Notoginsenoside R1 attenuates ischemic heart failure by modulating MDM2/ß arrestin2-mediated ß2-adrenergic receptor ubiquitination.

ß2 adrenergic receptor (ß2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged ß2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (ß-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased ß2AR levels and decreased ß2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and ß-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between ß-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of ß2AR to improve CHF.

Shear-strained Pd Single-atom Electrocatalysts for Nitrate Reduction to Ammonia.

Electrochemical nitrate reduction method (NitRR) is a low-carbon, environmentally friendly, and efficient method for synthesizing ammonia, which has received widespread attention in recent years. Copper-based catalysts have a leading edge in nitrate reduction due to their good adsorption of *NO3. However, the formation of active hydrogen (*H) on Cu surfaces is difficult and insufficient, resulting in a large amount of the by-product NO2-. In this work, Pd single atoms suspended on the interlayer unsaturated bonds of CuO atoms formed due to dislocations (Pd-CuO) were prepared by low temperature treatment, and the Pd single atoms located on the dislocations were subjected to shear stress and the dynamic effect of support formation to promote the conversion of nitrate into ammonia. The catalysis had an ammonia yield of 4.2 mol.gcat-1. h-1, and a Faraday efficiency of 90% for ammonia production at -0.5 V vs. RHE. Electrochemical in-situ characterization and theoretical calculations indicate that the dynamic effects of Pd single atoms and carriers under shear stress obviously promote the production of active hydrogen, reduce the reaction energy barrier of the decision-making step for nitrate conversion to ammonia, further promote ammonia generation.

Multiple-readout lateral flow immunoassay for the sensitive detection of nitrofurazone metabolites through ultrabright AIE-MOF coupled in-situ growth strategy.

The multiple-readout capability of multimodal detection enhances the flexibility, reliability, and accuracy of lateral flow immunoassay (LFIA). The conjugation of two different metal-organic frameworks (MOFs) as a new-generation composite material offers extraordinary opportunities for developing multimodal LFIA. It is anticipated to compensate limitations of traditional single colorimetric signal LFIA and improve the analysis performance. Herein, an ultra-bright fluorescent AIE-MOF was proposed and coupled with an in-situ growth of Prussian blue (PB) nanoparticles strategy to obtain a novel multimodal signal tracer (AIE-MOF@PB). Thereafter, it was successfully applied to develop the multimodal LFIA platform for the detection of nitrofurazone metabolites. The synergy of AIE-MOF and PB endows AIE-MOF@PB with superb water dispersibility, robust fluorescence emission, brilliant colorimetric signal, marvelous photothermal conversion, and enhanced antibody coupling efficiency, all of which facilitate a highly sensitive triple-readout LFIA platform. The detection sensitivity improved by at least 5-fold compared with the colloidal gold-based LFIA. This work not only inspires the rational design of aggregation-induced emission luminogens (AIEgen)-based complex materials but also highlights the promising potential in flexible point-of-care applications.

An injectable adhesive hydrogel for photothermal ablation and antitumor immune activation against bacteria-associated oral squamous cell carcinoma.

Pathogenic bacteria are closely associated with the occurrence, development and metastasis of oral squamous cell carcinoma (OSCC). Antibacterial therapy has been considered an enhancement strategy to suppress bacteria-associated tumors and promote anti-tumor immune responses. Herein, we developed an injectable adhesive hydrogel, PNIPAM/DL@TIR, for the in situ photothermal ablation and robust stimulation of antitumor immunity against OSCC colonized by Porphyromonas gingivalis (Pg), one of the major oral pathogenic bacteria. PNIPAM/DL@TIR, composed of poly(N-isopropylacrylamide), demethylated lignin, and TAT peptide-conjugated IR820, was prepared using a simple dissolve-dry-swell solvent exchange method. Upon 808 nm laser irradiation, PNIPAM/DL@TIR exerted photothermal effects to ablate Pg-colonized OSCC and generate dual tumor and bacterial antigens. Owing to its large number of catechol groups, PNIPAM/DL@TIR efficiently captured these antigens to form an in situ antigen repository, thereby eliciting robust and durable antitumor immune responses. Proteomic analysis revealed that the captured antigens comprised both tumor neoantigens and bacterial antigens. The catechol groups endowed PNIPAM/DL@TIR with antioxidant activity, which was also conducive to stimulating antitumor immunity. Altogether, this study develops an injectable adhesive hydrogel and provides a combination strategy for treating bacteria-associated OSCC. STATEMENT OF SIGNIFICANCE: In this study, we developed an injectable adhesive hydrogel, PNIPAM/DL@TIR, for in situ photothermal ablation and robust stimulation of antitumor immunity against OSCC colonized by Porphyromonas gingivalis, one of the major oral pathogenic bacteria. PNIPAM/DL@TIR, which consists of poly(N-isopropylacrylamide), demethylated lignin, and TAT peptide-conjugated IR820 exhibited outstanding photothermal performance. Owing to the presence of catechol groups, PNIPAM/DL@TIR has good bioadhesive properties and can capture protein antigens to form in situ antigen repository, thus initiating robust and long-term antitumor immune responses. In addition, PNIPAM/DL@TIR exhibited strong antioxidant activity that is favorable for promoting antitumor immunity. In the mouse model of OSCC with bacterial infection, PNIPAM/DL@TIR not only ablated the primary tumors upon NIR laser irradiation, but also induced tumor and bacterial vaccination in situ to suppress distant tumors and lung metastasis.

Demethylation C-C coupling reaction facilitated by the repulsive Coulomb force between two cations.

Carbon chain elongation (CCE) is normally carried out using either chemical catalysts or bioenzymes. Herein we demonstrate a catalyst-free approach to promote demethylation C-C coupling reactions for advanced CCE constructed with functional groups under ambient conditions. Accelerated by the electric field, two organic cations containing a methyl group (e.g., ketones, acids, and aldehydes) approach each other with such proximity that the energy of the repulsive Coulomb interaction between these two cations exceeds the bond energy of the methyl group. This results in the elimination of a methyl cation and the coupling of the residual carbonyl carbon groups. As confirmed by high-resolution mass spectrometry and isotope-labeling experiments, the C-C coupling reactions (yields up to 76.5%) were commonly observed in the gas phase or liquid phase, for which the mechanism was further studied using molecular dynamics simulations and stationary-point calculations, revealing deep insights and perspectives of chemistry.

Xinbao Pill ameliorates heart failure via regulating the SGLT1/AMPK/PPARα axis to improve myocardial fatty acid energy metabolism.

BACKGROUND: Heart failure (HF) is characterized by a disorder of cardiomyocyte energy metabolism. Xinbao Pill (XBW), a traditional Chinese medicine formulation integrating "Liushen Pill" and "Shenfu Decoction," has been approved by China Food and Drug Administration for the treatment of HF for many years. The present study reveals a novel mechanism of XBW in HF through modulation of cardiac energy metabolism. METHODS: In vivo, XBW (60, 90, 120 mg/kg/d) and fenofibrate (100 mg/kg/d) were treated for six weeks in Sprague-Dawley rats that were stimulated by isoproterenol to induce HF. Cardiac function parameters were measured by echocardiography, and cardiac pathological changes were assessed using H&E, Masson, and WGA staining. In vitro, primary cultured neonatal rat cardiomyocytes (NRCMs) were induced by isoproterenol to investigate the effects of XBW on myocardial cell damage, mitochondrial function and fatty acid energy metabolism. The involvement of the SGLT1/AMPK/PPARα signalling axis was investigated. RESULTS: In both in vitro and in vivo models of ISO-induced HF, XBW significantly ameliorated cardiac hypertrophy cardiac fibrosis, and improved cardiac function. Significantly, XBW improved cardiac fatty acid metabolism and mitigated mitochondrial damage. Mechanistically, XBW effectively suppressed the expression of SGLT1 protein while upregulating the phosphorylation level of AMPK, ultimately facilitating the nuclear translocation of PPARα and enhancing its transcriptional activity. Knockdown of SGLT1 further enhanced cardiac energy metabolism by XBW, while overexpression of SGLT1 reversed the cardio-protective effect of XBW, highlighting that SGLT1 is probably a critical target of XBW in the regulation of cardiac fatty acid metabolism. CONCLUSIONS: XBW improves cardiac fatty acid energy metabolism to alleviate HF via SGLT1/AMPK/PPARα signalling axis.

Clinical spectrum of late symptomatic neurosyphilis in China: an 11-year retrospective study.

OBJECTIVES: This study aimed to describe the clinical features of neurosyphilis in Chinese patients in an attempt to find clinical features that are helpful for the early identification of neurosyphilis. METHODS: This retrospective study included people with syphilis who visited Shanghai Skin Disease Hospital between January 2010 and December 2020. Lumbar puncture was performed on those who met the inclusion and exclusion criteria. The diagnosis of neurosyphilis was based on clinical and laboratory findings. The parameters were analysed statistically. RESULTS: Of the 3524 patients with neurosyphilis, 2111 (59.9%) and 1413 (40.1%) were asymptomatic and symptomatic neurosyphilis, respectively. General paresis was the most common type of symptomatic neurosyphilis (46.8%). The clinical manifestations of symptomatic neurosyphilis include psychiatric and neurotic symptoms, among which general paresis predominantly presented as psychiatric symptoms such as affective (66.7%) and memory disorder (72.9%). Tabes dorsalis is often presented as neurotic symptoms. One hundred fifty patients (10.6%) with symptomatic neurosyphilis presented candy signs, a rare and specific neurosyphilis symptom that is common in general paresis. Girdle sensation was presented in 13 patients, mainly with tabes dorsalis, which had not been reported in previous studies. CONCLUSIONS: Notably, the candy sign is identified as a specific symptom of general paresis, while girdle sensations are highlighted as a particular symptom of tabes dorsalis. This is the largest study describing the clinical spectrum of neurosyphilis since the onset of the penicillin era and could help doctors learn more about the disease. A comprehensive description of the possible clinical manifestations of late symptomatic neurosyphilis, particularly highlighting rare symptoms, can identify suspicious patients and prevent diagnostic delays.

Chemical components with biological activities in the roots of Ilex pubescens.

Two new triterpenoids, ilexsaponin U (1) and ilexsaponin V (2), and three new phenylpropanoids, pubescenoside S (3), pubescenoside T (38), and pubescenoside U (39), along with thirty-four existing compounds were isolated from the roots of Ilex pubescens. The elucidation of their structures involved comprehensive spectroscopic techniques, including IR, UV, HR-ESI-MS, and NMR experiments. The anti-inflammatory effects of almost all the compounds were evaluated in LPS-induced RAW264.7 cells. Among these, compounds 1, 4, 8, 11, 12, 26, 27, 29 and 33 exhibited varying degrees of inhibition of inflammatory factors. Notably, compounds 1, 4 and 8 significantly inhibited the mRNA levels of iNOS, IL-6, IL-1ß and TNFα, comparable to or exceeding the effect of the positive control (dexamethasone, DEX). We also evaluated the cardioprotective effects of these compounds in OGD/R-induced H9c2 cells. The results revealed that compounds 2, 3, 7, 8, 26, 35, 36 and 37 at 20 µM significantly increased cell viability by 24.9 ± 3.4%, 28.0 ± 0.3%, 37.6 ± 0.2%, 44.86 ± 0.5%, 9.47 ± 2.1%, 23.9 ± 0.4%, 39.5 ± 3.1% and 28.2 ± 0.1%, respectively. Some of them exhibited effects equal to or greater than that of the positive control (diazoxide, DZ) at 100 µM, showing a 21.9 ± 3.0% increase.

A Case of Perianal Annular Rash: Atypical Presentation of Recurrent Secondary Syphilis.

Syphilis is a complex, systemic infectious disease caused by Treponema pallidum subspecies pallidum. Secondary syphilitic lesions typically manifest within 3 months following initial exposure to T. pallidum. The predominant cutaneous manifestations of secondary syphilis are macula and papule. Certain individuals with syphilis may present with an atypical rash during the secondary stage owing to immunosuppression and other factors. Herein, we report a rare case of atypical recurrent secondary syphilis around the anus in a 65-year-old woman. Based on cerebrospinal fluid findings and skin biopsy results, the patient was ultimately diagnosed as neurosyphilis and recurrent secondary syphilis. Following intravenous antibiotic therapy, the patient's rash improved significantly. This case underscores the importance for physicians to remain vigilant regarding the possibility of syphilis when encountering cases exhibiting unusual clinical manifestations, as a definitive diagnosis necessitates a comprehensive evaluation.

Layer-By-Layer Designed Spark-Type AuCuPt Alloy with Robust Broadband Absorption to Enhance Sensitivity in Flexible Detection of Estriol by a Lateral Flow Immunoassay.

Excessive intake of estrogen poses significant health risks to the human body; hence, there is a necessity to develop rapid detection methods to monitor its levels of addition. Gold nanoparticles (AuNPs), commonly utilized as colorimetric signal labels, find extensive application in lateral flow immunoassay (LFIA). However, the detection sensitivity of traditional AuNPs-LFIA is typically constrained by low molar extinction coefficients and reliance on a single signal. Herein, in this work, unique spark-type AuCuPt nanoflowers modified with tannic acid (AuCuPt@TA) were precisely designed by reasonable layer-by-layer element composition and green modification. The obtained AuCuPt displays robust broadband absorption spanning the visible to near-infrared spectrum, showcasing a notable molar extinction coefficient of 2.38 × 1012 M-1 cm-1 and a photothermal conversion efficiency of 48.5%. Based on this, selecting estriol (E3) as a model analyte, colorimetric/photothermal dual-signal LFIA (CLFIA and PLFIA) was developed. Limits of detection (LOD) of the CLFIA and PLFIA were achieved at 0.033 ng mL-1 and 0.021 ng mL-1, respectively, which represent a 9.3- and 14.6-fold improvement compared to the visual LOD of AuNPs-LFIA. Moreover, the application feasibility of the immunoassay was further evaluated in the milk and pork with satisfactory recoveries ranging from 86.21% to 117.91%. Thus, this work has enhanced the performance of LFIA for E3 detection and exhibited enormous potential for other sensing platform construction.

Daldiconoids A-G: 3,4-Secolanostane triterpenoids from the fruiting bodies of Daldinia concentrica and their anti-inflammatory activity.

Seven undescribed 3,4-secolanostane triterpenoids, daldiconoids A-G (1-7), were isolated from the fruiting bodies of Daldinia concentrica. Daldiconoid A (1) was a highly modified 4,6,28,29-tetranorlanostane triterpenoid alkaloid featuring an unusual δ-lactam fused with a flanking cyclopentenone architecture. Their structures were determined by spectroscopic data, NMR calculations coupled with the DP4+ analysis, X-ray single-crystal diffraction, and chemical transformation. The plausible biosynthetic pathway for 1 was proposed. Compounds 1, 2, and 4-6 inhibited the expressions of IL-1ß, IL-6, and TNF-α in lipopolysaccharide stimulated RAW264.7 cells at a concentration of 10 µM. Mechanistically, Compounds 1 and 2 blocked the JAK2/STAT3 signaling pathway induced by lipopolysaccharide.

Identification of S100A8/A9 involved in thromboangiitis obliterans development using tandem mass tags-labeled quantitative proteomics analysis.

Thromboangiitis obliterans (TAO) is characterized by inflammation and obstruction of small-and medium-sized distal arteries, with limited pharmacotherapies and surgical interventions. The precise pathogenesis of TAO remains elusive. By utilizing the technology of tandem mass tags (TMT) for quantitative proteomics and leveraging bioinformatics tools, a comparative analysis of protein profiles was conducted between normal and TAO rats to identify key proteins driving TAO development. The results unveiled 1385 differentially expressed proteins (DEPs) in the TAO compared with the normal group-comprising 365 proteins with upregulated expression and 1020 proteins with downregulated expression. Function annotation through gene ontology indicated these DEPs mainly involved in cell adhesion, positive regulation of cell migration, and cytosol. The principal signaling pathways involved regulation of the actin cytoskeleton, vascular smooth contraction, and focal adhesion. The roles of these DEPs and associated signaling pathways serve as a fundamental framework for comprehending the mechanisms underpinning the onset and progression of TAO. Furthermore, we conducted a comprehensive evaluation of the effects of S100A8/A9 and its inhibitor, paquinimod, on smooth muscle cells (SMCs) and in TAO rats. We observed that paquinimod reduces SMCs proliferation and migration, promotes phenotype switching and alleviates vascular stenosis in TAO rats. In conclusion, our study revealed that the early activation of S100A8/A9 in the femoral artery is implicated in TAO development, targeting S100A8/A9 signaling may provide a novel approach for TAO prevention and treatment.

Homologous-targeting biomimetic nanoparticles co-loaded with melittin and a photosensitizer for the combination therapy of triple negative breast cancer.

Melittin (Mel) is considered a promising candidate drug for the treatment of triple negative breast cancer (TNBC) due to its various antitumor effects. However, its clinical application is hampered by notable limitations, including hemolytic activity, rapid clearance, and a lack of tumor selectivity. Here, we designed novel biomimetic nanoparticles based on homologous tumor cell membranes and poly(lactic-co-glycolic acid) (PLGA)/poly(beta-aminoester) (PBAE), denoted MDM@TPP, which efficiently coloaded the cytolytic peptide Mel and the photosensitizer mTHPC. Both in vitro and in vivo, the MDM@TPP nanoparticles effectively mitigated the acute toxicity of melittin and exhibited strong TNBC targeting ability due to the homologous targeting effect of the tumor cell membrane. Under laser irradiation, the MDM@TPP nanoparticles showed excellent photodynamic performance and thus accelerated the release of Mel by disrupting cell membrane integrity. Moreover, Mel combined with photodynamic therapy (PDT) can synergistically kill tumor cells and induce significant immunogenic cell death, thereby stimulating the maturation of dendritic cells (DCs). In 4T1 tumor-bearing mice, MDM@TPP nanoparticles effectively inhibited the growth and metastasis of primary tumors and finally prevented tumor recurrence by improving the immune response.

Arjunolic acid ameliorates lipopolysaccharide-induced depressive behavior by inhibiting neuroinflammation via microglial SIRT1/AMPK/Notch1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation is involved in the pathogenesis of depression disorder by activating microglia cells, increasing proinflammatory cytokines, effecting serotonin synthesis and metabolism, and neuronal apoptosis and neurogenesis. Arjunolic acid (ARG) is a triterpenoid derived from the fruits of Akebia trifoliata for treating psychiatric disorders in TCM clinic, which exhibits anti-inflammatory and neuroprotective effects. However, its anti-depressive effect and underlying mechanism are unknown. AIM OF THE STUDY: The aim of this study is to explore the effect of arjunolic acid on depression and its possible mechanisms. METHODS: Intraperitoneal injection of LPS in mice and LPS stimulated-BV2 microglia were utilized to set up in vivo and in vitro models. Behavioral tests, H&E staining and ELISA were employed to evaluate the effect of arjunolic acid on depression. RT-qPCR, immunofluorescence, molecular docking and Western blot were performed to elucidate the molecular mechanisms. RESULTS: Arjunolic acid dramatically ameliorated depressive behavior in LPS-induced mice. The levels of BDNF and 5-HT in the hippocampus of the mice were increased, while the number of iNOS + IBA1+ cells in the brain were decreased and Arg1+IBA1+ positive cells were increased after arjunolic acid treatment. In addition, arjunolic acid promoted the polarization of BV2 microglia from M1 to M2 type. Notably, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking technologies identified SIRT1 as the target of arjunolic acid. Moreover, after SIRT1 inhibition by using EX-527, the effects of arjunolic acid on ameliorating LPS-induced depressive behavior in mice and promoting M2 Microglia polarization were blocked. In addition, arjunolic acid activated AMPK and decreased Notch1 expression, however, inhibition of AMPK, the effect of arjunolic acid on the downregulation of Notch1 expression were weaken. CONCLUSIONS: This study elucidates that arjunolic acid suppressed neuroinflammation through modulating the SIRT1/AMPK/Notch1 signaling pathway. Our study demonstrates that arjunolic acid might serve as a potiential anti-depressant.

Predicting slight freezing of gait in Parkinson's disease with anticipatory postural adjustments and limits of stability.

INTRODUCTION: Gait initiation (GI) includes automatic and voluntary movements. However, research on their impact on the first step in patients with Parkinson's disease (PD) and their relationship to freezing of gait (FOG) is lacking. We examined the effects of automatic movements (anticipatory postural adjustments [APAs]) and voluntary movements (limits of stability [LOS]) on the first step (first-step duration and first-step range of motion), along with their early recognition and prediction of slight FOG. METHODS: Twenty-three patients with PD and slight freezing (PD + FOG) and 25 non-freezing patients with PD (PD-FOG) were tested while off medications and compared with 24 healthy controls (HC). All participants completed a 7-m Stand and Walk Test (7 m SAW) and wore inertial sensors to quantify the APAs and first step. LOS was quantified by dynamic posturography in different directions using a pressure platform. We compared differences among all three groups, analysed correlations, and evaluated their predictive value for slight FOG. RESULTS: In PD + FOG, APAs and LOS were worse than those in the PD-FOG and HC groups (p < 0.001), and the first step was worse than that in HC (p < 0.001). APAs were correlated mainly with the first-step duration. APAs and LOS were correlated with the first-step range of motion. APAs have been recognized as independent predictors of FOG, and their combination with LOS enhances predictive sensitivity. CONCLUSION: APAs and LOS in patients with PD directly affect the first step during GI. In addition, the combination of APAs and LOS helped predict slight FOG.

Comparison of the efficacy of Hydroquinone cream versus Hydroquinone cream plus Danggui Shaoyao powder in the treatment of melasma.

Introduction: Melasma is an acquired hypermelanosis and occurs in areas exposed to sunlight. Aim: To investigate the effectiveness of Danggui Shaoyao powder (DSP) as a complementary drug in the treatment of melasma. Material and methods: A total of 40 melasma patients over the age of 18 who met the inclusion criteria entered the study randomly in two DSP + Hydroquinone (DSP + H) and Hydroquinone (H) groups. Results: At the beginning of the study, the average MASI score of the two groups of patients had no statistical difference (DSP + H: 15.79 ±1.01 vs. H: 15.37 ±1.17, p = 0.23). But from the eighth week of treatment, the MASI score of the patients decreased significantly and in the DSP + H group it decreased statistically significantly compared to the H group (DSP + H: 5.83 ±0.97 vs. H: 8.29 ±2.23, p < 0.001 for the eighth week and DSP + H: 3.60 ±0.58 vs. H: 5.52 ±1.73, p < 0.001 for the twelfth week of the treatment). It means after 12 weeks of treatment, the average MASI score of patients in the DSP + H group decreased by 77.26 ±2.70%, but in the grroup H, it decreased by 64.31 ±9.68% (p < 0.001). Dynamic PGA showed that excellent treatment occurred in 65% of the + H group H, but only 20% of the H group (p = 0.01). Conclusions: Oral DSP for 12 weeks along with hydroquinone cream can significantly reduce the MASI score of melasma patients and increase the patients' recovery and satisfaction.

A simple fluorescence detection of acetylcholinesterase with peroxidase-like catalysis from iodide.

Acetylcholinesterase (AChE) is an important enzyme in the central and peripheral nervous system that regulates the balance of the neurotransmitter acetylcholine. In this work, a simple, selective and sensitive fluorescence assay was developed toward AChE activity. A conventional AChE substrate acetylthiocholine iodide (ATCI) was applied. Instead directly rendering a signaling, it was found that free iodide ions was released during the enzymatic hydrolysis of ATCI. These ions further catalyzed the oxidation of non-emissive o-phenylenediamine (OPD) into a fluorescent product. This gave a response differed from frequently-adopted sulfhydryl- -based signals and thus minimized related interferences. All materials included in this process were directly available and no additional syntheses were required. Due to the extra iodide-based catalysis included, this scheme was capable of providing a sensitive response toward AChE in the range of 0.01-8 U/L, with a limit of detection at 0.006 U/L. This method was further extended onto chlorpyrifos as an exemplary AChE inhibitor, with a detection down to 3 pM.

NCF4 regulates antigen presentation of cysteine peptides by intracellular oxidative response and restricts activation of autoreactive and arthritogenic T cells.

Autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematous, are regulated by polymorphisms in genes contributing to the NOX2 complex. Mutations in both Ncf1 and Ncf4 affect development of arthritis in experimental models of RA, but the different regulatory pathways mediated by NOX2-derived reactive oxygen species (ROS) have not yet been clarified. Here we address the possibility that intracellular ROS, regulated by the NCF4 protein (earlier often denoted p40phox) which interacts with endosomal membranes, could play an important role in the oxidation of cysteine peptides in mononuclear phagocytic cells, thereby regulating antigen presentation and activation of arthritogenic T cells. To study the role of NCF4 we used mice with an amino acid replacing mutation (NCF4R58A), which is known to affect interaction with endosomal membranes, leading to decreased intracellular ROS production. To study the impact of NCF4 on T cell activation, we used the glucose phosphate isomerase peptide GPI325-339, which contains two cysteine residues (325-339c-c). Macrophages from mice with the NCF458A mutation efficiently presented the peptide when the two cysteines were intact and not crosslinked, leading to a strong arthritogenic T cell response. T cell priming occurred in the draining lymph nodes (LNs) within 8 days after immunization. Clodronate treatment, which depletes antigen-presenting mononuclear phagocytes, ameliorated arthritis severity, whereas treatment with FYT720, which traps activated T cells in LNs, prohibited arthritis. We conclude that NCF4-dependent intracellular ROS maintains cysteine peptides in an oxidized crosslinked state, which prevents presentation of peptides recognized by non-tolerized T cells and thereby protects against autoimmune arthritis.

Comparison of Two Surgical Approaches for Periacetabular Osteotomy: A Retrospective Study of Patients with Developmental Dysplasia of the Hip.

OBJECTIVE: Given the intricate challenges and potential complications associated with periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH). Our study aimed to compare the clinical and imaging benefits and drawbacks of two surgical approaches, the modified Stoppa combined iliac spine approach and the modified Smith-Peterson approach, for treating PAO and to provide guidance for selecting clinical approaches. METHODS: A retrospective analysis of 56 patients with 62 DDHs was conducted from June 2018 to January 2022. The experimental group underwent surgery via the modified Stoppa combined iliac spine approach, while the control group underwent surgery via the modified Smith-Peterson approach for periacetabular osteotomy and internal fixation. Basic statistical parameters, including age, sex, BMI, and preoperative imaging data, were analyzed. Differences in surgical time, intraoperative blood loss, and postoperative imaging data were compared, as were differences in preoperative and postoperative imaging data between the two groups. RESULTS: There were 28 hips in the experimental group and 34 in the control group. Moreover, there was no significant difference in the basic parameters between the experimental and control groups. Before and after the operation, for the LCE angle, ACE angle, and Tonnis angle, there was no significant difference in acetabular coverage (p > 0.05). However, there were significant differences between the two groups in terms of the above four indicators before and after the operation (p < 0.05). After the operation, the experimental group exhibited significant increases in both lateral and anterior acetabular coverage of the femoral head. However, the experimental group had longer operation times and greater bleeding volumes than did the control group. Despite this, the experimental group demonstrated significant advantages in protecting the lateral femoral cutaneous nerve compared to the control group. CONCLUSION: The modified Stoppa combined iliac spine approach can be considered a practical approach for PAO and is more suitable for patients with DDH who plan to be treated by one operation than the classic modified Smith-Peterson approach for PAO.