Sex-specific effects of high-fat diet on rat brain glucose metabolism and early-onset dementia symptoms.

Peripheral metabolic disturbances are associated with a variety of clinical health consequences and may contribute to the development of neurocognitive disorders. This study investigates whether long-term high-fat diet (HFD) consumption changes the brain glucose metabolism and impairs memory performance in a sex-dependent manner. Male and female rats, after weaning, were fed HFD or normal chow diet (NCD) for 16 weeks. Behavioral tests for spatial memory and an 18 F-FDG-PET scan were performed. Also, the expression of brain insulin resistance markers and Alzheimer's pathology-related genes was assessed by qPCR. The Morris water maze and Y-maze results showed, respectively, that memory retrieval and spatial working memory were impaired only in HFD male rats compared to NCD controls. In addition, measuring whole brain 18 F-FDG uptake indicated a significant reduction in glucose metabolism in male but not female HFD rats. Analysis of 15 genes related to glucose metabolism and Alzheimer's pathology, in the hippocampus, showed that expression of GLUT3, IRS2, and IDE is significantly reduced in HFD male rats. Our results suggest that sex affects the HFD-induced dysregulation of brain glucose metabolism and cognitive performance.

Effects of photobiomodulation on mitochondrial function in diabetic adipose-derived stem cells in vitro.

Herein are reported the effects of photobiomodulation (PBM) on adenosine triphosphate (ATP) and reactive oxygen species (ROS) quantification and mitochondria membrane potential (MMP) of the mitochondria of diabetic adipose-derived stem cells (ADSCs) in vitro. Additionally, the expression of PTEN-induced kinase 1 (PINK1) and RBR E3 ubiquitin-protein ligase (PARKIN) genes, which are involved in mitochondrial quality, were quantified. First, type one diabetes was induced in 10 rats. The rats were then kept for 1 month, after which fat tissue was excised from subcutaneous regions, and stem cells were selected from the fat, characterized as ADSC, and cultivated and increased in elevated sugar conditions in vitro; these samples were considered diabetic-ADSC. Two groups were formed, namely, diabetic-control-ADSC and PBM-diabetic-ADSC. ATP, ROS quantification, and MMP of mitochondria of diabetic ADSCs in vitro were measured, and the expression of PINK1 and Parkin genes was quantified in vitro. The results revealed that PBM significantly increased ATP quantification (p = 0.05) and MMP activity (p = 0.000) in diabetic-ADSCs in vitro compared to the control diabetic-ADSCs; however, it significantly decreased ROS quantification (p = 0.002) and PINK1(p = 0.003) and PARKIN gene expression (p = 0.046) in diabetic-ADSCs. The current findings indicate for the first time that PBM has the potential to maintain the function and quality of mitochondrial diabetic-ADSCs by significantly increasing ATP quantification and MMP activity in diabetic-ADSCs in vitro while significantly decreasing ROS quantification and PINK1 and PARKIN gene expression, making PBM an attractive candidate for use in improving the efficacy of autologous stem cell remedies for diabetic patients with infected diabetic foot ulcers.

Insulin Promotes Schwann-Like Cell Differentiation of Rat Epidermal Neural Crest Stem Cells.

Schwann cells (SCs) are considered potentially attractive candidates for transplantation therapies in neurodegenerative diseases. However, problems arising from the isolation and expansion of the SCs restrict their clinical applications. Establishing an alternative Schwann-like cell type is a prerequisite. Epidermal neural crest stem cells (EPI-NCSCs) are well studied for their autologous accessibility, along with the ability to produce major neural crest derivatives and neurotrophic factors. In the current study, we explored insulin influence, a well-known growth factor, on directing EPI-NCSCs into the Schwann cell (SC) lineage. EPI-NCSCs were isolated from rat hair bulge explants. The viability of cells treated with a range of insulin concentrations (0.05-100 µg/ml) was defined by MTT assay at 24, 48, and 72 h. The gene expression profiles of neurotrophic factors (BDNF, FGF-2, and IL-6), key regulators involved in the development of SC (EGR-1, SOX-10, c-JUN, GFAP, OCT-6, EGR-2, and MBP), and oligodendrocyte (PDGFR-α and NG-2) were quantified 1 and 9 days post-treatment with 0.05 and 5 µg/ml insulin. Furthermore, the protein expression of nestin (stemness marker), SOX-10, PDGFR-α, and MBP was analyzed following the long-term insulin treatment. Insulin downregulated the early-stage SC differentiation marker (EGR-1) and increased neurotrophins (BDNF and IL-6) and pro-myelinating genes, including OCT-6, SOX-10, EGR-2, and MBP, as well as oligodendrocyte differentiation markers, upon exposure for 9 days. Insulin can promote EPI-NCSC differentiation toward SC lineage and possibly oligodendrocytes. Thus, employing insulin might enhance the EPI-NCSCs efficiency in cell transplantation strategies.

Fingolimod increases oligodendrocytes markers expression in epidermal neural crest stem cells.

Epidermal neural crest stem cells (EPI-NCSCs) are propitious candidates for cell replacement therapy and supplying neurotrophic factors in the neurological disorders. Considering the potential remyelinating and regenerative effects of fingolimod, in this study, we evaluated its effects on EPI-NCSCs viability and the expression of neurotrophic and oligodendrocyte differentiation factors. EPI-NCSCs, extracted from the bulge of rat hair follicles, were characterized and treated with fingolimod (0, 50, 100, 200, 400, 600, 1000, and 5000 nM). The cell viability was evaluated by MTT assay at 6, 24 and 72 h. The expression of neurotrophic and differentiation factors in the cells treated with 100 and 400 nM fingolimod were measured at 24 and 120 h. Fingolimod at 50-600 nM increased the cells viability after 6 h, with no change at the higher concentrations. The highest concentration (5000nM) induced toxicity at 24 and 72 h. NGF and GDNF genes expression were decreased at 120 h, but on the contrary, brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) were increased by both concentrations at both time points. Oligodendrocyte markers including platelet-derived growth factor receptor A (PDGFRα), neuron-glial antigen 2 (NG2) and growth associated protein 43 (GAP43) were elevated at 120 h, which was accompanied with reduce in stemness markers (Nestin and early growth response 1 (EGR1)). Fingolimod increased the expression of neurotrophic factors in EPI-NCSCs, and guided them to oligodendrocyte fate. Therefore, fingolimod in combination with EPI-NCSCs, can be considered as a promising approach for demyelinating neurological disorders.

Combination therapy with astaxanthin and epidermal neural crest stem cells improves motor impairments and activates mitochondrial biogenesis in a rat model of spinal cord injury.

Spinal cord injury (SCI), a multifactorial disease, can lead to irreversible motor and sensory disabilities. Cell therapy in combination with pharmacological agents can be a promising approach to attenuate SCI damages. Epidermal neural crest stem cells (EPI-NCSCs) extracted from bulge hair follicle in adults are attractive candidates due to the possibility of autologous transplantation. This study evaluated the effect of EPI-NCSCs combined with astaxanthin (Ast), a potent antioxidant, on damages induced by SCI. Male rats were treated with Ast (0.2 mM) and EPI-NCSCs (106/10 µl PBS) alone and combined together after SCI contusion. Motor function was assessed by Basso, Beattie and Bresnahan (BBB) test on days 1, 3, 7, 14, 21, 28, 35 and 42 post-injury. Motor neurons number and myelin level were evaluated on days 14 and 42 using Nissl and Luxol Fast Blue staining. The gene expression of mitochondrial biogenesis involved factors (PGC1α, NRF1 and TFAM) was measured by qPCR. All treatments improved motor function, with the highest BBB score in Ast + Cell compared to Ast and Cell. Decreased motor neurons number and myelin level following SCI, were increased by Ast, Cell and Ast + Cell, but combination therapy significantly had a better effect. We observed reduction in PGC1α, NRF1, and TFAM expression in spinal tissue after SCI, and treatment with Cell and Ast + Cell significantly restored NRF1 and TFAM mRNA levels. These results suggested that Ast in combination with EPI-NCSCs has better effects on behavioral dysfunction, motor neuron loss and demyelination after SCI. These protective effects may be attributed to mitochondrial biogenesis activation.