Impact of social support on the resilience of youth: mediating effects of coping styles.

Background: Chinese youth are at high risk for depression with a significantly higher detection rate of depression risk than other age groups, which brings about a huge challenge to the mental health work of universities. Developing supportive resources that promote resilience against adverse environmental influences in high-risk groups is quite more urgent than medical treatment for firm diagnoses of mental issues that have developed into depression in the current background. Methods: A total of 665 university students in China completed self-reported questionnaires measuring psychological resilience, social support, and coping styles. The structural equation model testing on the goodness of fit of the theoretical framework was first performed. Descriptive statistics and Pearson's correlation analysis among social support, resilience, and coping styles were then conducted. At last, we tested the mediating role of coping styles. Results: Social support has a significant positive effect on the psychological resilience of the youth. Mixed coping and immature coping styles have significant negative impacts on both social support and resilience, while mature coping styles have a significant positive effect on social support and resilience. Mature and immature coping styles mediate the association between social support and resilience in youth. Conclusion: Based on stress theory, this study explores mechanisms that facilitate the development of resilience in young people with regard to social support and coping styles. The current research depicts an interventional perspective of building a social support network that guides the youth to adopt mature coping styles to enhance their resilience and facilitate their mental health.

Caveolin-1 deficiency alleviates palmitate-induced intracellular lipid accumulation and inflammation in pancreatic β cells

Lipotoxicity-induced pancreatic β cell damage is a strong predictor of type 2 diabetes mellitus (T2DM). Our previous work showed that Caveolin-1 (Cav-1) depletion decreased β-cell apoptosis and improved β-cell viability. Further microarray analysis indicated significant changes in the expression of genes related to fatty acid metabolism and inflammation. The objective of this study was to explore the role of Cav-1 in intracellular lipid accumulation and inflammation in β cells under lipotoxic conditions. Here, we established a β-cell-specific Cav-1 knockout (β-Cav-1 KO) mouse model and a CAV-1 depleted β cell line (NIT-1). We found that Cav-1 silencing significantly reduced palmitate (PA)-induced intracellular triglyceride (TG) accumulation and decreased proinflammatory factor expression in both the mouse and cell models. Further mechanistic investigation revealed that amelioration of lipid metabolism was achieved through the downregulation of lipogenic markers (SREBP-1c, FAS and ACC) and upregulation of a fatty acid oxidation marker (CPT-1). Meanwhile, decrease of inflammatory cytokines (IL-6, TNF-α, and IL-1β) secretion was found with the involvement of the IKKβ/NF-κB signaling pathways. Our findings suggest that Cav-1 is of considerable importance in regulating lipotoxicity-induced β-cell intracellular lipid accumulation and inflammation. (AU)

Caveolin-1 deficiency alleviates palmitate-induced intracellular lipid accumulation and inflammation in pancreatic β cells

Lipotoxicity-induced pancreatic β cell damage is a strong predictor of type 2 diabetes mellitus (T2DM). Our previous work showed that Caveolin-1 (Cav-1) depletion decreased β-cell apoptosis and improved β-cell viability. Further microarray analysis indicated significant changes in the expression of genes related to fatty acid metabolism and inflammation. The objective of this study was to explore the role of Cav-1 in intracellular lipid accumulation and inflammation in β cells under lipotoxic conditions. Here, we established a β-cell-specific Cav-1 knockout (β-Cav-1 KO) mouse model and a CAV-1 depleted β cell line (NIT-1). We found that Cav-1 silencing significantly reduced palmitate (PA)-induced intracellular triglyceride (TG) accumulation and decreased proinflammatory factor expression in both the mouse and cell models. Further mechanistic investigation revealed that amelioration of lipid metabolism was achieved through the downregulation of lipogenic markers (SREBP-1c, FAS and ACC) and upregulation of a fatty acid oxidation marker (CPT-1). Meanwhile, decrease of inflammatory cytokines (IL-6, TNF-α, and IL-1β) secretion was found with the involvement of the IKKβ/NF-κB signaling pathways. Our findings suggest that Cav-1 is of considerable importance in regulating lipotoxicity-induced β-cell intracellular lipid accumulation and inflammation. (AU)

Discovery of novel NSAID hybrids as cPLA2/COX-2 dual inhibitors alleviating rheumatoid arthritis via inhibiting p38 MAPK pathway.

A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 ± 0.25 µΜ) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA2, and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA2 and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA2/COX-2/PGE2 pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA2 and COX-2 play a role in their etiology.

Caveolin-1 deficiency alleviates palmitate-induced intracellular lipid accumulation and inflammation in pancreatic ß cells.

Lipotoxicity-induced pancreatic ß cell damage is a strong predictor of type 2 diabetes mellitus (T2DM). Our previous work showed that Caveolin-1 (Cav-1) depletion decreased ß-cell apoptosis and improved ß-cell viability. Further microarray analysis indicated significant changes in the expression of genes related to fatty acid metabolism and inflammation. The objective of this study was to explore the role of Cav-1 in intracellular lipid accumulation and inflammation in ß cells under lipotoxic conditions. Here, we established a ß-cell-specific Cav-1 knockout (ß-Cav-1 KO) mouse model and a CAV-1 depleted ß cell line (NIT-1). We found that Cav-1 silencing significantly reduced palmitate (PA)-induced intracellular triglyceride (TG) accumulation and decreased proinflammatory factor expression in both the mouse and cell models. Further mechanistic investigation revealed that amelioration of lipid metabolism was achieved through the downregulation of lipogenic markers (SREBP-1c, FAS and ACC) and upregulation of a fatty acid oxidation marker (CPT-1). Meanwhile, decrease of inflammatory cytokines (IL-6, TNF-α, and IL-1ß) secretion was found with the involvement of the IKKß/NF-κB signaling pathways. Our findings suggest that Cav-1 is of considerable importance in regulating lipotoxicity-induced ß-cell intracellular lipid accumulation and inflammation.

Simulated microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia.

Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity-induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca2+ overload, and the latter was found to be caused by increased activity of Ca2+ channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A-elicited Ca2+ influx. Supplementation of HC-067047, a specific antagonist of TRPV4, attenuated microgravity-induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity-induced shortening of primary cilia led to increased TRPV4 levels and Ca2+ influx. When primary cilia were protected by miR-129-3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity-induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity-induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca2+ overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts.

Pharmacokinetics, tissue distribution and excretion of six bioactive components from total glucosides picrorhizae rhizoma, as simultaneous determined by a UHPLC-MS/MS method.

Total glucosides picrorhizae rhizome (TGPR) is an innovative traditional Chinese medicine, which is a candidate drug for the treatment of nonalcoholic steatohepatitis (NASH). However, there is still lack of deep research on the behaviors of TGPR in vivo. In this study, a reliable, specific, and sensitive liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been constructed for simultaneous determination of picroside I, picroside II, vanillic acid, androsin, cinnamic acid and picroside IV, the major active constituents of TGPR, in rat various biological matrices (plasma, tissue, bile, urine and feces) using diphenhydramine hydrochloride and paeoniflorin as the internal standard. All biosamples were prepared using a simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a waters UHPLC® HSS T3 (100×2.1 mm, 1.8 µm) column. The mobile phase consisted of methanol: acetonitrile1(1:1, V/V) and 0.5 mM ammonium formate in water, was employed to separate six components from endogenous interferences. The components were detected with a triple quadrupole mass spectrometer using positive and negative ion multiple reaction monitoring (MRM) mode. The newly developed method was successfully applied to investigate the pharmacokinetics, tissue distribution and excretion of six components in rats. The pharmacokinetic results indicated that the six components in TGPR could be quickly absorbed and slowly eliminated and their bioavailability were less than 12.37%, which implied the poor absorption after intragastric dosing. For tissue distribution, the six components in TGPR were detected in liver and only androsin could penetrate the blood-brain barrier. Meanwhile, the excretion study demonstrated that vanillic acid was mostly excreted as prototype drugs and the remaining five components might be widely metabolized in vivo as the metabolites, the unconverted form was excreted mainly by feces route. The pharmacokinetics, tissue distribution and excretion characteristics of six bioactive components in TGPR were firstly revealed, which will provide references for further clinical application of TGPR as an anti-NASH drug.

Three-dimensional heterogeneous electro-Fenton system with reduced graphene oxide based particle electrode for Acyclovir removal.

New pollutant pharmaceutical and personal care products (PPCPs), especially antiviral drugs, have received increasing attention not only due to their increase in usage after the outbreak of COVID-19 epidemics but also due to their adverse impacts on water ecological environment. Electro-Fenton technology is an effective method to remove PPCPs from water. Novel particle electrodes (MMT/rGO/Fe3O4) were synthesized by depositing Fe3O4 nanoparticles on reduced graphene oxide modified montmorillonite and acted as catalysts to promote oxidation performance in a three-dimensional Electro-Fenton (3D-EF) system. The electrodes combined the catalytic property of Fe3O4, hydrophilicity of montmorillonite and electrical conductivity of graphene oxides, and applied for the degradation of Acyclovir (ACV) with high efficiency and ease of operation. At optimal condition, the degradation rate of ACV reached 100% within 120 min, and the applicable pH range could be 3 to 11 in the 3D-EF system. The stability and reusability of MMT/rGO/Fe3O4 particle electrodes were also studied, the removal rate of ACV remained at 92% after 10 cycles, which was just slightly lower than that of the first cycle. Potential degradation mechanisms were also proposed by methanol quenching tests and FT-ICR-MS.

ALDH2 rs671 and MTHFR rs1801133 polymorphisms are risk factors for arteriosclerosis in multiple arteries.

BACKGROUND: Arteriosclerosis in multiple arteries has long been associated with heightened cardiovascular risk. Acetaldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR) play an important role in the pathogenesis of arteriosclerosis by participating in the oxidation and reduction reactions in vascular endothelial cells. The purpose was to investigate the relationship of ALDH2 and MTHFR gene polymorphisms with arteriosclerosis in multiple arteries. METHODS: 410 patients with arteriosclerosis in single artery and 472 patients with arteriosclerosis in multiple arteries were included. The relationship between ALDH2 rs671 and MTHFR rs1801133 polymorphisms and arteriosclerosis in single artery and arteriosclerosis in multiple arteries was analyzed. RESULTS: The proportion of ALDH2 rs671 A allele (35.6% vs. 30.9%, P = 0.038) and MTHFR rs1801133 T allele (32.6% vs. 27.1%, P = 0.012) in patients with arteriosclerosis in multiple arteries was significantly higher than that in arteriosclerosis in single artery, respectively. The proportion of history of alcohol consumption in patients with ALDH2 rs671 G/G genotype was higher than those in ALDH2 rs671 G/A genotype and A/A genotype (P < 0.001). The results of logistic regression analysis indicated that ALDH2 rs671 A/A genotype (A/A vs. G/G: OR 1.996, 95% CI: 1.258-3.166, P = 0.003) and MTHFR rs1801133 T/T genotype (T/T vs. C/C: OR 1.943, 95% CI: 1.179-3.203, P = 0.009) may be independent risk factors for arteriosclerosis in multiple arteries (adjusted for age, sex, smoking, drinking, hypertension, and diabetes). CONCLUSIONS: ALDH2 rs671 A/A and MTHFR rs1801133 T/T genotypes may be independent risk factors for arteriosclerosis in multiple arteries.

Utility of Artificial Intelligence for Real-Time Anatomical Landmark Identification in Ultrasound-Guided Thoracic Paravertebral Block.

Thoracic paravertebral block (TPVB) is a common method of inducing perioperative analgesia in thoracic and abdominal surgery. Identifying anatomical structures in ultrasound images is very important especially for inexperienced anesthesiologists who are unfamiliar with the anatomy. Therefore, our aim was to develop an artificial neural network (ANN) to automatically identify (in real-time) anatomical structures in ultrasound images of TPVB. This study is a retrospective study using ultrasound scans (both video and standard still images) that we acquired. We marked the contours of the paravertebral space (PVS), lung, and bone in the TPVB ultrasound image. Based on the labeled ultrasound images, we used the U-net framework to train and create an ANN that enabled real-time identification of important anatomical structures in ultrasound images. A total of 742 ultrasound images were acquired and labeled in this study. In this ANN, the Intersection over Union (IoU) and Dice similarity coefficient (DSC or Dice coefficient) of the paravertebral space (PVS) were 0.75 and 0.86, respectively, the IoU and DSC of the lung were 0.85 and 0.92, respectively, and the IoU and DSC of the bone were 0.69 and 0.83, respectively. The accuracies of the PVS, lung, and bone were 91.7%, 95.4%, and 74.3%, respectively. For tenfold cross validation, the median interquartile range for PVS IoU and DSC was 0.773 and 0.87, respectively. There was no significant difference in the scores for the PVS, lung, and bone between the two anesthesiologists. We developed an ANN for the real-time automatic identification of thoracic paravertebral anatomy. The performance of the ANN was highly satisfactory. We conclude that AI has good prospects for use in TPVB. Clinical registration number: ChiCTR2200058470 (URL: http://www.chictr.org.cn/showproj.aspx?proj=152839 ; registration date: 2022-04-09).

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study.

BACKGROUND: Genetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population. METHODS: The study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed. RESULTS: The genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291-1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638-2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390-1.882, P < 0.001) may increase risk of hypertension. CONCLUSIONS: CYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

The role of phytomelatonin receptor 1-mediated signaling in plant growth and stress response.

Phytomelatonin is a pleiotropic signaling molecule that regulates plant growth, development, and stress response. In plant cells, phytomelatonin is synthesized from tryptophan via several consecutive steps that are catalyzed by tryptophan decarboxylase (TDC), tryptamine 5-hydroxylase (T5H), serotonin N-acyltransferase (SNAT), and N-acetylserotonin methyltransferase (ASMT) and/or caffeic acid-3-O-methyltransferase (COMT). Recently, the identification of the phytomelatonin receptor PMTR1 in Arabidopsis has been considered a turning point in plant research, with the function and signal of phytomelatonin emerging as a receptor-based regulatory strategy. In addition, PMTR1 homologs have been identified in several plant species and have been found to regulate seed germination and seedling growth, stomatal closure, leaf senescence, and several stress responses. In this article, we review the recent evidence in our understanding of the PMTR1-mediated regulatory pathways in phytomelatonin signaling under environmental stimuli. Based on structural comparison of the melatonin receptor 1 (MT1) in human and PMTR1 homologs, we propose that the similarity in the three-dimensional structure of the melatonin receptors probably represents a convergent evolution of melatonin recognition in different species.

Secreted MUP1 that reduced under ER stress attenuates ER stress induced insulin resistance through suppressing protein synthesis in hepatocytes.

Disturbed endoplasmic reticulum (ER) stress response driven by the excessive lipid accumulation in the liver is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Restoring metabolic homeostasis by targeting ER stress is a potentially therapeutic strategy for NAFLD. Here we aim to identify novel proteins or pathways involved in regulating ER stress response and therapeutic targets for alleviating NAFLD. Proteomic and transcriptomic analysis demonstrated that major urinary proteins (MUPs) were significantly reduced in the livers from NAFLD mouse models. Then we confirmed that MUP1, the major secreted form of MUPs, was reduced at mRNA and protein expression levels in hepatocytes both in vivo and in vitro under ER stress. We further illustrated that MUP1 protein levels in the urine were reduced in mice with NAFLD, which was reversed by GLP-1 receptor agonist treatment. To study the relationship between ER stress and MUP1 biology, our analysis demonstrated that MUP1 was misfolded and trapped in the ER under ER stress in vivo. Interestingly, we discovered that recombinant MUP1 treatment in hepatocytes increased calcium efflux from the ER, which resulted in transient ER stress response, including reduced protein synthesis. These responses facilitated the alleviation of chemical induced ER stress in hepatocytes, which was suggested as "pre-adaptive ER stress". Besides, recombinant MUP1 pretreatment also improved ER stress-induced insulin resistance in hepatocytes. Our findings revealed a novel and critical role of MUP1, and recombinant MUP1 or its potential derivates may serve as a promising therapeutic target for alleviating NAFLD.

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.

Examining the impact perceptual learning artificial-intelligence-based on the incidence of paresthesia when performing the ultrasound-guided popliteal sciatic block: simulation-based randomized study.

OBJECTIVE: To explore the impact of artificial-intelligence perceptual learning when performing the ultrasound-guided popliteal sciatic block. METHODS: This simulation-based randomized study enrolled residents who underwent ultrasound-guided sciatic nerve block training at the Department of Anesthesiology of Beijing Jishuitan Hospital between January 2022 and February 2022. Residents were randomly divided into a traditional teaching group and an AI teaching group. All residents attended the same nerve block theory courses, while those in the AI teaching group participated in training course using an AI-assisted nerve identification system based on a convolutional neural network instead of traditional training. RESULTS: A total of 40 residents were included. The complication rates of paresthesia during puncture in the first month of clinical sciatic nerve block practice after training were significantly lower in the AI teaching group than in the traditional teaching group [11 (4.12%) vs. 36 (14.06%), P = 0.000093]. The rates of paresthesia/pain during injection were significantly lower in the AI teaching group than in the traditional teaching group [6 (2.25%) vs. 17 (6.64%), P = 0.025]. The Assessment Checklist for Ultrasound-Guided Regional Anesthesia (32 ± 3.8 vs. 29.4 ± 3.9, P = 0.001) and nerve block self-rating scores (7.53 ± 1.62 vs. 6.49 ± 1.85, P < 0.001) were significantly higher in the AI teaching group than in the traditional teaching group. There were no significant differences in the remaining indicators. CONCLUSION: The inclusion of an AI-assisted nerve identification system based on convolutional neural network as part of the training program for ultrasound-guided sciatic nerve block via the popliteal approach may reduce the incidence of nerve paresthesia and this might be related to improved perceptual learning. CLINICAL TRIAL: CHiCTR2200055115 , registered on 1/ January /2022.

Chlorogenic acid enhances alveolar macrophages phagocytosis in acute respiratory distress syndrome by activating G protein-coupled receptor 37 (GPR 37).

BACKGROUND: Impaired alveolar macrophages phagocytosis can contribute to pathogenesis of acute respiratory distress syndrome (ARDS) and negatively impacts clinical outcomes. Chlorogenic acid (CGA) is a naturally occurring polyphenolic compound with potential anti-inflammatory and antioxidant bioactivities. Studies have shown that CGA plays a protective role in ARDS, however, the precise protective mechanism of CGA against ARDS, is still unclear. PURPOSE: The aim of this study was to investigate whether CGA enhances alveolar macrophages phagocytosis to attenuate lung injury during ARDS. METHODS: RAW264.7 cells were stimulated with lipopolysaccharides (100 µg/ml for 24 h) and treated with CGA (100, 200, and 400 µM CGA for 1 h) to measure pro-inflammatory cytokine levels, GPR37 expression and macrophages phagocytosis. Mouse models of ARDS induced by cecal ligation and perforation (CLP) surgery were treated with CGA (100 or 200 mg/kg) to investigate lung inflammatory injury and alveolar macrophages phagocytosis. Computational modeling was performed to examine potential binding sites of G protein-coupled receptor 37 (GPR37) with CGA, and the results were validated by interfering with the binding sites. RESULT: In vitro, CGA notably ameliorated inflammatory response and increased phagocytosis in lipopolysaccharides-induced RAW264.7 cells. In vivo, CGA administration significantly alleviated lung inflammatory injury, decreased the bacteria load in the lung, promoted alveolar macrophages phagocytosis and improved the survival rate in mice with CLP-induced ARDS. Moreover, CGA markedly upregulated the expression of GPR37 in vivo and in vitro. However, the protective effect of CGA against ARDS were reversed after silencing the expression of GPR37. CONCLUSION: CGA has a protective effect against ARDS and may enhance alveolar macrophages phagocytosis and attenuate lung inflammatory injury by upregulating GPR37 expression.

Effective degradation of COVID-19 related drugs by biochar-supported red mud catalyst activated persulfate process: Mechanism and pathway.

With the global spread of the COVID-19 pandemic, the water pollution caused by extensive production and application of COVID-19 related drugs has aroused growing attention. Herein, a novel biochar-supported red mud catalyst (RM-BC) containing abundant free hydroxyl groups was synthesized. The RM-BC activated persulfate process was firstly put forward to degrade COVID-19 related drugs, including arbidol (ARB), chloroquine phosphate, hydroxychloroquine sulfate, and acyclovir. Highly effective removal of these pharmaceuticals was achieved and even 100% of ARB was removed within 12 min at optimum conditions. Mechanism study indicated that SO4 •- and HO• were the predominant radicals, and these radicals were responsible for the formation of DMPOX in electron spin resonance experiments. Fe species (Fe0 and Fe3O4) and oxygen-containing functional groups in RM-BC played crucial roles in the elimination of ARB. Effects of degradation conditions and several common water matrices were also investigated. Finally, the degradation products of ARB were identified by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and possible degradation pathways were proposed. This study demonstrated that RM-BC/PS system would have great potential for the removal of COVID-19 related drug residues in water by the catalyst synthesized from the solid waste.

The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress.

OBJECTIVE: Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS. METHODS: Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis. RESULTS: Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody. CONCLUSION: The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.

Inhibitory Effects of Macelignan on Tau Phosphorylation and Aß Aggregation in the Cell Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder mainly affecting old population. In this study, two Tau overexpressing cell lines (SH-SY5Y/Tau and HEK293/Tau), N2a/SweAPP cell line, and 3× Transgene (APPswe/PS1M146V/TauP301L) mouse primary nerve cell lines were used as AD models to study the activity and molecular mechanism of macelignan, a natural compound extracted from Myristica fragrans, against AD. Our study showed that macelignan could reduce the phosphorylation of Tau at Thr 231 site, Ser 396 site, and Ser 404 site in two overexpressing Tau cell lines. It also could decrease the phosphorylation of Tau at Ser 404 site in mouse primary neural cells. Further investigation of its mechanism found that macelignan could reduce the phosphorylation of Tau by increasing the level of autophagy and enhancing PP2A activity in Tau overexpressing cells. Additionally, macelignan could activate the PERK/eIF2α signaling pathway to reduce BACE1 translation, which further inhibits the cleavage of APP and ultimately suppresses Aß deposition in N2a/SweAPP cells. Taken together, our results indicate that macelignan has the potential to be developed as a treatment for AD.

Physiological and Molecular Changes in Cherry Red Tobacco in Response to Iron Deficiency Stress.

The genotype CR60 is a spontaneous Cherry Red variant (containing granular red dapples on flue-cured leaves) of the Yunyan 87 (Y87) tobacco; it accumulates higher concentration of iron (Fe) in leaves than Y87, but the physiological differences between them remain largely unknown. We investigated the physiological and molecular mechanisms of CR60 in response to Fe deficiency under hydroponic conditions. Our results showed no significant phenotypic difference between Y87 and CR60 at optimal (40 µM) and high Fe (160 and 320 µM) concentrations. By contrast, CR60 exhibited higher tolerance to Fe deficiency (0 µM) than Y87, as shown by higher concentrations of chlorophyll in CR60 leaves after 21-day Fe-deficiency stress. Transcriptome profiling coupled with RT-PCR analyses found that the expression of IRT1 and several genes associated with chlorophyll biosynthesis and photosynthesis (e.g., PRO, GSA, FD1, PsbO, and PC) was higher in CR60 than Y87. These results indicated that CR60 maintains sufficient Fe uptake, chlorophyll biosynthesis and photosynthetic rate when subjected to Fe starvation.