Penetrative Ionic Organic Molecular Cage Nanozyme for the Targeted Treatment of Keratomycosis.

Keratomycosis, caused by pathogenic fungi, is an intractable blinding eye disease. Corneal penetration is an essential requirement for conventional antifungal medications to address keratomycosis. Due to the distinctive anatomical and physiological structure of the cornea, the therapeutic efficacy is hampered by the inadequate penetration capacity. Despite the emergence of diverse antifungal drug delivery systems and advanced antifungal nanomaterials, it has remained challenging to achieve corneal penetration over the past decade. In the study, we fabricated a penetrative ionic organic molecular cage-based nanozyme (OMCzyme) for treating keratomycosis. The synthesis of OMCzyme involved two steps. Initially, the ionic OMC was synthesized by a [2+3] cycloimination reaction of triformylphloroglucinol and 2,3-diaminopropionic acid. Subsequently, OMCzyme was fabricated by coordination of Fe2⁺ with carboxyl anions and phenolic hydroxyls in the organic cage, and further deposition of silver nanoparticles on the surface of OMC-Fe complex. The as-prepared OMCzyme demonstrated excellent water dispersion, peroxidase-like activity, in vitro and in vivo biocompatibility, and corneal penetration. Notably, the nanozyme displayed targeted antifungal activity, effectively combating Fusarium solani with negligible cytotoxicity towards human corneal epithelial cells. The hybrid mimic was further demonstrated to be effective in treating keratomycosis in mice, indicating the potential of OMCzyme for curing fungal infectious diseases. This article is protected by copyright. All rights reserved.

Salvianolic acid B alleviates autoimmunity in Treg-deficient mice via inhibiting IL2-STAT5 signaling.

Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.

Effect of Roasting on the Chemical Composition and Oxidative Stability of Tomato (Solanum lycopersicum L.) Seed Oil.

In this study, tomato seed (TS) samples were subjected to different roasting conditions (90-170 °C and 10-30 min) to compare their effects on the chemical composition and oxidative stability of tomato seed oil (TSO). Unroasted TS was considered as a control sample. Our results revealed that moderate roasting (130 °C/20 min) can significantly increase the content of linoleic acid (54.01-54.89%), linolenic acid (2.17-2.41%), phytosterols (2789.56-3037.31 mg/kg), squalene (5.06-13.10 mg/kg), total phenols (22.37-22.67 mg GAE/100 g), and other functional components (p < 0.05) in TSO, while the antioxidant activity (via DPPH, ABTS, and FRAP assays) also increased. In addition, the tocopherol content decreased significantly (758.53-729.50 mg/kg). Accelerated oxidation experiments showed that roasting (170 °C/30 min) increased the oxidative stability index (OSI) of TSO from 5.35 to 7.07 h (p < 0.05). Furthermore, roasting gradually increased the content of 5-hydroxymethylfurfural (HMF) (0-1.74 mg/kg), which indicates that the oxidative stability and the degree of the Maillard reaction increased upon roasting. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) showed that moderate roasting (130 °C/20 min) improved the chemical composition, antioxidant activity, and oxidative stability of TSO. Furthermore, this work provides a useful theoretical basis for the processing and wide application of TSO in the pharmaceutical and food industries.

Nonstoichiometry-Induced Self-Activated Phosphors for Dynamic Anti-counterfeiting Applications.

Optical signals with distinctive properties, such as contactless, fast response, and high identification, are harnessed to realize advanced anti-counterfeiting. However, the simultaneous attainment of multi-color, -temporal, and -modal luminescence performance remains a compelling and imperative pursuit. In our work, a temperature/photon-responded dynamic self-activated luminescence originating from nonstoichiometric Zn2GeO4 is developed with the modulation of intrinsic defects. The increased concentration of oxygen vacancies (VO••) contributes to an enhanced recombination of ZnGe″-VO••, ultimately improving the self-activated luminescence performance. Additionally, the photoluminescence (PL) color of the representative Zn2.2GeO4 sample changes from green to blue-white with the increased ultraviolet (UV) irradiation time. Concurrently, the emission color undergoes a variation from blue to green as the ambient temperature raises from 280 to 420 K. Remarkably, green long persistent luminescence (LPL) and photostimulated luminescence (PSL) behaviors are observed. Herein, this study elucidates a sophisticated anti-counterfeiting approach grounded in the dynamic luminescent attributes of nonstoichiometric Zn2GeO4, presenting a promising frontier for the evolution of anti-counterfeiting technologies.

Astragaloside IV inhibits inflammation caused by influenza virus via reactive oxygen species/NOD-like receptor thermal protein domain associated protein 3/Caspase-1 signaling pathway.

BACKGROUND: Astragaloside IV (AS-IV) is the most active monomer in the traditional Chinese herbal medicine Radix Astragali, which has a wide range of antiviral, anti-inflammatory, and antifibrosis pharmacological effects, and shows protective effects in acute lung injury. METHODS: This study utilized the immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, and hematoxylin and eosin staining methods to investigate the mechanism of AS-IV in reducing viral pneumonia caused by influenza A virus in A549 cells and BALB/c mice. RESULTS: The results showed that AS-IV suppressed reactive oxygen species production in influenza virus-infected A549 cells in a dose-dependent manner, and subsequently inhibited the activation of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 inflammasome and Caspase-1, decreased interleukin (IL) -1ß and IL-18 secretion. In BALB/c mice infected with Poly (I:C), oral administration of AS-IV can significantly reduce Poly (I:C)-induced acute pneumonia and lung pathological injury. CONCLUSIONS: AS-IV alleviates the inflammatory response induced by influenza virus in vitro and lung flammation and structural damage caused by poly (I:C) in vivo.

The Rehabilitation Efficacy of the Novel Metronomic Breathing Technique for Gerontic Patients After Percutaneous Coronary Intervention for Acute Myocardial Infarction-A Pilot Study.

Background: The respiratory rehabilitation technique is a crucial component of early cardiac recovery in geriatric patients with acute myocardial infarction (AMI). This study primarily investigated the effectiveness of a novel respiratory rehabilitation technique, metronomic breathing (MB), on geriatric patients after percutaneous coronary intervention for AMI and compliance with home-based rehabilitation compared to traditional respiratory rehabilitation. Methods: From June 2022 to March 2023, 75 acute myocardial infarction (AMI) patients admitted to the Shanghai Tenth People's Hospital Cardiovascular Department were consecutively enrolled. Ultimately, 46 patients completed the follow-up in this study-26 in the MB group and 20 in the control group-who underwent the novel MB technique and conventional abdominal breathing training. The primary endpoint of the study was left ventricular function measured by noninvasive hemodynamics three months after discharge. The secondary endpoints were compliance and quality of life after three months of home rehabilitation. Results: After the intervention, several cardiac functional parameters (SV, SVI, CO, CI, LCW, and LCWI), myocardial contractility parameters (VI), and systemic vascular resistance parameters (SVR and SVRI) were significantly greater in the MB group than in the preintervention group (P < 0.05). Furthermore, post-treatment, the MB group exhibited greater SV, SVI, CO, CI, and VI; lower SVR, SVRI, and SBP; and a lower readmission rate three months later than did the control group. The SF-36 scores after three months of MB intervention, PE, BP, GH, VT, SF, RE, and MH, were all significantly greater than those before treatment (P < 0.05). Moreover, the MB group displayed greater compliance with home-based cardiac rehabilitation (P < 0.05). Conclusion: Compared to conventional respiratory rehabilitation training methods, short-term metronomic respiratory therapy is more effective for reducing systemic vascular resistance, enhancing left ventricular ejection function, enhancing quality of life, and increasing home-based rehabilitation compliance in geriatric patients following AMI with PCI.

The association between HLA-B variants and amoxicillin-induced severe cutaneous adverse reactions in Chinese han population.

Background: Amoxicillin (AMX) is among the most prescribed and the best tolerated antimicrobials worldwide. However, it can occasionally trigger severe cutaneous adverse reactions (SCAR) with a significant morbidity and mortality. The genetic factors that may be relevant to AMX-induced SCAR (AMX-SCAR) remain unclear. Identification of the genetic risk factor may prevent patients from the risk of AMX exposure and resume therapy with other falsely implicated drugs. Methodology: Four patients with AMX-SCAR, 1,000 population control and 100 AMX-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between AMX and risk HLA proteins. Results: Compared with AMX-tolerant controls, a significant association of HLA-B*15:01 with AMX-SCAR was validated [odds ratio (OR) = 22.9, 95% confidence interval (CI): 1.68-1275.67; p = 7.34 × 10-3]. Moreover, 75% carriers of HLA-B*15:01 in four patients with AMX-SCAR, and the carrier frequency of 10.7% in 1,000 control individuals and 11.0% in 100 AMX-tolerant controls, respectively. Within HLA-B protein, the S140 present in all cases and demonstrated the strongest association with AMX-SCAR [OR = 53.5, p = 5.18 × 10-4]. Molecular docking results also confirmed the interaction between AMX and S140 of the HLA-B protein, thus eliminating the false-positive results during in association analysis. Conclusion: Our findings suggest that genetic susceptibility may be involved in the development of AMX-SCAR in Han Chinese. However, whether the HLA-B variants observed in this study can be used as an effective genetic marker of AMX-induced SCAR still needs to be further explored in larger cohort studies and other ethnic populations.

Type 2 diabetes mellitus and cardiovascular health: Evidence of causal relationships in a European ancestry population.

AIMS: Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular disease (CVD) risk, but whether T2DM directly causes adverse cardiac remodelling is uncertain. We performed a comprehensive Mendelian randomization (MR) analysis to investigate the causal relevance of T2DM to CVD outcomes and cardiac structure/function. METHODS AND RESULTS: Bidirectional two-sample MR was conducted using summary-level data from European-ancestry genome-wide association studies. The T2DM GWAS data included 80 154 cases and 853 816 controls from the DIAGRAM consortium. Outcomes included coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure, atrial fibrillation, and various quantitative cardiac imaging traits assessed by magnetic resonance imaging. MR analysis revealed causal associations between genetic predisposition to T2DM and increased risk of CAD (odds ratio [OR] 1.104, 95% confidence interval [CI] 1.078-1.130, P = 2.59e-16), MI (OR 1.129, 95% CI 1.094-1.166, P = 6.02e-14) and stroke (OR 1.086, 95% CI 1.064-1.109, P = 1.02e-14). These associations were validated in the FinnGen cohort (CAD: OR 1.117, 95% CI 1.075-1.158, P = 1.56e-9; MI: OR 1.132, 95% CI 1.083-1.184, P = 4.27e-8; stroke: OR 1.138, 95% CI 1.107-1.170, P = 3.52e-20). Multivariable MR show consistent findings (CAD: OR 1.063, 95% CI 1.031-1.097, P = 1.11e-4; MI: OR 1.088, 95% CI 1.042-1.135, P = 1.12e-4; stroke: OR 1.066, 95% CI 1.032-1.101, P = 1.18e-4) after adjusting for cardiometabolic traits. T2DM was causally associated with higher left ventricular mass index (ß = 0.473, 95% CI 0.193 to 0.752, P = 0.001), lower indexed right atrial minimum (ß = -0.048, 95% CI -0.073 to -0.022, P = 2.1e-5), and maximum (ß = -0.042, 95% CI -0.065 to -0.019, P = 4.12e-5) areas. The effects on right atrial size remained significant after adjusting for risk factors (minimum area: ß = -0.041, 95% CI -0.072 to -0.010, P = 0.009; maximum area: ß = -0.039, 95% CI -0.069 to -0.008, P = 0.012). Both apolipoprotein A1 and SBP are important mediators in the causal relationship between T2DM and left ventricular mass index. No reverse causal associations were identified. CONCLUSIONS: Our MR study demonstrates that genetic liability to T2DM plays causal roles in CAD, MI, stroke, and cardiac structure changes including left ventricular hypertrophy and reduced right atrial dimensions. These findings provide genetic evidence supporting glycaemic control in T2DM to mitigate cardiovascular complications and adverse cardiac remodelling.

Single-tissue proteomics in Caenorhabditis elegans reveals proteins resident in intestinal lysosome-related organelles.

The nematode intestine is the primary site for nutrient uptake and storage as well as the synthesis of biomolecules; lysosome-related organelles known as gut granules are important for many of these functions. Aspects of intestine biology are not well understood, including the export of the nutrients it imports and the molecules it synthesizes, as well as the complete functions and protein content of the gut granules. Here, we report a mass spectrometry (MS)-based proteomic analysis of the intestine of the Caenorhabditis elegans and of its gut granules. Overall, we identified approximately 5,000 proteins each in the intestine and the gonad and showed that most of these proteins can be detected in samples extracted from a single worm, suggesting the feasibility of individual-level genetic analysis using proteomes. Comparing proteomes and published transcriptomes of the intestine and the gonad, we identified proteins that appear to be synthesized in the intestine and then transferred to the gonad. To identify gut granule proteins, we compared the proteome of individual intestines deficient in gut granules to the wild type. The identified gut granule proteome includes proteins known to be exclusively localized to the granules and additional putative gut granule proteins. We selected two of these putative gut granule proteins for validation via immunohistochemistry, and our successful confirmation of both suggests that our strategy was effective in identifying the gut granule proteome. Our results demonstrate the practicability of single-tissue MS-based proteomic analysis in small organisms and in its future utility.

Social support, health behavior self-efficacy, and anxiety on physical activity levels among lung cancer survivors: a structural equation modeling.

PURPOSE: The study aims to investigate the relationship among social support, health behavior self-efficacy, anxiety, and the physical activity (PA) levels of lung cancer survivors, and to analyze whether health behavior self-efficacy and anxiety mediate the relationship between social support and PA levels. METHODS: In a cross-sectional study of 1128 lung cancer survivors from 16 Chinese hospitals, we collected demographic data and administered the Social Support Rating Scale (SSRS), Self-Rated Abilities for Health Practices Scale (SRAHP), Anxiety Scale (AS), and International Physical Activity Questionnaire (IPAQ). SPSS 25.0 was used for descriptive analyses, while the structural equation model in SPSS AMOS 24.0 was used to identify the direct, indirect, and total effects among variables. RESULTS: There were significant correlations among SSRS, SRAHP, AS, and PA (P < 0.01). Model outcomes revealed a positive association between social support and health behavior self-efficacy (ß = 0.732, P < 0.001). Health behavior self-efficacy positively correlated with PA levels (ß = 0.228, P < 0.001) and negatively with anxiety (ß=-0.252, P = 0.001). Moreover, health behavior self-efficacy was found to partially mediate the relationship between social support and PA (ß = 0.174, P < 0.001). CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: This study revealed a positive correlation between social support and health behavior self-efficacy, and between health behavior self-efficacy and PA levels among lung cancer survivors. Additionally, health behavior self-efficacy mediated the relationship between social support and PA levels. In future clinical practice, medical and nursing staff should assess social support and health behavior self-efficacy in lung cancer survivors to inform personalized PA interventions.

Progress of research and application of Heyndrickxia coagulans (Bacillus coagulans) as probiotic bacteria.

Probiotics are defined as living or dead bacteria and their byproducts that maintain the balance of the intestinal microbiome. They are non-toxic, non-pathogenic, and do not release any toxins either within or outside the body. Adequate consumption of probiotics can enhance metabolite production, increase immunity, maintain a balanced intestinal flora, and stimulate growth. Probiotics do not have negative antibiotic effects and help maintain the natural flora in animals in a balanced state or prevent dysbacteriosis. Heyndrickxia coagulans (H. coagulans) is a novel probiotic species that is gradually being used for the improvement of human health. Compared to commonly used probiotic lactic acid bacteria, H. coagulans can produce spores, which provide the species with high resistance to adverse conditions. Even though they are transient residents of the gut, beneficial bacteria can have a significant impact on the microbiota because they can outnumber harmful germs, and vice versa. This article discusses the probiotic mechanisms of H. coagulans and outlines the requirements for a substance to be classified as a probiotic. It also addresses how to assess strains that have recently been discovered to possess probiotic properties.

Modulation of electronic structure of Ni3S2 via Fe and Mo co-doping to enhance the bifunctional electrocatalytic activities for HER and OER.

Heazlewoodite nickel sulfide (Ni3S2) is advocated as a promising nonnoble catalyst for electrochemical water splitting because of its unique structure configuration and high conductivity. However, the low active sites and strong sulfur-hydrogen bonds (S-Hads) formed on Ni3S2 surface greatly inhibit the desorption of Hads and reduce the hydrogen and oxygen evolution reaction (HER and OER) activity. Doping is a valid strategy to stimulate the intrinsic catalytic activity of pristine Ni3S2 via modifying the active site. Herein, the Ni foam supported Fe and Mo co-doped Ni3S2 electrocatalysts (Fe-MoS2/Ni3S2@NF) have been constructed using Keplerate polyoxomolybdate {Mo72F30} as precursor through a facile hydrothermal process. Experimental results certificate that Fe and Mo co-doping can effectively tune the local electronic structure, facilitate the interfacial electron transfer, and improve the intrinsic activity. Consequently, the Fe-MoS2/Ni3S2@NF display more excellent HER and OER activity than MoS2/Ni3S2@NF and bare Ni3S2@NF by delivering the 10 and 50 mA cm-2 current densities at ultra-low overpotentials of 74/175 and 80/160 mV for HER and OER. Moreover, when coupled in an alkaline electrolyzer, Fe-MoS2/Ni3S2@NF approached the current of 10 mA cm-2 under a cell voltage of 1.60 V and exhibit excellent stability. The strategy to realize tunable catalytic behaviors via foreign metal doping provides a new avenue to optimize the water splitting catalysts.

Topical ophthalmic instillation of engineered hMSCs-derived exosomes: A novel non-invasive therapeutic strategy for ocular posterior-segment disorder.

Due to the presence of protective mechanisms and blood-ocular barriers in the eye, drugs aimed at treating posterior segment ophthalmic disorder have to be administrated mostly through periocular or intravitreal injection. In the current study, we sought to investigate whether topical ophthalmic instillation of human mesenchymal stem cells (hMSCs)-derived exosomes can prevent and treat experimental autoimmune uveitis (EAU), a posterior segment ophthalmic disease induced in animals and considered a model of human autoimmune diseases of the eye. Our studies reveal that topical ophthalmic instillation of hMSCs-derived exosomes can effectively ameliorate EAU. More importantly, we demonstrate that exosomes modified by trans-activator of transcription peptide (TAT) were more effective than naive exosomes in penetrating ocular barrier and preventing/treating EAU. Taken together, these results indicate that topical ophthalmic instillation of TAT-peptide modified exosomes represents a novel non-invasive therapeutic strategy for posterior-segment ophthalmic disorders.

Low Driving Voltage Electroluminescence Device for Integrated Visual Strain Sensing.

As a pivotal component in human-machine interactions, display devices have undergone rapid development in modern life. Displays such as alternative current electroluminescence|alternative current electroluminescent (ACEL) devices with high flexibility and long operational lifetimes are essential for wearable electronics. However, ACEL devices are constrained by their inherent high driving voltage and complex fabrication processes. Our work presents an easy blade-coating method for fabricating flexible ACEL display devices based on an all-solution process. By dispersing BaTiO3 and ZnS/Cu powder into waterborne polyurethane, we successfully combined dielectric and fluorescence functionalities within a single layer, significantly reducing the device's driving voltage. Additionally, the ionic conducting hydrogel was chosen as a transparent electrode to achieve good electrical contact and strong interfacial adhesion through in situ polymerization. Owing to the unique method, our ACEL device exhibits high flexibility, low driving voltage (20-100 V), high brightness (300+ cd/m2 at 60 V), and environmental friendliness. Furthermore, by repurposing the hydrogel electrode, we integrated strain visualization capabilities within a single device, highlighting its potential for applications such as wearable healthcare monitoring.

Metabolic features of adolescent major depressive disorder: A comparative study between treatment-resistant depression and first-episode drug-naive depression.

Major depressive disorder (MDD) is a psychiatric illness that can jeopardize the normal growth and development of adolescents. Approximately 40% of adolescent patients with MDD exhibit resistance to conventional antidepressants, leading to the development of Treatment-Resistant Depression (TRD). TRD is associated with severe impairments in social functioning and learning ability and an elevated risk of suicide, thereby imposing an additional societal burden. In this study, we conducted plasma metabolomic analysis on 53 adolescents diagnosed with first-episode drug-naïve MDD (FEDN-MDD), 53 adolescents with TRD, and 56 healthy controls (HCs) using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) and reversed-phase liquid chromatography-mass spectrometry (RPLC-MS). We established a diagnostic model by identifying differentially expressed metabolites and applying cluster analysis, metabolic pathway analysis, and multivariate linear support vector machine (SVM) algorithms. Our findings suggest that adolescent TRD shares similarities with FEDN-MDD in five amino acid metabolic pathways and exhibits distinct metabolic characteristics, particularly tyrosine and glycerophospholipid metabolism. Furthermore, through multivariate receiver operating characteristic (ROC) analysis, we optimized the area under the curve (AUC) and achieved the highest predictive accuracy, obtaining an AUC of 0.903 when comparing FEDN-MDD patients with HCs and an AUC of 0.968 when comparing TRD patients with HCs. This study provides new evidence for the identification of adolescent TRD and sheds light on different pathophysiologies by delineating the distinct plasma metabolic profiles of adolescent TRD and FEDN-MDD.

Prediction of Prognosis in Patients with Sepsis Based on Platelet-Related Genes.

The study aimed to develop a risk prognostic model using platelet-related genes (PRGs) to predict sepsis patient outcomes. Sepsis patient data from the Gene Expression Omnibus (GEO) database and PRGs from the Molecular Signatures Database (MSigDB) were analyzed. Differential analysis identified 1139 differentially expressed genes (DEGs) between sepsis and control groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed enrichment in functions related to immune cell regulation and pathways associated with immune response and infectious diseases. A risk prognostic model was established using LASSO and Cox regression analyses, incorporating 10 PRGs selected based on their association with sepsis prognosis. The model demonstrated good stratification and prognostic effects, confirmed by survival and receiver operating characteristic (ROC) curve analyses. It served as an independent prognostic factor in sepsis patients. Further analysis using the CIBERSORT algorithm showed higher infiltration of activated natural killer (NK) cells and lower infiltration of CD8 T cells and CD4 T cells naïve in the high-risk group compared to the low-risk group. Additionally, expression levels of human leukocyte antigen (HLA) genes were significantly lower in the high-risk group. In conclusion, the 10-gene risk model based on PRGs accurately predicted sepsis patient prognosis and immune infiltration levels. This study provides valuable insights into the role of platelets in sepsis prognosis and diagnosis, offering potential implications for personalized treatment strategies.

Chemopreventive effects of atractylenolide-III on mammary tumorigenesis via activation of the Nrf2/ARE pathway through autophagic degradation of Keap1.

The incidence of breast cancer is increasing annually, making it a major health threat for women. Chemoprevention using natural, dietary, or synthetic products has emerged as a promising approach to address this growing burden. Atractylenolide-III (AT-III), a sesquiterpenoid present in various medicinal herbs, has demonstrated potential therapeutic effects against several diseases, including tumors, nonalcoholic fatty liver disease, and cerebral ischemic injury. However, its impact on breast cancer chemoprevention remains unexplored. In this study, we used an N-methyl-N-nitrosourea (NMU)-induced rat breast cancer model and 17ß-estradiol (E2)-treated MCF-10A cells to evaluate the chemopreventive potential of AT-III on mammary tumorigenesis. AT-III inhibited mammary tumor progression, evidenced by reduced tumor volume and multiplicity, prolonged tumor latency, and the reversal of NMU-induced weight loss. Furthermore, AT-III suppressed NMU-induced inflammation and oxidative stress through the Nrf2/ARE pathway in breast cancer tissues. In vitro, AT-III effectively suppressed E2-induced anchorage-independent growth and cell migration in MCF-10A cells. Nrf2 knockdown attenuated the protective effects of AT-III, highlighting the pivotal role of Nrf2 in AT-III-mediated suppression of tumorigenesis. The mechanism involves the induction of Nrf2 expression by AT-III through the autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Overall, the results of this study indicate that AT-III is a promising candidate for breast cancer chemoprevention and provide valuable insights into its molecular interactions and signaling pathways.

PE/PPE mutations in the transmission of Mycobacterium tuberculosis in China revealed by whole genome sequencing.

OBJECTIVE: This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China. METHODS: We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association. RESULTS: Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C). CONCLUSION: Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.

Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.