Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity.

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear. APPROACH AND RESULTS: Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice. CONCLUSIONS: LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.

Juvenile hormone regulates the photoperiodic plasticity of elytra coloration in the ladybird Harmonia axyridis.

Many animals, including insects, exhibit plasticity of body colour in response to environmental changes. Varied expression of carotenoids, major cuticle pigments, significantly contributes to body colour flexibility. However, the molecular mechanisms by which environmental cues regulate carotenoid expression remain largely unknown. In this study, we used the ladybird Harmonia axyridis as a model to investigate the photoperiodic-responsive plasticity of elytra coloration and its endocrine regulation. It was found that H. axyridis females under long-day conditions develop elytra that are much redder than those under short-day conditions, resulting from the differential accumulation of carotenoids. Exogenous hormone application and RNAi-mediated gene knockdown indicate that carotenoid deposition was directed through the juvenile hormone (JH) receptor-mediated canonical pathway. Moreover, we characterized an SR-BI/CD36 (SCRB) gene SCRB10 as the carotenoid transporter responding to JH signalling and regulating the elytra coloration plasticity. Taken together, we propose that JH signalling transcriptionally regulates the carotenoid transporter gene for the photoperiodic coloration plasticity of elytra in the beetles, which reveals a novel role of the endocrine system in the regulation of carotenoid-associated animal body coloration under environmental stimuli.

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn.

BACKGROUND: The noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury. METHODS: The Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro-adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated. RESULTS: Activation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1ß expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice. CONCLUSION: These findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Eph/ephrin signaling maintains the boundary of dorsal forerunner cell cluster during morphogenesis of the zebrafish embryonic left-right organizer.

The Kupffer's vesicle (KV) is the so-called left-right organizer in teleost fishes. KV is formed from dorsal forerunner cells (DFCs) and generates asymmetrical signals for breaking symmetry of embryos. It is unclear how DFCs or KV cells are prevented from intermingling with adjacent cells. In this study, we show that the Eph receptor gene ephb4b is highly expressed in DFCs whereas ephrin ligand genes, including efnb2b, are expressed in cells next to the DFC cluster during zebrafish gastrulation. ephb4b knockdown or mutation and efnb2b knockdown cause dispersal of DFCs, a smaller KV and randomization of laterality organs. DFCs often dynamically form lamellipodium-like, bleb-like and filopodium-like membrane protrusions at the interface, which attempt to invade but are bounced back by adjacent non-DFC cells during gastrulation. Upon inhibition of Eph/ephrin signaling, however, the repulsion between DFCs and non-DFC cells is weakened or lost, allowing DFCs to migrate away. Ephb4b/Efnb2b signaling by activating RhoA activity mediates contact and repulsion between DFCs and neighboring cells during gastrulation, preventing intermingling of different cell populations. Therefore, our data uncover an important role of Eph/ephrin signaling in maintaining DFC cluster boundary and KV boundary for normal left-right asymmetrical development.

Impairment of Cargo Transportation Caused by gbf1 Mutation Disrupts Vascular Integrity and Causes Hemorrhage in Zebrafish Embryos.

ADP-ribosylation factor GTPases are activated by guanine nucleotide exchange factors including Gbf1 (Golgi brefeldin A-resistant factor 1) and play important roles in regulating organelle structure and cargo-selective vesicle trafficking. However, the developmental role of Gbf1 in vertebrates remains elusive. In this study, we report the zebrafish mutant line tsu3994 that arises from N-ethyl-N-nitrosourea (ENU)-mediated mutagenesis and is characterized by prominent intracerebral and trunk hemorrhage. The mutant embryos develop hemorrhage accompanied by fewer pigments and shorter caudal fin at day 2 of development. The hemorrhage phenotype is caused by vascular breakage in a cell autonomous fashion. Positional cloning identifies a T → G nucleotide substitution in the 23rd exon of the gbf1 locus, resulting in a leucine → arginine substitution (L1246R) in the HDS2 domain. The mutant phenotype is mimicked by gbf1 knockouts and morphants, suggesting a nature of loss of function. Experimental results in mammalian cells show that the mutant form Gbf1(L1246R) is unable to be recruited to the Golgi apparatus and fails to activate Arf1 for recruiting COPI complex. The hemorrhage in tsu3994 mutants can be prevented partially and temporally by treating with the endoplasmic reticulum stress/apoptosis inhibitor tauroursodeoxycholic acid or by knocking down the proapoptotic gene baxb Therefore, endothelial endoplasmic reticulum stress and subsequent apoptosis induced by gbf1 deficiency may account for the vascular collapse and hemorrhage.

[Diagnosis of two neonates with galactosemia by using next generation sequencing].

OBJECTIVE: To explore the genetic basis of two neonates suspected for galactosemia. METHODS: Next generation sequencing(NGS) was used to screen the whole exome of the neonates. Suspected mutation was validated by PCR and Sanger sequencing. Potential impact of novel mutation was predicted by using PolyPhen-2, MutationTaste and SIFT software. RESULTS: Both neonates harbored compound heterozygous mutations of the GALT gene inherited from their parents. One has inherited two novel mutations c.564G>C(p.Q188H) and c.116A>T(p.D39V) respectively from his father and mother. The other has inherited mutations c.754C>T(p.Q252X) and c.904+1G>T from her father and mother, respectively. CONCLUSION: The galactosemia in the two neonates may be attributed to compound heterozygous mutations of the GALT gene. This is the first domestic report of using the NGS for the diagnosis of galactosemia.

[Thoracoscopic repair of congenital diaphragmatic hernia in neonates: a report of 47 cases].

OBJECTIVE: To review the application of thoracoscopic repair for treatment of congenital diaphragmatic hernia in neonates, so as to improve the cure rate. METHODS: Clinical data of 47 neonates with congenital diaphragmatic hernia receiving thoracoscopic repair from June 2012 to June 2017 were reviewed. The admission age, gestational age, birth weight, timing of diagnosis, hernia location, clinical manifestation, surgical timing, surgical method, operation time, postoperative mechanical ventilation time of patients were analyzed. RESULTS: There were 42 cases of left diaphragmatic hernia and 5 cases of right diaphragmatic hernia. Thirteen cases were diagnosed prenatally. Primary diaphragmatic repair was successfully accomplished under thoracoscope in 45 neonates without perioperative complications, while 2 patients were converted to open surgery. The average operation time was (63±13) min (42-150 min), the average blood loss was (3.0±1.7) mL (1.0-9.0 mL), and the average postoperative mechanical ventilation time was (3.9±1.4) d (2.0-11.0 d). Two patients died and the treatment was withdrawn in 3 patients with an overall cure rate of 89.4% (42/47). CONCLUSIONS: Thoracoscopic repair is effective and can be used as first-choice treatment of diaphragmatic hernia in neonates.

A dominant variant in DMXL2 is linked to nonsyndromic hearing loss.

PURPOSE: To explore the genetic etiology of deafness in a dominant family with late-onset, progressive, nonsyndromic hearing loss. METHODS: Genome-wide linkage analysis was performed for 21 family members. Candidate pathogenic variants were identified by whole-exome sequencing of selected family members and confirmed by Sanger sequencing of all family members. Cochlear expression of Dmxl2 was investigated by reverse-transcription polymerase chain reaction (RT-PCR) and immunostaining of the organ of Corti from mice. RESULTS: The causative gene was mapped to a 9.68-Mb candidate region on chromosome 15q21.2 (maximum logarithm of the odds score = 4.03) that contained no previously described deafness genes. Whole-exome sequencing identified heterozygous c.7250G>A (p.Arg2417His) in DMXL2 as the only candidate pathogenic variant segregating the hearing loss. In mouse cochlea, expression of DMXL2 was restricted to the hair cells and the spiral ganglion neurons. CONCLUSION: Our data indicated that the p.Arg2417His variant in DMXL2 is associated with dominant, nonsyndromic hearing loss and suggested an important role of DMXL2 in inner ear function.Genet Med advance online publication 22 September 2016.

The Kinase Activity-deficient Isoform of the Protein Araf Antagonizes Ras/Mitogen-activated Protein Kinase (Ras/MAPK) Signaling in the Zebrafish Embryo.

Raf kinases are important components of the Ras-Raf-Mek-Erk pathway and also cross-talk with other signaling pathways. Araf kinase has been demonstrated to inhibit TGF-ß/Smad2 signaling by directly phosphorylating and accelerating degradation of activated Smad2. In this study, we show that the araf gene expresses in zebrafish embryos to produce a shorter transcript variant, araf-tv2, in addition to the full-length variant araf-tv1. araf-tv2 is predicted to encode a C-terminally truncated peptide without the kinase activity domain. Araf-tv2 can physically associate with Araf-tv1 but does not antagonize the inhibitory effect of Araf-tv1 on TGF-ß/Smad2 signaling. Instead, Araf-tv2 interacts strongly with Kras and Nras, ultimately blocking MAPK activation by these Ras proteins. In zebrafish embryos, overexpression of araf-tv2 is sufficient to inhibit Fgf/Ras-promoted Erk activation, mesodermal induction, dorsal development, and neuroectodermal posteriorization. Therefore, different isoforms of Araf may participate in similar developmental processes but by regulating different signaling pathways.

Trimethylamine N-oxide impairs ß-cell function and glucose tolerance.

ß-Cell dysfunction and ß-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, ß-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on ß-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes ß-cell ER stress, dedifferentiation, and apoptosis and inhibits ß-cell transcriptional identity. Inhibition of TMAO production improves ß-cell GSIS, ß-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in ß-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.

Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL.

Necroptosis is a kind of programmed cell death that causes the release of damage-associated molecular patterns and inflammatory disease including skin inflammation. Activation of receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) is the hallmark of tumour necrosis factor α (TNF)-induced necroptosis. Here, we screened a small-molecule compound library and found that saracatinib inhibited TNF-induced necroptosis. By targeting MLKL, Saracatinib interfered with the phosphorylation, translocation, and oligomerization of MLKL induced by TNF. Consistently, mutation of the saracatinib-binding site of MLKL reduced the inhibitory effect of saracatinib on TNF-induced necroptosis. In an imiquimod (IMQ)-induced psoriasis mouse model, saracatinib effectively blocked MLKL phosphorylation and inflammatory responses in vivo. Taken together, these findings indicate that saracatinib inhibits necroptosis by targeting MLKL, providing a potential therapeutic approach for skin inflammation-related diseases such as psoriasis.

Galectin-3 impairs calcium transients and ß-cell function.

In diabetes, macrophages and inflammation are increased in the islets, along with ß-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in ß-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. ß-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic ß-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.

Economic burden attributable to healthcare-associated infections at western China hospitals: 6 Year, prospective cohort study.

OBJECTIVES: Healthcare-associated infections (HAIs) represent a major threat to patient safety and are associated with significant economic burden. Calculating the costs attributable to HAIs is challenging given the various sources of bias. Although HAIs as a reasonably preventable medical harm should have been closely linked to medical insurance incentives, there was little linkage between HAIs and medicare in western China owing to the lack of economic evaluation data. The present study aimed to generate estimates of the attributable costs associated with HAIs and the magnitude of costs growth. METHODS: In this cohort study designed horizontally and vertically from 2016 to 2022, we compared outcomes of randomly sampling patients with HAIs and individually matched patients without HAIs in two cohorts at a 6-year interval at 34 hospitals in western China. The primary outcome was the direct medical cost for the entire hospital stay, converted to US dollars ($ for the benchmark year), discounted at 3% annually, and estimated separately in the full analysis set (FAS) and the per protocol set (PPS). We used multiple linear regression to adjust the discounted costs and to assess subgroups effects within each cohort. We nested a dynamic vertical comparison of costs attributable to HAIs between the front and rear cohorts. RESULTS: A total of 230 patients with HAIs in 2016 and 204 patients with HAIs in 2022 were enrolled. After a 1:1 match, all 431 pairs were recruited as FAS, of which 332 pairs as PPS met all matching restrictions. Compared to the 2016 cohort in FAS, the patients with HAIs in 2022 had a significantly older age (64.40 ± 16.45 years), higher repeat hospitalization rate (65 [32.02%] of 203), and lower immune function (69 [33.99%] of 203). The discounted costs and adjusted-discounted costs for patients with HAIs in the 2022 cohort were found to be significantly higher than those of patients without HAIs (discounted costs: $5484.60 [IQR 8426.03] vs $2554.04(4530.82), P < 0.001; adjusted-discounted costs: $5235.90 [3772.12] vs $3040.21(1823.36), P < 0.001, respectively), and also higher than those of patients with HAIs in the 2016 cohort (discounted costs: $5484.60 [8426.03] vs $3553.00 [6127.79], P < 0.001; adjusted-discounted costs: $5235.90 [3772.12] vs $3703.82 [3159.14], P < 0.001, respectively). In vertical comparison of PPS, the incremental costs of the 2022 cohort are 1.48 times higher than those of the 2016 cohort ($964.63(4076.15) vs $652.43 [2533.44], P = 0.084). CONCLUSIONS: This meticulously designed study in western China has successfully and accurately examined the economic burden attributable to HAIs. Their rapidly increasing tendency poses a serious challenge to patients, hospitals, and the medical insurance. A closer linkage between HAIs and ongoing motivating system changes is urgently needed in western China.

[Rbb4l enhances TGF-ß/Nodal signaling and promotes zebrafish embryonic dorsolization].

The TGF-ß/Nodal signaling pathway plays an important role in the zebrafish dorsoventral patterning process. To further explore the function and mechanism of this signaling pathway, we identified a set of Smad2/3a interacting proteins by the yeast two-hybrid screen. Rbb4l (Retinoblastoma binding protein 4, like) is one of the identified proteins. Human RBBP4 (Retinoblastoma binding protein 4), the homolog of zebrafish Rbb4l, has been shown to form complexes with other chromatin modifiers, but its roles in embryonic development remain unknown. In this study, we showed that Rbb4l directly interacted with Smad3a and enhances TGF-ß/Nodal signaling. In zebrafish embryos, rbb4l overexpression resulted in an expanded expression of dorsal markers with a reduction of ventral markers expression, suggesting a dorsalizing function. On the contrary, rbb4l knockdown caused ventralized phenotype of the embryos at 24 hours post-fertilization (hpf). Furthermore, a series of rescue experiments showed that rbb4l failed to cause embryonic dorsalization in the absence of Nodal signal. Together, our data suggested that Rbb4l acts as an enhancer of Nodal/Smad2/3 signaling during embryogene-sis, and depends on the existence of Nodal signaling.

Chemo- and Diastereoselective Acylfluorination of Nonactivated Olefins to Access Benzo[b]azepines.

Here, we describe a transition-metal-free condition that realized the intramolecular acylfluorination of unactivated olefins. It was designed to access seven-membered-ring-containing benzo[b]annulenones from readily prepared 2-allylamino benzoic acids. The formation of a broad scope of electronically and sterically varied benzo[b]annulenones was demonstrated (>30 examples, up to 88% yield and >20:1 dr ratio). Mechanistic studies indicated that the in situ formed XatlFluor-E-activated anhydride was the active species and induced an electrophilic 7-endo-trig cyclization, followed by fluoride capture of the cation.

The Roles of Periaqueductal Gray and Dorsal Raphe Nucleus Dopaminergic Systems in the Mechanisms of Thermal Hypersensitivity and Depression in Mice.

Depression and thermal hypersensitivity share pathogenic features and symptomology, but their pathophysiologic interactions have not been fully elucidated. Dopaminergic systems in the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus have been implicated in these conditions due to their antinociception and antidepression effects, although their specific roles and underlying mechanisms remain obscure. In this study, chronic unpredictable mild stress (CMS) was used to induce depression-like behaviors and thermal hypersensitivity in C57BL/6J (wild-type) or dopamine transporter promoter mice to establish a mouse model of pain and depression comorbidity. Microinjections of quinpirole, a dopamine D2 receptor agonist, up-regulated D2 receptor expression in dorsal raphe nucleus and reduced depressive behaviors and thermal hypersensitivity with CMS, while dorsal raphe nucleus injections of JNJ-37822681, an antagonist of D2 receptors, had the reciprocal effect on dopamine D2 receptor expression and behaviors. Moreover, using a chemical genetics approach to activate or inhibit dopaminergic neurons in vlPAG ameliorated or exacerbated depression-like behaviors and thermal hypersensitivity, respectively, in dopamine transporter promoter-Cre CMS mice. Collectively these results demonstrated the specific role of vlPAG and dorsal raphe nucleus dopaminergic systems in the regulation of pain and depression comorbidity in mice. PERSPECTIVE: The current study provides insights into the complex mechanisms underlying thermal hypersensitivity induced by depression, and the findings suggest that pharmacological and chemogenetic modulation of dopaminergic systems in the vlPAG and dorsal raphe nucleus may be a promising therapeutic strategy to simultaneously mitigate pain and depression.

Fluorocitrate and neurotropin confer analgesic effects on neuropathic pain in diabetic rats via inhibition of astrocyte activation in the periaqueductal gray.

Currently, effective treatments for diabetic neuropathic pain (DNP) are still unmet clinical needs. Activation of astrocytes in the ventrolateral region of periaqueductal gray (vlPAG) has a regulating effect on pain responses. The present study was designed to confirm that repeated intra-vlPAG injection of fluorocitrate (FC), a selective inhibitor of astrocyte activation or intraperitoneal (IP) injection of neurotropin, a widely prescribed analgesic drug for chronic pain, inhibited the activation of astrocytes in vlPAG and thus produced an analgesic effect on DNP. An in vivo model was developed to study DNP in rats. The changes in mechanical withdrawal threshold (MWT) and activation levels of astrocytes in the vlPAG were evaluated in all experimental rats. Compared with normal rats, vlPAG-based glial fibrillary acid protein (GFAP) was clearly upregulated, whereas the MWTs of DNP rats were markedly diminished. The intra-vlPAG injections of FC or IP injections of neurotropin attenuated the alterations both in MWTs and expression levels of GFAP in vlPAG in DNP rats. Collectively, these findings suggest the antinociceptive effects of FC and neurotropin in DNP rats, which were associated with suppressing the activation of astrocytes in vlPAG.

The complete chloroplast genome sequence of the water fern Ceratopteris thalictroides (Pteridaceae).

This work determined and analyzed the complete chloroplast genome sequence of Ceratopteris thalictroides (Linnaeus) Brongniart 1822 (Pteridaceae). The results indicate that the total chloroplast genome size of C. thalictroides is 149,399 bp in length, and the genome contains a large single-copy (LSC) region of 83,580 bp, a small single-copy (SSC) region of 21,241 bp, and a pair of inverted repeat (IR) regions of 22,289 bp. The GC content of C. thalictroides is 36.7%. The genome encodes a total of 131 unique genes, including 82 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. The phylogenetic analysis results strongly suggest that C. thalictroides is closely related to C. cornuta.

PRG-1 prevents neonatal stimuli-induced persistent hyperalgesia and memory dysfunction via NSF/Glu/GluR2 signaling.

Neonatal repetitive noxious stimuli (RNS) has been shown to cause long-term harmful effects on nociceptive processing, learning, and memory which persist until adulthood. Plasticity-related gene 1 (PRG-1) regulates synaptic plasticity and functional reorganization in the brain during neuronal development. In this study, neonatal RNS rats were established by repetitive needle pricks to neonatal rats on all four feet to model repetitive pain exposure in infants. Neonatal RNS caused thermal hyperalgesia, mechanical allodynia, learning, and memory impairments which manifested in young rats and persisted until adulthood. Hippocampal PRG-1/N-ethylmaleimide sensitive fusion protein (NSF) interaction was determined to be responsible for the RNS-induced impairment via enhanced extracellular glutamate release and AMPAR GluR2 trafficking deficiency in a cell-autonomous manner. These pathways likely act synergistically to cause changes in dendritic spine density. Our findings suggest that PRG-1 prevents the RNS-induced hyperalgesia, learning, and memory impairment by regulating synaptic plasticity via NSF/Glu/GluR2 signaling.

Insulin induces insulin receptor degradation in the liver through EphB4.

Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.