ω-3PUFAs Inhibit Hypoxia-Induced Retinal Neovascularization via Regulating Microglial Pyroptosis through METTL14-Mediated m6A Modification of IFNB1 mRNA.

Retinal neovascular disease is the leading reason of vision impairment in all ages. Here, we figured out the function and mechanism of omega-3 polyunsaturated fatty acids (ω-3PUFAs) in hypoxia-induced retinal neovascularization by focusing on microglial pyroptosis. Microglia BV-2 cells were given ω-3PUFAs treatment and co-cultured with mouse retinal microvascular endothelial cells (MRMECs) under hypoxia. Tube formation assay, transwell assay and wound healing assay were utilized to monitor the MRMEC angiogenesis. Cell counting kit-8, western blot, lactate dehydrogenase assay, and enzyme-linked immunosorbent assay were used to assess pyroptosis of BV-2 cells. RNA sequencing and methylated RNA immunoprecipitation-polymerase chain reaction were utilized to identify the target gene of methyltransferase-like 14 (METTL14) and its N6-methyladenosine (m6A) level in BV-2 cells. BV-2 cells prominently enhanced MRMEC angiogenesis under hypoxia, but this effect was abolished after ω-3PUFAs treatment. ω-3PUFAs inhibited pyroptosis in hypoxia-induced BV-2 cells, and BV-2 cell pyroptosis boosted angiogenesis of MRMECs. Additionally, ω-3PUFAs markedly augment the expression of MELLL14 in BV-2 cells, and METTL14 knockdown promoted BV-2 cell pyroptosis and BV-2 cell-mediated angiogenesis in MEMECs. Mechanistically, interferon beta 1 (IFNB1) was a target of METTL14, and METTL14 silencing increased the mRNA expression and decreased the m6A modification of IFNB1 in BV-2 cells. Our results uncovered that ω-3PUFAs diminished hypoxia-induced retinal neovascularization through controlling microglial pyroptosis via METTL14-mediated m6A modification. This study offers a novel potential target for the treatment of retinal neovascular diseases.

Exploring the therapeutic potential of a nano micelle containing a carbon monoxide-releasing molecule for metabolic-associated fatty liver disease by modulating hypoxia-inducible factor-1α.

Metabolic-associated fatty liver disease (MAFLD) encompasses a spectrum of chronic liver diseases, including steatohepatitis, cirrhosis, and liver cancer. Despite the increasing prevalence and severity of MAFLD, no approved pharmacological interventions are currently available. Hypoxia-inducible factor-1α (HIF-1α) has emerged as a crucial early mediator in the pathogenesis of MAFLD. Previously, we demonstrated the potent anti-inflammatory properties of the nano-designed carbon monoxide (CO) donor, styrene maleic acid copolymer (SMA) encapsulating CO-releasing molecule (SMA/CORM2), which effectively suppressed HIF-1α in various inflammatory disorders. Here, we investigated the therapeutic potential of SMA/CORM2 in a mouse model of MAFLD induced by a high-fat methionine- and choline-deficient (HF-MCD) diet. Following 4 weeks of HF-MCD diet consumption, we observed pronounced hepatic lipid accumulation accompanied by disrupted lipid metabolism, polarization of macrophages towards the pro-inflammatory M1 phenotype, activation of the NLRP3 inflammasome, and upregulation of the TGF-ß fibrosis signaling pathway. Notably, the early and upstream event driving these pathological changes was the upregulation of HIF-1α. Treatment with SMA/CORM2 (10 mg/kg, three times per week) led to a significant increase in CO levels in both the circulation and liver, resulting in remarkable suppression of HIF-1α expression even before the onset of apparent pathological changes induced by the HF-MCD diet. Consequently, SMA/CORM2 administration exerted a significantly protective and therapeutic effect on MAFLD. In vitro studies using hepatocytes treated with high concentrations of fatty acids further supported these findings, as knockdown of HIF-1α using short hairpin RNA (shRNA) elicited similar effects to SMA/CORM2 treatment. Collectively, our results highlight the therapeutic potential of SMA/CORM2 in the management of MAFLD through suppression of HIF-1α. We anticipate that SMA/CORM2, with its ability to modulate HIF-1α expression, may hold promise for future applications in the treatment of MAFLD. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) is a crucial gaseous signaling molecule that plays a vital role in maintaining homeostasis and is a potential target for treating many inflammatory diseases. Developing drug delivery systems that can deliver CO stably and target specific tissues is of great interest. Our team previously developed a nano micellar CO donor, SMA/CORM2, which exhibits superior bioavailability to native CORM2 and shows therapeutic potential in many inflammatory disease models. In this study, we showed that SMA/CORM2, through controlled CO release, significantly ameliorated steatohepatitis and liver fibrosis induced by an HF-MCD diet by suppressing an HIF-1α mediated inflammatory cascade. These findings provide new insight into the anti-inflammatory function of CO and a promising approach for controlling metabolic-associated fatty liver disease.

Metabolomic Profiling of Long-Chain Polyunsaturated Fatty Acid Oxidation in Adults with Retinal Vein Occlusion: A Case-Control Study.

BACKGROUND: Long-chain polyunsaturated fatty acids (LCPUFAs) and their metabolites are closely related to neovascular eye diseases. However, the clinical significance of their oxylipins in retinal vein occlusion (RVO) remains inconclusive. OBJECTIVES: This case-control study aimed to explore metabolomic profiles of LCPUFA oxidation in RVO and to identify potential indicators for diagnosis and pathologic progression. METHODS: The plasma concentrations of ω-3 (n-3) and ω-6 (n-6) LCPUFA and their oxylipins in 44 adults with RVO and 36 normal controls were analyzed using ultraperformance liquid chromatography tandem mass spectrometry. Univariate analysis combined with principal component and orthogonal projections to latent structure discriminant analysis was used to screen differential metabolites. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of 5-oxo-eicosatetraenoic acids (ETE) on angiogenesis ex vivo. Tubule formation and wound healing assays were performed to verify its effects on human retinal microvascular endothelial cell functions. RESULTS: Higher ω-6 and lower ω-3 LCPUFA plasma concentrations were measured in the adults with RVO compared with control (odds ratio [OR]: 2.34; 95% confidence interval [CI]: 1.42, 3.86; P < 0.001; OR: 0.28; 95% CI: 0.15, 0.51; P < 0.001). Metabolomic analysis revealed 20 LCPUFA and their oxylipins dysregulated in RVO, including increased arachidonic acid (ω-6, OR: 1.85; 95% CI: 1.18, 2.90; P < 0.001) and its lipoxygenase product 5-oxo-ETE (OR: 11.76; 95% CI: 3.73, 37.11; P < 0.001), as well as decreased docosahexaenoic acid (ω-3, OR: 0.13; 95% CI: 0.05, 0.33; P < 0.001). Interestingly, 5-oxo-ETE was downregulated in ischemic compared with nonischemic central RVO. Exogenous 5-oxo-ETE attenuated aortic ring and choroidal explant sprouting and inhibited tubule formation and migration of human retinal microvascular endothelial cells in a dose-dependent manner, possibly via suppressing the vascular endothelial growth factor signaling pathway. CONCLUSIONS: The plasma concentrations of ω-6 and ω-3 LCPUFA and their oxylipins were associated with RVO. The ω-6 LCPUFA-derived metabolite 5-oxo-ETE was a potential marker of RVO development and progression.

Moderating role of mental health literacy on the relationship between bullying victimization during the life course and symptoms of anxiety and depression in Chinese college students.

BACKGROUND: Exposure to persistent bullying victimization across multiple periods results in a high risk of worse consequences. Although amples studies support the association between bullying victimization and symptoms of anxiety and depression, whether mental health literacy can serve as a moderator on this relationship remains unknown. Therefore, the aim of this study was to examine the patterns of bullying victimization across the life course, and disentangle the moderating effect of mental health literacy between bullying victimization patterns and symptoms of anxiety and depression in Chinese college students. METHODS: A total of 4036 college students were enrolled by cluster sampling from November 2020 to January 2021. Bullying victimization, mental health literacy, and symptoms of anxiety and depression were measured by self-report validated questionnaires. A latent class analysis was applied to identify bullying patterns. The PROCESS program was conducted to analyze whether mental health literacy moderates the link between bullying victimization patterns and symptoms of anxiety and depression. RESULTS: Three latent patterns of bullying victimization were identified as follows: persistent bullying pattern (6.2%), moderate bullying pattern (10.5%), and low bullying pattern (83.3%). Logisitic regression analysis of anxiety and depressive symptoms indicated that compared with low bullying pattern, persistent bullying pattern had the highest risk. Specifically, mental health literacy moderated the association between bullying victimization pattern and anxiety symptoms (B = -0.039, P < 0.05). CONCLUSIONS: It is important for practitioners to examine bullying victimization across the life course concurrently rather than a single period in isolation. Interventions and research should enhance mental health literacy to improve the mental health in college students with a history of bullying victimization.

Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway.

Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP exposure, whereas, an increase of HMGB1 was a late-stage event. Notably, SMA/CORM2 treatment suppressed significantly both TLR4 and HMGB1, consequently inhibiting the progression of inflammation and liver injury. Compared to CORM2 without SMA modification (native CORM2) of 1 mg/kg that is equivalent to 10 mg/kg of SMA/CORM2 (the amount of CORM2 in SMA/CORM2 is 10% [w/w]), SMA/CORM2 exhibited a much better therapeutic effect, indicating its superior therapeutic efficacy to native CORM2. These findings revealed that SMA/CORM2 protects against APAP-induced liver injury via mechanisms involving the suppression of TLR4 and HMGB1 signaling pathways. Taking together the results in this study and previous studies, SMA/CORM2 exhibits great therapeutic potential for APAP overdose-induced liver injury, we thus anticipate the clinical application of SMA/CORM2 for the treatment of APAP overdose, as well as other inflammatory diseases.

Gender difference in the associations between health literacy and problematic mobile phone use in Chinese middle school students.

BACKGROUND: Problematic mobile phone use (PMPU) is becoming increasingly popular and has serious harmful effects on physical and mental health among adolescents. Inadequate health literacy (HL) is related to some risky behaviors and mental health problems in adolescents. Nevertheless, few studies have explored the relationship between HL and PMPU and the gender difference in the relationship among Chinese adolescents. The aim of this study was to examine the associations between HL and PMPU and explore gender difference in the associations. METHODS: A total of 22,628 junior and senior high school students (10,990 males and 11,638 females) in 6 regions of China participated in this study. HL and PMPU were measured by self-report validated questionnaires. Chi-square tests and logistic regression analysis were conducted in the study. RESULTS: Logistic regression analysis showed that students with inadequate HL are likely to have PMPU (OR = 2.013, 95% CI: 1.840-2.202), and different degrees of association can be seen in six dimensions. Besides, in both males and females, students with inadequate HL had a higher risk of PMPU (OR male = 1.607, 95% CI: 1.428-1.807; OR female = 2.602, 95% CI: 2.261-2.994). Regarding the gender difference, the results showed that males had more PMPU than females, and the difference was more significant for students with adequate HL than those with inadequate HL (OR inadequate = 1.085, 95% CI: 1.016-1.159; OR adequate = 1.770, 95% CI: 1.490-2.101). Similarly, there were associations in the six dimensions. CONCLUSIONS: HL decreases PMPU, and males have a higher risk of PMPU than females. These findings suggest a reasonable strategy to reduce PMPU by improving the HL level of adolescents.

Association between health literacy, depressive symptoms, and suicide-related outcomes in adolescents: A longitudinal study.

BACKGROUND: Health literacy is associated with mental disorders in adolescents. This study aimed to examine the associations between health literacy, depressive symptoms, and suicide-related outcomes. METHODS: In terms of participants, 937 middle school students in Shenyang City, China were enrolled between December 2018 and December 2019 to assess health literacy, depressive symptoms and suicide-related outcomes. Multiple logistic regression models were used to examine possible associations. RESULTS: Adequate health literacy was negatively associated with 12-month follow-up depressive symptoms (RR = 0.115, 95 % CI: 0.032-0.411) and suicide-related outcomes (RR = 0.230, 95 % CI: 0.085-0.618) in females. Meanwhile, in females, interpersonal relationship, stress management, and self-actualization were negatively related to depressive symptoms, while physical activities, self-actualization, and health awareness are protective factors for suicide-related outcomes (P < 0.05 for each). LIMITATIONS: Recall and reporting bias might be inevitable for self-reported data, and due to the small sample size, the predictive effect may not be very significant. CONCLUSIONS: These findings suggest that adequate health literacy may serve as a critical and independent protective factor for poor long-term mental health outcomes and that the predictive effect is more pronounced in female students. Public health efforts to enhance health literacy levels are required to maintain and improve adolescents' mental health outcomes.

Association Between the Patterns of Five Unhealthy Behaviors and Suicidal Behaviors Among Adolescents in Six Provinces of China.

Background: In adolescents, multiple unhealthy behaviors frequently occur together and are likely to be associated with suicidal behaviors (SBs), increasing the risk of suicide. This study aimed to clarify the potential patterns of unhealthy behaviors in Chinese adolescents and to examine the associations between the different patterns of unhealthy behaviors and SBs. Methods: A total of 22,628 middle school students were enrolled in this study. Self-reported unhealthy behaviors and SBs were investigated using questionnaires. Latent class analysis (LCA) was performed based on five unhealthy behaviors [smoking, alcohol use (AU), diet pill use (DPU), screen time (ST), and problematic mobile phone use (PMPU)]. Multivariate logistic regressions were used to examine associations between the different patterns of unhealthy behaviors and SBs. Results: Four subgroups of unhealthy behaviors were identified by LCA, including high-risk class (smoking/AU/DPU/PMPU/ST), moderate-risk class 1 (DPU/PMPU), moderate-risk class 2 (smoking/AU/ST), and low-risk class. Compared with the low-risk class, moderate-risk class 1, moderate-risk class 2, and high-risk class had higher risks of suicidal ideation, suicide plan, and suicide attempt. Conclusions: These findings suggested that patterns of unhealthy behaviors were related to SBs in Chinese adolescents. Accordingly, considerations of different classes of unhealthy behaviors may be essential for developing effective preventive programs.

Nanoformulation of a carbon monoxide releasing molecule protects against cyclosporin A-induced nephrotoxicity and renal fibrosis via the suppression of the NLRP3 inflammasome mediated TGF-ß/Smad pathway.

Cyclosporin A (CsA) induced nephrotoxicity i.e., renal fibrosis is a critical clinical problem in renal transplant patients, in which chronic inflammatory response is the major cause. Previously, we developed a nano-drug delivery system for carbon monoxide (CO), a multi-functional gaseous molecule with a potent anti-inflammatory effect, i.e., SMA/CORM2, which showed therapeutic potential in several inflammatory disease models. Accordingly, in this study, we explored the potential and usefulness of SMA/CORM2 on CsA induced renal fibrosis. When mice were exposed to CsA for 4 weeks, severe injuries in the kidney as revealed by decreased kidney function and histological examination, and activation of NLRP3 inflammasome, as well as renal fibrosis along with the upregulation of transforming growth factor ß (TGFß)/Smad signaling molecule were observed, whereas SMA/CORM2 (1 mg/kg) treatment remarkably ameliorated the inflammatory injury and fibrosis in the kidney. CO is the major effector molecule of SMA/CORM2 which significantly suppressed the activation of NLRP3 inflammasome, and induced the downregulation of TGFß/Smad signaling. Inhibition of NLRP3 inflammasome by its inhibitor MCC950 also similarly decreased TGFß/Smad expression and subsequently improved kidney injury and renal fibrosis, suggesting SMA/CORM2 induced suppression of TGFß/Smad signaling and renal signaling via an NLRP3 inflammasome-dependent pathway. Compared to native CORM2, SMA/CORM2 exhibited better therapeutic/preventive effects owing to its superior water-solubility and bioavailability. These findings strongly indicated the applicability of SMA/CORM2 as an enhanced permeability and retention (EPR) effect-based nanomedicine for CsA induced renal fibrosis as well as other inflammatory diseases. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) is an important gaseous signaling molecule that plays a crucial role in the maintenance of homeostasis. Because of its versatile functions, it exhibits the potential as the target molecule for many diseases, including inflammatory diseases and cancer. The development of stable and disease-targeted delivery systems of CO is thus of interest and importance. Previously we developed a nano micellar CO donor SMA/CORM2 which shows superior bioavailability and therapeutic potential in many inflammatory disease models. We reported here, SMA/CORM2, through controlled release of CO, greatly ameliorated CsA-induced renal fibrosis via suppressing the NLRP3 inflammasome mediated TGF-ß/Smad pathway. These findings suggest a new anti-inflammatory mechanism of CO, which also provides a new approach for controlling CsA-induced nephrotoxicity.

Mediating Effect of Sleep Disorder Between Low Mental Health Literacy and Depressive Symptoms Among Medical Students: The Roles of Gender and Grade.

OBJECTIVE: In this study, we aimed to disentangle the mediating effect of sleep disorder between mental health literacy (MHL) and depressive symptoms in Chinese medical students, especially focusing on the impact of gender and grade. METHODS: Pooled longitudinal data of 5,504 medical students was collected between November 2019 and June 2020 to assess the MHL, sleep disorder and mental health of medical students in Anhui province, China. Mediation analyses were tested by using bootstrapping procedures. RESULTS: Sleep disorder were negatively correlated with adequate MHL, but positively correlated with depressive symptoms. The relationships between MHL and depressive symptoms were mediated by sleep disorder in total samples and the indirect effect accounted for 13.59% of the total effect. However, the ratio was 20.82% in female students, whereas no mediating effect was found in the male students. Moreover, the ratio was found higher in freshmen (15.11%) than that in sophomores (11.56%). CONCLUSION: Improving the sleep disorder by enhancing MHL is an effective way to reduce depressive symptoms in Chinese medical students. Further investigations elaborately considered by using more gender-balanced population with higher grade and lower level of education.

Nano-designed CO donor ameliorates bleomycin-induced pulmonary fibrosis via macrophage manipulation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease due to chronic inflammatory responses. The prognosis of IPF is very poor, however, the therapeutic options are very limited. Previously we developed a polymeric micellar drug delivery system of carbon monoxide (CO) that is a pivotal anti-inflammatory gaseous molecule, i.e., SMA/CORM2, which exhibited therapeutic potentials against dextran sulfate sodium (DSS)-induced mouse colitis and acetaminophen (APAP) induced liver injury. Along this line, here we investigate the applicability of SMA/CORM2 on IPF using a bleomycin (BLM)-induced pulmonary fibrosis model. Severe inflammation and the consequent pulmonary fibrosis were triggered by BLM, whereas SMA/CORM2 treatment remarkably suppressed the inflammation progression and ameliorated the formation of fibrosis. CO is the effector molecule of SMA/CORM2, which exerted the therapeutic/protective effect mostly through suppressing the reprogramming of anti-inflammatory macrophages as revealed by the decreased expressions of CD206 and arginase-1 that were remarkably upregulated by BLM exposure. The suppression of macrophage polarization accompanied the downregulated hypoxia-inducible factor-1α (HIF-1α) and its target molecule heme oxygenase-1 (HO-1), suggesting a HIF-1α/HO-1 pathway for modulating macrophage reprogramming. As the downstream event of anti-inflammatory macrophage polarization, the alveolar epithelial to mesenchymal transition that is the major source of myofibroblast, the hallmark of IPF, was significantly suppressed by SMA/CORM2 via a TGF-ß/Smad2/3 pathway. Compared to native CORM2 of equivalent dose, SMA/CROM2 exhibited a much better protective effect indicating its superior bioavailability as an enhanced permeability and retention (EPR) effect-based nanomedicine. We thus anticipate the application of SMA/CORM2 as a therapeutic candidate for IPF as well as other inflammatory diseases and disorders.

Patterns of six behaviors and psychosomatic symptoms in adolescents: A six-province study in China.

BACKGROUND: Psychosomatic symptoms are often related with behaviors. However, the association between different behaviors and their latent patterns and psychosomatic health status is unclear. Current study aimed to identify the patterns of six behaviors and explore the association between different patterns and psychosomatic symptoms in a school-based sample of Chinese adolescents. METHODS: From November 2015 to January 2016, the study enrolled 22,628 students from six cities in China (15.36 ± 1.79 years). Six behaviors [unintentional injury (UI), non-suicidal self-injury (NSSI), suicidal behaviors (SB), drinking, smoking, screen time (ST)] and psychosomatic symptoms (psychological and physical symptoms) were measured by self-report validated questionnaires. RESULTS: Six behaviors were all related to psychosomatic symptoms, among which SB was the strongest. Four patterns of behaviors were be identified as follows: low-risk pattern (64.0%), substance use pattern (4.5%), injury pattern (28.8%) and high-risk pattern (2.7%). Logistic regression analysis of psychological symptoms indicated that compared with low-risk pattern, high-risk pattern had the highest risk, followed by injury pattern, substance use pattern showed the lowest risk. Compared with low-risk pattern, the results of physical symptoms suggested the degree of risk was high-risk pattern, injury pattern and substance use pattern, respectively. LIMITATIONS: Cross-sectional data were used in the study that could not evaluate causal relationships between six behaviors and psychosomatic symptoms. CONCLUSIONS: Six behaviors and their latent patterns are related to psychosomatic symptoms among Chinese adolescents differently, so different intervention and prevention protocol need to be taken for different patterns of adolescents.

Inadequate Mental Health Literacy and Insufficient Physical Activity Potentially Increase the Risks of Anxiety and Depressive Symptoms in Chinese College Students.

Objective: The present study aimed to examine the interactive associations between physical activity and mental health literacy with anxiety and depressive symptoms in Chinese college students. Methods: A cross-sectional study was conducted from May to July 2020. A total of 7,512 students were recruited from two medical colleges in Hefei and Anqing city in Anhui Province, China. Physical activity, mental health literacy, anxiety and depressive symptoms were measured by self-reported validated instruments. Analyses were conducted with logistic regression models. Results: The prevalence of anxiety and depressive symptoms was 8.6% and 16.4%, respectively. Insufficient physical activity was significantly associated with depressive symptoms (OR = 1.359, 95%CI 1.184-1.561) and anxiety symptoms (OR = 1.492, 95%CI: 1.237-1.799). Inadequate mental health literacy was significantly associated with depressive symptoms (OR = 3.089, 95%CI: 2.607-3.662) and anxiety symptoms (OR = 3.675, 95%CI: 2.861-4.721). Low physical activity rank (OR = 1.438, 95%CI: 1.151-1.798) was significantly related with depressive symptoms but not anxiety symptoms. The students who had inadequate mental health literacy and insufficient physical activity had the highest risks of depressive symptoms (OR = 5.049, 95% CI: 3.649-6.987) and anxiety symptoms (OR = 5.270, 95% CI: 3.338-8.321). Conclusion: These finding indicated that Chinese college students having insufficient physical activity and inadequate mental health literacy are at risk of exhibiting anxiety and depressive symptoms. Early intervention programs for college students with mental health problems should be considered to enhance their mental health literacy and to increase their physical activities.

Cytochrome P450 2J2 inhibits the proliferation and angiogenesis of retinal vascular endothelial cells by regulating the Notch signaling pathway in a hypoxia-induced retinopathy model.

Retinopathy of Prematurity (ROP), a type of retinal neovascularization in premature infants, has become a serious problem that drastically affects the quality of life of premature infants. ROP is associated with angiogenesis and neovascularization. Here, we aimed to explain the function and latent roles of Cytochrome P450 2J2 (CYP2J2) in hypoxia-induced retinopathy in retinal vascular endothelial cells (HRVECs). HRVECs were stimulated with hypoxia for 24 h to establish an in vitro retinopathy model. Cell viability and migration were evaluated using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell assays, respectively. Protein and gene expression was determined by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis. We observed that pcDNA3.1(+)-CYP2J2 promoted CYP2J2 and Jagged1 expression, while Dll4 was down-regulated in hypoxia-stimulated HRVECs. Additionally, pcDNA3.1(+)-CYP2J2 inhibited HRVEC viability, reduced PCNA expression, and inhibited the migration of HRVECs. Further, the Notch pathway was inhibited in the Hypoxia+pcDNA3.1(+)-CYP2J2 group. Opposite results were observed upon Terfenadone treatment in hypoxia induced HRVECs. Finally, our findings further verified that DAPT promotes the effects of CYP2J2 on cell viability, migration, and Notch signaling in hypoxia-induced HRVECs, while EDTA reversed the inhibitory effects of CYP2J2 on hypoxia-induced HRVECs. In conclusions, CYP2J2 was found to inhibit the viability and angiogenesis of HRVECs by inhibiting Notch signaling in a hypoxia-induced retinopathy model.

Pitavastatin stimulates retinal angiogenesis via HMG-CoA reductase-independent activation of RhoA-mediated pathways and focal adhesion.

BACKGROUND: Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs). METHODS: The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining. RESULTS: Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway. CONCLUSION: Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway.

Gender differences in the association between health literacy and bully victimization among middle school students / 中国学校卫生

Objective@#To explore the association between middle school students health literacy and bully victimization and associated sex difference, and to provide guidance for bully prevention in adolescents.@*Methods@#During November 2017 to January 2018, 18 900 junior and senior high school students were enrolled from Hefei of Anhui Province, Shenyang of Liaoning Province, Yangjiang of Guangdong Province and Chongqing by multistage cluster sampling. A self rated questionnaires were used to collect demographic information, health literacy, and bully victimization. Group differences by different characteristics and the association between health literacy and bully victimization were analyzed.@*Results@#The detection rates of campus and cyber bullying victimization were 15.8% (2 992/18 900) and 9.1% (1 723/18 900). Boys, junior high school students, students with poor family financial status and few close friends had a detection rate of 28.0%, 18.8%, 23.3%, and 33.6% of school bullying, which are higher than those of the control group ( χ 2=225.64, 148.07, 141.13, 143.49, P <0.01); boys, students with poor household income and few close friends, the detection rates of cyber bullying were 10.9%, 14.4%, and 20.1%, respectively, are higher than the control group ( χ 2=62.96, 112.82, 88.49, P <0.01). Multivariate Logistic regression analysis indicated that students with low overall and dimensions scores of health literacy were more likely to suffer from campus and cyber bullying, except for the dimension of physical activity. In addition, at all levels of health literacy, males are more likely to be bullied than females ( P <0.05).@*Conclusion@#Health literacy of middle school students is related to bully victimization, which is sex specific. Intervention programs of bullying should focus on health literacy enhancement.

Development and application of the Adolescent Mental Health Literacy Assessment Questionnaire among medical undergraduates / 中国学校卫生

Objective@#To develop the Adolescent Mental Health Literacy Assessment Questionnaire (AMHLAQ), and to evaluate its reliability and validity among undergraduates.@*Methods@#On the basis of the definition of mental health literacy (MHL) and the Knowledge, Attitudes and Practices (KAP) theory, this study constructed a total of 36 items consisting of four dimensions, and scores were measured according to a five point Likert type scale. Using a cluster sampling method, a questionnaire survey was conducted among 3 826 freshmen and sophomore students from two medical schools in Anhui Province. The items were screened by performing t tests, Pearson s correlation coefficient analysis and factor analysis. The reliability and validity of the questionnaire were evaluated using indicators including homogeneity reliability, the split half reliability coefficient, and construct validity.@*Results@#Factor analysis revealed that the AMHLAQ consisted of 22 questions grouped into four domains. The variance cumulative contribution rate was 62.213%. The reliability result showed that the Cronbach s alpha coefficient of the total questionnaire was 0.897, the split half reliability was 0.800, the Cronbach s coefficient of each dimension was 0.796 to 0.885, the split half reliability of each dimension was 0.725 to 0.846, and the indicators had a high level of reliability. Confirmatory factor analysis showed that the model fit was good ( χ 2/df =19.319, P <0.01; RMSEA=0.069).@*Conclusion@#AMHLAQ is consistent with the evaluation standard of psychometrics, has good reliability and validity, and can be used to estimate the level of MHL among undergraduates.

Association of health literacy and drinking behaviors among middle school students in six provinces of China / 中国学校卫生

Objective@#To explore the association between health literacy and drinking behaviors among middle school students in six provinces of China, and to provide scientific basis for the prevention and intervention of drinking behaviors.@*Methods@#From November 2015 to January 2016, 22 628 students were enrolled from Ulanqab, Shenyang, Xinxiang, Bengbu, Chongqing and Yangjiang by multistage stratified cluster sampling method. And a questionnaire survey was conducted among them to collect demographic information, health literacy and drinking behaviors. Rates on drinking behaviors were compared in students with specific characteristics. Multiple Logistic regression analyses were conducted to examine the association between health literacy and drinking behaviors.@*Results@#The proportion of ever drinking, current drinking, binge drinking, drunkenness was 60.0%(13 580), 16.8%(3 799), 5.9%(1 344) and 9.9%(2 250), respectively. After adjusting for gender, grade, family address, siblings, accommodation type, parental educational level, and self reported family income, compared to the high level health literacy, the low level health literacy was significantly associated with ever drinking (OR=1.76, 95%CI=1.62-1.91), current drinking(OR=1.37, 95%CI=1.23-1.52), binge drinking (OR=1.39, 95%CI=1.18-1.63), and drunkenness(OR=1.68, 95%CI=1.47-1.92), respectively(P<0.01).@*Conclusion@#Health literacy of middle school students was related to drinking behaviors. The occurrence of health risk behaviors such as drinking can be prevented and reduced by improving students health literacy level.