Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.

M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages.

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non-coding RNA taurine-upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3-mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1-like macrophages in tumors, promoted the activation of CD8+ T cells through PD-L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD-L1 and CD47 expressions by acting as a sponge of miR-141 and miR-340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD-L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD-L1 and CD47 in HCC tissues. Moreover, the combination of Tug1-siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.

Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.

Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.Abbreviations: AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle's balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.

Progress and perspectives of metabolic biomarkers in human aortic dissection.

BACKGROUND: Aortic dissection (AD) significantly threated human cardiovascular health, extensive clinical-scientific research programs have been executed to uncover the pathogenesis and prevention. Unfortunately, no specific biomarker was identified for the causality or development of human AD. AIM OF REVIEW: Metabolomics, a high-throughput technique capable of quantitatively detecting metabolites, holds considerable promise in discovering specific biomarkers and unraveling the underlying pathways involved. Aiming to provide a metabolite prediction in human AD, we collected the metabolomics data from 2003 to 2023, and diligently scrutinized with the online system MetaboAnalyst 6.0. KEY SCIENTIFIC CONCEPTS OF REVIEW: Based on the data obtained, we have concluded the metabolic dynamics were highly correlated with human AD. Such metabolites (choline, serine and uridine) were frequently involved in the AD. Besides, the pathways, including amino acids metabolism and lipids metabolism, were also dysregulated in the disease. Due to the current limitation of metabolism analysis, the integrative omics data including genomics, transcriptomics, and proteomics were required for developing the specific biomarker for AD.

Molecular Characteristics of Salmonella Spp. Responsible for Bloodstream Infections in a Tertiary Hospital in Nanjing, China, 2019-2021.

Objective: To investigate the clinical and molecular characteristics of Salmonella spp. causing bloodstream infections (BSIs) in our hospital. Methods: We studied 22 clinical Salmonella isolates from BSIs and 16 from non-BSIs, performing antimicrobial susceptibility testing (AST) and whole genome sequencing (WGS). The analysis included serovars, antibiotic resistance genes (ARGs), virulence factors (VFs), sequence types (STs), plasmid replicons, and genetic relationships. We also assessed pathogenicity of the isolates causing BSIs through growth, biofilm formation, and anti-serum killing assays. Results: WGS analysis identified 13 Salmonella serovars, with four responsible for BSIs. S. Enteritidis was the most prevalent serovar, involved in 19 (50.0%) cases. BSIs were caused by 17S. Enteritidis, two S. Typhimurium, two S. Munster and one S. Diguel. Of the 38 isolates, 27 (71.1%) exhibited high resistance to ampicillin, and 24 (63.2%) to ampicillin/sulbactam. Thirty-six types of ARGs were identified, with blaTEM-1B (n = 25, 65.8%) being the most frequent. Ten plasmid replicons were found; the combination of IncFIB(S)-IncFII(S)-IncX1 was the most common in S. Enteritidis (94.7%). Fifteen STs were identified, among which ST11 was the most prevalent and clonally disseminated, primarily responsible for BSIs. A total of 333 different VFs were detected, 177 of which were common across all strains. No significant differences were observed between the BSI and non-BSI isolates in terms of resistance rates, ARGs, plasmid replicons, and VFs, except for seven VFs. No strong pathogenicity was observed in the BSI-causing isolates. Conclusion: BSIs were predominantly caused by clonally disseminated S. Enteritidis ST11, the majority of which carried multiple ARGs, VFs and plasmid replicons. This study provides the first data on clonally disseminated S. Enteritidis ST11 causing BSIs, highlighting the urgent need for enhanced infection control measures.

miR-744-5p promotes T-cell differentiation via inhibiting STK11.

T cells utilized in adoptive T cell immunotherapy are typically activated in vitro. Although these cells demonstrate proliferation and anti-tumor activity following activation, they often face difficulties in sustaining long-term survival post-reinfusion. This issue is attributed to the induction of T cells into a terminal differentiation state upon activation, whereas early-stage differentiated T cells exhibit enhanced proliferation potential and survival capabilities. In previous study, we delineated four T cell subsets at varying stages of differentiation: TN, TSCM, TCM, and TEM, and acquired their miRNA expression profiles via high-throughput sequencing. In the current study, we performed a differential analysis of miRNA across these subsets, identifying a distinct miRNA, hsa-miR-744-5p, characterized by progressively increasing expression levels upon T cell activation. This miRNA is not expressed in TSCM but is notably present in TEM. Target genes of miR-744-5p were predicted, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, revealing that these genes predominantly associate with pathways related to the 'Wnt signaling pathway'. We established that miR-744-5p directly targets STK11, influencing its expression. Further, we investigated the implications of miR-744-5p on T cell differentiation and functionality. Overexpression of miR-744-5p in T cells resulted in heightened apoptosis, reduced proliferation, an increased proportion of late-stage differentiated T cells, and elevated secretion of the cytokine TNF-α. Moreover, post-overexpression of miR-744-5p led to a marked decline in the expression of early-stage differentiation-associated genes in T cells (CCR7, CD62L, LEF1, BCL2) and a significant rise in late-stage differentiation-associated genes (KLRG1, PDCD1, GZMB). In conclusion, our findings affirm that miR-744-5p contributes to the progressive differentiation of T cells by downregulating the STK11 gene expression.

Eczema herpeticum in an immunocompetent man.

BACKGROUND: Eczema herpeticum is a rapidly progressing skin complication related to the herpes simplex virus, particularly in individuals with compromised immune systems or atopic dermatitis. Eczema herpeticum is characterized by cutaneous pain, scaling, and the presence of vesicular lesions, often accompanied by secondary infection. Dissemination of the infection can lead to severe morbidity and mortality in patients without appropriate antiviral and antibiotic therapy. CASE REPORT: We presented a case of ankylosing spondylitis in a relatively young patient who did not receive immunosuppressive therapy and had no history of Human Immunodeficiency Virus, herpes zoster infection or atopic dermatitis. The patient's symptoms improved following a course of antiviral and antibiotic treatments. INTRODUCTION: The incidence of eczema herpeticum has been on the rise in recent decades, primarily due to an increased number of individuals with compromised immune systems. This increase can be attributed to various factors, including the higher prevalence of Human Immunodeficiency Virus/ Acquired Immunodeficiency Syndrome, the more extensive use of immunosuppressive therapy, and what seems to be a growing incidence of atopic dermatitis.[1] This disease can be initially mistaken for Stevens-Johnson syndrome because of the rapid advancement of skin lesions, however, the atypical target lesions, flaccid bullae and prominent mucosal involvement found in Stevens-Johnson syndrome are absent in cases of eczema herpeticum. Other differential diagnoses include impetigo, disseminated herpes zoster, acute generalized exanthematous pustulosis, dermatitis herpetiformis.

Advances in the molecular regulation mechanism of tumor dormancy and its therapeutic strategy.

Tumor dormancy is a stage in the growth and development of malignant cells and is one of the biological characteristics of malignant cells. Complex transitions involving dormant tumor cells between quiescent and proliferative states pose challenges for tumor eradication. This paper explores the biological features and molecular mechanisms of tumor dormancy and highlights emerging therapies. The strategies discussed promise innovative clinical potential against malignant tumors. Understanding the mechanisms of dormancy can help provide valuable insights into the diagnosis and treatment of malignant tumors to advance the fight against this world problem.

Immune checkpoint inhibitors: breakthroughs in cancer treatment.

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.

Using machine learning algorithms based on patient admission laboratory parameters to predict adverse outcomes in COVID-19 patients.

Amidst the global COVID-19 pandemic, the urgent need for timely and precise patient prognosis assessment underscores the significance of leveraging machine learning techniques. In this study, we present a novel predictive model centered on routine clinical laboratory test data to swiftly forecast patient survival outcomes upon admission. Our model integrates feature selection algorithms and binary classification algorithms, optimizing algorithmic selection through meticulous parameter control. Notably, we developed an algorithm coupling Lasso and SVM methodologies, achieving a remarkable area under the ROC curve of 0.9277 with the use of merely 8 clinical laboratory parameters collected upon admission. Our primary contribution lies in the utilization of straightforward laboratory parameters for prognostication, circumventing data processing intricacies, and furnishing clinicians with an expeditious and precise prognostic assessment tool.

Antifungal activity of nisin against clinical isolates of azole-resistant Candida tropicalis.

The rapid emergence of invasive infections caused by azole-resistant Candida tropicalis has become a public health concern, and there is an urgent need for alternative treatment strategies. Studies have demonstrated the antibacterial effects of nisin, a well-known peptide naturally produced by Lactococcus lactis subsp. lactis. However, there is scant information about the antifungal effect of nisin against C. tropicalis. The present study aims to investigate the in vitro antifungal activity of nisin against clinical isolates of azole-resistant C. tropicalis strains, as well as its inhibitory effect on biofilm formation. A total of 35 C. tropicalis strains isolated from patients with invasive fungal infections were divided into the azole-resistant group and the azole-sensitive group, containing 21 and 14 strains, respectively. The relative expression levels of the ERG11 and UPC2 genes in the azole-resistant group were higher than those in the azole-sensitive group (p < 0.0001), while no significant differences were observed in the expression levels of the MDR1 and CDR1 genes. The minimum inhibitory concentration of nisin against C. tropicalis ranged from 2 to 8 µg/mL. Nisin treatment inhibited the growth of azole-resistant C. tropicalis, with over a four-fold reduction in OD600 nm values observed at the 8-h time point, while it promoted the transition of C. tropicalis from the spore phase to the hyphal phase, as observed on cryo-scanning electron microscopy. The results of biofilm quantification using crystal violet staining indicated a significant decrease in OD570 nm values in the nisin-treated group compared to the controls (p < 0.0001). Among the 21 azole-resistant C. tropicalis strains, the biofilm formation was inhibited in 17 strains (17/21, 81%), and more than 85% inhibition of biofilm formation was observed in the representative strains. With regard to the molecular mechanisms, the expression of the BCR1 and UPC2 genes in the azole-resistant strains was down-regulated on nisin treatment (p < 0.05). In conclusion, we demonstrated, for the first time, that nisin has antifungal activity and significant anti-biofilm activity against clinical isolates of azole-resistant C. tropicalis strains. Based on the findings, nisin could be a promising alternative antifungal agent for combating azole-resistant C. tropicalis infections.

A bio-fabricated tesla valves and ultrasound waves-powered blood plasma viscometer.

Introduction: There is clinical evidence that the fresh blood viscosity is an important indicator in the development of vascular disorder and coagulation. However, existing clinical viscosity measurement techniques lack the ability to measure blood viscosity and replicate the in-vivo hemodynamics simultaneously. Methods: Here, we fabricate a novel digital device, called Tesla valves and ultrasound waves-powered blood plasma viscometer (TUBPV) which shows capacities in both viscosity measurement and coagulation monitoring. Results: Based on the Hagen-Poiseuille equation, viscosity analysis can be faithfully performed by a video microscopy. Tesla-like channel ensured unidirectional liquid motion with stable pressure driven that was triggered by the interaction of Tesla valve structure and ultrasound waves. In few seconds the TUBPV can generate an accurate viscosity profile on clinic fresh blood samples from the flow time evaluation. Besides, Tesla-inspired microchannels can be used in the real-time coagulation monitoring. Discussion: These results indicate that the TUBVP can serve as a point-of-care device in the ICU to evaluate the blood's viscosity and the anticoagulation treatment.

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.

Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization.

The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic-pharmacodynamic theory. A prospective, two-armed, single-blind, randomized controlled trial compared management aided by a web-based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed up until the first outpatient appointment at least 3 months after warfarin initiation. We compared the percentage of time spent in the international normalized ratio acceptable range (%TIR) during the first 28 days following warfarin initiation, and %TIR and count of bleeding events over the entire follow-up period. Two hundred thirty-four participants were followed up to day 28 (NextDose: 116 and standard of care: 118), and 228 participants (114 per arm) were followed up to the final study visit. Median %TIR tended to be higher for participants receiving NextDose guided warfarin management during the first 28 days (63 vs. 56%, P = 0.13) and over the entire follow-up period (74 vs. 71%, P = 0.04). The hazard of clinically relevant minor bleeding events was lower for participants in the NextDose arm (hazard ratio: 0.21, P = 0.041). In NextDose, there were 89.3% of proposed doses accepted by prescribers. NextDose guided dose management in cardiac surgery patients requiring warfarin was associated with an increase in %TIR across the full follow-up period and fewer hemorrhagic events. A theory-based, pharmacologically guided approach facilitates higher quality warfarin anticoagulation. An important practical benefit is a reduced requirement for clinical experience of warfarin management.

Linc00673-V3 positively regulates autophagy by promoting Smad3-mediated LC3B transcription in NSCLC.

Since its first discovery, long noncoding RNA Linc00673 has been linked to carcinogenesis and metastasis of various human cancers. Linc00673 had five transcriptional isoforms and their biological functions remained to be explored. Here we have reported that Linc00673-V3, one of the isoforms of Linc00673, promoted non-small cell lung cancer chemoresistance, and increased Linc00673-V3 expression level was associated with enhanced autophagy. Mechanistically, we discerned the existence of a stem-loop configuration engendered by the 1-100-nt and 2200-2275-nt fragments within Linc00673-V3. This structure inherently interacted with Smad3, thereby impeding its ubiquitination and subsequent degradation orchestrated by E3 ligase STUB1. The accumulation of Smad3 contributed to autophagy via up-regulation of LC3B transcription and ultimately conferred chemoresistance in NSCLC. Our results revealed a novel transcriptional regulation network between Linc00673-V3, Smad3, and LC3B, which provided an important insight into the interplay between autophagy regulation and non-canonical function of Smad3. Furthermore, the results from in vivo experiments suggested Linc00673-V3 targeted antisense oligonucleotide as a promising therapeutic strategy to overcome chemotherapy resistance in NSCLC.

Continuous Renal Replacement Therapy Improves Indicators and Short-Term Survival in People with AIDS Manifesting Sepsis and Acute Kidney Injury.

Patients with acquired immune deficiency syndrome (AIDS) are susceptible to numerous complications, such as sepsis and acute kidney injury (AKI), leading to adverse outcomes. Continuous renal replacement therapy (CRRT) is becoming increasingly popular for treating sepsis and AKI. This study aimed to verify the effectiveness of CRRT in the treatment of patients with AIDS with sepsis and AKI to provide new directions for the treatment of severe AIDS. Data of 74 people with AIDS, sepsis, and AKI were collected. The patients were divided into CRRT and non-CRRT groups. There was no difference in the indicators between the two groups at admission. Vital signs, pH, serum potassium level, renal function, blood lactate level, acute physiology and chronic health evaluation II score, and sequential organ failure assessment score in the CRRT group demonstrated significant improvements over those in the non-CRRT group at both 24 and 72 h after admission (P < 0.05). The levels of interleukin 6 and procalcitonin declined more significantly in the CRRT group at 72 h after admission (P < 0.05). The CRRT group had a higher 28-day survival rate than the non-CRRT group (P < 0.05). CRRT improves the clinical indicators and increases the short-term survival rate of patients with AIDS, sepsis, and AKI.

Silver nanoparticles induce iron accumulation-associated cognitive impairment via modulating neuronal ferroptosis.

Silver nanoparticles (AgNPs) are widely used in daily life and medical fields owing to their unique physicochemical properties. Daily exposure to AgNPs has become a great concern regarding their potential toxicity to human beings, especially to the central nervous system. Ferroptosis, a newly recognized programmed cell death, was recently reported to be associated with the neurodegenerative process. However, whether and how ferroptosis contributes to AgNPs-induced neurotoxicity remain unclear. In this study, we investigated the role of ferroptosis in neurotoxic effects induced by AgNPs using in vitro and in vivo models. Our results showed that AgNPs induced a notable dose-dependent cytotoxic effect on HT-22 cells and cognitive impairment in mice as indicated by a decline in learning and memory and brain tissue injuries. These findings were accompanied by iron overload caused by the disruption of the iron transport system and activation of NCOA4-mediated autophagic degradation of ferritin. The excessive free iron subsequently induced GSH depletion, loss of GPX and SOD activities, differential expression of Nrf2 signaling pathway elements, down-regulation of GPX4 protein and production of lipid peroxides, initiating ferroptosis cascades. The mitigating effects of ferrostatin-1 and deferoxamine on iron overload, redox imbalance, neuronal cell death, impairment of mice learning and memory, Aß deposition and synaptic plasticity reduction suggested ferroptosis as a potential molecular mechanism in AgNPs-induced neurotoxicity. Taken together, these results demonstrated that AgNPs induced neuronal cell death and cognitive impairment with Aß deposition and reduction of synaptic plasticity, which were mediated by ferroptosis caused by iron-mediated lipid peroxidation. Our study provides new insights into the underlying mechanisms of AgNPs-induced neurotoxicity and predicts potential preventive strategies.

CircUSP1 as a novel marker promotes gastric cancer progression via stabilizing HuR to upregulate USP1 and Vimentin.

Circular RNAs (circRNAs) play a crucial role in regulating various tumors. However, their biological functions and mechanisms in gastric cancer (GC) have not been well understood. Here, we discovered a stable cytoplasmic circRNA named circUSP1 (hsa_circ_000613) in GC. CircUSP1 upregulation in GC tissues was correlated with tumor size and differentiation. We observed that circUSP1 promoted GC growth and metastasis. Mechanistically, circUSP1 mainly interacted with the RRM1 domain of an RNA-binding protein (RBP) called HuR, stabilizing its protein level by inhibiting ß-TrCP-mediated ubiquitination degradation. The oncogenic properties of HuR mediated promotive effects of circUSP1 in GC progression. Moreover, we identified USP1 and Vimentin as downstream targets of HuR in post-transcriptional regulation, mediating the effects of circUSP1. The parent gene USP1 also enhanced the viability and mobility of GC cells. Additionally, tissue-derived circUSP1 could serve as an independent prognostic factor for GC, while plasma-derived circUSP1 showed promise as a diagnostic biomarker, outperforming conventional markers including serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA19-9). Our study highlights that circUSP1 promotes GC progression by binding to and stabilizing oncogenic HuR, thereby facilitating the upregulation of USP1 and Vimentin at the post-transcriptional level. These findings suggest that circUSP1 could be a potential therapeutic target and a diagnostic and prognostic biomarker for GC.

Prevalence and causes of blindness and distance visual impairment in Chinese adult population in 2022 during the COVID-19 pandemic: a cross-sectional study.

This cross-sectional study aims to investigate the prevalence and causes of visual impairment (VI) and blindness in Jiangsu Province, China in 2022 during the COVID-19 pandemic. Participants (n = 13,208, aged 18-93) underwent comprehensive ocular examinations. The prevalence and causes of binocular VI (presenting visual acuity [VA] ≥ 20/400 and < 20/63 in the better eye) and blindness (presenting VA < 20/400 in the better eye) were assessed according to the World Health Organization (WHO) criteria. The estimation of refractive error prevalence was conducted using the following classification: myopia ≤ - 0.50 diopters (D), high myopia ≤ - 6.00 D, hyperopia ≥ 0.50 D, and anisometropia ≥ 1.00 D. The overall prevalence of binocular VI and blindness was 21.04% (95% confidence interval [CI] 20.35-21.74%) and 0.47% (95% CI 0.37-0.60%). The highest prevalence of binocular VI was in the population aged 18-24 years old (46.29%, [95% CI 44.30-48.28%]), those with education at university and above (43.47%, [95% CI 41.93-45.02%]), students (54.96%, [95% CI 52.73-57.17%]). Uncorrected refractive error (URE) was the leading cause of presenting binocular VI (93.40%) and blindness (50.79%). The prevalence of myopia was 54.75% (95% CI 53.90-55.60%). Actions are needed to control URE and myopia within the adult Chinese population, with a particular emphasis on the younger, well-educated demographic.