STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth.

SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.

Blue light-mediated gene expression as a promising strategy to reduce antibiotic resistance in Escherichia coli.

The discovery of antibiotics has noticeably promoted the development of human civilization; however, antibiotic resistance in bacteria caused by abusing and overusing greatly challenges human health and food safety. Considering the worsening situation, it is an urgent demand to develop emerging nontraditional technologies or methods to address this issue. With the expanding of synthetic biology, optogenetics exhibits a tempting prospect for precisely regulating gene expression in many fields. Consequently, it is attractive to employ optogenetics to reduce the risk of antibiotic resistance. Here, a blue light-controllable gene expression system was established in Escherichia coli based on a photosensitive DNA-binding protein (EL222). Further, this strategy was successfully applied to repress the expression of ß-lactamase gene (bla) using blue light illumination, resulting a dramatic reduction of ampicillin resistance in engineered E. coli. Moreover, blue light was utilized to induce the expression of the mechanosensitive channel of large conductance (MscL), triumphantly leading to the increase of streptomycin susceptibility in engineered E. coli. Finally, the increased susceptibility of ampicillin and streptomycin was simultaneously induced by blue light in the same E. coli cell, revealing the excellent potential of this strategy in controlling multidrug-resistant (MDR) bacteria. As a proof of concept, our work demonstrates that light can be used as an alternative tool to prolong the use period of common antibiotics without developing new antibiotics. And this novel strategy based on optogenetics shows a promising foreground to combat antibiotic resistance in the future.

The Association between Cyberbullying Victimization and Depression among Children: A Moderated Mediation Model.

Cyberbullying victimization is becoming more prevalent and adversely affects mental health. This research explores the relationship between the two variables and the underlying mechanism, especially for children, as the impact of mental health in childhood might last a lifetime. Primary school students (N = 344; Mage = 9.90; 43.90% girls) completed self-report questionnaires regarding cyberbullying victimization, self-perceived social competence, optimism, and depression at school. Gender and grade were controlled as covariates. Depression was positively predicted by cyberbullying victimization, while self-perceived social competence played a partially mediating role. In addition, optimism directly and indirectly moderated the effects of cyberbullying victimization on depression. Specifically, the effects were stronger for children with low levels of optimism. Therefore, efforts to enhance children's self-perceived social competence and optimism may reduce their depression resulting from cyberbullying victimization.

Comparative analysis of biofilm characterization of probiotic Escherichia coli.

Biofilms are thought to play a vital role in the beneficial effects of probiotic bacteria. However, the structure and function of probiotic biofilms are poorly understood. In this work, biofilms of Escherichia coli (E. coli) Nissle 1917 were investigated and compared with those of pathogenic and opportunistic strains (E. coli MG1655, O157:H7) using crystal violet assay, confocal laser scanning microscopy, scanning electron microscopy and FTIR microspectroscopy. The study revealed significant differences in the morphological structure, chemical composition, and spatial heterogeneity of the biofilm formed by the probiotic E. coli strain. In particular, the probiotic biofilm can secrete unique phospholipid components into the extracellular matrix. These findings provide new information on the morphology, architecture and chemical heterogeneity of probiotic biofilms. This information may help us to understand the beneficial effects of probiotics for various applications.

Enhancing the Cooling Efficiency of Aluminum-Filled Epoxy Resin Rapid Tool by Changing Inner Surface Roughness of Cooling Channels.

In low-pressure wax injection molding, cooling time refers to the period during which the molten plastic inside the mold solidifies and cools down to a temperature where it can be safely ejected without deformation. However, cooling efficiency for the mass production of injection-molded wax patterns is crucial. This work aims to investigate the impact of varying surface roughness on the inner walls of the cooling channel on the cooling efficiency of an aluminum-filled epoxy resin rapid tool. It was found that the cooling time for the injection-molded products can be determined by the surface roughness according to the proposed prediction equation. Employing fiber laser processing on high-speed steel rods allows for the creation of microstructures with different surface roughness levels. Results demonstrate a clear link between the surface roughness of cooling channel walls and cooling time for molded wax patterns. Employing an aluminum-filled epoxy resin rapid tool with a surface roughness of 4.9 µm for low-pressure wax injection molding can save time, with a cooling efficiency improvement of approximately 34%. Utilizing an aluminum-filled epoxy resin rapid tool with a surface roughness of 4.9 µm on the inner walls of the cooling channel can save the cooling time by up to approximately 60%. These findings underscore the significant role of cooling channel surface roughness in optimizing injection molding processes for enhanced efficiency.

Prevalence and associated factors of depression, anxiety and stress among clinical therapists in China in the context of early COVID-19 pandemic.

Objectives: To study the socio-demographic characteristics and the prevalence of depression, anxiety, and stress among clinical therapists in China during the early Coronavirus disease 2019 (COVID-19) pandemic and to identify associated factors. Method: This cross-sectional study was part of a multicenter, nationally representative survey conducted through WeChat from January 2021 to March 2021. Data, including socio-demographics, health-related behaviors, and information on whether they participated in the frontline work of treating COVID-19, were collected anonymously. Respondents also completed the Depression Anxiety Stress Scales-21 (DASS-21). Results: In total, 396 clinical therapists in the selected hospitals completed the questionnaires, with a response rate of 89.0%. Respondents were predominantly female (77.3%). About 6.6% of the participants were current tobacco users, and 20.7% had participated in the frontline work of treating COVID-19. Overall, 22.0%, 17.9%, and 8.8% of participants were classified as having clinically meaningful depression, anxiety, and stress, respectively, based on DASS-21 scores. Multiple logistic regression in Model 1 and Model 2 showed that depression, anxiety, and stress were associated with regular physical activity and frequent insomnia (all, p < 0.05). In anxiety model 2, the associated factors for anxiety during the pandemic were identified as education (master's degree or more, OR=0.520; 95% CI=0.283-0.955), marital status (single, OR=2.064; 95% CI=1.022-4.168), tobacco use (OR=4.265; 95% CI=1.352-13.454), regular physical activity (OR=0.357; 95% CI=0.192-0.663), frequent insomnia (OR=6.298; 95% CI =2.522-15.729), and participation in the frontline work of treating COVID-19 (OR=3.179; 95% CI=1.697-5.954). The COVID-19 epidemic did not significantly increase the depression and stress levels among clinical therapists, but it did significantly increase anxiety levels. Conclusion: During the COVID-19 pandemic, depression, anxiety and stress were relatively common among clinical therapists in China. Regular physical activity and good sleep were important protective factors against emotional problems. Therefore, encouraging regular physical activity and actively addressing clinical therapists' sleep problems is beneficial to improving the ability to cope with negative emotions. The COVID-19 epidemic significantly increased anxiety, and awareness and interventions should be recommended to reduce anxiety among clinical therapists during the COVID-19 pandemic.

Engineering a Lactobacillus Lysine Riboswitch to Dynamically Control Metabolic Pathways for Lysine Production in Corynebacterium glutamicum.

Knock-out of genes of metabolic pathways is conventionally used in the metabolic engineering of microorganisms, but it is not applicable for genes of essential pathways. In order to avoid undesirable effects caused by gene deletion, it is attractive to develop riboswitches to dynamically control the metabolic pathways of microbial cell factories. In this regard, the aim of this study is to utilize the lysine riboswitch to control gene expressions of the biosynthetic pathways and by-pathways and thus improve lysine production in Corynebacterium glutamicum. To achieve this, a natural lysine riboswitch from Lactobacillus plantarum (LPRS) was first detected and then fused with RFP to test its functionality. After that, engineered lysine-activated (Lys-A) and lysine-repressed (Lys-R) riboswitches were successfully screened by dual genetic selection. Furthermore, the optimized A263 and R152 were applied to control the expression of aspartate kinase III and homoserine dehydrogenase in the lysine-producing strain C. glutamicum QW45, respectively. In contrast with QW45, the growth of the resulting A263-lysC mutant QW48 was similar to that of QW45; however, the growth of the resulting R357-hom mutant QW54 was slightly inhibited, indicating an inhibition of threonine biosynthesis caused by the riboswitch upon binding of intracellular lysine. Importantly, the lysine production of QW48 and QW54 was, respectively, 35% and 43% higher than that of the parent strain QW45, implying more metabolic flux directed into the lysine synthesis pathway. Finally, the engineered A263 and R357 were simultaneously applied to the same mutant QW55, which greatly improved lysine production. Thus, the approach demonstrated in this work could be principally used as a powerful tool to dynamically control any other undesired metabolic pathways.

Ultrafast Process Characterization of Laser-Induced Damage in Fused Silica Using Pump-Probe Shadow Imaging Techniques.

This study delves into the intricate dynamics of laser-induced damage in fused silica using a time-resolved pump-probe (TRPP) shadowgraph. Three typical ultra-fast processes, laser-induced plasma evolution, shockwave propagation and material fracture splashing, were quantitatively investigated. The results indicate that the diameter of plasma is proportional to the pulse laser energy and increases linearly during the pulse laser duration with an expansion rate of approximately 6 km/s. The maximum shockwave velocity on the air side is 9 km/s, occurring at the end of the pulse duration, and then rapidly decreases due to air resistance, reaching approximately 1 km/s around a 300 ns delay. After hundreds of nanoseconds, there is a distinct particle splashing phenomenon, with the splashing particle speed distribution ranging from 0.15 km/s to 2.0 km/s. The particle sizes of the splashing particles range from 4 µm to 15 µm. Additionally, the smaller the delay, the faster the speed of the splashing particles. Overall, TRPP technology provides crucial insights into the temporal evolution of laser-induced damage in fused silica, contributing to a comprehensive understanding essential for optimizing the performance and safety of laser systems.

The impact of lymphadenectomy on ovarian clear cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) shares treatment strategies with epithelial ovarian cancer (EOC). Due to OCCC's rarity, there's a lack of prospective studies on its surgery, resulting in heterogeneous and limited existing data. This study aims to clarify the prognostic significance of lymphadenectomy in OCCC patients. METHODS: We systematically searched Web of Science, Scopus, PubMed, and Google Scholar until July 2023 for studies investigating lymphadenectomy's effects on OCCC patients. We calculated pooled hazard ratios (HR) with 95% confidence intervals (CI). This study is registered in PROSPERO (CRD42021270460). RESULTS: Among 444 screened articles, seven studies (2883 women) met inclusion criteria. Our analysis revealed that lymphadenectomy significantly improved disease-specific survival (DSS) (HR = 0.76, 95%CI = 0.60-0.95, P = 0.02) and disease-free survival (DFS) (HR = 0.58, 95%CI = 0.34-0.99, P = 0.05). However, it did not significantly affect overall survival (OS) (HR = 0.80, 95%CI = 0.60-1.06, P = 0.12) or progression-free survival (PFS) (HR = 0.95, 95%CI = 0.64-1.42, P = 0.79). Notably, some earlier studies reported no survival benefit, warranting cautious interpretation. CONCLUSION: Lymphadenectomy does not significantly enhance OS and PFS for OCCC but does improve DFS and DSS. Tailoring treatment to individual patient profiles is imperative for optimal outcomes. Precise preoperative or intraoperative lymph node metastasis detection is essential for identifying candidates benefiting from lymphadenectomy. Collaborative international efforts and an OCCC database are pivotal for refining future treatment strategies.

Prenatal diagnosis of developmental and epileptic encephalopathy 9 with a 10.05-Mb microdeletion at Xq21.31q22.1 inherited from mother: A case report and literature review.

BACKGROUND: Developmental and epileptic encephalopathy 9 (DEE9) is characterized by early infantile seizures and mild-to-severe neuropsychiatric symptoms. Despite being an X-linked dominant disorder, DEE9 mainly affects heterozygous females or mosaic males, while hemizygous males are less affected. PCDH19 gene has been documented as the causative gene. METHODS: Karyotyping analysis and copy number variation sequencing (CNV-seq) were performed on a pregnant woman with epilepsy, together with her husband, son, and fetus. RESULTS: A disease-causing microdeletion, seq[GRCh37] del(X)(q21.31q22.1) (90310001-100360000), was identified in the pregnant woman and her female fetus. The microdeletion includes the entire PCDH19 gene and is classified as "pathogenic" according to the American College of Medical Genetics and Genomics guidelines. CONCLUSION: In this case study, we have not only identified the epilepsy type of the woman as DEE9 but have also made an unfavorable prognosis for her fetus. Our findings from this prenatal case provide valuable clinical resources for prenatal diagnosis and genetic counseling, while also implying the potential of CNV-seq as a viable method for uncovering PCDH19-related epilepsy.

The association between mental health symptoms and alcohol use among Chinese psychiatrists during the early stage of the COVID-19 pandemic.

AIM: To investigate the association between mental health symptoms, alcohol use, and alcohol misuse among psychiatrists in China during the early stage of the COVID-19 pandemic. METHODS: We conducted an online survey to collect data regarding mental health symptoms and alcohol use among psychiatrists in early 2020. The Depression Anxiety Stress Scale-Chinese Version (DASS-21) was used to assess depression, anxiety, and stress symptoms, and the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) was used to assess alcohol use. RESULTS: In total, 3774 psychiatrists completed the survey. AUDIT-C scores were positively correlated with DASS total and depression, anxiety, and stress subscales (total: r = 0.015, depression: r = 0.121, anxiety: r = 0.103, and stress: r = 0.096, all p < 0.05). Alcohol misuse was associated with male sex (OR = 4.754), cigarette smoking (OR = 2.441), administrative position (OR = 1.811), depression (OR = 1.489), and stress (OR = 1.504). Those who reported increased alcohol use during the pandemic were more likely to be male (OR = 2.174), endorse anxiety symptoms (OR = 2.386), or increased stress (OR = 2.402). CONCLUSIONS: Mental health symptoms were common among psychiatrists during the COVID-19 pandemic. Depression and stress symptoms were significantly associated with alcohol misuse. Anxiety and stress symptoms were associated with reported increases in alcohol use. Though a causal relationship cannot be inferred, our findings suggest that strategies promoting healthcare professionals' mental well-being should include alcohol use.

Evolution of intrinsic defects and ring structures on the surface of fused silica optics after CO2 laser conditioning.

Recently and interestingly, experiments show that the CO2 laser conditioning can significantly increase the laser-induced damage threshold (LIDT) of fused silica optics, but its underlying mechanism has not been clearly revealed. This Letter reports the experimental studies on the evolution of the intrinsic point defects and intrinsic ring structures on the surface of fused silica optics under the CO2 laser irradiation. The laser conditioning can effectively reduce the intrinsic defect contents in the surface layer of mechanically processed fused silica. However, the suppression effect of defects can be affected by the initial surface state. If there are micro-cracks on the component surface, the effect of the laser conditioning would be limited. The evolution of the intrinsic ring structures indicate that most of the intrinsic defects tend to recombine as short (Si-O)n ring structures during the laser healing of the micro-fractures. The observed recombination behavior and suppression of the intrinsic defects can help find out the reason for the increase of the LIDT of the fused silica optics.

Excessive Daytime Sleepiness and Insomnia Symptoms in Adolescents With Major Depressive Disorder: Prevalence, Clinical Correlates, and the Relationship With Psychiatric Medications Use.

OBJECTIVE: Excessive daytime sleepiness (EDS) and insomnia symptoms are common in patients with major depressive disorder (MDD), which might lead to a poor prognosis and an increased risk of depression relapse. The current study aimed to investigate the prevalence, and sociodemographic and clinical correlates of EDS and insomnia symptoms among adolescents with MDD. METHODS: The sample of this cross-sectional study included 297 adolescents (mean age=15.26 years; range=12-18 years; 218 females) with MDD recruited from three general and four psychiatric hospitals in five cities (Hefei, Bengbu, Fuyang, Suzhou, and Ma'anshan) in Anhui Province, China between January and August, 2021. EDS and insomnia symptoms, and clinical severity of depressive symptoms were assessed using Epworth sleepiness scale, Insomnia Severity Index, and Clinical Global Impression-Severity. RESULTS: The prevalence of EDS and insomnia symptoms in adolescents with MDD was 39.7% and 38.0%, respectively. Binary logistic regression analyses showed that EDS symptoms were significantly associated with higher body mass index (odds ratio [OR]=1.097, 95% confidence interval [CI]=1.027-1.172), more severe depressive symptoms (OR=1.313, 95% CI=1.028-1.679), and selective serotonin reuptake inhibitors use (OR=2.078, 95% CI=1.199-3.601). And insomnia symptoms were positively associated with female sex (OR=1.955, 95% CI=1.052-3.633), suicide attempts (OR=1.765, 95% CI=1.037-3.005), more severe depressive symptoms (OR=2.031, 95% CI=1.523-2.709), and negatively associated with antipsychotics use (OR=0.433, 95% CI=0.196-0.952). CONCLUSION: EDS and insomnia symptoms are common among adolescents with MDD. Considering their negative effects on the clinical prognosis, regular screening and clinical managements should be developed for this patient population.

Phytochromes transmit photoperiod information via the evening complex in Brachypodium.

BACKGROUND: Daylength is a key seasonal cue for animals and plants. In cereals, photoperiodic responses are a major adaptive trait, and alleles of clock genes such as PHOTOPERIOD1 (PPD1) and EARLY FLOWERING3 (ELF3) have been selected for in adapting barley and wheat to northern latitudes. How monocot plants sense photoperiod and integrate this information into growth and development is not well understood. RESULTS: We find that phytochrome C (PHYC) is essential for flowering in Brachypodium distachyon. Conversely, ELF3 acts as a floral repressor and elf3 mutants display a constitutive long day phenotype and transcriptome. We find that ELF3 and PHYC occur in a common complex. ELF3 associates with the promoters of a number of conserved regulators of flowering, including PPD1 and VRN1. Consistent with observations in barley, we are able to show that PPD1 overexpression accelerates flowering in short days and is necessary for rapid flowering in response to long days. PHYC is in the active Pfr state at the end of the day, but we observe it undergoes dark reversion over the course of the night. CONCLUSIONS: We propose that PHYC acts as a molecular timer and communicates information on night-length to the circadian clock via ELF3.

SREBF1/SREBP-1 concurrently regulates lipid synthesis and lipophagy to maintain lipid homeostasis and tumor growth.

Cholesterol is an essential structural component of the cell membrane, whereas excess cholesterol can be toxic and thus is stored in intracellular lipid droplets (LDs). Malignant tumor cells grow rapidly and require abundant cholesterol to build new membranes. How they maintain cholesterol homeostasis is largely unknown. We recently revealed that SREBF1/SREBP-1 (sterol regulatory element binding transcription factor 1), a key lipogenic transcription factor, plays a critical role in maintaining cholesterol homeostasis in tumor cells. We found that in addition to activation of de novo lipid synthesis and cholesterol uptake, SREBF1 also upregulates macroautophagy/autophagy to hydrolyze LDs, and increases the expression of NPC2, a lysosome cholesterol transporter, actively mobilizing LD-stored cholesterol and fatty acids to promote tumor growth. Our study demonstrates that SREBF1 controls the balance of lipid synthesis, uptake, storage and liberation to maintain lipid homeostasis for rapid tumor growth, while suggesting it as a very promising molecular target for cancer treatment.

High-Power Femtosecond Laser Processing of SiC Ceramics with Optimized Material Removal Rate.

Silicon carbide (SiC) ceramics are widely used as structural materials for various applications. However, the extraordinarily high hardness, brittleness, low material removal rate, and severe tool wear of these materials significantly impact the performance of conventional mechanical processing techniques. In this study, we investigated the influence of different parameters on the material removal rate, surface quality, and surface oxidation during the laser processing of SiC ceramic samples using a high-repetition-frequency femtosecond laser at a wavelength of 1030 nm. Additionally, an experimental investigation was conducted to analyze the effects of a burst mode on the material removal rate. Our results demonstrate that the surface oxidation, which significantly affects the material removal rate, can be effectively reduced by increasing the laser scanning speed and decreasing the laser scanning pitch. The material removal rate and surface quality are mainly affected by laser fluence. The optimal material removal rate is obtained with a laser fluence of 0.4 J/cm2 at a pulse width of 470 fs.

Characteristics of Chaotic Weak Reflection in Carbonate Fracture-Cavity Reservoirs: A Case Study of Ordovician Reservoirs in Block 10 of the Tahe Oilfield, Tarim Basin, China.

The identification of carbonate reservoirs is a critical task in oil and gas exploration. Chaotic weak reflection is an important type of reflection characteristic in carbonate reservoirs. Widespread distribution of chaotic weak reflection has been observed in the Ordovician Yijianfang Formation in the Tahe area. However, there is still a lack of systematic research on the distribution, characteristics, reservoir space, and reservoir types of chaotic weak reflection in the Tahe area. To address this issue, this study conducted a comprehensive analysis of multiscale data and found that chaotic weak reflections are distributed within 100 ms below the top interface of the Middle Ordovician. Seismic profiles exhibit a "string of pearls" with a "tail" or "pearl-like" widening feature. On well logs, all three porosity curves exhibit localized peaks, with increases in acoustic (AC) and compensated neutron (CNL) and decreases in density (DEN), while the deep and shallow lateral resistivity (RD, RS) curves show positive amplitude differences. In the FMI, they are represented by dark sinusoidal curves and dark small patches. Based on these response characteristics, two types of reservoir spaces are identified for chaotic weak reflections: high-angle vertical fractures and caves with heights less than 7 m, which can form independent reservoirs or fracture-cavity complexes. Three types of reservoirs are distinguished: fracture, cavity, and cavity-fracture types.

Analysis of the dynamic changes in gut microbiota in patients with different severity in sepsis.

BACKGROUND: The gastrointestinal tract contains a massive microbiota, and targeting the gut could be a potential intervention for sepsis. However, the interaction between sepsis and the intestinal microbiota is defined as an "incompletely understood bidirectional relationship". METHODS: This retrospective observational cohort study investigated the fecal microbiota of sepsis patients admitted to the Department of Critical Care Medicine of the Central Hospital of Wuhan, China, from May 2019 to January 2020. 14 septic patients were divided into the non-severe group and the severe group according to the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Herein, fecal samples were serially collected on admission, the third, fourth, and fifth days, and ICU discharge. The fecal microbiota was analyzed by 16S rRNA gene sequencing and its correlation with clinical parameters was evaluated. RESULTS: Bacteroidetes, Firmicutes, and Proteobacteria were dominant phyla at ICU admission, and fecal biodiversity was not significantly different between the non-severe group (APACHE II < 15) and the severe group (APACHE II > 15). However, the diversity of the gut microbiota was significantly lower at ICU discharge than that at ICU admission with the extension of treatment time. Further significant difference flora analysis (LEfSe) showed that the genera Veillonella and Ruminococcus were the most discriminant biomarkers at ICU admission in non-severe and severe patients, respectively, while Enterococcus was the most discriminant biomarker at ICU discharge in all septic patients. Of note, liver function tests, including ALT, AST, TBIL, and DBIL correlated with the prevalence of various bacterial genera. CONCLUSIONS: The diversity of the gut microbiota in patients with sepsis decreases dramatically during ICU stay, and there are distinct dynamic changes in gut microbiota among patients with different severity in sepsis.

SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells.

Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.

Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/ß-catenin pathway.

BACKGROUND: Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes, which can progress to cirrhosis. AIM: To evaluate the effect and mechanism of action annexin (Anx)A1 in liver fibrosis and how this could be targeted therapeutically. METHODS: CCl4 (20%) and active N-terminal peptide of AnxA1 (Ac2-26) and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice, and to detect expression of inflammatory factors, collagen deposition, and the role of the Wnt/ß-catenin pathway in hepatic fibrosis. RESULTS: Compared with the control group, AnxA1, transforming growth factor (TGF)-ß1, interleukin (IL)-1ß and IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased, which promoted collagen deposition and expression of α-smooth muscle actin (α-SMA), collagen type I and connective tissue growth factor (CTGF), and increased progressively with time. CCl4 induced an increase in TGF-ß1, IL-1ß and IL-6 in liver tissue of AnxA1 knockout mice, and the degree of liver inflammation and fibrosis and expression of α-SMA, collagen I and CTGF were significantly increased compared with in wild-type mice. After treatment with Ac2-26, expression of liver inflammatory factors, degree of collagen deposition and expression of a-SMA, collagen I and CTGF were decreased compared with before treatment. Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26. AnxA1 downregulated expression of the Wnt/ß-catenin pathway in CCl4-induced hepatic fibrosis. In vitro, lipopolysaccharide (LPS) induced hepatocyte and hepatic stellate cell (HSC) expression of AnxA1. Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation, decreased expression of α-SMA, collagen I and CTGF in HSCs, and inhibited expression of the Wnt/ß-catenin pathway after HSC activation. These therapeutic effects were inhibited by Boc2. CONCLUSION: AnxA1 inhibited liver fibrosis in mice, and its mechanism may be related to inhibition of HSC Wnt/ß-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.