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.

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

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

SBC (Sanhuang Xiexin Tang combined with Baihu Tang plus Cangzhu) alleviates NAFLD by enhancing mitochondrial biogenesis and ameliorating inflammation in obese patients and mice.

In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis-a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.

CRISPR screen identifies the role of RBBP8 in mediating unfolded protein response induced liver damage through regulating protein synthesis.

Unfolded protein response (UPR) maintains the endoplasmic reticulum (ER) homeostasis, survival, and physiological function of mammalian cells. However, how cells adapt to ER stress under physiological or disease settings remains largely unclear. Here by a genome-wide CRISPR screen, we identified that RBBP8, an endonuclease involved in DNA damage repair, is required for ATF4 activation under ER stress in vitro. RNA-seq analysis suggested that RBBP8 deletion led to impaired cell cycle progression, retarded proliferation, attenuated ATF4 activation, and reduced global protein synthesis under ER stress. Mouse tissue analysis revealed that RBBP8 was highly expressed in the liver, and its expression is responsive to ER stress by tunicamycin intraperitoneal injection. Hepatocytes with RBBP8 inhibition by adenovirus-mediated shRNA were resistant to tunicamycin (Tm)-induced liver damage, cell death, and ER stress response. To study the pathological role of RBBP8 in regulating ATF4 activity, we illustrated that both RBBP8 and ATF4 were highly expressed in liver cancer tissues compared with healthy controls and highly expressed in Ki67-positive proliferating cells within the tumors. Interestingly, overexpression of RBBP8 in vitro promoted ATF4 activation under ER stress, and RBBP8 expression showed a positive correlation with ATF4 expression in liver cancer tissues by co-immunostaining. Our findings provide new insights into the mechanism of how cells adapt to ER stress through the crosstalk between the nucleus and ER and how tumor cells survive under chemotherapy or other anticancer treatments, which suggests potential therapeutic strategies against liver disease by targeting DNA damage repair, UPR or protein synthesis.

ER stress aggravates diaphragm weakness through activating PERK/JNK signaling in obesity hypoventilation syndrome.

OBJECTIVE: Obesity hypoventilation syndrome is associated with diaphragmatic dysfunction. This study aimed to explore the role of endoplasmic reticulum (ER) stress in mediating obesity-induced diaphragmatic dysfunction. METHODS: A pulmonary function test and ultrasound were applied to evaluate diaphragmatic function and magnetic resonance imaging was applied to measure diaphragmatic lipid deposition in human patients. For the mechanistic study, obese mice were introduced to a high-fat diet for 24 weeks, followed by diaphragmatic ultrasound measurement, transcriptomic sequencing, and respective biochemical analysis. Automatic force mapping was applied to measure the mechanical properties of C2C12 myotubes. RESULTS: People with obesity showed significant diaphragm weakness and lipid accumulation, which was further confirmed in obese mice. Consistently, diaphragms from obese mice showed altered gene expression profile in lipid metabolism and activation of ER stress response, indicated by elevated protein kinase R-like ER kinase (PERK) and c-Jun NH2 -terminal kinase (JNK) activation. In C2C12 myotubes, inhibition of PERK or JNK signaling abrogated lipotoxicity-induced intracellular lipid deposition and insulin resistance. Inhibition of JNK signaling reversed lipotoxicity-induced impairment of elasticity in C2C12 myotubes. CONCLUSIONS: These data suggest that ectopic lipid deposition impairs the diaphragmatic function of people with obesity. Activation of PERK/JNK signaling is involved in the pathogenesis of lipotoxicity-induced diaphragm weakness in obesity hypoventilation syndrome.

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

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

Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression.

Purpose: Diabetic retinopathy (DR) is one of the most common diabetic microvascular complications. However, the pathogenesis of DR has not yet been fully elucidated. This study aimed to discover novel and key molecules involved in the pathogenesis of DR, which could potentially be targets for therapeutic DR intervention. Methods: To identify potential genes involved in the pathogenesis of DR, we analyzed the public database of neovascular membranes (NVMs) from patients with proliferative diabetic retinopathy (PDR) and healthy controls (HCs) (GSE102485, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102485). Further, we compared these findings by performing RNA-sequencing analysis of peripheral blood mononuclear cells (PBMC) from patients with DR, control patients with non-complicated diabetes mellitus (DMC), and HCs. To determine the critical role of candidate genes in DR, knockdown or knockout was performed in human retinal vascular endothelial cells (HRVECs). The oxidative stress pathway, as well as tight junction integrity, was analyzed. Results: Transcriptional profiles showed distinct patterns between the NVMs of patients with DR and those of the HCs. Those genes enriched in either extracellular matrix (ECM)-receptor interaction or focal adhesion pathways were considerably upregulated. Both pathways were important for maintaining the integrity of retinal vascular structure and function. Importantly, the gene encoding the matricellular protein CCN1, a key gene in cell physiology, was differentially expressed in both pathways. Knockdown of CCN1 by small interfering RNA (siRNA) or knockout of CCN1 by the CRISPR-Cas9 technique in HRVECs significantly increased the levels of VE-cadherin, reduced the level of NADPH oxidase 4 (NOX4), and inhibited the generation of reactive oxygen species (ROS). Conclusion: The present study identifies CCN1 as an important regulator in the pathogenesis of DR. Increased expression of CCN1 stimulates oxidative stress and disrupts tight junction integrity in endothelial cells by inducing NOX4. Thus, targeting the CCN1/NOX4 axis provides a therapeutic strategy for treating DR by alleviating endothelial cell injury.

Interpersonal Trauma and Risk of Depression Among Adolescents: The Mediating and Moderating Effect of Interpersonal Relationship and Physical Exercise.

Interpersonal trauma in adolescent is an important public health concern. Depression can be a main consequence of interpersonal trauma, which subsequently results in various negative mental health outcomes. Previous research has investigated the independent effects of interpersonal trauma, interpersonal relationships and physical exercise on the risk of depression. However, the interaction effect of the three factors on depression remains unclear. We aim to investigate the associations between these potential factors and depression in adolescents, and explore the interaction effect of the three aforementioned factors. A cross-sectional study was conducted in Shenzhen, China, in 2017. A total of 1,883 adolescents from 11 middle schools and high schools were recruited. Demographic information, depressive symptoms, physical exercise, interpersonal relationships, interpersonal trauma, and academic record were collected through the use of standardized questionnaires. A linear regression model was performed to explore the association between these variables and depression. Pathway analysis was used to explore the role of potential mediators and moderators. The results showed that interpersonal trauma and poorer interpersonal relationships were significantly associated with depression (p < 0.05). We identified a mediating role of interpersonal relationships in the relationship between interpersonal trauma and depression, and a moderating role of physical exercise between interpersonal trauma and interpersonal relationships. This is the first study to examine the interaction effects of interpersonal trauma, interpersonal relationships and physical exercise on depression in adolescents. The current study therefore provides insights into factors which impact the mental health of adolescents. Through examining these factors one can gain further insight into potential factors associated with depression and therefore then develop more tailored interventions in order to support adolescents' mental well-being.

Internet addiction mediates the association between cyber victimization and psychological and physical symptoms:moderation by physical exercise.

BACKGROUND: The potential mechanisms underlying cyber victimization and the resulting psychological and physical symptoms remain unclear. Thus, the present study investigated whether Internet addiction mediates the association between peer victimization (e.g., cyberbullying) and psychological and physical symptoms. Furthermore, it was assessed whether physical exercise moderates the hypothetical mediation. METHODS: 1854 students from 11 middle and high schools in Shenzhen, Guangdong Province, China, were sampled for this study. Psychological and physical symptoms were assessed using the World Health Organization Quality of Life-BREF, while Internet addiction was evaluated using the Internet addiction test by Young. Cyber victimization was measured using a single question. In addition, this study examined whether Internet addiction mediated the association between cyber victimization and both psychological and physical symptoms. Additional work was conducted to test if physical exercise played a moderating role in the mediation hypothesized above. Mediation and moderation were analyzed using PROCESS macro for SPSS. RESULTS: Regression analysis showed that both cyber victimization (ß = - 0.102, p < 0.05) and Internet addiction (ß = - 0.278, p < 0.05) significantly predicted psychological and physical symptoms and demographic variables were controlled. Further mediation analysis suggested that Internet addiction mediated the relationship between cyber victimization and psychological and physical symptoms. The 95% CI (confidence interval) of the direct effect was (- 4.283, - 1.696) and the indirect effect (- 1.904, - 0.820), respectively, excluding zero. Finally, moderation analysis indicated that physical exercise moderated the relationship between Internet addiction and psychological and physical symptoms (p = 0.047). CONCLUSIONS: Internet addiction plays a mediating role in the association between cyber victimization and both psychological and physical symptoms, Thus, addressing Internet addiction among cyberbullying victims is worthwhile. Furthermore, physical exercise alleviates negative impacts on health and should thus be promoted.

Prevalence of depressive symptoms in primary school students in China: A systematic review and meta-analysis.

BACKGROUNDS: Depression in children and adolescents is usually under-recognized. The findings of epidemiological studies on depressive symptoms in primary school students are inconsistent across studies. This study reports a systematic review and meta-analysis on the prevalence of depressive symptoms in primary school students in China. METHODS: Literature search was performed in both international (PubMed, PsycINFO, EMBASE) and Chinese (China National Knowledge Internet, WANFANG Data and Chinese Biological Medical Literature) databases. The random-effects model was used to analyze data. RESULTS: Twenty-seven studies involving 42,374 subjects were included. The pooled prevalence of depressive symptoms in Chinese primary school students was 17.2% (95% CI: 14.3%-20.5%). Subgroup analyses found that the prevalence significantly varied between geographic regions, with western China reporting the highest prevalence. Meta-regression analyses found that year of survey and study quality were significantly associated with the prevalence of depressive symptoms. CONCLUSIONS: Given the high prevalence of depressive symptoms and its negative health outcomes, preventive measures, regular screening and effective treatments need to be implemented for this population.

BiSbS3@N-doped carbon core-shell nanorods as efficient anode materials for sodium-ion batteries.

BiSbS3@N-doped carbon (NC) core-shell nanorods were prepared through a simple preparation process. As anode materials for sodium-ion batteries (SIBs), BiSbS3@NC core-shell nanorods present excellent electrochemical performance with higher specific capacity and better rate capability compared with the unmodified pristine BiSbS3 nanorods. The BiSbS3@NC electrode delivers high sodium storage capacity (771.5 mA h g-1 in the 2nd cycle) and excellent rate performance (capacity of 518.4 mA h g-1 at 1000 mA g-1). The improvement in electrochemical performance results from the coated conductive NC layer which brings about fast ion/electron transfer and buffers volume expansion. The BiSbS3@NC core-shell nanorods are thus promising high performance anode materials for SIBs.

Prevalence of depressive symptoms in children and adolescents in China: A meta-analysis of observational studies.

Depressive symptoms are common in children and adolescents. The prevalence of depressive symptoms in children and adolescents in China vary significantly across studies. A meta-analysis of the prevalence of depressive symptoms in children and adolescents in China was conducted. Literature search was performed in both English (PubMed, PsycINFO and EMBASE) and Chinese (China National Knowledge Internet, WANFANG Data and SinoMed) databases. Random-effects model was used to synthesize the prevalence of depressive symptoms. Eighteen studies covering 29,626 participants were identified and analyzed. All these studies used the same measurement to identify depressive symptoms. The reported point prevalence of depressive symptoms ranged between 4% and 41% in the studies; the pooled prevalence of depressive symptoms was 19.85% (95% confidence interval: 14.75%-24.96%). In the subgroup analyses the prevalence of depressive symptoms was significantly associated with the region where the study was conducted: 17.8% in eastern, 23.7% in central, 22.7% in western, and 14.5% in northeast regions of China (P < 0.001). Considering the adverse impact of depressive symptoms on health outcomes, regular screening and effective interventions should be implemented in this population.

Campus bullying in Shenzhen middle school students and its associations with quality of life / 中国学校卫生

Objective@#To investigate the prevalence of bullying and its association with quality of life in Shenzhen middle school students’ and to provide scientific basis for intervention measures.@*Methods@#The study was a cross-sectional study with stratified cluster sampling. The short version of World Health Organization Quality of Life (WHOQOL-BREF), Center for Epidemiological Studies Depression Scale (CES-D) and Self-completed questionnaires, including demographic characteristics and bullying, were utilized to examine the study objectives. 2 103 school students from Shenzhen were selected to take part in the study during July-October of 2017. Multiple liner regression analysis was used to analyze the association between bullying and quality of life.@*Results@#418 middle school students (19.9%) suffered bully in the past year. 326 students (15.5%) suffered traditional bullying and 182 students (8.7%) suffered cyberbullying in the past year. Male students, junior middle school students and those with bad grades as well as bad relationship with family and classmates were more likely to suffer bullying(χ2=8.89, 41.56, 14.83, 23.42, 32.26, 46.75, P<0.05). The prevalence of depression in students with bullying experience was significantly higher than those without bullying. Students with bullying experience reported significantly lower scores than those without bullying experience in physical domain, psychological domain, social relationship domain and environment domain, and the differences were of statistical significance(t=-7.54, -7.08, -6.88, -6.02, P<0.01).@*Conclusion@#The prevalence of bullying in middle school students was high. It was negatively associated with students’ quality of life. The findings underscore the importance of developing psychological interventions for students with bullying.

Prevalence of major depressive disorder in children and adolescents in China: A systematic review and meta-analysis.

BACKGROUND: Prevalence figures of major depressive disorder (MDD) in children and adolescents across various epidemiological studies have been inconclusive. This is a systematic review and meta-analysis of the pooled prevalence of MDD and its associated factors in children and adolescents in China. METHOD: A systematic review and literature search were conducted covering PubMed, PsycINFO, EMBASE and Chinese databases (China National Knowledge Internet, WANFANG Data and SinoMed) to identify studies reporting the prevalence of MDD in children and adolescents in China. The pooled prevalence estimates and associated factors were examined using the Comprehensive Meta-Analysis program, Version 2. RESULTS: Fourteen studies involving 82,592 subjects were included in this meta-analysis. The pooled point prevalence of MDD in Chinese children and adolescents was 1.3% (95% CI: 0.8%-2.0%). Subgroup and meta-regression analyses revealed that diagnostic criteria, age, year of survey and study quality were significantly associated with the prevalence of MDD. CONCLUSIONS: The point prevalence of MDD in children and adolescents in China is similar to worldwide figures. Further national epidemiological studies with the view of developing effective intervention strategies should be considered.

The association between paternal depressogenic cognitive styles during pregnancy and offspring depressogenic cognitive styles: an 18-year prospective cohort study.

BACKGROUND: Preventing the development of depressogenic or negative cognitive styles could also prevent the development of depression, a leading public health problem worldwide. Maternal negative cognitive styles are a modifiable risk factor for the development of negative cognitive styles in offspring. However, evidence on the role of paternal negative cognitive styles is inconclusive and there have only been a few small studies, which may also have lacked statistical power. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate the association between paternal negative cognitive styles, measured when mothers were 18 weeks pregnant, and offspring negative cognitive styles 18 years later (N = 6,123). Associations were calculated using linear regression models, before and after adjustment for confounders including maternal negative cognitive styles. We compared associations before and after controlling for depression in parents and offspring, and used multiple imputation to reduce biases that may have arisen due to missing data. RESULTS: A two-standard deviation increase in paternal negative cognitive style was associated with a 3-point increase in offspring negative cognitive style (95% CI 1.36-4.37). This association remained after adjustment for confounders and was independent of depression in both parents and offspring. The effect size was equivalent to that of maternal negative cognitive style, and was also independent of maternal negative cognitive style. CONCLUSIONS: Our results suggest that fathers should be included in individual- and family-based interventions designed to prevent the development of depressogenic cognitive styles in adolescent offspring. This could possibly also prevent the development of depression.

Discrimination of in vitro and in vivo digestion products of meat proteins from pork, beef, chicken, and fish.

In vitro digestion products of proteins were compared among beef, pork, chicken, and fish. Gastric and jejunal contents from the rats fed these meat proteins were also compared. Cooked pork, beef, chicken, and fish were homogenized and incubated with pepsin alone or followed by trypsin. The digestion products with molecular weights of less than 3000 Da were identified with MALDI-TOF-MS and nano-LC-MS/MS. Gastric and jejunal contents obtained from the rats fed the four meat proteins for 7 days were also analyzed. After pepsin digestion, pork, and beef samples had a greater number of fragments in similarity than chicken and fish samples, but the in vitro digestibility was the greatest (p < 0.05) for pork and the smallest for beef samples. After trypsin digestion, the species differences were less pronounced (p > 0.05). A total of 822 and 659 peptides were identified from the in vitro and in vivo digestion products, respectively. Our results could interpret for the differences in physiological functions after the ingestion of different species of meat.

Effect of cooking on in vitro digestion of pork proteins: a peptidomic perspective.

This study was designed to investigate the effect of cooking on in vitro digestibility and peptide profiling of pork protein. We simulated gastrointestinal digestion of cooked pork that was treated with pepsin alone or followed by trypsin treatment. Digested products were identified using matrix-assisted laser desorption/ionization­time-of-flight mass spectrometry and liquid chromatography­mass spectrometry analyses. Cooking led to a reduction (p < 0.05) in digestibility and band intensities on sodium dodecyl sulfate­polyacrylamide gel electrophoresis gels. Peptide profiling and identification analyses also showed significant difference (p < 0.05) in the m/z ranges and number of peptides from the pepsin-digested products between raw (4 °C) and very well done samples (100 °C). Peptides sequenced from pepsin-digested samples under lower degrees of doneness disappeared as the temperature increased. Meanwhile, the trypsin cleavages appeared more consistent among different degrees of cooking. Further work may be needed to evaluate the bioavailability of the digested products under different cooking temperatures.