CNP Ameliorates Macrophage Inflammatory Response and Atherosclerosis.

BACKGROUND: CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. METHODS: Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE-/-) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain-containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. CONCLUSIONS: Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

Endothelial YAP Mediates Hyperglycemia-Induced Platelet Hyperactivity and Arterial Thrombosis.

BACKGROUND: Hyperglycemia-a symptom that characterizes diabetes-is highly associated with atherothrombotic complications. However, the underlying mechanism by which hyperglycemia fuels platelet activation and arterial thrombus formation is still not fully understood. METHODS: The profiles of polyunsaturated fatty acid metabolites in the plasma of patients with diabetes and healthy controls were determined with targeted metabolomics. FeCl3-induced carotid injury model was used to assess arterial thrombus formation in mice with endothelial cell (EC)-specific YAP (yes-associated protein) deletion or overexpression. Flow cytometry and clot retraction assay were used to evaluate platelet activation. RNA sequencing and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: The plasma PGE2 (prostaglandin E2) concentration was elevated in patients with diabetes with thrombotic complications and positively correlated with platelet activation. The PGE2 synthetases COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E synthase-1) were found to be highly expressed in ECs but not in other type of vessel cells in arteries from both patients with diabetes and hyperglycemic mice, compared with nondiabetic individuals and control mice, respectively. A combination of RNA sequencing and ingenuity pathway analyses indicated the involvement of YAP signaling. EC-specific deletion of YAP limited platelet activation and arterial thrombosis in hyperglycemic mice, whereas EC-specific overexpression of YAP in mice mimicked the prothrombotic state of diabetes, without affecting hemostasis. Mechanistically, we found that hyperglycemia/high glucose-induced endothelial YAP nuclear translocation and subsequently transcriptional expression of COX-2 and mPGES-1 contributed to the elevation of PGE2 and platelet activation. Blockade of EP3 (prostaglandin E receptor 3) activation by oral administration of DG-041 reversed the hyperactivity of platelets and delayed thrombus formation in both EC-specific YAP-overexpressing and hyperglycemic mice. CONCLUSIONS: Collectively, our data suggest that hyperglycemia-induced endothelial YAP activation aggravates platelet activation and arterial thrombus formation via PGE2/EP3 signaling. Targeting EP3 with DG-041 might be therapeutic for diabetes-related thrombosis.

Tudor-SN promotes cardiomyocyte proliferation and neonatal heart regeneration through regulating the phosphorylation of YAP.

BACKGROUND: The neonatal mammalian heart exhibits considerable regenerative potential following injury through cardiomyocyte proliferation, whereas mature cardiomyocytes withdraw from the cell cycle and lose regenerative capacities. Therefore, investigating the mechanisms underlying neonatal cardiomyocyte proliferation and regeneration is crucial for unlocking the regenerative potential of adult mammalian heart to repair damage and restore contractile function following myocardial injury. METHODS: The Tudor staphylococcal nuclease (Tudor-SN) transgenic (TG) or cardiomyocyte-specific knockout mice (Myh6-Tudor-SN -/-) were generated to investigate the role of Tudor-SN in cardiomyocyte proliferation and heart regeneration following apical resection (AR) surgery. Primary cardiomyocytes isolated from neonatal mice were used to assess the influence of Tudor-SN on cardiomyocyte proliferation in vitro. Affinity purification and mass spectrometry were employed to elucidate the underlying mechanism. H9c2 cells and mouse myocardia with either overexpression or knockout of Tudor-SN were utilized to assess its impact on the phosphorylation of Yes-associated protein (YAP), both in vitro and in vivo. RESULTS: We previously identified Tudor-SN as a cell cycle regulator that is highly expressed in neonatal mice myocardia but downregulated in adults. Our present study demonstrates that sustained expression of Tudor-SN promotes and prolongs the proliferation of neonatal cardiomyocytes, improves cardiac function, and enhances the ability to repair the left ventricular apex resection in neonatal mice. Consistently, cardiomyocyte-specific knockout of Tudor-SN impairs cardiac function and retards recovery after injury. Tudor-SN associates with YAP, which plays important roles in heart development and regeneration, inhibiting phosphorylation at Ser 127 and Ser 397 residues by preventing the association between Large Tumor Suppressor 1 (LATS1) and YAP, correspondingly maintaining stability and promoting nuclear translocation of YAP to enhance the proliferation-related genes transcription. CONCLUSION: Tudor-SN regulates the phosphorylation of YAP, consequently enhancing and prolonging neonatal cardiomyocyte proliferation under physiological conditions and promoting neonatal heart regeneration after injury.

The mediating role of sleep problems and depressed mood between psychological abuse/neglect and suicidal ideation in adolescent childhood: a multicentred, large sample survey in Western China.

BACKGROUND: Adolescent suicidal ideation are associated with factors including psychological abuse/neglect, sleep problems, and depressed mood, but the systematic effects of these factors on suicidal ideation remain unclear, which is a research gap this work aims to fill. METHODS: A multi-center, the cluster sampling method was employed to collect general demographic data, such as age, gender, the experience of being left behind, and parents' marital status, from 12,192 students across 17 secondary schools in China. The Child Psychological Abuse and Neglect Scale (CPANS), Pittsburgh Sleep Quality Index (PSQI), the Chinese version of the Depressed mood, Anxiety and Stress Scale - 21 Items (DASS-21) and Chinese version of Positive and Negative Suicide Ideation Inventory (PANSI) were utilized. Data were analyzed using t-tests, chi-square tests, correlation analyses, and structural equation modeling mediation analyses. RESULTS: The prevalence of psychological abuse/neglect and adolescent suicidal ideation was 34.8% and 13%, respectively. This mediation analysis suggests that, in the relationship between psychological abuse/neglect and suicidal ideation, sleep problems and depressed mood play both parallel and sequential mediating roles. CONCLUSION: Sleep problems and depressed mood play a mediating role in the development of suicidal ideation in adolescents. Good sleep habits and depressed mood interventions help reduce the risk of suicidal ideation in adolescents who experience psychological neglect/abuse.

Macrophage MST1/2 Disruption Impairs Post-Infarction Cardiac Repair via LTB4.

[Figure: see text].

Model incorporating multiple diffusion MRI features: development and validation of a radiomics-based model to predict adult-type diffuse gliomas grade.

OBJECTIVES: To develop and validate a radiomics-based model (ADGGIP) for predicting adult-type diffuse gliomas (ADG) grade by combining multiple diffusion modalities and clinical and imaging morphologic features. METHODS: In this prospective study, we recruited 103 participants diagnosed with ADG and collected their preoperative conventional MRI and multiple diffusion imaging (diffusion tensor imaging, diffusion kurtosis imaging, neurite orientation dispersion and density imaging, and mean apparent propagator diffusion-MRI) data in our hospital, as well as clinical information. Radiomic features of the diffusion images and clinical information and morphological data from the radiological reports were extracted, and multiple pipelines were used to construct the optimal model. Model validation was performed through a time-independent validation cohort. ROC curves were used to evaluate model performance. The clinical benefit was determined by decision curve analysis. RESULTS: From June 2018 to May 2021, 72 participants were recruited for the training cohort. Between June 2021 and February 2022, 31 participants were enrolled in the prospective validation cohort. In the training cohort (AUC 0.958), internal validation cohort (0.942), and prospective validation cohort (0.880), ADGGIP had good accuracy in predicting ADG grade. ADGGIP was also significantly better than the single-modality prediction model (AUC 0.860) and clinical imaging morphology model (0.841) (all p < .01) in the prospective validation cohort. When the threshold probability was greater than 5%, ADGGIP provided the greatest net benefit. CONCLUSION: ADGGIP, which is based on advanced diffusion modalities, can predict the grade of ADG with high accuracy and robustness and can help improve clinical decision-making. CLINICAL RELEVANCE STATEMENT: Integrated multi-modal predictive modeling is beneficial for early detection and treatment planning of adult-type diffuse gliomas, as well as for investigating the genuine clinical significance of biomarkers. KEY POINTS: • Integrated model exhibits the highest performance and stability. • When the threshold is greater than 5%, the integrated model has the greatest net benefit. • The advanced diffusion models do not demonstrate better performance than the simple technology.

Investigating structure and dynamics of unentangled poly(dimethyl-co-diphenyl)siloxane via molecular dynamics simulation.

Polysiloxane is one of the most important polymeric materials in technological use. Polydimethylsiloxane displays glass-like mechanical properties at low temperatures. Incorporation of phenyl siloxane, via copolymerization for example, improves not only the low-temperature elasticity but also enhances its performance over a wide range of temperatures. Copolymerization with the phenyl component can significantly change the microscopic properties of polysiloxanes, such as chain dynamics and relaxation. However, despite much work in the literature, the influence of such changes is still not clearly understood. In this work, we systematically study the structure and dynamics of random poly(dimethyl-co-diphenyl)siloxane via atomistic molecular dynamics simulations. As the molar ratio ϕ of the diphenyl component increases, we find that the size of the linear copolymer chain expands. At the same time, the chain-diffusivity slows down by over an order of magnitudes. The reduced diffusivity appears to be a result of a complex interplay between the structural and dynamic changes induced by phenyl substitution.

Evaluation of diffuse glioma grade and proliferation activity by different diffusion-weighted-imaging models including diffusion kurtosis imaging (DKI) and mean apparent propagator (MAP) MRI.

PURPOSE: To evaluate two advanced diffusion models, diffusion kurtosis imaging and the newly proposed mean apparent propagation factor-magnetic resonance imaging, in the grading of gliomas and the assessing of their proliferative activity. METHODS: Fifty-nine patients with clinically diagnosed and pathologically proven gliomas were enrolled in this retrospective study. All patients underwent DKI and MAP-MRI scans. Manually outline the ROI of the tumour parenchyma. After delineation, the imaging parameters were extracted using only the data from within the ROI including mean diffusion kurtosis (MK), return-to-origin probability (RTOP), Q-space inverse variance (QIV) and non-Gaussian index (NG), and the differences in each parameter in the classification of glioma were compared. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of these parameters. RESULTS: MK, NG, RTOP and QIV were significantly different amongst the different grades of glioma. MK, NG and RTOP had excellent diagnostic value in differentiating high-grade from low-grade glioma, with largest areas under the curve (AUCs; 0.929, 0.933 and 0.819, respectively; P < 0.01). MK and NG had the largest AUCs (0.912 and 0.904) when differentiating grade II tumours from III tumours (P < 0.01) and large AUCs (0.791 and 0.786) when differentiating grade III from grade IV tumours. Correlation analysis of tumour proliferation activity showed that MK, NG and QIV were strongly correlated with the Ki-67 LI (P < 0.001). CONCLUSION: MK, RTOP and NG can effectively represent the microstructure of these altered tumours. Multimodal diffusion-weighted imaging is valuable for the preoperative evaluation of glioma grade and tumour proliferative activity.

Health-related quality of life and associated factors in Chinese menstrual migraine patients: a cross-sectional study.

BACKGROUND: Menstrual migraine is a particular form of migraine with a significant impact on the quality of life for women afflicted. Presently, no study has reported the quality of life in menstrual migraine patients. This work aims to assess the health-related quality of life and identify its associated factors among Chinese menstrual migraine patients. METHODS: The cross-sectional study group consisted of 109 patients with menstrual migraine, and the control group consisted of 397 female patients with non-menstrual migraine. In total, 506 patients completed questionnaires for demographic and clinical information, the Self-rating Idea of Suicide Scale, the Hamilton Depression Scale, the Hamilton Anxiety Scale, the Headache Impact Test-6, the Perceived Social Support Scale, the Pittsburgh Sleep Quality Index. Health-related quality of life was measured using the 36-Item Short Form Survey. RESULTS: Compared with non-menstrual migraine patients, five dimensions of health-related quality of life were all found to be significantly impaired in menstrual migraine patients. Headache frequency (ß = - 0.218, P = 0.014), the impact of headache on daily life (ß = - 0.270, P = 0.002), depression symptoms (ß = - 0.345, P < 0.001) were significantly associated with physical component summary, depression symptoms (ß = - 0.379, P < 0.001), social support (ß = 0.270, P < 0.001), suicidal ideation (ß = - 0.344, P < 0.001) were closely related to mental component summary. CONCLUSION: Menstrual migraine patients had a significantly poorer health-related quality of life in many domains than non-menstrual migraine patients. Headache frequency, the impact of headache on daily life, depression symptoms, social support, and suicidal ideation were significantly associated with health-related quality of life in menstrual migraine patients. TRIAL REGISTRATION: ChiCTR1800014343. This study was registered prospectively on 7 January 2018 at Chinese Clinical Trial registry. http://www.chictr.org.cn/showproj.aspx?proj=24526.

Multiparametric MR radiomics in brain glioma: models comparation to predict biomarker status.

BACKGROUND: Genotype status of glioma have important significance to clinical treatment and prognosis. At present, there are few studies on the prediction of multiple genotype status in glioma by method of multi-sequence radiomics. The purpose of the study is to compare the performance of clinical features (age, sex, WHO grade, MRI morphological features etc.), radiomics features from multi MR sequence (T2WI, T1WI, DWI, ADC, CE-MRI (contrast enhancement)), and a combined multiple features model in predicting biomarker status (IDH, MGMT, TERT, 1p/19q of glioma. METHODS: In this retrospective analysis, 81 glioma patients confirmed by histology were enrolled in this study. Five MRI sequences were used for radiomic feature extraction. Finally, 107 features were extracted from each sequence on Pyradiomics software, separately. These included 18 first-order metrics, such as the mean, standard deviation, skewness, and kurtosis etc., 14 shape features and second-order metrics including 24 grey level run length matrix (GLCM), 16 grey level run length matrix (GLRLM), 16 grey level size zone matrix (GLSZM), 5 neighboring gray tone difference matrix (NGTDM), and 14 grey level dependence matrix (GLDM). Then, Univariate analysis and LASSO (Least absolute shrinkage and selection operator regression model were used to data dimension reduction, feature selection, and radiomics signature building. Significant features (p < 0.05 by multivariate logistic regression were retained to establish clinical model, T1WI model, T2WI model, T1 + C (T1WI contrast enhancement model, DWI model and ADC model, multi sequence model. Clinical features were combined with multi sequence model to establish a combined model. The predictive performance was validated by receiver operating characteristic curve (ROC analysis and decision curve analysis (DCA). RESULTS: The combined model showed the better performance in some groups of genotype status among some models (IDH AUC = 0.93, MGMT AUC = 0.88, TERT AUC = 0.76). Multi sequence model performed better than single sequence model in IDH, MGMT, TERT. There was no significant difference among the models in predicting 1p/19q status. Decision curve analysis showed combined model has higher clinical benefit than multi sequence model. CONCLUSION: Multi sequence model is an effective method to identify the genotype status of cerebral glioma. Combined with clinical models can better distinguish genotype status of glioma. KEY POINTS: The combined model showed the higher performance compare with other models in predicting genotype status of IDH, MGMT, TERT. Multi sequence model showed a better predictive model than that of a single sequence model. Compared with other models, the combined model and multi sequence model show no advantage in prediction of 1p/19q status.

Reinforcement Learning for Bit-Flipping Decoding of Polar Codes.

A traditional successive cancellation (SC) decoding algorithm produces error propagation in the decoding process. In order to improve the SC decoding performance, it is important to solve the error propagation. In this paper, we propose a new algorithm combining reinforcement learning and SC flip (SCF) decoding of polar codes, which is called a Q-learning-assisted SCF (QLSCF) decoding algorithm. The proposed QLSCF decoding algorithm uses reinforcement learning technology to select candidate bits for the SC flipping decoding. We establish a reinforcement learning model for selecting candidate bits, and the agent selects candidate bits to decode the information sequence. In our scheme, the decoding delay caused by the metric ordering can be removed during the decoding process. Simulation results demonstrate that the decoding delay of the proposed algorithm is reduced compared with the SCF decoding algorithm, based on critical set without loss of performance.

Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis.

Successful treatment of resistant hypertension accompanied by elevated human C-reactive protein (hCRP) remains a key challenge in reducing the burden of cardiovascular diseases. It is still unclear whether clinically relevant high-level hCRP is merely a marker or a key driver of hypertension. Here, we investigated the role and mechanism of clinically relevant high level of hCRP in hypertension. Elevated blood pressure was observed in all three hCRP overexpression models, including adeno-associated virus 9 (AAV9)-transfected mice, AAV9-transfected rats and hCRP transgenic (hCRPtg) rats. hCRPtg rats expressing clinically relevant high-level hCRP developed spontaneous hypertension, cardiac hypertrophy, myocardial fibrosis and impaired endothelium-dependent relaxation. Mechanistically, studies in endothelial nitric oxide (NO) synthase (eNOS) knockout mice transfected with AAV9-hCRP and phosphoproteomics analysis of hCRP-treated endothelial cells revealed that hCRP inhibited AMP-activated protein kinase (AMPK)-eNOS phosphorylation pathway. Further, activation of AMPK by metformin normalized endothelial-dependent vasodilation and decreased the blood pressure of hCRPtg rats. Our results show that clinically relevant high-level hCRP induces hypertension and endothelial dysfunction by inhibiting AMPK-eNOS signaling, and highlight hCRP is not only an inflammatory biomarker but also a driver of hypertension. Treatment with metformin or a synthetic AMPK activator may be a potential strategy for vaso-dysfunction and hypertension in patients with high hCRP levels.

Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells.

RATIONALE: Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that YAP (Yes-associated protein) plays an important role in regulating the angiogenic activity of ECs. OBJECTIVE: The objective of this study was to specify the effect of EC YAP on angiogenesis and its underlying mechanisms. METHOD AND RESULTS: In ECs, vascular endothelial growth factor reduced YAP phosphorylation time and dose dependently and increased its nuclear accumulation. Using Tie2Cre-mediated YAP transgenic mice, we found that YAP promoted angiogenesis in the postnatal retina and tumor tissues. Mass spectrometry revealed signal transducer and activator of transcription 3 (STAT3) as a potential binding partner of YAP in ECs. Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6-induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1-mediated STAT3 nuclear export without affecting its phosphorylation. Moreover, angiopoietin-2 expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or angiopoietin-2 blockage partly attenuated retinal angiogenesis in Tie2Cre-mediated YAP transgenic mice. CONCLUSIONS: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.

Productive screening of single aptamers with ddPCR.

Antibodies have now been widely used for clinical treatment of a number of tumors. However, there are serious problems associated with antibody therapy, such as potential interactions of antibodies with the immune system as well as long production cycles. Recently, aptamers have been found to function similar to antibodies in terms of affinity and specificity to certain proteins and are attracting much attention for their low immunogenicity, easy chemical synthesis, and efficient penetration into tissues due to their small size. However, how to access high affinity and selectivity aptamers efficiently for further analysis is still open to be resolved. Herein, an aptamer discovery method that combines the continuous flow ddPCR technology with cytometer sorting of beads is reported, such that we have obtained DNA aptamers binding specifically to PD-1 with an affinity of over 60-fold higher than that for the best-reported method.

Effect of 5-Line Signs in the Prediction of Staging, Progression, and Prognosis of Peripheral Lung Carcinoma: Preliminary Observation Report.

BACKGROUND: The single line of the normal interlobar fissure shown on a thin section image can be reconstructed as a 5-line sign on axial maximal intensity projection. The line between the lung nodule and the pleura is called the pleural tail sign on thin image. On the axial maximal intensity projection, it can also be reconstructed as the 5-line sign or fewer than 5 lines. OBJECTIVE: This study aimed to observe the effect of 5-line signs in staging, progression, and prognosis of peripheral lung carcinoma. MATERIALS AND METHODS: This study included 132 patients with peripheral lung carcinoma. Among these patients, 93 were men and 39 were women, with an age range of 27 to 82 years and a lung nodule range of 0.98 to 8.75 cm. Maximal intensity projection was reconstructed based on 1.0 or 1.25 mm of thin-slice images in multislice spiral computed tomography. Five-line signs on the margin of the nodule (mass) were observed and were classified into grades 1 to 4 according to the sharpness of the 5-line signs. RESULTS: Multivariate logistic regression analysis showed that the sharpness of the 5-line signs was correlated with N and TNM staging of peripheral lung carcinoma (P = 0.012, P = 0.016). The lower the sharpness of the 5-line signs, the greater the number of cases of progression of the tumor (P < 0.001), and thus the higher the mortality rate and the lower the survival rate (P = 0.001). The sensitivity and specificity of predicting tumor progression were 56.3% and 93.3%, and those of tumor prognosis were 61.1% and 82.4%, respectively. CONCLUSIONS: The sharpness of the 5-line signs has certain effects on the prediction of invasion, progression, and prognosis of lung carcinoma, particularly of small lung cancer (≤3.0 cm).

Chamazulene reverses osteoarthritic inflammation through regulation of matrix metalloproteinases (MMPs) and NF-kß pathway in in-vitro and in-vivo models.

This study was conducted to evaluate the protective effects of chamazulene against IL-1ß-induced rat primary chondrocytes and complete Freund's adjuvant (CFA)-induced osteoarthritic inflammation in rats. Oxidative stress markers, pro-inflammatory cytokines, and regulatory proteins were measured. Chamazulene significantly reverted (p < 0.05) the levels of lipid peroxidation and enhanced the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) enzymes against IL-1ß and CFA-induced oxidative stress. The levels of TNF-α and IL-6 were reduced (p < 0.05) in chamazulene treatment against IL-1ß and CFA-induced inflammation. Western blot analysis results on the expressions of MMP-3, MMP-9, p65 NF-kß, iNOS, and COX-2 showed chamazulene was able to protect the chondrocytes against IL-1ß-induced osteoarthritic inflammation. Histopathology of rat hind ankle showed chamazulene significantly protected against CFA-induced osteoarthritic inflammation. Therefore, chamazulene can be recommended as a therapeutic agent for clinical trials against osteoarthritic inflammation.

NF-κB Phosphorylation Inhibition Prevents Articular Cartilage Degradation in Osteoarthritis Rats via 2-Aminoquinoline.

BACKGROUND Osteoarthritis is a chronic degenerative disease of the joints that is common in older people worldwide. The characteristic features of osteoarthritis include cartilage degradation, synovitis, and remodelling of subchondral bone. The present study investigated the effect of 2-aminoquinoline on knee articular cartilage degradation in an osteoarthritis rat model. MATERIAL AND METHODS The rat model of osteoarthritis was established in Wistar rats by intra-articular injection of monosodium iodoacetate. The rats were randomly divided into 6 groups of 10 rats each: a normal control group, an untreated group, and 4 (5, 10, 15 and 20 mg/kg) treatment groups. The rats in treatment groups received 5, 10, 15, or 20 mg/kg doses of 2-aminoquinoline on day 2 of monosodium iodoacetate injection. RESULTS The 2-aminoquinoline treatment of monosodium iodoacetate-injected rats markedly decreased weight-bearing asymmetry, inhibited edema formation, and improved paw withdrawal thresholds. The expression of inflammatory cytokines was markedly higher in the osteoarthritis rats. Treatment with 2-aminoquinoline led to a significant reduction in inflammatory cytokine expression in osteoarthritis rats in a dose-dependent manner. In osteoarthritis rats, the expressions of prostaglandin E2 (PGE2), matrix metalloproteinase-13 (MMP-13), and substance P were also higher in comparison to the control group. The 2-aminoquinoline treatment supressed PGE2, MMP-13, and substance P levels in osteoarthritis rats. Moreover, the expression of phosphorylated nuclear factor kappaB (p-NF-kappaB) was markedly higher in the untreated rats. However, activation of NF-kappaB was downregulated in the osteoarthritis rats by treatment with 2-aminoquinoline. CONCLUSIONS The present study demonstrated that 2-aminoquinoline prevents articular cartilage damage in osteoarthritis rats through inhibition of inflammatory factors and downregulation of NF-kappaB activation, suggesting that 2-aminoquinoline would be effective in treatment of osteoarthritis.

Characterization and Sensing of Inert Gases with a High-Resolution SPR Sensor.

It is generally difficult to characterize inert gases through chemical reactions due to their inert chemical properties. The phase interference-sensing system based on high-resolution surface plasmon resonance (SPR) has an excellent refractive index detection limit. Based on this, this paper presents a simple and workable method for the characterization and detection of inert gases. The phase of light for the present SPR sensor is more sensitive to the change in the external dielectric environment than an amplitude SPR sensor. The limit of detection (LOD) is usually in the order of 10-6 to 10-7 RIU, which is superior to LSPR (Localized Surface Plasmon Resonance) sensors and traditional SPR sensors. The sensor parameters are simulated and optimized. Our simulation shows that a 36 nm-thick gold film is more suitable for the SPR sensing of inert gases. By periodically switching between the two inert gases, helium and argon, the resolution of the system is tested. The SPR sensing system can achieve distinguishable difference signals, enabling a clear distinction and characterization of helium and argon. The doping of argon in helium has a detection limit of 1098 ppm.

Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing ß-oxidation of fatty acid in mice.

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg-1·day-1 for the animal model and 1 µM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated ß-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

Elevating ATP-binding cassette transporter G1 improves re-endothelialization function of endothelial progenitor cells via Lyn/Akt/eNOS in diabetic mice.

Endothelial progenitor cell (EPC) dysfunction contributes to diabetes-induced delay in endothelium repair after vessel injury, prominently associated with diabetic cardiovascular complications such as neointima formation. ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux to HDL, which may favorably affect EPC function. However, whether ABCG1 improves EPC function, especially in diabetes, remains unknown. Here we investigated the role of ABCG1 in EPCs by using Tie2-mediated ABCG1 transgenic (Tie2- ABCG1Tg) mice. Mice were injected with streptozotocin to induce diabetes mellitus. As compared with wild-type (WT) mice, in Tie2- ABCG1Tg mice, diabetes-impaired EPC migration and tube formation were reversed. In vitro gain-of-function and loss-of-function studies further revealed that ABCG1-overexpressing EPCs showed increased migration and tube formation and differentiation via the Lck/Yes-related novel protein tyrosine kinase /Akt/endothelial NO synthase pathway by enhancing cellular cholesterol efflux. Finally, type 1 and type 2 diabetic mouse models with arterial injury were intravenously injected with labeled EPCs from WT or Tie2- ABCG1Tg mice. Re-endothelialization in diabetic mice was improved to a greater extent by injection of ABCG1-overexpressing than WT EPCs. Our study demonstrated that ABCG1 in EPCs improved repair after vascular injury in diabetes by increasing EPC function such as migration, tube formation and differentiation, and subsequent re-endothelialization. ABCG1 might be a promising therapeutic target for diabetes-associated vascular diseases.-Shi, Y., Lv, X., Liu, Y., Li, B., Liu, M., Yan, M., Liu, Y., Li, Q., Zhang, X., He, S., Zhu, M., He, J., Zhu, Y., Zhu, Y., Ai, D. Elevating ATP-binding cassette transporter G1 improves re-endothelialization function of endothelial progenitor cells via Lyn/Akt/eNOS in diabetic mice.