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Si-si Xie,1 Xiao-ting Luo,2 Ming-hua Dong,3 Qi Wang,3 Jian Li,4 Qing-feng Wu3 1School of Graduate, Gannan Medical University, Ganzhou, Jiangxi, People’s Republic of China; 2School of General Medicine, Gannan Medical University, Ganzhou, Jiangxi, People’s Republic of China; 3School of Public Health and Health Management, Gannan Medical University, Ganzhou, Jiangxi, People’s Republic of China; 4School of Basic Medical, Gannan Medical University, Ganzhou, Jiangxi, People’s Republic of ChinaCorrespondence: Qing-feng Wu, Gannan Medical University, Rongjiang New District College Park, Ganzhou, Jiangxi, 341000, People’s Republic of China, Tel/Fax +86 18970786090, Email wuqf0920@163.comPurpose: Hemoglobin glycation index (HGI) is used to describe the difference between estimated and measured glycated hemoglobin A1c (HbA1c). The present study aimed to investigate the association between metabolic syndrome (MetS) and HGI in middle-aged and elderly Chinese.Patients and Methods: In this cross-sectional study, a multi-stage random sampling method was used to select objects from the permanent residents aged 35 years and above living in Ganzhou, Jiangxi, China. The demographic information, history of illness, physical examination, and blood biochemistry data were obtained. HGI was calculated from fasting plasma glucose (FPG) and HbA1c (HGI = measured HbA1c value - predicted HbA1c value). All participants were divided into low HGI and high HGI groups using the median HGI as a cut-off value. Univariate analysis was used to detect the influencing factors of HGI, and Logistic regression analysis was adopted to analyze the relationship between significant variables found in univariate analysis, MetS, or MetS’s components and HGI.Results: A total of 1826 participants were enrolled in the study, and the prevalence of MetS was 27.4%. There were 908 in the low HGI group and 918 in the high HGI group, and the prevalence of MetS was 23.7% and 31.0%, respectively. Logistic regression analysis showed that the prevalence of MetS in the high HGI group was higher than that in the low HGI group (OR=1.384, 95% CI:1.110~1.725), further analysis showed that HGI was related with abdominal obesity (OR=1.287, 95% CI:1.061~1.561), hypertension (OR=1.349, 95% CI:1.115~1.632), and hypercholesterolemia (OR=1.376, 95% CI:1.124~1.684) (all P < 0.05). After adjusting for age, sex, and serum uric acid (UA), the relationship still existed.Conclusion: This study found that HGI is directly associated with MetS.Keywords: hemoglobin glycation index, metabolic syndrome, cross-sectional study

Jie Guo,1,&ast; Airen Xu,2,&ast; Maojun Cheng,1 Yang Wan,1 Rikang Wang,1 Yuanying Fang,1 Yi Jin,1 Sai-Sai Xie,1 Jing Liu3 1National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, People’s Republic of China; 2Clinical Pharmacology Research Center, The Second Hospital of Yinzhou, Ningbo, Zhejiang, People’s Republic of China; 3School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sai-Sai Xie, National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, No. 56, Yangming Road, Donghu District, Nanchang City, Jiangxi Province, 330006, People’s Republic of China, Email xiesaisainanchang@hotmail.com Jing Liu, School of Pharmacy, Jiangxi University of Chinese Medicine, No. 56, Yangming Road, Donghu District, Nanchang City, Jiangxi Province, 330006, People’s Republic of China, Email liujing860828@163.comBackground: Alzheimer’s disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports.Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1H)-quinolinone and dithiocarbamate.Methods: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo.Results: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC50=0.28 μM to eeAChE; IC50=0.34 μM to hAChE; IC50=2.81 μM to hMAO-B; IC50=0.91 μM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 μM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.).Conclusion: This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study.Graphical Abstract: Keywords: Alzheimer’s disease, cholinesterase, monoamine oxidase, 3,4-dihydro-2(1H)-quinolinone, dithiocarbamate

To investigate the image quality and dose performance of 80 kV high-pitch spiral (HPS) coronary CT angiography (CCTA). 106 patients consecutively enrolled into prospectively ECG-triggering HPS CCTA (pitch = 3.4) exam using kV/ref. mAs = 80/400, 100/370, and 120/370 when patient BMI was ≤22.5 (n = 40), between 22.5 and 27.5 (n = 53) and >27.5 kg/m² (n = 13). Image quality was assessed per-segment by two observers independently using a 4-point scale (1-excellent, 4-non-diagnosable). Image noise and signal-to-noise ratio (SNR), contrast-to-noise ratio were measured. Diagnostic image quality was obtained in 503 of 507, 687 of 693, 164 of 167 coronary segments in 80, 100, 120 kV groups without significant difference (P = 0.482). The proportions of segments with score 1-4 were not significantly different among three kV groups (all P > 0.05). Image noise were significantly higher in 80 kV group than 100 and 120 groups (P < 0.001), while SNR was not (P = 0.097). The effective dose of 80 kV group (0.36 ± 0.03 mSv) was significantly lower than that of 100 kV group (0.86 ± 0.08 mSv) and 120 kV group (1.77 ± 0.18 mSv). The mean ± SD of HR in all patients was 54.8 ± 5.1 bpm. 80 kV HPS CCTA is feasible for patient with BMI ≤ 22.5 kg/m² which can save 58% dose than 100 kV group, while maintain diagnosable image quality. [ABSTRACT FROM AUTHOR]

This study is to present a new scheme for the detection of human meridian system non-invasively. The optical transport properties along the pericardium meridian and a non-meridian path about 1 cm away from the meridian were measured non- invasively on 20 healthy people in vivo. 633 nm, 658 nm and 785 nm red lasers were used for irradiation, and the diffuse light emittances at different points on meridian and non-meridian directions were collected respectively and compared. Our study suggested that the light propagation characteristics along both the meridian and non-meridian directions conformed to the Beer's exponential attenuation law. Statistical analysis of the results suggested that the optical properties of human meridian differ from those of the surrounding tissue (p < 0.05), and the light attenuation is less when propagating along the pericardium meridian than along the non-meridian direction. These findings not only confirmed the objective existence of acupuncture meridians, but also shed new light on the understanding of meridians. [ABSTRACT FROM AUTHOR]

In this study, four previously undescribed flavonoids, named epimesatines P ( 1 ), Q ( 2 ), R ( 3 ), and S ( 4 ), were isolated from the aerial parts of Epimedium sagittatum Maxim. Their structures and absolute configurations were confirmed via spectroscopic analyses, quantum chemical electronic circular dichroism (ECD) calculations, Mo 2 (OAc) 4 -induced ECD, and Rh 2 (OCOCF 3 ) 4 -induced ECD experiments. Epimesatines Q and R were characterized by the presence of furan rings. A cytotoxicity assay demonstrated that epimesatines P-S exhibited significant inhibitory effects on the viability of MCF-7 human breast cancer cells, with IC 50 values ranging from 1.27 to 50.3 μM. Notably, epimesatines Q and R exhibited superior efficacy against MCF-7 cells compared to epimesatines P and S, suggesting that the presence of furan rings may enhance their activity against MCF-7 cells. Specifically, epimesatine Q displayed a more potent inhibitory effect at 1.27 μM compared to a positive control, docetaxel, which had an IC 50 of 2.13 μM, highlighting its potential as a therapeutic agent for breast cancer. Importantly, none of the tested compounds exhibited obvious toxicity toward MCF-10A human breast epithelial cells. Furthermore, compounds 1 , 3 , and 4 were found to significantly inhibit the expression of sphingosine kinase 1 (Sphk1) in MCF-7 cells.

Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA's mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE., (© 2024. The Author(s).)

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 μM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg -1 ·d -1 , i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objective: Thromboangiitis obliterans (TAO) remains clinical challenging due to its rarity and underwhelming management outcomes. This study aimed to describe a novel TAO rabbit model that demonstrates a closer resemblance to TAO., Methods: Thirty-six New Zealand rabbits underwent the surgical implantation of calibrated gelatin sponge particles (CGSPs) into their right femoral artery. The CGSPs were soaked in different solutions to simulate different types of thrombi: normal (NT; normal saline); inflammatory TAO thrombus (TAO; dimethylsulfoxide [DMSO]), and DMSO with methotrexate (MTX). All groups underwent clinical assessment, digital subtraction angiography (DSA) and histopathological analysis at time points day 0 (immediate), week 1 (acute), week 2 (subacute), and week 4 (chronic)., Results: The TAO rabbit presented with signs of ischemia of the right digit at week 4. On DSA, the TAO rabbits exhibited formation of corkscrew collaterals starting week 1. On H&E staining, gradual CGSP degradation was observed along with increased red blood cell aggregation and inflammatory cells migration in week 1. On week 2, disorganization of the tunica media layer and vascular smooth muscle cell (VSMC) proliferation was observed. In the TAO rabbit, migrated VSMCs, inflammatory cells, and extracellular matrix with collagen-like substances gradually occluded the lumen. On week 4, the arterial lumen of the TAO rabbit was filled with relatively-organized VSMC and endothelial cell clusters with less inflammatory cells. Neorevascularization was found in the MTX-treated group., Conclusion: The novel TAO rabbit model shows a closer resemblance to human TAO clinically, radiographically, and histopathologically. Histological analysis of the IT progression in the TAO model suggests that it is of VSMC origin., (© 2024. The Author(s).)

Background: The Chinese medicine Yangyin Huowei mixture (YYHWM) exhibits good clinical efficacy in the treatment of chronic atrophic gastritis (CAG), but the mechanisms underlying its activity remain unclear., Aim: To investigate the therapeutic effects of YYHWM and its underlying mechanisms in a CAG rat model., Methods: Sprague-Dawley rats were allocated into control, model, vitacoenzyme, and low, medium, and high-dose YYHWM groups. CAG was induced in rats using N-methyl-N'-nitro-N-nitrosoguanidine, ranitidine hydrochloride, hunger and satiety perturbation, and ethanol gavage. Following an 8-wk intervention period, stomach samples were taken, stained, and examined for histopathological changes. ELISA was utilized to quantify serum levels of PG-I, PG-II, G-17, IL-1β, IL-6, and TNF-α. Western blot analysis was performed to evaluate protein expression of IL-10, JAK1, and STAT3., Results: The model group showed gastric mucosal layer disruption and inflammatory cell infiltration. Compared with the blank control group, serum levels of PGI, PGII, and G-17 in the model group were significantly reduced (82.41 ± 3.53 vs 38.52 ± 1.71, 23.06 ± 0.96 vs 11.06 ± 0.70, and 493.09 ± 12.17 vs 225.52 ± 17.44, P < 0.01 for all), whereas those of IL-1β, IL-6, and TNF-α were significantly increased (30.15 ± 3.07 vs 80.98 ± 4.47, 69.05 ± 12.72 vs 110.85 ± 6.68, and 209.24 ± 11.62 vs 313.37 ± 36.77, P < 0.01 for all), and the protein levels of IL-10, JAK1, and STAT3 were higher in gastric mucosal tissues (0.47 ± 0.10 vs 1.11 ± 0.09, 0.49 ± 0.05 vs 0.99 ± 0.07, and 0.24 ± 0.05 vs 1.04 ± 0.14, P < 0.01 for all). Compared with the model group, high-dose YYHWM treatment significantly improved the gastric mucosal tissue damage, increased the levels of PGI, PGII, and G-17 (38.52 ± 1.71 vs 50.41 ± 3.53, 11.06 ± 0.70 vs 15.33 ± 1.24, and 225.52 ± 17.44 vs 329.22 ± 29.11, P < 0.01 for all), decreased the levels of IL-1β, IL-6, and TNF-α (80.98 ± 4.47 vs 61.56 ± 4.02, 110.85 ± 6.68 vs 89.20 ± 8.48, and 313.37 ± 36.77 vs 267.30 ± 9.31, P < 0.01 for all), and evidently decreased the protein levels of IL-10 and STAT3 in gastric mucosal tissues (1.11 ± 0.09 vs 0.19 ± 0.07 and 1.04 ± 0.14 vs 0.55 ± 0.09, P < 0.01 for both)., Conclusion: YYHWM reduces the release of inflammatory factors by inhibiting the IL-10/JAK1/STAT3 pathway, alleviating gastric mucosal damage, and enhancing gastric secretory function, thereby ameliorating CAG development and cancer transformation., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest for this paper., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Research suggests that a defendant's history of experiencing childhood abuse, and its effects on their life and later decision-making, may impact public support for a defendant's sentencing, particularly mitigation. However, no existing research has examined how and why sentencing support may vary based on the time period when the abuse occurs during a defendant's childhood. This experiment, using a sample of the U.S. public (N = 400), examines how the age at which a defendant's childhood physical abuse occurs affects lay support for the goals of their sentencing. We hypothesized that participants with higher levels of social and biological trait essentialism would moderate their increased support for more punitive sentencing goals-particularly when a defendant was abused earlier, rather than later, in childhood. Results suggest that social essentialism is associated with increased support for restoration and rehabilitation toward defendants with histories of childhood physical abuse, potentially indicating that the public views the effects of child abuse as more of a social, versus biological, process which may affect support for utilitarian punishment goals., (© 2024 The Author(s). Behavioral Sciences & The Law published by John Wiley & Sons Ltd.)

The aim of this study was to investigate the effects of solid-state fermented cottonseed meal (FCSM) inclusion levels on the growth performance, serum biochemical parameters and hepatic lipid metabolism in geese from 28 to 70 d of age. A total of 288 twenty-eight-d-old male geese were randomly divided into 4 treatments with FCSM levels of 0, 5, 15 and 25% including 0, 22.74, 67.33, 111.27 mg FG/kg diet, respectively. Each treatment contained 6 replicates and 12 birds per replicate. Treatments of FCSM inclusions from 0 to 25% had no effect on growth rate and feed intake in geese during d 28 to 70. The F/G ratio was increased (P < 0.05) in geese fed the diet with 25% FCSM compared with birds fed the diet with 0% FCSM. Treatment with 25% FCSM levels had no effect on the contents of TC, TG, HDL-C, LDL-C, but increased (P < 0.05) AST and ALT activities in serum of geese at d 70. Treatment with 25% FCSM increased the contents of FG, HDL-C, TC, C18:2n6, C20:4n6 and PUFA and decreased (P < 0.05) the contents of NEFA, SFA, MUFA in liver compared with treatment of 0% FCSM inclusion. Additionally, treatment with 25% FCSM decreased (P < 0.05) the PPARα, AMPK, and LXR mRNA expression related to lipid deposition, and increased (P < 0.05) PPARγ and ACC mRNA expression related to lipolysis in liver compared with birds fed the diet with 0% FCSM. Overall, treatment with 0 to 15% FCSM (<=67.33 mg FG/kg diet) had no adverse effects on the growth performance and lipid metabolism of geese. However, treatment fed 25% FCSM (111.27 mg FG/kg diet) decreased feed efficiency and promoted hepatic lipid deposition associated with the alteration of related gene expression in geese at 28 to 70 d of age., (Copyright © 2024. Published by Elsevier Inc.)

Computational analysis of fluorescent timelapse microscopy images at the single-cell level is a powerful approach to study cellular changes that dictate important cell fate decisions. Core to this approach is the need to generate reliable cell segmentations and classifications necessary for accurate quantitative analysis. Deep learning-based convolutional neural networks (CNNs) have emerged as a promising solution to these challenges. However, current CNNs are prone to produce noisy cell segmentations and classifications, which is a significant barrier to constructing accurate single-cell lineages. To address this, we developed a novel algorithm called Single Cell Track (SC-Track), which employs a hierarchical probabilistic cache cascade model based on biological observations of cell division and movement dynamics. Our results show that SC-Track performs better than a panel of publicly available cell trackers on a diverse set of cell segmentation types. This cell-tracking performance was achieved without any parameter adjustments, making SC-Track an excellent generalized algorithm that can maintain robust cell-tracking performance in varying cell segmentation qualities, cell morphological appearances and imaging conditions. Furthermore, SC-Track is equipped with a cell class correction function to improve the accuracy of cell classifications in multiclass cell segmentation time series. These features together make SC-Track a robust cell-tracking algorithm that works well with noisy cell instance segmentation and classification predictions from CNNs to generate accurate single-cell lineages and classifications., (© The Author(s) 2024. Published by Oxford University Press.)

The involvement of CDC20 in promoting tumor growth in different types of human cancers and it disturbs the process of cell division and impedes tumor proliferation. In this work, a novel of Apcin derivatives targeting CDC20 were designed and synthesized to evaluate for their biological activities. The inhibitory effect on the proliferation of four human tumor cell lines (MCF-7, MDA-MB-231, MDA-MB-468 and A549) was observed. Among them, compound E1 exhibited the strongest inhibitory effect on the proliferation of MDA-MB-231 cells with an IC 50 value of 1.43 μM, which was significantly superior to that of Apcin. Further biological studies demonstrated that compound E1 inhibited cancer cell migration and colony formation. Furthermore, compound E1 specifically targeted CDC20 and exhibited a higher binding affinity to CDC20 compared to that of Apcin, thereby inducing cell cycle arrest in the G2/M phase of cancer cells. Moreover, it has been observed that compound E1 induces autophagy in cancer cells. In 4T1 Xenograft Models compound E1 exhibited the potential antitumor activity without obvious toxicity. These findings suggest that E1 could be regarded as a CDC20 inhibitor deserved further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yong Yin reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

A heterobifunctional cross-linker with one sulfhydryl-reactive dinitroimidazole end and another amine-reactive N -hydroxysuccinimide (NHS) ester end was designed and synthesized. The two motifs of this cross-linker, dinitroimidazole and NHS ester, proved to react with thiol and amine, respectively, in an orthogonal way. The cross-linker was further applied to construct stapled peptides of different sizes and mono- and dual functionalization (including biotinylation, PEGylation, and fluorescence labeling) of protein.

Objectives: To evaluate the performance of a radiomics nomogram developed based on gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) MRI for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC), and to identify patients who may benefit from the postoperative adjuvant transarterial chemoembolization (PA-TACE)., Methods: A total of 260 eligible patients were retrospectively enrolled from three hospitals (140, 65, and 55 in training, standardized external, and non-standardized external validation cohort). Radiomics features and image characteristics were extracted from Gd-EOB-DTPA MRI image before hepatectomy for each lesion. In the training cohort, a radiomics nomogram which incorporated the radiomics signature and radiological predictors was developed. The performance of the radiomics nomogram was assessed with respect to discrimination calibration, and clinical usefulness with external validation. A score (m-score) was constructed to stratify the patients and explored whether it could accurately predict patient who benefit from PA-TACE., Results: A radiomics nomogram integrated with the radiomics signature, max-D(iameter)  > 5.1 cm, peritumoral low intensity (PTLI), incomplete capsule, and irregular morphology had favorable discrimination in the training cohort (AUC = 0.982), the standardized external validation cohort (AUC = 0.969), and the non-standardized external validation cohort (AUC = 0.981). Decision curve analysis confirmed the clinical usefulness of the novel radiomics nomogram. The log-rank test revealed that PA-TACE significantly decreased the early recurrence in the high-risk group (p = 0.006) with no significant effect in the low-risk group (p = 0.270)., Conclusions: The novel radiomics nomogram combining the radiomics signature and clinical radiological features achieved preoperative non-invasive MVI risk prediction and patient benefit assessment after PA-TACE, which may help clinicians implement more appropriate interventions., Clinical Relevance Statement: Our radiomics nomogram could represent a novel biomarker to identify patients who may benefit from the postoperative adjuvant transarterial chemoembolization, which may help clinicians to implement more appropriate interventions and perform individualized precision therapies., Key Points: • The novel radiomics nomogram developed based on Gd-EOB-DTPA MRI achieved preoperative non-invasive MVI risk prediction. • An m-score based on the radiomics nomogram could stratify HCC patients and further identify individuals who may benefit from the PA-TACE. • The radiomics nomogram could help clinicians to implement more appropriate interventions and perform individualized precision therapies., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

This study aims to investigate the intervention effect of the aqueous extract of Epimedium sagittatum Maxim on the mouse model of bleomycin(BLM)-induced pulmonary fibrosis, so as to provide data support for the clinical treatment of pulmonary fibrosis. Ninety male C57BL/6N mice were randomized into normal(n=10), model(BLM, n=20), pirfenidone(PFD, 270 mg·kg~(-1), n=15), and low-, medium-, and high-dose E. sagittatum extract(1.67 g·kg~(-1), n=15; 3.33 g·kg~(-1), n=15; 6.67 g·kg~(-1), n=15) groups. The model of pulmonary fibrosis was established by intratracheal instillation of BLM(5 mg·kg~(-1)) in the other five groups except the normal group, which was treated with an equal amount of normal saline. On the day following the modeling, each group was treated with the corresponding drug by gavage for 21 days. During this period, the survival rate of the mice was counted. After gavage, the lung index was calculated, and the morphology and collagen deposition of the lung tissue were observed by hematoxylin-eosin(HE) and Masson staining, respectively. The levels of reactive oxygen species(ROS) in lung cell suspensions were measured by flow cytometry. The levels of glutathione peroxidase(GSH-Px), total superoxide dismutase(T-SOD), and malondialdehyde(MDA) the in lung tissue were measured. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling(TUNEL) was employed to examine the apoptosis of lung tissue cells. The content of interleukin-6(IL-6), chemokine C-C motif ligand 2(CCL-2), matrix metalloproteinase-8(MMP-8), transforming growth factor-beta 1(TGF-β1), alpha-smooth muscle actin(α-SMA), E-cadherin, collagen Ⅰ, and fibronectin in the lung tissue was measured by enzyme-linked immunosorbent assay(ELISA). The expression levels of F4/80, Ly-6G, TGF-β1, and collagen Ⅰ in the lung tissue were determined by immunohistochemistry. The mRNA levels of CCL-2, IL-6, and MMP-7 in the lung tissue were determined by qRT-PCR. The content of hydroxyproline(HYP) in the lung tissue was determined by alkaline hydrolysation. The expression of α-SMA and E-cadherin was detected by immunofluorescence, and the protein levels of α-SMA, vimentin, E-cadherin in the lung tissue were determined by Western blot. The results showed the aqueous extract of E. sagittatum increased the survival rate, decreased the lung index, alleviated the pathological injury, collagen deposition, and oxidative stress in the lung tissue, and reduced the apoptotic cells. Furthermore, the aqueous extract of E. sagittatum down-regulated the protein levels of F4/80 and Ly-6G and the mRNA levels of CCL-2, IL-6, and MMP-7 in the lung tissue, reduced the content of IL-6, CCL-2, and MMP-8 in the alveolar lavage fluid. In addition, it lowered the levels of HYP, TGF-β1, α-SMA, collagen Ⅰ, fibronectin, and vimentin, and elevated the levels of E-cadherin in the lung tissue. The aqueous extract of E. sagittatum can inhibit collagen deposition, alleviate oxidative stress, and reduce inflammatory response by regulating the expression of the molecules associated with epithelial-mesenchymal transition, thus alleviating the symptoms of bleomycin-induced pulmonary fibrosis in mice.

Background: This study aimed to develop a computed tomography (CT) model to predict Ki-67 expression in hepatocellular carcinoma (HCC) and to examine the added value of radiomics to clinico-radiological features., Methods: A total of 208 patients (training set, n = 120; internal test set, n = 51; external validation set, n = 37) with pathologically confirmed HCC who underwent contrast-enhanced CT (CE-CT) within 1 month before surgery were retrospectively included from January 2014 to September 2021. Radiomics features were extracted and selected from three phases of CE-CT images, least absolute shrinkage and selection operator regression (LASSO) was used to select features, and the rad-score was calculated. CE-CT imaging and clinical features were selected using univariate and multivariate analyses, respectively. Three prediction models, including clinic-radiologic (CR) model, rad-score (R) model, and clinic-radiologic-radiomic (CRR) model, were developed and validated using logistic regression analysis. The performance of different models for predicting Ki-67 expression was evaluated using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis (DCA)., Results: HCCs with high Ki-67 expression were more likely to have high serum α-fetoprotein levels (P = 0.041, odds ratio [OR] 2.54, 95% confidence interval [CI]: 1.04-6.21), non-rim arterial phase hyperenhancement (P = 0.001, OR 15.13, 95% CI 2.87-79.76), portal vein tumor thrombus (P = 0.035, OR 3.19, 95% CI: 1.08-9.37), and two-trait predictor of venous invasion (P = 0.026, OR 14.04, 95% CI: 1.39-144.32). The CR model achieved relatively good and stable performance compared with the R model (AUC, 0.805 [95% CI: 0.683-0.926] vs. 0.678 [95% CI: 0.536-0.839], P = 0.211; and 0.805 [95% CI: 0.657-0.953] vs. 0.667 [95% CI: 0.495-0.839], P = 0.135) in the internal and external validation sets. After combining the CR model with the R model, the AUC of the CRR model increased to 0.903 (95% CI: 0.849-0.956) in the training set, which was significantly higher than that of the CR model (P = 0.0148). However, no significant differences were found between the CRR and CR models in the internal and external validation sets (P = 0.264 and P = 0.084, respectively)., Conclusions: Preoperative models based on clinical and CE-CT imaging features can be used to predict HCC with high Ki-67 expression accurately. However, radiomics cannot provide added value., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPR Flox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPR Flox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Due to the higher birth rate of preterm infants and improvements in their management, metabolic bone disease of prematurity (MBDP) has a high incidence and is attracting attention. However, clear indicators for the early diagnosis of MBDP are lacking. We aimed to explore simple and feasible early warning indicators for diagnosing MBDP. Our study collected case data of premature infants from two medical centers in Chongqing from January 2020 to February 2022. According to the inclusion and exclusion criteria, data from 136 cases were collected. The correlation between 14 variables in each case and the occurrence of MBDP was analyzed. According to area under the receiver operating characteristic curve (AUROC) analysis, the best cutoff value for each variable was determined. Potential predictors were selected, and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to establish the association of two models with MBDP, whose results were used to develop a diagnostic nomogram. Furthermore, a model decision curve was analyzed. Four predictors were selected from 14 clinical variables by LASSO regression, and Model I was established, including the following characteristics: height (>36 cm), head circumference (≤29.49 cm), total serum calcium (Ca) (>2.13 mmol/L), and alkaline phosphatase (ALP) (>344 U/L) levels. A single predictor, the ALP level (>344 U/L), was used to establish Model II. The AUROC values of the two models were 0.959 for Model I and 0.929 for Model II. In conclusion, in this study, two diagnostic models of MBDP were developed using four combinations of predictors and ALP as a single predictor. Both models showed good sensitivity and specificity for the early diagnosis of metabolic bone disease (MBD), and an ALP level of 344 U/L was defined as a simple and effective diagnostic threshold. In future studies, using larger samples, diagnostic threshold values of ALP for premature infants of different ages should be established, and internal and external validations are needed to improve the adaptability of the current model., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite extensive investigations in mammals and yeasts, the importance and specificity of COMPASS-like complex, which catalyzes histone 3 lysine 4 methylation (H3K4me), are not fully understood in plants. Here, we report that JMJ28, a Jumonji C domain-containing protein in Arabidopsis, recognizes specific DNA motifs through a plant-specific WRC domain and acts as an interacting factor to guide the chromatin targeting of ATX1/2-containing COMPASS-like complex. JMJ28 associates with COMPASS-like complex in vivo via direct interaction with RBL. The DNA-binding activity of JMJ28 is essential for both the targeting specificity of ATX1/2-COMPASS and the deposition of H3K4me at specific loci but exhibit functional redundancy with alternative COMPASS-like complexes at other loci. Finally, we demonstrate that JMJ28 is a negative regulator of plant immunity. In summary, our findings reveal a plant-specific recruitment mechanism of COMPASS-like complex. These findings help to gain deeper insights into the regulatory mechanism of COMPASS-like complex in plants., Competing Interests: Declaration of interests The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The abbreviated version of Penn State Worry Questionnaire (PSWQ-A) has been widely used to assess worry. However, its measurement invariance has been not yet warranted. With a cross-sectional and a longitudinal sample of Chinese adolescents (N1 = 1,329, N2 = 408), this study examined age, gender, and longitudinal invariance of PSWQ-A. Results supported strict invariance, including configural, metric, scalar, and error level, across gender and age in the cross-sectional sample; strict longitudinal measurement invariance was also supported in the longitudinal sample. This study suggests the application of the PSWQ-A in measuring adolescent worry and a basis for comparisons of different populations and occasions for worry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xie, Xiao and Lin.)

Facing a deteriorating natural environment and an increasing serious food crisis, bioengineering-based breeding is increasing in importance. To defend against pathogen infection, plants have evolved multiple defense mechanisms, including pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI). A complex regulatory network acts downstream of these PTI and ETI pathways, including hormone signal transduction and transcriptional reprogramming. In recent years, increasing lines of evidence show that epigenetic factors act, as key regulators involved in the transcriptional reprogramming, to modulate plant immune responses. Here, we summarize current progress on the regulatory mechanism of DNA methylation and histone modifications in plant defense responses. In addition, we also discuss the application of epigenetic mechanism-based resistance strategies in plant disease breeding., Competing Interests: Conflict of interestBoth authors declare no conflict of interest., (© The Author(s) 2023.)

Background: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder whose underlying pathogenesis is unknown. Our previous study showed that pulmonary endothelial cell (PAEC) ferroptosis is involved in the progression of PH by releasing High-mobility group box 1 (HMGB1) and activating Toll-like receptor 4/NOD-like receptor family pyrin domain containing 3 (TLR4/NLRP3) inflammasome signalling. The precise mechanisms that regulate ferroptosis in PH are unclear. This study aimed to investigate the effect of peroxiredoxin 6 (PRDX6) on PAEC ferroptosis in PH., Methods: A rat model of PH was established with monocrotaline (MCT), and the distribution and expression of PRDX6 in the pulmonary artery were examined. Lentiviral vectors carrying PRDX6 (LV-PRDX6) were transfected into PAECs and injected into MCT-induced PH rats. Cell viability, MDA levels, reactive oxygen species (ROS) levels, labile iron pool (LIP) levels and mitochondrial morphology were examined. Ferroptosis-related proteins (NADPH oxidase-4 (NOX4), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1(FTH1)), TLR4, NLRP3 inflammasome markers, HMGB1 and inflammatory cytokines were examined. Pulmonary vascular remodelling and right ventricular structure and function were measured., Results: PRDX6 was expressed in PAECs and was significantly decreased in PH. PRDX6 overexpression significantly inhibited ferroptosis in PAECs under PH conditions in vitro and in vivo, as indicated by increased cell viability, decreased MDA, ROS and LIP levels, inhibited mitochondrial damage, upregulated GPX4 and FTH1 expression, and downregulated NOX4 expression. PRDX6 overexpression attenuated pulmonary vascular remodelling and changes in right ventricle structure and function in MCT-induced PH rats. Moreover, PRDX6 overexpression prevented HMGB1 release by PAECs and decreased TLR4 and NLRP3 inflammasome expression and inflammatory cytokine release in macrophages, while RSL3, a specific activator of ferroptosis, reversed these effects., Conclusions: Taken together, these findings indicate that PRDX6 regulates PAEC ferroptosis through the release of HMGB1 and activation of the TLR4/NLRP3 inflammasome signalling pathway, providing novel therapeutic targets for the treatment of PH., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The NLRP3 inflammasome in macrophages is known to promote infection-related vascular growth, and NLRP3 inflammasome activation interacts with PAH. STING is a crucial inflammatory reaction link that can increase the overexpression of NLRP3. However, the expression and effect of STING in PAH have not been elucidated. We examined the expression and articulation of STING in PAH and researched its hidden mechanism., Methods: A SU5416 plus hypoxia (Su/Hy)-induced rat model of PAH was constructed to examine STING activation. Su/Hy induced PAH rats were given a prophylactic injection of STING the inhibitor C-176. After modeling, hemodynamic changes, right ventricular hypertrophy index, lung morphological features, inflammasome activation, and proinflammatory cytokine secretion levels were assessed. In addition, the STING agonist DMXAA or inhibitor C-176 was used to interfere with LPS-induced BMDMs, NLRP3 inflammasome activation and cytokine secretion were examined, and the effect on PASMCs was evaluated in a coculture system., Results: STING expression increased significantly in the lung tissue of Su/Hy-treated PAH rats compared with normoxia-treated rats. Moreover, STING inhibitors can alleviate the Su/Hy-induced increase in pulmonary artery pressure and restrain the activation of the NLRP3 inflammasome and proinflammatory cytokines. In vitro experiments confirmed that STING affected the expression of the NLRP3 inflammasome and the secretion of inflammatory cytokines in BMDMs and promoted the proliferation of PASMCs in the coculture system., Conclusion: Our study shows that STING is activated in Su/Hy-induced PAH and boosts the actuation of the macrophage NLRP3 inflammasome to advance the inflammatory response and vascular proliferation in rats with Su/Hy-induced pulmonary hypertension., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objectives: To study the protective effect of breviscapine against brain injury induced by intrauterine inflammation in preterm rats and its mechanism., Methods: A preterm rat model of brain injury caused by intrauterine inflammation was prepared by intraperitoneal injections of lipopolysaccharide in pregnant rats. The pregnant rats and preterm rats were respectively randomly divided into 5 groups: control, model, low-dose breviscapine (45 mg/kg), high-dose breviscapine (90 mg/kg), and high-dose breviscapine (90 mg/kg)+ML385 [a nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, 30 mg/kg] ( n =10 each). The number and body weight of the live offspring rats were measured for each group. Hematoxylin-eosin staining was used to observe the pathological morphology of the uterus and placenta of pregnant rats and the pathological morphology of the brain tissue of offspring rats. Immunofluorescent staining was used to measure the co-expression of ionized calcium binding adaptor molecule-1 (IBA-1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in the cerebral cortex of offspring rats. ELISA was used to measure the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β) in the brain tissue of offspring rats. Western blotting was used to measure the expression of Nrf2 pathway-related proteins in the brain tissue of offspring rats., Results: Pathological injury was found in the uterus, and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, and severe microglia pyroptosis occurred in the cerebral cortex of the offspring rats in the model group. Compared with the control group, the model group had significant reductions in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and heme oxygenase-1 (HO-1) in the brain tissue of the offspring rats ( P <0.05), but significant increases in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1β, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats ( P <0.05). Compared with the model group, the breviscapine administration groups showed alleviated pathological injury of the uterus and placenta tissue of the pregnant rats and the brain tissue of the offspring rats, significant increases in the number and body weight of the live offspring rats and the protein expression levels of Nrf2 and HO-1 in the brain tissue of the offspring rats ( P <0.05), and significant reductions in the relative fluorescence intensity of the co-expression of IBA-1 and NLRP3, the levels of the inflammatory factors IL-6, IL-8, and IL-1β, and the protein expression levels of NLRP3 and caspase-1 in the brain tissue of the offspring rats ( P <0.05). The high-dose breviscapine group had a significantly better effect than the low-dose breviscapine ( P <0.05). ML385 significantly inhibited the intervention effect of high-dose breviscapine ( P <0.05)., Conclusions: Breviscapine can inhibit inflammatory response in brain tissue of preterm rats caused by intrauterine inflammation by activating the Nrf2 pathway, and it can also inhibit microglial pyroptosis and alleviate brain injury.

Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (huBuChE IC 50  = 1.20 μM, huAChE IC 50  = 177.49 μM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for huBuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Fifteen previously undescribed minor iridoid glycosides, including four monomers and eleven dimers, were isolated from the fruits of Cornus officinalis Sieb. et Zucc. Their chemical structures were determined on the basis of spectroscopic data and chemical evidence. All of the isolated compounds were evaluated for their effects of the glucose consumption on the insulin resistant HepG2 cells, and four compounds, named cornuofficinalisides F, H, L, and O, increased the glucose consumption significantly at 10 μM, the EC 50 values of them were determined to be 0.898, 1.625, 0.923, and 8.589 μM, respectively. Moreover, the four compounds could improve the ability of glucose uptake significantly in insulin resistant HepG2 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c 2 displayed the mighty inhibitory activity to hAChE (IC 50  = 0.053 μM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c 2 bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c 2 as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c 2 rescued BV-2 cells from H 2 O 2 -induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c 2 , we observed that 4c 2 could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c 2 was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c 2 was a promising multi-targeted agent for treating AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Amoxicillin-associated reactions (AARs) contribute to substantial health care utilization, with a reutilization rate of 10% in pediatric emergency department (ED) and urgent care (UC) settings., Objective: To identify predictors of ED/UC reutilization by examining patients' clinical features and providers' management of AARs., Methods: Through a retrospective chart review of 668 patients presenting with AARs over 2 years to the pediatric ED/UC, we examined clinical features associated with ED/UC reutilization, including rash phenotype, systemic symptoms (fever, angioedema, joint involvement, gastrointestinal symptoms), and providers' management (pharmacologic treatment and counseling). We then constructed a statistical model to predict ED/UC reutilization using stepwise backward model selection., Results: ED/UC reutilizers were more likely to be male (P = .008) and have fever (P = .0001), angioedema (P < .0001), joint involvement (P < .0001), and gastrointestinal symptoms (P = .0001) during their AAR course. Rash phenotypes differed between groups (P < .0001), as ED/UC reutilizers more frequently exhibited urticaria. However, there were no differences in clinical management between groups, including pharmacologic recommendations, at the initial ED/UC encounter. In addition, our statistical model identified younger patients <2 years of age as more likely to reutilize ED/UC resources if providers did not document specific return precautions (odds ratio, 3.6; 95% confidence interval, 1.7-7.7)., Conclusion: Recognition of clinical features and treatment gaps associated with ED/UC reutilization will guide interventions to optimize care in children presenting with AARs, such as improved anticipatory guidance and early allergy consultation. Prospective studies are needed to determine whether these interventions will reduce ED/UC reutilization and facilitate timely allergy testing., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a clinical syndrome that is defined as a sudden decline in renal function and characterized by inflammation and programmed cell death of renal tubular epithelial cells. Necroptosis is a form of regulated cell death that requires activation of receptor interacting protein kinase 3 (RIPK3) and its phosphorylation of the substrate MLKL. RIPK3 plays an important role in acute kidney injury, and hence developing its inhibitors is considered as one of the promising strategies aimed at prevention and treatment of AKI. Recently, we discovered AZD5423 as a novel potent RIPK3 inhibitor using a computer-aided hybrid virtual screening strategy according to three-dimensional structure of RIPK3. Our findings revealed that AZD5423 strongly inhibits activation of RIPK3, and MLKL phosphorylation upon cisplatin-, hypoxia/reoxygenation (H/R)- and TNF-α stimuli as compared with GSK872, which is a previously identified RIPK3 inhibitor. Importantly, AZD5423 exerts effective protection against cisplatin- and ischemia/reperfusion (I/R)-induced AKI mouse model. The results of cellular thermal shift assay and experiments in RIPK3 knockout cells indicated that AZD5423 could directly target RIPK3 to inhibit RIPK3 kinase activity. Mechanistically, the docking of AZD5423 and RIPK3 suggested that the kinase domain of RIPK3 for Lys 50 , Arg 313 , Lys 29 , Arg 37 might form hydrogen bonds with AZD5423. Site-directed mutagenesis further revealed that AZD5423 reduces injury response via interacting with the key RIPK3 amino acid residues of Lys 50 and Arg 313 . In conclusion, our study has demonstrated that AZD5423 may serve as a potent inhibitor of RIPK3 kinase and a promising clinical candidate for AKI treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Amoxicillin-associated reactions (AARs) in children presenting as rashes are common, and recent data suggest that >90% tolerate amoxicillin on re-exposure. However, additional data would help pediatricians and allergists gain confidence in referring and testing children who experienced systemic symptoms perceived as "worrisome," thus leading to urgent medical evaluations. By characterizing the entire spectrum of AAR symptoms in pediatric patients presenting to emergency department (ED)/urgent care (UC) settings, we sought to increase our diagnostic acumen to guide subsequent allergy evaluations., Objective: To fully characterize clinical features of rash and systemic symptoms in children presenting to the ED/UC with AARs., Methods: A retrospective chart review of children seen in the ED/UC from July 1, 2015, to June 30, 2017, was conducted. Clinical features, chronology, and seasonality were detailed, and cases were classified into 3 previously described AAR phenotypes: maculopapular exanthem (MPE), urticaria, and serum sickness-like reactions (SSLRs), if they experienced joint symptoms., Results: Children (n = 668; median age: 1.8 years) presented to the ED/UC with urticaria (44%), MPE (36%), and SSLRs (11%) typically on days 7 to 10 of amoxicillin. Although children with SSLRs were more frequently treated with corticosteroids (28%, P < .0001) and exhibited higher rates of "worrisome" features (fever, angioedema, or gastrointestinal symptoms; 73%, P < .0001), delayed-onset systemic symptoms were identified frequently in all 3 groups. ED/UC reutilization was unexpectedly high with 66 children (10%) returning to the ED/UC for re-evaluation., Conclusion: "Worrisome" symptoms are common in children presenting to the ED/UC with AARs. Future studies are needed to determine the impact on subsequent referral and allergy testing., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) is an increasing public health concern, characterized by a reduced glomerular filtration rate and increased urinary albumin excretion. Renal fibrosis is an important pathological condition in patients with CKD. In this study, we evaluated the anti-fibrotic effect of Cpd-0225, a novel transforming growth factor-β (TGF-β) type I receptor (also known as ALK5) inhibitor, in vitro and in vivo, by comparing its effect with that of SB431542, a classic ALK5 inhibitor, which has not entered the clinical trial stage owing to multiple side effects. Our data showed that Cpd-0225 attenuated fibrotic response in TGF-β1-stimulated human kidney tubular epithelial cells and repeated hypoxia/reoxygenation-treated mouse tubular epithelial cells. We further confirmed that Cpd-0225 improved renal tubular injury and ameliorated collagen deposition in unilateral ureteral obstruction-, ischemia/reperfusion-, and aristolochic acid-induced mouse models of renal fibrosis. In addition, molecular docking and site-directed mutagenesis showed that Cpd-0225 exerted a higher reno-protective effect than SB431542, by physically binding to the key amino acid residues, Lys232 and Lys335 of ALK5, thereby suppressing the phosphorylation of Smad3 and ERK1/2. Taken together, these findings suggest that Cpd-0225 administration attenuates renal fibrosis via ALK5-dependent mechanisms and displays a more effective therapeutic effect than SB431542. Thus, Cpd-0225 may serve as a potential therapeutic agent for the treatment of CKD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to establish a reliable diagnostic score model for the preoperative determination of pathological grade in HCC based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced MRI and biochemical indicators., Methods: In this retrospective study, we analyzed 139 patients with HCC who underwent Gd-EOB-DTPA MRI between 2014 and 2020, including an establishment cohort of 76 patients and a validation cohort of 63 patients. Based on the imaging features demonstrated on Gd-EOB-DTPA MRI images and biochemical indicators of the establishment cohort, a scoring model based on logistic regression was developed, and compared with postoperative pathological findings in terms of effective determination of pathological grade. The validity of the scoring model was assessed by ROC curves and an independent external validation cohort., Results: Three parameters related to pathological grades were identified, including maximum diameter of the tumor, peritumoral hypointensity in the hepatobiliary phase, and [alkaline phosphatase (U/L) + gamma glutamyl transpeptidase (U/L)]/ lymphocyte count (× 10 9 /L) (AGLR) ratios. Based on these three parameters, a scoring model was developed. ROC curve showed that a score of > 5 was set as the threshold for determining pathological grades with accuracy, sensitivity, specificity, PPV, and NPV of 89.5%, 75.0%, 95.1%, 85.7%, and 90.7%, respectively., Conclusion: The study provided the groundwork for a promising and easily implementable scoring model for preoperative determination of HCC pathological grades, for which further validation should be pursued., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The novel biomarker, insulin-like growth factor binding protein 7 (IGFBP7), is used clinically to predict different types of acute kidney injury (AKI) and has drawn significant attention as a urinary biomarker. However, as a secreted protein in the circulation of patients with AKI, it is unclear whether IGFBP7 acts as a key regulator in AKI progression, and if mechanisms underlying its upregulation still need to be determined. Here we found that IGFBP7 is highly expressed in the blood and urine of patients and mice with AKI, possibly via a c-Jun-dependent mechanism, and is positively correlated with kidney dysfunction. Global knockout of IGFBP7 ameliorated kidney dysfunction, inflammatory responses, and programmed cell death in murine models of cisplatin-, kidney ischemia/reperfusion-, and lipopolysaccharide-induced AKI. IGFBP7 mainly originated from kidney tubular epithelial cells. Conditional knockout of IGFBP7 from the kidney protected against AKI. By contrast, rescue of IGFBP7 expression in IGFBP7-knockout mice restored kidney damage and inflammation. IGFBP7 function was determined in vitro using recombinant IGFBP7 protein, IGFBP7 knockdown, or overexpression. Additionally, IGFBP7 was found to bind to poly [ADP-ribose] polymerase 1 (PARP1) and inhibit its degradation by antagonizing the E3 ubiquitin ligase ring finger protein 4 (RNF4). Thus, IGFBP7 in circulation acts as a biomarker and key mediator of AKI by inhibiting RNF4/PARP1-mediated tubular injury and inflammation. Hence, over-activation of the IGFBP7/PARP1 axis represents a promising target for AKI treatment., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Renal fibrosis, a common feature of chronic kidney disease, causes the progressive loss of renal function, in which TGF-β 1 plays a critical role. In this study, we found that expression levels of TGF-β 1 and its receptor 1 (TGF-βR1) were both significantly increased in obstructive fibrosis kidneys. AZ12601011 is a small molecular inhibitor of TGF-βR1; however, its therapeutic potential for renal fibrosis remains unclear. During the experiments, AZ12601011 was applied to various models of renal fibrosis followed by unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) in vivo, in addition to renal tubular epithelial cells (TECs) challenged by hypoxia/reoxygenation (H/R) and TGF-β 1 in vitro. Our results revealed that AZ12601011 ameliorated renal injuries and fibrosis shown by PAS, HE, and Masson staining, which was consistent with the decrease in Col-1 and α-SMA expression in the kidneys from UUO and I/R mice. Similarly, in vitro data showed that AZ12601011 inhibited the induction of Col-1 and α-SMA in both TECs treated with TGF-β 1 and H/R. In addition, the results of cellular thermal shift assay (CETSA), molecular docking, and western bolt indicated that AZ12601011 could directly bind to TGF-βR1 and block activation of the downstream Smad3. Taken together, our findings suggest that AZ12601011 can attenuate renal fibrosis by blocking the TGF-β/Smad3 signaling pathway and it might serve as a promising clinical candidate in the fight against fibrotic kidney diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pseudorabies virus (PRV), an etiological agent of pseudorabies in livestock, has negatively affected the porcine industry all over the world. Epithelial cells are reported as the first site of PRV infection. However, the role of host proteins and its related signaling pathways in PRV replication is largely unclear. In this study, we performed a quantitative phosphoproteomics screening on PRV-infected porcine kidney (PK-15) epithelial cells. Totally 5723 phosphopeptides, corresponding to 2180 proteins, were obtained, and the phosphorylated states of 810 proteins were significantly different in PRV-infected cells compared with mock-infected cells (P ​< ​0.05). GO and KEGG analysis revealed that these differentially expressed phosphorylated proteins were predominantly related to RNA transport and MAPK signaling pathways. Further functional studies of NF-κB, transcription activator factor-2 (ATF2), MAX and SOS genes in MAPK signaling pathway were analyzed using RNA interference (RNAi) knockdown. It showed that only ATF2-knockdown reduces both PRV titer and viral genome copy number. JNK pathway inhibition and CRISPR/Cas9 gene knockout showed that ATF2 was required for the effective replication of PRV, especially during the biogenesis of viral genome DNA. Subsequently, by overexpression of the ATF2 gene and point mutation of the amino acid positions 69/71 of ATF2, it was further demonstrated that the phosphorylation of ATF2 promoted PRV replication. These findings suggest that ATF2 may provide potential therapeutic target for inhibiting PRV infection., (Copyright © 2022 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The fragments, 3,4-(methylenedioxy)cinnamic acid amide and dithiocarbamates, have received increasing attention because of their multiple pharmacological activities in recent years, especially in anti-tumor. We synthesized 17 novel 3,4-(methylenedioxy)cinnamic acid amide-dithiocarbamate derivatives based on the principle of pharmacophore assembly and discovered that compound 4a 7 displayed the most potent antiproliferative activity against HeLa cells with IC 50 value of 1.01 μM. Further mechanistic studies revealed that 4a 7 triggered apoptosis in HeLa cells via activating mitochondria-mediated intrinsic pathways and effectively inhibited colony formation. Also, 4a 7 had the ability to arrest cell cycle in the G2/M phase as well as to inhibit the migration in HeLa cells. More importantly, acute toxicity experiments showed that 4a 7 had good safety in vivo. All the results suggested that compound 4a 7 might serve as a promising lead compound that merited further attention in future anti-tumor drug discovery., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Objectives: This study aimed to establish a reliable diagnostic scoring model for the preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biochemical indicators., Methods: This retrospective study included 129 patients with HCC at our hospital from 2014 to 2020. Based on the intratumoral and peritumoral features on Gd-EOB-DTPA MRI and biochemical indicators, a scoring model was developed for preoperative prediction of MVI, and examined for diagnostic efficacy according to postoperative pathological results. The scoring model was further externally validated in an independent cohort of 63 HCC patients., Results: Logistic regression analysis was performed to identify five parameters related to MVI, including maximum tumor diameter, peritumoral low intensity in the hepatobiliary phase, incomplete capsule, apparent diffusion coefficient (ADC), and [alkaline phosphatase (ALP) (U/L) + gamma-glutamyl transpeptidase (GGT) (U/L)] / lymphocyte count (× 10 9 /L) ratio (AGLR). Based on these five parameters, a scoring model was developed, and the accuracy, sensitivity, specificity, PPV, and NPV in predicting MVI were 93.6%, 94.7%, 93.2%, 85.7%, and 97.6%, respectively, with a score > 8 set as the threshold., Conclusion: The scoring model based on Gd-EOB-DTPA MRI and biochemical indicators provides a reliable tool for preoperative prediction of MVI in HCC patients., Key Points: • The scoring model based on Gd-EOB-DTPA MRI and biochemical indicators is practical for preoperative prediction of MVI in HCC patients. • AGLR is an independent risk factor for MVI. • The scoring model could help implement more appropriate interventions, potentially leading to precise and individualized treatments based on the biological characteristics of the tumor., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Studies on the application of deep learning image reconstruction (DLIR) in pediatric computed tomography (CT) are limited and have so far been mostly based on phantom. The purpose of this study was to compare the image quality and radiation dose of DLIR with that of adaptive statistical iterative reconstruction-Veo (ASiR-V) during abdominal and chest CT for the pediatric population., Methods: A pediatric phantom was used for the pilot study, and 20 children were recruited for clinical verification. The preset scan parameter noise index (NI) was 5, 8, 11, 13, 15, and 18 for the phantom study, and 8 and 13 for the clinical pediatric study. We reconstructed CT images with ASiR-V 30%, ASiR-V 70%, DLIR-M (medium) and DLIR-H (high). The regions of interest (ROI) were marked on the organs of the abdomen (liver, kidney, and subcutaneous fat) and the chest (lung, mediastinum, and spine). The CT dose index volume (CTDI vol ), CT value, image noise (N), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured and calculated. The subjective image quality was assessed by 3 radiologists blindly using a 5-point scale. The dose reduction efficiency of DLIR was estimated., Results: In the phantom study, the interobserver assessment of the data measurement demonstrated good agreement [intraclass correlation coefficient (ICC) =0.814 for abdomen, 0.801 for chest]. Within the same dose level, the N, SNR, and CNR were statistically different among reconstructions, while the CT value remained the same. The N increased and SNR decreased as the radiation dose decreased. The DLIR-H performed better than ASiR-V when the radiation dose was reduced, without sacrificing image quality. In the patient study, the interobserver assessment of the data measurement demonstrated good agreement (ICC =0.774 for abdomen, 0.751 for chest). DLIR-H had the highest subjective and objective scores in the abdomen., Conclusions: Application of DLIR could help to reduce radiation dose without sacrificing the image quality of pediatric CT scans. Further clinical validation is required., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. ZHL, SZ, and JYS report that they are employees of GE Healthcare (available at https://qims.amegroups.com/article/view/10.21037/qims-21-936/coif). The other authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Alzheimer's disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports., Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1 H )-quinolinone and dithiocarbamate., Methods: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo., Results: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC 50 =0.28 µM to eeAChE; IC 50 =0.34 µM to hAChE; IC 50 =2.81 µM to hMAO-B; IC 50 =0.91 µM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 µM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.)., Conclusion: This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Guo et al.)