF/TrkB neurotrophic signaling is inversely coupled with an increase in JAK2/STAT3, C/EBPβ, and δ-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBPβ upregulation, δ-secretase activity, and Aβ and Tau alterations in murine brains.
- XBP-1 Remodels Lipid Metabolism to Extend Longevity. [Journal Article]
- CRCell Rep 2019 Jul 16; 28(3):581-589.e4
- The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influenc…
The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPRER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.
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- A strand-specific real-time quantitative RT-PCR assay for distinguishing the genomic and antigenomic RNAs of Rift Valley fever Phlebovirus. [Journal Article]
- JVJ Virol Methods 2019 Jul 14; :113701
- Rift Valley Fever Phlebovirus (RVFV), genus Phlebovirus, family Phenuiviridae, order Bunyavirales, has a single-stranded, negative-sense RNA genome, consisting of L, M and S segments. Here, we report…
Rift Valley Fever Phlebovirus (RVFV), genus Phlebovirus, family Phenuiviridae, order Bunyavirales, has a single-stranded, negative-sense RNA genome, consisting of L, M and S segments. Here, we report the establishment of a strand-specific, quantitative reverse transcription (RT)-PCR assay system that can selectively distinguish between the genomic and antigenomic RNAs of each of the three viral RNA segments produced in RVFV-infected cells. To circumvent the obstacle of primer-independent cDNA synthesis during RT, we used a tagged, strand-specific RT primer, carrying a non-viral 'tag' sequence at the 5' end, which ensured the strand-specificity through the selective amplification of only the tagged cDNA in the real-time PCR assay. We used this assay system to examine the kinetics of intracellular accumulation of genomic and antigenomic viral RNAs in mammalian cells infected with the MP-12 strain of RVFV. The genomic RNA copy numbers, for all three viral RNA segments, were higher than that of their corresponding antigenomic RNAs throughout the time-course of infection, with a notable exception, wherein the M segment genomic and antigenomic RNAs exhibited similar copy numbers at specific times post-infection. Overall, this assay system could be a useful tool to gain an insight into the mechanisms of RNA replication and packaging in RVFV.