Cholesterol-induced HRD1 reduction accelerates vascular smooth muscle cell senescence via stimulation of endoplasmic reticulum stress-induced reactive oxygen species.

Senescence of vascular smooth muscle cells (VSMCs) is a key contributor to plaque vulnerability in atherosclerosis (AS), which is affected by endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production. However, the crosstalk between ER stress and ROS production in the pathogenesis of VSMC senescence remains to be elucidated. ER-associated degradation (ERAD) is a complex process that clears unfolded or misfolded proteins to maintain ER homeostasis. HRD1 is the major E3 ligase in mammalian ERAD machineries that catalyzes ubiquitin conjugation to the unfolded or misfolded proteins for degradation. Our results showed that HRD1 protein levels were reduced in human AS plaques and aortic roots from ApoE-/- mice fed with high-fat diet (HFD), along with the increased ER stress response. Exposure to cholesterol in VSMCs activated inflammatory signaling and induced senescence, while reduced HRD1 protein expression. CRISPR Cas9-mediated HRD1 knockout (KO) exacerbated cholesterol- and thapsigargin-induced cell senescence. Inhibiting ER stress with 4-PBA (4-Phenylbutyric acid) partially reversed the ROS production and cell senescence induced by HRD1 deficiency in VSMCs, suggesting that ER stress alone could be sufficient to induce ROS production and senescence in VSMCs. Besides, HRD1 deficiency led to mitochondrial dysfunction, and reducing ROS production from impaired mitochondria partly reversed HRD1 deficiency-induced cell senescence. Finally, we showed that the overexpression of HDR1 reversed cholesterol-induced ER stress, ROS production, and cellular senescence in VSMCs. Our findings indicate that HRD1 protects against senescence by maintaining ER homeostasis and mitochondrial functionality. Thus, targeting HRD1 function may help to mitigate VSMC senescence and prevent vascular aging related diseases. TRIAL REGISTRATION: A real-world study based on the discussion of primary and secondary prevention strategies for coronary heart disease, URL:https://www.clinicaltrials.gov, the trial registration number is [2022]-02-121-01.

High-quality integratable microlasers from scalable perovskite heterostructures enabled by solution-phase processing.

High-performance transferable and integratable microlasers hold great promise to construct the integrated photonics and optoelectronics. However, the qualified candidates are still being pursued. Herein, a mass-production of low-threshold and wavelength-tunable microlasers that is readily integratable with the optical fiber platform is realized by a two-step solution-phase approach. The demonstration is enabled by the formation of a novel semiconductor heterostructure from halide perovskites featuring the quasi-free-standing and highly emissive properties. Corroborated by the in-situ optical characterization, we reveal that the lateral perovskite heterostructures are constructed through a sequential reaction driven by the surface energy contrast. These perovskite heterostructures exhibit low-threshold and broadband tunable lasing action thanks to the efficient spatial light conversion nature and the facile composition tunability. Taking the merits together, the heterostructure microlasers can be the competitive applicants for photonic integration as demonstrated by the laser-on-fiber configuration.

Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion.

BACKGROUND: Diabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated. METHODS: We first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells. RESULTS: We detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils. CONCLUSION: In this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.

Morphologies and magnetic properties of α-Fe2O3 nanoparticles calcined at different temperatures.

Different morphologies and sizes of α-Fe2O3 were prepared by a coprecipitation method using polyvinylpyrrolidone as a dispersant. In the preparation process, homogeneous and dispersed nanoscale FeOOH particles were first obtained by the coprecipitation method, and then the FeOOH particles were calcined at high temperature to form α-Fe2O3. The growth and aggregation of the α-Fe2O3 particles at different calcination temperatures resulted in α-Fe2O3 powders with diversiform morphologies (nanoscale microsphere, pinecone ellipsoidal, polyhedral, and quasi-spherical structures). By analyzing the SEM images, it was inferred that the polyhedral structure of α-Fe2O3 particles was formed by the accumulation of rhomboid sheet structures and high-temperature growth. In terms of the magnetic properties, the samples belonged to the class of canted antiferromagnetic materials, and the morphology, particle size, and crystallite size of the α-Fe2O3 particles were important factors affecting the coercivity. Among these, when the calcination temperature was increased from 700 °C to 800 °C, the growth rate of the particle size was significantly faster than that of the crystallite size, and the coercivity increased substantially from 1411 Oe to 2688 Oe.

HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress.

Phenotypic change of vascular smooth muscle cells (VSMCs) is the main contributor of vascular pathological remodeling in atherosclerosis. The endoplasmic reticulum (ER) is critical for maintaining VSMC function through elimination of misfolded proteins that impair VSMC cellular function. ER-associated degradation (ERAD) is an ER-mediated process that controls protein quality by clearing misfolded proteins. One of the critical regulators of ERAD is HRD1, which also plays a vital role in lipid metabolism. However, the function of HRD1 in VSMCs of atherosclerotic vessels remains poorly understood. The level of HRD1 expression was analyzed in aortic tissues of mice fed with a high-fat diet (HFD). The H&E and EVG (VERHOEFF'S VAN GIESON) staining were used to demonstrate pathological vascular changes. IF (immunofluorescence) and WB (western blot) were used to explore the signaling pathways in vivo and in vitro. The wound closure and transwell assays were also used to test the migration rate of VSMCs. CRISPR gene editing and transcriptomic analysis were applied in vitro to explore the cellular mechanism. Our data showed significant reduction of HRD1 in aortic tissues of mice under HFD feeding. VSMC phenotypic change and HRD1 downregulation were detected by cholesterol supplement. Transcriptomic and further analysis of HRD1-KO VSMCs showed that HRD1 deficiency induced the expression of genes related to ER stress response, proliferation and migration, but reduced the contractile-related genes in VSMCs. HRD1 deficiency also exacerbated the proliferation, migration and ROS production of VSMCs induced by cholesterol, which promoted the VSMC dedifferentiation. Our results showed that HRD1 played an essential role in the contractile homeostasis of VSMCs by negatively regulating ER stress response. Thus, HRD1 in VSMCs could serve as a potential therapeutic target in metabolic disorder-induced vascular remodeling.

Secreted MUP1 that reduced under ER stress attenuates ER stress induced insulin resistance through suppressing protein synthesis in hepatocytes.

Disturbed endoplasmic reticulum (ER) stress response driven by the excessive lipid accumulation in the liver is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Restoring metabolic homeostasis by targeting ER stress is a potentially therapeutic strategy for NAFLD. Here we aim to identify novel proteins or pathways involved in regulating ER stress response and therapeutic targets for alleviating NAFLD. Proteomic and transcriptomic analysis demonstrated that major urinary proteins (MUPs) were significantly reduced in the livers from NAFLD mouse models. Then we confirmed that MUP1, the major secreted form of MUPs, was reduced at mRNA and protein expression levels in hepatocytes both in vivo and in vitro under ER stress. We further illustrated that MUP1 protein levels in the urine were reduced in mice with NAFLD, which was reversed by GLP-1 receptor agonist treatment. To study the relationship between ER stress and MUP1 biology, our analysis demonstrated that MUP1 was misfolded and trapped in the ER under ER stress in vivo. Interestingly, we discovered that recombinant MUP1 treatment in hepatocytes increased calcium efflux from the ER, which resulted in transient ER stress response, including reduced protein synthesis. These responses facilitated the alleviation of chemical induced ER stress in hepatocytes, which was suggested as "pre-adaptive ER stress". Besides, recombinant MUP1 pretreatment also improved ER stress-induced insulin resistance in hepatocytes. Our findings revealed a novel and critical role of MUP1, and recombinant MUP1 or its potential derivates may serve as a promising therapeutic target for alleviating NAFLD.

Ferroelectric polarization effect on the photocatalytic activity of Bi0.9Ca0.1FeO3/CdS S-scheme nanocomposites.

BiFeO3 (BFO), as a kind of narrow band-gap semiconductor material, has gradually emerged advantages in the application of photocatalysis. In this paper, Ca doped BFO nanoparticles Bi0.9Ca0.1FeO3 (BCFO) were prepared by sol-gel method. And BCFO and CdS nanocomposites with two morphologies were obtained by controlling the time of loading CdS under a low temperature liquid phase process. It is found that the band gap becomes narrower after doping Ca into BFO, which is conducive to the absorption of visible light. Among all the samples, the composite of CdS nanowires and BCFO nanoparticles obtained by reaction time of 10 min has the best photocatalytic performance. The degradation rate of Methyl Orange solution was 94% after 90 min under visible light irradiation, which was much higher than that of pure BCFO and CdS. Furthermore, significant enhancement in the degradation rate (100% degradation in 60 min) can be achieved in poled samples after electric polarization process. The highest degradation rate is due to the promoted separation of photogenerated carriers induced by the internal polarization field and the formation of S-scheme heterostructure between BCFO and CdS. Such BCFO-CdS nanocomposites may bring new insights into designing highly efficient photocatalyst.

Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation.

Kallistatin is an inhibitor of tissue kallikrein and also inhibits the Wnt pathway. Its role in diabetic nephropathy (DN) is uncertain. Here we reported that serum kallistatin levels were significantly increased in diabetic patients with DN compared to those in diabetic patients without DN and healthy controls, and positively correlated with urinary albumin excretion. In addition, renal kallistatin levels were significantly upregulated in mouse models of type 1 (Akita, OVE26) and type 2 diabetes (db/db). To unveil the effects of kallistatin on DN and its underlying mechanism, we crossed transgenic mice overexpressing kallistatin with OVE26 mice (KS-tg/OVE). Kallistatin overexpression exacerbated albuminuria, renal fibrosis, inflammation, and oxidative stress in diabetes. Kallikrein activity was inhibited while the renin-angiotensin system (RAS) upregulated in the kidney of KS-tg/OVE mice compared to WT/OVE mice, suggesting a disturbed balance between the RAS and kallikrein-kinin systems. As shown by immunostaining of endothelial makers, renal vascular densities were decreased accompanied by increased HIF-1α and erythropoietin levels in the kidneys of KS-tg/OVE mice. Taken together, high levels of kallistatin exacerbate DN at least partly by inducing RAS overactivation and hypoxia. The present study demonstrated a positive correlation between kallistatin levels and DN, suggesting a potential biomarker for prognosis of DN.

Exchange-biased hybrid γ-Fe2O3/NiO core-shell nanostructures: three-step synthesis, microstructure, and magnetic properties.

A two-step solvothermal method combining a calcination process was conducted to synthesize γ-Fe2O3/NiO core-shell nanostructures with controlled microstructure. The formation mechanism of this binary system has been discussed, and the influence of microstructures on magnetic properties has been analyzed in detail. Microstructural characterizations reveal that the NiO shells consisted of many irregular nanosheets with disordered orientations and monocrystalline structures, packed on the surface of the γ-Fe2O3 microspheres. Both the grain size and NiO content of nanostructures increase with the increasing calcination temperature from 300 °C to 400 °C, accompanied by an enhancement of the compactness of NiO shells. Magnetic studies indicate that their magnetic properties are determined by four factors: the size effect, NiO phase content, interface microstructure, i.e. contact mode, area, roughness and compactness, and FM-AFM (where FM and AFM denote the ferromagnetic γ-Fe2O3 and the antiferromagnetic NiO components, respectively) coupling effect. At 5 K, the γ-Fe2O3/NiO core-shell nanostructures display certain exchange bias (HE = 60 Oe) and enhanced coercivity (HC = 213 Oe).

Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway.

Pigment epithelium-derived factor (PEDF) expression is downregulated in the kidneys of diabetic rats, and delivery of PEDF suppressed renal fibrotic factors in these animals. PEDF has multiple functions including anti-angiogenic, anti-inflammatory and antifibrotic activities. Since the mechanism underlying its antifibrotic effect remains unclear, we studied this in several murine models of renal disease. Renal PEDF levels were significantly reduced in genetic models of type 1 and type 2 diabetes (Akita and db/db, respectively), negatively correlating with Wnt signaling activity in the kidneys. In unilateral ureteral obstruction, an acute renal injury model, there were significant decreases of renal PEDF levels. The kidneys of PEDF knockout mice with ureteral obstruction displayed exacerbated expression of fibrotic and inflammatory factors, oxidative stress, tubulointerstitial fibrosis, and tubule epithelial cell apoptosis, compared to the kidneys of wild-type mice with obstruction. PEDF knockout enhanced Wnt signaling activation induced by obstruction, while PEDF inhibited the Wnt pathway-mediated fibrosis in primary renal proximal tubule epithelial cells. Additionally, oxidative stress was aggravated in renal proximal tubule epithelial cells isolated from knockout mice and suppressed by PEDF treatment of renal proximal tubule epithelial cells. PEDF also reduced oxidation-induced apoptosis in renal proximal tubule epithelial cells. Thus, the renoprotective effects of PEDF are mediated, at least partially, by inhibition of the Wnt pathway. Hence, restoration of renal PEDF levels may have therapeutic potential for renal fibrosis.

Receptor heterodimerization as a novel mechanism for the regulation of Wnt/ß-catenin signaling.

The Wnt pathway plays important roles in multiple physiological and pathophysiological processes. Here, we report a novel mechanism that regulates the Wnt pathway through heterodimerization of the Wnt co-receptor low-density lipoprotein-receptor-related protein 6 (LRP6) and very low-density lipoprotein receptor (VLDLR); the latter belongs to the same protein family as LRP6 and was originally known as a receptor for lipoproteins. Knockdown of Vldlr expression elevated LRP6 protein levels and activated Wnt/ß-catenin signaling, whereas overexpression of Vldlr suppressed Wnt signaling. Moreover, we demonstrate that the VLDLR ectodomain is essential and sufficient for inhibition of Wnt signaling. The VLDLR ectodomain accelerated internalization and degradation of LRP6 through heterodimerization with the LRP6 extracellular domain. Monoclonal antibodies specific for the VLDLR ectodomain blocked VLDLR-LRP6 heterodimerization, resulting in enhanced Wnt/ß-catenin signaling in vitro and in vivo. Taken together, these findings suggest that heterodimerization of receptors in the membrane accelerates the turnover of LRP6, and represent a new mechanism for the regulation of Wnt/ß-catenin signaling.

Pathogenic role of diabetes-induced PPAR-α down-regulation in microvascular dysfunction.

Two independent clinical studies have reported that fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has robust therapeutic effects on microvascular complications of diabetes, including diabetic retinopathy (DR) in type 2 diabetic patients. However, the expression and function of PPARα in the retina are unclear. Here, we demonstrated that PPARα is expressed in multiple cell types in the retina. In both type 1 and type 2 diabetes models, expression of PPARα, but not PPARß/δ or PPARγ, was significantly down-regulated in the retina. Furthermore, high-glucose medium was sufficient to down-regulate PPARα expression in cultured retinal cells. To further investigate the role of PPARα in DR, diabetes was induced in PPARα knockout (KO) mice and wild-type (WT) mice. Diabetic PPARα KO mice developed more severe DR, as shown by retinal vascular leakage, leukostasis, pericyte loss, capillary degeneration, and over-expression of inflammatory factors, compared with diabetic WT mice. In addition, overexpression of PPARα in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation. Furthermore, PPARα overexpression inhibited endothelial cell migration and proliferation. These findings revealed that diabetes-induced down-regulation of PPARα plays an important role in DR. Up-regulation or activation of PPARα may represent a novel therapeutic strategy for DR.

PEDF and its roles in physiological and pathological conditions: implication in diabetic and hypoxia-induced angiogenic diseases.

Pigment epithelium-derived factor (PEDF) is a broadly expressed multifunctional member of the serine proteinase inhibitor (serpin) family. This widely studied protein plays critical roles in many physiological and pathophysiological processes, including neuroprotection, angiogenesis, fibrogenesis and inflammation. The present review summarizes the temporal and spatial distribution patterns of PEDF in a variety of developing and adult organs, and discusses its functions in maintaining physiological homoeostasis. The major focus of the present review is to discuss the implication of PEDF in diabetic and hypoxia-induced angiogenesis, and the pathways mediating PEDF's effects under these conditions. Furthermore, the regulatory mechanisms of PEDF expression, function and degradation are also reviewed. Finally, the therapeutic potential of PEDF as an anti-angiogenic drug is briefly summarized.

Enhanced exchange bias and coercivity arising from heterojunctions in Ni-NiO nanocomposites.

By a reflux process, we prepared Ni-NiO nanocomposites that are face-centered cubic (fcc). By tuning the precursor concentration, we controlled the Ni content in the Ni-NiO nanocomposites. We found that both the interface of Ni and NiO crystal lattices and the weight fraction of Ni have significant impacts on their magnetic properties. There is increase of saturation magnetization and decrease of coercivity (HC) with the increase of the Ni weight fraction. Large exchange bias (HE) and enhanced HC are observed at 5 K, which are due to the creation of heterojunctions at the interfaces of ferromagnetic Ni and antiferromagnetic NiO. After optimization, it is observed that the Ni-NiO nanocomposites with an Ni content of 2.6% show an HC and HE of 1068 and 350 Oe, respectively.

Impact of meteorological variability on diurnal and seasonal net ecosystem productivity in a desert riparian forest ecosystem.

The desert riparian forests are susceptible to meteorological changes and contribute significantly to the net ecosystem productivity (NEP) variations of arid ecosystems. However, the responsive patterns of their NEP variations to the meteorological variabilities remain inadequately comprehended. To address this gap, we utilized seven years of eddy covariance flux measurements in a representative desert riparian forest to investigate the NEP variations and its response to changing meteorological factors across diverse temporal scales. The results revealed significant periodic variations in half-hourly NEP, with dominant cycles spanning from five hours to one year, with a principal oscillation period of one day. Key meteorological factors including global solar radiation (Rg), relative humidity (RH), air temperature (Ta), soil temperature (Ts), and vapor pressure deficit (VPD) exhibited synchronization with NEP on daily scales. This synchronization, coupled with the observed one-day periodic NEP variations, provides robust evidence supporting the existence of a circadian rhythm in the ecosystem carbon exchange of desert riparian forest regulated by meteorological conditions. Seasonal patterns were significant in the impact of Rg phase, Ta diurnal amplitude, and VPD diurnal amplitude on NEP diurnal amplitude and phase. The NEP diurnal amplitude significantly, directly, and positively affected daily NEP in both the dormant and growing seasons, whereas its phase yielded significant negative effects (P< 0.05). The averages, amplitudes, and phases of diurnal meteorological conditions controlled the daily NEP by regulating NEP diurnal amplitude and phase. These findings provide evidence that the variability in circadian rhythms, caused by the increase in diurnal Ta and VPD, significantly impact the daily NEP at an ecosystem scale. This study enriches our comprehension of the meteorological mechanisms governing diurnal and seasonal carbon uptake dynamics within desert riparian forests, providing fresh insights into the direct and indirect roles of climate change in shaping patterns of ecosystem carbon exchange.

Glucagon-like peptide-1 receptor agonists rescued diabetic vascular endothelial damage through suppression of aberrant STING signaling.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

Characterization of dietary and herbal sourced natural compounds that modulate SEL1L-HRD1 ERAD activity and alleviate protein misfolding in the ER.

Dysregulated production of peptide hormones is the key pathogenic factor of various endocrine diseases. Endoplasmic reticulum (ER) associated degradation (ERAD) is a critical machinery in maintaining ER proteostasis in mammalian cells by degrading misfolded proteins. Dysfunction of ERAD leads to maturation defect of many peptide hormones, such as provasopressin (proAVP), which results in the occurrence of Central Diabetes Insipidus. However, drugs targeting ERAD to regulate the production of peptide hormones are very limited. Herbal products provide not only nutritional sources, but also alternative therapeutics for chronic diseases. Virtual screening provides an effective and high-throughput strategy for identifying protein structure-based interacting compounds extracted from a variety of dietary or herbal sources, which could be served as (pro)drugs for preventing or treating endocrine diseases. Here, we performed a virtual screening by directly targeting SEL1L of the most conserved SEL1L-HRD1 ERAD machinery. Further, we analyzed 58 top-ranked compounds and demonstrated that Cryptochlorogenic acid (CCA) showed strong affinity with the binding pocket of SEL1L with HRD1. Through structure-based docking, protein expression assays, and FACS analysis, we revealed that CCA enhanced ERAD activity and promoted the degradation of misfolded proAVP, thus facilitated the secretion of well-folded proAVP. These results provide us with insights into drug discovery strategies targeting ER protein homeostasis, as well as candidate compounds for treating hormone-related diseases.

Multilevel resistive switching in stable all-inorganic n-i-p double perovskite memristor.

Memristors are promising information storage devices for commercial applications because of their long endurance and low power consumption. Particularly, perovskite memristors have revealed excellent resistive switching (RS) properties owing to the fast ion migration and solution fabrication process. Here, an n-i-p type double perovskite memristor with "ITO/SnO2/Cs2AgBiBr6/NiOx/Ag" architecture was developed and demonstrated to reveal three resistance states because of the p-n junction electric field coupled with ion migration. The devices exhibited reliable filamentary with an on/off ratio exceeding 50. The RS characteristics remained unchanged after 1000 s read and 300 switching cycles. The synaptic functions were examined through long-term depression and potentiation measurements. Significantly, the device still worked after one year to reveal long-term stability because of the all-inorganic layers. This work indicates a novel idea for designing a multistate memristor by utilizing the p-n junction unidirectional conductivity during the forward and reverse scanning.

Hyperlipidemia induces proinflammatory responses by activating STING pathway through IRE1α-XBP1 in retinal endothelial cells.

Diabetic retinopathy (DR) is one of the most prevalent microvascular complications caused by diabetes mellitus. Previous studies demonstrate that microvascular endothelial inflammation caused by chronic hyperglycemia and hyperlipidemia plays a key role in the pathogenesis of DR. However, the detailed mechanisms on how endothelial inflammation contributes to DR are not fully understood. The STING pathway is an important innate immune signaling pathway. Although STING has been implicated in multiple autoimmune and metabolic diseases, it is not clear whether STING is involved in the pathogenesis of DR. Thus, re-analysis of the public single cell RNA sequencing (sc-RNAseq) data demonstrated that STING was highly expressed in mouse retinal vessels. Moreover, our results demonstrated that STING and p-TBK1 protein levels in retinal endothelial cells are significantly increased in mice fed with high fat diet compared with chow diet. In vitro, palmitic acid treatment on HRVECs induced mitochondrial DNA leakage into the cytosol, and augmented p-TBK1 protein and IFN-ß mRNA levels. As STING is localized to the ER, we analyzed the relation between STING activation and ER stress. In HRVECs, STING pathway was shown to be activated under chemical-induced ER stress, but attenuated when IRE1α was abolished by genetic deletion or pharmacological inhibition. Taken together, our findings revealed that STING signaling plays an important role in mediating lipotoxicity-induced endothelial inflammatory and injury, and IRE1α-XBP1 signaling potentiated STING signaling. Thus, targeting the IRE1α or STING pathways to alleviate endothelial inflammation provides candidate therapeutic target for treating DR as well as other microvascular complications.