Medication non-adherence and self-inflicted violence behaviors among 185,800 patients with schizophrenia in the community: a 12-year cohort study.

BACKGROUND: Despite the importance of medication adherence in treatment effectiveness, little is known about the association between medication non-adherence and self-inflicted violence behaviors. We aimed to assess whether medication non-adherence increased the risk of self-inflicted violence behaviors among schizophrenics in communities (hypothesis 1) and whether the dose-response relationship existed (hypothesis 2). METHODS: This 12-year cohort study in western China recruited 292,667 community-dwelling schizophrenics. The proportion of regular medication (PRM) was calculated by dividing the time of "regular adherence" by the total time of antipsychotic treatment during follow-up period as an indicator of medication adherence. For hypothesis 1, medication adherence was designated as a binary variable with a threshold of 0.8 (PRM); for hypothesis 2, medication adherence was specified as five-category and continuous variables, respectively. Inverse probability weighting and mixed effects Cox proportional hazards models were conducted for confounders control and survival analyses. RESULTS: One hundred eighty-five thousand eight hundred participants were eligible for the final analyses, with a mean age of 47.49 years (SD 14.55 years), of whom 53.6% were female. For hypothesis 1, the medication non-adherence group (PRM < 0.8) had a lower risk of suicide (HR, 0.527, 95% CI, 0.447-0.620), an increased risk of NSSI (HR, 1.229, 95% CI, 1.088-1.388), and non-significant risk of attempted suicide compared with adherence group (PRM ≥ 0.8). For hypothesis 2, the lowest medication adherence (PRM < 0.2) was associated with increased risks of suicide attempt (HR, 1.614, 95% CI, 1.412-1.845), NSSI (HR, 1.873, 95% CI, 1.649-2.126), and a decreased risk of suicide (HR, 0.593, 95% CI, 0.490-0.719). The other non-adherence groups had lower risks for all three self-inflicted violence behaviors. The associations between medication adherence in continuous-variable and three outcomes were consistent with the categorical medication adherence results. CONCLUSIONS: Almost no medication taken as prescribed was associated with an increased risk of suicide attempt and NSSI. However, medication adherence did not appear to prevent completed suicide. Besides, patients with moderate adherence had a lower incidence of suicide attempt and NSSI. These findings highlight the need for a more detailed portrayal of medication adherence and the need to be vigilant for suicide intent in schizophrenics with good medication adherence who may be overlooked previously.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

[Dynamic Prediction of Recidivism in Violence in Community-Based Schizophrenia Spectrum Disorder Patients: A Joint Model]. / ç¤¾åŒºç²¾ç¥žåˆ†è£‚ç—‡è°±ç³»éšœç¢æ‚£è€ æš´åŠ›å†çŠ¯åŠ¨æ€é¢„æµ‹ï¼šä¸€ç§è”åˆæ¨¡åž‹.

Objective: To construct a model for predicting recidivism in violence in community-based schizophrenia spectrum disorder patients (SSDP) by adopting a joint modeling method. Methods: Based on the basic data on severe mental illness in Southwest China between January 2017 and June 2018, 4565 community-based SSDP with baseline violent behaviors were selected as the research subjects. We used a growth mixture model (GMM) to identify patterns of medication adherence and social functioning. We then fitted the joint model using a zero-inflated negative binomial regression model and compared it with traditional static models. Finally, we used a 10-fold training-test cross validation framework to evaluate the models' fitting and predictive performance. Results: A total of 157 patients (3.44%) experienced recidivism in violence. Medication compliance and social functioning were fitted into four patterns. In the counting model, age, marital status, educational attainment, economic status, historical types of violence, and medication compliance patterns were predictive factors for the frequency of recidivism of violence (P<0.05). In the zero-inflated model, age, adverse drug reactions, historical types of violence, medication compliance patterns, and social functioning patterns were predictive factors for the recidivism in violence (P<0.05). For the joint model, the average value of Akaike information criterion (AIC) for the train set was 776.5±9.4, the average value of root mean squared error (RMSE) for the testing set was 0.168±0.013, and the average value of mean absolute error (MAE) for the testing set was 0.131±0.018, which were all lower than those of the traditional static models. Conclusion: Joint modeling is an effective statistical strategy for identifying and processing dynamic variables, exhibiting better predictive performance than that of the traditional static models. It can provide new ideas for promoting the construction of comprehensive intervention systems.

Ghrelin improves cognition via activation of the cAMP- CREB signalling pathway in depressed male C57BL/6J mice.

BACKGROUND: Depression leads to a cognitive decline and decreases in ghrelin are observed in depression. Ghrelin affects the level of Brain-derived nerve growth factor (BDNF) through the cAMP-CREB signalling pathway, and lower BDNF levels lead to cognitive decline. Therefore, it is reasonable to assume that in depression, lower ghrelin causes a decrease in BDNF levels and cognitive decline though the cAMP- CREB signalling pathway. METHODS: A total of 120 C57BL/6J male mice were randomly divided into six groups of 20 mice: non-depression groups (sham group, ghrelin group, and ghrelin + (D-lys3)-GHRP-6 group) and depression groups (depression group, depression + ghrelin group and depression + ghrelin + (D-lys3)-GHRP group). A depression mouse model was established by injecting normal saline, ghrelin or ghrelin + (D-lys3) -GHRP-6 into the lateral ventricle of each group. Cognition, hippocampal long-term potentiation (LTP), ghrelin mRNA and protein level, BDNF level and CREB level in the hippocampus were detected. RESULTS: In the depression mouse model groups, all comparison indexes (cognition and hippocampal levels of LTP, ghrelin mRNA and proteins, and BDNF and CREB) had significant negative changes. In the mice with depression, ghrelin or ghrelin + (D-lys3)-GHRP-6 was injected, and all the comparison indicators showed significant positive changes. Supplementation of ghrelin+(D-lys3))-GHRP-6 resulted in more significant positive changes in all comparison indexes than those of ghrelin alone. CONCLUSIONS: In the depression model, lower ghrelin causes hippocampal BDNF to decrease and results in cognitive decline via the cAMP-CREB signalling pathway.

[Factors Influencing Suicide Deaths in Patients With Schizophrenia Based on Cohort Data: An Empirical Study of a Sample of 170006 Patients in Sichuan Province].

Objective: To prospectively explore the risk factors of suicide in patients with schizophrenia. Methods: Data on schizophrenia patients in Sichuan Province between 2006 and 2018 were obtained from the National Severe Mental Disorders Information System, and the Cox proportional hazards regression model was used to explore for risk factors for suicide in schizophrenia patients. Result: A total of 170006 patients with schizophrenia were included in the study. At the end of the follow-up period, 160570 patients were alive and 9436 died from various causes, 929 of which being suicide deaths, resulting in a suicide rate of 223.61/100, 000 person-years. The Cox proportional hazards regression model suggested that risk factors for suicide in patients with schizophrenia included poverty ( HR=1.20, 95% CI: 1.02-1.41), higher education level (primary school [ HR=1.32, 95% CI: 1.09-1.60], middle school [ HR=1.40, 95% CI: 1.14-1.73], high school and above [ HR=1.93, 95% CI: 1.49-2.52]) in comparison with illiteracy and semi-literacy, suicide attempts ( HR=2.70, 95% CI: 1.70-4.29), strict medication compliance ( HR=1.91, 95% CI: 1.66-2.20), history of antipsychotic drug therapy ( HR=1.42, 95% CI: 1.06-1.90), younger age group of patients of 46-60 ( HR=1.95, 95% CI: 1.60-2.39), 31-45 ( HR=3.61, 95% CI: 2.92-4.47), and 15-30 ( HR=12.37, 95% CI: 9.69-15.78) compared with the 61-90 age group, and doing agriculture jobs ( HR=1.36, 95% CI: 1.13-1.65). Conclusion: Young and middle-aged schizophrenia patients with higher education levels, especially those with a history of suicide attempts, are at high risk for suicide. Focused interventions should be directed at high-risk groups to reduce suicide deaths in patients with schizophrenia.

A longitudinal study on emotional distress among local government staff seven years after the 2008 Wenchuan earthquake in China.

BACKGROUND: The current study examined the change in local government staff's emotional distress over 7 years after the 2008 Wenchuan earthquake, and the influence of earthquake exposure and professional quality of life (ProQOL) on emotional distress. METHODS: This longitudinal study assessed 250 participants at 1 year after the earthquake; 162 (64.8%) were followed up at 7 years. Emotional distress was assessed with the Self-Reporting Questionnaire (SRQ) at both time points. We assessed ProQOL, including compassion satisfaction, burnout, and secondary traumatic stress, and earthquake exposure at 1 year. Wilcoxon signed-rank tests were performed to test longitudinal changes in emotional distress. Hierarchical multiple regression was conducted to examine the effect of earthquake exposure and ProQOL. RESULTS: The positive screening rate of emotional distress (SRQ ≥ 8) was 37.6 and 15.4% at one and 7 years, respectively. Emotional distress scores declined over time (p < 0.001). Earthquake exposure and ProQOL predicted one-year (ps < 0.05) but not seven-year emotional distress, whereas burnout predicted both one-year (p = 0.018) and seven-year (p = 0.047) emotional distress. CONCLUSIONS: Although emotional distress can recover over time, it persists even 7 years later. Actions to reduce burnout during the early stage of post-disaster rescue have long-term benefits to staff's psychological outcomes.

Nanometal Oxides with Special Surface Physicochemical Properties to Promote Electrochemical Detection of Heavy Metal Ions.

Heavy metal ions (HMIs) are one of the major environmental pollution problems currently faced. To monitor and control HMIs, rapid and reliable detection is required. Electrochemical analysis is one of the promising methods for on-site detection and monitoring due to high sensitivity, short response time, etc. Recently, nanometal oxides with special surface physicochemical properties have been widely used as electrode modifiers to enhance sensitivity and selectivity for HMIs detection. In this work, recent advances in the electrochemical detection of HMIs using nanometal oxides, which are attributed to specific crystal facets and phases, surficial defects and vacancies, and oxidation state cycle, are comprehensively summarized and discussed in aspects of synthesis, characterization, electroanalysis application, and mechanism. Moreover, the challenges and opportunities for the development and application of nanometal oxides with functional surface physicochemical properties in electrochemical determination of HMIs are presented.

[Role of microRNAs in erectile dysfunction: An update].

MicroRNAs (miRNAs) are short non-coding RNAs consisting of approximately 19－23 nucleotides and involved in many pathological and physiological processes by regulating post-transcriptional gene expressions. ED is one of the common male sexual dysfunctions seriously affecting the patient's quality of life, for which there is currently a lack of effective treatments clinically. More and more experiments have demonstrated that miRNAs are involved in the pathological process of different types of ED. This article presents an overview of the progress in the studies of the pathogenic role of miRNAs in ED.

SP1, MYC, CTNNB1, CREB1, JUN genes as potential therapy targets for neuropathic pain of brain.

Neuropathic pain (NP) may cause serious brain diseases, but the genes associated with the metabolic pathway and transcript factors of NP remain unclear. This study is aimed to identify the therapy target genes for NP and to investigate the metabolic pathways and transcript factors associated with NP. The differentially expressed genes of three brain tissues (nucleus accumbens, periaqueductal gray, and prefrontal cortex) dealt with NP stimulation were analyzed. Besides, The Database for Annotation, Visualization, and Integrated Discovery and Tfacts datasets were used in the analysis of the genes related to the metabolic pathway and transcript factors of the brain. Eight genes were found to coexpress in all three tissues. A functional enrichment analysis showed that the upregulated genes were mostly enriched in pathways as inflammatory response, calcium-mediated signaling, cytokine-cytokine receptor interaction, and extracellular matrix (ECM)-receptor interaction, whereas the downregulated genes were mostly enriched in pathways as phospholipid metabolic processes, positive regulation of protein kinase B signaling, and metabolism of xenobiotics by cytochrome P450. Finally, 135 and 98 transcript factors genes were upregulated and downregulated, among which SP1, MYC, CTNNB1, CREB1, JUN were identified as the most critical genes because the number of up- and downregulated gene ranked at the top. In conclusion, the pathways of immune response and cytokine-cytokine receptor interaction were determined as the main metabolic pathways of NP affecting the brain, and SP1, MYC, CTNNB1, CREB1, JUN genes were recognized as the most enriched genes in this process, which may provide evidence for the diagnosis and treatment research of neuropathic pain.

The HO-1-expressing bone mesenchymal stem cells protects intestine from ischemia and reperfusion injury.

BACKGROUND: Bone mesenchymal stromal cells (BMSC) showed protective potential against intestinal ischemia. Oxygenase-1(HO-1) could alleviate oxidative stress. In the present study, we constructed HO-1-expressing BMSC and detected the effects of it on survival, intestinal injury and inflammation following intestinal ischemia and reperfusion injury (I/R). METHODS: In this experiment, eighty adult male mice were divided into Sham, I/R, I/R + BMSC, I/R + BMSC/HO-1 groups. Mice were anesthetized and intestinal I/R model were established by temporarily occluding the superior mesenteric artery for 60 min with a non-crushing clamp. Following ischemia, the clamp was removed and the intestines were allowed for reperfusion. Prior to abdominal closure, BMSC/ HO-1 (2 × 106 cells) or BMSC (2 × 106 cells) were injected into the peritoneum of I/R mice respectively. Mice were allowed to recover for 24 h and then survival rate, intestinal injury and inflammation were determined. Reactive oxygen species (ROS) was assayed by fluorescent probe. TNFα and IL-6 were assayed by ELISA. RESULTS: BMSC/HO-1 increased seven day survival rate, improved intestinal injury and down-regulated inflammation after intestinal I/R when compared with sole BMSC (p < 0.05 respectively). Multiple pro-inflammatory media were also decreased following application of BMSC/HO-1, when compared with sole BMSC (p < 0.05) respectively, suggesting that BMSC /HO-1 had a better protection to intestinal I/R than BMSC therapy. CONCLUSION: Administration of BMSC/HO-1 following intestinal I/R, significantly improved intestinal I/R by limiting intestinal damage and inflammation.

Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.

Cannabinoid CB1 receptors (CB1Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB1R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB1R antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.

Applicability of traumatic brain injury rehabilitation interventions in natural disaster settings.

Objective: To evaluate published traumatic brain injury (TBI) clinical practice guidelines (CPGs) and assess rehabilitation intervention recommendations for applicability in disaster settings. Methods: Recommendations for rehabilitation interventions were synthesized from currently published TBI CPGs, developed by the Department of Labor and Employment (DLE); Scottish Intercollegiate Guidelines Network (SIGN); Department of Veterans Affairs/Department of Defence (DVA/DOD); and American Occupational Therapy Association (AOTA). Three authors independently extracted, compared, and categorized evidence-based rehabilitation intervention recommendations from these CPGs for applicability in disaster settings. Results: The key recommendations from a rehabilitation perspective for TBI survivors in disaster settings included patient/carer education, general physical therapy, practice in daily living activities and safe equipment use, direct cognitive/behavioral feedback, basic compensatory memory/visual strategies, basic swallowing/communication, and psychological input. More advanced interventions are generally not applicable following disasters due to limited access to services, trained staff/resources, equipment, funding, and operational issues. Conclusions: Many recommendations for TBI care are challenging to implement in disaster settings due to complexities related to the environment, resources, service provision, workforce, and other reasons. Further research is needed to identify and address barriers for implementation.

Clinical practice guidelines for rehabilitation in traumatic brain injury: a critical appraisal.

This review aim to provide an overview of recommendations and quality of existing clinical practice guidelines (CPGs) for the management of traumatic brain injury (TBI) from the rehabilitation perspective. Comprehensive literature search, including health databases, CPG clearinghouse/developer websites, and grey literature using Internet search engines up to September 2017. All TBI CPGs published in the last decade were selected if their scope included management of TBI, systematic methods for evidence search, clear defined recommendations, and supporting evidence for rehabilitation interventions. Three authors independently critically appraised the quality of included CPGs using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) Instrument. Four of 13 potential CPGs met the inclusion criteria. Despite variation in scope, target population, size, and guideline development processes, all four CPGs assessed were good quality (AGREE score of 5-7/7). Key rehabilitation recommendations included education, physical rehabilitation, integrated computer-based management, repetitive task-specific practice in daily living activities, safe equipment usage, cognitive/behavioral feedback, compensatory memory/visual strategies, swallowing/communication, and psychological input for TBI survivors. In conclusion, although rehabilitation is an integral component in TBI management, many published CPGs do not include rehabilitation. These CPGs, however, recommend comprehensive, flexible coordinated multidisciplinary care and appropriate follow-up, education, and support for patients with TBI (and carers).

Inhibition of miR-200b/miR-429 contributes to neuropathic pain development through targeting zinc finger E box binding protein-1.

Many studies have reported that microRNAs participate in neuropathic pain development. Previously, miR-200b and miR-429 are reported to be involved in various diseases. In our current study, we focused on their roles in neuropathic pain and we found that miR-200b and miR-429 were significantly decreased in chronic constriction injury (CCI) rat spinal cords and isolated microglials. miR-200b and miR-429 overexpression were able to relieve neuropathic pain through modulating PWT and PWL in CCI rats. Meanwhile, we observed that both miR-200b and miR-429 upregulation could repress neuroinflammation via inhibiting inflammatory cytokines such as IL-6, IL-1ß, and TNF-α in CCI rats. By carry out bioinformatics technology, Zinc finger E box binding protein-1 (ZEB1) was predicted as target of miR-200b, and miR-429 and dual-luciferase reporter assays confirmed the correlation between them. ZEB1 has been reported to regulate a lot of diseases. Here, we found that ZEB1 was greatly increased in CCI rats and miR-200b and miR-429 overexpression markedly suppressed ZEB1 mRNA expression in rat microglial cells. In addition, knockdown of ZEB1 can reduce neuropathic pain development and co-transfection of LV-anti-miR-200b/miR-429 reversed this phenomenon in vivo. Taken these together, our results suggested that miR-200b/miR-429 can serve as an important regulator of neuropathic pain development by targeting ZEB1.

XIST accelerates neuropathic pain progression through regulation of miR-150 and ZEB1 in CCI rat models.

LncRNAs are reported to participate in neuropathic pain development. LncRNA X-inactive specific transcript (XIST) is involved in the progression of various cancers. However, the role of XIST in neuropathic pain remains unclear. In our present study, we established a chronic constriction injury (CCI) rat model and XIST was found to be greatly upregulated both in the spinal cord tissues and in the isolated microglias of CCI rats. Inhibition of XIST inhibited neuropathic pain behaviors including mechanical and thermal hyperalgesia. Moreover, decrease of XIST repressed neuroinflammation through inhibiting COX-2, tumor necrosis factor (TNF)-α and IL-6 and in CCI rats. Previously, miR-150 has been reported to restrain neuropathic pain by targeting TLR5. Currently, miR-150 was predicted to be a microRNA target of XIST, which indicated a negative correlation between miR-150 and XIST. miR-150 was remarkably decreased in CCI rats and overexpression of miR-150 can significantly suppress neuroinflammation-related cytokines. Furthermore, ZEB1 was exhibited to be a direct target of miR-150 and we found it was overexpressed in CCI rats. Silencing ZEB1 was able to inhibit neuropathic pain in vivo and downreguation of XIST decreased ZEB1, which can be reversed by miR-150 inhibitors. Taken these together, we indicated that XIST can induce neuropathic pain development in CCI rats via upregulating ZEB1 by acting as a sponge of miR-150. It was revealed that XIST/miR-150/ZEB1 axis can be provided as a therapeutic target in neuropathic pain.

miR-93-5p Transferred by Exosomes Promotes the Proliferation of Esophageal Cancer Cells via Intercellular Communication by Targeting PTEN.

OBJECTIVE: To investigate the relationship between plasma miR-93-5p and the risk of esophageal cancer, as well as the influence of miR-93-5p on the biological function of esophageal cancer cells, exerted through exosomes. METHODS: The expression of plasma miR-93-5p in esophageal cancer patients and healthy controls was analysed by real-time quantitative PCR. The influence of miR-93-5p on the risk and prognosis of esophageal carcinoma was analyzed by conditional logistic regression and survival analysis. The effect of miR-93-5p on the biological function of recipient cells was investigated by establishing an in vitro donor cell co-culture model. The target gene of miR-93-5p was validated by luciferase reporter assay and Western Blotting. RESULTS: Upregulation of plasma miR-93-5p expression significantly increases the risk of esophageal cancer and is associated with poor prognosis. miR-93-5p transferred by exosomes promotes the proliferation of recipient esophageal cancer cells and affects the expression of PTEN and its downstream proteins p21 and cyclin D1. CONCLUSION: Our study provides a reference for the identification of biomarkers for the diagnosis and prognosis of esophageal cancer.

Transduced PEP-1-heme oxygenase-1 fusion protein reduces remote organ injury induced by intestinal ischemia/reperfusion.

BACKGROUND: A fusion protein composed of heme oxygenase-1 (HO-1) and cell-penetrating peptide PEP-1 has been shown to reduce local intestinal injury after intestinal ischemia/reperfusion (I/R). In this study, we investigated the effects of PEP-1-HO-1 fusion protein on remote organ injury induced by intestinal I/R in rats. MATERIAL AND METHODS: We randomly assigned 24 male Sprague-Dawley rats to 3 groups: Sham, I/R, and I/R plus PEP-1-HO-1 treatment (HO). The model of intestinal I/R was established by occluding the superior mesenteric artery for 45 min followed by 120-min reperfusion. In HO group, PEP-1-HO-1 was administered intravenously 30 min before ischemia, while animals in the Sham and I/R groups received the equal volume of physiological saline. At the end of the experiment, lung, liver, and blood samples were collected and analyzed. RESULTS: Malondialdehyde levels and histological injury scores were increased, and superoxide dismutase activities were decreased in the lung and liver tissues in the I/R group compared with the Sham group (P<0.05). Serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α, interleukin-6, and lung tissue wet weight to dry weight ratio were increased in the I/R group compared with the Sham group (P<0.05). NF-κB expression in intestinal tissues was significantly higher in the I/R group than in the Sham group. These changes were significantly reversed by treatment with PEP-1-HO-1. CONCLUSIONS: This study demonstrates that administration of PEP-1-HO-1 has a protective role against lung and liver injury after intestinal I/R, attributable to the reduction of released proinflammatory cytokines regulated by NF-κB.

Transduced PEP-1-heme oxygenase-1 fusion protein protects against intestinal ischemia/reperfusion injury.

BACKGROUND: Heme oxygenase-1 (HO-1) has been shown to have antioxidant and anti-apoptotic properties. The present study transduced HO-1 protein into intestinal tissues using PEP-1, a cell-penetrating peptide, and investigated its potentiality in prevention against intestinal ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: PEP-1-HO-1 fusion protein was administered intravenously to explore the time and dose characteristics through measuring serum HO-1 levels. Twenty-four male Sprague-Dawley rats were randomly divided into three groups: sham, intestinal I/R (II/R), II/R + PEP-1-HO-1 fusion protein (HO). The model was established by occluding the superior mesenteric artery for 45 min followed by 120 min reperfusion. In HO group, PEP-1-HO-1 was administered intravenously 30 min before ischemia, whereas animals in sham and II/R groups received the equal volume of physiological saline. After the experiment, the intestines were harvested for determination of histologic injury, wet/dry ratio, enzyme activity, apoptosis, and His-probe protein (one part of PEP-1-HO-1). RESULTS: Levels of serum HO-1 were dose- and time-dependent manner after intravenous injection of PEP-1-HO-1. I/R caused deterioration of histologic characteristics and increases in histologic injury scoring, wet/dry ratio, myeloperoxidase activity, malondialdehyde, and intestinal apoptosis. These changes were also accompanied by a decrease in superoxide dismutase activity (P < 0.05). PEP-1-HO-1 treatment significantly reversed these changes (P < 0.05). Furthermore, His-probe protein expression was only detected in PEP-1-HO-1-treated animals. CONCLUSION: Treatment of PEP-1-HO-1 attenuates intestinal I/R injury, which might be attributable to its antioxidant and anti-apoptotic roles of HO-1.

Investigation of the spatial effects on PM2.5 in relation to land use and ecological restoration in urban agglomerations.

Heavy pollution of particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) poses increasing threats to the living environment worldwide. Urban agglomerations often lead to regional rather than local air pollution problems. This study explored the underlying global and local spatial driving mechanisms of PM2.5 variations of the 195 county-level administrative units in the urban agglomeration in the middle reaches of the Yangtze River, China, in 2020, using the global spatial regression and geographically weighted regression methods. Results showed that (1) at the county level, there were spatial variations of PM2.5, fluctuating from 20.1263 µg/m3 to 44.8416 µg/m3. (2) The concentrations of PM2.5 presented a positive spatial autocorrelation with a remarkable direct spatial spillover effect. (3) Forestland, grassland, elevation and ecological restoration were negatively correlated with PM2.5 concentrations, the indirect spatial spillover effect of elevation was noticeable. (4) The indirect reduction effects of ecological restoration on PM2.5 concentrations were substantial in the Wuhan urban agglomeration. (5) The reduction effect of forestland, grassland, ecological restoration and elevation on PM2.5 showed a noticeable spatial heterogeneity. In the future, it is suggested regional variability and the spatial spillover effect of air pollution be taken into account in environmental governance. Simultaneously, utilization of the mitigation effect of ecological restoration on PM2.5 is anticipated for the concerted effort in air pollution governance.

A novel cancer-germline gene DAZL promotes progression and cisplatin resistance of non-small cell lung cancer by upregulating JAK2 and MCM8.

Germline-specific genes are usually activated in cancer cells and drive cancer progression; such genes are called cancer-germline or cancer-testis genes. The RNA-binding protein DAZL is predominantly expressed in germ cells and plays a role in gametogenesis as a translational activator or repressor. However, its expression and role in non-small cell lung cancer (NSCLC) are unknown. Here, mining of RNA-sequencing data from public resources and immunohistochemical analysis of tissue microarrays showed that DAZL was expressed exclusively in testis among normal human tissues but ectopically expressed in NSCLC tissues. Testis and NSCLC cells expressed the shorter and longer transcript variants of the DAZL gene, respectively. Overexpression of the longer DAZL transcript promoted tumor growth in a mouse xenograft model. Silencing of DAZL suppressed cell proliferation, colony formation, migration, invasion, and cisplatin resistance in vitro and tumor growth in vivo. Quantitative proteomic analysis based on tandem mass tag and Western blot analysis showed that DAZL upregulated the expression of JAK2 and MCM8. RNA-binding protein immunoprecipitation assays showed that DAZL bound to the mRNA of JAK2 and MCM8. The JAK2 inhibitor fedratinib attenuated the oncogenic outcomes induced by DAZL overexpression, whereas silencing MCM8 counteracted the effects of DAZL overexpression on cisplatin-damaged DNA synthesis and half-maximal inhibitory concentration of cisplatin. In conclusion, DAZL was identified as a novel cancer-germline gene that enhances the translation of JAK2 and MCM8 to promote NSCLC progression and resistance to cisplatin, respectively. These findings suggest that DAZL is a potential therapeutic target in NSCLC.