The role of Nrf2 in neural stem/progenitors cells: From maintaining stemness and self-renewal to promoting differentiation capability and facilitating therapeutic application in neurodegenerative disease.

Exercise has been shown to have beneficial effects on brain functions in humans and animals. Exercise can improve memory and learning in age-related neurodegenerative diseases. In animal models, physical exercise regulates epigenetics, promotes synaptic plasticity and hippocampal neurogenesis, regulates the expression levels of neurotrophic factors, and improves cognitive function. Therefore, exercise is very important for brain rehabilitation and remodeling. The purpose of this review is to explore the mechanisms by which exercise exerts positive effects on brain function. This knowledge implies that physical exercise can be used as a non-drug therapy for neurological diseases.

Physical exercise promotes brain remodeling by regulating epigenetics, neuroplasticity and neurotrophins.

The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract, collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota's ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment. 

/pdf/microbiota-gut-brain-axis-regulation-of-adult-hippocampal-1oel7lfr.pdf

Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis

Fetal brain development is closely dependent on maternal nutrition and metabolic status. Maternal protein restriction (PR) is known to be associated with alterations in the structure and function of the hypothalamus, leading to impaired control of energy homeostasis and food intake. The objective of this study was to identify the cellular and molecular systems underlying these effects during fetal development. We combined a global transcriptomic analysis on the fetal hypothalamus from a rat model of maternal PR with in vitro neurosphere culture and cellular analyses. Several genes encoding proteins from the mitochondrial respiratory chain complexes were overexpressed in the PR group and mitochondrial metabolic activity in the fetal hypothalamus was altered. The level of the N6-methyladenosine epitranscriptomic mark was reduced in the PR fetuses, and the expression of several genes involved in the writing/erasing/reading of this mark was indeed altered, as well as genes encoding several RNA-binding proteins. Additionally, we observed a higher number of neuronal-committed progenitors at embryonic day 17 (E17) in the PR fetuses. Together, these data strongly suggest a metabolic adaptation to the amino acid shortage, combined with the post-transcriptional control of protein expression, which might reflect alterations in the control of the timing of neuronal progenitor differentiation.

https://www.mdpi.com/2072-6643/12/5/1464/pdf

Maternal Protein Restriction in Rats Alters the Expression of Genes Involved in Mitochondrial Metabolism and Epitranscriptomics in Fetal Hypothalamus.

The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract, collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota’s ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment.

https://content.iospress.com/download/brain-plasticity/bpl220141?id=brain-plasticity/bpl220141

Physical exercise-induced enhancement of learning and memory and alleviation of age-related cognitive decline in humans have been widely acknowledged. However, the mechanistic relationship between exercise and cognitive improvement remains largely unknown. In this study, we found that exercise-elicited cognitive benefits were accompanied by adaptive hippocampal proteasome activation. Voluntary wheel running increased hippocampal proteasome activity in adult and middle-aged mice, contributing to an acceleration of neurogenesis that could be reversed by intrahippocampal injection of the proteasome inhibitor MG132. We further found that increased levels of insulin-like growth factor-1 (IGF-1) in both serum and hippocampus may be essential for exercise-induced proteasome activation. Our in vitro study demonstrated that IGF-1 stimulated proteasome activity in cultured adult neural progenitor cells (NPCs) by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), followed by elevated expressions of proteasome subunits such as PSMB5. In contrast, pretreating adult mice with the selective IGF-1R inhibitor picropodophyllin diminished exercise-induced neurogenesis, concurrent with reduced Nrf2 nuclear translocation and proteasome activity. Likewise, lowering Nrf2 expression by RNA interference with bilateral intrahippocampal injections of recombinant adeno-associated viral particles significantly suppressed exercise-induced proteasome activation and attenuated cognitive function. Collectively, our work demonstrates that proteasome activation in hippocampus through IGF-1/Nrf2 signaling is a key adaptive mechanism underlying exercise-related neurogenesis, which may serve as a potential targetable pathway in neurodegeneration.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/stem.3102

Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis.

The invention belongs to the field of biomedicine and provides preparation of a secoiridoid glycoside complex and application of the secoiridoid glycoside complex in improving the viability of bone-marrow mesenchymal stem cells in order to solve the problems about changes in the cellular morphology, metabolism, proliferation and differentiation potential of bone-marrow mesenchymal stem cells (BMSCs) cultured in vitro, improve the proliferation of the BMSCs cultured in vitro and keep the BMSCs good in differentiation potential. The secoiridoid glycoside complex is prepared by mixing oleuropein, rehmaionoside A and gentiopicroside with a conventional in-vitro cell culture medium in a certain proportion. By means of the secoiridoid glycoside complex, the proliferation capacity of the BMSCs can be improved, short-term proliferation is promoted, so that a lot of cells are obtained to be used for transplantation for treatment, and moreover, the survival rate of the transplanted cells in vivo can be improved. When the complex acts on the BMSCs for a long time, the oxidative-damage-resistant ability of the cells can be improved, and the BMSC differentiation tending to neurons is promoted without changing the biological characteristics of the BMSCs. A method is provided for the wide application of the BMSCs in research of medical tissue engineering.

Preparation of secoiridoid glycoside complex and application of secoiridoid glycoside complex in improving viability of bone-marrow mesenchymal stem cells

Xuechun Zhao

Papers

Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis.

Preparation of secoiridoid glycoside complex and application of secoiridoid glycoside complex in improving viability of bone-marrow mesenchymal stem cells