Stenotrophomonas maltophilia Isolated from the Gut Symbiotic Community of the Plastic-Eating Tenebrio molitor.

Polyvinyl chloride (PVC) waste is a major environmental challenge. In this study, we found that a PVC-eating insect, Tenebrio molitor, could survive by consuming PVC as a dietary supplement. To understand the gut symbiotic community, metagenomic analysis was performed to reveal the biodiversity of a symbiotic community in the midgut of Tenebrio molitor. Among them, seven genera were enriched from the midgut of the insect under culture conditions with PVC as carbon source. A strain of Stenotrophomonas maltophilia was isolated from the midgut symbiotic community of the plastic-eating Tenebrio molitor. To unravel the functional gene for the biodegradation enzyme, we sequenced the whole genome of Stenotrophomonas maltophilia and found that orf00390, annotated as a hydrolase, was highly expressed in the PVC culture niche.

The role of microglial activation on ischemic stroke: Modulation by fibroblast growth factors.

Stroke is one of the devastating clinical conditions that causes death and permanent disability. Its occurrence causes the reduction of oxygen and glucose supply, resulting in events such as inflammatory response, oxidative stress, and apoptosis in the brain. Microglia are brain-resident immune cells in the central nervous system (CNS) that exert diverse roles and respond to pathological process after an ischemic insult. The discovery of fibroblast growth factors (FGFs) in mammals, resulted to the findings that they can treat experimental models of stroke in animals effectively. FGFs function as homeostatic factors that control cells and hormones involved in metabolism, and they also regulate the secretion of proinflammatory (M1) and anti-inflammatory (M2) cytokines after stroke. In this review, we outline current evidence of microglia activation in experimental models of stroke focusing on its ability to exacerbate damage or repair tissue. Also, our review sheds light on the pharmacological actions of FGFs on multiple targets to regulate microglial modulation and highlighted their theoretical molecular mechanisms to provide possible therapeutic targets, as well as their limitations for the treatment of stroke. DATA AVAILABILITY: Not applicable.

Maternal LPS Exposure Enhances the 5-HT Level in the Prefrontal Cortex of Autism-like Young Offspring.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social interactions, impaired communication, and stereotyped behavior. The aim of this research is to investigate the changes in serotonin (5-HT) in the medial prefrontal cortex (PFC) of autism-like offspring induced by maternal lipopolysaccharide (LPS) exposure. Pregnant Sprague-Dawley rats were intraperitoneally injected with LPS to establish an autism-like model in their offspring. Offspring prenatally exposed to LPS showed autism-like behavior. The serotonin level in the mPFC of 2-week-old offspring was noticeably increased after maternal LPS exposure. Differentially expressed genes (DEGs) were enriched in pathways related to tryptophan metabolism and the serotonin system, as shown in RNA-seq findings. Consistently, tryptophan and serotonin metabolisms were altered in 2-week-old LPS-exposed offspring. The mRNA expression levels of 5-HT catabolic enzymes were remarkably reduced or tended to decrease. Moreover, maternal LPS exposure resulted in a higher serotonin 1B receptor (5-HT1BR) expression level in the mPFC but no difference in tryptophan hydroxylase 2 (TPH2) or serotonin reuptake transporter (SERT). The concentrations of 5-HT in serum and colon were increased in LPS-exposed offspring. Meanwhile, the expression level of tryptophan hydroxylase 1 (TPH1) in the colon was increased after maternal LPS treatment, whereas SERT was reduced. Furthermore, Golgi-Cox staining showed that neuronal dendritic length and spine density were significantly reduced in the mPFC of LPS-exposed offspring. The current study reveals that maternal LPS treatment resulted in an exaltation of the 5-HT of mPFC in ASD-like young rats, which may partly be caused by the abnormal elevation of 5-HT metabolism in its colon.

Sodium butyrate facilitates CRHR2 expression to alleviate HPA axis hyperactivity in autism-like rats induced by prenatal lipopolysaccharides through histone deacetylase inhibition.

Short-chain fatty acids (SCFAs, especially butyric acid) have been demonstrated to play a promising role in the development of autism spectrum disorders (ASD). Recently, the hypothalamic-pituitary-adrenal (HPA) axis is also suggested to increase the risk of ASD. However, the mechanism underlying SCFAs and HPA axis in ASD development remains unknown. Here, we show that children with ASD exhibited lower SCFA concentrations and higher cortisol levels, which were recaptured in prenatal lipopolysaccharide (LPS)-exposed rat model of ASD. These offspring also showed decreased SCFA-producing bacteria and histone acetylation activity as well as impaired corticotropin-releasing hormone receptor 2 (CRHR2) expression. Sodium butyrate (NaB), which can act as histone deacetylases inhibitors, significantly increased histone acetylation at the CRHR2 promoter in vitro and normalized the corticosterone as well as CRHR2 expression level in vivo. Behavioral assays indicated ameliorative effects of NaB on anxiety and social deficit in LPS-exposed offspring. Our results imply that NaB treatment can improve ASD-like symptoms via epigenetic regulation of the HPA axis in offspring; thus, it may provide new insight into the SCFA treatment of neurodevelopmental disorders like ASD. IMPORTANCE Growing evidence suggests that microbiota can affect brain function and behavior through the "microbiome-gut-brain'' axis, but its mechanism remains poorly understood. Here, we show that both children with autism and LPS-exposed rat model of autism exhibited lower SCFA concentrations and overactivation of HPA axis. SCFA-producing bacteria, Lactobacillus, might be the key differential microbiota between the control and LPS-exposed offspring. Interestingly, NaB treatment contributed to the regulation of HPA axis (such as corticosterone as well as CRHR2) and improvement of anxiety and social deficit behaviors in LPS-exposed offspring. The potential underlying mechanism of the ameliorative effect of NaB may be mediated via increasing histone acetylation to the CRHR2 promoter. These results enhance our understanding of the relationship between the SCFAs and the HPA axis in the development of ASD. And gut microbiota-derived SCFAs may serve as a potential therapeutic agent to neurodevelopmental disorders like ASD.

rFGF4 alleviates lipopolysaccharide-induced acute lung injury by inhibiting the TLR4/NF-κB signaling pathway.

Acute lung injury (ALI) is a serious and common clinical disease. Despite significant progress in ALI treatment, the morbidity and mortality rates remain high. However, no effective drug has been discovered for ALI. FGF4, a member of the FGF family, plays an important role in the regulation of various physiological and pathological processes. Therefore, in the present study, we aimed to study the protective effects of FGF4 against LPS-induced lung injury in vivo and in vitro. We found that rFGF4 treatment improved the lung W/D weight ratio, the survival rate, immune cell infiltration and protein concentrations in mice with LPS-induced ALI. Histological analysis revealed that rFGF4 significantly attenuated lung tissue injury and cell apoptosis. Furthermore, rFGF4 inhibited the activation of the TLR4/NF-κB signaling pathway and the production of pro-inflammatory mediators in LPS-injured lung tissues, murine alveolar macrophages (MH-S) and murine pulmonary epithelial (MLE-12) cells. The results of cell experiments further verified that rFGF4 inhibited the production of inflammatory mediators in MH-S cells and MLE-12 cells by regulating the TLR4/NF-κB signaling pathway. These results revealed that rFGF4 protected lung tissues and inhibited inflammatory mediators in mice with LPS-induced ALI by inhibiting the TLR4/NF-κB signaling pathway in MH-S and MLE-12 cells.

Discrete RNA-DNA hybrid cleavage by the EXD2 exonuclease pinpoints two rate-limiting steps.

EXD2 is a recently identified exonuclease that cleaves RNA and DNA in double-stranded (ds) forms. It thus serves as a model system for investigating the similarities and discrepancies between exoribonuclease and exodeoxyribonuclease activities and for understanding the nucleic acid (NA) unwinding-degradation coordination of an exonuclease. Here, using a single-molecule fluorescence resonance energy transfer (smFRET) approach, we show that despite stable binding to both substrates, EXD2 barely cleaves dsDNA and yet displays both exoribonuclease and exodeoxyribonuclease activities toward RNA-DNA hybrids with a cleavage preference for RNA. Unexpectedly, EXD2-mediated hybrid cleavage proceeds in a discrete stepwise pattern, wherein a sudden 4-bp duplex unwinding increment and the subsequent dwell constitute a complete hydrolysis cycle. The relatively weak exodeoxyribonuclease activity of EXD2 partially originates from frequent hybrid rewinding. Importantly, kinetic analysis and comparison of the dwell times under varied conditions reveal two rate-limiting steps of hybrid unwinding and nucleotide excision. Overall, our findings help better understand the cellular functions of EXD2, and the cyclic coupling between duplex unwinding and exonucleolytic degradation may be generalizable to other exonucleases.

RhFGF21 Protects Epidermal Cells against UVB-Induced Apoptosis through Activating AMPK-Mediated Autophagy.

Ultraviolet irradiation, especially ultraviolet B (UVB) irradiation, increases the risks of various skin diseases, such as sunburn, photo-aging and cancer. However, few drugs are available to treat skin lesions. Therefore, the discovery of drugs to improve the health of irradiated skin is urgently needed. Fibroblast growth factor 21 (FGF21) is a metabolic factor that plays an important role in the protection and repair of various types of pathological damage. The effects of FGF21 on skin injury caused by UVB-irradiation were the focus of this study. We found that UVB irradiation promoted the expression of FGF21 protein in mouse epidermal cells, and exogenous recombinant human FGF21 (rhFGF21) protected mouse skin tissue against UVB-induced injury. RhFGF21 inhibited the inflammatory responses and epidermal cell apoptosis as well as promotion of autophagy in UVB-irradiated mice. Moreover, we found that rhFGF21 protected HaCaT cells against UVB-induced apoptosis, and the protective effect was enhanced by treatment with an autophagy activator (rapamycin) but was inhibited by treatment with an autophagy inhibitor (3-methyladenine, 3MA). AMP-activated protein kinase (AMPK), as a cellular energy sensor, regulates autophagy. RhFGF21 increased the expression of p-AMPK protein in epidermal cells irradiated with UVB in vivo and in vitro. Moreover, rhFGF21 increased autophagy levels and the viability were diminished by treatment with an AMPK inhibitor (compound C). RhFGF21 protects epidermal cells against UVB-induced apoptosis by inducing AMPK-mediated autophagy.

Computed Tomography Angiography and B-Mode Ultrasonography under Artificial Intelligence Plaque Segmentation Algorithm in the Perforator Localization for Preparation of Free Anterolateral Femoral Flap.

This research was aimed to investigate the accuracy of U-shaped network (UNet)-based computed tomography angiography (CTA) and B-mode ultrasonography (US) in the perforator localization of free anterolateral thigh flap (ALTF). Based on UNet, a fusion of deep supervision mechanism, squeeze-and-excitation module, and attention mechanism was introduced to optimize the algorithm. Then, a CTA segmentation model, DA-UNet, was established. The segmentation performance of DA-UNet and other algorithms was compared under the same conditions. 30 patients who were planned to receive ALTF surgery were selected as the research objects. According to different preoperative localization methods, they were divided into group A (CTA) and group B (B-mode US), 15 cases in each group. Combined with the actual situation during surgery, the diagnostic accordance rate, sensitivity (Sen), specificity, and the distance between the perforator location and the actual location were compared between the two groups. The Dice coefficient, Jaccard index, Sen, the area under curve (AUC), and average Hausdorff distance (AVD) of the DA-UNet segmentation algorithm were 80.70%, 69.97%, 77.56%, 0.887, and 2.48, respectively. These results were significantly better than those of other algorithms (P < 0.05). In group A, the diagnostic accordance rate, Sen, and specificity of patients were 96.55%, 90.52%, and 73.58%, respectively, which were higher than 91.53%, 81.36%, and 15.60% of patients in group B significantly (P < 0.05). There was no statistical difference in the distance between the perforator location and the actual location (P > 0.05). It showed that the accuracy of CTA under the UNet-based DA-UNet segmentation model in the perforator localization of ALTF was better than that of B-mode US. Thus, a reference could be provided for the preparation of free ALTF and its clinical application.

Non-mitogenic fibroblast growth factor 1 protects against ischemic stroke by regulating microglia/macrophage polarization through Nrf2 and NF-κB pathways.

Microglia are immune cells in the central nervous system (CNS) that participate in response to pathological process after ischemic injury. Non-mitogenic fibroblast growth factor 1 (nmFGF1) is an effective neuroprotective factor that is also known as a metabolic regulator. The present study aimed to investigate the effects and mechanism of the neuroprotective ability of nmFGF1 on microglia in mice after photothrombosis (PT) stroke model, to determine whether it could ameliorate ischemic injury in stroke experiment. We discovered that the intranasal administration of nmFGF1 reduced infarct size and ameliorated neurological deficits in behavioral assessment by regulating the secretion of proinflammatory and anti-inflammatory cytokines. Furthermore, in the in vitro experiments, we found that nmFGF1 regulated the expression levels of proinflammatory and anti-inflammatory cytokines in oxygen-glucose deprivation (OGD) and lipopolysaccharide (LPS) stimulation. Evidence have shown that when nuclear factor erythroid 2-related factor 2 (Nfr2) is activated, it inhibits nuclear factor-kappa B (NF-κB) activation to alleviate inflammation. Interestingly, nmFGF1 treatment in vivo remarkably inhibited NF-κB pathway activation and activated Nrf2 pathway. In addition, nmFGF1 and NF-κB inhibitor (BAY11-7082) inhibited NF-κB pathway in LPS-stimulated BV2 microglia. Moreover, in LPS-stimulated BV2 microglia, the anti-inflammatory effect produced by nmFGF1 was knocked down by Nrf2 siRNA. These results indicate that nmFGF1 promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via Nrf2 and NF-κB signaling pathways, making nmFGF1 a potential agent against ischemic stroke.

Research progress of fibroblast growth factor in nervous system diseases.

Fibroblast growth factors (FGF) are a group of structurally related polypeptides which constitute an elaborate signaling system with their receptors. Evidence accumulated in the years suggests that the FGF family plays a key role in the repair of central nervous system injury. The main protective mechanisms include activating the expression of PI3K-Akt, peroxisome proliferator-activated receptor (PPARγ) and other signals; inhibiting NF-κB-mediated inflammatory response, oxidative stress and apoptosis; regulating neuronal differentiation and neuronal excitability as well as participating in protection of neurovascular units and nerve function repair. This paper comprehensively summarizes the latest research progress in FGF signaling related to diseases of the central nervous system such as cerebral infarction, cerebral hemorrhage, traumatic brain injury, Alzheimer's disease, Parkinson's disease, epilepsy and depression, aiming to provide scientific basis and reference for the development of innovative FGF drugs for the prevention and treatment of neurological diseases.

NmFGF1-Regulated Glucolipid Metabolism and Angiogenesis Improves Functional Recovery in a Mouse Model of Diabetic Stroke and Acts via the AMPK Signaling Pathway.

Diabetes increases the risk of stroke, exacerbates neurological deficits, and increases mortality. Non-mitogenic fibroblast growth factor 1 (nmFGF1) is a powerful neuroprotective factor that is also regarded as a metabolic regulator. The present study aimed to investigate the effect of nmFGF1 on the improvement of functional recovery in a mouse model of type 2 diabetic (T2D) stroke. We established a mouse model of T2D stroke by photothrombosis in mice that were fed a high-fat diet and injected with streptozotocin (STZ). We found that nmFGF1 reduced the size of the infarct and attenuated neurobehavioral deficits in our mouse model of T2D stroke. Angiogenesis plays an important role in neuronal survival and functional recovery post-stroke. NmFGF1 promoted angiogenesis in the mouse model of T2D stroke. Furthermore, nmFGF1 reversed the reduction of tube formation and migration in human brain microvascular endothelial cells (HBMECs) cultured in high glucose conditions and treated with oxygen glucose deprivation/re-oxygenation (OGD). Amp-activated protein kinase (AMPK) plays a critical role in the regulation of angiogenesis. Interestingly, we found that nmFGF1 increased the protein expression of phosphorylated AMPK (p-AMPK) both in vivo and in vitro. We found that nmFGF1 promoted tube formation and migration and that this effect was further enhanced by an AMPK agonist (A-769662). In contrast, these processes were inhibited by the application of an AMPK inhibitor (compound C) or siRNA targeting AMPK. Furthermore, nmFGF1 ameliorated neuronal loss in diabetic stroke mice via AMPK-mediated angiogenesis. In addition, nmFGF1 ameliorated glucose and lipid metabolic disorders in our mouse model of T2D stroke without causing significant changes in body weight. These results revealed that nmFGF1-regulated glucolipid metabolism and angiogenesis play a key role in the improvement of functional recovery in a mouse model of T2D stroke and that these effects are mediated by the AMPK signaling pathway.

MicroRNA-29c Acting on FOS Plays a Significant Role in Nonalcoholic Steatohepatitis Through the Interleukin-17 Signaling Pathway.

Nonalcoholic fatty liver disease is the most common hepatic disease in western countries and is even more ubiquitous in Asian countries. Our study determined that TH17/Treg cells were imbalanced in animal models. Based on our interest in the mechanism underlying TH17/Treg cell imbalance in nonalcoholic fatty liver mice, we conducted a joint bioinformatics analysis to further investigate this process. Common gene sequencing analysis was based on one trial from one sequencing platform, where gene expression analysis and enrichment analysis were the only analyses performed. We compared different sequencing results from different trials performed using different sequencing platforms, and we utilized the intersection of these analytical results to perform joint analysis. We used a bioinformatics analysis method to perform enrichment analysis and map interaction network analysis and predict potential microRNA sites. Animal experiments were also designed to validate the results of the data analysis based on quantitative polymerase chain reaction (qPCR) and western blotting. Our results revealed 8 coexisting differentially expressed genes (DEGs) and 7 hinge genes. The identified DEGs may influence nonalcoholic steatosis hepatitis through the interleukin-17 pathway. We found that microRNA-29c interacts with FOS and IGFBP1. Polymerase chain reaction analyses revealed both FOS and microRNA-29c expression in NASH mice, and western blot analyses indicated the same trend with regard to FOS protein levels. Based on these results, we suggest that microRNA-29c acts on FOS via the interleukin-17 signaling pathway to regulate TH17/Treg cells in NASH patients.

Proximal Single-Stranded RNA Destabilizes Human Telomerase RNA G-Quadruplex and Induces Its Distinct Conformers.

Single-stranded guanine-rich RNA sequences have a propensity to fold into compact G-quadruplexes (RG4s). The conformational transitions of these molecules provide an important way to regulate their biological functions. Here, we examined the stability and conformation of an RG4-forming sequence identified near the end of human telomerase RNA. We found that a proximal single-stranded (ss) RNA significantly impairs RG4 stability at physiological K+ concentrations, resulting in a reduced RG4 rupture force of ∼ 24.4 pN and easier accessibility of the G-rich sequence. The destabilizing effect requires a minimum of six nucleotides of ssRNA and is effective at either end of RG4. Remarkably, this RG4-forming sequence, under the influence of such a proximal ssRNA, exhibits interconversions between at least three less stable RG4 conformers that might represent potential intermediates along its folding/unfolding pathway. This work provides insights into the stability and folding dynamics of RG4 that are essential for understanding its biological functions.

Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring.

Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure. Methods: Pregnant TLR4-/- (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1ß, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring's autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring. Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4-/- offspring. Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.

A study of knowledge, attitudes, and practices of primary care physicians toward anticoagulant therapy in patients with non-valvular atrial fibrillation in Shanghai, China.

BACKGROUND: As a large number of Community Health Service (CHS) centers in China face the majority of patients with non-valvular atrial fibrillation (NVAF), primary care physicians (PCPs) play a primary role in the prevention of embolization. Therefore, an awareness of anticoagulant management in patients with NVAF must be brought into focus among PCPs in China. This study investigated PCPs' knowledge, attitudes, and practices toward anticoagulant therapy in patients with NVAF, to help them understand their shortcomings regarding oral anticoagulant (OAC) therapy in preventing embolization. METHOD: This was a cross-sectional observational study of 462 PCPs in CHS centers across Shanghai. We used a self-administered questionnaire to collect data from September to December 2017. A stratified random cluster sampling was adopted in the 90 CHS centers with the family medicine residency program. RESULT: Among 462 participants, 69.3% (320/462) of females received a medical bachelor's degree and over 50% of participants had more than 10 years of work experience. Each section for knowledge, attitude, and practice were categorized as poor (≤39.0%), fair (40.0-69.0%), and good (≥70.0%). The level of knowledge of OAC therapy for patients with NVAF among PCPs was insufficient in over half (75.8%) of the participants. The majority (89.8%) of PCPs had a positive attitude and 68.0% had modest performance in the anticoagulant management of patients with NVAF. CONCLUSIONS: The knowledge and behaviors of PCPs were insufficient for OAC therapy to prevent embolization in patients with NVAF. The study also revealed that there is good potential for PCPs' educational interventions to positively impact the care of patients with NVAF.

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway.

Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)-induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia in vitro. The current study demonstrated that LPS induced depressive-like behaviors, upregulated proinflammatory cytokines, and activated microglia in the mouse hippocampus and activated the inflammatory response in primary microglia, while pretreatment with rhFGF21 markedly improved depression-like behavior deficits, as shown by an increase in the total distance traveled and number of standing numbers in the open field test (OFT) and a decrease in the duration of immobility in the tail suspension test (TST) and forced swimming test (FST). Furthermore, rhFGF21 obviously suppressed expression levels of the proinflammatory cytokines interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) and inhibited microglial activation and the nuclear factor-κB (NF-κB) signing pathway. Moreover, coadministration of rhFGF21 with the fibroblast growth factor receptor 1 (FGFR1) inhibitor PD173074 significantly reversed these protective effects, indicating that the antidepressant effects of rhFGF21 occur through FGFR1 activation. Taken together, the results of the current study demonstrated for the first time that exogenous rhFGF21 ameliorated LPS-induced depressive-like behavior by inhibiting microglial expression of proinflammatory cytokines through NF-κB suppression. This new discovery suggests rhFGF21 as a new therapeutic candidate for depression treatment.

Non-Mitogenic Fibroblast Growth Factor 1 Enhanced Angiogenesis Following Ischemic Stroke by Regulating the Sphingosine-1-Phosphate 1 Pathway.

Ischemic strokes account for about 80% of all strokes and are associated with a high risk of mortality. Angiogenesis of brain microvascular endothelial cells may contribute to functional restoration following ischemia. Fibroblast growth factor 1 (FGF1), a member of FGF superfamily, involved in embryonic development, angiogenesis, wound healing, and neuron survival. However, the mitogenic activity of FGF1 is known to contribute to several human pathologies, thereby questioning the safety of its clinical applications. Here, we explored the effects and mechanism of action of non-mitogenic FGF1 (nmFGF1) on angiogenesis in mice after ischemia stroke and an oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) injury model. We found that intranasal administration nmFGF1 significantly promoted angiogenesis in mice after stroke, and significantly increased the formation of matrigel tube and promoted scratch migration in a dose-dependent manner in OGD-induced HBMECs in vitro. However, the co-administration of an FGF receptor 1 (FGFR1)-specific inhibitor PD173074 significantly reversed the effects of nmFGF1 in vitro, suggesting that nmFGF1 functions via FGFR1 activation. Moreover, nmFGF1 activated sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) in mice after stroke in vivo. S1P1 protein antagonist VPC23019 and agonist FTY720 were used to confirm that nmFGF1 promotes angiogenesis in vitro partially through the S1P1 pathway. OGD induced downregulation of S1P1 expression. The S1P1 antagonist VPC23019 blocked the stimulatory effects of nmFGF1, whereas the S1P1 agonist FTY720 exerted effects comparable with those of nmFGF1. Furthermore, PD173074 reversed the effect of nmFGF1 on upregulating S1P1 signaling. In conclusion, nmFGF1 enhanced angiogenesis in mice following stroke and OGD-induced HBMECs through S1P1 pathway regulation mediated via FGFR1 activation. This new discovery suggests the potential therapeutic role of nmFGF1 for the treatment of ischemic strokes.

FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response.

Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3ß pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.