Current Medicinal Chemistry - Online First

Ciprofol is a novel sedative-anesthetic that functions similarly to propofol. This study aimed to evaluate the efficacy and safety of ciprofol for the induction and maintenance of general anesthesia in patients undergoing thoracoscopic surgery.

A total of 120 patients undergoing thoracoscopic surgery for pulmonary nodules under general anesthesia were randomly assigned to the ciprofol group or the propofol group. Patients in the ciprofol group received an initial dose of 0.4 mg.kg^-1 of ciprofol for anesthesia induction, followed by an infusion rate ranging from 0.4 mg.kg^-1.h^-1 to 2.4 mg.kg^-1.h^-1 for maintenance. In the propofol group, patients were administered an initial dose of 2.0 mg.kg^-1 of propofol for induction, with a maintenance infusion rate ranging from 4.0 mg.kg^-1.h^-1 to 12 mg.kg^-1h^-1. The primary outcome measured was the success rate of sedation. Secondary outcomes included the time to successful induction of anesthesia, changes in hemodynamics and bispectral index (BIS) within 10 minutes after the initial administration of the study medication, time to respiratory recovery and full alertness, and the incidence of adverse events.

The sedation success rate was 100% in both groups. In this study, statistical analyses revealed no significant differences in the time to eyelash reflex disappearance (p=0.599), induction success time (p=0.431), the moment when the BIS value first fell below 60 (p=0.538), the time to respiratory recovery (p=0.505), or the interval until full wakefulness (p=0.837). Notably, within the first 10 minutes following the initial administration of the study medication, the reduction in blood pressure was significantly more pronounced in the propofol group (p<0.05). Additionally, the mean BIS value was significantly higher in the propofol group (p<0.01). The required dosage of sedative medication was significantly lower in the ciprofol group (p<0.001). Compared to the propofol group, the ciprofol group exhibited a significant reduction in the incidence of adverse events during intubation (p=0.01), a marked decrease in injection pain (p=0.001), and a significant decrease in the incidence of intraoperative hypotension (p<0.05).

Ciprofol exhibits comparable efficacy and safety profiles for both the induction and maintenance of general anesthesia in patients undergoing thoracoscopic surgery. Furthermore, it has been associated with a reduced dosage requirement, significantly lower mean BIS values, and a notable decrease in the incidence of injection pain and intraoperative hypotension.

(ChiCTR2400086976).

The pathogenesis of Delayed Encephalopathy After Acute Carbon Monoxide Poisoning (DEACMP) remains mysterious, and specific predictive markers are lacking. This study aimed to elucidate the molecular underpinnings and identify predictive biomarkers of DEACMP through multi-omics and single-nucleusRNA sequencing (snRNA-seq).

Clinical data and blood samples were collected from 105 participants. Untargeted metabolomics sequencing was employed to profile serum metabolites across these participants. Additionally, individuals from the Healthy Controls (HCs), Acute Carbon Monoxide Poisoning patients (ACOP), Non-Delayed Encephalopathy After ACOP (DEACMP-N), and DEACMP groups (n=3 each) were randomly selected for transcriptome sequencing to identify potential predictive targets and pivotal signaling pathways associated with DEACMP. Furthermore, Severe DEACMP and Control rat models were established. Three rats from the Control, DEACMP, and DEACMP + Dexamethasone + Selenomethionine groups were selected for snRNA-seq. Immunofluorescence multiplexing and qRT-PCR (quantitative Reverse Transcription Polymerase Chain Reaction) were then performed to validate the identified predictive targets.

Analysis of clinical data from 105 participants highlights the pivotal role of inflammation in influencing the prognosis of carbon monoxide poisoning. Metabolomics analysis identified 19 metabolites that significantly differed between the DEACMP-N and DEACMP groups. Transcriptomics analysis of 12 participants indicated that DEACMP is primarily associated with six signaling pathways, including lysosome and tuberculosis. Considering that microglia are central nervous system immune effectors, the snRNA-seq analysis revealed altered gene expression and signaling pathways in microglia during DEACMP, with KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis highlighting neutrophil extracellular trap formation, lysosome, and tuberculosis as the predominant pathways. Differential gene analysis from transcriptome and snRNA-seq identified 28 genes differentially expressed in DEACMP. The STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database, immune multiplexing, and qRT-PCR confirmed the pivotal role of the Ifngr1/Stat1/Ctss axis in DEACMP.

This research identifies the Ifngr1/Stat1/Ctss axis as a key inflammatory mechanism in the pathogenesis of DEACMP, thereby clarifying previous uncertainties regarding the sequelae of carbon monoxide poisoning. The intersection of lysosomal and tuberculosis pathways, as revealed through metabolomic, transcriptomic, and single-nucleus RNA sequencing analyses—especially within microglia—offers novel mechanistic insights that could inform therapeutic interventions. While the integration of multiple omics methodologies enhances the robustness of these findings, their biological relevance to the pathogenesis of DEACMP requires rigorous validation through independent cohort verification approaches.

This study provides a comprehensive overview of serum metabolite expression, differential gene expression, and signaling pathways in DEACMP, offering a theoretical foundation for understanding the pathogenesis of DEACMP.

Human oncostatin M (OSM) is a pleiotropic cytokine that regulates inflammatory and immune responses by binding to the heterodimer receptor complex OSM receptor beta (OSMRβ) and glycoprotein 130 (gp130). The distinct signaling pathways triggered by OSM are involved in multiple chronic inflammatory conditions, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and cancers, making the OSM-bound receptor complex a significant therapeutic target. Currently, no 3D structure of human OSM recognition complex is available, and thus, the molecular mechanisms underlying OSM signaling remain poorly understood.

In this study, for the first time, we proposed a full-length structural model of the human OSM-OSMRβ-gp130, generated using AlphaFold2 protein structure prediction and all-atom molecular dynamics (MD) simulation (~ 1.12 million atoms with explicit solvent), enabling investigation of the geometric and dynamic profiles of OSM-OSMRβ-gp130 structure at atomic-level.

Analysis of the simulation trajectory demonstrated that the structural rearrangements of the heterodimer receptors (i.e., OSMRβ and gp130) initiated by OSM binding mediated the signal transduction from the extracellular to the intracellular domains. In the representative conformation identified through clustering analysis, two main allosteric pathways contributed were found to mediate signal transduction from the allosteric region of OSM to the active sites of OSMRβ and gp130. Finally, two druggable binding sites located on OSM and gp130 were detected by dynamically monitoring pocket flexibility throughout the simulation. A comprehensive analysis of the OSM-OSMRβ-gp130 model was carried out with respect to OSM signaling.

The findings of this study not only enhance the mechanistic understanding of OSM binding to the heteromeric OSMRβ/gp130 but also identify druggable binding sites for structure-based design of small molecules to inhibit the intracellular signal transduction.

Staphylococcus aureus infections have become a significant public health issue due to increasing the resistance against known antibiotics, especially by Methicillin-Resistant Staphylococcus aureus (MRSA). Fluoroquinolones are broad-spectrum class of antibiotics mostly utilized in treating various bacterial infections and those caused by S. aureus. Reported data indicated that mutations of Ser84 to Leu, Ser85 to Pro and Glu88 to Lys in DNA gyrase A enzyme are the major cause of fluoroquinolone resistance against S. aureus. Therefore, the development of a novel targeted molecule with potential activity against mutant S. aureus is essential. The antibacterial activity of quinoline-clubbed hydrazone derivatives against S. aureus is noteworthy. However, the mechanism of action of quinoline hydrazone derivatives has not been reported by inhibiting these common mutations of DNA gyrase A.

In this concern, some quinoline hydrazone derivatives as antibacterial agents reported by several research groups have been further studied as mutated S. aureus DNA gyrase A (Pdb id: 8bp2) inhibitors using in-silico techniques viz., molecular docking, MD simulation, DFT analysis, and ADMET predictions.

Among the studied compounds, 42, 43, 48 and 49 were found to be the most active and showed the highest docking score (-7.71 to -9.29 kcalmol^-1) by interaction with mutant (Leu84 and Pro85) S. aureus DNA gyrase A. Further, MD simulation results indicated that these compounds exhibited good stability with the targeted macromolecule under dynamic conditions. The most active compound 49 (ʌE = 0.159 eV) attributed to its lower HOMO-LUMO gap, which was an indicator of a potential inhibitor of fluoroquinolone- resistant S. aureus DNA gyrase A enzyme. ADMET prediction study emphasized that both compounds showed a significant safety profile.

The future perspective emphasized that compounds 42, 43, 48 and 49 could be developed as novel inhibitors against fluoroquinolone-resistant DNA gyrase A enzyme on the completion of drug discovery approaches.

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with a poor prognosis. Ubiquitination is a complex post translational modification involved in cancer progression. However, ubiquitination related genes (URGs) in immunotherapy of NPC remains largely unexplored.

Differentially expressed URGs were screened based on the single-cell RNA sequencing (scRNA-seq) dataset and a risk model of NPC was constructed and evaluated for prognostic significance. The oncogenic role of RNF149 in NPC was investigated through in vitro and in vivo experiments, including tumor cells, NPC-like organoids, and tumor-bearing mice.

scRNA-seq data showed that URGs scores were higher in cancer cells than in normal epithelial cells. We identified 216 differentially expressed URGs between cancer and normal epithelial cells, but only 33 differentially expressed URGs associated with prognosis. Based on 33 URGs, TCGA-HNSC samples were classified into two distinct subtypes with significant differences in the tumor immune microenvironment, immunotherapy effect, and survival-prognostic genes. Using LASSO algorithm, 13 URGs were selected to construct a risk model, which demonstrated high predictive performance. The expression profiles of these 13 URGs were analyzed in TCGA-HNSC tumor and adjacent non-cancerous samples, and six URGs (BSPRY, OTUB1, PJA1, RNF149, RNF181, USP10) exhibited consistent expression trends. Moreover, quantitative real- time PCR revealed that RNF149 was up-regulated expression in NPC cells compared to the NP69 cells. RNF149 knockdown significantly impeded the proliferative, migratory, and invasive capabilities and exaggerated apoptosis of NPC cells. RNF149 knockdown cells exhibited a reduced capacity to form NPC organoids in a 3D culture system. shRNA-RNF149 diminished subcutaneous tumorigenic capacity of HK-1 cells compared to the control group.

The URGs-based prognostic risk model offers a robust tool for predicting immunotherapy efficacy in NPC and RNF149 promotes NPC progression.

A URGs-related prognostic risk model capable of predicting clinical outcomes in NPC patients and RNF149 promotes NPC progression. Our findings are expected to provide new strategies to improve outcomes for NPC patients.

Ultra-rare diseases (URDs) are defined based on point prevalence and are classified as conditions affecting fewer than 1 in 50,000 individuals, and they are more likely to exist among communities with higher consanguinity rates requiring evidence-based data.

In this multi-center study, we used next-generation sequencing to identify 30 pediatric patients with URDs. Along with the demographic information about their parents, clinical, laboratory, and radiological data was also obtained. Multinomial regression was carried out to assess statistical differences and determine associations using the Quality of Life of Childhood Epilepsy (QOLCE)-55 scale.

There were 19 male (63.33%) and 11 (36.67%) female patients. Their current age range was 2-15 years (mean=8.83 years). The majority were diagnosed with sodium channelopathy (64.51%). The average Quality of Life (QoL) score of all participants was 51.43 ± 9.01 (reference range 0-100) with quartiles Q1=40, Q2=43.5, and Q3=56.

We propose that URDs complicated by epilepsy can significantly impair the QoL of patients and their families.

The cyclin-dependent kinases (CDKs) play a crucial role in the normal progression of these stages. In tumor cells, CDKs are often highly expressed, leading to uncontrolled cell proliferation. Inhibiting the activity of CDKs in tumor cells can inhibit their growth and proliferation, thereby achieving anti-tumor effects. In recent years, many CDKs inhibitors have been developed, but due to side effects and drug resistance issues, only a few CDKs inhibitors have been approved by the FDA.

Publications on CDK-based dual-target inhibitors were reviewed using SciFinder and PubMed, excluding reviews, patents, and studies with irrelevant content.

The study outlines advancements in CDK-based dual-target inhibitors as antitumor agents, offering insights to support the development and application of more effective cancer therapies.

Dual-targeted anti-tumor drugs may have better therapeutic effects than single-targeted drugs, which may address drug resistance issues and overcome drug interactions and pharmacokinetic issues associated with combination therapy. As an important direction in cancer treatment, dual target inhibitors have broad development prospects. By continuing to explore and improve dual target therapies, it has potential to overcome many limitations of single target therapy and provide more effective and lasting treatment outcomes for cancer patients.

Glioblastoma is the most common and aggressive brain tumor, with low survival rates and high recurrence rates. Therefore, it is crucial to understand the precise molecular mechanisms involved in the oncogenesis of glioblastoma.

To investigate the regulatory mechanisms of long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (miRNA) network related to glioblastoma, in the present study, a comprehensive analysis of the genomic landscape between glioblastoma and normal brain tissues from the Gene Expression Omnibus (GEO) dataset was first conducted to identify differentially expressed genes (DEGs) in glioblastoma. Following a series of analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, protein-protein interaction (PPI), and key model analyses. In addition, we used the L1000CDS2 database bioinformatic tool to identify candidates for therapy based on glioblastoma specific genetic profile.

In our results, 100 key genes, 50 upregulated and 50 downregulated, were ultimately identified. The results of KEGG pathway enrichment gene analysis showed that the five regulatory pathways. Furthermore, 3 small molecule signatures (trichostatin A, TG-101348, and vorinostat) were recommended as the top-ranked candidate therapeutic agents. Nevertheless, the constructed miRNA-mRNA network revealed a convergence on 40 miRNAs. We found that dysregulation of lncRNAs such as KCNQ1OT1 and RP11-13N13.5 could sequester several miRNAs such as hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-106a-5p, etc., and promote the development and progression of glioblastoma.

Our study identified key genes and related lncRNA-miRNA-mRNA network that contribute to the oncogenesis of glioblastoma.

Hepatocellular carcinoma (HCC) has a poor prognosis due to late diagnosis and rapid progression, highlighting the need for a deeper understanding of its pathogenesis. Lysine crotonylation (Kcr), a unique post-translational modification, plays a crucial role in epigenetic regulation. However, the role of crotonylation-related genes (CRGs) in HCC remains poorly understood, necessitating an investigation of their prognostic and therapeutic relevance.

Transcriptomic and clinical data were obtained from TCGA and GEO databases. A CRG-based risk score was developed using Cox and LASSO regression analyses. To enhance survival prediction, a nomogram incorporating the risk score was constructed. Immune cell infiltration and drug sensitivity were assessed using CIBERSORT and 'OncoPredict.' Single-cell sequencing was employed to examine CRG expression within the HCC tumor microenvironment.

An 8-gene risk score model (HDAC2, ACADS, HDAC1, ENO1, PPARG, ACADL, ACSL6, and AGPAT5) was established, effectively stratifying patients into high- and low-risk groups in the training set. Cox regression and Kaplan-Meier analyses validated its prognostic value in the test set. The nomogram demonstrated enhanced prognostic accuracy for survival prediction. Differences in immune cell infiltration and immune checkpoint expression between risk groups highlighted the association between CRGs and the tumor immune microenvironment. Single-cell sequencing revealed that CRGs were highly expressed in key immune cells within the HCC microenvironment. Additionally, drug sensitivity analysis suggested that specific targeted therapies may be more effective in HCC patients.

Crotonylation-related gene signature demonstrates strong prognostic value in hepatocellular carcinoma (HCC), effectively stratifying patients into high- and low-risk groups and recapitulating known oncogenic roles of HDAC1/2, ENO1, PPARG, AGPAT5 and the protective functions of ACADS, ACADL, and ACSL6. It was found that crotonylation not only influences tumor cell metabolism and epigenetic regulation but also shapes the immune microenvironment, highlighted by distinct checkpoint expression, differential immune cell infiltration, and drug sensitivity profiles, which position our model as a promising tool for personalized therapeutic decision-making. However, clinical translation will require standardized, reproducible assays for crotonylation measurement and rigorous validation across diverse HCC etiologies (e.g., viral vs. non-viral), along with mechanistic and longitudinal studies to dissect causality versus correlation, assess off- target effects of crotonylation modulators, and confirm functional impacts on immune modulation before routine diagnostic or therapeutic use.

This study identifies a prognostic CRG signature for HCC and provides novel insights into personalized treatment strategies.