Fibroblast growth factor 10 ameliorates neurodegeneration in mouse and cellular models of Alzheimer's disease via reducing tau hyperphosphorylation and neuronal apoptosis.

Alzheimer's disease (AD) is characterized with senile plaques formed by Aß deposition, and neurofibrillary tangles composed of hyperphosphorylated tau protein, which ultimately lead to cognitive impairment. Despite the heavy economic and life burdens faced by the patients with AD, effective treatments are still lacking. Previous studies have reported the neuroprotective effects of FGF10 in CNS diseases, but its role in AD remains unclear. In this study, we demonstrated that FGF10 levels were reduced in the serum of AD patients, as well as in the brains of 3xTg-AD mice and APPswe-transfected HT22 cells, suggesting a close relationship between FGF10 and AD. Further investigations revealed that intranasal delivery of FGF10 improved cognitive functions in 3xTg-AD mice. Additionally, FGF10 treatment reduced tau hyperphosphorylation and neuronal apoptosis, thereby mitigating neuronal cell damage and synaptic deficits in the cortex and hippocampus of 3xTg-AD mice, as well as APPswe-transfected HT22 cells. Furthermore, we evaluated the therapeutic potential of FGF10 gene delivery for treating AD symptoms and pathologies. Tail vein delivery of the FGF10 gene using AAV9 improved cognitive and neuronal functions in 3xTg-AD mice. Similarly, endogenous FGF10 overexpression ameliorated tau hyperphosphorylation and neuronal apoptosis in the cortex and hippocampus of 3xTg-AD mice. Importantly, we confirmed that the FGFR2/PI3K/AKT signaling pathway was activated following intranasal FGF10 delivery and AAV9-mediated FGF10 gene delivery in 3xTg-AD mice and APPswe-transfected HT22 cells. Knockdown of FGFR2 attenuated the protective effect of FGF10. Collectively, these findings suggest that intranasal delivery of FGF10 and AAV9-mediated FGF10 gene delivery could be a promising disease-modifying therapy for AD.

Relationships between urban expansion and socioenvironmental indicators across multiple scales of watersheds: a case study among watersheds running through China.

Understanding the relationships between urban expansion and social/environmental features is fundamental to managing watershed and urban expansion. However, such relationships remain unclear, especially across multiple scales of watersheds. Here, we quantified the correlation between urban expansion measures and 255 socioenvironmental indicators across three scales of watersheds running through China (20, 103, and 349 watersheds) during 1992-2016 and analyzed their scaling relations. The results showed that the number of indicators showing a significant correlation with the area and speed of urban expansion increased from 132 and 153 to 234 and 237, respectively, from level 1 to level 3 watersheds. Among these indicators, urban expansion was significantly correlated with indicators of climate and anthropogenic impact. From a large scale (level 1 watershed) to a small scale (level 3 watershed), 104 and 84 socioenvironmental indicators shifted from uncorrelated to significantly correlated with urban expansion area and speed. The constraint line analysis further confirmed that some relationships were nonlinear, which suggested that the drivers and impacts of urban expansion have scaling effects. We argue that it is crucial to consider the scaling effects of urban expansion when we formulate urban or watershed management plans.

Fibroblast-Conditioned Media Enhance the Yield of Microglia Isolated from Mixed Glial Cultures.

Microglia are the main immune cells of the central nervous system (CNS) and comprise various model systems used to investigate inflammatory mechanisms in CNS disorders. Currently, shaking and mild trypsinization are widely used microglial culture methods; however, the problems with culturing microglia include low yield and a time-consuming process. In this study, we replaced normal culture media (NM) with media containing 25% fibroblast-conditioned media (F-CM) to culture mixed glia and compared microglia obtained by these two methods. We found that F-CM significantly improved the yield and purity of microglia and reduced the total culture time of mixed glia. The microglia obtained from the F-CM group showed longer ramified morphology than those from the NM group, but no difference was observed in cell size. Microglia from the two groups had similar phagocytic function and baseline phenotype markers. Both methods yielded microglia were responsive to various stimuli such as lipopolysaccharide (LPS), interferon-γ (IFN-γ), and interleukin-4 (IL-4). The current results suggest that F-CM affect the growth of primary microglia in mixed glia culture. This method can produce a high yield of primary microglia within a short time and may be a convenient method for researchers to investigate inflammatory mechanisms and some CNS disorders.

Hydroxychloroquine attenuates neuroinflammation following traumatic brain injury by regulating the TLR4/NF-κB signaling pathway.

BACKGROUND: After traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood-brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway. METHODS: C57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated. RESULTS: HCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ. CONCLUSIONS: HCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.

Mesenchymal Stem Cell-Conditioned Medium Protects Hippocampal Neurons From Radiation Damage by Suppressing Oxidative Stress and Apoptosis.

OBJECTIVE: To investigate the effects of mesenchymal stem cell-conditioned medium (MSC-CM) on radiation-induced oxidative stress, survival and apoptosis in hippocampal neurons. METHODS: The following groups were defined: Control, radiation treatment (RT), RT+MSC-CM, MSC-CM, RT + N-Acetylcysteine (RT+NAC), and RT + MSC-CM + PI3 K inhibitor (LY294002). A cell Counting Kit-8 (CCK-8) was used to measure cell proliferation. Apoptosis was examined by AnnexinV/PI flow cytometric analyses. Intracellular reactive oxygen species (ROS) were detected by DCFH-DA. Intracellular glutathione (GSH), malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity were detected by colorimetric assays. Protein levels of γ-H2AX, PI3K-AKT, P53, cleaved caspase-3, Bax, and BCl-2 were analyzed by Western blotting. RESULTS: The proliferation of HT22 cells was significantly inhibited in the RT group, but was significantly preserved in the RT + MSC-CM group (P < 0.01). Apoptosis was significantly higher in the RT group than in the RT+ MSC-CM group (P < 0.01). MSC-CM decreased intracellular ROS and MDA content after irradiation (P < 0.01). GSH level and SOD activity were higher in the RT + MSC-CM group than in the RT group, as was MMP (P < 0.01). MSC-CM decreased expression of γ-H2AX, P53, Bax, and cleaved-caspase-3, but increased Bcl-2 expression (P < 0.01). CONCLUSION: MSC-CM attenuated radiation-induced hippocampal neuron cell line damage by alleviating oxidative stress and suppressing apoptosis.