Huang Lian Jie Du decoction attenuated colitis via suppressing the macrophage Csf1r/Src pathway and modulating gut microbiota.

Introduction: Ulcerative colitis, a subtype of chronic inflammatory bowel disease (IBD), is characterized by relapsing colonic inflammation and ulcers. The traditional Chinese herbal formulation Huang Lian Jie Du (HLJD) decoction is used clinically to treat diarrhea and colitis. However, the mechanisms associated with the effects of treatment remain unclear. This study aims to elucidate the molecular mechanistic effects of HLJD formulation on colitis. Methods: Chronic colitis in mice was induced by adding 1% dextran sulfate sodium (DSS) to their drinking water continuously for 8 weeks, and HLJD decoction at the doses of 2 and 4 g/kg was administered orally to mice daily from the second week until experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon tissues were collected for biochemical analyses. In addition, the fecal microbiome of treated mice was characterized using 16S rRNA amplicon sequencing. Results: HLJD decoction at doses of 2 and 4 g/kg relieved DSS-induced chronic colitis in mice by suppressing inflammation through compromised macrophage activity in colonic tissues associated with the colony-stimulating factor 1 receptor (Csf1r)/Src pathway. Furthermore, the HLJD formula could modify the gut microbiota profile by decreasing the abundance of Bacteroides, Odoribacter, Clostridium_sensu_stricto_1, and Parasutterella. In addition, close correlations between DAI, colon length, spleen weight, and gut microbiota were identified. Discussion: Our findings revealed that the HLJD formula attenuated DSS-induced chronic colitis by reducing inflammation via Csf1r/Src-mediated macrophage infiltration, as well as modulating the gut microbiota profile.

Dissecting shared genetic architecture between depression and body mass index.

BACKGROUND: A growing body of evidence supports the comorbidity between depression (DEP) and obesity, yet the genetic mechanisms underlying this association remain unclear. Our study explored the shared genetic architecture and causal associations of DEP with BMI. METHODS: We investigated the multigene overlap and genetic correlation between DEP (N > 1.3 million) and BMI (N = 806,834) based on genome-wide association studies (GWAS) and using the bivariate causal mixture model and linkage disequilibrium score regression (LDSC). The causal association was explored by bi-directional Mendelian randomization (MR). Common risk loci were identified through cross-trait meta-analyses. Stratified LDSC and multi-marker gene annotation analyses were applied to investigate single-nucleotide polymorphisms enrichment across tissue types, cell types, and functional categories. Finally, we explored shared functional genes by Summary Data-Based Mendelian Randomization (SMR) and further detected differential expression genes (DEG) in brain tissues of individuals with depression and obesity. RESULTS: We found a positive genetic correlation between DEP and BMI (rg = 0.19, P = 4.07 × 10-26), which was more evident in local genomic regions. Cross-trait meta-analyses identified 16 shared genetic loci, 5 of which were newly identified, and they had influence on both diseases in the same direction. MR analysis showed a bidirectional causal association between DEP and BMI, with comparable effect sizes estimated in both directions. Combined with gene expression information, we found that genetic correlations between DEP and BMI were enriched in 6 brain regions, predominantly in the nucleus accumbens and anterior cingulate cortex. Moreover, 6 specific cell types and 23 functional genes were found to have an impact on both DEP and BMI across the brain regions. Of which, NEGR1 was identified as the most significant functional gene and associated with DEP and BMI at the genome-wide significance level (P < 5 × 10-8). Compared with healthy controls, the expression levels of NEGR1 gene were significant lower in brain tissues of individuals with depression and obesity. CONCLUSIONS: Our study reveals shared genetic basis underpinnings between DEP and BMI, including genetic correlations and common genes. These insights offer novel opportunities and avenues for future research into their comorbidities.

A strategy of Q-markers identification based on effect, property flavour material basis and rapid quantitative evaluation via near-infrared spectroscopy and chemometric methods for the quality control of Flos Trollii (FT).

ETHNOPHARMACOLOGICAL RELEVANCE: Flos Trollii (FT) is the dried flower of Trollius Chinensis Bunge of Ranunculaceae with the pharmacological properties of anti-inflammatory, antibacterial, antiviral, anti-oxidative. The herb FT is not only a traditional Chinese medicine (TCM) but also an extensively utilized ethnic medicine, employed by diverse ethnic groups including Mongolian, Tibetan, and Kazakh. AIM OF STUDY: FT was taken as an example to construct a strategy of quality markers (Q-markers) identification based on effect, property flavor material basis, and rapid quantitative evaluation using near-infrared (NIR) spectroscopy and chemometric methods of TCM. MATERIALS AND METHODS: Initially, the anti-inflammatory efficacy of FT from three places of origin was evaluated using the RAW264.7-cell inflammatory model, and the bitter property flavor was characterized using an electronic tongue. The high-performance liquid chromatography(HPLC) fingerprint of FT was generated, and the quality of FT from different origins was evaluated employing chemometrics. Next, potential anti-inflammatory and bitter property flavor compounds were screened utilizing a fingerprinting-effect relationship and fingerprinting-property flavor relationship model using partial least squares regression (PLSR). The Q-markers of the FT were confirmed based on the testability principle. Then, a swift, uncomplicated, and precise Q-marker content of the FT prediction model was developed by adopting NIR. RESULTS: The main common fingerprinting peaks affecting FT's efficacy and property flavor were screened. Five of these compounds, 2″-O-beta-L-galactopyranosylorientin, orientin, vitexin, veratric acid, and isoquercitrin, characterized using HPLC and ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS), could be regarded as Q-markers of FT. Q-marker content of the FT prediction model developed adopting NIR spectroscopy was rapid and effective. CONCLUSION: According to the strategy proposed in this study, a quantitative NIR spectroscopic method to identify Q-markers could be a tool to improve the QC efficiency of TCM.

Exploring the binding characteristics between lorlatinib and human alpha-1-acid glycoprotein: Multispectral and molecular modeling techniques.

Approval in 2019 was granted for the highly selective, targeted agent lorlatinib, which primary target is ROS1 and ALK. The purpose of this work was to examine the binding mechanism between lorlatinib (LOR) and HAG employing multispectral and molecular modeling techniques. Fluorescence data demonstrated that LOR quenched HAG fluorescence as a static quenching, interecalated into the hydrophobic cavity of HAG with a moderate affinity. Thermodynamic and competitive experiments pointed out that LOR bound with HAG primarily through hydrogen bonding, hydrophobic, and van der Waals forces. Circular dichroism, three-dimensional and synchronous fluorescence spectroscopic studies noted that the secondary structure of HAG and microenvironments around tyrosine (Tyr) and tryptophan (Trp) residues were altered due to binding with LOR. The contribution of each energy involved in binding process of LOR and HAG has been analyzed by molecular simulation techniques. Besides, the environmental conditions with metal ions have also been studied. The present study is expected to provide a theoretical basis for further studying the metabolism of LOR in vivo, which may help to gain a deeper understanding of the general pharmacological activity of the drug.

Generating and characterizing a comprehensive panel of CHO cells glycosylation mutants for advancing glycobiology and biotechnology research.

This report describes the development and characterization of a comprehensive collection of CHO cell glycosylation mutants with significant potential for advancing glycobiology and biotechnology. EPO-Fc and trastuzumab, two model molecules, were produced using these mutants to assess the effects of mutated glycogenes, and LC-MS/MS analysis was employed to quantitatively analyse their N-glycans. EPO-Fc exhibited exclusively homogeneous Man9 glycans only when nearly all α-mannosidases in the genome were inactivated, except lysosomal MAN2B1. Some mutants lacking GnT-I activity produce mostly Man5 N-glycans, while their O-glycan and glycolipid profiles can differ due to other mutations in the cell. GnT-II deficiency prevents GnT-V from adding GlcNAc to the core N-glycan, resulting in branches attaching solely to the α1,3-linked mannose, leaving the α1,6-linked mannose free. The mutant-produced antibody's single-branched glycan contains more sialic acid than the dual-branched glycans produced in CHO-K1 cells. Trastuzumab produced in these mutants provided insights into how Fc N-glycans impact the antibody's interaction with FcγR1 and FcγR2a, FcγR3a, and their influence on antibody-dependent cellular cytotoxicity (ADCC). In the study of Fc glycans in Fc-FcγR1 and FcγR2a interactions, we observed a consistent glycan-related impact on binding to both receptors, indicating a common interaction mechanism between Fc glycans and both FcγRI and FcγRIIa. CHO mutants produced trimeric gp120 demonstrated distinct reactivity with multiple broadly neutralizing anti-HIV antibodies, confirming the involvement of gp120 glycans in interactions with specific broadly neutralizing antibodies. Finally, one of the mutants produced human ß-glucocerebrosidase with uniform Man5 N-glycans, showcasing its potential for glycoengineered production and enhancement in therapeutic efficacy.

Anti-inflammatory bicyclic polyprenylated acylphloroglucinols with diverse architectures including an unprecedented 6/6/6 tricyclic core from Garcinia yunnanensis.

Garciyunnanol A (1), an unprecedented 1,2-seco-bicyclic polyprenylated acylphloroglucinol (BPAP) possessing a unique 6/6/6 tricyclic core, was characterized from Garcinia yunnanensis together with 16 BPAPs, including eight new compounds (garciyunnanols B-I, 2-9). Biogenetically, the bicyclo[3.3.1]nonane-2,4,9-trione moiety of 12 reconstructed the bicyclic δ-lactone core of 2 through Norrish type Ⅰ cleavage and cyclization, followed by a cyclization of two side chains to form an intriguing 6/6/6 tricyclic core of 1. Their structures were elucidated through analysis of spectroscopic data, calculation and comparison of ECD spectra. Bioactivity evaluation manifested that compounds 1, 2, 5, 6 and 14 demonstrated superior inhibition of NO production compared to the positive control dexamethasone. Notably, compound 5 exhibited a dose-dependent inhibitory effect on NO production, with an IC50 value of 0.25 ± 0.87 µM. Furthermore, experiments involving ELISA, Western blotting, and immunofluorescence staining revealed that 5 effectively reduced the secretion of interleukin-1ß in LPS plus nigericin-stimulated THP-1 macrophages by inhibiting the activation of the NLRP3 inflammasome.

Temporal dynamics of negative emotional memory reprocessing during sleep.

Memory reprocessing during sleep is a well-established phenomenon in numerous studies. However, it is unclear whether the intensity of memory reprocessing is consistently maintained throughout the night or exhibits dynamic changes. This study investigates the temporal dynamics of negative emotional memory reprocessing during sleep, with a specific focus on slow oscillation (SO)-spindle coupling and its role in memory reprocessing. In the first experiment (N = 40, mean age = 22.5 years), we detected the negative emotional memory reprocessing strength in each sleep cycle, we found that the 2nd sleep cycle after negative emotional memory learning constitute the most sensitive window for memory reprocessing, furthermore, SO-spindle coupling signals in this window plays a role in stabilizing negative emotional memory. To verify the role of SO-spindle coupling in negative emotional memory reprocessing, we utilized transcranial alternating current stimulation (tACS) to disrupt SO-spindle coupling during the 2nd sleep cycle (N = 21, mean age = 19.3 years). Notably, the outcomes of the tACS intervention demonstrated a significant reduction in the recognition of negative emotional memories. These findings offer new insights into the mechanisms that regulate emotional memory consolidation during sleep and may have implications for addressing psychiatric disorders associated with pathological emotional memory.

NEU4-mediated desialylation enhances the activation of the oncogenic receptors for the dissemination of ovarian carcinoma.

Glycosylation profoundly influences the interactions between cancer cells and microenvironmental stromal cells during the peritoneal disseminated metastasis of ovarian carcinoma (OC), which is the major cause of cancer-related death. Although the characteristic cancer glycoconjugates are widely used as biomarkers for cancer diagnosis, our knowledge about cancer glycome remains quite fragmented due to the technique limitations in analyzing glycan chains with tremendous structural and functional heterogeneity. Given the dysregulated cancer glycome is defined by the altered glycosylation machinery, here we performed a systematic loss-of-function screen on 498 genes involved in glycosylation for key regulators of OC dissemination. We identified neuraminidase 4 (NEU4), an enzyme capable of hydrolyzing terminal sialic acid from glycoconjugates, as a vital peritoneal dissemination-promoting modifier of OC glycome. In human patients with high-grade serous OC (HGSOC), increased NEU4 was detected in the disseminated OC cells when compared with that in the primary tumor cells, which significantly correlated with the worse survival. Among three alternative splice-generated isoforms of human NEU4, we revealed that only the plasma membrane-localized NEU4 isoform 2 (NEU4-iso2) and intracellular isoform 3 promoted the peritoneal dissemination of OC by enhancing the cell motility and epithelial-mesenchymal transition. We also identified NEU4-iso2-regulated cell surface glycoproteome and found that NEU4-iso2 desialylated the epithelial growth factor receptor (EGFR), in particular at N196 residue, for the hyperactivation of EGFR and its downstream tumor-promoting signaling cascades. Our results provide new insights into how the OC glycome is dysregulated during OC progression and reveal a functionally important glycosite on EGFR for its abnormal activation in cancer.

ML-enhanced peroxisome capacity enables compartmentalization of multienzyme pathway.

Repurposing an organelle for specialized metabolism provides an avenue for fermentable, unicellular organisms such as Saccharomyces cerevisiae to mimic compartmentalization of metabolic pathways within different plant tissues. Peroxisomes are attractive organelles for repurposing as they are not required for yeast viability when grown on glucose and can efficiently compartmentalize heterologous enzymes to enable physical separation of cytosolic native metabolism and peroxisomal engineered metabolism. However, when not required, peroxisomes are repressed, leading to low functional capacities for heterologous proteins. Here we engineer peroxisomes with enhanced functional capacities, with the goal of compartmentalizing up to eight metabolic enzymes to enhance titers. We implement a machine learning pipeline that allows the identification of factors to overexpress, culminating in a 137% increase in peroxisome functional capacity compared to a wild-type strain. Improved pathway compartmentalization enables an 80% increase in the biosynthesis titers of the monoterpene geraniol, up to 9.5 g L-1.

Exploring correlations between Conners' Continuous Performance Test and subjective measures of attention deficit hyperactivity disorder symptoms in a paediatric clinical sample.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental condition characterised by inattention and/or hyperactivity-impulsivity. The ADHD symptoms are often evaluated and quantified using various assessment tools, such as the Conners' Continuous Performance Test II (CCPT-II), ADHD Rating Scale (ADHD-RS), Child Behaviour Checklist (CBCL), Clinical Global Assessment Scale (CGAS) and Clinical Global Impression Scale (CGIS). This study sought to compare CCPT-II with parent- and clinician-rated rating scales (ADHD-RS, CBCL, CGAS and CGIS) in measuring the core ADHD symptoms within the paediatric ADHD population. METHODS: The data, gathered from a large-scale randomised controlled trial involving 172 children aged 6-12 years with ADHD, was pooled, and a Pearson correlation analysis was conducted. RESULTS: No significant correlations were observed between CCPT-II and ADHD-RS, as well as the various subscales of CBCL, CGAS and CGIS. CONCLUSION: While CCPT-II may offer insights into ADHD symptomatology, its relationship with parent- and clinician-rated rating scales such as ADHD-RS, CBCL, CGAS and CGIS appears limited. Further research is warranted to elucidate the nuances of these assessment tools and their roles in evaluating ADHD.

Incidence and risk factors of antidepressant withdrawal symptoms: a meta-analysis and systematic review.

Antidepressants are among the most extensively prescribed psychotropic drugs worldwide. Discontinuation induced withdrawal symptoms have been reported for almost all antidepressants. The incidence of antidepressant withdrawal syndrome (AWS) and other characteristics remain unknown. We searched the PubMed, Embase, PsycINFO, MEDLINE, CINAHL, and Cochrane Central Register of Controlled Trials databases from inception to December 31, 2023. Randomized double-blinded trials, longitudinal or cross-sectional studies that reported the incidence and other characteristics of antidepressant withdrawal symptoms were included. The pooled incidence of AWS was calculated by a random effects model. We included 35 studies, of which 2 studies just provided incidence of specific withdrawal symptoms, and 4 studies only described other characteristics. The pooled incidence of AWS from all available studies was 42.9%, from 11 RCTs was 44.4%, in studies in which the treatment duration was mostly 8-12 weeks, which usually appear within 2 weeks, and were generally measured for <4 weeks. The incidence in selective serotonin-norepinephrine reuptake inhibitors was the lowest (29.7%), followed by selective serotonin reuptake inhibitors (45.6%) and tricyclic antidepressants (59.7%), without significant differences (p = 0.221). Treatment duration showed a dose-response to the incidence of AWS (6-12 W: 35.1%, 12-24 W: 42.7%, >24 W: 51.4%). The half-life did not show such a simple dose-dependent relationship. The pooled estimate was robust regardless whether withdrawal symptoms were measured in RCTs or observational studies (including face-to-face and online survey studies). Tapering the dose reduced the incidence of AWS compared with abrupt stoppage (34.5% vs 42.5%), without a significant difference (p = 0.484). Risk factors for withdrawal symptoms included being female, younger, experiencing adverse effects early in treatment, taking higher doses or longer duration of medication, abrupt cessation of drugs, and those with a lower clearance of drugs or with serotonin 1A receptor gene variation. The findings suggest the incidence of AWS are common and some clinical characteristics and risk factors which can help clinicians identify who is at greater risk of experiencing AWS. Discontinuation studies on long-term antidepressant users with long follow-up periods are required in the future.

Retinal microcirculation changes in prediabetic patients with short-term increased blood glucose using optical coherence tomography angiography.

BACKGROUND: Retinal microcirculation alterations are early indicators of diabetic microvascular complications. Optical coherence tomography angiography (OCTA) is a noninvasive method to assess these changes. This study analyzes changes in retinal microcirculation in prediabetic patients during short-term increases in blood glucose using OCTA. AIM: To investigate the changes in retinal microcirculation in prediabetic patients experiencing short-term increases in blood glucose levels using OCTA. METHODS: Fifty volunteers were divided into three groups: Group 1 [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)], Group 2 (both IFG and IGT), and a control group. Retinal microcirculation parameters, including vessel density (VD), perfusion density (PD), and foveal avascular zone (FAZ) metrics, were measured using OCTA. Correlations between these parameters and blood glucose levels were analyzed in both the fasting and postprandial states. RESULTS: One hour after glucose intake, the central VD (P = 0.023), central PD (P = 0.026), and parafoveal PD (P < 0.001) were significantly greater in the control group than in the fasting group. In Group 1, parafoveal PD (P < 0.001) and FAZ circularity (P = 0.023) also increased one hour after glucose intake. However, no significant changes were observed in the retinal microcirculation parameters of Group 2 before or after glucose intake (P > 0.05). Compared with the control group, Group 1 had a larger FAZ area (P = 0.032) and perimeter (P = 0.018), whereas Group 2 had no significant differences in retinal microcirculation parameters compared with the control group (P > 0.05). Compared with Group 1, Group 2 had greater central VD (P = 0.013) and PD (P = 0.008) and a smaller FAZ area (P = 0.012) and perimeter (P = 0.010). One hour after glucose intake, Group 1 had a larger FAZ area (P = 0.044) and perimeter (P = 0.038) than did the control group, whereas Group 2 showed no significant differences in retinal microcirculation parameters compared with the control group (P > 0.05). Group 2 had greater central VD (P = 0.042) and PD (P = 0.022) and a smaller FAZ area (P = 0.015) and perimeter (P = 0.016) than Group 1. At fasting, central PD was significantly positively correlated with blood glucose levels (P = 0.044), whereas no significant correlations were found between blood glucose levels and OCTA parameters one hour after glucose intake. CONCLUSION: A short-term increase in blood glucose has a more pronounced effect on retinal microcirculation in prediabetic patients with either IFG or IGT.

Primary Sjogren's Syndrome Associated with Lung Adenocarcinoma: Probing the Potential Common Pathogenic Mechanisms and Experimental Verification.

This study aimed to probe the potential common pathogenic mechanisms linking primary Sjogren's syndrome (pSS) and lung adenocarcinoma (LUAD) through bioinformatics analysis and experimental verification. The relevant genes associated with pSS and LUAD were retrieved from the Gene Expression Omnibus (GEO) database and Genecard database. Subsequently, differentially expressed genes (DEGs) associated with pSS and LUAD were screened as pSS-LUAD-DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed to elucidate the significant biological functions of pSS-LUAD-DEGs. Core targets were identified by constructing the protein-protein interaction (PPI) network, further assessing hub gene diagnostic accuracy through Receiver Operating Characteristic (ROC) curve analyses. In this study, NOD/Ltj mice served as pSS animal models and were stimulated with particulate matter 2.5 (PM2.5) to generate an inflammatory reaction. Quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and western blotting were employed for relevant molecular biology experiment verification. The results revealed through KEGG and GO enrichment analyses indicate that inflammation plays a critical role in linking pSS and LUAD. IL6, CCNA2, JAK2, IL1B, ASPM, CCNB2, NUSAP1, and CEP55 were determined as key targets of pSS-LUAD. BALB/c mice and NOD/Ltj mice exhibited enhanced expression of inflammatory cytokines IL-6 and IL-1ß in lung tissues following 21 days of stimulation with PM2.5, activating the JAK2/STAT3 signaling pathway and up-regulating the expression of tumor-associated genes CCNA2, CCNB2, and CEP55, with NOD/Ltj mice exhibiting more pronounced changes than BALB/c mice. This protocol demonstrates that carcinogenesis induced by the pulmonary inflammatory microenvironment may be a key reason for the high incidence of LUAD in pSS patients. Additionally, blocking-related mechanisms may help prevent the occurrence of LUAD in pSS patients.

Therapeutic potential of ADSCs in diabetic wounds: a proteomics-based approach.

Background: Diabetes mellitus (DM), a chronic metabolic disease characterized by elevated blood sugar, leads to delayed or non-healing wounds, increasing amputation risks, and placing a significant burden on patients and society. While extensive research has been conducted on adipose-derived stem cells (ADSCs) for promoting wound healing, there is a scarcity of studies focusing on diabetic wounds, particularly those employing proteomics and bioinformatics approaches. Objective: This study aimed to investigate the mechanisms by which ADSCs promote diabetic wound healing using proteomics and bioinformatics techniques. Methods: Healthy rat fat tissue was used to isolate ADSCs. A T2DM rat model with back wounds was established. The experimental group received ADSC injections around the wound, while the control group received PBS injections. Wound healing rates were documented and photographed on days 0, 3, 7, 10, and 14. On day 7, wound tissues were excised for HE and Masson's staining. Additionally, on day 7, tissues were analyzed for protein quantification using 4D-DIA, with subsequent GO and KEGG analyses for differentially expressed proteins (DEPs) and protein-protein interaction (PPI) network analysis using STRING database (String v11.5). Finally, Western blot experiments were performed on day 7 wounds to verify target proteins. Results and Conclusions: In all measured days postoperatively, the wound healing rate was significantly higher in the ADSC group than in the PBS group (day 7: p < 0.001, day 10: p = 0.001, day 14: p < 0.01), except on day 3 (p > 0.05). Proteomic analysis identified 474 differentially expressed proteins, with 224 key proteins after PPI analysis (78 upregulated and 146 downregulated in the ADSC group). The main cellular locations of these proteins were "cellular anatomical entity" and "protein-containing complex", while the biological processes were "cellular processes" and "biological regulation". The primary molecular functions were "binding" and "catalytic activity", with GO enrichment focused on "Wnt-protein binding", "neural development", and "collagen-containing extracellular matrix". Further analysis of PPI network nodes using LASSO regression identified Thy1 and Wls proteins, significantly upregulated in the ADSC group, as potentially crucial targets for ADSC application in diabetic wound treatment.

Schisandra chinensis lignans improve insulin resistance by targeting TLR4 and activating IRS-1/PI3K/AKT and NF-κB signaling pathways.

Schisandra chinensis, a traditional Chinese medicine, has been widely applied in China to treat diabetes and its complications. The aim of this study was to discover the active compounds and explain related molecular mechanism contributing to the anti-diabetic effect of Schisandra chinensis. Herein, the therapeutic effects of Schisandra chinensis extracts on type 2 diabetes mellitus (T2DM) were firstly confirmed in vivo. Subsequently, various lignans were isolated from Schisandra chinensis and tested for hypoglycemic activity in palmitic acid-induced insulin-resistant HepG2 (IR-HepG2) cells. Among these lignans, R-biar-(7S,8R)-6,7,8,9-tetrahydro-1,2,3,12,13,14-hexamethoxy-7,8-dimethyl-7-dibenzo [a, c] cyclooctenol (compound 2) and Gomisin A (compound 4) were identified significantly increased the glucose consumption in IR-HepG2 cells. Meanwhile, compounds 2 and 4 activated the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) pathway, which regulates glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pase), essential for gluconeogenesis and glucose uptake. These compounds also inhibited the nuclear factor-κB (NF-κB) signaling pathway, reducing interleukin-6 (IL-6) levels. Importantly, the hypoglycemic effects of compounds 2 and 4 were diminished after Toll-like receptor 4 (TLR4) knockdown. Cellular thermal shift assays confirmed increased TLR4 protein stability upon treatment with these compounds, indicating direct binding to TLR4. Furthermore, TLR4 knockdown reversed the effects of compounds 2 and 4 on the NF-κB and IRS-1/PI3K/AKT pathways. Taken together, compounds 2 and 4 alleviate IR by targeting TLR4, thereby modulating the NF-κB and IRS-1/PI3K/AKT pathways. These findings suggest that compounds 2 and 4 could be developed as therapeutic agents for T2DM.

Eleven internal fixations for young vertical femoral neck fractures: A protocol for systematic review and network meta-analysis.

BACKGROUND AND OBJECTIVES: Vertical femoral neck fractures (VFNFs) in young patients lead to significant biomechanical instability. Multitudinous internal fixation devices have been developed and utilized in clinical interventions. However, there has yet to be a consensus expert opinion regarding the optimal internal fixation configurations. This study aims to conduct a network meta-analysis to evaluate the safety and efficacy of all currently recognized internal fixation procedures for the treatment of VFNFs in young individuals. METHODS: Comprehensive literature searches will be performed in China National Knowledge Infrastructure, the Cochrane Library, PubMed, Web of Science, Embase, the Wanfang Database, and the Chinese Biomedical Literature Database, covering the entire database history up until May 21, 2024. Individual papers will be evaluated for possible bias using RoB 2.0, the most recent version of the randomized trial Cochrane risk-of-bias approach. Pairwise meta-analysis and network meta-analysis (NMA) will be conducted for data analysis using STATA 15.0 and R 4.1.3. Inconsistency tests, subgroup analyses, sensitivity analyses, and assessments of publication bias will also be performed. CONCLUSION: The study will provide evidence-based recommendations for the optimal internal fixation methods in treating young patients with VFNFs. TRIAL REGISTRATION: INPLASY202460017.

Male sling versus artificial urinary sphincter for the treatment of incontinence after prostate surgery: a systematic review with meta-analysis.

Background: Urinary incontinence following prostate treatment (IPT) represents a significant complication that detrimentally impacts the quality of life for patients who have undergone prostate surgery. Presently, there is a scarcity of evidence regarding the preferred surgical techniques for IPT. We conducted a meta-analysis to compare the outcomes of the male sling and artificial urinary sphincter (AUS) in the treatment of IPT. Methods: Data were extracted through electronic literature searches on PubMed, Web of Science, and Embase databases until September 2023. Eligible studies included patients who underwent AUS or male sling procedures for IPT and had a follow-up duration exceeding 12 months. The primary end point was the success rate, with the secondary outcome focusing on complication rates. A fixed-effects or random-effects models were used to calculate the pooled estimate and its 95% confidence interval (CI). The publication bias was assessed using funnel plots and Egger's regression test. Results: The meta-analysis included nine studies, involving a total of 1,350 participants. No statistically significant difference in success rates was found between AUS and male sling [odds ratio (OR): 0.96, 95% CI: 0.91-1.01]. In terms of the complication rate, there was no significant disparity between the two procedures (OR: 0.87, 95% CI: 0.86-1.12). Conclusions: The findings from this study indicated that male sling surgery yielded success and complication rates comparable to those of AUS. This suggests that male sling could serve as a viable alternative surgical option in the treatment of IPT.

Multispectral and molecular simulation of the interaction of human α1-acid glycoprotein with palbociclib.

Palbociclib, a selective CDK4/6 inhibitor with potent anti-tumor effects, was investigated for its interaction with human α1-acid glycoprotein (HAG). Spectral analysis revealed that palbociclib forms a ground state complex with HAG, exhibiting binding constant (Kb) of 104 M-1 at the used temperature range. The interaction between the two was determined to be driven mainly by hydrogen bonding and hydrophobic forces. Multispectral studies indicated that the bound palbociclib altered the secondary structure of HAG and reduced polarity around Trp and Tyr amino acids. And, molecular docking and dynamics simulations verified the experimental findings. Finally, most of the metal ions present in plasma, such as K+, Cu2+, Ca2+, Mg2+, Ni2+, Fe3+, and Co2+, are detrimental to the binding of palbociclib to HAG, with the exception of Zn2+, which is favorable.

The value of computed tomography angiography for evaluation of left atrial enlargement in patients with persistent atrial fibrillation.

BACKGROUND: The post-processing technology of CTA offers significant advantages in evaluating left atrial enlargement (LAE) in patients with persistent atrial fibrillation (PAF). This study aims to identify parameters for rapidly and accurately diagnosing LAE in patients with PAF using CT cross-sections. METHODS: Left atrial pulmonary venous (PV) CT was performed to 300 PAF patients with dual-source CT, and left atrial volume (LAV), left atrial anteroposterior diameter (LAD1), left atrial transverse diameter (LAD2), and left atrial area (LAA) were measured in the ventricular end systolic (ES) and middle diastolic (MD). LA index (LAI) = LA parameter/body surface area (BSA). Left atrial volume index (LAVIES) > 77.7 ml/m2 was used as the reference standard for the LAE diagnosis. RESULTS: 227 patients were enrolled in the group, 101 (44.5%) of whom had LAE. LAVES and LAVMD (r = 0.983), LAVIES and LAVIMD (r = 0.984), LAAES and LAVIES (r = 0.817), LAAMD and LAVIES (r = 0.814) had strong positive correlations. The area under curve (AUC) showed that all measured parameters were suitable for diagnosing LAE, and the diagnostic efficacy was compared as follows: LAA/LAAI> LAD> the relative value index of LAD, LAD2> LAD1. LAA and LAAI demonstrated comparable diagnostic efficacy, with LAA being more readily available than LAAI. CONCLUSIONS: The axial LAA measured by CTA can be served as a parameter for the rapid and accurate diagnosis of LAE in patients with PAF.

Characterization and Performance Evaluation of Liquid Biodegradable Mulch Films and Its Effects on Peanut Cultivation.

With the development of material science and increasing awareness of ecological environmental protection, liquid biodegradable mulch films (LBDMs) have garnered significant public interest. In this research, new LBDMs were developed using hydrophobically modified polymer materials, surfactants, and photosensitive catalysts. Characterization by scanning electron microscopy (SEM) revealed good material compatibility. LBDMs exhibited excellent wettability and degradability, effectively covering soil surfaces and enhancing soil moisture conservation, with a degradation rate of 76.09% after 80 days of burial. The field performance experiment was conducted over two consecutive years, 2021 and 2022, to assess differences in soil temperature and moisture, peanut agronomic traits, pod traits, and yield under four treatments: non-mulching (CK), LBDMs, clear polyethylene mulch films (CPEMs), and black polyethylene mulch films (BPEMs). LBDMs increased soil temperature by 0.56 °C and soil moisture by 19.25%, accelerated the seedling stage by 4-to-6 days, and improved the average emergence rate by 15.91%. Furthermore, LBDMs significantly promoted peanut growth, and it increased yield by 14.34% compared to CK. LBDMs performed comparably to the two types of PE films in maintaining soil conditions and different crop phenotype traits, including plant height, branch number, yield, and quality, and they even outperformed PE films in productivity per plant and 100-kernel weight. These findings suggest that LBDMs are a promising eco-friendly alternative to traditional PE films.