ABSTRACT
Tetrandrine (TET) is a natural bis-benzylisoquinoline alkaloid isolated from Stephania species with a wide range of biological and pharmacologic activities; it mainly serves as an anti-inflammatory agent or antitumor adjuvant in clinical applications. However, limitations such as prominent hydrophobicity, severe off-target toxicity, and low absorption result in suboptimal therapeutic outcomes preventing its widespread adoption. Nanoparticles have proven to be efficient devices for targeted drug delivery since drug-carrying nanoparticles can be passively transported to the tumor site by the enhanced permeability and retention (EPR) effects, thus securing a niche in cancer therapies. Great progress has been made in nanocarrier construction for TET delivery due to their outstanding advantages such as increased water-solubility, improved biodistribution and blood circulation, reduced off-target irritation, and combinational therapy. Herein, we systematically reviewed the latest advancements in TET-loaded nanoparticles and their respective features with the expectation of providing perspective and guidelines for future research and potential applications of TET.
ABSTRACT
PURPOSE: We developed a novel guider-assisted osteotomy (GAO) procedure to improve the safety of open wedge high tibial osteotomy (OWHTO) and aimed to compare its efficacy and complications with the conventional pendulum-saw osteotomy (PSO). METHODS: This is a retrospective cohort study of patients undergoing either GAO or PSO procedure in the OWHTO to treat varus knee osteoarthritis, who had a minimum of 2 years of follow-up. Patients were propensity score matched (PSM) in a 1:1 ratio based on demographic and clinical data with a caliper width of 0.02. The outcomes assessed involved the hospital for special surgery (HSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and the Intraoperative and postoperative complications. RESULTS: 199 patients were included in each group after PSM. The mean duration of follow-up was 38.3 ± 8.9 months. The GAO group had a shorter operation duration (104.5 ± 35.7 vs. 112.1 ± 36.0 min, p = 0.027) and fewer times of intraoperative fluoroscopy (4.2 ± 1.4 vs. 6.0 ± 1.4, p < 0.001). At the last follow-up, clinical scores for knee achieved significant improvements in both GAO and PSO groups: HSS (67.5 ± 10.5 vs. 90.2 ± 7.0, p < 0.001; 69.4 ± 8.2 vs. 91.7 ± 6.8, p < 0.001) and WOMAC (65.7 ± 11.6 vs. 25.2 ± 10.4, p < 0.001; 63.3 ± 12.2 vs. 23.8 ± 9.5, p < 0.001). However, no significant difference was observed between groups for any measures (p > 0.05). In addition, the intraoperative complications (0.5% vs. 3.5%, p = 0.068) and the postoperative bone delayed union and nonunion (1.0% vs. 4.5%, p = 0.032) were marginally or significantly reduced in the GAO versus PSO group. CONCLUSION: GAO demonstrates improvements in intraoperative radiation exposure and complications, with comparable short-term efficacy to PSO, and could be considered a viable alternative in clinical practice.
Subject(s)
Osteoarthritis, Knee , Osteotomy , Propensity Score , Tibia , Humans , Osteotomy/methods , Female , Male , Middle Aged , Retrospective Studies , Osteoarthritis, Knee/surgery , Tibia/surgery , Treatment Outcome , Cohort Studies , Aged , Follow-Up Studies , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Operative TimeABSTRACT
Targeted delivery and precise release of toxins is a prospective strategy for the treatment of triple-negative breast cancer (TNBC), yet the flexibility to incorporate both properties simultaneously remains tremendously challenging in the X-drug conjugate fields. As critical components in conjugates, linkers could flourish in achieving optimal functionalities. Here, we pioneered a pH-hypersensitive tumor-targeting aptamer AS1411-triptolide conjugate (AS-TP) to achieve smart release of the toxin and targeted therapy against TNBC. The multifunctional acetal ester linker in the AS-TP site-specifically blocked triptolide toxicity, quantitatively sustained aptamer targeting, and ensured the circulating stability. Furthermore, the aptamer modification endowed triptolide with favorable water solubility and bioavailability and facilitated endocytosis of conjugated triptolide by TNBC cells in a nucleolin-dependent manner. The integrated superiorities of AS-TP promoted the preferential intra-tumor triptolide accumulation in xenografted TNBC mice and triggered the in-situ triptolide release in the weakly acidic tumor microenvironment, manifesting striking anti-TNBC efficacy and virtually eliminated toxic effects beyond clinical drugs. This study illustrated the therapeutic potential of AS-TP against TNBC and proposed a promising concept for the development of nucleic acid-based targeted anticancer drugs.
Subject(s)
Aptamers, Nucleotide , Diterpenes , Epoxy Compounds , Phenanthrenes , Triple Negative Breast Neoplasms , Diterpenes/pharmacology , Diterpenes/therapeutic use , Diterpenes/chemistry , Epoxy Compounds/pharmacology , Epoxy Compounds/therapeutic use , Epoxy Compounds/chemistry , Phenanthrenes/pharmacology , Phenanthrenes/therapeutic use , Phenanthrenes/chemistry , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Animals , Humans , Mice , Female , Aptamers, Nucleotide/pharmacology , Aptamers, Nucleotide/therapeutic use , Xenograft Model Antitumor Assays , Cell Line, Tumor , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic useABSTRACT
BACKGROUND: The association of low-density lipoprotein cholesterol (LDL-C) and lymphocyte counts with the development of deep vein thrombosis (DVT) has been demonstrated in many fields but remains lacking in open wedge high tibial osteotomy (OWHTO). This study aimed to assess the predictive value of LDL-C to lymphocyte count ratio (LLR) in screening for postoperative new-onset DVT. METHODS: Clinical data were retrospectively collected from patients who underwent OWHTO between June 2018 and May 2023. The limited restricted cubic spline (RCS) was conducted to evaluate the nonlinear relationship between LLR and the risk of postoperative new-onset DVT. The receiver operating characteristic (ROC) curves were plotted and the predictive value of biomarkers was assessed. After adjusting for intergroup confounders by propensity score matching, the univariate logistic regression was applied to assess the association between LLR and DVT. RESULTS: 1293 eligible patients were included. RCS analysis showed a linear positive correlation between LLR and the risk of DVT (P for overall = 0.008). We identified LLR had an area under the curve of 0.607, accuracy of 74.3%, sensitivity of 38.5%, and specificity of 80.7%, and LLR > 1.75 was independently associated with a 1.45-fold risk of DVT (95% CI: 1.01-2.08, P = 0.045). Furthermore, significant heterogeneities were observed in the subgroups of age, BMI, diabetes mellitus, hypertension, Kellgren-Lawrence grade, the American Society of Anesthesiologists (ASA) score, and intraoperative osteotomy correction size. CONCLUSION: LLR is a valuable biomarker for predicting postoperative new-onset DVT in patients with OWHTO, and routine screening is expected to yield positive benefits.
ABSTRACT
Aberrant FGF2/FGFR signaling is implicated in lung squamous cell carcinoma (LSCC), posing treatment challenges due to the lack of targeted therapeutic options. Designing drugs that block FGF2 signaling presents a promising strategy different from traditional kinase inhibitors. We previously reported a ColVα1-derived fragment, HEPV (127AA), that inhibits FGF2-induced angiogenesis. However, its large size may limit therapeutic application. This study combines rational peptide design, molecular dynamics simulations, knowledge-based prediction, and GUV and FRET assays to identify smaller peptides with FGF2-blocking properties. We synthesized two novel peptides, HBS-P1 (45AA) and HBS-P2 (66AA), that retained the heparin-binding site. Both peptides demonstrated anti-LSCC and antiangiogenesis properties in cell viability and microvessel network induction assays. In two LSCC subcutaneous models, HBS-P1, with its affinity for FGF2 and enhanced penetration ability, demonstrated substantial therapeutic potential without apparent toxicities. Our study provides the first evidence supporting the development of collagen V-derived natural peptides as FGF2-blocking agents for LSCC treatment.
Subject(s)
Carcinoma, Squamous Cell , Drug Design , Fibroblast Growth Factor 2 , Lung Neoplasms , Peptides , Fibroblast Growth Factor 2/antagonists & inhibitors , Fibroblast Growth Factor 2/metabolism , Fibroblast Growth Factor 2/chemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Humans , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Animals , Peptides/pharmacology , Peptides/chemistry , Peptides/chemical synthesis , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Molecular Dynamics Simulation , Mice, NudeABSTRACT
Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients' peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words).
Subject(s)
Echinococcosis , Echinococcus multilocularis , Immune Checkpoint Inhibitors , Myeloid-Derived Suppressor Cells , Programmed Cell Death 1 Receptor , T-Lymphocytes , Animals , Myeloid-Derived Suppressor Cells/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Echinococcosis/immunology , Mice , Humans , T-Lymphocytes/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Female , Echinococcus multilocularis/immunology , Mice, Inbred C57BL , Male , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , B7-H1 Antigen/immunology , Disease Models, Animal , Immunotherapy/methods , Middle Aged , AdultABSTRACT
Asymmetric catalytic processes promoted by N-heterocyclic carbenes (NHCs) hold great potential for the sustainable preparation of chiral molecules. However, catalyzing the reactions by manipulating the reactive intermediates is challenging. We report herein that the known NHC-catalyzed [3 + 2] annulation reaction between ketimine and enal can also be turned into a [2 + 3] annulation reaction for the highly enantioselective direct synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactams (4) through timely catalysis of the intermediates. DFT calculations revealed that this transformation included the key step of the nucleophilic attack of the Breslow intermediate M2 derived from NHC and enal (2) to the unattacked ketimine (1). Our study demonstrates that it is possible to tune the desired selectivities through the dynamic catalysts of the reactive intermediates.
ABSTRACT
Alveolar, the smallest structural and functional units within the respiratory system, play a crucial role in maintaining lung function. Alveolar damage is a typical pathological hallmark of respiratory diseases. Nevertheless, there is currently no simple, rapid, economical, and unbiased method for quantifying alveolar size for entire lung tissue. Here, firstly, we conducted lung sample slicing based on the size, shape, and distribution of airway branches of different lobes. Next, we performed HE staining on different slices. Then, we provided an unbiased quantification of alveolar size using free software ImageJ. Through this protocol, we demonstrated that C57Bl/6 mice exhibit varying alveolar sizes among different lobes. Collectively, we provided a simple and unbiased method for a more comprehensive quantification of alveolar size in mice, which holds promise for a broader range of respiratory research using mouse models.
Subject(s)
Eosine Yellowish-(YS) , Hematoxylin , Lung , Mice, Inbred C57BL , Pulmonary Alveoli , Staining and Labeling , Animals , Mice , Pulmonary Alveoli/pathology , Staining and Labeling/methods , Lung/pathology , MaleABSTRACT
BACKGROUND: Ultrasound-guided thermal ablation (TA) has emerged as a robust therapeutic approach for treating solid tumors in multiple organs, including the thyroid. Yet, its efficacy and safety profile in the management of Graves' Disease (GD) remains to be definitively established. METHODS: A retrospective study was conducted on 50 GD patients treated with TA between October 2017 and December 2021. Key metrics like thyroid volume, volume reduction rate (VRR), thyroid hormones, and basal metabolic rate (BMR) were evaluated using paired Wilcoxon tests. RESULTS: The intervention of ultrasound-guided TA yielded a statistically significant diminution in total thyroid volume across all postoperative follow-up intervals-1, 3, 6, and 12 months-relative to pre-intervention baselines (p < 0.001). The median VRR observed at these time points were 17.5%, 26.5%, 34.4%, and 39.8%, respectively. Euthyroid status was corroborated in 96% of patients at the one-year follow-up milestone. Transient tachycardia and dysphonia were observed in three patients, while a solitary case of skin numbness was noted. Crucially, no instances of enduring injury to the recurrent laryngeal nerve (RLN) were documented. CONCLUSIONS: Our investigation substantiates ultrasound-guided TA as a pragmatic, well-tolerated, and safe therapeutic modality for GD. It effectively improves symptoms of hyperthyroidism, engenders a substantial reduction in thyroid volume, and restores thyroid hormone and BMR to physiological levels. Given its favorable safety profile, enhanced cosmetic outcomes, and minimally invasive nature, ultrasound-guided TA is a compelling alternative to thyroidectomy for GD patients.
ABSTRACT
For di-nitroaromatics hydrogenation, it is a challenge to achieve the multi-step hydrogenation with high activity and selectivity due to the complexity of the process involving two nitro groups. Consequently, many precious metal catalysts suffer from low activity for this multi-step hydrogenation reaction. Herein, we employ a fully exposed Pt clusters catalyst consisting of an average of four Pt atoms on nanodiamond@graphene (Ptn/ND@G), demonstrating excellent catalytic performance for the multi-step hydrogenation of 2,4-dinitrotoluene. The TOF (40647 h-1) of Ptn/ND@G is significantly superior to that of single Pt atoms catalyst, Pt nanoparticles catalyst, and even all the known catalysts. Density functional theory calculations and absorption experiments reveal that the synergetic interaction between the multiple active sites of Ptn/ND@G facilitate the co-adsorption/activation of reactants and H2, as well as the desorption of intermediates/products, which is the key for the higher catalytic activity than single Pt atoms catalyst and Pt nanoparticles catalyst.
ABSTRACT
Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R.
Subject(s)
Alkaloids , Apoptosis , Drug Design , Matrines , Myocardial Reperfusion Injury , Quinolizines , Rats, Sprague-Dawley , Alkaloids/pharmacology , Alkaloids/chemistry , Alkaloids/chemical synthesis , Animals , Quinolizines/pharmacology , Quinolizines/chemical synthesis , Quinolizines/chemistry , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/pathology , Rats , Apoptosis/drug effects , Male , Structure-Activity Relationship , Molecular Structure , Cardiotonic Agents/pharmacology , Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/chemistry , Dose-Response Relationship, Drug , Cell Line , Neovascularization, Physiologic/drug effects , AngiogenesisABSTRACT
BACKGROUND: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. METHODS: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. RESULTS: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. CONCLUSION: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.
Subject(s)
G-Quadruplexes , Mitochondria , G-Quadruplexes/drug effects , Humans , Mitochondria/metabolism , Mitochondria/drug effects , Cell Line, Tumor , Genome, Mitochondrial , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Platinum/pharmacology , AnimalsABSTRACT
The single-unit monomer insertion (SUMI), derived from living/controlled polymerization, can be directly functionalized at the end or within the chain of polymers prepared by living/controlled polymerization, offering potential applications in the preparation of polymers with complex architectures. Many scenarios demand the simultaneous incorporation of monomers suitable for different polymerization methods into complex polymers. Therefore, it becomes imperative to utilize SUMI technologies with diverse mechanisms, especially those that are compatible with each other. Here, we reported the orthogonal SUMI technique, seamlessly combining radical and cationic SUMI approaches. Through the careful optimization of monomer and chain transfer agent pairs and adjustments to reaction conditions, we can efficiently execute both radical and cationic SUMI processes in one pot without mutual interference. The utilization of orthogonal SUMI pairs facilitates the integration of radical and cationic reversible addition-fragmentation chain transfer (RAFT) polymerization in various configurations. This flexibility enables the synthesis of diblock, triblock, and star polymers that incorporate both cationically and radically polymerizable monomers. Moreover, we have successfully implemented a mixing mechanism of free radicals and cations in RAFT step-growth polymerization, resulting in the creation of a side-chain sequence-controlled polymer brushes.
ABSTRACT
This study examines why and when proactive employees share knowledge. By integrating the Motivation-Opportunity-Ability Framework and Trait Activation Theory, and incorporating Mindsponge Theory, our multi-level model proposed that job autonomy moderates the impact of proactive personality on knowledge sharing (KS) within and between teams. Transformational leadership exhibits a cross-level effect on job autonomy. Utilizing a two-source, three-time-point research design, we collected data from 63 team leaders and 241 team members across six Chinese companies. Multilevel regression analysis revealed that within teams, increased job autonomy coupled with a proactive personality significantly enhanced KS. Between teams, job autonomy had a positive moderating effect. When job autonomy was low, more proactive teams exhibited less KS, whereas this negative effect was mitigated when job autonomy was high. The cross-level effect of transformational leadership on job autonomy was demonstrated. The theoretical and practical implications of these findings are discussed.
Subject(s)
Leadership , Humans , Male , Female , Adult , Personality/physiology , Motivation , Employment , Information Dissemination , China , Middle AgedABSTRACT
Celastrol is a quinone methyl triterpenoid monomeric ingredient extracted from the root of Tripterygium wilfordii. Celastrol shows potential pharmacological activities in various diseases, which include inflammatory, obesity, cancer, and bacterial diseases. However, the application prospect of celastrol is largely limited by its low bioavailability, poor water solubility, and undesired off-target cytotoxicity. To address these problems, a number of drug delivery methods and technologies have been reported to enhance the efficiency and reduce the toxicity of celastrol. We classified the current drug delivery technologies into two parts. The direct chemical modification includes nucleic acid aptamer-celastrol conjugate, nucleic acid aptamer-dendrimer-celastrol conjugate, and glucolipid-celastrol conjugate. The indirect modification includes dendrimers, polymers, albumins, and vesicular carriers. The current technologies can covalently bond or encapsulate celastrol, which improves its selectivity. Here, we present a review that focalizes the recent advances of drug delivery strategies in enhancing the efficiency and reducing the toxicity of celastrol.
ABSTRACT
BACKGROUND: Photosynthesis is a fundamental process that underlies the formation of crop yield, wherein light serves as the driving force and carbon dioxide (CO2) as the raw material. These two factors have a direct influence on the progress and efficiency of photosynthesis in crops. Rapeseed is one of the four major oilseed crops worldwide. Plateau rapeseed has now become a research hotspot. However, the lack of high-yielding rapeseed germplasm resources on the plateau and the highly efficient strategy for screening them severely affect the development of rapeseed industry in plateau. RESULTS: In the rapeseed experimental fields located on the plateau (Lhasa, Tibet), we measured abundant sunlight, characterized by an average daily photosynthetically active radiation (PAR) of 1413 µmol m-2 s-1. In addition, the atmospheric CO2 concentrations range from 300 to 400 ppm, which is only two-thirds of that in the plain (Chengdu, Sichuan). We found that under different measurement conditions of light intensity and CO2 concentration, different rapeseed genotypes showed significant differences in leaf photosynthetic efficiency during the seedling stage. Moreover, the rapeseed materials with high photosynthetic efficiency under low CO2 concentrations rather than high light intensity, exhibited significant advantages in biomass, yield, and oil content when cultivated on the plateau, indicating that the CO2 is the key environmental factor which limited rapeseed production in plateau. Based on photosynthetic efficiency screening under low CO2 concentrations, six rapeseed varieties SC3, SC10, SC25, SC27, SC29 and SC37, shown significantly higher yields in plateau environment compared to local control variety were obtained. In addition, the adaptability of rapeseed to plateau was found to be related to the activities of key Calvin cycle enzymes and the accumulation of photosynthetic products. CONCLUSIONS: This study established a screening strategy for plateau high-yielding rapeseed materials, obtained six varieties which were suitable for plateau cultivation, explored the mechanism of rapeseed response to the plateau environment, and thus provides a feasible strategy for plateau-adapted rapeseed breeding.
ABSTRACT
The sympathetic nervous system (SNS) affects many functions of the body. SNS fibers regulate many aspects of liver function, repair, and regeneration. However, in the model of bile duct ligation (BDL) in rats, the kind of impact caused by the regulation of liver SNS on liver fibrosis and liver regeneration is unclear. The main research objective of this experiment is to examine the effect of SNS on liver fibrosis and liver regeneration. Twenty-four male Sprague-Dawley (SD) rats were assigned randomly to four groups. These groups included the sham surgery group (sham), model group (BDL), 6-hydroxydopamine group (BDL+6-OHDA), and spinal cord injury group (BDL+SCI). In the sham group, only exploratory laparotomy was performed without BDL. In the 6-OHDA group, 6-OHDA was used to remove sympathetic nerves after BDL. In the spinal cord injury group, rats underwent simultaneous BDL and spinal cord injury. After 3 weeks of feeding, four groups of rats were euthanized using high-dose anesthesia without pain. Moreover, liver tissue and blood were taken to detect liver fibrosis and regeneration indicators. After intraperitoneal injection of 6-OHDA into BDL rats, liver fibrosis indicators decreased. The administration of the injection effectively alleviated liver fibrosis and inhibited liver regeneration. However, after SCI surgery in BDL rats, liver fibrosis indicators increased. This resulted in exacerbating liver fibrosis and activating liver regeneration. The SNS plays a role in contributing to the liver injury process in the rat BDL model. Therefore, regulating the SNS may become a novel method for liver injury treatment.
Subject(s)
Liver Cirrhosis , Spinal Cord Injuries , Animals , Male , Rats , Bile Ducts/surgery , Oxidopamine/pharmacology , Rats, Sprague-Dawley , Sympathetic Nervous SystemABSTRACT
Epigenetic alterations at cis-regulatory elements (CRE) fine-tune transcriptional output. Epigenetic readers interact with CREs and can cooperate with other chromatin regulators to drive oncogene transcription. Here, we found that the YEATS domain-containing histone acetylation reader ENL (eleven-nineteen leukemia) acts as a key regulator of super-enhancers (SE), which are highly active distal CREs, across cancer types. ENL occupied the majority of SEs with substantially higher preference over typical enhancers, and the enrichment of ENL at SEs depended on its ability to bind acetylated histones. Rapid depletion of ENL by auxin-inducible degron tagging severely repressed the transcription of SE-controlled oncogenes, such as MYC, by inducing the decommissioning of their SEs, and restoring ENL protein expression largely reversed these effects. Additionally, ENL was indispensable for the rapid activation of SE-regulated immediate early genes in response to growth factor stimulation. Furthermore, ENL interacted with the histone chaperone FACT complex and was required for the deposition of FACT over CREs, which mediates nucleosome reorganization required for transcription initiation and elongation. Proper control of transcription by ENL and ENL-associated FACT was regulated by the histone reader BRD4. ENL was overexpressed in colorectal cancer and functionally contributed to colorectal cancer growth and metastasis. ENL degradation or inhibition synergized with BET inhibitors that target BRD4 in restraining colorectal cancer progression. These findings establish the essential role of epigenetic reader ENL in governing SE-driven oncogenic transcription and uncover the potential of ENL intervention to increase sensitivity to BET inhibition. SIGNIFICANCE: ENL plays a key role in decoding epigenetic marks at highly active oncogenic super-enhancers and can be targeted in combination with BET inhibition as a promising synergistic strategy for optimizing cancer treatment.
Subject(s)
Colorectal Neoplasms , Histones , Humans , Histones/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Nuclear Proteins/metabolism , Epigenesis, Genetic , Colorectal Neoplasms/genetics , Bromodomain Containing Proteins , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolismABSTRACT
The epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in tumor formation and growth by mediating cell growth and other physiological processes. Therefore, EGFR is a promising target for the treatment of cancer. In this work, we combined ligand-based and structure-based virtual screening methods to identify novel EGFR inhibitors from a library of more than 103 thousand compounds. We first obtained hundreds of compounds with similar physiochemical properties through 3D molecular shape and electrostatic similarity screening with potent inhibitors AEE788 and Afatinib as queries. Next, we identified compounds with strong binding affinities to the EGFR pocket through molecular docking, which makes good use of the structure information of the receptor. After molecular scaffold analysis, our bioassay confirmed 13 compounds with EGFR inhibitory activity and three compounds had IC50 values below 1000 nM. In addition, we collected 5371 EGFR inhibitors from online databases, and clustered them into 7 groups by K-means method using their ECFP4 fingerprints as input. Each cluster had typical molecular fragments and corresponding activity characteristics, which could guide the design of EGFR inhibitors, and we concluded that the fragments from some of the hits are indicated in the highly active scaffolds.