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Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract.

Triple-negative breast cancer (TNBC) is incurable and prone to widespread metastasis. Therefore, identification of key targets for TNBC progression is urgently needed. Our previous study revealed that isotoosendanin (ITSN) reduced TNBC metastasis by targeting TGFβR1. ITSN is currently used as an effective chemical probe to further discover the key molecules involved in TNBC metastasis downstream of TGFβR1. The results showed that GOT2 was the gene downstream of Smad2/3 and that ITSN decreased GOT2 expression by abrogating the activation of the TGF-β-Smad2/3 signaling pathway through directly binding to TGFβR1. GOT2 was highly expressed in TNBC, and its knockdown decreased TNBC metastasis. However, GOT2 overexpression reversed the inhibitory effect of ITSN on TNBC metastasis both in vitro and in vivo. GOT2 interacted with MYH9 and hindered its binding to the E3 ubiquitin ligase STUB1, thereby reducing MYH9 ubiquitination and degradation. Moreover, GOT2 also enhanced the translocation of MYH9 to mitochondria and thus induced DRP1 phosphorylation, thereby promoting mitochondrial fission and lamellipodia formation in TNBC cells. ITSN-mediated inhibition of mitochondrial fission and lamellipodia formation was associated with reduced GOT2 expression. In conclusion, ITSN prevented MYH9-regulated mitochondrial fission and lamellipodia formation in TNBC cells by enhancing MYH9 protein degradation through a reduction in GOT2 expression, thus contributing to its inhibition of TNBC metastasis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The development of photocatalytic systems that enable the simultaneous production of H2O2 and value-added organic chemicals presents a dual advantage: generating valuable products while maximizing the utilization of solar energy. Despite the potential, there are relatively few reports on photocatalysts capable of such dual functions. In this study, we synthesized a series of donor-acceptor covalent organic frameworks (COFs), designated as JUC-675 to JUC-677, to explore their photocatalytic efficiency in the co-production of H2O2 and N-benzylbenzaldimine (BBAD). Among them, JUC-675 exhibited exceptional performance, achieving a H2O2 production rate of 22.8 mmol g-1 h-1 with an apparent quantum yield of 15.7%, and its solar-to-chemical conversion efficiency was calculated to be 1.09%, marking it as the most effective COF-based photocatalyst reported to date. Additionally, JUC-675 demonstrated a high selectivity (99.9%) and yield (96%) for BBAD in the oxidative coupling of benzylamine. The underlying reaction mechanism was thoroughly investigated through validation experiments and density functional theory (DFT) calculations. This work represents a significant advancement in the design of COF-based photocatalysts and the development of efficient dual-function photocatalytic platforms, offering new insights and methodologies for enhanced solar energy utilization and the synthesis of value-added products., (© 2024 Wiley‐VCH GmbH.)

Ethnopharmacological Relevance: Plantaginis Semen (PS) is widely utilized as a common herb in several Asian countries, particularly China, due to its diuretic, anti-hypertensive, anti-hyperlipidemic, and anti-hyperglycemic properties. Furthermore, it is acknowledged for its ability to mitigate renal complications associated with metabolic syndrome. Despite its extensive usage, there is limited systematic literature elucidating its therapeutic mechanisms, thus emphasizing the necessity for comprehensive investigations in this field., Aim: This study aims to comprehensively evaluate the therapeutical potential of PS in treating diabetic kidney disease (DKD) and to elucidate the underlying mechanisms through in vivo and in vitro models., Methods: The main composition of PS were characterized using the UPLC-QTOF-MS method. For the in vivo investigation, a mouse model mediated by streptozocin (STZ) associated with a high-fat diet (HFD) and unilateral renal excision was established. The mice were split into 6 groups (n = 8): control group (CON group), DKD group, low-dose of Plantago asiatica L. seed extract group (PASE-L group, 3 g/kg/d), medium-dose of PASE group (PASE-M, 6 g/kg/d), high-dose of PASE group (PASE-H, 9 g/kg/d), and positive drug group (valsartan, VAS group, 12 mg/kg/d). After 8 weeks of treatment, the damage induced by DKD was evaluated by using relevant parameters of urine and blood. Furthermore, indicators of inflammation and factors associated with the SphK1-S1P signaling pathway were investigated. For the in vitro study, the cell line HBZY-1 was stimulated by high glucose (HG), they were then co-cultured with different concentrations of PASE, and the corresponding associated inflammatory and sphingosine kinase 1/sphingosine-1-phosphate (SphK1-S1P) factors were examined., Results: A total of 59 major components in PS were identified, including flavonoids, iridoids, phenylethanol glycosides, guanidine derivatives, and fatty acids. In the mouse model, PS was found to significantly improve body weight, decrease fasting blood glucose (FBG) levels, increased glucose tolerance and insulin tolerance, improved kidney-related markers compared to the DKD group, pathological changes in the kidneys also improved dramatically. These effects showed a dose-dependent relationship, with higher PASE concentrations yielding significantly better outcomes than lower concentrations. However, the effects of the low PASE concentration were not evident for some indicators. In the cellular model, the high dose of PASE suppressed high glucose (HG) stimulated renal mesangial cell proliferation, suppressed inflammatory factors and NF-κB, and decreased the levels of fibrillin-1(FN-1) and collagen IV(ColIV)., Conclusion: Our results indicate that PS exerts favorable therapeutic effects on DKD, with the possible mechanisms including the inhibition of inflammatory pathways, suppression of mRNA levels and protein expressions of SphK1 and S1P, consequently leading to reduced overexpression of FN-1 and ColIV, thereby warranting further exploration., 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.)

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aβ42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aβ42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aβ42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aβ pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aβ pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aβ pathology. Fibrinogen was associated with both cognition and Aβ pathology. Aβ pathology may be a critical mediator for impacts of fibrinogen on cognition., (© 2024 International Society for Neurochemistry.)

Background: Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition., Methods: A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition., Results: Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (P FDR = 0.012) and amyloid biomarkers (P FDR < 0.05), as well as cognitive scores (P FDR < 0.05) and hippocampal volume (P FDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2., Conclusions: MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology., (© 2024. The Author(s).)

Objectives: To develop the EQ-5D-5L (5L) population norms for China and to assess the relationship between various factors and 5L data., Methods: This study used data derived from the Psychology and Behavior Investigation of Chinese Residents, a national sample survey of 21 909 representative participants aged 12 years and above. Participants' health-related quality of life (HRQoL) was measured by the 5L. Their socioeconomic characteristics, behavioral factors, and health conditions were also obtained from the survey. Norm scores were generated and compared for different socioeconomic variables. Multiple linear and logistic regressions were used to assess the relationships of the 3 kinds of variables with the 5L utility, visual analog scale (VAS) scores and 5L health problems., Results: The mean (SD) age of participants was 39.4 (18.9) years, and 50.0% of them were female. The mean (SD) utility and VAS scores were 0.940 (0.138) and 73.4 (21.6), respectively. Participants reported considerably more problems in anxiety/depression (26.2%) and pain/discomfort (22.2%) dimensions. The gender difference in HRQoL is attenuated. The participants older than 75 years suffered from a sharp decline in HRQoL; the participants in Shanghai and Tibet provinces reported lower utility and VAS scores and more health problems. Those who were younger, with better socioeconomic status and healthier lifestyles, and without diseases tended to report higher utility and VAS scores and fewer health problems., Conclusions: This study derived the 5L population norms for China based on a representative population sample., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology and neuroinflammation., Methods: Within the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline., Results: The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: P FDR  < 0.001; Model 2: P FDR  < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: P FDR  < 0.001; Model 2: P FDR  < 0.001), total tau (T-tau, Model 1: P FDR  < 0.001; Model 2: P FDR  < 0.001), P-tau/Aβ42 ratio (Model 1: P FDR  = 0.023; Model 2: P FDR  = 0.028), T-tau/Aβ42 ratio (Model 1: P FDR  < 0.001; Model 2: P FDR  < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: P FDR  < 0.001; Model 2: P FDR  < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: P FDR  = 0.045; Model 2: P FDR  < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: P FDR  = 0.005; Model 2: P FDR  < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: P FDR  = 0.045; Model 2: P FDR  < 0.001), and higher score on the Alzheimer's Disease Assessment Scale (ADAS13, Model 1: P FDR  = 0.045; Model 2: P FDR  < 0.001)., Discussion: The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment., 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 Li, Fu, Cui, Wang and Tan.)

Background & Aims: Patients with intrahepatic cholangiocarcinoma (iCCA) respond poorly to immune checkpoint blockades (ICBs). In this study, we aimed to dissect the potential mechanisms underlying poor response to ICBs and explore a rational ICB-based combination therapy in iCCA., Methods: scRNA-seq dataset GSE151530 was analyzed to investigate the differentially expressed genes in malignant cells following ICBs therapy. RNA-seq analysis and western blot assays were performed to examine the upstream and downstream signaling pathways of CD73. Subcutaneous tumor xenograft models were utilized to investigate the impact of CD73 on iCCA growth. Plasmid AKT/NICD-induced spontaneous murine iCCAs were used to explore the therapeutic efficacy of CD73 enzymatic inhibitor AB680 combined with PD-1 blockade. Time-of-flight mass cytometry (CyTOF) was conducted to identify the tumor-infiltrating immune cell populations and their functional changes in murine iCCAs treated with AB680 in combination with PD-1 antibody., Results: scRNA-seq analysis identified elevated CD73 expression in malignant cells in response to ICBs therapy. Mechanistically, ICBs therapy upregulated CD73 expression in malignant cells via TNF-α/NF-κB signaling pathway. In vivo studies revealed that CD73 inhibition suppressed the growth of subcutaneous tumors, and achieved synergistic depression effects with gemcitabine and cisplatin (GC). Adenosine produced by CD73 activates AKT/GSK3β/β-catenin signaling axis in iCCA cells. CD73 inhibitor AB680 potentiates anti-tumor efficacy of PD-1 antibody in murine iCCAs. CyTOF analysis showed that AB680 combined with anti-PD-1 therapy promoted the infiltration of CD8 + T, CD4 + T cells, and NK cells in murine iCCAs, while simultaneously decreased the proportions of macrophages and neutrophils. Moreover, AB680 combined with anti-PD-1 significantly upregulated the expression of Granzyme B, Tbet and co-stimulatory molecule ICOS in infiltrating CD8 + T cells., Conclusions: CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response., (© 2024. The Author(s).)

Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg -1 ·d -1 ) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 μM) promoted wound healing and reduced cell apoptosis. NGR1 (100 μM) also increased Lgr5 + cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5 + ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5 + stem cells and intestinal reconstruction, at least partially via activation of the Wnt/β-Catenin signaling pathway. Schematic diagram of the mechanism of NGR1 in alleviating colitis. DSS caused widespread mucosal inflammation epithelial injury. This was manifested by the decreased expression of tight junction proteins, reduced mucus production in goblet cells, and increased intestinal permeability in colitis mice. Additionally, Lgr5 + ISCs were in obviously deficiency in colitis mice, with aberrant down-regulation of the Wnt/β-Catenin signaling. However, NGR1 amplified the expression of the ISC marker Lgr5, elevated the expression of genes associated with ISC differentiation, enhanced the incorporation of BrdU in the crypt and promoted epithelial restoration to alleviate DSS-induced colitis in mice, at least partially, by activating the Wnt/β-Catenin signaling pathway., (© 2024. The Author(s).)

Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8 + T cell infiltration and better prognoses in ICC patients. Mechanistically, β-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, β-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic β-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or β-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control., (© 2024. The Author(s).)

Purpose: Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC., Methods: 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software., Results: The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE., Conclusion: This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification., (© 2024. The Author(s).)

Background: Wnt/FZD-mediated signaling pathways are activated in more than 90% of hepatocellular carcinoma (HCC) cell lines. As a well-known secretory glycoprotein, Wnt3 can interact with FZD receptors on the cell surface, thereby activating the Wnt/β-catenin signaling pathway. However, the N-glycosylation modification site of Wnt3 and the effect of this modification on the biological function of the protein are still unclear., Aim: To investigate the effect of Wnt3 N-glycosylation on the biological function of HCC cells., Methods: Site-directed mutagenesis was used to verify the Wnt3 N-glycosylation sites, actinomycin D treatment was used to detect the stability of Wnt3 after site-directed mutation, the binding of the N-glycosylation site-directed mutant Wnt3 to FZD7 was observed by laser confocal microscopy, and the effects of the N-glycosylation site-directed mutation of Wnt3 on the Wnt/β-catenin signaling pathway and the progression of HCC cells were detected by western blot and cell function experiments., Results: Wnt3 has two N-glycosylation-modified sites (Asn90 and Asn301); when a single site at amino acid 301 is mutated, the stability of Wnt3 is weakened; the binding ability of Wnt3 to FZD7 decreases when both sites are mutated simultaneously; and the level of proteins related to the Wnt/β-catenin signaling pathway is downregulated. Cell proliferation, migration and invasion are also weakened in the case of single 301 site and double-site mutations., Conclusion: These results indicate that by inhibiting the N-glycosylation of Wnt3, the proliferation, migration, invasion and colony formation abilities of liver cancer cells can be weakened, which might provide new therapeutic strategies for clinical liver cancer in the future., Competing Interests: Conflict-of-interest statement: Dr. Sun has nothing to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: The lifetime risk of urinary tract infection is known from first-degree relative studies to be highly heritable. Associations have also been observed across the life course from pediatric urinary tract infection to recurrent urinary tract infection in adulthood, suggesting lifelong susceptibility factors. Candidate gene studies and genome-wide association studies have tested for genetic associations of urinary tract infection; however, no contemporary systematic synthesis of studies is available., Objective: We conducted a systematic review to identify all genetic polymorphisms tested for an association with urinary tract infection in children and adults; and to assess their strength, consistency, and risk of bias among reported associations., Data Sources and Study Eligibility Criteria: PubMed, HuGE Navigator and Embase were searched from January 1, 2005 to November 16, 2023, using a combination of genetic and phenotype key words., Study Appraisal and Synthesis Methods: Fixed and random effects meta-analyses were conducted using codominant models of inheritance in metan. The interim Venice criteria were used to assess their credibility of pooled associations., Results: After removing 451 duplicates, 1821 studies reports were screened, with 106 selected for full-text review, 22 were included in the meta-analysis (7 adult studies and 15 pediatric studies). Our meta-analyses demonstrated significant pooled associations for pediatric urinary tract infection with variation in CXCR1, IL8, TGF, TLR4 and VDR; all of which have plausible roles in the pathogenesis of urinary tract infection. Our meta-analyses also demonstrated a significant pooled association for adult urinary tract infection with variation in CXCR1. All significant pooled associations were graded according to their epidemiological credibility, sample sizes, heterogeneity between studies, and risk of bias., Conclusion: This systematic review provides a current synthesis of the known genetic architecture of urinary tract infection in childhood and adulthood; and should provide important information for researchers analysing future genetic association studies. Although, overall, the credibility of pooled associations was weak, the consistency of findings for rs2234671 single nucleotide polymorphisms of CXCR1 in both populations suggest a key role in the urinary tract infection pathogenesis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The gut microbiota plays a pivotal role in upholding intestinal health, fostering intestinal development, fortifying organisms against pathogen intrusion, regulating nutrient absorption, and managing the body's lipid metabolism. However, the influence of different cultivation modes on the growth indices and intestinal microbes of Salmo trutta fario remains underexplored. In this study, we employed high-throughput sequencing and bioinformatics techniques to scrutinize the intestinal microbiota in three farming modes: traditional pond aquaculture (TPA), recirculating aquaculture (RA), and flow-through aquaculture (FTA). We aimed to assess the impact of different farming methods on the water environment and Salmo trutta fario 's growth performance. Our findings revealed that the final weight and weight gain rate in the FTA model surpassed those in the other two. Substantial disparities were observed in the composition, relative abundance, and diversity of Salmo trutta fario gut microbiota under different aquaculture modes. Notably, the dominant genera of Salmo trutta fario gut microbiota varied across farming modes: for instance, in the FTA model, the most prevalent genera were SC-I-84 (7.34%), Subgroup&#95;6 (9.93%), and UTCFX1 (6.71%), while, under RA farming, they were Bacteroidetes&#95;vadinHA17 (10.61%), MBNT15 (7.09%), and Anaeromyxoactor (6.62%). In the TPA model, dominant genera in the gut microbiota included Anaeromyxobacter (8.72%), Bacteroidetes&#95;vadinHA17 (8.30%), and Geobacter (12.54%). From a comparative standpoint, the genus-level composition of the gut microbiota in the RA and TPA models exhibited relative similarity. The gut microbiota in the FTA model showcased the most intricate functional diversity, while TPA farming displayed a more intricate interaction pattern with the gut microbiota. Transparency, pH, dissolved oxygen, conductivity, total dissolved solids, and temperature emerged as pivotal factors influencing Salmo trutta fario gut microbiota under diverse farming conditions. These research findings offer valuable scientific insights for fostering healthy aquaculture practices and disease prevention and control measures for Salmo trutta fario , holding substantial significance for the sustainable development of the cold-water fish industry in the Qinghai-Tibet Plateau.

Numerous dams disrupt freshwater animals. The uppermost population of the critically endangered Yangtze finless porpoise has been newly formed below the Gezhouba Dam, however, information regarding the local porpoise is scarce. Passive acoustic monitoring was used to detect the behaviors of porpoises below the Gezhouba Dam. The influence of shipping, pandemic lockdown, hydrological regime, and light intensity on the biosonar activity of dolphins was also examined using Generalized linear models. Over the course of 4 years (2019-2022), approximately 848, 596, and 676 effective monitoring days were investigated at the three sites, from upstream to downstream. Observations revealed significant spatio-temporal biosonar activity. Proportion of days that are porpoise positive were 73%, 54%, and 61%, while porpoise buzz signals accounted for 78.49%, 62.35%, and 81.30% of all porpoise biosonar at the three stations. The biosonar activity of porpoises was much higher at the confluence area, particularly at the MZ site, during the absence of boat traffic, and during the Pandemic shutdown. Temporal trends of monthly, seasonal, and yearly variation were also visible, with the highest number of porpoises biosonar detected in the summer season and in 2020. Significant correlations also exist between the hydrological regime and light intensity and porpoise activity, with much higher detections during nighttime and full moon periods. Hydropower cascade development, establishment of a natural reserve, fish release initiatives, and implementation of fishing restrictions may facilitate the proliferation of the porpoise population downstream of the Gezhouba Dam within the Yichang section of the Yangtze River. Prioritizing restoration designs that match natural flow regimes, optimize boat traffic, and reduce noise pollution is crucial for promoting the conservation of the local porpoises., 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. Ecology and Evolution published by John Wiley & Sons Ltd.)

Gas explosion is one of the main accident risks during underground coal gasification (UCG). There are significant differences in the gas composition and explosive environment between UCG syngas and other gases. Previous research on the explosion characteristics of UCG syngas is not comprehensive enough, especially without considering the influence of the initial temperature on various characteristic parameters. A set of calculation methods for explosion characteristic parameters of UCG syngas based on existing research was proposed, which was applied to analyze explosion characteristics of syngas produced by different gasifying processes in the Huating UCG industrial test. The results showed that with the initial temperature improving, the maximum temperature and upper explosion limit of different gases increased, while the maximum pressure, lower explosion limit, and oxygen content safety limit decreased. However, the explosion thermal effect, pressure rise rate, and explosion characteristic values showed small changes. When the initial temperature increased from 298 to 1473 K, the explosion temperature of different gas explosions increased from 1645-2286 to 2652-3238 K, the maximum pressure dropped from 0.59-0.81 MPa (absolute pressure) to 0.19-0.23 MPa, the lower explosion limit dropped from 12.34-29.79% to 0.58-1.77%, the upper explosion limit increased from 55.68-83.35% to 70.89-93.73%, and the safety limit of oxygen content dropped from 4.86-6.37% to 0.26-0.34%. In addition, the gas calorific value also affected the values of various explosion characteristic parameters, among which the explosive thermal effect, maximum temperature, maximum pressure, pressure rise rate, explosion characteristic value, and safety limit of oxygen content in the syngas were all proportional to the calorific value of gas, while the lower and upper limits of explosion were inversely proportional to it. Based on the above research, syngas explosion-prone stages and causes of each potential risk area in the Huating UCG project were analyzed, the explosion characteristic parameters were determined, and targeted prevention and control measures were proposed accordingly. This study can lay a theoretical foundation for the study of syngas explosion characteristics and risk control for the UCG project., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Wuhan, a highly urbanized and rapidly growing region within China's Yangtze Economic Zone, has historically been identified as a gap area for the critically endangered Yangtze finless porpoise ( Neophocaena asiaeorientalis asiaeorientalis ) based on daytime visual surveys. However, there has been a noticeable increase in porpoise sightings since 2020. This study employed passive acoustic monitoring to investigate porpoise distribution in Wuhan between 2020 and 2022. Generalized linear models were used to explore the relationship between shipping, hydrological patterns, light intensity, and porpoise biosonar activity. Over 603 days of effective monitoring, the daily positive rate for porpoise biosonar detection reached 43%, with feeding-related buzz signals accounting for 55% of all porpoise biosonar signals. However, the proportion of minutes during which porpoise presence was detected was 0.18%, suggesting that while porpoises may frequent the area, their visits were brief and mainly focused on feeding. A significant temporal trend emerged, showing higher porpoise biosonar detection during winter (especially in February) and 2022. Additionally, periods without boat traffic correlated with increased porpoise activity. Hydrological conditions and light levels exhibited significant negative correlations with porpoise activity. Specifically, porpoise sonar detections were notably higher during the night, twilight, and new moon phases. It is highly conceivable that both fishing bans and COVID-19 pandemic-related lockdowns contributed to the heightened presence of porpoises in Wuhan. The rapid development of municipal transportation and shipping in Wuhan and resulting underwater noise pollution have emerged as a significant threat to the local porpoise population. Accordingly, it is imperative for regulatory bodies to effectively address this environmental stressor and formulate targeted protection measures to ensure the conservation of the finless porpoise., 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. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: It has been reported that the risk of Alzheimer's disease (AD) could be predicted by the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) scores. However, among non-demented Chinese adults, the correlations of ANU-ADRI scores with cerebrospinal fluid (CSF) core biomarkers and cognition remain unclear., Methods: Individuals from the Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study were grouped into three groups (low/intermediate/high risk groups) based on their ANU-ADRI scores. The multiple linear regression models were conducted to investigate the correlations of ANU-ADRI scores with several biomarkers of AD pathology. Mediation model and structural equation model (SEM) were conducted to investigate the mediators of the correlation between ANU-ADRI scores and cognition., Results: A total of 1078 non-demented elders were included in our study, with a mean age of 62.58 (standard deviation [SD] 10.06) years as well as a female proportion of 44.16% (n = 476). ANU-ADRI scores were found to be significantly related with MMSE (β = -0.264, P < 0.001) and MoCA (β = -0.393, P < 0.001), as well as CSF t-tau (β = 0.236, P < 0.001), p-tau (β = 0.183, P < 0.001), and t-tau/Aβ42 (β = 0.094, P = 0.005). Mediation analyses indicated that the relationships of ANU-ADRI scores with cognitive scores were mediated by CSF t-tau or p-tau (mediating proportions ranging from 4.45% to 10.50%). SEM did not reveal that ANU-ADRI scores affected cognition by tau-related pathology and level of CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2)., Conclusion: ANU-ADRI scores were associated with cognition and tau pathology. We also revealed a potential pathological mechanism underlying the impact of ANU-ADRI scores on cognition., (© 2024. The Author(s).)

Background: There is no doubt that both Hashimoto thyroiditis and Graves' disease are autoimmune thyroid diseases (AITDs), but the relationship between anti-nuclear antibody (ANA) and AITDs is poorly studied. The association between thyroid autoantibody levels and ANA positivity was evaluated to assess the role of ANA in AITDs., Methods: We conducted an analysis using data from 1,149,893 patients registered at our hospital and 53,021 patients registered in the National Health and Nutrition Examination Survey databases. We focused on patients with data for thyroid peroxidase antibody (TPOAb)/ANA, TPOAb/immunoglobulin G (IgG), thyroid-stimulating hormone (TSH) receptor antibody (TRAb)/ANA, TRAb/IgG, TSH/ANA, or TSH/IgG., Results: ANA positivity rates were 12.88% and 21.22% in TPOAb/ANA and TSH/ANA patients, respectively. In TPOAb/IgG and TSH/IgG data, high IgG levels (≥15 g/L) were detected in 2.23% and 4.06% of patients, respectively. There were significant differences in ANA positivity rates and high IgG proportions among patients with different TPOAb and TSH levels. TPOAb level was correlated with ANA positivity rate and high IgG proportion, and TSH level was correlated with ANA positivity rate. Regression analysis showed positive correlations between TPOAb levels and ANA positivity risk or high IgG risk, TSH levels and high IgG risk, and elevated TSH and ANA positivity risk. Of patients with TRAb/ANA data, 35.99% were ANA-positive, and 13.93% had TRAb levels ≥1.75IU/L; 18.96% of patients with TRAb/IgG data had high IgG levels, and 16.51% had TRAb levels ≥1.75IU/L. ANA positivity rate and high IgG proportion were not significantly different among different TRAb levels. TRAb levels, ANA positivity risk and high IgG risk were not correlated., Conclusion: ANA positivity and high IgG are related to Hashimoto thyroiditis but not Graves' disease, which implies distinct pathophysiological mechanisms underlying the AITDs., 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 Ruan, Heng, Yang, He, Li, Wang, Huang, Chen and Han.)

Purpose: Marital status has been reported to influence the survival outcomes of various cancers, but its impact on patients with mantle cell lymphoma (MCL) remains unclear. This study aimed to assess the influence of marital status at diagnosis on overall survival (OS) and cancer-specific survival (CSS) in patients with MCL., Methods: The study utilized data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 databases, including 6437 eligible individuals diagnosed with MCL from 2000 to 2018. A 1:1 propensity matching method (PSM) minimized confounding factor. Univariate and multivariate analyses determined hazard ratios (HR). Stratified hazard models were developed for married and unmarried statuses across time intervals., Results: Married patients exhibited better 5-year OS and CSS rates compared to unmarried patients (54.2% vs. 39.7%, log-rank p < 0.001; 62.6% vs. 49.3%, log-rank p < 0.001). Multivariate analysis indicated that being unmarried was an independent risk factor for OS (adjusted HR 1.420, 95% CI 1.329-1.517) and CSS (adjusted HR 1.388, 95% CI 1.286-1.498). After PSM, being unmarried remained an independent risk factor for both OS and CSS. Among unmarried patients, widowed individuals exhibited the poorest survival outcomes compared to patients with other marital statuses, with 5-year OS and CSS rates of 28.5% and 41.0%, respectively. Furthermore, in the 10-year OS and CSS hazard model for widowed individuals had a significantly higher risk of mortality, with the probability of overall and cancer-specific mortality increased by 1.7-fold and 1.6-fold, respectively., Conclusion: Marital status at diagnosis is an independent prognostic factor for MCL patients, with widowed individuals showing worse OS and CSS than those who are married, single, or divorced/separated. Adequate psychological and social support for widowed patients is crucial for improving outcomes in this patient population., (© 2024. The Author(s).)

Tumor immunity is a promising topic in the area of cancer therapy. The 'soil' function of the tumor microenvironment (TME) for tumor growth has attracted wide attention from scientists. Tumor-infiltrating immune cells in the TME, especially the tumor-infiltrating lymphocytes (TILs), serve a key role in cancer. Firstly, relevant literature was searched in the PubMed and Web of Science databases with the following key words: 'Tumor microenvironment'; 'TME'; 'tumor-infiltrating immunity cells'; 'gynecologic malignancies'; 'the adoptive cell therapy (ACT) of TILs'; and 'TIL-ACT' (https://pubmed.ncbi.nlm.nih.gov/). According to the title and abstract of the articles, relevant items were screened out in the preliminary screening. The most relevant selected items were of two types: All kinds of tumor-infiltrating immune cells; and advanced research on TILs in gynecological malignancies. The results showed that the subsets of TILs were various and complex, while each subpopulation influenced each other and their effects on tumor prognosis were diverse. Moreover, the related research and clinical trials on TILs were mostly concentrated in melanoma and breast cancer, but relatively few focused on gynecological tumors. In conclusion, the present review summarized the biological classification of TILs and the mechanisms of their involvement in the regulation of the immune microenvironment, and subsequently analyzed the development of tumor immunotherapy for TILs. Collectively, the present review provides ideas for the current treatment dilemma of gynecological tumor immune checkpoints, such as adverse reactions, safety, personal specificity and efficacy., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Wang et al.)

Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the pathogenesis of BPH remains unclear. Some studies demonstrated that the incidence of BPH was related to the change in the levels of steroid hormones. Too high content of dihydrotestosterone(DHT) in the body may cause BPH and other related diseases. Testosterone(T) is converted to DHT by 5α-reductase(SRD5A). By inhibiting the activity of this enzyme, the production of DHT can be reduced, and then the incidence of BPH can be lowered. Therefore, it has drawn great attention to screen and discover safer and more effective 5α-reductase inhibitors from natural medicines to treat prostatic hyperplasia without affecting the physiological function of men. This review summarizes the characteristics and tissue distribution of 5α-reductase, the discovery of 5α-reductase inhibitors in traditional Chinese medicine and natural medicines, 5α-reductase inhibitors commonly used in clinical practice and their side effects, as well as the animal models of prostatic hyperplasia and common detection indicators, aiming to provide a reference for more in-depth understanding and research about BPH and development of drugs.

Objective: In recent years, Helicobacter pylori (H. pylori) has been increasingly associated with extra-digestive manifestations, including scleroderma, rheumatism, and blood system diseases. Iron deficiency anemia (IDA) is a common chronic disease worldwide, with an insidious onset, but as the disease progresses, it will eventually seriously affect the quality of life of patients. The aim of our study was to investigate the relationship between H. pylori infection, iron deficiency (ID), and IDA, and to identify potential serological markers., Patients and Methods: We conducted a cross-sectional study of 998 individuals who had regular physical examinations at Beijing Shijitan Hospital from January 2021 to March 2022. We detected H. pylori infection by the 13C breath test, and recorded the patient's serum iron, ferritin, transferrin saturation, blood count, etc. We assessed the association between IDA and H. pylori infection and related serum markers using logistic regression and multiple linear regression. Afterward, we analyzed the correlation between sex and potential serum biomarkers., Results: Among all study participants, 57.5% of patients had H. pylori and 42.5% did not have H. pylori. ID and IDA were significantly associated with H. pylori infection in women (p=0.031). This association persisted after further adjustment for sex, metabolic variables, liver function, and kidney function. Fasting blood glucose, triglycerides, and uric acid may be associated with IDA., Conclusions: In women, H. pylori infection is associated with ID and IDA. The relationship between H. pylori and IDA may be mediated by glycometabolism, lipid metabolism, and uric acid metabolism.

Heart failure (HF) can damage various organs, including the liver, a phenomenon known as "cardiohepatic syndrome." The latter is characterized by liver congestion and hepatic artery hypoperfusion, which can lead to liver damage. In this study, we aimed to assess liver damage quantitatively in chronic HF (CHF) with sound touch elastography (STE). A total of 150 subjects were enrolled, including HF with reduced ejection fraction (HFrEF) groups (left ventricular ejection fraction ≤40%, n = 45), HF with mildly reduced ejection fraction (HFmrEF) groups (left ventricular ejection fraction between 41% and 49%, n = 40), and right-sided HF (RHF) groups (n = 25); normal groups (n = 40). Liver stiffness measurement (LSM) was performed in all subjects by STE. The other hepatic parameters were also measured. The LSM was 5.4 ± 1.1 kPa in normal subjects and increased slightly to 5.9 ± 0.7 kPa in patients with HFmrEF. However, the HFrEF and RHF groups had significantly higher LSMs of 8.4 ± 2.0 kPa and 10.3 ± 2.7 kPa, respectively. The LSM of HFrEF was significantly higher than that of HFmrEF, whereas the increase in LSM in patients with RHF was significant relative to HFmrEF and HFrEF. In addition, the other parameters showed abnormal values in only RHF and HFrEF. In conclusion, STE is a useful clinical technique for the noninvasive evaluation of liver stiffness associated with CHF, which could help patients with CHF manage their treatment regimens., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The advancement of single-cell sequencing technology has smoothed the ability to do biological studies at the cellular level. Nevertheless, single-cell RNA sequencing (scRNA-seq) data presents several obstacles due to the considerable heterogeneity, sparsity and complexity. Although many machine-learning models have been devised to tackle these difficulties, there is still a need to enhance their efficiency and accuracy. Current deep learning methods often fail to fully exploit the intrinsic interconnections within cells, resulting in unsatisfactory results. Given these obstacles, we propose a unique approach for analyzing scRNA-seq data called scMPN. This methodology integrates multi-layer perceptron and graph neural network, including attention network, to execute gene imputation and cell clustering tasks. In order to evaluate the gene imputation performance of scMPN, several metrics like cosine similarity, median L1 distance and root mean square error are used. These metrics are utilized to compare the efficacy of scMPN with other existing approaches. This research utilizes criteria such as adjusted mutual information, normalized mutual information and integrity score to assess the efficacy of cell clustering across different approaches. The superiority of scMPN over current single-cell data processing techniques in cell clustering and gene imputation investigations is shown by the experimental findings obtained from four datasets with gold-standard cell labels. This observation demonstrates the efficacy of our suggested methodology in using deep learning methodologies to enhance the interpretation of scRNA-seq data., (© The Author(s) 2024. Published by Oxford University Press.)

To study the chemical constituents in the non-alkaloid part of stems of Dendrobium nobile. The macroporous adsorption resin, MCI, silica gel, RP-C&#95;(18), and Sephadex LH-20 gel, preparative thin layer chromatography, and preparative high-performance liquid chromatography(HPLC) were used to isolate and purify the compounds. The structures of the compound were determined according to the spectra data, physicochemical properties, and relevant references. A total of 8 compounds were isolated from D. nobile, which were soltorvum F(1), p-hydroxyphenylpropionic acid(2), vanillic acid(3), p-hydroxybenzoic acid(4), N-trans-cinnamic acid acyl-p-hydroxybenzene ethylamine(5),(+)-(1R,2S,3R,4S,5R,6S,9R)-2,11,12-trihydroxypicrotoxane-3(15)-lactone(6), dendronobilin H(7), soltorvum E(8). Compound 1 was a novel compound, named as soltorvum F. Compound 8 was isolated from Dendrobium species for the first time.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8 + effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3 + macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies., (Copyright © 2023. Published by Elsevier Inc.)

Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, possesses anti-inflammatory and immune-modulatory properties. Chemokine-like factor 1 (CKLF1) is known to play a crucial role in both peripheral and central inflammatory processes. This study aimed to investigate the potential anti-NP effects of TET and the involvement of CKLF1 in the action of TET. A male C57BL/6J mice model of NP caused by spared nerve injury (SNI) was established and mechanical withdrawal thresholds were measured using von Frey filaments. The results showed that TET improved mechanical allodynia in SNI mice and the propofol-induced sleep assay demonstrated that the TET group did not exhibit central inhibition, while the pregabalin (PGB) group showed significant central inhibition. Western blotting and immunofluorescence staining showed that TET significantly inhibited spinal protein expression levels of CKLF1, p-NF-κB/NF-κB, p-IKK/IKK, pro-inflammatory cytokines IL-1β and TNF-α, and increased protein expression levels of the anti-inflammatory cytokine IL-10, while inhibiting the expression levels of microglia and astrocyte markers IBA-1 and GFAP of SNI mice. Moreover, immunofluorescence double-labeling results revealed that CKLF1 was predominantly colocalized with microglia of the spinal cord (SC) in SNI mice. C19 (an antagonism peptide of CKLF1) alleviated SNI-induced mechanical pain hypersensitivity, while C27 (an analog peptide of CKLF1) induced mechanical allodynia in normal mice. TET significantly attenuated mechanical allodynia induced by C27 in mice. TET may effectively alleviate NP by reducing neuroinflammation and decreasing CKLF1., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aim of this study is to investigate the effects of Gynostemma pentaphyllum dried with two different methods(air drying and heating) on inflammation in acute lung injury(ALI) mice in vivo and in vitro. Lipopolysaccharide(LPS) was sprayed into the airway of wild type C57BL/6J male mice to establish the model, and the drug was injected into the tail vein 24 h after modeling. Lung function, lung tissue wet/dry weight(W/D) ratio, the total protein concentration, interleukin 6(IL-6), IL-1β, and tumor necrosis factor-α(TNF-α) in the bronchoalveolar lavage fluid(BALF), and pathological changes of the lung tissue were used to evaluate the effects of different gypenosides on ALI mice. The results showed that total gypenosides(YGGPs) and the gypenosides substituted with one or two glycosyl(GPs&#95;(1-2)) in the air-dried sample improved the lung function, significantly lowered the levels of IL-1β and TNF-α in BALF, and alleviated the lung inflammation of ALI mice. Moreover, GPs&#95;(1-2) had a more significant effect on inhibiting NO release in RAW264.7 cells. This study showed that different drying methods affected the anti-inflammatory activity of G. pentaphyllum, and the rare saponins in the air-dried sample without heating had better anti-inflammatory activity.

Under increasing anthropogenic pressure, species with a previously contiguous distribution across their ranges have been reduced to small fragmented populations. The critically endangered Yangtze finless porpoise ( Neophocaena asiaeorientalis asiaeorientalis ), once commonly observed in the Yangtze River-Poyang Lake junction, is now rarely seen in the river-lake corridor. In this study, static passive acoustic monitoring techniques were used to detect the biosonar activities of the Yangtze finless porpoise in this unique corridor. Generalized linear models were used to examine the correlation between these activities and anthropogenic impacts from the COVID-19 pandemic lockdown and boat navigation, as well as environmental variables, including hydrological conditions and light levels. Over approximately three consecutive years of monitoring (2020-2022), porpoise biosonar was detected during 93% of logged days, indicating the key role of the corridor for finless porpoise conservation. In addition, porpoise clicks were recorded in 3.80% of minutes, while feeding correlated buzzes were detected in 1.23% of minutes, suggesting the potential existence of localized, small-scale migration. Furthermore, both anthropogenic and environmental variables were significantly correlated with the diel, lunar, monthly, seasonal, and annual variations in porpoise biosonar activities. During the pandemic lockdown period, porpoise sonar detection showed a significant increase. Furthermore, a significant negative correlation was identified between the detection of porpoise click trains and buzzes and boat traffic intensity. In addition to water level and flux, daylight and moonlight exhibited significant correlations with porpoise biosonar activities, with markedly higher detections at night and quarter moon periods. Ensuring the spatiotemporal reduction of anthropogenic activities, implementing vessel speed restrictions (e.g., during porpoise migration and feeding), and maintaining local natural hydrological regimes are critical factors for sustaining porpoise population viability.

The Compound Cheqian Tablets are derived from Cheqian Power in Comprehensive Recording of Divine Assistance, and they are made by modern technology with the combination of Plantago asiatica and Coptis chinensis. To investigate the material basis of Compound Cheqian Tablets in the treatment of diabetic nephropathy, in this study, the chemical components of Compound Cheqian Tablets were characterized and analyzed by UPLC-Q-TOF-MS/MS, and a total of 48 chemical components were identified. The identified chemical compounds were analyzed by network pharmacology. By validating with previous literature, six bioactive compounds including acteoside, isoacteoside, coptisine, magnoflorine, palmatine, and berberine were confirmed as the index components for qua-lity evaluation. Furthermore, the content of the six components in the Compound Cheqian Tablets was determined by the &quot;double external standards&quot; quantitative analysis of multi-components by single marker(QAMS), and the relative correction factor of isoacteoside was calculated as 1.118 by using acteoside as the control; the relative correction factors of magnoflorine, palmatine, and berberine were calculated as 0.729, 1.065, and 1.126, respectively, by using coptisine as the control, indicating that the established method had excellent stability under different conditions. The results obtained by the &quot;double external standards&quot; QAMS approximated those obtained by the external standard method. This study qualitatively characterized the chemical components in the Compound Cheqian Tablets by applying UPLC-Q-TOF-MS/MS and screened the pharmacodynamic substance basis for the treatment of diabetic nephropathy via network pharmacology, and primary pharmacodynamic substance groups were quantitatively analyzed by the &quot;double external stan-dards&quot; QAMS method, which provided a scientific basis for clarifying the pharmacodynamic substance basis and quality control of Compound Cheqian Tablets.

Objective: To investigate the mechanism by which Chinese medicine Shengmai Yin (SMY) reverses epithelial-mesenchymal transition (EMT) through lipocalin-2 (LCN2) in nasopharyngeal carcinoma (NPC) cells CNE-2R., Methods: Morphological changes in EMT in CNE-2R cells were observed under a microscope, and the expressions of EMT markers were detected using quantitative real-time PCR (RT-qPCR) and Western blot assays. Through the Gene Expression Omnibus dataset and text mining, LCN2 was found to be highly related to radiation resistance and EMT in NPC. The expressions of LCN2 and EMT markers following SMY treatment (50 and 100 µ g/mL) were detected by RT-qPCR and Western blot assays in vitro. Cell proliferation, migration, and invasion abilities were measured using colony formation, wound healing, and transwell invasion assays, respectively. The inhibitory effect of SMY in vivo was determined by observing a zebrafish xenograft model with a fluorescent label., Results: The CNE-2R cells showed EMT transition and high expression of LCN2, and the use of SMY (5, 10 and 20 µ g/mL) reduced the expression of LCN2 and reversed the EMT in the CNE-2R cells. Compared to that of the CNE-2R group, the proliferation, migration, and invasion abilities of SMY high-concentration group were weakened (P<0.05). Moreover, SMY mediated tumor growth and metastasis in a dose-dependent manner in a zebrafish xenograft model, which was consistent with the in vitro results., Conclusions: SMY can reverse the EMT process of CNE-2R cells, which may be related to its inhibition of LCN2 expression. Therefore, LCN2 may be a potential diagnostic marker and therapeutic target in patients with NPC., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979-1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825-0.939]), and educational level (OR per 1 SD, 0.698 [0.602-0.810]) were associated with lower risk of late-onset Alzheimer's disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066-1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080-1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention., (© 2023. The Author(s).)

Background: Upadacitinib was approved to treat rheumatoid arthritis, psoriasis, ulcerative colitis, ankylosing spondylitis, and atopic dermatitis. This study assessed the adverse events (AEs) associated with upadacitinib by mining data from the US Food and Drug Administration Adverse Event Reporting System (FAERS)., Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of upadacitinib-associated AEs., Results: A total of 3,837,420 reports of AEs were collected from the FAERS database, of which 4494 reports were identified with upadacitinib as the "primary suspect (PS)". Upadacitinib-induced AEs occurrence targeted 27 system organ clases (SOCs). A total of 200 significant disproportionality PTs conforming to the four algorithms were simultaneously retained. Unexpected significant AEs, such as arthralgia, musculoskeletal stiffness, diverticulitis, and cataract might also occur. The median onset time of upadacitinib-associated AEs was 65 days (interquartile range [IQR] 21-182 days), and most of the onsets occurred within the first 1, 2, 3, and 4 months after initiation of upadacitinib., Conclusion: This study found potential new AEs signals and might provide important support for clinical monitoring and risk identification of upadacitinib.

Objective: To analyze the effect of CD56 expression on the prognosis of newly diagnosed multiple myeloma (MM) patients and explore the relationship between CD56 with clinical characteristics., Methods: In this retrospective study, the clinical data and laboratory parameters of 175 newly diagnosed MM patients from February 2015 to December 2020 in the Second Hospital of Anhui Medical University were collected. The patients were divided into CD56 + and CD56 - groups based on the expression of CD56, and the general data and laboratory parameters of the two groups were compared. The patients were followed up to June 30, 2021, and progression-free survival (PFS) and overall survival (OS) were recorded. PFS and OS curves of the two groups were plotted respectively, and the survival differences were compared. Univariate and multivariate Cox regression analyses were performed to analyze the effect of CD56 on the prognosis of newly diagnosed MM patients., Results: In 175 newly diagnosed MM patients, 57(32.6%) cases were in the CD56 - group and 118 (67.4%) cases in the CD56 + group. There was significant correlation between CD56 expression and ISS stage, ECOG score, platelets, β 2 -microglobulin, creatinine, and extramedullary disease (all P <0.05). The incidence of extramedullary disease in the CD56 - group was significantly higher than that in the CD56 + group (29.8% vs 12.7%, P =0.006). The median follow-up time of the whole cohort was 23.6 (1.0-78.6) months. The median PFS of patients in CD56 + group and CD56 - group were 18.6 (1.2-77.6) and 12.2 (1.0-49.0) months, respectively, and the median OS of the two groups were 27.6 (1.4-77.7) and 19.7 (1.0-78.6) months, respectively. The 2-year PFS rate in the CD56 + group was significantly higher than that in the CD56 - group (57.6% vs 36.8%, P =0.010), and the 2-year OS rate in the CD56 + group was higher than that in the CD56 - group, but it didn't reach statistical significance (74.6% vs 64.9%, P =0.158). The results of univariate Cox regression analysis showed that the PFS was significantly shorter in newly diagnosed MM patients with advanced age, type IgG, high ECOG score, decreased platelet count, increased lactate dehydrogenase level, extramedullary disease, and CD56 - (all P <0.05), the OS was significantly shorter in patients with high ECOG score, decreased platelet count, increased lactate dehydrogenase level, extramedullary disease, and CD56 - (all P <0.05). The results of multivariate Cox regression analysis showed that advanced age, type IgG, elevated lactate dehydrogenase level, extramedullary disease, and CD56 - were independent prognostic factors for poor PFS (all P <0.05); and decreased platelet count, elevated lactate dehydrogenase level, and extramedullary disease were independent adverse prognostic factors for OS (all P <0.05), while there was no significant independent correlation between CD56 and OS ( P >0.05)., Conclusion: Most of the newly diagnosed MM patients have positive expression of CD56. Loss of CD56 expression was associated with unfavorable biological and clinical parameters and poor prognosis, suggesting that CD56 has important clinical value in the prognosis of newly diagnosed MM patients.

Introduction and Aims: Genetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD and TREM1 gene polymorphisms (SNPs) remained lacking. We sought to examine the associations between TREM1 SNPs and AD., Methods: Based on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in the TREM1 gene. AD cases (1081) and healthy control subjects (870) were collected and genotyped, and the associations between candidate SNPs and AD risk were analyzed. We explored the associations between target SNP and AD biomarkers. Moreover, 842 individuals from ADNI were selected to verify these results. Linear mixed models were used to estimate associations between the target SNP and longitudinal cognitive changes., Results: The rs2062323 was identified to be associated with AD risk in the Han population, and rs2062323T carriers had a lower AD risk (co-dominant model: OR, 0.67, 95% CI, 0.51-0.88, p = 0.0037; additive model: OR, 0.82, 95% CI, 0.72-0.94, p = 0.0032). Cerebrospinal fluid (CSF) sTREM2 levels were significantly increased in middle-aged rs2062323T carriers (additive model: β = 0.18, p = 0.0348). We also found significantly elevated levels of CSF sTREM2 in the ADNI. The rate of cognitive decline slowed down in rs2062323T carriers., Conclusions: This study is the first to identify significant associations between TREM1 rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

To evaluate the release and activity of Indian jujube phenolics in vivo , its peel and pulp were subjected to simulated digestions. The phenolics content and antioxidant activity of the digested samples were determined. The results showed that the total phenolics/flavonoids in the peel were respectively 4.63 and 4.48 times higher than that in the pulp. The release of phenolics and flavonoids respectively increased by 79.75% and 39.98% in the peel and 86.34% and 23.54% in the pulp after the intestinal digestion. The correlation between the total phenolics/flavonoids and antioxidant activity was higher in the peel ( r  > 0.858, p  < 0.01) than that in the pulp. The phenolics profiles of the peel were almost the same after the digestion, and four phenolics including naringenin tri-glycoside, quercetin-3- O -[(2-hexosyl)-6-rhamnosyl] -hexoside, quercetin-3- O -pentosylhexoside and quercetin-3- O -(2-pentosyl -rhamnoside)-4'- O -rhamnoside were found to be the main flavonoids of Indian jujube peel, and they showed high recovery (>89.88%) during the digestion, implying that these phenolics may play a vital role in the function of Indian jujubes., 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 References, (© 2023 The Authors. Published by Elsevier Ltd.)

Five new triterpenoids, including four ursane types ( 1 - 4 ) and one oleanane type ( 5 ), together with 15 known ursane types pentacyclic triterpenoids ( 6 - 20 ) were isolated from the fruit spikes of Prunella vulgaris L., a traditional Chinese herbal medicine. Their structures were elucidated based on IR, HR-ESI-MS, and NMR spectroscopic data. The SW579 cell line was used to evaluate anti-thyroid cancer activities of ( 1 - 20) . The results indicated that ( 7 - 9) , ( 16), and ( 19) exhibited apparent inhibitory activity with IC 50 values of 25.73-71.41 μM (cisplatin as positive control, IC 50 14.49 ± 0.97 μM). Network pharmacology and molecular docking were also used for the prediction of the synergistic actions and the underlying mechanisms. Accordingly, four potential targets have been characterized.