Exploring the mechanism of dendrobine in treating metabolic associated fatty liver disease based on network pharmacology and experimental validation.

BACKGROUND: This study investigates the therapeutic mechanisms of dendrobine, a primary bioactive compound in Dendrobium nobile, for Metabolic Associated Fatty Liver Disease (MASLD) management. Utilizing network pharmacology combined with experimental validation, the clinical effectiveness of dendrobine in MASLD treatment was assessed and analyzed. RESULTS: The study demonstrates significant improvement in liver function among MASLD patients treated with Dendrobium nobile. Network pharmacology identified key targets such as Peroxisome Proliferator-Activated Receptor Gamma (PPARG), Interleukin 6 (IL6), Tumor Necrosis Factor (TNF), Interleukin 1 Beta (IL1B), and AKT Serine/Threonine Kinase 1 (AKT1), with molecular docking confirming their interactions. Additionally, dendrobine significantly reduced ALT and AST levels in palmitic acid-treated HepG2 cells, indicating hepatoprotective properties and amelioration of oxidative stress through decreased Malondialdehyde (MDA) levels and increased Superoxide Dismutase (SOD) levels. CONCLUSION: Dendrobine mitigates liver damage in MASLD through modulating inflammatory and immune responses and affecting lipid metabolism, potentially by downregulating inflammatory mediators like TNF, IL6, IL1B, and inhibiting AKT1 and Signal Transducer and Activator of Transcription 3 (STAT3). This study provides a theoretical basis for the application of dendrobine in MASLD treatment, highlighting its potential as a therapeutic agent.

Development of a machine learning-based prediction model for clinical pregnancy of intrauterine insemination in a large Chinese population.

PURPOSE: This study aimed to evaluate the effectiveness of a random forest (RF) model in predicting clinical pregnancy outcomes from intrauterine insemination (IUI) and identifying significant factors affecting IUI pregnancy in a large Chinese population. METHODS: RESULTS: A total of 11 variables, including eight from female (age, body mass index, duration of infertility, prior miscarriage, and spontaneous abortion), hormone levels (anti-Müllerian hormone, follicle-stimulating hormone, luteinizing hormone), and three from male (smoking, semen volume, and sperm concentration), were identified as the significant variables associated with IUI clinical pregnancy in our Chinese dataset. The RF-based prediction model presents an area under the receiver operating characteristic curve (AUC) of 0.716 (95% confidence interval, 0.6914-0.7406), an accuracy rate of 0.6081, a sensitivity rate of 0.7113, and a specificity rate of 0.505. Importance analysis indicated that semen volume was the most vital variable in predicting IUI clinical pregnancy. CONCLUSIONS: The machine learning-based IUI clinical pregnancy prediction model showed a promising predictive efficacy that could provide a potent tool to guide selecting targeted infertile couples beneficial from IUI treatment, and also identify which parameters are most relevant in IUI clinical pregnancy.

Injectable ChitHCl-DDA tissue adhesive with high adhesive strength and biocompatibility for torn meniscus repair and regeneration.

Suture pull-through is a clinical problem in meniscus repair surgery due to the sharp leading edge of sutures. Several tissue adhesives have been developed as an alternative to traditional suturing; however, there is still no suitable tissue adhesive specific for meniscus repair treatment due to unsatisfactory biosafety, biodegradable, sterilizable, and tissue-bonding characteristics. In this study, we used a tissue adhesive composed of chitosan hydrochloride reacted with oxidative periodate-oxidized dextran (ChitHCl-DDA) combined with a chitosan-based hydrogel and oxidative dextran to attach to the meniscus. We conducted viscoelastic tests, viscosity tests, lap shear stress tests, Fourier transform infrared (FTIR) spectroscopy, swelling ratio tests, and degradation behavior tests to characterize these materials. An MTT assay, alcian blue staining, migration assay, cell behavior observations, and protein expression tests were used to understand cell viability and responses. Moreover, ex vivo and in vivo tests were used to analyze tissue regeneration and biocompatibility of the ChitHCl-DDA tissue adhesive. Our results revealed that the ChitHCl-DDA tissue adhesive provided excellent tissue adhesive strength, cell viability, and cell responses. This tissue adhesive has great potential for torn meniscus tissue repair and regeneration.

Dietary Factors and Risk of Gout: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Dietary intervention is the preferred approach for the prevention and clinical management of gout. Nevertheless, the existing evidence regarding the influence of specific foods on gout is insufficient. METHODS: We used two-sample Mendelian randomization for genetic prediction to analyze the relationship between the intake of more than a dozen daily food items, such as pork, beef, cheese, and poultry, and dietary macronutrient intake (fat, protein, carbohydrates, and sugar) and the risk of developing gout and elevating the serum uric acid level. Inverse-variance weighted MR analyses were used as the main evaluation method, and the reliability of the results was tested by a sensitivity analysis. RESULTS: Cheese intake was associated with lower serum uric acid levels, and tea intake (OR = 0.523, [95%CI: 0.348~0.784], p = 0.002), coffee intake (OR = 0.449, [95%CI: 0.229~0.882], p = 0.020), and dried fruit intake (OR = 0.533, [95%CI: 0.286~0.992], p = 0.047) showed a preventive effect on the risk of gouty attacks. In contrast, non-oily fish intake (ß = 1.08, [95%CI: 0.24~1.92], p = 0.012) and sugar intake (ß = 0.34, [95%CI: 0.03~0.64], p = 0.030) were risk factors for elevated serum uric acid levels, and alcohol intake frequency (OR = 1.422, [95%CI: 1.079~1.873], p = 0.012) was a risk factors for gout predisposition. CONCLUSIONS: These results will significantly contribute to the formulation and refinement of nutritional strategies tailored to patients afflicted with gout.

Current advances and development strategies of targeting son of sevenless 1 (SOS1) in drug discovery.

The Son of Sevenless 1 (SOS1) guanine nucleotide exchange factor, prevalent across eukaryotic species, plays a pivotal role in facilitating the attachment of RAS protein to GTP, thereby regulating the activation of intracellular RAS proteins. This regulation is part of a feedback mechanism involving SOS1, which allows both activators and inhibitors of SOS1 to exert control over downstream signaling pathways, demonstrating potential anti-tumor effects. Predominantly, small molecule modulators that target SOS1 focus on a hydrophobic pocket within the CDC25 protein domain. The effectiveness of these modulators largely depends on their ability to interact with specific amino acids, notably Phe890 and Tyr884. This interaction is crucial for influencing the protein-protein interaction (PPI) between RAS and the catalytic domain of SOS1. Currently, most small molecule modulators targeting SOS1 are in the preclinical research phase, with a few advancing to clinical trials. This progression raises safety concerns, making the assurance of drug safety a primary consideration alongside the enhancement of efficacy in the development of SOS1 modulators. This review encapsulates recent advancements in the chemical categorization of SOS1 inhibitors and activators. It delves into the evolution of small molecule modulation targeting SOS1 and offers perspectives on the design of future generations of selective SOS1 small molecule modulators.

Comparison of surgical and oncological outcomes between different surgical approaches for overweight or obese cervical cancer patients.

The purpose was to investigate the safety and advantages of different surgical approaches applied to overweight or obese cervical cancer patients by comparing their surgical and oncological outcomes. This is a retrospective cohort study. 382 patients with a body mass index of at least 24.0 kg/m2 and stage IB-IIA (The International Federation of Gynecology and Obstetrics, FIGO 2009) cervical cancer were enrolled, and then were divided into three groups: open radical hysterectomy (ORH) group, laparoscopic radical hysterectomy (LRH) group, and robot-assisted radical hysterectomy (RRH) group according to the surgical approach. IBM SPSS version 25.0 was used to analyze data. There were 51 patients in ORH group, 225 patients in LRH group and 106 patients in RRH group. In the comparison of surgical outcomes, compared to LRH and ORH, RRH had the shortest operating time, the least estimated blood loss, the shortest postoperative hospital stay, and the shortest recovery time for bowel function (P < 0.05). In the comparison of postoperative complications, ORH has the highest rate of postoperative infection and wound complication compared to LRH and RRH (P < 0.05), and RRH has the highest proportion of urinary retention. After a median follow-up time of 61 months, there was no statistically significant difference between the three groups in terms of 5-year overall survival (OS) rate and 5-year recurrence-free survival (RFS) rate, (P = 0.262, P = 0.453). In patients with overweight or obese cervical cancer, the long-term outcomes of the three surgical approaches were comparable, with RRH showing significant advantages over ORH and LRH in terms of surgical outcomes.

Intraoperative implantation of 125I seeds improves prognosis in refractory stage IIIB cervical cancer: a case report and literature review.

BACKGROUND: Concurrent chemoradiation is the standard treatment for advanced cervical cancer. However some patients still have a poor prognosis, and currently, there is no effective treatment for recurrence. In recent years, 125I seed implantation therapy has emerged as a treatment for advanced malignant tumors including surgically unresectable tumors, residual tumors after surgical resection, and metastatic tumors. However, the use of 125I seeds implantation in primary advanced cervical cancer has not been reported. In this study, we present a case of stage IIIB cervical cancer in a patient who had poor response to radiotherapy and chemotherapy. Subsequently, a radical hysterectomy was performed, and 125I radioactive seeds were successfully implanted during the surgery. This effectively controlled the lesions that were resistant to radiotherapy and had the potential to improve the prognosis. CASE PRESENTATION: A 56-year-old woman was diagnosed with stage IIIB (FIGO 2009) IIIC1r (FIGO 2018) squamous carcinoma of the cervix. After receiving 4 cycles of platinum-based chemotherapy and 30 rounds of radiotherapy, she underwent a radical hysterectomy. The localized cervical lesions were reduced, but there was no reduction in the size of the enlarged pelvic lymph nodes. Therefore, 125I seed implantation was performed under direct surgical vision for the right paracervical lesion and the enlarged pelvic lymph nodes on the right side. During the 18-month follow-up period, the enlarged lymph nodes subsided without any signs of recurrence or metastasis. CONCLUSION: Intraoperative implantation of 125I seeds in lesions that are difficult to control with radiotherapy or in sites at high risk of recurrence is a feasible and effective treatment option for patients with advanced squamous cervical cancer, and it may contribute to improved survival.

Modified exfoliated graphene functionalized with carboxylic acid-group and thionine on a screen-printed carbon electrode as a platform for an electrochemical enzyme immunosensor.

An enzyme immunoassay was developed based on the coulometric measurement of immunoglobulin M (IgM) against Hantaan viruses (HTNV) by using virus-like particles (VLPs) as recognition molecules. The surface functionalization of screen-printed carbon electrodes (SPCEs) was achieved through paste-exfoliated graphene that was modified with a COOH group and a thionine mediator through supramolecular-covalent scaffolds, on SPCEs by using the binder contained in the ink. After the covalent immobilization of the antibody, the sensor was used for the sandwich enzyme immunoassay of IgM against HTNV. By using HTNV VLPs as the second recognization molecules, the resulting sensor efficiently monitored the reaction of IgM against HTNV and anti-IgM antibody with high specificity. By attaching HTNV nucleocapsid protein antibody conjugate with horseradish peroxidase (HRP) onto VLPs, the signal response of the assay was derived from the coulometric measurement of H2O2 reduction mediated by thionine on the electrode surface after the application of a potential (- 0.2 V vs. Ag/AgCl). The ratio of charges measured before or after H2O2 addition was used to quantify IgM because these charges could be used as background charges or total charges, respectively. The ratio exhibited good agreement with IgM concentration within a range 0.1 to 1000 pg mL-1, and a detection limit of 0.06 pg mL-1 was obtained. The assay demonstrated high sensitivity and specificity toward HTNV-specific IgM in serum.

Immunohistochemical markers Ki67 and P16 help predict prognosis in locally advanced cervical cancer.

OBJECTIVE: To investigate the relationship between Ki-67 and P16 expression levels after neoadjuvant chemotherapy, and the clinicopathological characteristics and prognosis of patients with locally advanced cervical cancer. METHODS: Patients with FIGO 2009 stage IB2 or IIA2 cervical cancer, who underwent neoadjuvant chemotherapy combined with radical hysterectomy at the First Affiliated Hospital of Chongqing Medical University between January 2015 and December 2019, were identified retrospectively to correlate postoperative Ki-67 and P16 expression levels with clinicopathological factors. The optimal threshold for predicting recurrence was analysed using receiver operating characteristic (ROC) curves for the Ki-67 index, and univariate and multi-factorial Cox regression analysis were used to investigate the association between clinicpathological features including Ki-67 and P16 and recurrence-free survival. RESULTS: In total, 334 patients were included after screening. The cut-off value of Ki-67 for determining recurrence was 67.5 % according to the ROC curve. On multi-factorial Cox analysis, lymphatic vascular space (p = 0.003) and Ki-67 index (p = 0.005) were shown to increase the risk of recurrence, and were independent prognostic factors for recurrence, while the expression of P16 was not significantly associated with the risk of recurrence (p = 0.097, odds ratio = 0.319). Patients with cervical cancer in the high Ki-67 expression group (Ki-67 ≥ 67.5 %) had lower recurrence-free survival and overall survival than patients in the low Ki-67 expression group (Ki-67 < 67.5 %) (p = 0.001 and 0.036, respectively). CONCLUSION: The expression levels of Ki-67 and P16 after neoadjuvant chemotherapy for locally advanced cervical cancer correlated with tumour differentiation. High expression of Ki-67 (Ki-67 ≥ 67.5 %) may indicate poorer recurrence-free survival and overall survival.

Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels the molecular feature of M2 macrophages of head and neck squamous cell carcinoma.

The connection between head and neck squamous cell carcinoma (HNSC) and M2 tumour-associated macrophages is not yet fully understood. We gathered gene expression profiles and clinical data from HNSC patients in the TCGA database. Using Consensus Clustering, we categorized these patients into M2 macrophage-related clusters. We developed a M2 macrophage-related signature (MRS) through statistical analyses. Additionally, we assessed gene expression in HNSC cells using single-cell sequencing data (GSE139324). We identified three distinct M2 macrophage-related clusters in HNSC, each with different prognostic outcomes and immune characteristics. Patients with different MRS profiles exhibited variations in immune infiltration, genetic mutations and prognosis. FCGR2A may play a role in creating an immunosuppressive tumour microenvironment and could potentially serve as a therapeutic target for HNSC. Our study demonstrated that M2 macrophage-related genes significantly impact the development and progression of HNSC. The M2 macrophage-related model offered a more comprehensive assessment of HNSC patient prognosis, genetic mutations and immune features. FCGR2A was implicated in immunosuppressive microenvironments and may hold promise for the development of novel immunotherapeutic strategies for HNSC.

Raising the Asymmetric Catalytic Efficiency of Chiral Covalent Organic Frameworks by Tuning the Pore Environment.

Chiral covalent organic frameworks (COFs) hold considerable promise in the realm of heterogeneous asymmetric catalysis. However, fine-tuning the pore environment to enhance both the activity and stereoselectivity of chiral COFs in such applications remains a formidable challenge. In this study, we have successfully designed and synthesized a series of clover-shaped, hydrazone-linked chiral COFs, each with a varying number of accessible chiral pyrrolidine catalytic sites. Remarkably, the catalytic efficiencies of these COFs in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde correlate well with the number of accessible pyrrolidine sites within the frameworks. The COF featuring nearly one pyrrolidine moiety at each nodal point demonstrated excellent reaction yields and enantiomeric excess (ee) values, reaching up to 97 and 83%, respectively. The findings not only underscore the profound impact of a deliberately controlled chiral pore environment on the catalytic efficiencies of COFs but also offer a new perspective for the design and synthesis of advanced chiral COFs for efficient asymmetric catalysis.

Tuning the Topology of Two-Dimensional Covalent Organic Frameworks through Site-Selective Synthetic Strategy.

Tuning the topology of two-dimensional (2D) covalent organic frameworks (COFs) is of paramount scientific interest but remains largely unexplored. Herein, we present a site-selective synthetic strategy that enables the tuning of 2D COF topology by simply adjusting the molar ratio of an amine-functionalized dihydrazide monomer (NH2 -Ah) and 4,4',4''-(1,3,5-triazine-2,4,6-triyl)tribenzaldehyde (Tz). This approach resulted in the formation of two distinct COFs: a clover-like 2D COF with free amine groups (NH2 -Ah-Tz) and a honeycomb-like COF without amine groups (Ah-Tz). Both COFs exhibited good crystallinity and moderate porosity. Remarkably, the clover-shaped NH2 -Ah-Tz COF, with abundant free amine groups, displayed significantly enhanced adsorption capacities toward crystal violet (CV, 261 mg/g) and congo red (CR, 1560 mg/g) compared to the non-functionalized honeycomb-like Ah-Tz COF (123 mg/g for CV and 1340 mg/g for CR), underscoring the pivotal role of free amine functional groups in enhancing adsorption capacities for organic dyes. This work highlights that the site-selective synthetic strategy paves a new avenue for manipulating 2D COF topology by adjusting the monomer feeding ratio, thereby modulating their adsorption performances toward organic dyes.

African American race does not confer an increased risk of clinical events in patients with primary sclerosing cholangitis.

BACKGROUND: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. METHODS: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. RESULTS: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models. CONCLUSIONS: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.

Transjugular intrahepatic portosystemic shunt for portal hypertension with chronic portal vein occlusion.

PURPOSE: This study aims to evaluate the long-term patency of transjugular intrahepatic portosystemic shunt (TIPS) and determine the predictors of shunt dysfunction in patients with chronic portal vein occlusion (CPVO). METHOD: This retrospective study was conducted from December 2010 to December 2020 in patients with portal hypertension and CPVO. Patients were followed up from initial TIPS insertion to December 2022 or death. Details of TIPS procedure, adverse events and clinical outcomes were recorded. The cumulative rate of shunt patency was calculated by the Kaplan-Meier method and compared by using the log-rank test. Independent predictors of shunt dysfunction were calculated with the Cox regression model. A nomogram comprising independent variables was developed to enhance the predictive accuracy of shunt patency. RESULTS: One hundred six patients (mean age, 45.3 years ± 13.6; 71 males and 35 females) were enrolled in the study. TIPS procedure was technically successful in 100 of 106 patients (94.3 %). The primary shunt patency rates for all 100 patients were 78.9 %, 74.7 %, 67.2 %, and 62.4 % at 6, 12, 24, and 36 months, respectively, and the overall shunt patency rates were 88.9 %, 86.8 %, 83.6 %, and 81.2 % at 6, 12, 24, and 36 months, respectively. Independent predictor of shunt dysfunction were inadequate inflow from superior mesenteric vein or splenic vein (the maximum diameter < 8 mm) and platelet count ≥ 300 × 109/L. The developed nomogram is a simple tool for accurately predicting shunt patency. CONCLUSIONS: In patients with CPVO, inadequate inflow and high platelet count are important factors for TIPS dysfunction.

Purification of fibrinolytic enzyme from Bacillus amyloliquefaciens GUTU06 and properties of the enzyme.

A producing-fibrinolytic enzyme strain was isolated with high yield. The strain was identified as Bacillus amyloliquefaciens. B. amyloliquefaciens GUTU06 fibrinolytic enzyme was purified by acetone precipitation and reverse micelle. Acetone precipitation condition and reverse micelle condition were examined. Results showed that the total reverse micelle extraction efficiency was 64.49 % ± 1.6 %. The purification fold of the entire process reached 13.38. The optimum pH of purified enzyme is 5, and the optimum temperature is 45 °C. Fe3+ and K+ can enhance the fibrinolytic activity of the enzyme. Compared to commercial fibrinolytic enzymes such as urokinase and lumbrukinase, GUTU06 fibrinolytic enzymes have a lower pH optimal range and higher temperature stability. The molecular weight of the enzyme was approximately 28 kDa. Reverse micelle extraction with cetyl trimethylammonium bromide as a surfactant combined with acetone precipitation is suitable for separating and purifying fibrinolytic enzymes and a promising technique for obtaining active proteins.

Microglia facilitate and stabilize the response to general anesthesia via modulating the neuronal network in a brain region-specific manner.

General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.

The gut-lung axis in influenza A: the role of gut microbiota in immune balance.

Influenza A, the most common subtype, induces 3 to 5 million severe infections and 250,000 to 500,000 deaths each year. Vaccination is traditionally considered to be the best way to prevent influenza A. Yet because the Influenza A virus (IAV) is highly susceptible to antigenic drift and Antigenic shift, and because of the lag in vaccine production, this poses a significant challenge to vaccine effectiveness. Additionally, much information about the resistance of antiviral drugs, such as Oseltamivir and Baloxavir, has been reported. Therefore, the search for alternative therapies in the treatment of influenza is warranted. Recent studies have found that regulating the gut microbiota (GM) can promote the immune effects of anti-IAV via the gut-lung axis. This includes promoting IAV clearance in the early stages of infection and reducing inflammatory damage in the later stages. In this review, we first review the specific alterations in GM observed in human as well as animal models regarding IAV infection. Then we analyzed the effect of GM on host immunity against IAV, including innate immunity and subsequent adaptive immunity. Finally, our study also summarizes the effects of therapies using probiotics, prebiotics, or herbal medicine in influenza A on intestinal microecological composition and their immunomodulatory effects against IAV.