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Peng Zhang, Xiu-Wu Han, Xin Zhang, Xu-Hui Zhu, Tao Li, Yan-Sheng Li, Yuan-Hao Chen, Gao Li Department of Urology, Beijing Chao-Yang Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xiu-Wu HanDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical University, 5 Jingyuan Road, Shijingshan District, Beijing, People’s Republic of ChinaTel +86 10-13501356960Email hanxiuwu47859@163.comObjective: The present study aimed to observe and discuss the effectiveness and safety of the UreTron single-probe ultrasonic intracorporeal lithotripter in ureteroscopic lithotripsy.Methods: The clinical data of patients with unilateral solitary ureteral calculi treated with ureteroscopic lithotripsy who were hospitalized at the Department of Urology (West District) of Beijing Chaoyang Hospital between March 2016 and August 2020 were selected for retrospective analysis. The patients were divided into the UreTron group (group U) and holmium laser group (group H) according to the lithotripsy method adopted. The operation duration, length of hospital stay, stone clearance rate, proportion of patients requiring flexible ureteroscopy-assisted lithotripsy, and complications were compared between the groups.Results: There was no statistical difference between the groups in terms of the general characteristics, operation duration, or length of hospital stay (P > 0.05). Regarding the stone clearance rate (group U=93.5%; group H=75%), proportion of patients requiring flexible ureteroscopy-assisted lithotripsy (group U=6.5%; group H=27.8%), and incidence of surgical complications (group U=1 case; group H=9 cases), group U was superior to group H, and the differences between the groups were statistically significant (P < 0.05). However, the differences in other complications (cardiocerebral complications and lower extremity thrombosis) were not statistically significant between the groups (P > 0.05).Conclusion: The UreTron system is a new lithotripsy apparatus that is safe and effective for ureteroscopic lithotripsy and has certain advantages in terms of the stone clearance rate, proportion of patients requiring flexible ureteroscopy-assisted lithotripsy, and surgical complications, making it worthy of clinical application.Keywords: UreTron, holmium laser, ureteral calculi, lithotripsy

Jianmin Liu,1 Ji Zhang,2 Liangwen Huang,1 Xuhong Zhu,1 Wei Chen,1 Peng Hu1 1Department of Neurosurgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, 2Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China Background: XuefuZhuyu Tang (XZT) is a traditional Chinese herb used for destagnation and is currently being used for oncotherapy. This study was intended to assess the effects of XZT on glioma along with its anticancer mechanism.Materials and methods: U251 cells were divided into five groups: CNC (cells were cultured with normal saline), TSC (cells were treated with TaohongSiwu Tang [TST]), XSC (cells were treated with XZT), THC (cells were treated with homogenate of TST), and XHC (cells were treated with homogenate of XZT). The mRNA and protein expression of VEGF/VEGFR, CXCR4/CXCL12, and TIMP1/MMP9/MMP2 were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. Moreover, MTT assay, transwell assay, wound-healing assay, and flow cytometry were conducted to assess the cell viability, cell migration and invasion, cell motility, and cell apoptosis of U251 cells, respectively. In vivo, three mice models (group CNM, gavaging saline; group TSM, gavaging TST; group XZM, gavaging XZT) were constructed after establishing xenograft mice models. Then, models were examined using hematoxylin and eosin staining, RT-PCR, and Western blotting. Results: In vitro, XZT significantly upregulated TIMP1 expression and downregulated the expression of VEGF, VEGFR, CXCR4, CXCL12, MMP9, and MMP2 in U251 cells (all P

The complete type of anomalous systemic arterial supply to normal basal lung segments is characterized by anomalous systemic artery supply to all or some of the normal basal segments with an absent corresponding pulmonary artery. Surgical intervention generally is required. This study reports on four patients with this anomaly with hemoptysis or a combination of other symptoms who underwent successful transarterial embolization using metallic coils or an Amplatzer vascular plug. To our knowledge, only six such cases treated with transarterial embolization have been reported previously in adult patients. [ABSTRACT FROM AUTHOR]

Background: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials., Objective: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis., Methods: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale., Results: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events., Conclusions: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021)., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Numerous studies indicate that natural polysaccharides have immune-enhancing effects as a host defense potentiator. Few reports are available on hormetic effects of natural polysaccharides, and the underlying mechanisms remain unclear., Purpose: AELP-B6 (arabinose- and galactose-rich pectin polysaccharide) from Aralia elata (Miq.) Seem was taken as a case study to clarify the potential mechanism of hormetic effects of natural polysaccharides., Methods: The pharmacodynamic effect of AELP-B6 was verified by constructing the CTX-immunosuppressive mouse model. The hormetic effects were explored by TMT-labeled proteomics, energy metabolism analysis, flow cytometry and western blot. The core-affinity target of AELP-B6 was determined by pull down, nanoLC-nanoESI + -MS, CETSA, immunoblot and SPR assay. The RAW264.7 Clec4G-RFP and RAW264.7 Rab1A-RFP cell lines were simultaneously constructed to determine the affinity difference between AELP-B6 and targets by confocal laser scanning live-cell imaging. Antibody blocking assays were further used to verify the mechanism of hormetic effects., Results: AELP-B6 at low and medium doses may maintain the structural integrity of thymus and spleen, increase the concentrations of TNF-α, IFN-γ, IL-3 and IL-8, and alleviate CTX-induced reduction of immune cell viability in vivo. Proteomics and energy metabolism analysis revealed that AELP-B6 regulate HIF-1α-mediated metabolic programming, causing Warburg effects in macrophages. AELP-B6 at low and medium doses promoted the release of intracellular immune factors, and driving M1-like polarization of macrophages. As a contrast, AELP-B6 at high dose enhanced the expression levels of apoptosis related proteins, indicating activation of the intrinsic apoptotic cascade. Two highly expressed transmembrane proteins in macrophages, Clec4G and Rab1A, were identified as the primary binding targets of AELP-B6 which co-localized with the cell membrane and directly impacted with immune cell activation and apoptosis. AELP-B6 exhibits affinity differences with Clec4G and Rab1A, which is the key to the hormetic effects., Conclusion: We observed hormesis of natural polysaccharide (AELP-B6) for the first time, and AELP-B6 mediates the hormetic effects through two dose-related targets. Low dose of AELP-B6 targets Clec4G, thereby driving the M1-like polarization via regulating NF-κB signaling pathway and HIF-1α-mediated metabolic programming, whereas high dose of AELP-B6 targets Rab1A, leading to mitochondria-dependent apoptosis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Dysregulated deubiquitinating enzymes (DUBs) execute as intrinsic oncogenes or tumor suppressors and are involved in chemoresistance in cancers. However, the functions and exact molecular mechanisms remain largely unclear in neuroblastoma., Methods: Here, a R2 screening strategy based on the standard deviation values was used to identify the most important DUB, USP44, in neuroblastoma with stage 4. We validated the role of USP44 regulation upon cisplatin treatment in vitro and in vivo experiments, revealing the molecular mechanisms associated with USP44 regulation and cisplatin sensitivity in neuroblastoma., Results: We found that low USP44 expression was associated with an inferior prognosis in neuroblastoma patients. Overexpression of USP44 enhanced neuroblastoma cell sensitivity to cisplatin in vitro and in vivo. Mechanistically, USP44 recruited and stabilized the E3 ubiquitin ligase STUB1 by removing its K48-linked polyubiquitin chains at Lys30, and STUB1 further reinforced the K48-linked polyubiquitination of LRPPRC at Lys453 and promoted its protein degradation, thus enhancing the accumulation of mitochondrial reactive oxygen species (mROS), in turn facilitating neuroblastoma cell apoptosis and cisplatin sensitivity. Additionally, overexpression of LRPPRC reversed the promoting effect of USP44 on cell apoptosis in cisplatin-treated neuroblastoma cells., Conclusions: Our findings demonstrate that the USP44-STUB1-LRPPRC axis plays a pivotal role in neuroblastoma chemoresistance and provides potential targets for neuroblastoma therapy and prognostication., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Purpose: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis., Methods: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-β-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo., Results: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs., Conclusion: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The precise association between lncRNA H19 and ferroptosis in the context of atherosclerosis remains uncertain., Objective: This study is to clarify the underlying process and propose novel approaches for the advancement of therapeutic interventions targeting atherosclerosis., Methods: Assessment of ferroptosis, which entails the evaluation of cell viability using CCK-8 and the quantification of intracellular MDA, GSH, and ferrous ions. Simultaneously, the protein expression levels of assessed by western blot analysis, while the expression level of lncRNA H19 was also determined. Furthermore, HAECs that were cultured with ox-LDL were subjected to Fer-1 interference. HAECs were exposed to ox-LDL and then transfected with H19 shRNA and H19 overexpression vector pcDNA3.1. The level of ferroptosis in the cells was then measured. Then, HAECs were subjected to incubation with ox-LDL, followed by transfection with H19 shRNA and treated with Erastin to assess the levels of ferroptosis, cell viability, and inflammatory factor production. and the ability for blood vessel development., Results: The survival rate of HAECs in the ox-LDL group was much lower. Ox-LDL resulted in an upregulation of ACSL4 expression in HAECs, while the expression of SLC7A11 and GPX4 decreased., Conclusions: lncRNA H19 enhances ferroptosis and exacerbates arterial endothelial cell damage induced by LDL.

Background: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown., Methods: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism., Results: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH., Conclusions: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH., Competing Interests: Disclosures None.

An efficient and mild protocol for the visible light-induced radical cascade difluoromethylation/cyclization of imidazoles with unactivated alkenes using easily accessible and bench-stable difluoromethyltriphenylphosphonium bromide as the precursor of the -CF 2 H group has been developed to afford CF 2 H-substituted polycyclic imidazoles in moderate to good yields. This strategy, along with the construction of Csp 3 -CF 2 H/C-C bonds, is distinguished by mild conditions, no requirement of additives, simple operation, and wide substrate scope. In addition, the mechanistic experiments have indicated that the difluoromethyl radical pathway is essential for the methodology., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Described herein is an efficient copper-catalyzed tandem alkyne indolylcupration-initiated 1,2-indole migration/6π-electrocyclic reaction of allene-ynamides with indoles by the in situ-generated metal carbenes. This method allows the efficient synthesis of valuable indole-fused spirobenzo[ f ]indole-cyclohexanes with high regio- and stereoselectivity. In addition, this reaction affords rapid access to the functionalized spirobenzo[ f ]indole-cyclohexanes in the absence of indoles by a presumable 5-exo-dig cyclization/Friedel-Crafts alkylation via copper-containing all-carbon 1,4-dipoles.

Introduction: Nicotinamide adenine dinucleotide (NAD) is a crucial molecule in cellular metabolism and signaling. Mapping intracellular NAD content of human brain has long been of interest. However, the sub-millimolar level of cerebral NAD concentration poses significant challenges for in vivo measurement and imaging., Methods: In this study, we demonstrated the feasibility of non-invasively mapping NAD contents in entire human brain by employing a phosphorus-31 magnetic resonance spectroscopic imaging ( 31 P-MRSI)-based NAD assay at ultrahigh field (7 Tesla), in combination with a probabilistic subspace-based processing method., Results: The processing method achieved about a 10-fold reduction in noise over raw measurements, resulting in remarkably reduced estimation errors of NAD. Quantified NAD levels, observed at approximately 0.4 mM, exhibited good reproducibility within repeated scans on the same subject and good consistency across subjects in group data (2.3 cc nominal resolution). One set of higher-resolution data (1.0 cc nominal resolution) unveiled potential for assessing tissue metabolic heterogeneity, showing similar NAD distributions in white and gray matter. Preliminary analysis of age dependence suggested that the NAD level decreases with age., Discussion: These results illustrate favorable outcomes of our first attempt to use ultrahigh field 31 P-MRSI and advanced processing techniques to generate a whole-brain map of low-concentration intracellular NAD content in the human brain., Competing Interests: RG is currently an employee of Siemens Medical Solutions USA, Inc. The remaining 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 © 2024 Guo, Yang, Wiesner, Li, Zhao, Liang, Chen and Zhu.)

Objective: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients., Methods: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias., Results: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001)., Conclusions: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285)., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To assess pelvic floor muscle (PFM) strength and influencing factors among healthy women at different life stages., Design: Multicentre cross-sectional study., Setting: Fourteen hospitals in China., Population: A total of 5040 healthy women allocated to the following groups (with 1680 women per group): premenopausal nulliparous, premenopausal parous and postmenopausal., Methods: The PFM strength was evaluated by vaginal manometry. Multivariate logistic regression was used to determine the influencing factors for low PFM strength., Main Outcome Measures: Maximum voluntary contraction pressure (MVCP)., Results: The median MVCP values were 36, 35 and 35 cmH 2 O in premenopausal nulliparous (aged 19-51 years), premenopausal parous (aged 22-61 years), and postmenopausal (aged 40-86 years) women, respectively. In the premenopausal nulliparous group, physical work (odds ratio, OR 2.05) was the risk factor for low PFM strength, which may be related to the chronic increased abdominal pressure caused by physical work. In the premenopausal parous group, the number of vaginal deliveries (OR 1.28) and diabetes (OR 2.70) were risk factors for low PFM strength, whereas sexual intercourse (<2 times per week vs. none, OR 0.55; ≥2 times per week vs. none, OR 0.56) and PFM exercise (OR 0.50) may have protective effects. In the postmenopausal group, the number of vaginal deliveries (OR 1.32) and family history of pelvic organ prolapse (POP) (OR 1.83) were risk factors for low PFM strength., Conclusions: Physical work, vaginal delivery, diabetes and a family history of POP are all risk factors for low PFM strength, whereas PFM exercises and sexual life can have a protective effect. The importance of these factors varies at different stages of a woman's life., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

A highly convenient copper(I)-catalyzed oxidation-initiated cyclopropanation of indolyl ynamide for the rapid construction of indole-fused cyclopropane-lactams is described, which represents, to the best of our knowledge, the first non-noble-metal-catalyzed indolyl ynamide oxidation/dearomatization by the in situ generated α-oxo copper carbenes. Compared to hydrazone and diazo, the use of alkynes as carbene precursors allows cyclopropanation to occur under a safe and convenient pathway. Moreover, this transformation can lead to the divergent synthesis of pentacyclic spiroindolines involving the reversal of ynamide regioselectivity by engineering substrate structures.

Objectives: Oligo-/polysaccharides from Cyathula officinalis Kuan (COPs) and Achyranthes bidentata Blume (ABPs) have attracted researchers' attention in the fields of healthy food supplements and traditional Chinese medicine (Niúxī) due to their multiple bioactivities combined with their nontoxic and highly biocompatible nature. The purpose of this paper was to provide a systematic and comprehensive overview of the extraction, purification, and structural analysis methods, chemical characteristics, biological activities, and structure bioactivity relationship. Furthermore, the possible development trends and perspectives for future research, and traditional uses of Niúxī are also summarized., Methods: All the information was gathered from a library search and scientific databases., Key Findings: Although COPs and ABPs are derived from different plants, they have similar structural features in type, structure, and glycosidic linkage patterns and biological activities in vivo and in vitro. However, there are differences in monosaccharide compositions, which can be used as an identification mark., Conclusions: As traditional Chinese herbal medicine, C. officinalis and A. bidentata have similar pharmacological activities. The COPs and ABP possess wide pharmacological effects such as antitumor, antioxidant, anti-osteoporosis, and anti-inflammatory. Meanwhile, the biological activity and structure-activity relationship of purified COPs and ABPs are less studied, future research should focus on them., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Growing evidence has found the health protective effects of greenness exposure on tuberculosis (TB) and the impact of ambient air pollutants on TB drug-resistance. However, it remains unclear whether residential greenness is also beneficial to reduce TB drug-resistance, and whether air pollution modify the greenness-TB resistance relationship. We enrolled 5006 newly-diagnosed TB patients from Shandong, China, during 2014 to 2021. Normalized Difference Vegetation Index (NDVI) in 250 m and 500 m buffer around individuals' residential zone was used to assess greenness exposure. All patients were divided by quartiles of NDVI 250-m and NDVI 500-m (from low to high: Q1, Q2, Q3, Q4) respectively. Six logistic regression models (NDVI, NDVI + PM 2.5 /PM 10 /SO 2 /NO 2 /O 3 ) were used to estimate the association of NDVI and TB drug-resistance when adjusting different air pollutants or not. All models were adjusted for age, gender, body mass index, complications, smoking, drinking, population density, nighttime light index, road density. Compared with participants in NDVI 250-m Q1 and NDVI 500-m Q1, other groups had lower rates of MDR-TB, PDR-TB, RFP-resistance, SM-resistance, RFP + SM resistance, INH + RFP + EMB + SM resistance. NDVI 500-m reduced the risk of multidrug resistant tuberculosis (MDR-TB) and the adjusted odds ratio (aOR, 95% confidence interval, CI) compared with NDVI 500-m Q1 were 0.736 (0.547-0.991) in NDVI + PM 10 model, 0.733 (0.544-0.986) in NDVI + PM 2.5 model, 0.735(0.546-0.99) in NDVI + SO 2 model, 0.736 (0.546-0.991) in NDVI + NO2 model, respectively, P < 0.05. NDVI 500-m contributed to a decreased risk of streptomycin (SM)-resistance. The aOR of rifampicin (RFP) + SM resistance were 0.132 (NDVI 250-m , Q4 vs Q1, 95% CI: 0.03-0.578), 0.199 (NDVI 500-m , Q3 vs. Q1, 95% CI: 0.057-0.688) and 0.264 (NDVI 500-m , Q4 vs. Q1, 95% CI: 0.087-0.799). The adjusted ORs (Q2 vs. Q1, 95% CI) of isoniazid (INH) + RFP + ethambutol (EMB) + SM resistance in 500 m buffer were 0.276 (0.119-0.639) in NDVI model, 0.279 (0.11-0.705) in NDVI + PM 10 model, 0.281 (0.111-0.713) in NDVI + PM 2.5 model, 0.279 (0.11-0.709) in NDVI + SO2 model, 0.296 (0.117-0.754) in NDVI + NO 2 model, 0.294 (0.116-0.748) in NDVI + O 3 model, respectively. The study showed, for the first time, that residential greenness exposure in 500 m buffer is beneficial for reducing newly-diagnosed DR-TB (including PDR-RB, MDR-TB, MR-TB), and ambient air pollutants may partially mediate this association., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The heart is a highly aerobic organ consuming most of the oxygen the body in supporting heart function. Quantitative imaging of myocardial oxygen metabolism and perfusion is essential for studying cardiac physiopathology in vivo. Here, we report a new imaging method that can simultaneously assess myocardial oxygen metabolism and blood flow in the rat heart., Methods: This novel method is based on the 17 O-MRSI combined with brief inhalation of 17 O-isotope labeled oxygen gas for quantitative imaging of myocardial metabolic rate of oxygen consumption (MVO 2 ), myocardial blood flow (MBF), and oxygen extraction fraction (OEF). We demonstrate this imaging method under basal and high workload conditions in rat hearts at 9.4 T., Results: We show that this 17 O MRSI-based approach can directly measure and image MVO 2 (1.35-4.06 μmol/g/min), MBF (0.49-1.38 mL/g/min), and OEF (0.33-0.44) in the heart of anesthetized rat under basal and high workload (21.6 × 10 3 -56.7 × 10 3 mmHg • bpm) conditions. Under high workload condition, MVO 2 and MBF values in healthy rats approximately doubled, whereas OEF remained unchanged, indicating a strong coupling between myocardial oxygen metabolic demand and supply through blood perfusion., Conclusion: The 17 O-MRSI method has been used to simultaneously image the myocardial metabolic rate of oxygen consumption, blood flow, and oxygen extraction fraction in small animal hearts, which are sensitive to the physiological changes induced by high workload. This approach could provide comprehensive measures that are critical for studying myocardial function in normal and diseased states and has a potential for translation., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Although socioeconomic support is recommended for frailty management, its association with the prognosis of frailty is unclear., Methods: Using data from participants aged ≥65 years in the Chinese Longitudinal Healthy Longevity Survey (2008-2018), the associations between socioeconomic support (source of income, medical insurance, community support, living status), onset of prefrailty/frailty, and worsening of prefrailty, were analyzed using multinominal logistic regression models. The associations between self-reported low quality of life (QoL) and reversion of prefrailty/frailty were analyzed using multivariate logistic regression models. Associations with mortality risk were analyzed using Cox proportional hazard regression models., Results: A total of 13,859 participants (mean age: 85.8 ± 11.1 years) containing 2056 centenarians were included. Financial dependence was a risk factor for low QoL among prefrail/frail individuals, but not among robust individuals. Having commercial or other insurance, and receiving social support from the community were protective factors for low QoL among prefrail/frail individuals and for the worsening of prefrailty. Continuing to work was a risk factor for low QoL, but a protective factor for worsening of prefrailty. A negative association between continuing to work and mortality existed in prefrail individuals aged <85 years and ≥85 years. Living alone was a risk factor for low QoL, but was not significantly associated with frailty prognosis., Conclusions: Prefrail and frail individuals were vulnerable to changes in socioeconomic support and more sensitive to it compared with robust individuals. Preferential policies regarding financial support, social support, and medical insurance should be developed for individuals with frailty., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Health Care Science published by John Wiley & Sons, Ltd on behalf of Tsinghua University Press.)

ETHNIC PHARMACOLOGICAL RELEVANCE: "Yin-Jing" medicine (YJM) has been widely used by both ancient and modern Chinese medicine practitioners during long-term clinical practice. However, it remains unclear how to best guide other medicines to the targeted organs in a traditional Chinese medicine (TCM) prescription. Here, in an attempt to explain the scientific connotation of the YJM property (YJMP) attributed to a basic TCM theory, Platycodon grandiflorum (PG) was chosen as a case study to reveal the mystery of YJMP theory., Aim of the Study: The main purpose of this study is to employ modern chemical and molecular biology methods to confirm the "Yin-Jing" effect of PG, and further clarify its material basis and related possible mechanism., Materials and Methods: The ammonia-induced lung injury rat model was utilized to determine the optimal dosage of traditional prescription Hui Yan Zhu Yu decoction (HYZYD) using Wright Giemsa staining, HE staining, Masson staining, and TUNEL analysis. With the same way, PG was confirmed to have potentiating therapeutic effect (PTE) by comparison with HYZYD and [HYZYD-PG]. TMT proteomics was used to reveal the "Yin-Jing" mechanism of action. Western blot assay (WB) was employed for verification of differentially expressed proteins. Additionally, four non-crossing fragmentations (Fr. A-D) were characterized by RPLC/SEC-ELSD and HILIC-ESI - -Q-OT-IT-MS techniques. The PTE and guidance property assays were utilized to evaluate "Yin-Jing" functions by a compatible combination of hydroxysafflor yellow A (HYA) using qPCR, FCM, WB, HPLC, high content cell imaging (HCI) and high-resolution live-cell imaging (HRLCI) techniques., Results: The HYZYD-M (medium dose group) significantly improved the lung injury level in a pneumonia model of rats. PG enhanced the therapeutic effect of HYZYD ascribed to Yin-Jing PTE functions. TMT proteomics revealed a category of differentially expressed proteins ascribed to Golgi-ER between HYZYD and [HYZYD-PG]. Fr. C (i.e., saponins) and Fr. D (i.e., lipids) were determined as therapeutic fragmentations via the LPS-induced A549 cell injury model; however, Fr. B (fructooligosaccharides and small M w fructans) had no therapeutic effect. Further compatibility PTE assays confirmed Fr. B significantly improved efficiency by a combination of HYA. The guidance assays showed Fr. B could significantly increase the uptake and distribution of HYA into lung cells and tissues. HCI assays showed that Fr. B increased uptake of HYA accompanied by significant activation of Golgi-ER. Unlike Fr. B, HRLCI showed that Fr. A, C and D were not only unobvious activations of Golgi-ER but also insignificant facilitation of colocalizations between HYA and Golgi-ER., Conclusions: Fr. B is believed to be a key YJMP material basis of PG attributed to Yin-Jing PTE with characteristic of lung-oriented guidance property, whereas another abound Fr. C was determined to have synergistic effects rather than Yin-Jing material basis., 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 B.V. All rights reserved.)

Background: Polygonatum cyrtonema Hua is a traditional Chinese medicinal food herb which can regulate the liver and Qi, nourish the heart and blood, moisten the lungs and nourish the kidneys with the potential to treat emotional diseases. However, few studies have explored the effects of Polygonatum cyrtonema Hua on postpartum depression. Therefore, we investigated whether processed Polygonatum cyrtonema Hua could improve postpartum depression in rat models by regulating monoamines and hormones., Methods: Female Sprague-Dawley rats were randomized into normal control (0.9%Nacl), Sham operation (0.9%Nacl), postpartum depression model (0.9%Nacl), fluoxetine (2.5 mg/kg Fluoxetine), low, medium and high dose of processed Polygonatum cyrtonema Hua (2.5 g/kg, 5 g/kg, 10 g/kg) groups. Rats in these groups received drug intervention, and then subjected to Open-field test and Forced swimming test. Brain tissues and serum samples were collected and used to quantify levels of monoamines, hypothalamic-pituitary-adrenal axis and serum Estradiol. The status of neuronal cells in hippocampus 1 region was examined through hematoxylin-eosin staining, whereas expression of estrogen receptor α and β was detected by immunohistochemistry., Results: Rats in the model group showed decreased mobility time, the disorder of neuronal cells in hippocampus 1 area, and decreased concentration of 5-hydroxytryptamine and dopamine in brain tissue, norepinephrine and estradiol in serum as well as estrogen receptor α and β expression. They also exhibited increased adrenocorticotropic hormone, corticosterone and corticotropin releasing hormone in serum. However, the treatment with processed Polygonatum cyrtonem Hua or fluoxetine reversed the above abnormalities., Conclusion: The H group showed significant improvement in postpartum depression in rats, and processed Polygonatum cyrtonema Hua can be used as a developing drug for the prevention or treatment of depression., Competing Interests: 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., (© 2024 The Authors.)

Myocardial ischemia-reperfusion (I/R) injury most commonly occurs in coronary artery disease when prompt reperfusion is used to salvage the ischemic myocardium. Cardiomyocyte death is a significant component of myocardial I/R injury and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of cell death, ferroptosis, necroptosis, and pyroptosis have been shown to be involved in myocardial I/R. These new forms of regulated cell death cause cardiomyocyte loss and exacerbate I/R injury by affecting reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, subsequently mediating adverse remodeling, cardiac dysfunction, and heart failure. Herein, we review the roles of ferroptosis, necroptosis, and pyroptosis in myocardial I/R and discuss their contribution to pathology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Perioperative sleep disturbance may increase delirium risk. However, the role of perioperative sleep disturbance in delirium following total joint arthroplasty remains unclear. This prospective cohort study aimed to observe the delirium risk in patients with sleep disturbances. After excluding pre-existing sleep disturbances, older patients scheduled for total joint arthroplasty from July 17, 2022, to January 12, 2023, were recruited. Preoperative sleep disturbance or postoperative sleep disturbance was defined as a Chinese version of the Richards-Campbell Sleep Questionnaire (RCSQ) score of <50 during hospitalisation. A cut-off score of 25 was used to classify the severity of sleep disturbance. The primary outcome was the incidence of postoperative delirium. In all, 11.6% of cohort patients (34/294) developed delirium. After multivariate analysis, a preoperative Day 1 RCSQ score of ≤25 (odds ratio [OR] 3.62, 95% confidence interval [CI] 1.19-10.92; p = 0.02), occurrence of sleep disturbances (OR 2.76, 95% CI 1.19-6.38; p = 0.02) and RCSQ score of ≤25(OR 2.91, 95% CI 1.33-6.37; p = 0.007) postoperatively were strong independent predictors of delirium. After sensitivity analysis for daily delirium, a postoperative Day 1 RCSQ score of ≤25 (OR 9.27, 95% CI 2.72-36.15; p < 0.001) was associated with a greater risk of delirium on postoperative Day 1, with a reasonable discriminative area under the curve of 0.730. We concluded that postoperative but not preoperative sleep disturbances may be an independent factor for delirium risk. Sleep disturbance on the first night after surgery was a good predictor of subsequent delirium, no matter the nature of self-reported sleep disturbance., (© 2024 European Sleep Research Society.)

Purpose: To estimate the effect of atropine eyedrops at different concentrations for myopia control in children., Methods: We conducted a Bayesian random-effects network meta-analysis based on randomized controlled trials (RCT). Primary outcomes include changes in spherical equivalent error (SER) and changes in axial length (AL), mean difference (MD) together with 95% credible interval (CrI) were used to evaluate the efficacy., Results: 28 RCTs (6608 children) were included in this review. Comparing ten atropine eyedrops (0.0025%, 0.005%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, 0.25%, 0.5% and 1% concentrations) with the placebo, the MDs and 95%CrIs of changes in SER are -0.006 (-0.269, 0.256) D, 0.216 (-0.078, 0.508) D, 0.146 (0.094, 0.199) D, 0.167 (0.039, 0.297) D, 0.201 (0.064, 0.341) D, 0.344 (0.251, 0.440) D, 0.255 (0.114, 0.396) D, 0.296 (0.140, 0.452) D, 0.331 (0.215, 0.447) D, and 0.286 (0.195, 0.337) D, respectively. The MDs and 95%CrIs of changes in AL are -0.048 (-0.182, 0.085) mm, -0.078 (-0.222, 0.066) mm, -0.095 (-0.130, -0.060) mm, -0.096 (-0.183, -0.009) mm, -0.083 (-0.164, -0.004) mm, -0.114 (-0.176, -0.056) mm, -0.134 (-0.198, -0.032) mm, -0.174 (-0.315, -0.061) mm, -0.184 (-0.291, -0.073) mm, and -0.171 (-0.203, -0.097) mm, respectively.Whether evaluated by SER or AL, 1% concentration ranks first in efficacy, but the risk of photophobia is 17 times higher than 0.01% concentration., Conclusions: 0.01% or higher concentration atropine eyedrops are effective for myopia control, while 0.0025% and 0.005% concentrations may not. As the concentration increases, the effect tends to increase, 1% concentration may have the strongest effect., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recently, some inhibitors of soluble epoxide hydrolase (sEH) showed limited potential in treating sepsis by increasing survival time, but they have unfortunately failed to improve survival rates. In this study, we initially identified a new hit 11D, belonging to a natural skeleton known as stilbene and having an IC 50 of 644 nM on inhibiting murine sEH. Natural scaffold-based sEH inhibitors are paid less attention. A combination of structure-activity relationships (SARs)-guided structural optimization and computer-aided skeleton growth led to a highly effective lead compound 70P (IC 50 : 4.0 nM). The dose-response study indicated that 70P (at doses of 0.5-5 mg/kg, ip.) significantly increased survival rates and survival time by reducing the levels of the inflammatory factors TNF-α and IL-6 in the liver. Interestingly, 70P exhibited much higher accumulation in the liver than in plasma (AUC ratio: 175). In addition, 70P exhibits equal IC50 value (1.5 nM) on inhibiting human sEH as EC5026 (1.7 nM). In conclusion, the natural scaffold-extended sEH inhibitor 70P has the potential to become a new promising lead for addressing the unmet medical need in sepsis treatment, which highlighted the importance of natural skeleton in developing sEH inhibitors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jian-Hua Liang has patent #CN202310704634.4 pending to Beijing Institute of Technology. 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.)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN 5-HT ) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN 5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN 5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood., Methods: Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3., Results: The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells., Conclusions: Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment., (© 2024. The Author(s).)

Introduction: Tuberculosis (TB) is an infectious disease caused by a bacterium called Mycobacterium tuberculosis ( Mtb ). Previous studies have primarily focused on the transmissibility of multidrug-resistant (MDR) or extensively drug-resistant (XDR) Mtb . However, variations in virulence across Mtb lineages may also account for differences in transmissibility. In Mtb , polyketide synthase (PKS) genes encode large multifunctional proteins which have been shown to be major mycobacterial virulence factors. Therefore, this study aimed to identify the role of PKS mutations in TB transmission and assess its risk and characteristics. Methods: Whole genome sequences (WGSs) data from 3,204 Mtb isolates was collected from 2011 to 2019 in China. Whole genome single nucleotide polymorphism (SNP) profiles were used for phylogenetic tree analysis. Putative transmission clusters (≤10 SNPs) were identified. To identify the role of PKS mutations in TB transmission, we compared SNPs in the PKS gene region between "clustered isolates" and "non-clustered isolates" in different lineages. Results: Cluster-associated mutations in ppsA, pks12, and pks13 were identified among different lineage isolates. They were statistically significant among clustered strains, indicating that they may enhance the transmissibility of Mtb . Conclusion: Overall, this study provides new insights into the function of PKS and its localization in M. tuberculosis . The study found that ppsA, pks12, and pks13 may contribute to disease progression and higher transmission of certain strains. We also discussed the prospective use of mutant ppsA , pks12 , and pks13 genes as drug targets., 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 © 2024 Wang, Hu, Li, Kong, Li, Sun, Wang, Li, Zhang, Han, Zhu, An, Liu, Liu and Li.)

Platycodon grandiflorum (PG) has been widely applied as a conductant drug by ancient and modern traditional Chinese medicine practitioners during long-term clinical practice. However, determining how to guide other medicines to the targeted lungs in traditional Chinese medicine (TCM) prescription remains unclear. An ethanol soluble fraction (Fr. B) was obtained by macroporous resin and 75 % ethanol precipitate. The components were unambiguously determined as fructooligosaccharides and small molecule weight (M w ) fructans according to HILIC-ESI - -MS/MS, MS/MS and 1/2D NMR. We discovered that the Fr. B possesses the lung-oriented guidance and targetability by activating Golgi apparatus and endoplasmic reticulum (Golgi-ER) transport system. Rab21, a highly expressed transmembrane protein in the lungs, was found to be the core-affinity target of Fr. B which physically colocalized with the Golgi-ER and directly interacted with Rab21 to accelerate the uptake of extracellular therapeutic substances. The lung-oriented guidance and targetability of Fr. B was validated by the transient knockdown and overexpression of Rab21 considering dynamic observations of colocalization interactions among Fr. B, extracellular substances, and the Golgi-ER. Together, our results delineate a potential mechanism of Fr. B toward lung-oriented guidance and targetability via a direct targeting affinity of Rab21 and resulting collective stimulation of key Golgi-ER transport effectors for the acceleration of extracellular substances into the lungs., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Alopecia areata (AA) is an autoimmune disorder characterized by hair loss on the scalp, face, and other body areas. Despite affecting approximately 2% of the global population, there has been no previous bibliometric analysis specifically focusing on AA treatment that can guide researchers in exploring promising treatment options and directing future research efforts., Summary: This study conducted a bibliometric analysis of AA treatment research, encompassing publications from 2003 to 2022. A total of 1,323 papers from 65 countries, predominantly led by the USA and China, were included in the analysis. The number of publications related to AA treatment showed a notable increase over the years. Prominent research institutions included the University of Manchester, Icahn School of Medicine at Mount Sinai, University of Miami, and Columbia University. Among the journals, Dermatologic Therapy stood out as the most popular, while the Journal of the American Academy of Dermatology appeared as the most frequently co-cited publication., (© 2023 S. Karger AG, Basel.)

Histone methyltransferase SETDB1 (SET domain bifurcated histone lysine methyltransferase 1, also known as ESET or KMT1E) is known to be involved in the deposition of the di- and tri-methyl marks on H3K9 (H3K9me2 and H3K9me3), which are associated with transcription repression. SETDB1 exerts an essential role in the silencing of endogenous retroviruses (ERVs) in embryonic stem cells (mESCs) by tri-methylating H3K9 (H3K9me3) and interacting with DNA methyltransferases (DNMTs). Additionally, SETDB1 is engaged in regulating multiple biological processes and diseases, such as ageing, tumors, and inflammatory bowel disease (IBD), by methylating both histones and non-histone proteins. In this review, we provide an overview of the complex biology of SETDB1, review the upstream regulatory mechanisms of SETDB1 and its partners, discuss the functions and molecular mechanisms of SETDB1 in cell fate determination and stem cell, as well as in tumors and other diseases. Finally, we discuss the current challenges and prospects of targeting SETDB1 for the treatment of different diseases, and we also suggest some future research directions in the field of SETDB1 research., (© 2023. The Author(s).)

Pyridalyl, as a novel insecticide with an unknown mode of action, has shown excellent control efficacy against lepidopterous larvae and thrips. Previous modifications of this compound have mostly focused on the pyridine moiety, with limited information available about modifications to other parts of pyridalyl. In this paper, we report the synthesis and insecticidal activity of a series of azidopyridryl-containing dichlorolpropene ether derivatives, based on modifications to the middle alkyl chain of pyridalyl. Screening results for insecticidal activity indicate that our synthesized compounds show moderate to high activities at the tested concentrations against P. xylostella . Particularly, compound III-10 exhibits a LC 50 value of 0.831 mg L -1 , compared to the LC 50 value of pyridalyl at 2.021 mg L -1 . Furthermore, compound III-10 also displays a relatively broad insecticidal spectrum against Lepidoptera pests M. separata , C. suppressalis , O. nubilalis , and C. medinalis . Finally, in field trials, III-10 demonstrates better control efficiency against Chilo suppressalis compared to pyridalyl. Overall, our findings suggest that the modification of the middle alkyl chain of pyridalyl may be a promising approach for developing insecticides with improved efficacy.

This article analyzed the clinical data and on-site occupational health survey results of a patient with occupational acute methyl acetate poisoning in Zhejiang. Based on the pathways of methyl acetate poisoning and the characteristics of target organ damage, diagnosis and treatment experience were summarized, providing reference for the diagnosis and treatment of occupational acute methyl acetate poisoning and occupational health monitoring of methyl acetate.

Objectives: To study the efficacy and safety of Xiyanping injection through intramuscular injection for the treatment of acute bronchitis in children., Methods: A prospective study was conducted from December 2021 to October 2022, including 78 children with acute bronchitis from three hospitals using a multicenter, randomized, parallel-controlled design. The participants were divided into a test group (conventional treatment plus Xiyanping injection; n =36) and a control group (conventional treatment alone; n =37) in a 1:1 ratio. Xiyanping injection was administered at a dose of 0.3 mL/(kg·d) (total daily dose ≤8 mL), twice daily via intramuscular injection, with a treatment duration of ≤4 days and a follow-up period of 7 days. The treatment efficacy and safety were compared between the two groups., Results: The total effective rate on the 3rd day after treatment in the test group was significantly higher than that in the control group ( P <0.05), while there was no significant difference in the total effective rate on the 5th day between the two groups ( P >0.05). The rates of fever relief, cough relief, and lung rale relief in the test group on the 3rd day after treatment were higher than those in the control group ( P <0.05). The cough relief rate on the 5th day after treatment in the test group was higher than that in the control group ( P <0.05), while there was no significant difference in the fever relief rate and lung rale relief rate between the two groups ( P >0.05). The cough relief time, daily cough relief time, and nocturnal cough relief time in the test group were significantly shorter than those in the control group ( P <0.05), while there were no significant differences in the fever duration and lung rale relief time between the two groups ( P >0.05). There was no significant difference in the incidence of adverse events between the two groups ( P >0.05)., Conclusions: The overall efficacy of combined routine treatment with intramuscular injection of Xiyanping injection in the treatment of acute bronchitis in children is superior to that of routine treatment alone, without an increase in the incidence of adverse reactions.

Excessive oxidative stress will cause significant injury to osteoblasts, serving as one major pathological mechanism of osteoporosis. Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein and is expressed in the bone. We here explored its potential activity against hydrogen peroxide (H 2 O 2 )-induced oxidative injury in cultured osteoblasts. In primary murine and human osteoblasts, NLGN3 stimulation dose-dependently induced Akt, Erk1/2 and S6K activation. NLGN3 pretreatment ameliorated H 2 O 2 -induced cytotoxicity and death in osteoblasts. Moreover, H 2 O 2 -induced reactive oxygen species (ROS) production and oxidative injury were alleviated with NLGN3 pretreatment in cultured osteoblasts. Further studies showed that NLGN3 activated Nrf2 signaling cascade and induced Nrf2 protein Serine-40 phosphorylation, Keap1-Nrf2 dissociation, Nrf2 protein stabilization and nuclear translocation in osteoblasts. NLGN3 also increased antioxidant response element (ARE) activity and induced expression of Nrf2-ARE-dependent genes (HO1, GCLC and NQO1) in osteoblasts. Moreover NLGN3 mitigated osteoblast oxidative injury by dexamethasone or sodium fluoride (NaF). Nrf2 cascade activation is essential for NLGN3-induced cytoprotective activity in osteoblasts. Nrf2 shRNA or knockout (KO) abolished NLGN3-induced osteoblast cytoprotection against H 2 O 2 . Contrarily forced Nrf2 cascade activation by Keap1 KO mimicked NLGN3-induced anti-oxidative activity in murine osteoblasts. Importantly, NLGN3-induced Serine-40 phosphorylation and Nrf2 cascade activation were blocked by an Akt inhibitor MK-2206 or by Akt1 shRNA. Importantly, Akt inhibition, Akt1 silencing or Nrf2 S40T mutation largely inhibited NLGN3-induced osteoblast cytoprotection against H 2 O 2 . At last, we showed that NLGN3 mRNA and protein expression was significantly downregulated in necrotic bone tissues of dexamethasone-taken patients. Taken together, NLGN3 activated Akt-dependent Nrf2 cascade to protect osteoblasts from oxidative stress., Competing Interests: Declaration of competing interest All the authors listed assure that the data in the manuscript is original and the manuscript is not under consideration elsewhere. None of the manuscript contents have been previously published. All authors have made significant contributions of this work, and have read and approved all versions of the manuscript, its content, and its submission to the Free Radical Biology and Medicine. The authors have no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer is a common gynecological malignant tumor in women. Most patients have reached the advanced stage when they visit the hospital. In order to diagnose ovarian cancer at an early stage, treat it at an early stage, and improve the survival rate of patients, this study has used the imaging computed tomography (CT) method to diagnose stage IA ovarian cancer., Purpose: The purpose of this work was to study CT features of stage IA ovarian cancer, and compare the borderline tumor and stage IC ovarian cancer at the same time so as to improve the CT diagnosis of early ovarian cancer., Methods: We retrospectively collected clinical and CT data of patients with stage I ovarian cancer and borderline ovarian tumor admitted to Nantong Tumor Hospital from 2013 to 2021. Altogether, 23 cases of patients (borderline ovarian tumor, 9 cases; stage IA ovarian cancer, 5 cases; stage IC ovarian cancer, 9 cases) were involved. CT characteristics of these patients were analyzed in terms of the tumor diameter, cystic solid structure, solid component, septation, enhancement, peritoneal thickening, ascites, and abdominal lymph nodes., Results: CT features of stage IA ovarian cancer included large tumor size (average diameter: 15 cm), cystic solid structure (4/5; 80%), septation (4/5; 80%), and enhanced cystic wall, septum, or solid components of the tumor on contrast-enhanced CT (5/5; 100%) no peritoneal thickening (0/5; 0%), no ascites (0/5; 0%), and no abdominal lymph node enlargement (0/5; 0%). The tumor structure did not differ significantly between stage IA and IC ovarian cancers (p > 0.05), while intraperitoneal ascites did (χ2 = 0.031; p < 0.05). Stage IA and borderline ovarian tumors did not differ significantly in ovarian tumor structure (p > 0.05)., Conclusion: CT features of stage IA ovarian cancer included large tumor size, cystic solid structure, septation, and enhanced cystic wall and solid parts in the tumors. No pelvic or abdominal metastasis was observed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments., (© 2023. The Author(s).)

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-β (Aβ) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aβ metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aβ is essential for preventing Aβ deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The behavior of vascular smooth muscle cells (VSMCs) contributes to the formation of neointima. We previously found that EHMT2 suppressed autophagy activation in VSMCs. BRD4770, an inhibitor of EHMT2/G9a, plays a critical role in several kinds of cancers. However, whether and how BRD4770 regulates the behavior of VSMCs remain unknown. In this study, we evaluate the cellular effect of BRD4770 on VSMCs by series of experiments in vivo and ex vivo. We demonstrated that BRD4770 inhibited VSMCs' growth by blockage in G2/M phase in VSMCs. Moreover, our results demonstrated that the inhibition of proliferation was independent on autophagy or EHMT2 suppression which we previous reported. Mechanistically, BRD4770 exhibited an off-target effect from EHMT2 and our further study reveal that the proliferation inhibitory effect by BRD4770 was associated with suppressing on SUV39H2/KTM1B. In vivo, BRD4770 was also verified to rescue VIH. Thus, BRD4770 function as a crucial negative regulator of VSMC proliferation via SUV39H2 and G2/M cell cycle arrest and BRD4770 could be a molecule for the therapy of vascular restenosis., (© 2023. The Author(s).)