Enhanced Interface Charge Carrier Transport of SnO2/CeO2 via Oxygen Vacancy Synergized Heterojunction for Triethylamine Sensing Property.

Efficient charge carrier transport characteristics are critical to achieving the excellent performance of metal-oxide semiconductor gas sensors. Herein, SnO2/CeO2 heterojunction layered nanosheets with abundant oxygen vacancies were successfully synthesized through a simple solvothermal assisted high-temperature calcination method. The synergistic effect of oxygen vacancies and heterojunctions promoting the charge carrier transport properties at the SnO2/CeO2 interface for the enhanced sensing properties of triethylamine (TEA) was highlighted. As a result, the optimized SnO2/CeO2 exhibits improved gas sensing performance at 173 °C to 50 ppm of TEA. These include high response (205), excellent selectivity, low detection limit, and good long-term stability. This enhanced gas sensing property of SnO2/CeO2 is mainly attributed to the fact that the heterojunction and oxygen vacancies act as dual active sites synergistically inducing electron transfer, thereby effectively modulating the transport properties of the interfacial charge carriers, and thus facilitate the surface reactions efficiently. In this work, the dual-engineering strategy of synergistic interaction of heterojunction and oxygen vacancies can provide new perspectives for the design of advanced gas sensing materials.

Cost-Effectiveness Analysis of Remimazolam and Midazolam in Goal-Guided Sedation in ICU.

Objective: This study aimed to compare the direct medication costs and clinical effectiveness of using remimazolam versus midazolam for goal-guided sedation therapy in the ICU patients. Methods: This randomized controlled study was conducted in the ICU of People's Hospital Affiliated to Shandong First Medical University. Eighty adult patients admitted to the ICU and requiring sedation were enrolled and randomly assigned in a 1:1 ratio to receive either remimazolam-based sedation (study group, n=40) or midazolam-based sedation (control group, n=40). The inclusion criteria for patient selection were age 18-80 years, requirement for mechanical ventilation, and an expected ICU stay of at least 24 hours. Patients with significant liver or kidney dysfunction, neurological disorders, or contraindications to the study drugs were excluded. The target sedation depth for both groups was a Ramsay Sedation Scale score of 3-4, which was maintained by titrating the infusion rates of remimazolam or midazolam as needed. Vital signs, sedation scores, and respiratory parameters were closely monitored throughout the sedation period. Results: The time to onset of sedation, time to reach the target sedation depth, time to awakening, and length of ICU stay were all significantly shorter in the remimazolam group compared to the midazolam group (P < .05 for all). The remimazolam group had a mean time to onset of 5.2 ± 1.8 minutes versus 8.9 ± 2.4 minutes in the midazolam group. The mean time to reach the target Ramsay Sedation Scale score of 3-4 was 12.6 ± 3.1 minutes in the remimazolam group compared to 18.4 ± 4.2 minutes in the midazolam group. The mean time to awakening was 10.2 ± 2.7 minutes in the remimazolam group versus 16.5 ± 3.9 minutes in the midazolam group. The remimazolam group also had a significantly shorter mean ICU length of stay of 5.1 ± 1.3 days compared to 7.8 ± 2.1 days in the midazolam group (P < .01). The remimazolam group had a significantly higher metabolic clearance rate compared to the midazolam group (P < .001). The Ramsay sedation scores and Wong-Baker FACES pain scores were also significantly lower in the remimazolam group throughout the sedation period (P < .01). There were no significant differences in heart rate between the two groups at any timepoint. However, the overall incidence of adverse events was significantly lower in the remimazolam group compared to the midazolam group (P < .05). Conclusion: This study demonstrated that the use of remimazolam-based goal-directed sedation in the ICU setting resulted in significantly faster onset of action, quicker achievement of the target sedation depth, shorter time to awakening, and shorter ICU length of stay compared to midazolam-based sedation. The remimazolam group also had a higher metabolic clearance rate, lower sedation and pain scores, and a lower incidence of adverse events.These findings suggest that remimazolam may provide advantages over midazolam for ICU sedation, potentially leading to improved patient comfort, more efficient utilization of ICU resources, and potentially better clinical outcomes. The rapid onset, titratability, and favorable safety profile of remimazolam make it a promising sedative agent that could help optimize sedation practices in the critical care setting. Further research is warranted to fully evaluate the impact of remimazolam on long-term patient-centered outcomes and overall healthcare costs in the ICU.

Seed development-related genes contribute to high yield heterosis in integrated utilization of elite autotetraploid and neo-tetraploid rice.

Introduction: Autotetraploid rice holds high resistance to abiotic stress and substantial promise for yield increase, but it could not be commercially used because of low fertility. Thus, our team developed neo-tetraploid rice with high fertility and hybrid vigor when crossed with indica autotetraploid rice. Despite these advances, the molecular mechanisms underlying this heterosis remain poorly understood. Methods: An elite indica autotetraploid rice line (HD11) was used to cross with neo-tetraploid rice, and 34 hybrids were obtained to evaluate agronomic traits related to yield. WE-CLSM, RNA-seq, and CRISPR/Cas9 were employed to observe endosperm structure and identify candidate genes from two represent hybrids. Results and discussion: These hybrids showed high seed setting and an approximately 55% increase in 1000-grain weight, some of which achieved grain yields comparable to those of the diploid rice variety. The endosperm observations indicated that the starch grains in the hybrids were more compact than those in paternal lines. A total of 119 seed heterosis related genes (SHRGs) with different expressions were identified, which might contribute to high 1000-grain weight heterosis in neo-tetraploid hybrids. Among them, 12 genes had been found to regulate grain weight formation, including OsFl3, ONAC023, OsNAC024, ONAC025, ONAC026, RAG2, FLO4, FLO11, OsISA1, OsNF-YB1, NF-YC12, and OsYUC9. Haplotype analyses of these 12 genes revealed the various effects on grain weight among different haplotypes. The hybrids could polymerize more dominant haplotypes of above grain weight regulators than any homozygous cultivar. Moreover, two SHRGs (OsFl3 and SHRG2) mutants displayed a significant reduction in 1000-grain weight and an increase in grain chalkiness, indicating that OsFl3 and SHRG2 positively regulate grain weight. Our research has identified a valuable indica autotetraploid germplasm for generating strong yield heterosis in combination with neo-tetraploid lines and gaining molecular insights into the regulatory processes of heterosis in tetraploid rice.

Association Between rs2278426 Polymorphism of the ANGPTL8 Gene and Polycystic Ovary Syndrome.

Purpose: To study the relationship between the single nucleotide polymorphism (SNP) rs2278426 in the angiopoietin-like protein 8 gene (ANGPTL8) and polycystic ovary syndrome (PCOS). Patients and methods: A total of 122 patients with PCOS and 108 controls were recruited for comparison of glucose, lipid, insulin, sex hormone, and ANGPTL8 levels. Polymerase chain reaction (PCR) and gene sequencing were performed for comparison of the frequency of the CC, CT, and TT rs2278426 genotypes and the rs2278426 allele distributions between the PCOS and control groups and between the obese and non-obese subgroups of the PCOS and control groups. Results: The frequency of the T allele was significantly higher in the PCOS group than that in the controls (P = 0.037). In the dominant genetic model, the proportion of the CT+TT genotype in the PCOS group was significantly higher than that in the controls (P = 0.047). Subgroup analysis demonstrated that the T allele proportion was significantly higher in obese PCOS group than obese control group (P = 0.027). PCOS with the CT+TT genotype had significantly higher body mass index (BMI; P = 0.001), triglyceride (TG; P = 0.005), homeostasis model assessment of insulin resistance (HOMA-IR; P = 0.035), testosterone (P = 0.041), and ANGPTL8 (P = 0.037) levels and significantly lower high-density lipoprotein (HDL) levels (P = 0.025) than PCOS with the CC genotype. Obese PCOS group with the CT+TT genotype had significantly higher TG (P = 0.015), luteinizing hormone (LH; P = 0.030), fasting insulin (FINS; P = 0.039), HOMA-IR (P = 0.018), and ANGPTL8 (P = 0.049) levels than obese PCOS group with the CC genotype. Conclusion: Polymorphisms of rs2278426 may induce glycolipid metabolic disorders by affecting ANGPTL8 levels and functions in Han Chinese females with obesity from the Shandong region, increasing the risk of PCOS in this population.

Yanggan Jiangmei Formula alleviates hepatic inflammation and lipid accumulation in non-alcoholic steatohepatitis by inhibiting the NF-κB/NLRP3 signaling pathway.

The role of NF-κB and the NLRP3 inflammasome in the chronic inflammatory microenvironment of non-alcoholic steatohepatitis (NASH) has been posited as crucial. The Yanggan Jiangmei Formula (YGJMF) has shown promise in ameliorating hepatic steatosis in NASH patients, yet its pharmacological mechanisms remain largely unexplored. This study was conducted to investigate the efficacy of YGJMF in NASH and to elucidate its pharmacological underpinnings. To simulate NASH both in vivo and in vitro, high-fat-diet (HFD) rats and HepG2 cells stimulated with free fatty acids (FFAs) were utilized. The severity of liver injury and lipid deposition was assessed using serum indicators, histopathological staining, micro-magnetic resonance imaging (MRI), and the liver-to-muscle signal intensity ratio (SIRL/M). Furthermore, a combination of enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), immunofluorescence, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting analyses was employed to investigate the NF-κB/NLRP3 signaling pathway and associated cytokine levels. The results from liver pathology, MRI assessments, and biochemical tests in rat models demonstrated YGJMF's significant effectiveness in reducing liver damage and lipid accumulation. Additionally, YGJMF markedly reduced hepatocyte inflammation by downregulating inflammatory cytokines in both liver tissue and serum. Furthermore, YGJMF was found to disrupt NF-κB activation, consequently inhibiting the assembly of the NLRP3 inflammasome in both the in vitro and in vivo models. The preliminary findings of this study suggest that YGJMF may alleviate hepatic steatosis and inhibit the NF-κB/NLRP3 signaling pathway, thereby exerting anti-inflammatory effects in NASH.

Silicon and iron nanoparticles protect rice against lead (Pb) stress by improving oxidative tolerance and minimizing Pb uptake.

Lead (Pb) is toxic to the development and growth of rice plants. Nanoparticles (NPs) have been considered one of the efficient remediation techniques to mitigate Pb stress in plants. Therefore, a study was carried out to examine the underlying mechanism of iron (Fe) and silicon (Si) nanoparticle-induced Pb toxicity alleviation in rice seedlings. Si-NPs (2.5 mM) and Fe-NPs (25 mg L-1) were applied alone and in combination to rice plants grown without (control; no Pb stress) and with (100 µM) Pb concentration. Our results revealed that Pb toxicity severely affected all rice growth-related traits, such as inhibited root fresh weight (42%), shoot length (24%), and chlorophyll b contents (26%). Moreover, a substantial amount of Pb was translocated to the above-ground parts of plants, which caused a disturbance in the antioxidative enzyme activities. However, the synergetic use of Fe- and Si-NPs reduced the Pb contents in the upper part of plants by 27%. It reduced the lethal impact of Pb on roots and shoots growth parameters by increasing shoot length (40%), shoot fresh weight (48%), and roots fresh weight (31%). Both Si and Fe-NPs synergistic application significantly elevated superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and glutathione (GSH) concentrations by 114%, 186%, 135%, and 151%, respectively, compared to plants subjected to Pb stress alone. The toxicity of Pb resulted in several cellular abnormalities and altered the expression levels of metal transporters and antioxidant genes. We conclude that the synergistic application of Si and Fe-NPs can be deemed favorable, environmentally promising, and cost-effective for reducing Pb deadliness in rice crops and reclaiming Pb-polluted soils.

Multipath diffusion process and spatial accumulation simulation of Cd in lead-zinc mining areas.

This study combined process simulation and actual measurement to construct a multipath diffusion and spatial accumulation model of Cd in a typical lead-zinc mining area through accuracy and root mean square error(RMSE) analysis. The results indicated that (1) the diffusion of Cd was in a quadratic inverse proportional relationship with the distance from the pollution source within watershed. The average annual atmospheric Cd sedimentation in study area was 0.71 * 10-6 g and the contribution of runoff diffusion to Cd exceeded 80%. (2) With the increase in the concentration range of Cd content (k) carried by unit runoff sediment, the model accuracy and RMSE showed decreasing trends. However, when the lower and upper limits of k were 10% and 90%, the model accuracy reached 75%. (3) Two sub-watersheds with same dominant wind direction but different runoff directions were selected to verify the model accuracy, indicating that the model construction method can precisely simulate the spatial accumulation of Cd in similar mining areas. The results provide a scientific basis for the prevention of heavy metal diffusion in lead-zinc mines. Future research should focus on the migration pathways of heavy metals through vertical infiltration caused by rainfall to further optimise the model structure and accuracy.

Rapamycin can alleviate the submandibular gland pathology of Sjögren's syndrome by limiting the activation of cGAS-STING signaling pathway.

BACKGROUND: Sjögren's Syndrome (SS) is also known as autoimmune exocrine gland disease. Previous studies have confirmed that adaptive immunity plays an important role in the development of this disease. But less is known about the role of the innate immune system. METHODS: To identify the core pathways, and local infiltrated immune cells in the local immune microenvironment of SS. We verified the activation of these core genes and core signaling pathways in SS model mice by in vivo experiment and transcriptome sequencing. RESULTS: Finally, we identified 6 core genes EPSTI1, IFI44L, MX1, CXCL10, IFIT3, and IFI44. All the 6 genes had good diagnostic value. Based on multi-omics sequencing results and experimental studies, we found that cGAS-STING signaling pathway is most relevant to the pathogenesis of SS. By in vivo experiments, we verified that autophagy is the key brake to limit the activation of cGAS-STING signaling pathway. CONCLUSIONS: Maladaptive activation of autophagy and cGAS-STING signaling pathway are central contributors to the SG pathogenesis of pSS patient. Regulating autophagy by rapamycin may be a possible treatment for Sjögren's syndrome in the future.

U-Shaped Association Between Monocyte-Lymphocyte Ratio and Risk of Cardiac Conduction Block.

Purpose: Inflammation plays a critical role in the development of cardiac conduction block (CCB), which is associated with an increased risk of morbidity and mortality. The monocyte-lymphocyte ratio (MLR) acts as a novel inflammatory marker; however, its association with CCB has not yet been studied. This study aimed to investigate the association between MLR and CCB risk. Patients and Methods: In total, 82,472 CCB-free participants were identified from the Kailuan study. MLR was calculated using the monocyte count/lymphocyte count. The participants were stratified based on quartiles of MLR levels. Incident CCB and its subtypes were ascertained from electrocardiograms at biennial follow-up visits. The Cox proportional hazards model and restricted cubic spline analysis were used to investigate the association between MLR with CCB and its subtypes. Results: During a median follow-up of 10.4 years, 3222 incident CCB cases were observed. A U-shaped association was observed between MLR and CCB risk (Pnonlinearity <0.05). After multivariate adjustment, individuals in the highest MLR quartile had a hazard ratio (HR) of 1.212 (95% CI: 1.097-1.340; Q4 vs Q2), while those in the lowest MLR quartile had an HR of 1.106 (95% CI: 1.000-1.224; Q1 vs Q2). Sensitivity and subgroup analyses yielded consistent results. The U-shaped association persisted for atrioventricular block (AVB) in subtype analyses. Conclusion: MLR was significantly associated with an increased risk of new-onset CCB. Assessing MLR may have clinical relevance for predicting CCB risk, providing valuable insights for preventive strategies and patient management. Pre-Registered Clinical Trial Number: The pre-registered clinical trial number is ChiCTR-TNC-11001489.

Exploring Associations Between Short-Term Air Pollution and Daily Outpatient Visits for Allergic Rhinitis.

Purpose: Many studies have reported that exposure to air pollution increases the likelihood of acquiring allergic rhinitis (AR). This study investigated associations between short-term air pollution exposure and AR outpatient visits. Patients and Methods: The Department of Otorhinolaryngology, Affiliated Hospital of Hangzhou Normal University provided AR outpatient data from January 1, 2019 to December 31, 2021. Daily air quality information for that period was gathered from the Hangzhou Air Quality Inspection Station. We used the Poisson's generalized additive model (GAM) to investigate relationships between daily outpatient AR visits and air pollution, and investigated lag-exposure relationships across days. Subgroup analyses were performed by age (adult (>18 years) and non-adult (<18 years)) and sex (male and female). Results: We recorded 20,653 instances of AR during the study period. Each 10 g/m3 increase in fine particulate matter (PM10 and PM2.5) and carbon monoxide (CO) concentrations was associated with significant increases in AR outpatient Visits. The relative risks (RR) were: 1.007 (95% confidence interval (CI): 1.001-1.013), 1.026 (95% CI: 1.008-1.413), and 1.019 (95% CI: 1.008-1.047). AR visits were more likely due to elevated PM2.5, PM10, and CO levels. Additionally, children were more affected than adults. Conclusion: To better understand the possible effects of air pollution on AR, short-term exposure to ambient air pollution (PM2.5, PM10, and CO) may be linked to increased daily outpatient AR visits.

The protective role of tetraploidy and nanoparticles in arsenic-stressed rice: Evidence from RNA sequencing, ultrastructural and physiological studies.

Genome doubling in plants induces physiological and molecular changes to withstand environmental stress. Diploid rice (D-2x) and its tetraploid (T-4x) plants were treated with 25 µM Arsenic (As) and 15 mg L-1 TiO2 nanoparticles (NPs), and results indicated decreased growth and photosynthetic activity with high accumulation of reactive oxygen species (ROS) due to the As-toxicity in rice lines, significantly in D-2x rice plants. The treatment of As-contaminated rice with TiO2 NPs resulted in increased root length (8.17%) and chlorophyll AB (13.28%) and decreased electrolyte leakage (21.76%) and H2O2 (17.65%) contents than its counterpart diploid rice. Moreover, TiO2 NPs improved the activity of peroxidase, catalase, glutathione, and superoxide dismutase and reduced lipid peroxidation due to lower ROS production in D-2x and T-4x under As toxicity. Transcriptome analysis revealed abrupt changes in the expression levels of key signaling heat shock proteins, tubulin, aquaporins, As, and metal transporters under As toxicity in T-4x and D-2x lines. The KEGG and GO studies highlighted the striking distinctions between rice lines under As-stress in glutathione metabolism, H2O2 catabolic process, MAPK signaling pathway, and carotenoid biosynthesis terms, revealing consistency between physiological and molecular results. Root cells from D-2x rice were significantly more distorted by As poisoning than those from 4x rice, and cell organelles, such as mitochondria and endoplasmic reticulum, were changed or deformed. These findings proved the superiority of tetraploid rice lines over their diploid counterpart in coping with As-stress.

Factors influencing normal blood pressure maintenance in young adults.

Despite an alarming increase in the prevalence of hypertension among Chinese young adults, longitudinal studies investigating factors that affect the maintenance of normal blood pressure (BP) in this population are lacking. Our study aimed to address this knowledge gap. A total of 7100 participants from the Kailuan Study who had normal BP and were aged <30 years at their first physical examination between 2006 and 2016 were included in this study. Cox proportional hazards regression models were used to assess hazard ratios (HR), and 95% confidence intervals (CI) were calculated to assess the associations between influencing factors and the maintenance of normal BP in young adults. Analyses were stratified by sex. During the follow-up period (mean, 7.98 years), 1921 participants (27.06%) maintained normal BP. Higher education levels (HR, 1.11; 95% CI, 1.00-1.22), low salt intake (HR, 1.25; 95% CI, 1.04-1.51), being underweight (HR, 1.16; 95% CI, 1.02-1.31), and having normal weight (HR, 1.19; 95% CI, 1.01-1.39), normal blood glucose (HR, 1.22; 95% CI, 1.02-1.46), and no family history of hypertension (HR, 1.65; 95% CI, 1.41-1.92) at baseline were found to be associated with maintaining normal BP. Compared with female smokers, female non-smokers had 1.68 times higher odds of maintaining normal BP. This study identified factors that influence the maintenance of normal BP in the young population in China. This information can assist clinicians in establishing comprehensive and effective primary prevention measures for hypertension.

Role of the chloride channel blocker in the formation of filtering tract scars after glaucoma surgery in rats.

Filtration surgery is commonly performed for glaucoma treatment to reduce intraocular pressure (IOP); however, scarring of the filtering bleb is the main cause of failure. In this study, we evaluated the effects of the chloride channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) on scar formation in filtering blebs. A glaucoma filtering surgery model was generated using Sprague-Dawley rats, divided into the control and NPPB groups receiving injections of different NPPB concentrations. The IOP of all rats decreased 1-day post-surgery and gradually increased afterward. However, IOP in rats from the NPPB groups recovered more slowly than that of the control group rats. In addition, the area and survival times of filtering blebs in rats from the NPPB groups were substantially larger and longer than those in the control group. Twenty-eight days after surgery, the protein and mRNA expression of collagen I, fibronectin and α-smooth muscle actin in the filtering area of rats from the NPPB groups were significantly lower than that in the control group rats. Collectively, our study demonstrates that NPPB inhibits filtering bleb scar formation, maintains filtering bleb morphology and prolongs filtering bleb survival time by inhibiting the differentiation of conjunctival fibroblasts and extracellular matrix synthesis.

Synthesis and electrochemical properties of Mn-doped Li2Mn0.1Ti1.9(PO4)3 materials.

The hunt for a higher power storage, relatively inexpensive, non-polluting battery technology is currently a pressing issue because of the rapid growth of the worldwide economic and the progressively significant environmental pollution. Among the possible nanomaterials for rechargeable batteries that can have heteroatoms applied to it in order to improve its electrochemical behavior is LixTiy(PO4)3. Carbon-coated Mn-doped Li2Mn0.1Ti1.9(PO4)3 materials was synthesized by spray drying method. The material was characterized by XRD, SEM, TEM, BET, TGA et al. Crystal data refinement results by Rietveld method showed that the symmetry space group is Pbcn.The lattice parameters of Li2Mn0.1Ti1.9(PO4)3 are a = 11.9372 Å, b = 8.5409 Å, c = 8.5979 Å, α = ß = γ = 90°, V = 876.59 Å3 and Z = 4). Rietveld refinement was performed, and the confidence factors are Rwp = 11.79%, Rp = 9.14%, and χ2 = 1.425. It was exhibited that LMTP0.1/CA-700 material has good crystallinity. Testing the cells with LAND test procedure (200 mA/g current density for 200 cycles), the LMTP0.1/CA-700 material has a discharge specific capacity of about 65 mAh/g. The capacity decayed by only 3% during the cycle. It has some potential application values as cathode of lithium ion battery in the future.

Polyploidy and zinc oxide nanoparticles alleviated Cd toxicity in rice by modulating oxidative stress and expression levels of sucrose and metal-transporter genes.

The Cd toxicity causes severe perturbations to the plant's growth and development. Here, polyploid and diploid rice lines were treated with zinc-oxide nanoparticles (ZnO-NPs) and Cd, and physiological, cytological and molecular changes were observed. The Cd toxicity significantly reduced plant's growth attributes (such as shoot length, biological yield, dry matter, and chlorophyll contents, which decreased by 19%, 18%, 16%, 19% in polyploid and 35%, 43%, 45% and 43% in diploid rice, respectively), and disturbed the sugar level through the production of electrolytes, hydrogen peroxide, and malondialdehyde. The application of ZnO-NPs significantly alleviated the Cd toxicity in both lines by improving the antioxidant enzymes activities and physiochemical attributes. Semi-thin sections and transmission electron microscope revealed more and different types of abnormalities in diploid rice compared to polyploid rice under Cd stress. Moreover, RNA-seq analysis identified several differentially expressed genes between polyploid and diploid rice, especially metal and sucrose transporter genes. The GO, COG, and KEGG analyses revealed ploidy-specific pathways associated with plant growth and development. In conclusion, ZnO-NPs application to both rice lines significantly improved plant growth and decreased Cd accumulation in plants. We inferred that polyploid rice is more resistant to Cd stress than diploid rice.

Yang-Gan-Jiang-Mei formula alleviates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome through mitophagy.

As an effective formula of traditional Chinese medicine, Yang-Gan-Jiang-Mei (YGJM) formula exhibited a unique advantage in ameliorating liver injury and hepatic steatosis of non-alcoholic steatohepatitis (NASH). Nevertheless, the related pharmacological mechanism needs to be elucidated. This study aimed to explore the molecular mechanism of YGJM formula on mitophagy mediated by PINK1/parkin signaling pathway and NOD-like receptor protein 3 (NLRP3) inflammasome in NASH. High-fat-diet rats and HepG2 cells induced by free fatty acid were used as NASH models in vivo and in vitro. Liver pathology and serum indicator embodying liver function (aspartate transferase, alanine transferase, triglyceride, and total cholesterol) were applied to evaluate the extent of hepatic damage and lipid accumulation. Besides, transmission electron microscopy, JC-1 and 2',7'-dichlorofluorescein diacetate were utilized to observe hepatic mitochondrial morphology, as well as cellular mitochondrial membrane potential and reactive oxygen species level. Additionally, expression of PINK1/parkin-mediated mitophagy and NLRP3 inflammasome was detected to elucidate the underlying mechanism of YGJM formula by immunohistochemistry, immunofluorescence, RT-PCR (reverse transcription-polymerase chain reaction) and Western blot. The manifestations of pathology and biochemical detection confirmed the efficacy of YGJM formula in relieving hepatic damage and lipid deposition. Simultaneously, YGJM formula could obviously improve mitochondrial function. In addition, YGJM formula exhibited the promotion of PINK1/parkin-mediated mitophagy, which could perturb NLRP3 inflammasome activation, and as a result, the hepatocyte inflammation was also suppressed both in vitro and in vivo. Our preliminary results indicate that YGJM formula can ameliorate NASH mechanistically by interfering with PINK1/parkin-mediated mitophagy and NLRP3 inflammasome to exert anti-inflammation ability and promote mitochondrial function restoration.

Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression.

The WD-repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1-6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune-competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid-derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF-κB to activate the transcription of WDR6, establishing a WDR6-TNFα loop. Clinically, the WDR6/UVRAG/NF-κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR-like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti-PD-L1 against HCC with WDR6 dysregulation.