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.

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.

Metallic Carbonitride MXene Based Photonic Hyperthermia for Tumor Therapy.

Photothermal therapy (PTT) as a noninvasive hyperthermia exhibits high potential for anti-cancer treatments. The explosion of efficient photothermal agents (PTAs) keeps developing rapidly. MXene stands out due to its intriguing structures, fantastic photodynamic properties, and good biocompatibility. However, the potential of MXenes has not been sufficiently explored in PTT. Its versatile chemical compositions of MXenes provide vast opportunities to discover new candidates. Considering that the metallic feature is mainly attributed to the metal element, anionic modulation may open a distinct avenue to propel efficient PTAs with metallic nature, which is expected for high light-harvesting over near-infrared (NIR)-I and NIR-II. As a paradigm, metal carbonitride is chosen to visualize the influences of anionic modulation. Taking advantage of electron injection from nitrogen, the distinct carbonitride Ti3 C1.15 N0.85 F0.88 O0.56 (OH)0.56 exhibits a strong NIR absorption (36.6 L g-1 cm-1 at 808 nm, 43.5 L g-1 cm-1 at 1064 nm), resulting in efficient photonic hyperthermia against tumors in vitro and in vivo. Looking through a large family of MXenes, this proof-of-principle demonstration offers a deep understanding between atomic composition and physicochemical properties, which further solidifies MXenes with all the potential for biomedical applications.

[Determination of domoic acid in shellfish by liquid chromatography- tandem mass spectrometry coupled with dispersive solid phase extraction].

OBJECTIVE: A method utilizing liquid chromatography-tandem mass spectrometry(LC-MS/MS) coupled with dispersive solid phase extraction for quantitative analysis of domoic acid in four kinds of shellfish was established. METHODS: The sample of 0. 1 g was extracted with 25% methanol aqueous solution, the extract was purified by dispersive solid phase extraction with 50 mg HLB and 5 mg GCB, and then filtered through a PTFE membrane. The analytes were separated on a C_(18) column(100 mm×2. 1 mm, 1. 9 µm), and detected in selected reaction monitoring(SRM) mode via positive electrospray ionization. The matrix matching and external standard method was used for quantitation. RESULTS: Domoic acid showed good linearity in the concentration range between 1. 0 ng/mL and 50. 0 ng/mL with correlation coefficients higher than 0. 9994. The detection limits of domoic acid in shellfish was 5 µg/kg. The inter-and intra-day recoveries were 91. 6%-109. 2% and 90. 9%-109. 3%, respectively. The inter-and intra-day ralitive standard deviations(RSDs) were lower than 8. 2% at spiked concentrations of 20, 50 and 100 µg/kg. CONCLUSION: The method is accurate, fast, easy to operate, which can satisfy the requirements of public health emergency testing or routine testing.

Utility of the EncephalApp Stroop Test for covert hepatic encephalopathy screening in Chinese cirrhotic patients.

BACKGROUND AND AIM: Considering the large size of the potential population and limitations of common detection methods, covert hepatic encephalopathy (CHE) is difficult to screen for routinely. The present study aims to explore EncephalApp Stroop Test as a smartphone-based CHE screening tool in China. METHODS: A multicenter, single-visit study was carried out. The cutoff of the Chinese EncephalApp translation was determined by using Chinese standardized psychometric hepatic encephalopathy score (PHES) in cirrhotic patients as the gold standard. Indicators reflecting time required and number of tests on subtask on (naming the color of pound signs) and off (naming the color of the word in discordant coloring) were recorded, with the feedback from investigators and patients. RESULTS: One hundred forty-four patients were included; 58 (40.28%) patients were diagnosed with CHE by PHES. The cutoff of > 97.34 s for off time and > 186.63 s for on time + off time had the maximum area under the curve values (0.77) in all patients. Furthermore, with the cutoff of 186.63 s, on time + off time has the highest sensitivity (0.86). However, the specificity was unsatisfactory (0.59). Age and alcoholic hepatitis (odds ratio = 1.05 and 3.12, both P < 0.05) were positively correlated with the risk of CHE. The experience with electronic devices and education duration were negatively correlated (odds ratio = 0.21 and 0.92, both P < 0.05). Compared with PHES, EncephalApp represented 38% time saving. Furthermore, it was superior to PHES regarding accessibility, convenience, and acceptability by administrators (all P < 0.05). CONCLUSIONS: The EncephalApp Stroop Test is an efficient screening tool for CHE in Chinese cirrhotic patients.

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Self-Gradient Compensation of Full-Tensor Airborne Gravity Gradiometer.

In the process of airborne gravity gradiometry for the full-tensor airborne gravity gradiometer (FTAGG), the attitude of the carrier and the fuel mass will seriously affect the accuracy of gravity gradiometry. A self-gradient is the gravity gradient produced by the surrounding masses, and the surrounding masses include distribution mass for the carrier mass and fuel mass. In this paper, in order to improve the accuracy of airborne gravity gradiometry, a self-gradient compensation model is proposed for FTAGG. The self-gradient compensation model is a fuction of attitude for carrier and time, and it includes parameters ralated to the distribution mass for the carrier. The influence of carrier attitude and fuel mass on the self-gradient are simulated and analyzed. Simulation shows that the self-gradient tensor element Γ x x , Γ x y , Γ x z , Γ y z and Γ z z are greatly affected by the middle part of the carrier, and the self-gradient tensor element Γ y z is affected by the carrier's fuel mass in three attitudes. Further simulation experiments show that the presented self-gradient compensation method is valid, and the error of the self-gradient compensation is within 0.1 Eu. Furthermore, this method can provide an important reference for improving the accuracy of aviation gravity gradiometry.

Ras GTPase-Activating-Like Protein IQGAP1 (IQGAP1) Promotes Breast Cancer Proliferation and Invasion and Correlates with Poor Clinical Outcomes.

BACKGROUND Breast cancer is one of the most common female cancers in the world. As a key integrator of cell signaling pathways, IQGAP1 contributes to the development and progression of several cancers. However, the exact effects and molecular mechanisms of IQGAP1 in breast cancer progression remain poorly understood. MATERIAL AND METHODS In the present study, IQGAP1 expression was measured in 96 paired breast cancer samples and the corresponding adjacent non-cancerous tissues by immunohistochemistry and quantitative polymerase chain reaction. To further explore the biological function of IQGAP1 in breast cancer cells, we knocked down IQGAP1 expression in MCF-7 cells and overexpressed it in SK-BR-3 cells. RESULTS IQGAP1 was specifically upregulated in breast cancer tissues compared with the corresponding adjacent non-cancerous tissues. Moreover, IQGAP1 expression was positively correlated with breast cancer survival rate. IQGAP1 also promoted breast cancer cell proliferation and cell cycle progression and suppressed apoptosis. CONCLUSIONS In conclusion, our results suggest that IQGAP1 plays an important role in the cell proliferation and invasion of human breast cancer cells, thus indicating that IQGAP1 may be a potential therapeutic target for the treatment of human breast cancer.

HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing.

Mesenchymal stem cell-derived exosomes (MSC-Ex) play important roles in tissue injury repair, however, the roles of MSC-Ex in skin damage repair and its mechanisms are largely unknown. Herein, we examined the benefit of human umbilical cord MSC-derived exosome (hucMSC-Ex) in cutaneous wound healing using a rat skin burn model. We found that hucMSC-Ex-treated wounds exhibited significantly accelerated re-epithelialization, with increased expression of CK19, PCNA, collagen I (compared to collagen III) in vivo. HucMSC-Ex promoted proliferation and inhibited apoptosis of skin cells after heat-stress in vitro. We also discovered that Wnt4 was contained in hucMSC-Ex, and hucMSC-Ex-derived Wnt4 promoted ß-catenin nuclear translocation and activity to enhance proliferation and migration of skin cells, which could be reversed by ß-catenin inhibitor ICG001. In vivo studies confirmed that the activation of Wnt/ß-catenin by hucMSC-Ex played a key role in wound re-epithelialization and cell proliferation. Furthermore, knockdown of Wnt4 in hucMSC-Ex abrogated ß-catenin activation and skin cell proliferation and migration in vitro. The in vivo therapeutic effects were also inhibited when the expression of Wnt4 in hucMSC-Ex was interfered. In addition, the activation of AKT pathway by hucMSC-Ex was associated with the reduction of heat stress-induced apoptosis in rat skin burn model. Collectively, our findings indicate that exosome-delivered Wnt4 provides new aspects for the therapeutic strategy of MSCs in cutaneous wound healing. Stem Cells 2015;33:2158-2168.

[Glucose characteristics in normal glucose tolerance subjects with metabolic syndrome].

OBJECTIVE: To explore the characteristics of glycemic variability in normal glucose tolerance (NGT) subjects with metabolic syndrome (MetS). METHODS: A total of 40 NGT subjects diagnosed by oral glucose tolerance test (OGTT) were divided into two groups of metabolic syndrome (MetS) or without MetS (Non-MetS) according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria. Fasting blood glucose (FBG), OGTT 2 h blood glucose (2 h BG), hemoglobin A1c (HbA1c) and glycemic variability were assessed. Glycemic variability was assessed by calculating standard deviation of MBG (SDBG), mean amplitude of glycemic excursions (MAGE), largest amplitude of glycemic excursions (LAGE) and means of daily differences (MODD) from the 72 h data of continuous glucose monitoring system (CGMS) in real life. The time of diurnal glycemic variability was also calculated. RESULTS: No significant inter-group difference existed in FBG, 2 h BG or HbA1c. Glycemic variability was higher in MetS than that in Non-MetS group. But only MAGE (2.12±0.92 vs 1.50±0.68 mmol/L, P=0.02) showed significant inter-group difference. Logistic regression analysis revealed that MAGE was significantly correlated with MetS (OR=2.74, 95% CI: 1.08-6.97, P=0.03) and independently from FBG, PBG, HbA1c and other glycemic variability indices. CONCLUSIONS: Glycemic variability increases in NGT subjects with MetS. And MAGE may better describe the population's glucose metabolism.

Effects of timing of vitrectomy performed for open-globe injury patients on the thickness of retinal nerve fiber layer.

OBJECTIVE: To study the effects of timing of vitrectomy performed for open-globe injury patients on the thickness of retinal nerve fiber layer (RNFL). METHODS: A total of 120 patients with traumatic optic neuropathy (TON) were selected and divided into a treatment group and a control group by random draw (n=60). Vitrectomy was performed within one week upon injury for treatment group and after one week for control group. The thickness of RNFL was observed by optical coherence tomography. RESULTS: All surgeries were conducted successfully, without severe complications. The best corrected visual acuity of treatment group surpassed that of control group one month after surgery, and treatment group had an obviously higher overall effective rate (95.0%) than control group did (81.7%). The incidence rate of postoperative complications in treatment group (6.7%) was significantly lower than that of control group (28.3%) (P<0.05). Logistic multivariate regression analysis showed that vitrectomy timing and postoperative complications were independent risk factors of prognosis (P<0.05). Both groups had significantly thinner RNFLs one week after surgery (P<0.05), and treatment group almost recovered within one month (P>0.05). CONCLUSION: Early vitrectomy effectively augmented the visual acuity of patients with TON, decreased complications, affected RNFL thickness reversibly, and improved prognosis.

Cationic lipid-assisted polymeric nanoparticle mediated GATA2 siRNA delivery for synthetic lethal therapy of KRAS mutant non-small-cell lung carcinoma.

Synthetic lethal interaction provides a conceptual framework for the development of wiser cancer therapeutics. In this study, we exploited a therapeutic strategy based on the interaction between GATA binding protein 2 (GATA2) downregulation and the KRAS mutation status by delivering small interfering RNA targeting GATA2 (siGATA2) with cationic lipid-assisted polymeric nanoparticles for treatment of non-small-cell lung carcinoma (NSCLC) harboring oncogenic KRAS mutations. Nanoparticles carrying siGATA2 (NPsiGATA2) were effectively taken up by NSCLC cells and resulted in targeted gene suppression. NPsiGATA2 selectively inhibited cell proliferation and induced cell apoptosis in KRAS mutant NSCLC cells. However, this intervention was harmless to normal KRAS wild-type NSCLC cells and HL7702 hepatocytes, confirming the advantage of synthetic lethality-based therapy. Moreover, systemic delivery of NPsiGATA2 significantly inhibited tumor growth in the KRAS mutant A549 NSCLC xenograft murine model, suggesting the therapeutic promise of NPsiGATA2 delivery in KRAS mutant NSCLC therapy.

[Insulin requirement profiles and related factors of type 2 diabetics with insulin pump therapy].

OBJECTIVE: To explore the insulin requirement profiles and analyze the related factors of type 2 diabetics on insulin pump therapy. METHODS: A total of 296 patients were admitted to hospital for 1-2 weeks of insulin pump therapy and received a diet of 25-30 kcal/kg ideal body weight per day. Insulin infusion was adjusted to achieve normoglycemia. It was defined as fasting capillary blood glucose of no more than 7.0 mmol/L and capillary blood glucose at 2 hours after each of three meals of no more than 10.0 mmol/L. After goal-reaching for 3 days, the insulin requirement profiles and related factors were analyzed. RESULTS: The average time of achieving normoglycemia was (5.1 ± 2.9) days. The total daily insulin dose per kilogram was (0.80 ± 0.27) U/kg and the ratio of total basal insulin dose to total bolus insulin dose 40%: 60%. Patients with central obesity needed a higher ratio of total basal insulin dose to total daily insulin dose (P < 0.05). Associations existed between the ratio of total basal insulin dose to total daily insulin dose and disease duration, waist circumference and ratio of 2 hour-postprandial C-peptide to fasting C-peptide (r = 0.169, 0.143, -0.107, all P < 0.05). Multivariate linear regression analyses showed that waist circumference, disease duration and ratio of 2 hour-postprandial C-peptide to fasting C-peptide were independently related with the ratio of total basal insulin dose to total daily insulin dose. Also waist circumference, fasting plasma glucose and hemoglobin A1c levels were independently associated with total daily insulin dose per kilogram. CONCLUSION: The ratio of total basal insulin dose to total bolus insulin dose is 40%: 60% in Chinese type 2 diabetics with insulin pump therapy. And it is associated with central obesity level and ß-cell function. Parameters indicating glycemic control and central obesity should be taken into consideration for total insulin requirements.

[Factors associated with glycemic control in adults with type 1 diabetes mellitus on an insulin pump].

OBJECTIVE: To explore the factors associated with glycemic control in adults with type 1 diabetes mellitus (T1D) on an insulin pump. METHODS: A total of 108 patients aged over 18 years and on an insulin pump therapy for >6 months were selected from 16 centers of Guangdong Type 1 diabetes Translational Medicine Study. They were classified into two groups according to the (American Diabetes Association) ADA Hemoglobin A1c target (7.0%). Those reaching the target (n = 59) were compared with those failed (n = 49) using ANOVA and Logistic regression. RESULTS: There were 75 females and 33 males with a median age of 32.0 (25.9-40.9) years and a median disease duration of 7.9(4.2-12.3) years. Logistic regression analysis revealed an odds ratio of 4.48(95%CI 1.53-13.15, P = 0.00) for total daily basal insulin dose within 0.2-0.3 units per kilogram, an OR of 1.31 (95%CI 1.05-1.63, P = 0.01) for self-monitoring of blood glucose (SMBG) and an OR of 3.43 (95%CI 1.18-10.01, P = 0.02) for males. CONCLUSION: Higher frequencies of SMBG and appropriate basal insulin dose are essential for adult patients with T1D on an insulin pump.

Stimuli-responsive peptide hydrogels for biomedical applications.

Stimuli-responsive hydrogels can respond to external stimuli with a change in the network structure and thus have potential application in drug release, intelligent sensing, and scaffold construction. Peptides possess robust supramolecular self-assembly ability, enabling spontaneous formation of nanostructures through supramolecular interactions and subsequently hydrogels. Therefore, peptide-based stimuli-responsive hydrogels have been widely explored as smart soft materials for biomedical applications in the last decade. Herein, we present a review article on design strategies and research progress of peptide hydrogels as stimuli-responsive materials in the field of biomedicine. The latest design and development of peptide hydrogels with responsive behaviors to stimuli are first presented. The following part provides a systematic overview of the functions and applications of stimuli-responsive peptide hydrogels in tissue engineering, drug delivery, wound healing, antimicrobial treatment, 3D cell culture, biosensors, etc. Finally, the remaining challenges and future prospects of stimuli-responsive peptide hydrogels are proposed. It is believed that this review will contribute to the rational design and development of stimuli-responsive peptide hydrogels toward biomedical applications.

Heterogeneous-Structure-Based AuNBs@TiO2 Nano-Photosensitizers for Computed Tomography Imaging Guided NIR-II Photodynamic Therapy and Cancer Metastatic Prevention.

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that, despite its significant attention, faces limitations in penetration depth, which restrict its effectiveness. Herein, it is found that gold nanobipyramid (AuNBs) coated with TiO2 can form a core-shell heterogeneous structure (AuNBs@TiO2) with strong absorption at second near infrared (NIR-II) region. A substantial quantity of reactive oxygen species (ROS), including singlet oxygen (1O2), superoxide anion radicals, and hydroxyl radicals, can be rapidly generated when subjecting the AuNBs@TiO2 aqueous suspension to 1064 nm laser irradiation. The quantum yield for sensitization of 1O2 by AuNBs@TiO2 is 0.36 at 1064 nm light excitation. In addition, the Au element as high-Z atoms in the nanosystem can improve the ability of computed tomographic (CT) imaging. As compared to commercial iohexol, the AuNBs@TiO2 nanoparticle exhibits significantly better CT imaging effect, which can be used to guide PDT. In addition, the nano-photosensitizer shows a remarkable therapeutic effect against established solid tumors and prevents tumor metastasis and potentiates immune checkpoint blockade therapy. More importantly, here the great potentials of AuNBs@TiO2 are highlighted as a theranostic platform for CT-guided cancer photodynamic immunotherapy.

CircRNA LDLR promotes proliferation and aerobic glycolysis of gastric cancer cells by targeting CHD1 with miR-449b-5p.

Background/aim: Circular RNAs can serve as detection biomarkers and therapeutic targets for tumors. Our study aimed to elucidate the mechanisms associated with circRNA LDLR (circLDLR) in gastric cancer (GC) proliferation and aerobic glycolysis. Materials and methods: Expression signatures of circLDLR, miR-449b-5p, and CHD1 were examined in GC samples using quantitative PCR. Proliferation ability of MKN-45 cells was assessed via CCK-8 and EdU assays, and cell apoptosis was measured by flow cytometry. Glucose uptake, lactate production, ATP/ADP ratios, and NAD+/NADH ratios in cell supernatants were quantified to evaluate aerobic glycolysis. Subcellular isolation assay, quantitative PCR, immunoblot analysis, RNA immunoprecipitation (RIP), and dual luciferase reporter assay were employed to investigate the relationship between genes. Results: Expression of circLDLR and CHD1 was elevated, while miR-449b-5p expression decreased in GC. Functionally, overexpression of circLDLR enhanced proliferation and aerobic glycolysis and hampered apoptosis of MKN-45 cells. However, upregulation of miR-449b-5p or downregulation of CHD1 reversed these effects. CircLDLR acted as an miRNA spongeand regulated the expression of miR-449b-5p, thereby affecting CHD1 and accelerating GC malignant progression. Conclusion: CircLDLR drives the proliferation and aerobic glycolysis of GC cells by targeting CHD1 with miR-449b-5p, which is an ideal potential target for early diagnosis and clinical treatment of GC.

Arsenic-induced downregulation of BRWD3 suppresses proliferation and induces apoptosis in lung adenocarcinoma cells through the p53 and p65 pathways.

Bromodomain and WD-repeat domain-containing protein 3 (BRWD3) exhibits high expression in lung adenocarcinoma (LUAD) tissues and cells; however, its function in arsenic-induced toxicological responses remains unclear. This study aimed to investigate BRWD3 expression in response to arsenic-induced conditions and its impact on the proliferation and apoptosis of LUAD cell line SPC-A1 upon BRWD3 knockdown. The results revealed a decrease in BRWD3 expression in SPC-A1 cells treated with sodium arsenite (NaAsO2), but not sodium arsenite's metabolites. BRWD3 knockdown suppressed cell proliferation and induced apoptosis in SPC-A1 cells. Western blot analysis revealed that BRWD3 knockdown resulted in the upregulation of p53, phospho-p53-Ser392, and its downstream factors including MDM2, Bak, and Bax. Additionally, we observed the downregulation of p65, phospho-p65-Ser276, phospho-p65-Ser536, and its downstream factors, including IκBα, BIRC3, XIAP and CIAP1. Moreover, polymerase chain reaction analysis showed that BRWD3 knockdown also resulted in the downregulation of proliferation-related genes and upregulation of apoptosis-related genes. In conclusion, BRWD3 mediated proliferation and apoptosis via the p53 and p65 pathways in response to arsenic exposure, suggesting potential implications for LUAD treatment through BRWD3 downregulation by arsenic.

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.

Two free radical pathways mediate chemical hypoxia-induced glutamate release in synaptosomes from the prefrontal cortex.

It has been known that the inhibition of mitochondrial cytochrome c oxidase is one of the earliest events occurring under hypoxia and this inhibition can lead to neuronal damages. Thus, the cytochrome c oxidase inhibitor sodium cyanide (NaCN) is widely used to produce a model of chemical hypoxia by inhibiting this enzyme. However, the downstream signaling pathways of the inhibition of the cytochrome c oxidase remain to be studied. In the present paper, we used sodium cyanide to mimic the inhibition of the mitochondrial cytochrome c oxidase and studied its effect on glutamate release in synaptosomes from the prefrontal cortex using on-line fluorimetry. We also further investigated the mechanisms underlying the enhancing effect of sodium cyanide on glutamate release using pharmacological approaches combined with other techniques. The results showed that sodium cyanide significantly increased glutamate release from synaptosomes of prefrontal cortex; the broad-spectrum free radical scavenger MnTBAP and melatonin completely abolished the effect of sodium cyanide on glutamate release; the H2O2-NMDA receptor pathway mediated one part, whereas the lipid peroxyl radicals-ATP synthase pathway mediated another part of the sodium cyanide-induced glutamate release; scavenging H2O2 and enhancing ATP synthase activity could completely abolish the sodium cyanide-induced glutamate release.