Corrigendum: NmFGF1-regulated glucolipid metabolism and angiogenesis improves functional recovery in a mouse model of diabetic stroke and acts via the AMPK signaling pathway.

[This corrects the article DOI: 10.3389/fphar.2021.680351.].

FGF17 protects cerebral ischemia reperfusion-induced blood-brain barrier disruption via FGF receptor 3-mediated PI3K/AKT signaling pathway.

Maintaining blood-brain barrier (BBB) integrity is critical components of therapeutic approach for ischemic stroke. Fibroblast growth factor 17 (FGF17), a member of FGF8 superfamily, exhibits the strongest expression throughout the wall of all major arteries during development. However, its molecular action and potential protective role on brain endothelial cells after stroke remains unclear. Here, we observed reduced levels of FGF17 in the serum of patients with ischemic stroke, as well as in the brains of mice subjected to middle cerebral artery occlusion (MCAO) injury and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (bEnd.3) cells. Moreover, treatment with exogenous recombinant human FGF17 (rhFGF17) decreased infarct volume, improved neurological deficits, reduced Evans Blue leakage and upregulated the expression of tight junctions in MCAO-injured mice. Meanwhile, rhFGF17 increased cell viability, enhanced trans-endothelial electrical resistance, reduced sodium fluorescein leakage, and alleviated reactive oxygen species (ROS) generation in OGD/R-induced bEnd.3 cells. Mechanistically, the treatment with rhFGF17 resulted in nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and upregulation of heme oxygenase-1 (HO-1) expression. Additionally, based on in-vivo and in-vitro research, rhFGF17 exerted protective effects against ischemia/reperfusion (I/R) -induced BBB disruption and endothelial cell apoptosis through the activation of the FGF receptor 3/PI3K/AKT signaling pathway. Overall, our findings indicated that FGF17 may hold promise as a novel therapeutic strategy for ischemic stroke patients.

Ciprofloxacin degradation performances and mechanisms by the heterogeneous electro-Fenton with flocculated fermentation biochar.

Antibiotic fermentation residue flocculated by polymeric ferric sulfate (PFS) has been classified as a "hazardous waste" in China. In this study, it was recycled into antibiotic fermentation residue biochar (AFRB) by pyrolysis and used as a heterogeneous electro-Fenton (EF) catalyst for ciprofloxacin (CIP) degradation. The results show that PFS was reduced to Fe0 and FeS during pyrolysis, which was beneficial for the EF process. The AFRB with mesoporous structures exhibited soft magnetic features, which were convenient for separation. CIP was completely degraded within 10 min by the AFRB-EF process at an initial concentration of 20 mg/L. Increasing the working current and catalyst dosage within a certain range could improve the degradation rate. ·OH and O2·- were the dominant reactive oxygen species that played critical roles for CIP degradation. The antibacterial groups of CIP have been destroyed by the heterogeneous electro-Fenton process and its toxicity was negligible. The AFRB showed satisfactory performance, even though it was recycled five times. This study provide new insights into the resourceful treatment of antibiotic fermentation residues.

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.

Water disinfection by the UVA/electro-Fenton process under near neutral conditions: Performance and mechanisms.

An efficient and thorough water disinfection is critical for human health. In this study, UVA-LEDs, nitrilotriacetic acid (NTA) and a boron-doped diamond anode were respectively used as the UVA source, the iron chelator and the anode for the UVA/electro-Fenton (E-Fenton) reaction to treat wastewater. The disinfection performance of the UVA/E-Fenton had been investigated. The mechanisms of the E. coli inactivation had been clarified. The results showed that complete disinfection (about 5.6-log removal) could be achieved within 50 min at a certain condition due to the synergistic effort of the UVA, anodic oxidation and the electro-Fenton. The quenching experiments and the electron paramagnetic resonance (EPR) detection indicated that •OH, •O2- and 1O2 play important roles for inactivating E. coli. The results of SEM images and genomic DNA electrophoresis suggested that both the cell structure and the DNA had been thoroughly destroyed during the UVA/E-Fenton process. Increasing the UVA irradiation, oxygen bubbling could improve the disinfection rate, while it also would increase the energy consumption. The appropriate Fe and NTA ratio was 1:2 to realize an efficient Fenton reaction under near neutral condition. Complete disinfection was also achieved within 50 min when it used for treating real wastewater. Thus, the UVA/E-Fenton process is a satisfied way for water disinfection.

The drinking water disinfection performances and mechanisms of UVA-LEDs promoted by electrolysis.

In this study, the UVA (Ultraviolet A) drinking water disinfection was promoted by electrolysis. The influences of the UVA, electrolysis current, bubbling and temperature were investigated. The disinfection mechanisms and bacterial reactivation had been studied. The results revealed that the treatment time needed to reach the DL (detection limit, about 5.4 log removal) was shortened from 180 to 80 min by the electrolysis. The total electricity consumption decreased from about 126-57.0 kJ/L. Compared with increasing the UVA irradiation, increasing the electrolysis current in a certain range was more preferred to improve the disinfection rate. Oxygen bubbling or higher temperature could enhance the E. coli inactivation. The quenching experiment and EPR (Electron paramagnetic resonance) detection confirmed that ROSs (1O2, ·O2- and ·OH) played important roles for the disinfection. Compared with the treatment with UVA alone, the cell membrane damage was more severe by the promoting method. In addition to the dramatically reduced enzyme activity, the synergistic process degraded most of the bacterial genomic DNA, and the bacteria were completely killed. Therefore, hybrid with electrolysis is a better way for the application of the UVA-LED disinfection.

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.

Spontaneous nutrient recovery and disinfection of aquaculture wastewater via Mg-coconut shell carbon composites.

Aquaculture wastewater contained large amounts of pathogenic microorganisms, nitrogen (N) and phosphorus (P). In this study, the nutrient recoveries and wastewater disinfection were simultaneously achieved using Mg-coconut shell carbon (Mg-CSC). The composites were prepared by a ball milling method. The hydrogen peroxide (H2O2) was in-situ generated by the dissolved oxygen reduction driven by Mg corrosion on the CSC surface, which inactivated the microorganisms. Besides that, Mg corrosion provided sufficient Mg ions and appropriate pH conditions for struvite formation. The results show that 5.4-log E.coli removal was achieved under different conditions. Improving the Mg/CSC ratio and composite dosage could shorten the time required for disinfection. In addition to H2O2, singlet oxygen played a critical role. Reactive oxygen species destroyed the cellular structure and killed the bacteria. The recoveries of NH4+-Nand P under certain conditions were about 60% and 91%, respectively. An increased composite dosage could improve the recovery ratio of P. Excessive dosages were not beneficial for removing NH4+-N. The characterization result revealed that struvite crystals were the main precipitates on the CSC surface. The Mg-CSC composites also revealed satisfied nutrient recovery and disinfection performances in the real aquaculture wastewater treatment process.

rhFGF20 promotes angiogenesis and vascular repair following traumatic brain injury by regulating Wnt/ß-catenin pathway.

The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20 (FGF20) is a brain-derived neurotrophic factor, that has been shown to play an important role in the survival of dopaminergic neurons and the treatment of Parkinson's disease (PD). However, little is known about the role of FGF20 in the treatment of TBI and its underlying mechanism. The purpose of this study was to evaluate the protective effect of recombinant human FGF20 (rhFGF20) on protecting cerebral blood vessels after TBI. In this study, we indicated that rhFGF20 could reduce brain edema, Evans blue penetration and upregulated the expression of blood-brain barrier (BBB)-related tight junction (TJ) proteins, exerting a protective effect on the BBB in vivo after TBI. In the TBI repair phase, rhFGF20 promoted angiogenesis, neurological and cognitive function recovery. In tumor necrosis factor-α (TNF-α)-induced human brain microvascular endothelial cells (hCMEC/D3), an in vitro BBB disruption model, rhFGF20 reversed the impairment in cell migration and tube formation induced by TNF-α. Moreover, in both the TBI mouse model and the in vitro model, rhFGF20 increased the expression of ß-catenin and GSK3ß, which are the two key regulators in the Wnt/ß-catenin signaling pathway. In addition, the Wnt/ß-catenin inhibitor IWR-1-endo significantly reversed the effects of rhFGF20. These results indicate that rhFGF20 may prevent vascular repair and angiogenesis through the Wnt/ß-catenin pathway.

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.

Acidic fibroblast growth factor attenuates type 2 diabetes-induced demyelination via suppressing oxidative stress damage.

Prolonged type 2 diabetes mellitus (T2DM) produces a common complication, peripheral neuropathy, which is accompanied by nerve fiber disorder, axon atrophy, and demyelination. Growing evidence has characterized the beneficial effects of acidic fibroblast growth factor (aFGF) and shown that it relieves hyperglycemia, increases insulin sensitivity, and ameliorates neuropathic impairment. However, there is scarce evidence on the role of aFGF on remodeling of aberrant myelin under hyperglycemia condition. Presently, we observed that the expression of aFGF was rapidly decreased in a db/db T2DM mouse model. Administration of exogenous aFGF was sufficient to block acute demyelination and nerve fiber disorganization. Furthermore, this strong anti-demyelinating effect was most likely dominated by an aFGF-mediated increase of Schwann cell (SC) proliferation and migration as well as suppression of its apoptosis. Mechanistically, the beneficial biological effects of aFGF on SC behavior and abnormal myelin morphology were likely due to the inhibition of hyperglycemia-induced oxidative stress activation, which was most likely activated by kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-like 2 (Nrf2) signaling. Thus, this evidence indicates that aFGF is a promising protective agent for relieving myelin pathology through countering oxidative stress signaling cascades under diabetic conditions.

Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages.

Transplant-associated inflammatory responses generate an unfavorable microenvironment for tissue engraftment, particularly for cells susceptible to inflammatory stress, such as pancreatic islets. The localized delivery of anti-inflammatory agents, such as glucocorticoids, offers a promising approach to minimize the detrimental side effects associated with systemic delivery; however, the dosage must be carefully tailored to avoid deleterious responses, such as poor engraftment. Herein, we employed a polydimethylsiloxane (PDMS)-based three-dimensional scaffold platform for the local and controlled delivery of dexamethasone (Dex). Incorporation of 0.1% or 0.25% Dex within the scaffold was found to significantly accelerate islet engraftment in a diabetic mouse model, resulting in improved control of blood glucose levels during the early transplant period. Investigation into the mechanism of this impact found that local Dex delivery promotes macrophage polarization towards an anti-inflammatory (M2) phenotype and suppresses inflammatory pathways during the first week post-implantation. Alternatively, higher Dex loadings (0.5% and 1%) significantly delayed islet engraftment and function by impairing host cell migration into the implanted graft. Our results demonstrate the dose-dependent impact of local glucocorticoid delivery on the modulation of inflammatory responses at the implant site in vivo. Outcomes highlight the potential of this platform for generating favorable host responses that improve overall cellular transplant outcomes.