Current Medicinal Chemistry - Online First

Sodium Selenite (NaSe) is a molecule with various biological activities. Bone fractures and osteoporotic diseases are increasingly common health issues, prompting the search for alternative treatments. Therefore, the purpose of this study was to examine the antioxidant and osteogenic properties of NaSe.

The experiments were conducted using the hFOB1.19 osteoblast cell line. The MTT assay was used to assess the effects of NaSe on cell viability, while cytotoxicity was evaluated with Lactate Dehydrogenase (LDH) assays. Osteogenic differentiation was assessed by alizarin red staining, and Alkaline Phosphatase (ALP) activity and intracellular Reactive Oxygen Species (ROS) levels were also analyzed.

The results showed that NaSe significantly enhanced cell viability in a dose-dependent manner at low doses (0.01-1μM), with the most effective dose being 1μM (p<0.05). LDH activity remained similar to the control within the 0.01-1μM range but increased significantly at higher concentrations (5-50 μM) in both 24- and 48-hour experiments (p<0.05). NaSe reduced intracellular ROS levels significantly between 0.01-1 μM, with 1 μM being the most effective concentration (p<0.05). The highest ALP activity was observed at 0.1 μM NaSe (p < 0.05), and calcium deposition increased in a concentration-dependent manner (p<0.05). The most effective dose for enhancing mineralization was 0.1 μM (p<0.05).

This study demonstrates that NaSe has antioxidant and osteogenic effects at low doses in hFOB cells. These positive effects suggest that NaSe could be a promising candidate for in-vitro, in-vivo, and clinical trials, providing hope for new treatments for bone diseases.

Sepia Ink Polysaccharide (SIP) is a well-characterized, marine-derived glycosaminoglycan with demonstrated multifunctional properties; however, its pharmacological mechanisms remain unclear. This study aims to investigate the anti-tumor mechanism of SIP1 from Sepia esculenta ink in the treatment of triple-negative breast cancer (TNBC), with a focus on apoptosis and autophagy.

MDA-MB-231 cells exposed to cisplatin (CP) and SIP1 were assessed for apoptosis and autophagy by evaluating cell morphology, apoptosis and autophagy rates, and the expression of key genes involved in these processes using double staining, flow cytometry, and Western blotting.

The data revealed that SIP1 induced apoptosis in TNBC cells, as demonstrated by an increased apoptosis rate, an elevated expression level of the Caspase-3 protein, a decreased expression of Bcl-2, and an elevated Bax/Bcl-2 ratio. Additionally, SIP1 did not impact autophagy. CP induced both apoptosis and autophagy of breast cancer cells. The combination of SIP1 and CP exhibited synergistic effects, enhancing apoptosis by 2.33-fold compared to SIP1 alone and 1.25-fold compared to CP alone, while simultaneously reducing autophagy levels (0.84-fold compared to CP alone), as verified by the Beclin 1 protein content.

This work discovered that SIP1, a sulfated glycosaminoglycan with a low content of sulfate ester groups derived from Sepia esculenta ink, induced apoptosis by inhibiting autophagy, providing a novel perspective for a deeper understanding of the anti- tumor mechanism of SIP. Currently, the underlying molecular mechanisms by which SIP1 modulates the crosstalk between apoptosis and autophagy in TNBC cells remain unknown and require further investigation.

This study demonstrates that SIP1 is effective in inducing apoptosis and promotes cisplatin-induced apoptosis by repressing cisplatin-induced autophagy in MDA-MB-231 cells.

Neurodevelopmental disorders (NDDs) represent a diverse and heterogeneous group of conditions, including global developmental delay (GDD), autism spectrum disorder (ASD), and neurodevelopmental encephalopathy with epilepsy (NDEE). While these disorders often share phenotypic similarities, their underlying genetic causes can vary widely, making clinical diagnosis challenging.

In this study, we performed whole-genome sequencing (WGS) on a family having an autosomal recessive neurodevelopmental disorder. The proband (II-2) underwent WGS, followed by variant filtering through an in-house bioinformatics pipeline. Sanger sequencing and 3D protein modeling were performed to confirm the pathogenicity of the identified variant.

A novel biallelic missense variant in the NAV3 (c.3430T>C; p.Ser1144Pro) was detected using WGS and Sanger sequencing. Subsequently, 3D protein modeling revealed significant alterations in the secondary structure of NAV3, indicating a potential pathogenic effect.

The identification of a novel biallelic missense variant in NAV3 adds a new layer to our understanding of its potential contribution to autosomal recessive neurodevelopmental disorders. This case expands the mutational landscape of NAV3 and underscores its emerging significance in neurodevelopment.

This study reports a novel NAV3 variant in association with autosomal recessive NDD, contributing to the growing body of evidence supporting the involvement of NAV3 in human neurodevelopment. Functional validation and identification of additional patients will be essential to establish definitive genotype-phenotype correlations and uncover the mechanistic pathways underlying NAV3-associated disorders.

The objective of this study is to obtain inhibitors against mTOR targets with virtual screening, dynamic simulation and bioactivity assessment. This pursuit aims to obtain a rapid and accurate method for the discovery of new mTOR inhibitors.

Firstly, the researchers obtained nearly 9000 compounds by using ROC-guided machine learning from a library of over 200000 compounds. Secondly, virtual screening was used to evaluate the affinity of 45 compounds. Further analysis was performed to identify 6 hit compounds. Simultaneously, MTT antitumor activity evaluation and kinase inhibition assays are conducted for the active compounds to discern the most promising candidates. Furthermore, AO staining and JC-1 assays are performed for the selected compounds. Simultaneously, MTT antitumor activity evaluation and kinase inhibition assays are conducted for the active compounds to discern the most promising candidates. Furthermore, AO staining, JC-1 and hemolytic toxicity evaluation assays are performed for the selected compounds.

The kinase assay demonstrates that these 6 compounds display greater sensitivity to mTOR than to PI3K. Among them, compounds AJ-292/12941271 and AG-205/12550019 show better activity against mTOR target than PI3K, with an IC50 of 2.55 and 4.48 μM, respectively. Additionally, the anti-proliferative activity of the six hit compounds was also considered. Compound AJ-292/12941271 shows the best anticancer activity against A549 cell lines with an IC50 value of 4.3 μM. Further analysis reveals that compound AJ-292/12941271 induces apoptosis in the A549 cell line in a concentration-dependent or time-dependent manner. Hemolytic toxicity evaluation suggests that the compound AJ-292/12941271 is safe for further in vivo study.

This research proposes that the fused method of ROC-based machine learning, virtual screening, and bioactivity evaluation could be used to discover novel mTOR inhibitors quickly and precisely.

Regulatory T cells (Tregs) play an important role in the tumor microenvironment (TME). Currently, there have been no studies of Treg-related genes (TRGs) in lung adenocarcinoma (LUAD).

We integrated the Cancer Genome Atlas (TCGA) dataset with the Gene Expression Omnibus (GEO) dataset and divided the TCGA-GEO dataset patient samples into different cohorts by unsupervised clustering analysis based on the expression of TRGs in LUAD. By analyzing the TME characteristics of different cohorts, we assessed immune cell infiltration and function. In addition, we constructed Cox risk proportional regression models based on TRGs to predict patient prognosis.

The results of unsupervised cluster analysis classified the TCGA-GEO dataset as “immune desert”, “immune evasion” and “immune inflammation”. Moreover, there was a significant survival differential among the three cohorts (p-value < 0.05). Based on the expression of 61 TRGs in LUAD, we screened TFRC, CTLA4, IL1R2, NPTN NPTN and METTL7A to construct a Cox risk proportional regression model to divide the TCGA-GEO dataset into a training cohort and a test cohort. Survival was significantly worse in the high-risk group than in the low-risk group in both the training and test cohorts (p-value < 0.05). Finally, the nomogram scoring system constructed by integrating the model risk scores with clinical parameters can well predict the 1, 3 and 5 year survival of patients.

In conclusion, based on our analysis of the TRGs of LUAD patients, we can classify the patient TME into different immune statuses, which provides insights into adopting appropriate treatment regimens for different patients.

In 2022, the World Health Organisation (WHO) announced new cases of the developing Monkeypox Virus (MPXV), a zoonotic orthopoxvirus viral infection that mimics smallpox signs. Despite the ongoing infection, no proper medication is available to completely overcome this infection.

The study aims to construct a multi-epitope vaccine targeting Monkeypox Virus (MPXV) membrane glycoprotein to provoke robust immune responses.

To construct a potential immuno-dominant epitope vaccine to combat MPXV.

The target sequence, sourced from the UAE-to-India travel case, was analyzed to identify potential B-cell and T-cell epitopes (MHC-I and MHC-II). Immunodominant epitopes were selected and fused with β-defensin-I and PADRE to increase immunogenicity. The vaccine was modeled, docked with TLR3, and subjected to a 500 ns molecular dynamics simulation for stability analysis. Immune responses and bacterial expression were also evaluated.

The vaccine, comprising 230 amino acids, demonstrated antigenicity (0.6620), non-allergenicity, and broad population coverage. Selected epitopes included 3 B-cells, 4 MHC-I, and 2 MHC-II, ensuring a potent immunodominant profile. Docking with TLR3 revealed a binding affinity of -17.2 kcal/mol, while simulations confirmed their stability. Cloning (pET28a (+)) and immune response analyses showed a strong immunogenic profile, including elevated IgG1, IgM, and antigen levels, supported by a Codon Adaptation Index (CAI) of 1.0.

The proposed multi-epitope vaccine shows promise against MPXV. However, further in vivo and in vitro investigations are essential to confirm its immune efficacy.

Endoplasmic reticulum stress (ER stress) plays a crucial role in influencing the malignant behaviors of various tumors. Targeting the expression or degradation of transcription factors (TFs) offers a promising avenue for cancer treatment. However, a detailed understanding of how ER stress affects TF function and their interactions remains limited. This study aims to develop a prognostic model and identify TFs associated with ER stress in pancreatic ductal adenocarcinoma (PDAC).

We obtained gene expression profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA). To develop a prognostic signature, we performed several analyses, including unsupervised clustering, enrichment analysis, immune infiltration assessment, as well as univariate, LASSO, and multivariate Cox regression analyses. Four transcription factors—STAT1, IRF6, NRF1, and RXRA—were incorporated into a risk model, which was subsequently validated using the GSE dataset. Additionally, we examined IRF6 through quantitative PCR, western blotting, flow cytometry, and immunohistochemistry in vitro using pancreatic cancer cell lines and a tissue microarray.

The high-risk group identified by the model exhibited significant associations with immune cell infiltration and poorer survival outcomes, though there was no significant correlation with tumor purity (p = 0.19). Furthermore, IRF6 downregulation in vitro was found to inhibit pancreatic cancer cell proliferation and promote apoptosis. IRF6 depletion also increased the expression of key molecules involved in ER stress at both the transcriptional and translational levels. Immunohistochemical analysis revealed marked differences in IRF6 expression between tumor and adjacent non-tumor tissues (59.29±29.88 vs. 95.22±40.80, p<0.001).

This study provides evidence that the constructed risk model can effectively predict prognosis in PDAC patients. Transcription factors related to ER stress, such as IRF6, show promise as both prognostic biomarkers and potential therapeutic targets for PDAC.

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.

Considering infants and young children, it is well established that their physiological and developmental peculiarities should not be confused with those of other patient categories, such as adults or vulnerable patients. Indeed, their anatomic-functional characteristics specifically influence the drug pharmacokinetic/pharmacodynamic profile. Therefore, the availability of specialists devoted to pediatric pharmacology within multidisciplinary teams is highly desirable to improve the care of these patients.

This work aims to describe the role of pediatric clinical pharmacologists in the context of pediatric clinical care in Italy, using a qualitative method based on the type of articles published.

A literature review was conducted according to the PRISMA guidelines, considering articles published on the PubMed database between January 2017 and March 2022 and using specific MeSH terms. The papers were attributed to two blind assessors and then processed for discussion. To support article screening, focusing on the words contained in article titles, the R package evidence synthesis tool revtools was used.

The search identified a total of 1544 articles, of which 93 were selected. The articles analyzed mainly concern therapeutic drug monitoring and pharmacovigilance with adverse drug reactions.

An insight into multidisciplinary work to prevent, diagnose, and treat pediatric diseases and to monitor treatments is provided in this study. However, this concept needs to be strengthened in the long term.

Acute myeloid leukemia (AML) is the most common adult hematologic malignancy, with relapse and drug resistance posing major challenges despite treatment advances. Cryptotanshinone (CTS), a diterpenoid compound derived from Salvia miltiorrhiza, exhibits anticancer activity in various tumors. However, its role and mechanisms in AML remain unclear. This study aims to investigate the inhibitory effects of CTS on AML cells and its potential mechanisms.

Network pharmacology was employed to identify potential AML-related targets of CTS, and a disease-drug-target interaction network was constructed. The effects of CTS on KG-1 cells were assessed using CCK-8 proliferation assays, cell cycle analysis and apoptosis detection. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to analyze the regulatory effects of CTS on the endoplasmic reticulum stress (ERS) signaling pathway. The role of the Hippo-YAP signaling pathway in CTS-induced AML inhibition was further explored.

Network pharmacology analysis identified key AML-related targets of CTS, enriched in multiple cancer-related signaling pathways. Experimental results showed that CTS inhibited KG-1 cell proliferation in a dose-dependent manner, induced S-phase arrest, and promoted apoptosis. Furthermore, CTS treatment significantly upregulated ERS-related key proteins. While YAP overexpression attenuated CTS-induced ERS activation and reduced apoptosis levels.

This study indicates that CTS inhibits AML cell proliferation and induces apoptosis while activating the ERS signaling pathway. However, aberrant activation of the Hippo-YAP pathway weakens this effect. These findings provide novel theoretical insights into potential therapeutic strategies for AML.

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.

Diabetes mellitus (DM) is a chronic metabolic disorder that seeks treatment instead of available mitigative therapy.

Six (E)-3-(aryl)-1-phenylprop-2-en-1-one chalcones were synthesized and characterized through various spectroscopic techniques. Their anti-diabetic potential was examined through in-vitro (α-glucosidase and α-amylase inhibition assays), in-vivo (alloxan-induced hyperglycemia), and in-silico studies.

All the chalcones derivatives significantly inhibited α-glucosidase and α-amylase. Compounds 11 (IC50 = 1.10 ± 0.02) and 13 (IC50 = 3.25 ± 0.10 µM) exhibited the most potent activity against α-glucosidase. The effect of compounds 11 and 13 was also significant against α-amylase with IC50 of 13.2 ± 0.50 and 10.2 ± 0.4 µM, respectively. In alloxan-induced hyperglycemic model, a significant (p<0.001) reduction in blood glucose level (BGL) was observed by compounds 10, 11 and 14 with maximum percent inhibition of 47.48, 47.22 and 47.55, respectively. In the oral glucose tolerance test, a continuous reduction in BGL was noted at 60 minutes. No negative effect was seen on lipid profile, and in liver and renal function tests. However, a slight gain in body weight was noted. Moreover, docking result indicates good interaction of these molecules with the target enzymes, α-glucosidase and α-amylase.

These results demonstrate that all these molecules have significant anti-diabetic potential.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, with a steadily increasing prevalence. However, the mechanisms underlying AD remain unclear, and current treatments have only limited efficacy.

This study aimed to identify potential biomarker genes for AD and to explore the underlying mechanisms by integrating microarray analysis, Mendelian randomization (MR), and experimental validation.

AD-related microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis identified differentially expressed genes (DEGs) between AD and control samples. Summary-level data from genome-wide association studies on AD were integrated with expression quantitative trait loci data to identify genes with potential causal relationships with AD using MR. The intersections between DEGs and causal genes were identified as hub genes. Functional analysis was performed to explore underlying mechanisms. Quantitative real-time PCR was applied to validate the expression of hub genes in clinical samples.

Differential expression analysis identified 312 DEGs, whereas MR identified 202 genes with causal effects on AD. The intersection of these two sets identified four hub genes: FCRLB, MT2A, PFKFB3, and SRGN. Functional analysis indicated significant associations between AD and immune-related pathways. Correlation analysis revealed significant connections between hub genes and immune cells in AD. The expression of MT2A, PFKFB3, and SRGN was significantly upregulated, whereas FCRLB was downregulated in clinical AD samples compared with controls.

The integration of microarray analysis, MR, and experimental validation identified and validated four potential biomarker genes with causal effects on AD, namely FCRLB, MT2A, PFKFB3, and SRGN. Functional analysis indicated a pivotal role of the immune microenvironment in AD. These findings offer insights into the molecular mechanisms of AD and have implications for improving its diagnosis and treatment strategies.

RNA sequencing data and clinical information from GC patients were collected from the TCGA and GEO databases, excluding cases of pure IGC and DGC. Based on ECMR and CA-related genes, supervised clustering via non-negative Matrix Factorization (NMF) was used to identify molecular subtypes in MGC. Differential expression and Cox regression analyses were performed to identify prognostic genes, and an ECMR and CA-based gene signature (ECRS) was developed using machine learning techniques. Gene Set Variation Analysis (GSVA) was conducted to assess functional differences between risk groups, while TIDE and pRRophetic analyses were used to predict responses to immunotherapy and chemotherapy.

A total of 239 MGC patients were classified into two molecular subtypes with significant differences in prognosis. Subtype 2 displayed distinct ECM interactions and connective tissue development pathways. To refine the ECRS model, we tested 117 model combinations across 10 machine learning algorithms, selecting the configuration with the best predictive accuracy. This optimized model distinguished biological and immune characteristics between high- and low-risk groups, with low-risk patients showing greater sensitivity to immunotherapy and standard chemotherapy.

This study identifies novel molecular subtypes of MGC based on ECMR and CA-related genes and establishes an effective ECRS model to predict prognosis, immunotherapy response, and chemotherapy sensitivity. This model supports personalized treatment strategies for MGC.

Hepatocellular carcinoma (HCC) is a life-threatening cancer with rising incidence and mortality rates. Identifying new prognostic biomarkers is crucial for improving HCC management.

This study investigates the role of Double PHD Fingers 1 (DPF1) in hepatocellular carcinoma (HCC), exploring its potential as a prognostic indicator and therapeutic target.

We analyzed DPF1 expression in 374 hepatocellular carcinoma (HCC) tissues and 50 normal tissues from the TCGA-HCC database, as well as in 240 HCC tissues and 202 normal tissues from the ICGC-HCC repository. We examined the correlation between DPF1 expression and clinical parameters, immune cell infiltration, drug response profiles, cancer stem cell (CSC) characteristics, and its diagnostic/prognostic potential using various bioinformatics tools and statistical analyses. Validation was performed using the ICGC and HPA databases, and qRT-PCR was used to confirm DPF1 expression in HCC cell lines.

DPF1 exhibited abnormal expression in HCC and several other malignancies. Elevated DPF1 levels were significantly associated with higher Alpha-fetoprotein (AFP) levels (p = 0.043) and poorer clinical outcomes, including diminished overall survival (OS) (p = 0.002), progression-free survival (PFS) (p = 0.018), and disease-specific survival (DSS) (p = 0.001). DPF1 expression was also linked to immune cell infiltration, immune checkpoint gene expression, drug sensitivity, and CSC characteristics. Notably, DPF1 was significantly overexpressed in HCC tissues and cell lines at both transcriptional and translational levels.

Our study reveals that DPF1 is a novel prognostic biomarker in HCC, with potential implications for immunotherapy and drug resistance. Elevated DPF1 expression is associated with adverse clinical outcomes and may serve as a target for future therapeutic interventions in HCC.

High glucose-induced angiogenesis is the main component in Proliferative Diabetic Retinopathy (PDR) development. In PDR, ischemia and hypoxia have been identified as key stimuli that promote pathological neoangiogenesis by increasing Vascular Endothelial Growth Factor A (VEGFA). Furthermore, it has been demonstrated that TRIM65 knockdown in tumor cells reduces VEGFA expression. Building on these findings, the present study aimed to study the role of TRIM protein members in proliferative diabetic retinopathy.

In comparison to the control group, TRIM65 expression was significantly increased in human retinal endothelial cells (HREC) after high glucose treatment. Moreover, FITC/PI staining, cell wound scratch assay, transwell assay, tube formation assay, and immunofluorescence staining of VEGFA and HIF-3α were carried out, which indicated that TRIM65 knockdown inhibited high glucose-induced HREC cell apoptosis and angiogenesis and decreased the expression of VEGFA and HIF-3α, both of which are potential targets of miR-29a-3p. MIR-29a-3p inhibitor significantly reduced the effects of TRIM65 knockdown on VEGFA and HIF-3α expression levels in cells. TRIM65 induced ubiquitination and degradation of TNRC6A, resulting in suppressed miR-29a-3p expression.

Furthermore, in vivo studies revealed that intravitreal injection of miR-29a-3p inhibited neoangiogenesis in mice with Oxygen-Induced Retinopathy (OIR). The retinal tissues of OIR mice showed higher TRIM65 mRNA expression and lower miR-29a-3p expression than those of control mice. Furthermore, the analysis showed a negative correlation between the expression of miR-29a-3p and TRIM65 in the retinal tissues of OIR mice.

In conclusion, this study demonstrated that the knockdown of TRIM65 inhibits neoangiogenesis in proliferative diabetic retinopathy by regulating miR-29a-3p.

Stanniocalcin 1 (STC1) has been implicated in cancer pathogenesis, yet its pan-cancer implications and mechanistic roles in tumor progression and immune modulation remain incompletely characterized. The clinical relevance of STC1 in predicting prognosis and its interaction with tumor immune microenvironment components requires systematic investigation.

This study aims to establish the pan-cancer prognostic significance of STC1 and elucidate its associations with immunological characteristics, including immune checkpoint proteins, tumor mutational burden (TMB), microsatellite instability (MSI), and immune cell infiltration. This study focuses specifically on validating its role in the pathogenesis of gastric adenocarcinoma (STAD).

Multi-omics analysis was performed using TCGA pan-cancer datasets and bioinformatics tools (UALCAN, cBioPortal, HPA, GTA). Experimental validation included multiplex fluorescence staining of STAD tissue microarrays (n=30) and Western blot analysis of STAD cell lines. Key parameters analyzed encompassed clinical outcomes, cancer stemness indices, neoantigen load, and epithelial-mesenchymal transition (EMT) signatures.

Pan-cancer analysis revealed significant STC1 overexpression in 18/33 cancer types (54.5%), particularly in prostate adenocarcinoma (94% deep deletions). STC1 expression correlated with poor prognosis (HR=1.32, p<0.01), elevated TMB (r=0.43), and MSI (r=0.38) across multiple malignancies. Single-cell RNA sequencing demonstrated a strong association with EMC (NES=2.18, FDR<0.001). In STAD, this study confirmed 3.7-fold protein overexpression (p=0.008) and identified positive correlations with CD8+ T cell infiltration (r=0.62, p=0.002) and CD4+ T cell infiltration (r=0.58, p=0.004).

This multi-modal study establishes STC1 as a novel pan-oncogenic factor with dual roles in tumor progression (via EMT and stemness regulation) and immune microenvironment remodeling. The strong association with immune checkpoints (PD-L1, CTLA4) and T cell infiltration patterns positions STC1 as a promising immunotherapeutic target, particularly in STAD and MSI-high cancers. These findings provide mechanistic insights for developing STC1-directed therapeutic strategies.

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.

Over 85% of biologically active compounds are heterocycles or contain heterocyclic groups, underscoring their vital importance in contemporary drug development. Among them, nitrogen-containing derivatives, such as pyridines and pyrimidines, are considered privileged structures in approved drugs or are extensively studied due to their promising therapeutic effects.

In the current work, we would like to verify the hypothesis that incorporating heterocyclic pharmacophores into derivatives of pyrimidine-2(1H)-thione (PMT), 2-pyridone (P), pyridine-2(1H)-thione (PT), dihydropyrimidine-2(1H)-thione (DHPMT), dihydropyridin-2(1H)-one (DHP), and dihydropyridine-2(1H)-thione (DHPT) rings enhances antitumor activity.

A range of novel pyridine- and pyrimidine-based compounds were synthesized and assessed for their anticancer properties against the melanoma A375 cell line. The two most potent compounds (16b and 29) were then chosen for further evaluation of their effects on non-cancerous human dermal fibroblasts, cancer cell apoptosis, cell cycle phase distribution, and tubulin polymerization. Furthermore, in silico analyses were performed to assess the pharmacokinetics, toxicity, drug-likeness, and molecular target of the selected compounds.

Among the 33 compounds tested, pyridine analogs 16b and 29 demonstrated the strongest antiproliferative activity (with IC50 values of 1.85 ± 0.44 µM and 4.85 ± 1.67 µM, respectively) and selectivity (SI=65.08 and SI> 100, respectively) against cancer cells. Additional studies revealed that compound 16b, which features a thiophene ring at the C-5 position and a 3,4,5-trimethoxyphenyl (TMP) group, showed the most promising cell cycle arrest and tubulin polymerization inhibition (IC50=37.26 ± 10.86 µM), resulting in cancer cell apoptosis. In silico ADMET analysis confirmed the drug- likeness of the synthesized compounds.

This research reinforced the significance of heterocyclic rings as valuable pharmacophores. Additionally, it highlighted the antiproliferative and antimitotic potential of modified pyridine derivatives.

Boron-containing compounds (BCC) are attracting attention in drug design. Certain chemical features invite the exploration of efficacious interactions on known and potential drug targets for human use.

The objective of this study is to analyze the reported crystal structure studies to determine trends resulting from the inclusion of boron atoms in potential drugs.

Published data in the Protein Data Bank (PDB) with at least one BCC were analyzed; both ligands and targets were analyzed to describe the inferred or reported biological activity and the potential application as a drug in the treatment of human diseases.

Data from the PDB indicated targets for certain infectious diseases and cancers; however, potential treatments may extend to many other human pathologies as a consequence of the careful analysis of BCCs with proteins. All classes of enzymes and receptors have been crystallized with BCCs as ligands with most complexes demonstrating interactions in the regions known as relevant to protein function.

The number of crystallized BCC-proteins complexes is increasing, and the variability of proteins expands the possibilities of medical applications. Currently, most systems are related to cancer growth and treatment, but deeper analysis may expand BCC utility and efficacy to many other chronic and degenerative diseases.

This study investigated the causes of Mitochondrial Dysfunction (MD) in Diabetic Kidney Disease (DKD) progression, and identified genes associated with DKD, especially those with significant genetic causal effects, to provide a theoretical basis for DKD treatment.

Using a large database and single-cell RNA sequencing (scRNA-seq) data, 333 MDRDEGs were discovered. MDRDEGs were linked to AGE-RAGE signaling, RNA processing, protein transport, and energy metabolism using functional enrichment analysis. Seven MDRDEGs with significant genetic causal effects in DKD were discovered using SMR and MR analyses: ACTN1, ALG11, CCNB1, HIVEP2, MANBA, TUBA1A, and WFS1. Co-localization and scRNA-seq analyses examined these genes' DKD connections. Due to the high significance of its prediction model and DKD expression, ACTN1 was studied in depth. PheWAS and molecular dynamics analysis assessed ACTN1's safety and efficacy as a therapeutic target, and its connection with other symptoms. ACTN1 protein expression in DKD tissues was confirmed by immunofluorescence.

Functional enrichment analysis revealed that MDRDEGs were mostly related to AGE-RAGE signaling, RNA processing, protein transport, and energy metabolism. Seven MDRDEGs caused DKD genetically in SMR and MR investigations. Genetic variations in ACTN1, ALG11, MANBA, and TUBA1A were linked to DKD by co-localization studies. scRNA-seq showed a dramatic increase in ACTN1 expression in DKD. Molecular dynamics analysis demonstrated that Dihydroergocristine can safely bind to ACTN1, while the PheWAS investigation found no significant relationships. DKD tissues exhibited higher ACTN1 protein levels via immunofluorescence.

This study identified MDRDEGs linked to inflammation, cytoskeletal stabilization, and glucose metabolism pathways critical in Diabetic Kidney Disease (DKD) pathogenesis, highlighting their clinical potential as therapeutic targets. Notably, ACTN1 emerged as a causally linked gene overexpressed in DKD, with the prediction of dihydroergocristine as a targeting compound, offering novel avenues for clinical intervention.

This study suggests that ACTN1 may be a therapeutic target for DKD and sheds light on its molecular pathogenesis, clinical prevention, and treatment.

Ovarian cancer, a significant contributor to global female mortality and the third most prevalent gynecological cancer in India, poses challenges for conventional treatments like chemotherapy and radiotherapy.

This study explores the effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on the efficacy of chemotherapy, particularly doxorubicin (DOXO), in ovarian teratocarcinoma (PA-1) cells. Rigorous cell viability assays demonstrated that n-3 PUFAs in combination significantly enhanced DOXO-induced cytotoxicity, reducing cell survival and migration potential. N-3 PUFAs and DOXO synergistically reduced colony formation in the group receiving the combination treatment as seen in the clonogenic assays, as further validated by hanging drop and apoptosis assays results.

Network pharmacological investigations pinpointed the gene topoisomerase II A (TOP2A) as a pivotal target, while molecular docking simulations revealed structural similarities between n-3 PUFAs (DHA or EPA) and DOXO, implying probable common mechanisms such as DNA intercalation and topoisomerase II inhibition. Molecular dynamics simulations delineated distinct interaction profiles for Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) with TOP2A, offering mechanistic insights. Combining computational and experimental methodologies reveals the synergistic benefits of n-3 PUFAs and DOXO in treating ovarian cancer, leading to improved therapeutic outcomes.

These results provide a comprehensive view of the potential of combining n-3 PUFAs with DOXO for more potent ovarian cancer treatments.

This study aimed to establish a PANoptosis related prognostic signature and identify potential prognostic markers and therapeutic targets for HCC.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The survival rate of patients with HCC remains relatively low. PANoptosis can be mediated by lncRNA to involve the pathophysiology of HCC, but the mechanism is still unclear.

TCGA and GEO hepatocellular carcinoma databases and previous research results were used to construct the PANoptosis related risk model.

Based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, this study identified long non-coding RNAs (lncRNAs) associated with PANoptosis in HCC. Univariate, LASSO-Cox, and multivariate COX analyses were employed to gradually screen prognostic lncRNAs and construct prognostic models. Further analysis was conducted on the core lncRNA-AC034229.4.

A total of 8 differentially expressed lncRNAs closely correlated with HCC prognosis were discovered. A prognostic model comprising 6 lncRNAs (AC090192.2, LINC01703, AC034229.4, AC073352.1, AC004816.1, and AL136162.1) was established demonstrating good predictive ability for prognosis. Moreover, this prognostic model exhibited close associations with tumor immune microenvironment and immune checkpoints. Subsequent investigations revealed that AC034229.4 independently influenced HCC prognosis by regulating cell cycle progression and inhibiting the immune microenvironment response. Drug sensitivity analysis indicated that AC034229 .4 displayed sensitivity to various anticancer drugs as well. In addition, inhibition of AC034229 .4 expression suppressed HCC migration and invasion abilities.

This study generated a novel and efficient prognostic signature model while identifying AC034229 .4 as a promising diagnostic and prognostic biomarker in HCC.

The purpose of this study is to construct and validate a neuroendocrine differentiation-related molecular model for predicting prognosis in patients with prostate cancer (PCa).

Transcriptome data for PCa were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) websites. Differentially expressed neuroendocrine differentiation related genes (NDGs) were identified. By utilizing multivariate Cox analysis, a neuroendocrine differentiation-related molecular model for predicting prognosis was constructed and validated. The study investigated the novel model’s association with the tumor immune microenvironment, clinicopathological characteristics, tumor stemness, and anticancer treatment sensitivity. Additionally, preliminary experimental verifications of Diencephalon / Mesencephalon Homeobox 1 (DMBX1) were conducted.

Finally, we identified a total of 19 differentially expressed NDGs. A neuroendocrine differentiation-related molecular model was established and successfully validated both internally and externally. The high-risk group   exhibited   significantly   poorer biochemical recurrence-free survival (BCRFS) in the training, testing, and validating cohorts. The areas under the receiver operating characteristic curves for the training, testing, and validating cohorts were 0.825, 0.719, and 0.729, respectively. The tumor immune microenvironment, clinicopathological features, tumor stemness, and anti-cancer drug sensitivity was significantly different between high and low-risk patients. Preliminary experiments revealed that higher expression of DMBX1 significantly enhanced the proliferation, migration, and neuroendocrine differentiation of PCa cells.

This research developed a unique neuroendocrine differentiation-related molecular model that is highly suitable for predicting BCRFS. High DMBX1 expression may promote the development and neuroendocrine differentiation of prostate cancer.

Icaritin is a bioactive flavonol isolated from the Chinese medicinal herb Epimedium. The comprehensive understanding of antifibrotic effects and associated molecular mechanisms of icaritin remains incomplete. This study aims to explore the protective effects of icaritin against liver fibrosis and to further elucidate the mechanisms involved.

Human hepatic stellate LX-2 cells stimulated with TGF-β1 and a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model were employed. In vitro assays were carried out to evaluate collagen type I (COL I) and α-smooth muscle actin (α-SMA) expression, while in vivo studies assessed fibrosis alleviation. Molecular mechanisms were explored via analysis of TGF-β1, phosphorylated Smad2/3, and HIF-1α protein levels using Western blotting.

Icaritin suppressed TGF-β1-induced COL I and α-SMA expression in LX-2 cells and ameliorated liver fibrosis in CCl4-treated mice. Mechanistically, it significantly reduced TGF-β1 levels, inhibited Smad2/3 phosphorylation, and downregulated HIF-1α protein expression in LX-2 cells.

Icaritin attenuated experimental liver fibrosis through the inhibition of the TGF-β/Smad and HIF-1α signaling pathways, highlighting its therapeutic potential for fibrotic liver diseases.

Inflammatory osteolysis often characterizes many orthopedic diseases, with an important role played by the overactivity of osteoclasts. This research endeavoured to investigate the effects of spinosin, a potent ingredient in traditional Chinese medicine, on Lipopolysaccharide (LPS)-induced osteoclast activity and formation to alleviate osteolysis.

Based on the molecular structure of spinosin, network pharmacology was used to predict its primary targets and mechanisms. LPS was used to stimulate pre-osteoclasts and to simulate an inflammatory environment. The effect of spinosin on osteoclast biology was subsequently examined via morphological study, qPCR, and Western blot (WB). Moreover, LPS-induced cranial osteolysis mice were utilized, followed by micro-CT analysis, to reveal the curative effects in vivo.

Network pharmacology and molecular docking suggested that EGFR and Akt might be the key targets for the efficacy of spinosin in inflammatory osteolysis. The results of in vitro experiments demonstrated that spinosin significantly inhibited osteoclast function and activity in the inflammatory environment, and this effect might be achieved through regulating EGFR-Akt signaling. The results of animal experiments also showed spinosin-protected mice against LPS-induced bone loss.

Spinosin can inhibit EGFR-mediated Akt phosphorylation, which in turn negatively affects downstream Nfatc1-mediated osteoclast-associated gene expression and subsequent osteoclast formation and functionality, mitigating the LPS-induced osteolysis. Our study proves that spinosin holds the promise of being an innovative drug to prevent inflammatory osteolysis.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies. Treatment options are limited and often unsatisfactory, leading to a poor prognosis in most subtypes.

This study aimed to identify potential biomarker genes for PTCL and to explore the underlying mechanisms by integrating machine learning, Mendelian Randomization (MR), and experimental validation.

Microarray datasets (GSE6338, GSE14879, and GSE59307) were downloaded from the Gene Expression Omnibus database. Differential expression analysis was conducted to identify the Differentially Expressed Genes (DEGs) between patients with PTCL and controls. A machine learning algorithm was then used to further refine the selection of characteristic genes for PTCL. We integrated genome-wide association studies data with expression quantitative trait loci data to identify genes with potential causal relationships to PTCL. Functional analysis was performed to explore underlying mechanisms. Finally, the identified gene was validated in clinical samples from patients with PTCL and controls.

Based on 60 DEGs, the least absolute shrinkage and selection operator algorithm identified nine characteristic genes for PTCL. MR analysis revealed 203 genes with causal effects on PTCL, ultimately identifying one co-expressed gene: Basic Leucine Zipper ATF-like Transcription Factor 3 (BATF3). It demonstrated good predictive performance across various PTCL subtypes, with AUC values ranging from 0.7 to 1. Functional analysis suggested that BATF3 may play a role in PTCL through immune-related pathways. Experimental validation using clinical samples further suggested the potential of this biomarker gene in PTCL.

By combining machine learning, MR, and experimental validation, we identified and validated BATF3 as a promising biomarker of PTCL. These findings provide insights into the molecular mechanisms underlying PTCL and may inform the development of effective treatment strategies for this disease.

Metastasis is the leading cause of death in lung cancer patients. Pre-metastatic niche (PMN) plays an important role in pre-metastatic tumors. However, the development of clinical applications of PMN is still limited.

Expression data for lung adenocarcinoma (LUAD) patients and PMN-related genes were downloaded from the UCSC Xena website and GeneCards database, respectively. Multiple combinations based on machine learning algorithms were used to screen signature genes and construct a PMN-associated index. Spearman analysis explored the correlation between the PMN-associated index and immune cell infiltration. In addition, we analyzed the clinical value of the PMN-associated index based on drug sensitivity analysis and TIDE scores.

The enrichment analyses suggested that PMN-related genes were mainly enriched in the PI3K-Akt and HIF-1 signaling pathways. We chose random survival forest, Lasso, and multivariate Cox regression analyses to construct the PMN-associated index based on the results of multiple machine learning algorithms. Six signature genes (SNAI2, CXCR4, TNFSF11, ENG, TIMP1, and PDGFB) were screened to construct the PMN-associated index. KM analysis suggested that the survival probability was greater in the low PMN-associated index group than in the high PMN-associated index group. In addition, we confirmed that LUAD patients with a low PMN-associated index were more likely to benefit from immunotherapy.

We confirmed that the PMN-associated index is a valid predictor of prognosis, immune characteristics, and antitumor therapy efficacy in LUAD patients, which provides additional evidence for the potential clinical value of PMN development.

Sepsis remains a leading cause of global morbidity and mortality.

To identify candidate biomarkers that may be mechanistically related to the pathogenesis of sepsis.

The Gene Expression Omnibus database was leveraged to identify differentially expressed genes (DEGs) between the healthy control and septicemia groups. Genes causally related to sepsis were probed through the integration of GWAS and expression quantitative trait loci (eQTL) data in a two-sample Mendelian randomization (MR) analysis. A set of key sepsis-related genes was then selected based on the overlap between these putative causal genes and the DEGs. These genes were then subjected to enrichment analyses, testing set validation, and analyses of their expression dynamics in clinical samples.

An examination of the overlap between 228 sepsis-related DEGs identified in the training dataset and 275 candidate causal genes linked to sepsis derived from the MR analysis led to the selection of four overlapping (SLC22A15, IL5RA, HDC, and SLC46A2) that may play a key role in sepsis. Enrichment analyses indicated that these genes were involved in the regulation of histidine metabolism and immune/inflammatory responses. In immune cell infiltration analyses, these genes were positively correlated with inflammatory response activation and the suppression of adaptive immunity. Consistent findings were obtained through qPCR verification in clinical samples.

These results offer potential insight into the mechanisms that govern septicemia and thus suggest a promising series of candidates that may be amenable to targeting to prevent or treat sepsis more effectively.

Neuroblastoma (NB) is a prevalent pediatric solid malignancy associated with significant morbidity and mortality, largely driven by epigenetic alterations. This review aims to identify novel biomarkers related to long non-coding RNAs (lncRNAs) and DNA methylation in NB to enhance prognostic capabilities.

We conducted a detailed analysis of the interplay between lncRNAs and DNA methylation in NB, focusing on regulatory variations and their implications for disease progression. Key lncRNAs, including GTL2/MEG3, DALI, NBAT-1, and DLX6-AS1, were examined for their regulation by DNA methylation through cis- and trans-methylation mechanisms.

There are clinical and biological implications of lncRNAs in NB and related cancers. Notably, GTL2 and its alias MEG3 are implicated in tumorigenesis through epigenetic modifications, such as hypermethylation, leading to the loss of gene expression and aggressive tumor behavior. Similarly, the interactions of DALI with adjacent genes illustrate the crucial role lncRNAs play in neuronal differentiation and tumor progression, suggesting their potential to impact prognosis through regulatory effects. Furthermore, NBAT-1 emerges as a promising tumor suppressor with strong correlations to NB prognosis, where its methylation-induced silencing is associated with negative outcomes. DLX6-AS1 is also linked to increased NB risk, with expression patterns correlating to disease stage and survival rates; however, more extensive survival data are required to establish its prognostic value.

This review highlights the potential of lncRNAs as prognostic indicators in NB, emphasizing the need for further research to elucidate their roles and validate them as biomarkers for improved patient outcomes.

Angiogenesis plays an important role in progression of tumors including breast cancer, which accounts for the vast majority of women's malignant tumors globally, to meet the excessive requirement of oxygen and nutrition for growth, metastasis, and invasion of the tumor. Therefore, targeting tumor angiogenesis has turned into a significant target for cancer therapy. Erbin has a significant effect on the initiation and progression of cancer, including breast cancer, but its role in inhibiting vascular endothelial cell proliferation and angiogenesis by breast cancer cells remains unclear.

In this study, human SKBR3 and MCF-7 breast cancer cells were used and transfected with the plasmid and siRNA for overexpression and silence of Erbin, respectively. Western blot, qRT-PCR, CLEIA, CCK-8 and Matrigel Tube Formation Assay were used for the proteins detection, mRNAs detection, detection of VEGF in the culture supernatants, detection of cell proliferation and detection of the angiogenic ability of HUVECs in vitro, respectively.

It was shown that the expression of both Erbin protein and mRNA in SKBR3 cells was lower compared to that in MCF-7 cells (p < 0.05). While the expression of VEGF protein was higher in SKBR3 cells than that in MCF-7 cells (p < 0.05). Furthermore, the VEGF protein and mRNA in the cells, VEGF protein in the culture supernatant, HUVEC proliferation in the conditioned medium at 16 h and 24 h, the total length of tube formation in the conditioned medium, and pSTAT3 protein in the cells, were downregulated by transfection of Erbin gene in SKBR3 cells and upregulated (excluding HUVEC proliferation at 16 h) by transfection of Erbin siRNA in MCF-7 cells compared with their NC cells (p < 0.05).

It can be concluded that Erbin, with inhibiting the STAT3 pathway, suppresses the proangiogenic effects of breast cancer cells, thereby suggesting its potential as a therapeutic target for breast cancer.

Prevention of the formation of β-haematin is the target of several existing antimalarials drugs, most notably chloroquine. This target is therefore attractive for the development of new molecules with antimalarial potential.

In this study, we have used a combination of ab-initio molecular dynamics and density functional tight-binding to examine the possible interaction mechanisms between five amodiaquine analogues and four conformations of haematin. Reactivity and stability of these complexes were investigated using bond length (Fe-N and Fe-O), energies (HOMO-LUMO) and molecular dynamics.

Results revealed a good interaction between haem and the compounds, stable geometries of complexes.

The findings from this study are valuable because they can aid the design and understanding of new therapeutic molecules that could be used to treat drug-resistant malaria, a global threat of today.

Collagen type IV alpha 1 chain (COL4A1), which has been proven to be a potential biomarker in Gastric Cancer (GC), but its role in tumors and the tumor microenvironment (TME) needs further explanation.

We analysed the relationship between COL4A1 and clinical characteristics based on The Cancer Genome Atlas (TCGA) database and verified by tissue microarrays as well as GC cell lines using immunohistochemistry, Q-PCR, Western blot, cell proliferation assays, colony formation assays, cell invasion and migration assays. The immune infiltration and drug sensitivity information between high and low COL4A1 expression were analysed by R package and pRRophetic package. Finally, we established a nomogram based on COL4A1 expression using the bootstrap method.

COL4A1 was overexpressed in gastric carcinoma compared with normal gastric tissue, indicating a poor prognosis of GC patients in the TCGA database which were also validated by GC tissue microarrays. GO, KEGG and hallmark enrichment analyses indicated that COL4A1 was mainly associated with the extracellular matrix than malignant proliferation. By siRNA transfection, we found that COL4A1 knockdown inhibited cell colony formation, invasion and migration but did not affect cell proliferation, similar to previous results. Immune infiltration and drug sensitivity analysis showed that COL4A1 was negatively correlated with antitumor immunity and positively correlated with multidrug resistance. By developing a nomogram model based on 8 risk factors, including COL4A1, patients with better clinical outcomes could be accurately distinguished.

COL4A1 is identified as a prognostic marker and potential therapeutic target in gastric cancer. Its overexpression correlates with poor prognosis, tumor invasion, and immunosuppression. A nomogram based on COL4A1 can predict patient outcomes. Future research should validate these findings and explore targeted therapies.

ZNF280A, a pivotal member of the zinc finger protein family, is significantly involved in vital cellular functions including cell proliferation, programmed cell death, cellular invasion, metastasis, and resistance to therapeutic drugs across various malignancies. However, its comprehensive role in pan-cancer has not been thoroughly investigated.

This research aims to elucidate the oncogenic and immunological functions of ZNF280A across different types of cancer. We conducted an extensive analysis of ZNF280A expression levels, prognostic significance, functional pathways, methylation status, and interactions with immune cells, while also examining immune infiltration patterns and responses to immunotherapy using diverse databases.

Our findings reveal that ZNF280A expression is significantly upregulated in numerous cancers, correlating with adverse patient prognosis. This association appears to be linked to its involvement in key cancer-related pathways, including the Ras signaling pathway, and its correlation with ZNF280A methylation levels, microsatellite instability (MSI), tumor mutational burden (TMB), and the dynamics of immune cells. Notably, ZNF280A seems to undermine anti-tumor immunity and the effectiveness of immunotherapeutic approaches by promoting the infiltration of immune cells and compromising the functionality of cytotoxic T lymphocytes.

These findings suggest that ZNF280A holds promise as a valuable indicator for forecasting patient outcomes and assessing the effectiveness of immunotherapy, thereby opening avenues for further exploration into targeted therapeutic approaches.

Ovarian cancer (OV) is one of the deadliest gynecologic cancers, and approximately 75% of serous ovarian cancer (SOC) patients are diagnosed at advanced stages due to the lack of effective biomarkers.

Immunogenic cell death (ICD) has been investigated in many comprehensive studies, and the role of ICD in ovarian cancer and its impact on immunotherapy is not yet known.

The NMF clustering analysis was employed to categorize OV samples into different subgroups. Survival, mutation, and CNV analyses were performed in these clusters. ESTIMATE, CIBERSORT, TIDE, and drug sensitivity analyses (based on GDSC) were also performed on the subtypes. Then, differentially expressed immunogenic cell death genes (DE-ICDGs) in OV were obtained by crossing the DEGs between cluster3 vs. cluster1, DEGs from the TCGA-GTEx dataset, and DEGs from the GSE40595 dataset. Functional enrichment analysis of DE-ICDGs was then performed. The signature genes related to the prognosis of OV in three OV datasets were excavated by drawing Kaplan-Meier curves. Finally, quantitative real-time PCR (qRT-PCR) was performed to verify the expression trends of the signature genes.

The NMF clustering analysis categorized OV samples into three distinct groups according to the expression levels of ICDGs, with differential analysis indicating that Cluster3 represented the subgroup with high ICD expression. Mutation and CNV analysis did not differ significantly between clusters, but Amp and Del's numbers did. Immuno-infiltration analysis revealed that cluster3 showed significant differences from cluster1 and cluster2. Immunotherapy and drug sensitivity analysis showed differences in immunotherapy and chemotherapy sensitivity between the clusters. The DEGs in cluster3 vs. cluster1, TCGA-GTEx dataset and GSE40595 dataset were intersected to obtain a total of 71 DE-ICDGs, and functional enrichment result suggested that the DE-ICDGs were significantly correlated with inflammatory response, complement system and positive regulation of cytokine production. 2 DE-ICDGs (FN1 and LUM) were identified that were associated with OV prognosis and were validated significantly down-regulated in the SOC group with PCR.

We identified ICD-associated subtypes of OV and mined 2 OV prognostic genes (FN1 and LUM) associated with ICD, which may have important implications for OV prognosis and therapy.