Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.

Qualitative and quantitative analysis methods for quality control of rhubarb in Taiwan's markets.

Introduction: Rhubarb is a traditional Chinese medicine (TCM) used to release heat and has cathartic effects. Official rhubarb in Taiwan Herbal Pharmacopeias 4th edition (THP 4th) and China Pharmacopeia 2020 (CP 2020) are the roots and rhizomes of Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., and Rheum officinale Baill. However, the Rheum genus is a large genus with many different species, and owing to the similarity in appearance and taste with official rhubarb, there needs to be more clarity in the distinction between the species of rhubarb and their applications. Given the time-consuming and complicated extraction and chromatography methods outlined in pharmacopeias, we improved the qualitative analysis and quantitative analysis methods for rhubarb in the market. Hence, we applied our method to identify the species and quality of official and unofficial rhubarb. Method: We analyzed 21 rhubarb samples from the Taiwanese market using a proposed HPLC-based extraction and qualitative analysis employing eight markers: aloe-emodin, rhein, emodin, chrysophanol, physcion, rhapontigenin, rhaponticin, and resveratrol. Additionally, we developed a TLC method for the analysis of rhubarb. KEGG pathway analysis was used to clarify the phytochemical and pharmacological knowledge of official and unofficial rhubarb. Results: Rhein and rhapontigenin emerged as key markers to differentiate official and unofficial rhubarb. Rhapontigenin is abundant in unofficial rhubarb; however, rhein content was low. In contrast, their contents in official rhubarb were opposite to their contents in unofficial rhubarb. The TLC analysis used rhein and rhapontigenin to identify rhubarb in Taiwan's markets, whereas the KEGG pathway analysis revealed that anthraquinones and stilbenes affected different pathways. Discussion: Eight reference standards were used in this study to propose a quality control method for rhubarb in Taiwanese markets. We propose a rapid extraction method and quantitative analysis of rhubarb to differentiate between official and unofficial rhubarb.

Acacetin inhibits activation of microglia to improve neuroinflammation after subarachnoid hemorrhage through the PERK signaling pathway mediated autophagy.

PURPOSE: To explore the effect of acacetin on subarachnoid hemorrhage (SAH) and its possible mechanism. METHODS: SAH model of rat was established, and intraperitoneally injected with three doses of acacetin. To verify the role of PERK pathway, we used the CCT020312 (PERK inhibitor) and Tunicamycin (activators of endoplasmic reticulum stress). The SAH score, neurological function score, brain edema content, and Evans blue (EB) exudate were evaluated. Western blot was used to determine the expression of inflammation-associated proteins and PERK pathway. The activation of microglia was also determined through Iba-1 detection. TEM and immunofluorescence staining of LC3B were performed to observe the autophagy degree of SAH rats after acacetin. Tunel/NeuN staining, HE and Nissl' staining were performed for neuronal damage. RESULTS: Acacetin increased the neurological function score, reduce brain water content, Evans blue exudation and SAH scores. The microglia in cerebral cortex were activated after SAH, while acacetin could inhibit its activation, and decreased the expression of TNF-α and IL-6 proteins. The pathological staining showed the severe neuronal damage and increased neuronal apoptosis after SAH, while acacetin could improve these pathological changes. We also visualized the alleviated autophagy after acacetin. The expression of Beclin1 and ATF4 proteins were increased, but acacetin could inhibit them. Acacetin also inactivated PERK pathway, which could improve the neuronal injury and neuroinflammation after SAH, inhibit the microglia activation and the overactivated autophagy through PERK pathway. CONCLUSION: Acacetin may alleviate neuroinflammation and neuronal damage through PERK pathway, thus having the protective effect on EBI after SAH.

Integrating single-cell and spatial transcriptomics to elucidate the crosstalk between cancer-associated fibroblasts and cancer cells in hepatocellular carcinoma with spleen-deficiency syndrome.

Background and aim: Most patients with hepatocellular carcinoma (HCC) in China have been diagnosed with spleen deficiency syndrome (SDS), which accelerates the progression of HCC by disrupting the tumor microenvironment homeostasis. This study aimed to investigate the intercellular crosstalk in HCC with SDS. Experimental procedure: An HCC-SDS mouse model was established using orthotopic HCC transplantation based on reserpine-induced SDS. Single-cell data analysis and cancer cell prediction were conducted using Seurat and CopyKAT package, respectively. Intercellular interactions were explored using CellPhoneDB and CellChat and subsequently validated using co-culture assays, ELISA and histological staining. We performed pathway activity analysis using gene set variation analysis and the Seurat package. The extracellular matrix (ECM) remodeling was assessed using a gel contraction assay, atomic force microscopy, and Sirius red staining. The deconvolution of the spatial transcriptomics data using the "CARD" package based on single-cell data. Results and conclusion: We successfully established the HCC-SDS mouse model. Twenty-nine clusters were identified. The interactions between cancer cells and cancer-associated fibroblasts (CAFs) were significantly enhanced via platelet-derived growth factor (PDGF) signaling in HCC-SDS. CAFs recruited in HCC-SDS lead to ECM remodeling and the activation of TGF-ß signaling pathway. Deconvolution of the spatial transcriptome data revealed that CAFs physically surround cancer cells in HCC-SDS. This study reveals that the crosstalk of CAFs-cancer cells is crucial for the tumor-promoting effect of SDS. CAFs recruited by HCC via PDGFA may lead to ECM remodeling through activation of the TGF-ß pathway, thereby forming a physical barrier to block immune cell infiltration under SDS.

Nanofiber-induced hierarchically-porous magnesium phosphate bone cements accelerate bone regeneration by inhibiting Notch signaling.

Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM in vivo. Overall, our novel SM exhibited promising prospects for the treatment of critical-sized bone defects.

Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief.

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα "don't eat me" pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.

Effects of temporal changes in resting heart rate on future diabetes-related outcomes.

Background and aims: Most studies have analyzed the relationship between resting heart rate (RHR) measured at only one time point and future clinical events. The current study aims to investigate the impact of long-term RHR changes on future clinical outcomes in a decade-long cohort with type 2 diabetes mellitus (T2DM). Methods: The two-staged follow-up involved 2,513 T2DM participants. The first stage (2008-2014) intended to identify levels and trends in RHR changes, while the second stage (2014-2018) attempted to collect new occurrence records of clinical results. Cox proportional hazards models were applied to predict hazard ratios (HRs), along with 95% confidence interval (CI) for the correlation between RHR changes and future events. Results: There is no significant correlation between baseline RHR levels and long-term clinical events. According to the range of RHR change, compared with the stable RHR group, the adjusted HRs for cardiovascular events and all-cause death in the large increase group were 3.40 (95% CI: 1.33-8.71, p=0.010) and 3.22 (95% CI: 1.07-9.64, p=0.037), respectively. While the adjusted HRs for all-cause death and major adverse cardiac and cerebrovascular events (MACCE) in the moderate decrease group were 0.55 (95% CI: 0.31-0.96, p=0.037) and 0.51 (95% CI: 0.26-0.98, p=0.046). According to the trend of RHR, compared with the normal-normal group, the adjusted HRs for composite endpoint events and cerebrovascular events in the normal-high group were 1.64 (95% CI: 1.00-2.68, p=0.047) and 2.82 (95% CI: 1.03-7.76, p=0.043), respectively. Conclusion: Changes in RHR had predictive value for long-term clinical events in diabetic populations. Individuals with significantly elevated RHR over a particular period of time showed an increased risk of adverse events.

Reliability and validity tests of the Chinese version of the Geriatric Locomotive Function Scale (GLFS-25) in tumor survivors.

Objective: To evaluate the reliability and validity of the Chinese-translated Geriatric Locomotive Function Scale (GLFS-25) for the assessment of locomotive syndrome (LS) in individuals surviving malignancies. Methods: 393 tumor survivors at a general hospital in China were recruited. The Chinese version of GLFS-25 was utilized to conduct a cross-sectional survey to ascertain the tool's efficacy in measuring LS in this cohort. The scale's validity was examined through content, structural and discriminant validity assessments, while its reliability was investigated by determining the internal consistency (via Cronbach's α coefficient) and test-retest reliability (via intragroup correlation coefficient, ICC). Results: The Chinese-adapted GLFS-25 demonstrated a robust scale-level content validity index of 0.94, while item-level content validity indices ranged from 0.83 to 1.00 across individual items. The suitability of the scale for structural validity assessment was confirmed via exploratory factor analysis, yielding a Kaiser-Meyer-Olkin measure of 0.930 and a significant Bartlett's test of sphericity (χ2 = 3217.714, df = 300, P < 0.001). Subsequent confirmatory factor analysis (CFA) extracted four distinct factors: Social Activity Engagement, Daily Living Ability, Pain Experience and Physical Mobility. These factors accounted for 72.668 % of the variance, indicating substantial construct validity for measuring LS among this population. CFA supported the model's fit with the following indices: χ2/df = 1.559, RMSEA = 0.077, GFI = 0.924, CFI = 0.941, NFI = 0.919, and TLI = 0.933. The factor loadings for the four factors ranged from 0.771 to 0.931, indicating the items corresponding to the four factors effectively represented the constructs they were designed to measure. The correlation coefficients among the four factors were between 0.306 and 0.469, all lower than the square roots of the respective AVEs (0.838-0.867). This suggests a moderate correlation among the four factors and a distinct differentiation between them, indicating the Chinese version of the GLFS-25 exhibits strong discriminant validity in Chinese tumor survivors. Reliability testing revealed a high Cronbach's α coefficient for the overall scale at 0.961, with the subscales yielding coefficients of 0.751, 0.836, 0.930, and 0.952. The overall ICC was determined to be 0.935, with subscale ICCs ranging from 0.857 to 0.941, reinforcing the scale's reliability in this context. Conclusions: The Chinese version of the GLFS-25 exhibits strong reliability and validity for the assessment of LS in tumor survivors. It may serve as a diagnostic tool for LS, contributing to the prevention and management of musculoskeletal disorders and enhancing the prognosis for this patient population.

A Child With Concomitant Neuroblastoma and IgA Nephropathy: A Case Report and Literature Review.

Concurrent malignancy and IgA nephropathy are rare. Despite the lack of solid experimental evidence, there are theoretical hypotheses of pathophysiology for the development of glomerular damage in cancer patients, like aberrant immune activities. Here, we describe a nine-year-old child who was admitted due to nephrotic syndrome. Abdominal imaging examination accidentally revealed a retroperitoneal tumor, and surgical resection was performed with a pathological diagnosis of neuroblastoma. However, complete removal of the tumor had no impact on the clinical manifestation of nephrotic syndrome, like proteinuria. The use of corticosteroids alone only led to a partial resolution of proteinuria, and resistance developed after one month of treatment. A further kidney biopsy was performed, which suggested IgA nephropathy. Clinical remission of IgA nephropathy was achieved after standard combination treatment of corticosteroids and mycophenolate mofetil for 10 months. This study represented the first case report of neuroblastoma associated with IgA nephropathy. We postulated that IgA nephropathy pathogenesis might be associated with neuroblastoma, though a coincidence of these two conditions cannot be fully excluded. Standard treatment for IgA nephropathy is applicable for patients with concomitant cancer.

Exposure to per- and polyfluoroalkyl substances in lung cancer patients and their associations with clinical health indicators.

Per- and polyfluoroalkyl substances (PFASs) have potential carcinogenicity, immunotoxicity, and hepatotoxicity. Research has been conducted on PFAS exposure in people to discuss their potential health effects, excluding lung cancer. In this study, we recruited participants (n = 282) with lung cancer from Heilongjiang Province, northeast China. The PFAS concentrations were measured in their serum to fill the data gap of exposure, and relationships were explored in levels between PFASs and clinical indicators of tumor, immune and liver function. Ten PFASs were found in over 80 % of samples and their total concentrations were 5.27-152 ng/mL, with the highest level for perfluorooctanesulfonate (median: 12.4 ng/mL). Long-chain PFASs were the main congeners and their median concentration (20.5 ng/mL) was nearly three times to that of short-chain PFASs (7.61 ng/mL). Significantly higher concentrations of perfluorobutanoic acid, perfluorononanoic acid and perfluorohexanesulfonate were found in males than in females (p < 0.05). Serum levels of neuro-specific enolase were positively associated with perfluoropentanoic acid in all participants and were negatively associated with perfluorononanesulfonate in females (p < 0.05, multiple linear regression models). Exposure to PFAS mixture was significantly positively associated with the lymphocytic absolute value (difference: 0.224, 95% CI: 0.018, 0.470; p < 0.05, quantile g-computation models) and serum total bilirubin (difference: 2.177, 95% CI: 0.0335, 4.33; p < 0.05). Moreover, PFAS exposure can affect γ-glutamyl transpeptidase through several immune markers (p < 0.05, mediating test). Our results suggest that exposure to certain PFASs could interfere with clinical indicators in lung cancer patients. To our knowledge, this is the first study to detect serum PFAS occurrence and check their associations with clinical indicators in lung cancer patients.

Paradoxical herniation associated with hyperbaric oxygen therapy after decompressive craniectomy: A case report.

BACKGROUND: Whether hyperbaric oxygen therapy (HBOT) can cause paradoxical herniation is still unclear. CASE SUMMARY: A 65-year-old patient who was comatose due to brain trauma underwent decompressive craniotomy and gradually regained consciousness after surgery. HBOT was administered 22 d after surgery due to speech impairment. Paradoxical herniation appeared on the second day after treatment, and the patient's condition worsened after receiving mannitol treatment at the rehabilitation hospital. After timely skull repair, the paradoxical herniation was resolved, and the patient regained consciousness and had a good recovery as observed at the follow-up visit. CONCLUSION: Paradoxical herniation is rare and may be caused by HBOT. However, the underlying mechanism is unknown, and the understanding of this phenomenon is insufficient. The use of mannitol may worsen this condition. Timely skull repair can treat paradoxical herniation and prevent serious complications.

A Sporadic Family of Lipoid Proteinosis with Novel ECM1 Gene Mutations.

Lipoid proteinosis (LP) is an uncommon, autosomal recessive genetic disorder. Multigene panel testing was conducted to confirm the diagnosis of a sporadic family with suspected LP. In the proband, we identified two mutations of ECMI and provided genetic evidence for informed genetic counselling.

Clinical application of two types of Hook-Wire needle localization procedures for pulmonary small nodule biopsy.

BACKGROUND: With the widespread use of low-dose spiral computed tomography (LDCT) and increasing awareness of personal health, the detection rate of pulmonary nodules is steadily rising. OBJECTIVE: To evaluate the success rate and safety of two different models of Hook-Wire needle localization procedures for pulmonary small nodule biopsy. METHODS: Ninety-four cases with a total of 97 pulmonary small nodules undergoing needle localization biopsy were retrospectively analyzed. The cases were divided into two groups: Group A, using breast localization needle steel wire (Bard Healthcare Science Co., Ltd.); Group B, using disposable pulmonary nodule puncture needle (SensCure Biotechnology Co., Ltd.). All patients underwent video-assisted thoracoscopic surgery (VATS) for nodule removal on the same day after localization and biopsy. The puncture localization operation time, success rate, complications such as pulmonary hemorrhage, pneumothorax, hemoptysis, and postoperative comfort were observed and compared. RESULTS: In Group A, the average localization operation time for 97 nodules was 15.47 ± 5.31 minutes, with a success rate of 94.34%. The complication rate was 71.69% (12 cases of pneumothorax, 35 cases of pulmonary hemorrhage, 2 cases of hemoptysis), and 40 cases of post-localization discomfort were reported. In Group B, the average localization operation time was 25.32 ± 7.83 minutes, with a 100% success rate. The complication rate was 29.55% (3 cases of pneumothorax, 15 cases of pulmonary hemorrhage, 0 cases of hemoptysis), and 3 cases reported postoperative discomfort. According to the data analysis in this study, Group B had a lower incidence of puncture-related complications than Group A, along with a higher success rate and significantly greater postoperative comfort. CONCLUSIONS: The disposable pulmonary nodule puncture needle is safer and more effective in pulmonary small nodule localization biopsy, exhibiting increased comfort compared to the breast localization needle. Additionally, the incidence of complications is significantly lower.

Dietary intake changes the associations between long-term exposure to fine particulate matter and the surrogate indicators of insulin resistance.

The relationship of fine particulate matter (PM2.5) exposure and insulin resistance remains inclusive. Our study aimed to investigate this association in the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR). Specifically, we examined the associations between long-term PM2.5 exposure and three surrogate indicators of insulin resistance: the triglyceride-glucose index (TyG), TyG with waist circumference (TyG-WC) and metabolic score for insulin resistance (METS-IR). Additionally, we explored potential effect modification of dietary intake and components. Generalized estimating equations were used to evaluate the associations between PM2.5 and the indicators with an unbalanced repeated measurement design. Our analysis incorporated a total of 162,060 observations from 99,329 participants. Each 10 µg/m3 increment of PM2.5 was associated with an increase of 0.22 % [95 % confidence interval (CI): 0.20 %, 0.25 %], 1.60 % (95 % CI: 1.53 %, 1.67 %), and 2.05 % (95 % CI: 1.96 %, 2.14 %) in TyG, TyG-WC, and METS-IR, respectively. These associations were attenuated among participants with a healthy diet, particularly those with sufficient intake of fruit and vegetable, fish or tea (pinteraction < 0.0028). For instance, among participants with a healthy diet, TyG increased by 0.11 % (95 % CI: 0.08 %, 0.15 %) per 10 µg/m3 PM2.5 increment, significantly lower than the association observed in those with an unhealthy diet. The findings of this study emphasize the potential of a healthy diet to mitigate these associations, highlighting the urgency for improving air quality and implementing dietary interventions among susceptible populations in China.

Etching of Ag nanoparticles triggered bidirectional regulation for electrochemiluminescence ratiometric immunoassay.

A highly efficient ratiometric electrochemiluminescence (ECL) immunoassay was explored by bidirectionally regulating the ECL intensity of two luminophors. The immunoassay was conducted in a split-type mode consisting of an ECL detection procedure and a sandwich immunoreaction. The ECL detection was executed using a dual-disk glassy carbon electrode modified with two potential-resolved luminophors (g-C3N4-Ag and Ru-MOF-Ag nanocomposites), and the sandwich immunoreaction using glucose oxidase (GOx)-modified SiO2 nanospheres as labels was carried out in a 96-well plate. The Ag nanoparticles (NPs) acted as bifunctional units both for triggering the resonance energy transfer (RET) with g-C3N4 and for accelerating the electron transfer rate of the Ru-MOF-Ag ECL reaction. When the H2O2 catalyzed by GOx in the 96-well plate was transferred to the dual-disk glass carbon electrode, the doped Ag NPs in the two luminophors could be etched, thus destroying the RET between C3N4 and the accelerated reaction to Ru-MOF, resulting in an opposite trend in the ECL signal outputted from the dual disks. Using the ratio of the two signals for quantification, the constructed immunosensor for a model target, i.e. myoglobin, exhibited a low detection limit of 4.7 × 10-14 g/mL. The ingenious combination of ECL ratiometry, bifunctional Ag NPs, and a split-type strategy effectively reduces environmental and human errors, offering a more precise and sensitive analysis for complex samples.

[Elesclomol-Cu Induces Cuproptosis in Human Acute Myeloid Leukemia Cells].

OBJECTIVE: To investigate the effects of elesclomol-Cu (ES-Cu) on the proliferation and cuproptosis of human acute myeloid leukemia (AML) cells. METHODS: The effects of ES-Cu on the proliferation of AML cells and the AML cells pre-treated with ammonium tetrathiomolybdate (TTM) were examined by CCK-8 assay. The Calcein/PI kit was used to detected the changes in activity and cytotoxicity of AML cells induced by ES-Cu. Flow cytometry and Cytation3 fully automated cell imaging multifunctional detection system were used to analyze DCFH-DA fluorescence intensity, so as to determine the level of reactive oxygen species (ROS). The GSH and GSSG detection kits were used to measure the intracellular GSH content. Western blot was used to detected the expression of cuproptosis-related proteins ATP7B, FDX1, DLAT and DPYD. RESULTS: ES-Cu inhibited the proliferation of Kasumi-1 and HL-60 cells in a concentration-dependent manner (r Kasumi-1=-0.99， r HL-60=-0.98). As the concentration of ES-Cu increased, the level of intracellular ROS also increased (P <0.01-0.001). TTM could significantly reverse the inhibitory effect of ES-Cu on cell proliferation and its promoting effect on ROS. With the increase of ES-Cu concentration, the content of GSH was decreased (r =-0.98), and Western blot showed that the protein expressions of ATP7B, FDX1, DLAT and DPYD were significantly reduced (P <0.05). CONCLUSION: ES-Cu can induce cuproptosis in AML cells, which provides a new idea for the treatment of AML.

PPARγ alleviates preeclampsia development by regulating lipid metabolism and ferroptosis.

The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.

Effect of decentration and tilt on the in vitro optical quality of monofocal and trifocal intraocular lenses.

PURPOSE: To evaluate and compare the effect of decentration and tilt on the optical quality of monofocal and trifocal intraocular lenses (IOL). METHODS: Optical quality of a monofocal IOL (AcrySof IQ SN60WF; Alcon Laboratories, Inc., USA) and a trifocal IOL (AcrySof IQ PanOptix; Alcon Laboratories, Inc., USA) was assessed using an in vitro optical bench (OptiSpheric IOL R&D; Trioptics GmbH, Germany). At apertures of 3.0 mm and 4.5 mm, modulation transfer function (MTF) at spatial frequency of 50 lp/mm, MTF curve and the United States Air Force (USAF) resolution test chart of the two IOLs were measured and compared at their focus with different degrees of decentration and tilt. Optical quality at infinity, 60 cm and 40 cm and the through-focus MTF curves were compared when the two IOLs were centered at apertures of 3.0 mm and 4.5 mm. Spectral transmittance of the two IOLs was measured by the UV-visible spectrophotometer (UV 3300 PC; MAPADA, China). RESULTS: The SN60WF and the PanOptix filtered blue light from 400 to 500 nm. Both IOLs at the far focus and the PanOptix at the intermediate focus showed a decrease in optical quality with increasing decentration and tilt. The PanOptix demonstrated enhanced optical quality compared to the previous gradient at the near focus at a decentration range of 0.3-0.7 mm with a 3.0 mm aperture, and 0.5 mm with a 4.5 mm aperture, whereas other conditions exhibited diminished optical quality with increasing decentration and tilt at the focus of both IOLs. When the two IOLs were centered, the SN60WF had better optical quality at infinity, while the PanOptix had better optical quality at 60 cm and 40 cm defocus. The optical quality of the SN60WF exceeded that of the PanOptix at far focus, with a 3 mm aperture decentration up to 0.7 mm and a 4.5 mm aperture decentration up to 0.3 mm; this observation held true for all tilts, irrespective of aperture size. As both decentration and tilt increased, the optical quality of the SN60WF deteriorated more rapidly than that of the PanOptix at the far focal point. CONCLUSIONS: The SN60WF showed a decrease in optical quality with increasing decentration and tilt. Optical quality of the PanOptix at the near focus increased in some decentration conditions and decreased in some conditions, while it showed a decrease at the other focuses with increasing decentration. While tilt only had a negative effect on optical quality. When both IOLs were centered, the PanOptix provided a wider range of vision, while the SN60WF provided better far distance vision. At the far focus, the SN60WF has better resistance to tilt than the PanOptix, but the optical quality degrades more quickly when decentered and tilted.