Maintenance of persistent transmission of a plant arbovirus in its insect vector mediated by the Toll-Dorsal immune pathway.

Throughout evolution, arboviruses have developed various strategies to counteract the host's innate immune defenses to maintain persistent transmission. Recent studies have shown that, in addition to bacteria and fungi, the innate Toll-Dorsal immune system also plays an essential role in preventing viral infections in invertebrates. However, whether the classical Toll immune pathway is involved in maintaining the homeostatic process to ensure the persistent and propagative transmission of arboviruses in insect vectors remain unclear. In this study, we revealed that the transcription factor Dorsal is actively involved in the antiviral defense of an insect vector (Laodelphax striatellus) by regulating the target gene, zinc finger protein 708 (LsZN708), which mediates downstream immune-related effectors against infection with the plant virus (Rice stripe virus, RSV). In contrast, an antidefense strategy involving the use of the nonstructural-protein (NS4) to antagonize host antiviral defense through competitive binding to Dorsal from the MSK2 kinase was employed by RSV; this competitive binding inhibited Dorsal phosphorylation and reduced the antiviral response of the host insect. Our study revealed the molecular mechanism through which Toll-Dorsal-ZN708 mediates the maintenance of an arbovirus homeostasis in insect vectors. Specifically, ZN708 is a newly documented zinc finger protein targeted by Dorsal that mediates the downstream antiviral response. This study will contribute to our understanding of the successful transmission and spread of arboviruses in plant or invertebrate hosts.

Unveiling the Hidden Regulators: The Impact of lncRNAs on Zoonoses.

Zoonoses are diseases and infections naturally transmitted between humans and vertebrate animals. They form the dominant group of diseases among emerging infectious diseases and represent critical threats to global health security. This dilemma is largely attributed to our insufficient knowledge of the pathogenesis regarding zoonotic spillover. Long non-coding RNAs (lncRNAs) are transcripts with limited coding capacity. Recent technological advancements have enabled the identification of numerous lncRNAs in humans, animals, and even pathogens. An increasing body of literature suggests that lncRNAs function as key regulators in zoonotic infection. They regulate immune-related epigenetic, transcriptional, and post-transcriptional events across a broad range of organisms. In this review, we discuss the recent research progress on the roles of lncRNAs in zoonoses. We address the classification and regulatory mechanisms of lncRNAs in the interaction between host and zoonotic pathogens. Additionally, we explore the surprising function of pathogen-derived lncRNAs in mediating the pathogenicity and life cycle of zoonotic bacteria, viruses, and parasites. Understanding how these lncRNAs influence the zoonotic pathogenesis will provide important therapeutic insights to the prevention and control of zoonoses.

Bioinspired Robust Water Repellency in High Humidity by Micro-meter-Scaled Conical Fibers: Toward a Long-Time Underwater Aerobic Reaction.

Superhydrophobic surfaces have suffered from being frequently penetrated by micro-/nano-droplets in high humidity, which severely deteriorates their water repellency. So far, various biological models for the high water repellency have been reported, which, however, focused mostly on the structural topology with less attention on the dimension character. Here, we revealed a common dimension character of the superhydrophobic fibrous structures of both Gerris legs and Argyroneta abdomens, featured as the conical topology and the micro-meter-scaled cylindrical diameter. In particular, it can be expressed by using a parameter of rp/l > 0.75 µm (r, l, and p are the radius, length, and apex spacing between fibers, respectively). Drawing inspiration, we developed a superhydrophobic micro-meter-scaled conical fiber array with a rather high rp/l value of 0.85 µm, which endows ultra-high water repellency even in high humidity. The micro-meter-scale asymmetric confined space between fibers enables generating a big difference in the Laplace pressure enough to propel the condensed dews away, while the tips help pin the air pocket underwater with a rather long life over 41 days. Taking advantage, we demonstrated a sustainable underwater aerobic reaction where oxygen was continuously supplied from the trapped air pocket by a gradually diffusing process. As a parameter describing both the dimension character and structural topology, the rp/l offers a new perspective for fabricating superhydrophobic fibrous materials with robust water repellency in high humidity, which inspires the innovative underwater devices with a robust anti-wetting performance.

miR-155 and miR-146a collectively regulate meningitic Escherichia coli infection-mediated neuroinflammatory responses.

BACKGROUND: Escherichia coli is the most common Gram-negative bacterium causing meningitis, and E. coli meningitis is associated with high mortality and morbidity throughout the world. Our previous study showed that E. coli can colonize the brain and cause neuroinflammation. Increasing evidence supports the involvement of miRNAs as key regulators of neuroinflammation. However, it is not clear whether these molecules participate in the regulation of meningitic E. coli-mediated neuroinflammation. METHODS: The levels of miR-155 and miR-146a, as well as their precursors, in E. coli-infected astrocytes were measured using quantitative real-time PCR (qPCR). Overexpression and knockdown studies of miR-155 and miR-146a were performed to observe the effects on bacterial loads, cytokines, chemokines, and NF-κB signaling pathways. Bioinformatics methods were utilized to predict the target genes, and these target genes were validated using qPCR, Western blotting, and luciferase reporter system. In vivo knockdown of miR-155 and miR-146a was carried out to observe the effects on bacterial loads, inflammatory genes, astrocyte activation, microglia activation, and survival in a mouse model. RESULTS: The levels of miR-155, miR-146a, and their precursors were significantly increased in astrocytes during E. coli infection. miR-155 and miR-146a were induced by the NF-κB-p65 signaling pathway upon infection. Overexpressing and inhibiting miR-155 and miR-146a in astrocytes did not affect the bacterial loads. Further, the in vitro overexpression of miR-155 and miR-146a suppressed the E. coli-induced inflammatory response, whereas the inhibition of miR-155 and miR-146a enhanced it. Mechanistically, miR-155 inhibited TAB2, and miR-146a targeted IRAK1 and TRAF6; therefore, they functioned collaboratively to modulate TLR-mediated NF-κB signaling. In addition, both miR-155 and miR-146a could regulate the EGFR-NF-κB signaling pathway. Finally, the in vivo suppression of E. coli-induced miR-155 and miR-146a further promoted the production of inflammatory cytokines, aggravated astrocyte and microglia activation, and decreased mouse survival time, without affecting the bacterial loads in the blood and brain. CONCLUSIONS: E. coli infection induced miR-155 and miR-146a, which collectively regulated bacteria-triggered neuroinflammatory responses through negative feedback regulation involving the TLR-mediated NF-κB and EGFR-NF-κB signaling pathways, thus protecting the central nervous system from further neuroinflammatory damage.

Non-coding RNAs: the extensive and interactive regulators of the blood-brain barrier permeability.

The blood-brain barrier (BBB), which controls permeability into and out of the nervous system, is a tightly connected, structural, and functional separation between the central nervous system (CNS) and circulating blood. CNS diseases, such as Alzheimer's disease, multiple sclerosis, traumatic brain injury, stroke, meningitis, and brain cancers, often develop with the increased BBB permeability and further leads to irreversible CNS injury. Non-coding RNAs (ncRNAs) are functional RNA molecules that generally lack the coding abilities but can actively regulate the mRNA expression and function through different mechanisms. Various types of ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), are highly expressed in brain microvascular endothelial cells and are potential mediators of BBB permeability. Here, we summarized the recent research progress on miRNA, lncRNA, and circRNA roles regulating the BBB permeability in different CNS diseases. Understanding how these ncRNAs affect the BBB permeability shall provide important therapeutic insights into the prevention and control of the BBB dysfunction.

Development of a nanobody-based ELISA for the detection of the insecticides cyantraniliprole and chlorantraniliprole in soil and the vegetable bok choy.

Cyantraniliprole and chlorantraniliprole are anthranilic diamide insecticides acting on ryanodine receptors. In this study, two camel-derived nanobodies (Nbs, named C1 and C2) recognizing cyantraniliprole as well as chlorantraniliprole were generated. C1-based enzyme-linked immunosorbent assays (ELISAs) for the detection of the two insecticides were developed. The half-maximum signal inhibition concentrations (IC50) of cyantraniliprole and chlorantraniliprole by ELISA were 1.2 and 1.5 ng mL-1, respectively. This assay was employed to detect these two insecticides in soil and vegetables. The average recoveries of cyantraniliprole from both bok choy (Brassica chinensis L.) and soil samples were 90-129%, while those of chlorantraniliprole were in a range of 89-120%. The insecticide residues in soil and bok choy, which were collected from plots sprayed with cyantraniliprole and chlorantraniliprole, were simultaneously detected by the resulting ELISA and a high-performance liquid chromatography (HPLC) method, showing a satisfactory correlation. Higher concentrations of chlorantraniliprole than cyantraniliprole were detected in soil and vegetables, which indicates the longer persistence of chlorantraniliprole in the environment.

LncRSPH9-4 Facilitates Meningitic Escherichia coli-Caused Blood-Brain Barrier Disruption via miR-17-5p/MMP3 Axis.

Brain microvascular endothelial cells (BMECs) constitute the structural and functional basis for the blood-brain barrier (BBB) and play essential roles in bacterial meningitis. Although the BBB integrity regulation has been under extensive investigation, there is little knowledge regarding the roles of long non-coding RNAs (lncRNAs) in this event. The present study aimed to investigate the roles of one potential lncRNA, lncRSPH9-4, in meningitic E. coli infection of BMECs. LncRSPH9-4 was cytoplasm located and significantly up-regulated in meningitic E. coli-infected hBMECs. Electrical cell-substrate impedance sensing (ECIS) measurement and Western blot assay demonstrated lncRSPH9-4 overexpression in hBMECs mediated the BBB integrity disruption. By RNA-sequencing analysis, 639 mRNAs and 299 miRNAs were significantly differentiated in response to lncRSPH9-4 overexpression. We further found lncRSPH9-4 regulated the permeability in hBMECs by competitively sponging miR-17-5p, thereby increasing MMP3 expression, which targeted the intercellular tight junctions. Here we reported the infection-induced lncRSPH9-4 aggravated disruption of the tight junctions in hBMECs, probably through the miR-17-5p/MMP3 axis. This finding provides new insights into the function of lncRNAs in BBB integrity during meningitic E. coli infection and provides the novel nucleic acid targets for future treatment of bacterial meningitis.

Ultrafast Self-Propelled Directional Liquid Transport on the Pyramid-Structured Fibers with Concave Curved Surfaces.

Self-propelled directional liquid transport (SDLT) has been observed on many natural substrates, serving as an efficient strategy to utilize surrounding liquids for a better habitat to the local environment. Drawing inspiration, various artificial materials capable of SDLT have been developed. However, the liquid transport velocity is normally very low (ca. 3-30 µm/s), which limits its practical applications. Herein, we developed novel pyramid-structured fibers with concave curved surfaces (P-concave curved-fiber, PCCF), which enable the ultrafast SDLT. Specifically, the liquid transport velocity can be up to ∼28.79 mm/s on a dry tri-PCCF, over 50 times faster than that on the surface of Sarracenia trichome (∼520 µm/s). The velocity is even faster on a wet fiber by two times (∼47.34 mm/s). Here, the Laplace pressure difference (FL) induced by the tapered structure determines the liquid transport direction. It is proposed that both the capillary rises imparted by the concave curved surfaces and the oriented microridges/valleys and the enhanced FL aroused by the reduced cross-sectional area accelerate the SDLT on surfaces of the PCCFs. Consequently, the PCCF takes a different liquid transport strategy with a convex-shaped advancing meniscus, differing from that on traditional conical fibers. Moreover, the as-developed PCCF is also applicable for underwater ultrafast SDLT of oil. We envision that the result will open a new perspective for fabricating a fibrous system for microfluidic and liquid manipulation.

Meningitic Escherichia coli-induced upregulation of PDGF-B and ICAM-1 aggravates blood-brain barrier disruption and neuroinflammatory response.

BACKGROUND: Blood-brain barrier (BBB) disruption and neuroinflammation are considered key mechanisms of pathogenic Escherichia coli invasion of the brain. However, the specific molecules involved in meningitic E. coli-induced BBB breakdown and neuroinflammatory response remain unclear. Our previous RNA-sequencing data from human brain microvascular endothelial cells (hBMECs) revealed two important host factors: platelet-derived growth factor-B (PDGF-B) and intercellular adhesion molecule-1 (ICAM-1), which were significantly upregulated in hBMECs after meningitic E. coli infection. Whether and how PDGF-B and ICAM-1 contribute to the development of E. coli meningitis are still unclear. METHODS: The western blot, real-time PCR, enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence were applied to verify the significant induction of PDGF-B and ICAM-1 by meningitic E. coli in vivo and in vitro. Evan's blue assay and electric cell-substrate impedance sensing assay were combined to identify the effects of PDGF-B on BBB permeability. The CRISPR/Cas9 technology, cell-cell adhesion assay, and electrochemiluminescence assay were used to investigate the role of ICAM-1 in neuroinflammation subversion. RESULTS: We verified the significant induction of PDGF-B and ICAM-1 by meningitic E. coli in mouse as well as monolayer hBMECs models. Functionally, we showed that the increase of PDGF-B may directly enhance the BBB permeability by decreasing the expression of tight junction proteins, and the upregulation of ICAM-1 contributed to neutrophils or monocytes recruitment as well as neuroinflammation subversion in response to meningitic E. coli infection. CONCLUSIONS: Our findings demonstrated the roles of PDGF-B and ICAM-1 in mediating bacterial-induced BBB damage as well as neuroinflammation, providing new concepts and potential targets for future prevention and treatment of bacterial meningitis.

Unidirectional transport of both wettable and nonwettable liquids on an asymmetrically concave structured surface.

Unidirectional liquid transport (UDLT) has been widely used in various fields as an important process for transferring both mass and energy. However, UDLT driven by a structural gradient has been witnessed for a long time only in wettable liquids. For nonwettable liquids, UDLT can hardly proceed merely by a structural gradient. Herein, we propose an asymmetrically concave structured surface (AMC-surface), featuring tip-to-base periodically arranged pyramid-shaped concave structures with a certain degree of overlap, which enables the UDLT of both wettable and nonwettable liquids. For wettable liquids, the capillary force along each corner leads to the UDLT pointing toward the base side of the concave pyramid, while for nonwettable liquids, the UDLT is attributable to the static liquid pressure overwhelming the repulsive Laplace pressure induced by the asymmetric grooves and overlapping part. As a result, both wettable and nonwettable liquids transport spontaneously and unidirectionally on the AMC-surface with no energy input. Moreover, the concave structure endows good mechanical stability and can be easily prepared using a facile nail-punching approach over a large area. We also demonstrated its application in a continuous chemical reaction in a confined area. We envision that the unique UDLT behavior on the as-developed AMC-surface will shed new light on the programmable manipulation of various liquids.

Continuous Homogeneous Thin Liquid Film on a Single Cross-Shaped Profiled Fiber with High Off-Circularity: Toward Quick-Drying Fabrics.

Quick-drying fabrics, renowned for their rapid sweat evaporation, have witnessed various applications in strenuous exercise. Profiled fiber textiles exhibit enhanced quick-drying performance, which is attributed to the excellent wicking effect within fibrous bundles, facilitating the rapid transport of sweat. However, the evaporation process is not solely influenced by macroscopic liquid transport but also by microscopic liquid spreading on the fibers where periodic liquid knots induced by spontaneous fluidic instability significantly reduce the evaporation area. Here, a cross-shaped profiled fiber with high off-circularity, featured as multiple concavities along the fibrous longitude-axis, which enables the formation of a homogeneous thin liquid film on a single fiber without any periodic liquid knots, is developed. The high off-circularity cross-sections help overcoming Plateau-Rayleigh instability by tuning the Laplace pressure difference, further facilitated by capillary flow along the concave surface. The homogeneous thin liquid film on a single fiber is responsible for maximizing the evaporation area, resulting in excellent overall evaporation capacity. Consequently, fabrics made from such fibers exhibit rapid evaporation behavior, with evaporation rates ≈50% higher than those of cylindrical fabrics. It is envisioned that profiled fibers may provide inspiration for the manipulating homogeneous liquid films for applications in fluid coatings and functional textiles.

Bioinspired Superhydrophobic Fibrous Materials.

Natural fibers with robust water repellency play an important role in adapting organisms to various environments, which has inspired the development of artificial superhydrophobic fibrous materials with applications in self-cleaning, antifogging, water harvesting, heat exchanging, catalytic reactions, and microrobots. However, these highly textured surfaces (micro/nanotextured) suffer from frequent liquid penetration in high humidity and abrasion-induced destruction of the local environment. Herein, bioinspired superhydrophobic fibrous materials are reviewed from the perspective of the dimension scale of fibers. First, the fibrous dimension characteristics of several representative natural superhydrophobic fibrous systems are summarized, along with the mechanisms involved. Then, artificial superhydrophobic fibers are summarized, along with their various applications. Nanometer-scale fibers enable superhydrophobicity by minimizing the liquid-solid contact area. Micrometer-scale fibers are advantageous for enhancing the mechanical stability of superhydrophobicity. Micrometer-scale conical fibrous structures endow a Laplace force with a particular magnitude for self-removing condensed tiny dewdrops in highly humid air and stably trapping large air pockets underwater. Furthermore, several representative surface modification strategies for constructing superhydrophobic fibers are presented. In addition, several conventional applications of superhydrophobic systems are presented. It is anticipated that the review will inspire the design and fabrication of superhydrophobic fibrous systems.

Solution-Processed Flexible Transparent Electrodes for Printable Electronics.

Flexible transparent electrodes (FTEs) have been widely witnessed in various printable electronic devices, especially those involving light. So far, solution processes have demonstrated increasing advantages in preparing FTEs not only in their mild operation conditions and high-throughput but also in the diversity in micropatterning conductive nanomaterials into networks. For the FTEs, both high transparency and high conductivity are desirable, which therefore create requirements for the conductive network by considering the trade-off relationship between the coverage and the micropatterns of the network. In addition, the conductive networks also affect the flexibility of FTEs due to the deformation during bending/stretching. Consequently, solution processes capable of micropatterning conductive nanomaterials including nanoparticles, nanowires/polymers, and graphene/MXene play a crucial role in determining the performance of FTEs. Here, we reviewed recent research progress on solution-processed FTEs, including the solution processes, the solution-processable conductive nanomaterials and the substrates for making FTEs, and applications of FTEs in flexible electronics. Finally, we proposed several perspective outlooks of the FTEs, which aim at not only the enhanced performance but also the performances in extreme conditions and in integration. We believe that the review would offer inspiration for developing functional FTEs.

Electrochemical On-Site Switching of the Directional Liquid Transport on a Conical Fiber.

Directional liquid transport (DLT), especially that proceeding on a conical fiber (DLT-CF), is an important mass-transfer process widely used both by natural organisms and in practical applications. However, on-site switching of the DLT-CF remains a challenge due to the nontunable driving force imparted by the structural gradient, which greatly limits its application. Here, unprecedently, a facile electrochemical strategy is developed for reaching the on-site switchable DLT-CF, featuring in situ control and fast response. Depending on the poised electric potential, the droplet can either move directionally or be pinned at any position for a tunable duration time, exhibiting completely different moving characteristics from the traditional DLT-CF with no control. It is proposed that the surface hysteresis resistance, closely related to both the surface hydrogen-bonding network and the droplet topology on the fiber, can be largely altered electrochemically. The tunable hysteresis resistance works synergistically with the conical-structure-induced Laplace pressure to on-site tune the forces acting on the droplet, leading to various controllable DLTs-CF, including those with tunable distance and direction, array manipulation, and assembly line processing of droplets. The strategy is applicable for versatile liquids, offering a general approach for controllable liquid transport in fibrous systems.

Long Non-coding Antisense RNA DDIT4-AS1 Regulates Meningitic Escherichia coli-Induced Neuroinflammation by Promoting DDIT4 mRNA Stability.

Our previous studies have shown that meningitic Escherichia coli can colonize the brain and cause neuroinflammation. Controlling the balance of inflammatory responses in the host central nervous system is particularly vital. Emerging evidence has shown the important regulatory roles of long non-coding RNAs (lncRNAs) in a wide range of biological and pathological processes. However, whether lncRNAs participate in the regulation of meningitic E. coli-mediated neuroinflammation remains unknown. In the present study, we characterized a cytoplasm-enriched antisense lncRNA DDIT4-AS1, which showed similar concordant expression patterns with its parental mRNA DDIT4 upon E. coli infection. DDIT4-AS1 modulated DDIT4 expression at both mRNA and protein levels. Mechanistically, DDIT4-AS1 promoted the stability of DDIT4 mRNA through RNA duplex formation. DDIT4-AS1 knockdown and DDIT4 knockout both attenuated E. coli-induced NF-κB signaling as well as pro-inflammatory cytokines expression, and DDIT4-AS1 regulated the inflammatory response by targeting DDIT4. In summary, our results show that DDIT4-AS1 promotes E. coli-induced neuroinflammatory responses by enhancing the stability of DDIT4 mRNA through RNA duplex formation, providing potential nucleic acid targets for new therapeutic interventions in the treatment of bacterial meningitis.

Meningitic Escherichia coli-Induced Interleukin-17A Facilitates Blood-Brain Barrier Disruption via Inhibiting Proteinase 3/Protease-Activated Receptor 2 Axis.

Bacterial meningitis is a life-threatening infectious disease with high morbidity and mortality worldwide, among which meningitic Escherichia coli is a common Gram-negative pathogenic bacterium causing meningitis. It can penetrate the blood-brain barrier (BBB), invoke local inflammatory responses and consequently disrupt the integrity of the BBB. Interleukin-17A (IL-17A) is recognized as a pro-inflammatory cytokine that is released during meningitic E. coli infection. It has been reported that IL-17A is involved in several pathological tissue injuries. However, the function of IL-17A in BBB breakdown remains rarely discussed. Here, our study found that E. coli-induced IL-17A led to the degradation of tight junction proteins (TJs) and adherens junction proteins (AJs) in human brain microvascular endothelial cells (hBMECs) through inhibiting protease proteinase 3 (PRTN3)/protease-activated receptor 2 (PAR-2) axis, thus increasing the permeability of BBB. In summary, this study uncovered the involvement of IL-17A in regulating BBB integrity and proposed a novel regulatory mechanism, which could be potential therapeutic targets of E. coli meningitis.

Long non-coding RNA lncC11orf54-1 modulates neuroinflammatory responses by activating NF-κB signaling during meningitic Escherichia coli infection.

Escherichia coli is the most common gram-negative pathogenic bacterium causing meningitis. It penetrates the blood-brain barrier (BBB) and activates nuclear factor kappa B (NF-κB) signaling, which are vital events leading to the development of meningitis. Long non-coding RNAs (lncRNAs) have been implicated in regulating neuroinflammatory signaling, and our previous study showed that E. coli can induce differential expression of lncRNAs, including lncC11orf54-1, in human brain microvascular endothelial cells (hBMECs). The hBMECs constitute the structural and functional basis for the BBB, however, it is unclear whether lncRNAs are involved in the regulation of inflammatory responses of hBMECs during meningitic E. coli infection. In this study, we characterized an abundantly expressed lncRNA, lncC11orf54-1, which was degraded by translocated coilin to produce mgU2-19 and mgU2-30 in hBMECs during E. coli infection. Functionally, lncC11orf54-1-originated non-coding RNA mgU2-30 interacted with interleukin-1 receptor-associated kinase 1 (IRAK1) to induce its oligomerization and autophosphorylation, thus promoting the activation of NF-κB signaling and facilitating the production of pro-inflammatory cytokines. In summary, our study uncovers the involvement of lncC11orf54-1 in IRAK1-NF-κB signaling, and it functions as a positive regulator of inflammatory responses in meningitic E. coli-induced neuroinflammation, which may be a valuable therapeutic and diagnostic target for bacterial meningitis.

Meningitic Escherichia coli α-hemolysin aggravates blood-brain barrier disruption via targeting TGFß1-triggered hedgehog signaling.

Bacterial meningitis is a life-threatening infectious disease with severe neurological sequelae and a high mortality rate, in which Escherichia coli is one of the primary Gram-negative etiological bacteria. Meningitic E. coli infection is often accompanied by an elevated blood-brain barrier (BBB) permeability. BBB is the structural and functional barrier composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGFß1 physiologically maintained the BBB permeability by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic E. coli infection could subvert this intercellular communication within BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we identified E. coli α-hemolysin as the critical determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction and triggering Ca2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG exhibited promising protection against the infection-caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism during meningitic E. coli-caused BBB disruption and suggested that activating hedgehog signaling within BBB could be a potential protective strategy for future therapy of bacterial meningitis.

Resveratrol Attenuates Meningitic Escherichia coli-Mediated Blood-Brain Barrier Disruption.

Meningitic Escherichia coli can infiltrate the central nervous system (CNS), consequently increasing the levels of proinflammatory cytokines and chemokines and deteriorating the integrity of the blood-brain barrier (BBB). Resveratrol has emerged in recent years as a compound with antioxidant and anti-inflammatory properties. However, it is still unknown how resveratrol affects meningitic E. coli-induced CNS dysfunction. Here, by using in vivo and in vitro BBB models, we demonstrated that resveratrol treatment significantly inhibited meningitic E. coli invasion of the BBB, protected the integrity of the BBB, and reduced neuroinflammation and lethality. In mechanism, resveratrol inhibited bacterial penetration of the BBB by attenuating the upregulation of caveolin-1 (CAV-1), a class of lipid rafts maintaining endothelial cell function. Resveratrol treatment also maintained BBB permeability by suppressing the ERK1/2-VEGFA signaling cascade. In vivo treatment of resveratrol decreased the production of inflammatory cytokines and improved the survival rate in mice challenged with meningitic E. coli. These findings collectively indicated that resveratrol could attenuate meningitic E. coli-induced CNS injury, which might constitute a new approach for future prevention and treatment of E. coli meningitis.

Astrocyte-Derived TGFß1 Facilitates Blood-Brain Barrier Function via Non-Canonical Hedgehog Signaling in Brain Microvascular Endothelial Cells.

The blood-brain barrier is a specialized structure in mammals, separating the brain from the bloodstream and maintaining the homeostasis of the central nervous system. The barrier is composed of various types of cells, and the communication between these cells is critical to blood-brain barrier (BBB) function. Here, we demonstrate the astrocyte-derived TGFß1-mediated intercellular communication between astrocytes and brain microvascular endothelial cells (BMECs). By using an in vitro co-culture model, we observed that the astrocyte-derived TGFß1 enhanced the tight junction protein ZO-1 expression in BMECs and the endothelial barrier function via a non-canonical hedgehog signaling. Gli2, the core transcriptional factor of the hedgehog pathway, was demonstrated to modulate ZO-1 expression directly. By the dual-luciferase reporter system and chromatin immunoprecipitation, we further identified the exact sites on Smad2/3 that bound to the gli2 promotor and on Gli2 that bound to the zo-1 promotor. Our work highlighted the TGFß1-mediated intercellular communication of astrocytes with BMECs in BBB, which shall extend current knowledge on the BBB homeostasis physiologically, and more importantly suggests TGFß1 as a potential effector for future prevention and amelioration of BBB dysfunction.