Isorhamnetin alleviates ferroptosis-mediated colitis by activating the NRF2/HO-1 pathway and chelating iron.

Ferroptosis of intestinal epithelial cells (IECs) had been identified as a key factor in the development of ulcerative colitis (UC). Therefore, targeted inhibition of ferroptosis may provide a new strategy for the treatment of UC. Isorhamnetin (ISO) was an O-methylated flavonol with therapeutic effects on a variety of diseases, such as cardiovascular disease, neurological disorders and tumors. However, the role and mechanism of ISO in ferroptosis and associated colitis were rarely investigated. In this study, we demonstrated that ISO could effectively alleviate intestinal inflammation by inhibiting ferroptosis of IECs in DSS-induced mice. Moreover, our results shown that ISO acted as a potent and common ferroptosis inhibitor in multiple human and murine cell lines. Mechanistically, ISO inhibited ferroptosis independent of its previously reported targets MEK1 and PI3K, but alleviated oxidative stress by targeting and activating NRF2. Furthermore, ISO could also directly chelate iron to hinder ferroptosis. In conclusion, our study indicated that ISO as a novel potential ferroptosis inhibitor, providing a promising therapeutic strategy for ferroptosis-related colitis.

Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases.

Ferroptosis is a form of iron-dependent, lipid peroxidation-driven regulatory cell death that has been implicated in the pathogenesis of multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, inhibitors that directly and specifically target ferroptosis are not yet available. Here, we identify the compound AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. Our results show that AS effectively inhibits lipid peroxidation and ferroptosis in both human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4 to inhibit its enzymatic activity, resulting in the suppression of lipid peroxidation and ferroptosis. By using nanoparticle-based delivery systems, treatment with AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). Thus, our results identify that AS is a specific and targeted inhibitor of ACSL4 with remarkable antiferroptosis function, providing a potential therapeutic for ferroptosis-related diseases.

A Comparative Study of the Effects of Electronic Cigarette and Traditional Cigarette on the Pulmonary Functions of C57BL/6 Male Mice.

INTRODUCTION: Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms. METHODS: A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells. RESULTS: Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS: The findings of the present study indicate that the safety of E-cig should be further evaluated. IMPLICATIONS: Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.

Entrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7.

Excessive inflammation caused by abnormal activation of the NLRP3 inflammasome contributes to the pathogenesis of multiple human diseases, but clinical drugs targeting the NLRP3 inflammasome are still not available. In this study, we identify entrectinib (ENB), a US Food and Drug Administration (FDA)-approved anti-cancer agent, as a target inhibitor of the NLRP3 inflammasome to treat related diseases. ENB specifically blocks NLRP3 without affecting activation of other inflammasomes. Furthermore, we demonstrate that ENB directly binds to arginine 121 (R121) of NEK7 and blocks the interaction between NEK7 and NLRP3, thereby inhibiting inflammasome assembly and activation. In vivo studies show that ENB has a significant ameliorative effect on mouse models of NLRP3 inflammasome-related diseases, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate (MSU)-induced peritonitis, and high-fat diet (HFD)-induced type 2 diabetes (T2D). These data show that ENB is a targeted inhibitor of NEK7 with strong anti-NLRP3 inflammasome activity, making it a potential candidate drug for the treatment of inflammasome-related diseases.

Effects of Bullying on Anxiety, Depression, and Posttraumatic Stress Disorder Among Sexual Minority Youths: Network Analysis.

BACKGROUND: Bullying victimization is highly prevalent among sexual minority youths, particularly in educational settings, negatively affecting their mental health. However, previous studies have scarcely explored the symptomatic relationships among anxiety, depression, and posttraumatic stress disorder (PTSD) among sexual minority youths who experienced bullying on college campuses. OBJECTIVE: The objectives of our study were to (1) characterize the anxiety-depression-PTSD network structures of gay or lesbian, bisexuals, and other sexual minority youths previously bullied on college campuses; and (2) compare symptomatic associations in the anxiety-depression-PTSD networks among bullied sexual minority youths and heterosexual youths' groups. METHODS: This cross-sectional study recruited college participants from Jilin Province, China. Data were analyzed using a subset of the data extracted after screening for sexual orientation and history of bullying victimization. Sexual minority youths were then divided into 3 subgroups: gay or lesbian (homosexual), bisexual, and other. Mental health symptom severity was assessed using scales: the 7-item Generalized Anxiety Disorder Scale measuring anxiety, the 9-item Patient Health Questionnaire measuring depression, and the 10-item Trauma Screening Questionnaire measuring PTSD symptoms. Combining the undirected and Bayesian network analyses, the anxiety-depression-PTSD networks were compared among sexual minority youths subgroups, and the difference between heterosexual youths and sexual minority youths was investigated. Chi-square tests were used to compare the difference in categorical variables, while independent-sample t tests were run on continuous variables. RESULTS: In this large-scale sample of 89,342 participants, 12,249 identified as sexual minority youths, of which 1603 (13.1%, 95% CI 12.5%-13.7%) reported being bullied on college campuses in the past year. According to the expected influence (EI) and bridge expected influence (bEI) index, in the global network structure of anxiety, depression, and PTSD, sad mood (EI=1.078, bEI=0.635) and irritability (EI=1.077, bEI=0.954) were identified as central and bridge symptoms; emotional cue reactivity (EI=1.015) was a central symptom of PTSD in this global network. In the anxiety-depression-PTSD Bayesian network, anhedonia had the highest prediction priority for activating other symptoms; and feeling afraid linked symptoms from anxiety to the PTSD community. Compared to their heterosexual counterparts, sexual minority youths exhibited a stronger association between difficulty concentrating and appetite. The "sad mood-appetite" edge was strongest in the gay or lesbian network; the "irritability-exaggerated startle response" edge was strongest in the bisexual network. CONCLUSIONS: For the first time, this study identified the most central and bridge symptoms (sad mood and irritability) within the depression-anxiety-PTSD network of sexual minority youths with past bullying-victim experiences on college campuses. Emotional cue reactivity, anhedonia, and feeling afraid were other vital symptoms in the comorbid network. Symptomatic relationships existed showing heterogeneity in bullied heterosexual youths and sexual minority youth networks, which also was present within the sexual minority youth subgroups. Consequently, refined targeted interventions are required to relieve anxiety, depression, and PTSD symptoms.

Anxiety and Depression Symptoms among Youth Survivors of Childhood Sexual Abuse: A Network Analysis.

BACKGROUND: Previous studies have frequently reported a high prevalence of co-occurring anxiety and depression among people who experienced stressful events in childhood. However, few have noted the symptomatic relationship of this comorbidity among childhood sexual abuse (CSA) survivors. Therefore, this study's objectives were as follows: (1) to examine the relationship across symptoms between anxiety and depression among CSA survivors; (2) to compare differences between male and female network structures among CSA survivors. METHODS: A total of 63 Universities and Colleges in Jilin Province, China, covered 96,218 participants in this study, a sub-set data of which met the criteria of CSA was analyzed with the network analysis. The Childhood Trauma Questionnaire-Short Form (CTQ-SF), measured CSA. Anxiety was measured by the seven-item Generalized Anxiety Disorder Scale (GAD-7), and depression was measured by the Patient Health Questionnaire (PHQ-9). The sex difference between anxiety and depression among CSA survivors was compared. RESULTS: 3,479 college students reported the experience of CSA (CTQ-SF total scores ≥ 8), with a prevalence of 3.62% (95% CI: 3.50-3.73%). Among CSA survivors, control worry, sad mood, and energy were central and bridge symptoms of the anxiety and depression network. Meanwhile, male CSA survivors appeared to have a stronger correlation between guilt and suicide, but female CSA survivors seemed to have a stronger correlation between control worry and suicide. Moreover, the edge of control worry-relax-afraid was stronger in the male network, while the edge of restless-relax was stronger in the female network. CONCLUSION: Control worry, sad mood, and energy are crucial to offer targeted treatment and to relieve anxiety and depression symptoms for CSA survivors. Guilt needs more attention for male CSA survivors, while control worry remains more important for female CSA survivors to reduce suicidal ideation and suicide attempts.

Green Cleaning of 3D-Printed Polymeric Products by Micro-/Nano-Bubbles.

3D printing technology has been used to directly produce various actual products, ranging from engines and medicines to toys, especially due to its advantage in producing items of complicated, porous structures, which are inherently difficult to clean. Here, we apply micro-/nano-bubble technology to the removal of oil contaminants from 3D-printed polymeric products. Micro-/nano-bubbles show promise in the enhancement of cleaning performance with or without ultrasound, which is attributed to their large specific surface area enhancing the adhesion sites of contaminants, and their high Zeta potential which attracts contaminant particles. Additionally, bubbles produce tiny jets and shock waves at their rupture, driven by coupled ultrasound, which can remove sticky contaminants from 3D-printed products. As an effective, efficient, and environmentally friendly cleaning method, micro-/nano-bubbles can be used in a range of applications.

A network approach to the symptom-level associations between smoking and posttraumatic stress disorder (PTSD) among young adults exposed to childhood sexual abuse.

Background: Previous empirical literature has examined the associations between childhood sexual abuse (CSA) exposure, posttraumatic stress disorder (PTSD), and smoking. However, few studies examined symptom-level associations between smoking and PTSD among CSA victims. Thus, the aims of this study were 1) to explore symptom-level associations between smoking and PTSD among combustible cigarette (CC) and electronic cigarette (EC) users exposed to CSA and 2) to compare the differences manifested in two network structures between EC and CC users with CSA experiences. Methods: This cross-sectional study covers all 63 universities and colleges in Jilin province, China, from October 26 to November 18, 2021. A total of 117 769 students participated in this study, while 3479 young adults were exposed to CSA (3.62%, 95% CI = 3.50%-3.73%). Childhood sexual abuse, PTSD, and smoking symptoms were measured using the Childhood Trauma Questionnaire-Short Form (CTQ-SF), 10-item Trauma Screening Questionnaire (TSQ-10), and the 6-item Fagerstrom Test for Nicotine Dependence (FTND-6), respectively. In addition, network analysis was applied to analyse psychopathological symptoms between EC and CC users with CSA experiences. Both the edges and centralities were computed, and the network properties were compared among the two groups. Results: Four symptoms of PTSD (i.e. emotional cue reactivity, hypervigilance, nightmares, and difficulty concentrating) were both central and bridge symptoms between PTSD and smoking among EC and CC users with CSA experiences. Moreover, compared with CC users with CSA, there were significantly stronger associations between "nightmares" - "difficulty with restrictions" and "irritability / anger" - "more during wake up" among young EC users with CSA. Conclusions: The four symptoms (i.e. emotional cue reactivity, hypervigilance, nightmares, and difficulty concentrating) were keystones for treatments or interventions targeting these CSA victims with PTSD and smoking symptoms. Increasing efforts should be taken to restrict morning smoking among EC users with CSA. In addition, target interventions and strategies founded on these core symptoms and associations should be implemented to relieve the comorbid PTSD and smoking in EC and CC users with CSA experiences.

Mapping associations between anxiety and sleep problems among outpatients in high-altitude areas: a network analysis.

BACKGROUND: Anxiety and sleep problems are common comorbidities among outpatients living in high-altitude areas. Network analysis is a novel method to investigate the interaction and the association between symptoms across diverse disorders. This study used network analysis to investigate the network structure symptoms of anxiety and sleep problems among outpatients in high-altitude areas, and to explore the differences in symptom associations in various sex, age, educational levels and employment groups. METHODS: The data was collected from the Sleep Medicine Center of The First People's Hospital of Yunnan Province from November 2017 to January 2021 with consecutive recruitment (N = 11,194). Anxiety and sleep problems were measured by the Chinese version of the seven-item Generalized Anxiety Disorder Scale (GAD-7) and the Pittsburgh Sleep Quality Index (PSQI) respectively. Central symptoms were identified based on centrality indices and bridge symptoms were identified with bridge indices. The difference of network structures in various sex, age, educational levels and employment groups were also explored. RESULTS: Among all the cases, 6,534 (58.37%; 95% CI: 57.45-59.29%) reported experiencing anxiety (GAD-7 total scores ≥ 5), and 7,718 (68.94%; 95% CI: 68.08-69.80%) reported experiencing sleep problems (PSQI total scores ≥ 10). Based on the results of network analysis, among participants, "Nervousness", "Trouble relaxing", "Uncontrollable worry" were the most critical central symptoms and bridge symptoms within the anxiety and sleep problems network structure. The adjusted network model after controlling for covariates was significantly correlated with the original (r = 0.75, P = 0.46). Additionally, there were significant differences in edge weights in the comparisons between sex, age and educational levels groups (P < 0.001), while the employed and unemployed groups did not show significant differences in edge weights (P > 0.05). CONCLUSIONS: In the anxiety and sleep problems network model, among outpatients living in high-altitude areas, nervousness, uncontrollable worry, and trouble relaxing were the most central symptoms and bridge symptoms. Moreover, there were significant differences between various sex, age and educational levels. These findings can be used to provide clinical suggestions for psychological interventions and measures targeting to reduce symptoms that exacerbate mental health.

Validation of ESM1 Related to Ovarian Cancer and the Biological Function and Prognostic Significance.

Background: Ovarian cancer (OC), a serious gynecological malignant disease, remains an enormous challenge in early diagnosis and medical treatment. Based on the GEO and TCGA databases in R language, endothelial cell-specific molecule 1 (ESM1) was confirmed separately with the bioinformatic analysis tool. ESM1 has been demonstrated to be upregulated in multiple cancer types, but the oncogenic mechanism by which ESM1 promotes OC is still largely unknown. Methods: In this study, we used WGCNA and random survival forest variable screening to filter out ESM1 in OC differentially expressed genes (DEGs). Next, we confirmed the mRNA and protein levels of ESM1 in OC samples via PCR and IHC. The correlation between the ESM1 level and clinical data of OC patients was further confirmed, including FIGO stage, lymph node metastasis, and recurrence. The role of ESM1 in OC development was explored by several functional experiments in vivo and in vitro. Then, the molecular mechanisms of ESM1 were further elucidated by bioinformatic end experimental analysis. Results: ESM1 was significantly upregulated in OC and was positively correlated with PFS but negatively correlated with OS. ESM1 knockdown inhibited cell proliferation, apoptosis escape, the cell cycle, angiogenesis, migration and invasion in multiple experiments. Moreover, GSVA found that ESM1 was associated with the Akt pathway, and our results supported this prediction. Conclusion: ESM1 was closely correlated with OC development and progression, and it could be considered a novel biomarker and therapeutic target for OC patients.

Identification of Biomarkers Related to CD8+ T Cell Infiltration With Gene Co-expression Network in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LSCC) is one of the most common types of lung cancer in adults worldwide. With the development of modern medicine, cancer treatment that harnesses the power of the immune system might be particularly effective for treating LSCC. In this research, LSCC expression data, which quantify the cellular composition of immune cells, were analyzed by weighted gene coexpression network analysis (WGCNA) and a deconvolution algorithm based on the Gene Expression Omnibus (GEO) database, and the results indicated a close relationship between LSCC and CD8+ T cells. Six hub genes (SYT3, METTL8, HSPB3, GFM1, ERLIN2, and CLCN2) were verified by gene-gene network and protein-protein interaction (PPI) network analyses. We found that the six hub genes were increased in cancer tissues and were closely correlated with cancer development and progression. After immune correlation analysis, METTL8 was selected as a prognostic biomarker. Finally, we found that the METTL8 levels were increased in multiple lung cancer cell lines and LSCC tissues. METTL8 inhibition could clearly induce G1 cell cycle arrest and suppress proliferation. Therefore, METTL8, which is related to CD8+ T cell infiltration, might be identified as a potential biomarker and gene therapy target in LSCC.

Electronic cigarette exposure on insulin sensitivity of ApoE gene knockout mice.

INTRODUCTION: The current study aimed to investigate the effects of electronic cigarettes on insulin sensibility in ApoE gene knockout mice. METHODS: In total, 48 male ApoE gene knockout mice were randomly divided into four exposure groups: 1) electronic cigarette (e-cigarette) containing 12 mg/mL of nicotine, 2) e-cigarette without nicotine (0mg), 3) traditional cigarette (cigarette), and 4) fresh air (control). The first three groups were exposed to the associated smoke for 18 weeks. The body weight was recorded regularly in the four groups. After the last exposure, the concentrations of lipids, hs-CRP and TNF-α in serum were detected and the effect of electronic cigarettes on insulin tolerance was measured. RESULTS: The levels of serum lipid, hs-CRP and TNF-α in the e-cigarette, 0mg and cigarette groups were significantly increased compared with those in the control group (p<0.05). Also, the insulin tolerance in the e-cigarette, 0mg and cigarette groups was significantly decreased compared to that in the control group (p<0.05). CONCLUSIONS: Electronic cigarettes showed comparable effects to traditional cigarettes in influencing the metabolic functions in ApoE gene knockout mice.

How does financial burden influence the crash rate among taxi drivers? A self-reported questionnaire study in China.

Objective: Taxis play an important role in the transportation system of China, but they have a relatively high accident rate. The current study discusses the driver's financial burden in the Chinese context and explores its correlation with working conditions, risky driving behavior, and other characteristics of taxi drivers who are involved in accidents.Method: A total of 2,391 taxi drivers from 29 companies in four Chinese cities were interviewed and then asked to complete a questionnaire concerning their socio-demographic characteristics, working conditions, risky driving behavior, and accident frequency during the previous two years. Given the increase in the management fee (measured in CNY) charged by taxi companies, the drivers were divided into three groups: the "less than 150" group, the" 150 to 180" group and the "over 180" group, where were named Group 1, Group 2 and Group 3, respectively. Finally, the zero-inflated Poisson model was used to investigate the factors that contributed to the accident rate for each group.Result: The significant factors that lead to accidents differed significantly for drivers with different levels of financial burden. First, most of the factors were weakly correlated with the crash rate among Group 1 drivers. Second, many factors related to working conditions and risky driving behavior were significant for drivers in Groups 2 and 3, while working hours and off-duty days were significant only for drivers in Group 3. Third, working hours were negatively correlated with accident rates for drivers in Group 3, and the drivers who suffered from the heaviest financial burden were most affected by fatigue and sleep problems.Conclusion: Financial burden is the root cause behind the propensity of taxi drivers to be involved in accidents. Taxi companies should find ways to reduce drivers' expenses, and new technologies, such as taxi-calling or location and navigation based on mobile applications, should be introduced into the traditional taxi industry.