Cracking the Code: Enhancing Molecular Tools for Progress in Nanobiotechnology.

Nature continually refines its processes for optimal efficiency, especially within biological systems. This article explores the collaborative efforts of researchers worldwide, aiming to mimic nature's efficiency by developing smarter and more effective nanoscale technologies and biomaterials. Recent advancements highlight progress and prospects in leveraging engineered nucleic acids and proteins for specific tasks, drawing inspiration from natural functions. The focus is developing improved methods for characterizing, understanding, and reprogramming these materials to perform user-defined functions, including personalized therapeutics, targeted drug delivery approaches, engineered scaffolds, and reconfigurable nanodevices. Contributions from academia, government agencies, biotech, and medical settings offer diverse perspectives, promising a comprehensive approach to broad nanobiotechnology objectives. Encompassing topics from mRNA vaccine design to programmable protein-based nanocomputing agents, this work provides insightful perspectives on the trajectory of nanobiotechnology toward a future of enhanced biomimicry and technological innovation.

[Research progress on the role of endothelial mechanically sensitive ion channel protein Piezo1 in diseases].

Endothelial cells have important physiological functions and regulatory effects related to the occurrence and development of various diseases. Piezo1 is a mechanically sensitive ion channel protein, which is widely distributed in various tissues of the body and participates in the occurrence and development of various diseases. Piezo1 is highly expressed in endothelial cells and plays an important regulatory role in endothelial cell function. This article reviews the structure and function of Piezo1, the physiological function and pathological damage mechanism of endothelial cells, and the role of endothelial cell Piezo1 in various diseases, in order to understand the function and regulation mechanism of endothelial cell Piezo1, and provide new targets and strategies for the treatment of related diseases.

Exosome-related lncRNA score: A value-based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non-coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. AIMS: The purpose of this study is to construction a exosomes-related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. METHODS: Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes-related lncRNAs (ERLRs) from Top10 exosomes-related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs-based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high- and low-risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. RESULTS: A score consisting of 4ERLRs was identified, and patients with higher ERLRs-based score tended to have a worse prognosis than those with lower ERLRs-based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III-IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa-miR-31-5p/TLN2 axis. CONCLUSIONS: Based on machine learning, a novel ERLRs-based score was constructed for predicting the survival of ccRCC patients. The ERLRs-based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa-miR-31-5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

Generalized Multifunctional Coating Strategies Based on Polyphenol-Amine-Inspired Chemistry and Layer-by-Layer Deposition for Blood Contact Catheters.

Blood-contacting catheters play a pivotal role in contemporary medical treatments, particularly in the management of cardiovascular diseases. However, these catheters exhibit inappropriate wettability and lack antimicrobial characteristics, which often lead to catheter-related infections and thrombosis. Therefore, there is an urgent need for blood contact catheters with antimicrobial and anticoagulant properties. In this study, we employed tannic acid (TA) and 3-aminopropyltriethoxysilane (APTES) to create a stable hydrophilic coating under mild conditions. Heparin (Hep) and poly(lysine) (PL) were then modified on the TA-APTES coating surface using the layer-by-layer (LBL) technique to create a superhydrophilic TA/APTES/(LBL)4 coating on silicone rubber (SR) catheters. Leveraging the superhydrophilic nature of this coating, it can be effectively applied to blood-contacting catheters to impart antibacterial, antiprotein adsorption, and anticoagulant properties. Due to Hep's anticoagulant attributes, the activated partial thromboplastin time and thrombin time tests conducted on SR/TA-APTES/(LBL)4 catheters revealed remarkable extensions of 276 and 103%, respectively, when compared to uncoated commercial SR catheters. Furthermore, the synergistic interaction between PL and TA serves to enhance the resistance of SR/TA-APTES/(LBL)4 catheters against bacterial adherence, reducing it by up to 99.9% compared to uncoated commercial SR catheters. Remarkably, the SR/TA-APTES/(LBL)4 catheter exhibits good biocompatibility with human umbilical vein endothelial cells in culture, positioning it as a promising solution to address the current challenges associated with blood-contact catheters.

New directions for Ψ and m1A decoding in mRNA: deciphering the stoichiometry and function.

Over the past decade, advancements in epitranscriptomics have significantly enhanced our understanding of mRNA metabolism and its role in human development and diseases. This period has witnessed breakthroughs in sequencing technologies and the identification of key proteins involved in RNA modification processes. Alongside the well-studied m6A, Ψ and m1A have emerged as key epitranscriptomic markers. Initially identified through transcriptome-wide profiling, these modifications are now recognized for their broad impact on RNA metabolism and gene expression. In this Perspective, we focus on the detections and functions of Ψ and m1A modifications in mRNA and discuss previous discrepancies and future challenges. We summarize recent advances and highlight the latest sequencing technologies for stoichiometric detection and their mechanistic investigations for functional unveiling in mRNA as the new research directions.

Improving Blood Pressure Control and Pregnancy Outcomes: The Impact of Evidence-Based Care and Aerobic Exercise in Patients with Hypertensive Disorders During Pregnancy.

Objective: To explore the effect of evidence-based care plus aerobic exercise on blood pressure control and pregnancy outcome in patients with hypertensive disorders during pregnancy. Methods: A total of 100 patients diagnosed with hypertensive disorder in pregnancy treated in our hospital between February 2020 and November 2021 were recruited, analyzed and assigned at a ratio of 1:1 to receive routine nursing (control group) or evidence-based care plus aerobic exercise (experimental group) via random number table method. Outcome measures included blood pressure, negative emotions, sleep duration, and pregnancy outcome. Results: The blood pressure of both groups decreased after nursing, and the diastolic and systolic blood pressure of patients in the experimental group (79.84±5.18 mmHg, 111.62±7.96 mmHg) were lower than those in the control group (88.65±5.69 mmHg, 132.15±8.14 mmHg) (P < .05). After the completion of the nursing period, assessments using the Self-Rating Anxiety Scale and Hamilton Depression Scale were conducted. The results revealed significantly lower scores in the experimental group, which received evidence-based care along with aerobic exercise, compared to the control patients who received routine care. The sleep duration was prolonged in both groups after nursing, and patients in the experimental group got longer sleep duration than those in the control group (P < .05). The experimental group showed a significantly lower incidence of adverse pregnancy outcomes than the control group (P < .05). Limitations: While our study demonstrates the positive impact of evidence-based care combined with moderate aerobic exercise on patients with hypertensive disorders during pregnancy, it is essential to acknowledge some notable limitations. First, the sample size was relatively small, which may limit the generalizability of our findings to a larger population. Furthermore, our study primarily focused on short-term outcomes, and future research could explore the sustained benefits of this approach. Finally, individual variations in exercise tolerance and compliance may also affect the effectiveness of the intervention. Despite these limitations, our findings hold promise and provide a foundation for further research in this area. Conclusion: Evidence-based care combined with moderate aerobic exercise has proven to be an effective approach in enhancing the overall management of patients with hypertensive disorders during pregnancy. This combined intervention not only effectively regulates blood pressure levels but also mitigates adverse emotional states, enhances sleep quality, and ultimately leads to improved pregnancy outcomes. These findings hold significant promise for clinical application. Healthcare providers may consider implementing this approach to improve the well-being of pregnant individuals with hypertensive disorders, potentially reducing the risk of complications and enhancing the overall quality of care. Pregnant individuals, on the other hand, can benefit from a more comprehensive and holistic approach to their care, which may result in better health and pregnancy outcomes. Future research in this area could explore the long-term sustainability and cost-effectiveness of this intervention, as well as its potential applicability to diverse patient populations and healthcare settings.

Understanding COVID-19-associated endothelial dysfunction: role of PIEZO1 as a potential therapeutic target.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Due to its high infectivity, the pandemic has rapidly spread and become a global health crisis. Emerging evidence indicates that endothelial dysfunction may play a central role in the multiorgan injuries associated with COVID-19. Therefore, there is an urgent need to discover and validate novel therapeutic strategies targeting endothelial cells. PIEZO1, a mechanosensitive (MS) ion channel highly expressed in the blood vessels of various tissues, has garnered increasing attention for its potential involvement in the regulation of inflammation, thrombosis, and endothelial integrity. This review aims to provide a novel perspective on the potential role of PIEZO1 as a promising target for mitigating COVID-19-associated endothelial dysfunction.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

N6-methyladenosine-modified circ_104797 sustains cisplatin resistance in bladder cancer through acting as RNA sponges.

BACKGROUND: Bladder cancer (BCa) ranks among the predominant malignancies affecting the urinary system. Cisplatin (CDDP) remains a cornerstone therapeutic agent for BCa management. Recent insights suggest pivotal roles of circular RNA (circRNA) and N6-methyladenosine (m6A) in modulating CDDP resistance in BCa, emphasizing the importance of elucidating these pathways to optimize cisplatin-based treatments. METHODS: Comprehensive bioinformatics assessments were undertaken to discern circ_104797 expression patterns, its specific interaction domains, and m6A motifs. These findings were subsequently corroborated through experimental validations. To ascertain the functional implications of circ_104797 in BCa metastasis, in vivo assays employing CRISPR/dCas13b-ALKBH5 were conducted. Techniques, such as RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assays, and western blotting, were employed to delineate the underlying molecular intricacies. RESULTS: Our investigations revealed an elevated expression of circ_104797 in CDDP-resistant BCa cells, underscoring its pivotal role in sustaining cisplatin resistance. Remarkably, demethylation of circ_104797 markedly augmented the potency of cisplatin-mediated apoptosis. The amplification of circ_104797 in CDDP-resistant cells was attributed to enhanced RNA stability, stemming from an augmented m6A level at a distinct adenosine within circ_104797. Delving deeper, we discerned that circ_104797 functioned as a microRNA reservoir, specifically sequestering miR-103a and miR-660-3p, thereby potentiating cisplatin resistance. CONCLUSIONS: Our findings unveil a previously uncharted mechanism underpinning cisplatin resistance and advocate the potential therapeutic targeting of circ_104797 in cisplatin-administered patients with BCa, offering a promising avenue for advanced BCa management.

Simultaneous single-cell analysis of 5mC and 5hmC with SIMPLE-seq.

Dynamic 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications to DNA regulate gene expression in a cell-type-specific manner and are associated with various biological processes, but the two modalities have not yet been measured simultaneously from the same genome at the single-cell level. Here we present SIMPLE-seq, a scalable, base resolution method for joint analysis of 5mC and 5hmC from thousands of single cells. Based on orthogonal labeling and recording of 'C-to-T' mutational signals from 5mC and 5hmC sites, SIMPLE-seq detects these two modifications from the same molecules in single cells and enables unbiased DNA methylation dynamics analysis of heterogeneous biological samples. We applied this method to mouse embryonic stem cells, human peripheral blood mononuclear cells and mouse brain to give joint epigenome maps at single-cell and single-molecule resolution. Integrated analysis of these two cytosine modifications reveals distinct epigenetic patterns associated with divergent regulatory programs in different cell types as well as cell states.

Multiple organs injury and myocardial energy metabolism disorders induced by isoproterenol.

The study sought to assess the detrimental effects of isoproterenol (ISO) on major organs and investigate the potential reversibility of these adverse reactions in mice. Male mice were divided into normal control, 0.2 mg/kg.d and 3.0 mg/kg.d ISO groups, and were subcutaneously administered of the respective doses for 14 consecutive days. Subsequently, a recovery period experiment was conducted, replicating the aforementioned procedure, followed by an additional 2-week recovery period for the mice. Following 14 consecutive days of administration, mice treated with ISO exhibited notable cardiac damage manifested by abnormal ECG patterns, dysregulated energy metabolism, elevated cardiac hypertrophy, and increased heart pathological score. Additionally, the administration of ISO resulted in liver and kidney damage, as evidenced by increased pathological score, serum albumin level, and urea level. Lung damage was also observed, indicated by an increase in lung pathological score. Furthermore, the administration of ISO at a dosage of 3.0 mg/kg.d resulted in a decrease in liver mass index, serum iron content, and an increase in lung mass index. After a 2-week recovery period, mice treated with ISO showed abnormalities in ECG patterns and dysregulated myocardial energy metabolism, accompanied by a decrease in serum iron content. Histopathological examinations revealed continued pathological changes in the heart and lung, as well as significant hemosiderin deposition in the spleen. Furthermore, the group treated with ISO at a dosage of 3.0 mg/kg.d showed an increase in serum AST and TP levels. In summary, the study demonstrates that both 0.2 mg/kg.d and 3.0 mg/kg.d doses of ISO can induce damage to the heart, liver, lung, kidney, and spleen, with the higher dose causing more severe injuries. After a 2-week withdrawal period, the liver, kidney, and thymus injuries caused by 0.2 mg/kg ISO shows signs of recovery, while damage to the heart, lung, and spleen persists. The thymus injury mostly recovers, with minimal kidney pathology, but significant damage to the heart, liver, and lung remains even after the withdrawal period for the 3.0 mg/kg ISO dose.

Major cardiovascular events under biologic psoriasis therapies: a 19-year real-world analysis of FAERS data.

Objective: Over the years when biologic psoriasis therapies (TNF inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, and IL-17 inhibitors) have been used in psoriasis patients, reports of major cardiovascular events (MACEs) have emerged. This study aims to investigate the association between MACEs and biologic psoriasis therapies by using information reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: FAERS data (January 2004 to December 2022) were reviewed. For each drug-event pair, the proportional reporting ratio (PRR) and the multi-item gamma Poisson shrinker (MGPS) algorithms were used to identify drug-adverse event associations. Results: We filtered the query for indication and identified 173,330 reports with psoriasis indication in FAERS throughout the analyzed time frame. MACEs occurred in 4,206 patients treated with biologics. All the four biological classes had an elevated and similar reporting rates for MACEs relative to other alternative psoriasis treatments (PRR from 2.10 to 4.26; EB05 from 1.15 to 2.45). The descending order of association was IL-12/23 inhibitors>IL-17 inhibitors>IL-23 inhibitors>TNF inhibitors. The signal strength for myocardial infarction (PRR, 2.86; χ2, 296.27; EBGM 05, 1.13) was stronger than that for stroke, cardiac fatality, and death. All the biological classes demonstrated a little higher EBGM 05 score≥1 for the MACEs in patients aged 45-64 years. The time-to-onset of MACEs was calculated with a median of 228 days. Conclusions: Analysis of adverse event reports in the FAERS reflects the potential risk of MACEs associated with the real-world use of biological therapies in comparison to other alternative psoriasis treatments. Future long-term and well-designed studies are needed to further our knowledge regarding the cardiovascular safety profile of these agents.

Age-related noncanonical TRMT6-TRMT61A signaling impairs hematopoietic stem cells.

Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity and differentiation bias toward myeloid lineages. However, the molecular mechanism behind HSC aging remains largely unknown. In this study, we observed that RNA N1-methyladenosine-generating methyltransferase TRMT6-TRMT61A complex is increased in aged murine HSCs due to aging-declined CRL4DCAF1-mediated ubiquitination degradation signaling. Unexpectedly, no difference of tRNA N1-methyladenosine methylome is observed between young and aged hematopoietic stem and progenitor cells, suggesting a noncanonical role of the TRMT6-TRMT61A complex in the HSC aging process. Further investigation revealed that enforced TRMT6-TRMT61A impairs HSCs through 3'-tiRNA-Leu-CAG and subsequent RIPK1-RIPK3-MLKL-mediated necroptosis cascade. Deficiency of necroptosis ameliorates the self-renewal capacity of HSCs and counters the physiologically deleterious effect of enforced TRMT6-TRMT61A on HSCs. Together, our work uncovers a nonclassical role for the TRMT6-TRMT61A complex in HSC aging and highlights a therapeutic target.

Efficacy of Quality Care on Maternal and Infant Outcomes in Patients with Hypertensive Disorders Complicating Pregnancy Complicated with Cerebral Hemorrhage.

Objective: This study aimed to evaluate the impact of quality care on maternal and infant outcomes in patients with hypertensive disorders complicating pregnancy (HDCP) complicated by cerebral hemorrhage. Methods: From February 2020 to September 2021, 68 women with HDCP complicated by cerebral hemorrhage hospitalized at our hospital were included and divided into a routine group (standard care) and a quality group (quality care). Outcome measures included National Institutes of Health Stroke Scale (NIHSS) scores, blood pressure, self-rating anxiety scale (SAS) scores, self-rating depression scale (SDS) scores, and maternal and infant outcomes. Results: Patients in the quality group (3.22±1.89) had significantly lower NIHSS scores aftercare than those in the routine group (6.15±3.24) (P < .05). Quality care resulted in lower diastolic blood pressure (Quality group:81.23±6.15; Routine: 90.58±7.98), systolic blood pressure (Quality group:125.49±13.37; Routine: 139.74±16.67), SAS scores (Quality group: 48.42±2.65; Routine: 58.15±2.43), and SDS scores versus routine care (Quality group:48.42±2.65; Routine: 58.15±2.43)(P < .05). The quality group showed a lower incidence of adverse maternal and infant pregnancy outcomes than the routine group (P < .05). Conclusion: The findings underscore the positive impact of quality care in reducing adverse maternal and newborn pregnancy outcomes. This reduction is particularly significant for clinical practice, as it is achieved through the amelioration of various factors, such as neurological impairments, blood pressure regulation, and the alleviation of negative emotions, including anxiety and depression, in patients with HDCP complicated by cerebral hemorrhage. The practical implications of these findings for healthcare providers and patients are substantial. They highlight the potential to improve patient outcomes, enhance the overall quality of care, and reduce the burden on healthcare systems. By addressing these factors, healthcare providers can enhance the well-being of both mothers and newborns, leading to improved clinical outcomes and increased patient satisfaction.

Enhancing Ki-67 Prediction in Breast Cancer: Integrating Intratumoral and Peritumoral Radiomics From Automated Breast Ultrasound via Machine Learning.

RATIONALE AND OBJECTIVES: Traditional Ki-67 evaluation in breast cancer (BC) via core needle biopsy is limited by repeatability and heterogeneity. The automated breast ultrasound system (ABUS) offers reproducibility but is constrained to morphological and echoic assessments. Radiomics and machine learning (ML) offer solutions, but their integration for improving Ki-67 predictive accuracy in BC remains unexplored. This study aims to enhance ABUS by integrating ML-assisted radiomics for Ki-67 prediction in BC, with a focus on both intratumoral and peritumoral regions. MATERIALS AND METHODS: A retrospective analysis was conducted on 936 BC patients, split into training (n = 655) and testing (n = 281) cohorts. Radiomics features were extracted from intra- and peritumoral regions via ABUS. Feature selection involved Z-score normalization, intraclass correlation, Wilcoxon rank sum tests, minimum redundancy maximum relevance, and least absolute shrinkage and selection operator logistic regression. ML classifiers were trained and optimized for enhanced predictive accuracy. The interpretability of the optimized model was further augmented by employing Shapley additive explanations (SHAP). RESULTS: Of the 2632 radiomics features in each patient, 15 were significantly associated with Ki-67 levels. The support vector machine (SVM) was identified as the optimal classifier, with area under the receiver operating characteristic curve values of 0.868 (training) and 0.822 (testing). SHAP analysis indicated that five peritumoral and two intratumoral features, along with age and lymph node status, were key determinants in the predictive model. CONCLUSION: Integrating ML with ABUS-based radiomics effectively enhances Ki-67 prediction in BC, demonstrating the SVM model's strong performance with both radiomics and clinical factors.

A NIR-driven green affording-oxygen microrobot for targeted photodynamic therapy of tumors.

Photodynamic therapy (PDT) is a light-activated local treatment modality that has promising potential in cancer therapy. However, ineffective delivery of photosensitizers and hypoxia in the tumor microenvironment severely restrict the therapeutic efficacy of PDT. Herein, phototactic Chlorella (C) is utilized to carry photosensitizer-encapsulated nanoparticles to develop a near-infrared (NIR) driven green affording-oxygen microrobot system (CurNPs-C) for enhanced PDT. Photosensitizer (curcumin, Cur) loaded nanoparticles are first synthesized and then covalently attached to C through amide bonds. An in vitro study demonstrates that the developed CurNPs-C exhibits continuous oxygen generation and desirable phototaxis under NIR treatment. After intravenous injection, the initial 660 nm laser irradiation successfully induces the active migration of CurNPs-C to tumor sites for higher accumulation. Upon the second 660 nm laser treatment, CurNPs-C produces abundant oxygen, which in turn induces the natural product Cur to generate more reactive oxygen species (ROS) that significantly inhibit the growth of tumors in 4T1 tumor-bearing mice. This contribution showcases the ability of a light-driven green affording-oxygen microrobot to exhibit targeting capacity and O2 generation for enhancing photodynamic therapy.

Prediction of Early Atherosclerotic Plaques Using a Sequence-Activated Fluorescence Probe for the Simultaneous Detection of γ-Glutamyl Transpeptidase and Hypobromous Acid.

Atherosclerosis is a lipoprotein-driven disease, and there is no effective therapy to reverse atherosclerosis or existing plaques. Therefore, it is urgently necessary to create a noninvasive and reliable approach for early atherosclerosis detection to prevent initial plaque formation. Atherosclerosis is intimately associated with inflammation, which is accompanied by an excess of reactive oxygen species (ROS), leading to cells requiring more glutathione (GSH) to resist severe oxidative stress. Therefore, the GSH-hydrolyzed protein γ-glutamyl transpeptidase (GGT) and the ROS-hypobromous acid (HBrO) are potential biomarkers for predicting atherogenesis. Hence, to avoid false-positive diagnoses caused by a single biomarker, we constructed an ingenious sequence-activated double-locked TP fluorescent probe, C-HBrO-GGT, in which two sequential triggers of GGT and HBrO are meticulously designed to ensure that the probe fluoresces in response to HBrO only after GGT hydrolyzes the probe. By utilization of C-HBrO-GGT, the voltage-gated chloride channel (CLC-1)-HBrO-catalase (CAT)-GGT signaling pathway was confirmed in cellular level. Notably, the forthcoming atherosclerotic plaques were successfully predicted before the plaques could be observed via the naked eye or classical immunofluorescent staining. Collectively, this research proposed a powerful tool to indicate the precise position of mature plaques and provide early warning of atherosclerotic plaques.

High-dose ascorbic acid potentiates immune modulation through STAT1 phosphorylation inhibition and negative regulation of PD-L1 in experimental sepsis.

Sepsis is a complex, multifactorial syndrome characterized by a dysregulated host response to infection, leading to severe organ dysfunction and high mortality rates among critically ill patients. Hypovitaminosis C and vitamin C deficiency are frequently observed in septic patients, prompting interest in the potential therapeutic role of ascorbic acid. Although intravenous administration of ascorbic acid has been investigated in multiple clinical trials for sepsis treatment, the specific immunomodulatory mechanisms underlying its effects remain elusive. This study aimed to investigate the protective effects of high-dose ascorbic acid on experimental sepsis. Results show that intravenous administration of high-dose ascorbic acid (250 mg/kg) attenuated sepsis-induced organ dysfunctions in a cecal ligation and puncture (CLP)-induced septic mouse model. Ascorbic acid improved splenic cell apoptosis and increased the number of CD3+ T cells in septic mice induced by CLP. Furthermore, ascorbic acid downregulated PD-L1 expression in livers, reduced PD-1 expression in spleens, and inhibited the phosphorylation of STAT1 at Y701 in multiple organs of CLP-induced septic mice. The in vitro experiments also revealed that 800 µM ascorbic acid suppressed STAT1 phosphorylation and inhibited lipopolysaccharide (LPS) and IFN-γ-induced PD-L1 expression in macrophages. These findings suggest that ascorbic acid prevents sepsis-associated organ dysfunction through the p-STAT1/PD-L1 signaling pathway. Our study provides new insights into the potential therapeutic use of ascorbic acid in sepsis.

Inhibition of Pi4kb activity causes malformation of vestibular apparatus in zebrafish by downregulating hey1.

Phosphatidylinositol 4 kinase-ß (PI4KB) plays critical roles in human genetic diseases. In zebrafish, Pi4kb is strongly expressed in hair cells (HCs), which are necessary for detecting sound vibrations, head movements, and water motion. However, the role of PI4KB in HC or semicircular canal development is unclear. Herein, we report that pi4kb morphants exhibit insensitivity to sound stimulation and abnormal morphological vestibular organs, including cilium loss in HCs of the cristae and semicircular canal malformation. As bone morphogenetic protein (BMP) signaling is associated with HC and semicircular canal development, we analyzed the expression of BMP-related genes; the phosphorylated Smad1/5/9 (p-Smad1/5/9) expression was markedly reduced in otic HCs. RNA-sequencing data indicated that the transcriptional levels of BMP membrane receptor 2 (bmpr2a and bmpr2b) and hes-related family of bHLH transcription factors with YRPW motif 1 (hey1), a direct downstream target gene of p-Smad, were significantly reduced in the pi4kb morphants, as verified using quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Co-injection of hey1 mRNA and pi4kb morpholino notably recovered vestibular apparatus development, including the number and length of cilia in HCs of the cristae and semicircular canal formation. Collectively, these results suggest that Pi4kb is involved in vestibular apparatus development in zebrafish by regulating BMP membrane receptor 2 and p-Smad1/5/9 levels, thereby affecting the transcriptional activation of the target gene hey1. This study sheds light on the interaction between Pi4kb and the BMP-Hey1 signaling axis, which is critical for HC and semicircular canal formation.