Feasibility and effectiveness study of applying a hallucinogen harm reduction and integration model to a mindfulness thinking intervention using virtual reality: A randomized controlled trial.

Objective: The purpose of this study was to investigate whether a virtual reality (VR) program designed and developed based on the hallucinogenic harm reduction and integration (PHRI) clinical model could be more effective in guiding positive thinking training, improving positive thinking awareness and ability, and, to some extent, facilitating personal efficacy and emotional state compared to a traditional VR program that places users in a virtual natural ecological environment to guide positive thinking training. We also sought to understand the factors that may influence the effectiveness of VR interventions and user experience. Method: Seventy-six randomly recruited participants were divided into a control group and an experimental group of 38 participants, each according to a random number table, and were trained in VR meditation for eight weeks. The experimental group used a PHRI-based mindfulness program, while the control group used a traditional mindfulness meditation program. We used The Mindful Attention Awareness Scale and the PAD emotional three-dimensional scale to assess the level of state mindfulness and changes in the emotional state before and at the end of the experiment. The Immersive Tendencies Questionnaire measured the user's sense of presence and immersion in the virtual environment. The Five Facet Mindfulness Questionnaires and the Depression Anxiety and Stress Scale (DASS-21) were used at the baseline assessment stage before and at the 4-week follow-up after the experiment to assess the change in trait mindfulness levels due to the mindfulness training. The Five Facet Mindfulness Questionnaires and the DASS-21 were used to assess changes in mindfulness and mental health trait levels. Results: At the end of the experiment, the MMSQ score was significantly lower in the control group than in the experimental group, while the ITQ score was significantly higher than in the experimental group, and both scores were statistically significant (p < 0.05). In the follow-up assessment four weeks after the end of the experiment, the FFMQ-15 score and the DASS-21 were significantly and statistically higher in the experimental group than in the control group (p < 0.05). Since the scores of the PAD scale did not obey a normal distribution, we used the Wilcoxon signed-rank test to assess the results, which proved that the experimental group had higher levels of emotional activation and arousal. Conclusion: The VR positive thinking program developed based on PHRI can significantly increase the positive thinking state and emotional arousal and activation of the general population participants but does not directly lead to the growth of positive emotions. Moreover, this detached psychedelic scene brings users a weaker sense of presence and presence than traditional natural space scenes. Furthermore, it does not bring any intense simulator motion sickness symptoms. These findings suggest that VR programs developed based on PHRI have a more positive facilitation effect on the positive state and that this increase lasts longer than conventional VR-positive programs.

Highly Promiscuous Flavonoid Di-O-glycosyltransferases from Carthamus tinctorius L.

Safflower (Carthamus tinctorius L.) has been recognized for its medicinal value, but there have been limited studies on the glycosyltransferases involved in the biosynthesis of flavonoid glycosides from safflower. In this research, we identified two highly efficient flavonoid O-glycosyltransferases, CtOGT1 and CtOGT2, from safflower performing local BLAST alignment. By constructing a prokaryotic expression vector, we conducted in vitro enzymatic reactions and discovered that these enzymes were capable of catalyzing two-step O-glycosylation using substrates such as kaempferol, quercetin, and eriodictyol. Moreover, they exhibited efficient catalytic activity towards various compounds, including flavones (apigenin, scutellarein), dihydrochalcone (phloretin), isoflavones (genistein, daidzein), flavanones (naringenin, glycyrrhizin), and flavanonols (dihydrokaempferol), leading to the formation of O-glycosides. The broad substrate specificity of these enzymes is noteworthy. This study provides valuable insights into the biosynthetic pathways of flavonoid glycosides in safflower. The discovery of CtOGT1 and CtOGT2 enhances our understanding of the enzymatic processes involved in synthesizing flavonoid glycosides in safflower, contributing to the overall comprehension of secondary metabolite biosynthesis in this plant species.

Identification of the Roles of Coagulation-Related Signature and its Key Factor RABIF in Hepatoma Cell Malignancy.

BACKGROUND: Hepatoma is a high morbidity and mortality cancer, and coagulation is a potential oncogenic mechanism for hepatoma development. OBJECTIVE: In this study, we aimed to reveal the role of coagulation in hepatoma. METHODS: We applied the LASSO to construct a coagulation-related risk score (CRS) and a clinical nomogram with independent validation. The heterogeneity of various aspects, including functional enrichment, SNV, CN, immunocyte infiltration, immune pathways, immune checkpoint, and genomic instability indexes, was evaluated. Besides, the prognostic value of the CRS genes was tested. We selected the critical risky gene related to coagulation from the LASSO coefficients, for which we applied transwell and clone formation assays to confirm its roles in hepatoma cell migration and clone formation ability, respectively. RESULTS: The CRS and the nomogram predicted patients' survival with good accuracy in both two datasets. The high-CRS group was associated with higher cell cycle, DNA repair, TP53 mutation rates, amplification, and lower deletion rates at chromosome 1. For immunocyte infiltration, we noticed increased Treg infiltration and globally upregulated immune checkpoints and genomic instability indexes. Additionally, every single CRS gene affected the patient's survival. Finally, we observed that RABIF was the riskiest gene in the CRS. Its knockdown suppressed hepatoma cell migration and clone formation capability, which could be rescued by RABIF overexpression. CONCLUSION: We built a robust CRS with great potential as a prognosis and immunotherapeutic indicator. Importantly, we identified RABIF as an oncogene, promoting hepatoma cell migration and clone formation, revealing underlying pathological mechanisms, and providing novel therapeutic targets for hepatoma treatment.

Depression is associated with heart failure in patients with type 2 diabetes mellitus.

Background: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of heart failure (HF). Depression, a common comorbidity of T2DM, may further increase the risk of heart failure (HF). We investigated the association between depression and incident HF in patients with T2DM. Methods and results: Depressive symptoms were assessed in the ACCORD Health-Related Quality of Life study participants at baseline, 12, 36, and 48 months using the nine-item Patient Health Questionnaire (PHQ-9). The severity of depressive symptoms was categorized as none (0-4 points), mild (5-9 points), or moderate-severe (10-24 points). Cox regression with PHQ-9 as a time-dependent covariate was used to assess the association between depression and incident HF. During the median follow-up of 8.1 years, 104 participants developed HF (incidence: 7.1/1,000 person-years). Half of the participants with moderate-severe depression were relieved and a significant percentage of participants without depression or with mild depression worsened to mild or moderate-severe depression during the follow-up period, respectively. Each unit increase in the PHQ-9 score was associated with a 5% higher risk of HF (hazard ratio [HR]:1.05, 95% confidence interval [CI]: 1.01-1.10). Patients with depression ever (HR: 2.23, 95% CI: 1.25-3.98) or persistent depression (HR: 2.13, 95% CI: 1.05-4.44) had a higher risk of HF than those without depression ever. Conclusion: Depressive symptoms change greatly in T2DM patients, depressive symptoms are an independent risk factor for HF. These results reinforce the importance of continuous evaluation and management of mental health status in T2DM patients with high HF risk.

Comparative effectiveness of school-based exercise interventions on physical fitness in children and adolescents: a systematic review and network meta-analysis.

Background: Schools provide a favorable setting for health education, however, the most effective school-based exercise mode for improving physical fitness remains unclear. This network meta-analysis was designed to assess and rank the comparative efficacy of six exercise modalities on physical fitness indicators in a school-based setting. Methods: An online search of the Web of Science, PubMed, SPORTDiscus, and Scopus databases was conducted. Randomized and quasi-randomized controlled trials were considered. Outcomes included measures of anthropometry and body composition, muscular fitness, and cardiorespiratory fitness. Data were pooled with a random effects model using the frequentist framework. Results: A total of 66 studies with 8,578 participants (48% girls) were included. High-intensity interval training was the most effective intervention reducing body mass index (mean difference (MD) = -0.60 kg·m-2, 95% confidence interval (95%CI) = -1.04 to -0.15, p = 0.009), elevating VO2max (MD = 3.59 mL·kg-1·min-1, 95% CI = 2.45 to 4.74, p < 0.001), and 20-meter sprint performance (MD = -0.35 s, 95% CI = -0.55 to -0.14, p = 0.001). Aerobic training had the highest probability of reducing waist circumference (standardized mean difference (SMD) = -0.60, 95% CI = -0.88 to -0.32, p < 0.001). Active video games emerged as a promising modality for improving countermovement jump (MD = 2.43 cm, 95% CI = 0.06 to 4.80, p = 0.041) and shuttle running performance (SMD = 0.86, 95% CI = 0.29 to 1.43, p = 0.003). Strength training was the best exercise mode for improving standing long jump performance (SMD = 1.03, 95% CI = 0.07 to 1.98, p = 0.035) while combined training was rated the first for decreasing body fat percent (MD = -2.56%, 95% CI = -4.73 to -0.40, p = 0.022) and increasing push-up repetitions (SMD = 3.59, 95% CI = 0.81 to 6.37, p = 0.012). Conclusion: School-based exercise interventions have multiple effects on physical fitness. The findings of this study will help to inform physical education teachers and coaches how best to deliver exercise programs in a school setting. Since the study was limited by the original research, the conclusions will require further verification using high-quality randomized controlled trials. Systematic Review Registration: PROSPERO, Identifier: CRD42023401963.

Preparation of chitosan/retinoic acid @ nanocapsules/TiO2 self-cleaning one-dimensional photonic crystals and the study of the visual detection of acute promyelocytic leukemia.

Sample exposure to air during optical detection leads to the widespread dispersal of microorganisms in the air, posing a health threat to patients and healthcare workers and potentially causing numerous nosocomial infections. In this study, a TiO2/CS-nanocapsules-Va visualization sensor was developed by alternatively spin-coating TiO2, CS and nanocapsules-Va. The uniformly distributed TiO2 can endow the visualization sensor with good photocatalytic performance, and the nanocapsules-Va can bind specifically to the antigen and change its volume. The research results showed that the visualization sensor cannot only detect acute promyelocytic leukemia conveniently, quickly and accurately, but also kill bacteria, decompose organic residues in blood samples under the influence of sunlight, and have an extensive application prospect in substance detection and disease diagnosis.

Complex Interplay Between Metabolism and CD4+ T-Cell Activation, Differentiation, and Function: a Novel Perspective for Atherosclerosis Immunotherapy.

Atherosclerosis is a complex pathological process that results from the chronic inflammatory reaction of the blood vessel wall and involves various immune cells and cytokines. An imbalance in the proportion and function of the effector CD4+ T-cell (Teff) and regulatory T-cell (Treg) subsets is an important cause of the occurrence and development of atherosclerotic plaques. Teff cells depend on glycolytic metabolism and glutamine catabolic metabolism for energy, while Treg cells mainly rely on fatty acid oxidation (FAO), which is crucial for determining the fate of CD4+ T cells during differentiation and maintaining their respective immune functions. Here, we review recent research achievements in the field of immunometabolism related to CD4+ T cells, focusing on the cellular metabolic pathways and metabolic reprogramming involved in the activation, proliferation, and differentiation of CD4+ T cells. Subsequently, we discuss the important roles of mTOR and AMPK signaling in regulating CD4+ T-cell differentiation. Finally, we evaluated the links between CD4+ T-cell metabolism and atherosclerosis, highlighting the potential of targeted modulation of CD4+ T-cell metabolism in the prevention and treatment of atherosclerosis in the future.

The effect of hotel employee resilience during COVID-19: The moderation role of perceived risk and challenge stressors.

The effect of hotel employee resilience during major crises lacks sufficient empirical investigation. This research aimed to develop a conceptual model of hotel employee resilience effects on turnover intentions and service quality with belief restoration as mediation and challenge stressors and perceived risk as moderation variables. A questionnaire survey was conducted with 28 star-rated hotels (including two 3-star, fifteen 4-star, and eleven 5-star hotels) in southeastern, northeastern, central, and western China against the background of the COVID-19 pandemic, and with operational (e.g., front office, food and beverage, housekeeping) and administrative (e.g., human resource, sales, finance) departments. A total of 1318 valid questionnaires were collected. The results showed that: (1) employee resilience predicted employee service quality positively and turnover intentions negatively; (2) belief restoration partially mediated the impact of employee resilience on service quality and turnover intentions; and (3) perceived risk and challenge stressors had diverse moderation effects (e.g., U-shaped, linear) in the impacts of resilience, and they were important external and internal situational factors that influenced the impact of employee resilience. This research revealed the effects and situational conditions of hotel employee resilience during a major crisis, which provides a theoretical basis for establishing hotel crisis response strategies.

Genetically engineered mesenchymal stem cells with dopamine synthesis for Parkinson's disease in animal models.

Although striatal delivery of three critical genes for dopamine synthesis by viruses is a potential clinical approach for treating Parkinson's disease (PD), the approach makes it difficult to finely control dopamine secretion amounts and brings safety concerns. Here, we generate genetically engineered mesenchymal stem cells encoding three critical genes for dopamine synthesis (DOPA-MSCs). DOPA-MSCs retain their MSC identity and stable ability to secrete dopamine during passaging. Following transplantation, DOPA-MSCs reinstate striatal dopamine levels and correct motor function in PD rats. Importantly, after grafting into the caudate and putamen, DOPA-MSCs provide homotopic reconstruction of midbrain dopamine pathways by restoring striatal dopamine levels, and safely and long-term (up to 51 months) correct motor disorders and nonmotor deficits in acute and chronic PD rhesus monkey models of PD even with advanced PD symptoms. The long-term benefits and safety results support the idea that the development of dopamine-synthesized engineered cell transplantation is an important strategy for treating PD.

The influence of arts engagement on the mental health of isolated college students during the COVID-19 outbreak in China.

Objectives: The COVID-19 pandemic significantly impacted the mental health of college students. This study aimed to investigate the buffering effect of arts engagement on anxiety and resilience in college students during the COVID-19 pandemic. Study design: A cross-sectional study. Methods: The data were collected via an online survey during a wave of SARS-CoV-2 infections in Shanghai (March 15 to April 15, 2022). In total, 2,453 college students throughout China reported general anxiety symptom levels (according to the GAD-7), resilience (according to the Connor-Davidson Resilience Scale), frequency of receptive arts engagement in the previous year, exposure to risk situations, and behavioral changes due to the pandemic. Results: During the current stage of the pandemic, 43.7% of college students suffered from varying degrees of anxiety, and 2.6% showed severe anxiety. Gender and learning stage were not associated with anxiety. Hierarchical regression analysis showed that the decision to return to academic institution, the degree of exposure to COVID-19, and the frequency of accepting art participation and resilience could significantly predict the anxiety level of college students. Gender, study stage, behavioral changes arising from COVID-19, and exposure to COVID-19 significantly predict the resilience level of college students. There was an association between high frequency music activities, reading activities and low anxiety level (p < 0.001). There was an association between high frequency digital art, music activities, reading and high resilience (p < 0.01). Conclusions: Arts engagement appears to help students cope with mental health problems and those at risk. Policymakers should encourage college students to participate in art activities, especially in the context of social distancing.

Locoregional progression-free survival of bone metastases from differentiated thyroid cancer.

To evaluate the locoregional progression-free survival (LPFS) of bone metastatic lesions from differentiated thyroid cancer (DTC) after radioiodine therapy (RAIT) and to define its influencing factors, we performed a retrospective cohort analysis of 89 patients with bone metastases from DTC who received RAIT in our department over a 17-year period. The median follow-up time was calculated using the reverse Kaplan-Meier method. The log-rank test and a multivariate Cox proportional hazards regression model were performed in the analysis of prognostic indicators for LPFS. In this research, the median follow-up time for all patients was 47 (95% CI, 35.752-58.248) months, and that for patients with no progression was 42 months. The longest follow-up time was 109 months. The median LPFS time was 58 (95% CI, 32.602-83.398) months, and the 3- and 5-year LPFS probabilities were 57.8 and 45.1%, respectively. Multivariate analysis revealed bone structural changes as an independent risk factor for LPFS (P= 0.004; hazard ratio, 49.216; 95% CI, 3.558-680.704). Furthermore, the non-total-lesion uptake subgroup presented a worse LPFS than the total-lesion uptake subgroup in patients with structural bone lesions (P = 0.027). RAIT can improve the LPFS of radioiodine-avid bone metastases from DTC, especially those without bone structural changes.

New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy.

Pathological cardiac hypertrophy is a process of abnormal remodeling of the myocardium in response to stress overload or ischemia that results in myocardial injury, which is an independent risk factor for the increased morbidity and mortality of heart failure. Elevated circulating glucocorticoids (GCs) levels are associated with an increased risk of pathological cardiac hypertrophy, but the exact role remains unclear. In the heart, GCs exerts physiological and pharmacological effects by binding the glucocorticoid receptor (GR, NR3C1). However, under the state of tissue damage or oxidative stress, GCs can also bind the closely related mineralocorticoid receptor (MR, NR3C2) to exert a detrimental effect on cardiac function. In addition, the bioavailability of GCs at the cellular level is mainly regulated by tissue-specific metabolic enzymes 11ß-hydroxysteroid dehydrogenases (11ß-HSDs), including 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and type 2 (11ß-HSD2), which catalyze the interconversion of active GCs. In this paper, we provide an overview of GC signaling and its physiological roles in the heart and highlight the dynamic and diverse roles of GC signaling dysregulation, mediated by excessive ligand GCs levels, GR/MR deficiency or overexpression, and local GCs metabolic disorder by 11ß-HSDs, in the pathology of cardiac hypertrophy. Our findings will provide new ideas and insights for the search for appropriate intervention targets for pathological cardiac hypertrophy.

Transcriptome Analysis of Colletotrichum fructicola Infecting Camellia oleifera Indicates That Two Distinct Geographical Fungi Groups Have Different Destructive Proliferation Capacities Related to Purine Metabolism.

Anthracnose, caused by Colletotrichum spp., is a significant disease affecting oil tea (Camellia oleifera Abel.). Extensive molecular studies have demonstrated that Colletotrichum fructicola is the dominant pathogen of oil tea anthracnose in China. This study aims to investigate differences in molecular processes and regulatory genes at a late stage of infection of C. fructicola, to aid in understanding differences in pathogenic mechanisms of C. fructicola of different geographic populations. We compared the pathogenicity of C. fructicola from different populations (Wuzhishan, Hainan province, and Shaoyang, Hunan province) and gene expression of representative strains of the two populations before and after inoculation in oil tea using RNA sequencing. The results revealed that C. fructicola from Wuzhishan has a more vital ability to impact oil tea leaf tissue. Following infection with oil tea leaves, up-regulated genes in the strains from two geographic populations were associated with galactosidase activity, glutamine family amino acid metabolism, arginine, and proline metabolism. Additionally, up-regulated gene lists associated with infection by Wuzhishan strains were significantly enriched in purine metabolism pathways, while Shaoyang strains were not. These results indicate that more transcriptional and translational activity and the greater regulation of the purine metabolism pathway in the C. fructicola of the Wuzhishan strain might contribute to its stronger pathogenicity.

Soluble Epoxide Hydrolase Inhibitors Regulate Ischemic Arrhythmia by Targeting MicroRNA-1.

Background: Soluble epoxide hydrolase inhibitors (sEHis) inhibit the degradation of epoxyeicosatrienoic acids (EETs) in cells, and EETs have antiarrhythmic effects. Our previous experiments confirmed that t-AUCB, a preparation of sEHis, inhibited ischemic arrhythmia by negatively regulating microRNA-1 (miR-1), but its specific mechanism remained unclear. Aim: This study aimed to examine the role of serum response factor (SRF) and the PI3K/Akt/GSK3ß pathway in t-AUCB-mediated regulation of miR-1 and the interaction between them. Methods/Results: We used SRF small interfering RNA (siSRF), SRF small hairpin (shSRF) RNA sequence adenovirus, PI3K/Akt/GSK3ß pathway inhibitors, t-AUCB, and 14,15-EEZE (a preparation of EETs antagonists) to treat mouse cardiomyocytes overexpressing miR-1 and mice with myocardial infarction (MI). We found that silencing SRF attenuated the effects on miR-1 and its target genes KCNJ2 and GJA1 in the presence of t-AUCB, and inhibition of the PI3K/Akt/GSK3ß pathway antagonized the effects of t-AUCB on miR-1, KCNJ2, and GJA1, which were associated with PI3Kα, Akt, and Gsk3ß but not PI3Kß or PI3Kγ. Moreover, the PI3K/Akt/GSK3ß pathway was involved in the regulation of SRF by t-AUCB, and silencing SRF inhibited the t-AUCB-induced increases in Akt and Gsk3ß phosphorylation. Conclusions: Both the SRF and the PI3K/Akt/GSK3ß pathway are involved in the t-AUCB-mediated regulation of miR-1, and these factors interact with each other.

Long non-coding RNA TUG1 accelerates abnormal growth of airway smooth muscle cells in asthma by targeting the miR-138-5p/E2F3 axis.

Asthma is a chronic airway inflammatory disease. The present study aimed to explore the effect of the long non-coding RNA taurine-upregulated gene 1 (TUG1) on the viability and migration of airway smooth muscle cells (ASMCs) in asthma. Rat asthma models were constructed with ovalbumin sensitization and challenge and the level of serum immunoglobulin E (IgE) and the rates of inspiratory and expiratory resistance were measured. Reverse transcription-quantitative PCR was also performed to determine the expression levels of TUG1. Platelet-derived growth factor-BB (PDGF-BB)-treated ASMCs were then used as a cell model of asthma. The viability and migratory abilities of ASMCs were analysed with the MTT and Transwell assays. Additionally, a dual-luciferase reporter assay was used to confirm the relationship between TUG1 and microRNA (miR)-138-5p and between transcription factor E2F3 and miR-138-5p. The expression of TUG1, level of serum IgE, inspiratory resistance and expiratory resistance were clearly increased in the rat asthma model in comparison with controls. Knockdown of TUG1 the viability and migration of PDGF-BB-induced ASMCs and reduced the inspiratory and expiratory resistances. In addition, TUG1 functioned as a bait of miR-138-5p, and miR-138-5p modulated E2F3 expression. Knockdown of E2F3 hindered the abnormal growth of ASMCs. Moreover, miR-138-5p inhibition or E2F3 overexpression reversed the inhibitory effects of TUG1 knockdown on viability and migration of PDGF-BB-induced ASMCs. The TUG1/miR-138-5p/E2F3 regulatory axis appeared to play a critical role in accelerating the viability and migration of ASMCs and may therefore have a role in asthma.

Asymmetric Lipid Membranes under Shear Flows: A Dissipative Particle Dynamics Study.

We investigate the phase behavior of the asymmetric lipid membranes under shear flows, using the dissipative particle dynamics simulation. Two cases, the weak and strong shear flows, are considered for the asymmetric lipid microstructures. Three typical asymmetric structures, the membranes, tubes, and vesicle, are included in the phase diagrams, where the effect of two different types of lipid chain length on the formation of asymmetric membranes is evaluated. The dynamic processes are demonstrated for the asymmetric membranes by calculating the average radius of gyration and shape factor. The result indicates that different shear flows will affect the shape of the second type of lipid molecules; the shape of the first type of lipid molecules is more stable than that of the second type of lipid molecules. The mechanical properties are investigated for the asymmetric membranes by analyzing the interface tension. The results reveal an absolute pressure at the junctions of different types of particles under the weak shear flow; the other positions are almost in a state of no pressure; there is almost no pressure inside the asymmetric lipid membrane structure under the strong shear flow. The findings will help us to understand the potential applications of asymmetric lipid microstructures in the biological and medical fields.

Progressive changes in the major salivary gland after radioiodine therapy for differentiated thyroid cancer: a single-center retrospective ultrasound cohort study.

This study aimed to determine the prevalence of radioiodine-induced salivary gland damage by evaluating progressive changes in salivary glands using ultrasound. Four hundred forty-six patients with differentiated thyroid carcinoma who underwent total or near-total thyroidectomy and postoperative radioiodine therapy were retrospectively reviewed. From the first to the fifth follow-up visits, the positive rate of major salivary gland changes on ultrasound gradually increased from 2.0% to 33.0% (P<0.001) and possibly stabilized at the fifth visit (approximately 36 months). The first positive result was detected at an average of 20.78±8.72 months. Only 21 of the 161 positive cases eventually achieved negative ultrasound results (Fisher's test, P<0.001), and the 21 cases simply showed a coarse echotexure. In conclusion, ultrasound changes appeared late, and most of these changes were not reversed.

ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation.

Cancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.

Methotrexate can prevent cardiovascular events in patients with rheumatoid arthritis: An updated meta-analysis.

AIMS: The incidence of cardiovascular events (CVEs) in patients with rheumatoid arthritis (RA) is higher than that in people without RA. This may be because inflammation promotes the progression of atherosclerosis. Anti-inflammatory drugs might reduce the occurrence of CVEs in patients with RA. Methotrexate (MTX) is a conventional synthetic anti-rheumatic drug that is widely used in the treatment of RA. We performed a meta-analysis to determine whether MTX can prevent CVEs in RA patients. Then, we discussed the possibility of using MTX to prevent recurred CVEs in patients with coronary heart disease (CHD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library using the key words "methotrexate," "cardiovascular," "acute coronary syndrome," "coronary heart disease," "myocardial infarction," "angina pectoris," and "rheumatoid arthritis." The efficacy outcome was defined as a composite of CVEs, including stable angina, acute coronary syndrome, stroke, heart failure, and cardiac death. RESULTS: A total of 10 studies and 195,416 RA patients were included in our meta-analysis, and the effect size of relative risk (RR) was pooled using a fixed effect model. The results showed that MTX prevented CVEs in RA patients (RR: 0.798, 95% CI 0.726-0.876, P = .001, I2 = 27. 9%). CONCLUSION: MTX can prevent CVEs in RA patients, but there is not sufficient evidence for using MTX to treat patients with CHD.

Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer's disease mouse model.

There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer's disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer's disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer's disease.