Current Medicinal Chemistry - Online First

Fructose, like other sugars and sugar metabolites, is capable of glycating protein. Insulin's fructosylation leads to the generation of Advanced Glycation End Products (AGEs). Reducing sugars reaction with proteins to form Schiff’s bases, which are characterized by the presence of an imine (C=N) bond. The Schiff bases then undergo irreversible rearrangements, followed by the production of much more stable compounds called Amadori products. These Amadori products can further undergo oxidation, dehydration, cyclization, and condensation to form highly toxic advanced glycation end-products (AGEs). These processes are accompanied by oxidative stress, secondary structural perturbations, and altered morphology, progressing toward amyloidogenesis. Metformin, a biguanide, is the most common drug used to treat type 2 Diabetes Mellitus (T2DM).

The aim of this study was to evaluate the protective effect of metformin against fructosylation-induced cross-β structures and amyloid aggregations of human insulin.

UV-absorbance and fluorescence spectroscopy, determination of carbonyl content, free lysine and arginine residues, determination of fructosamine content, SDS-PAGE, circular dichroism (CD) spectroscopy, dynamic light scattering, and scanning and transmission electron microscopy.

Physicochemical studies in the presence or absence of metformin revealed a concentration-dependent structural restoration of fructosylated insulin. Results from the thioflavin-T fluorescence assay suggested that metformin limited the transition of insulin from native to fibrillar state, which was validated by scanning and transmission electron microscopy. Metformin lowered the ThT fluorescence intensity in a concentration-dependent manner. The ThT-specific fluorescence intensity was reduced to 114 and 112.5%. The fluorescence intensity at 2.5 mM metformin was close to native insulin. Electron microscopy revealed that insulin fructosylated by 25 mM fructose in the presence of 2.5 mM metformin suppressed the formation of fibrillar structures. Dynamic light scattering data revealed the potential of metformin to conserve and reinstate the increased hydrodynamic radii (Rh) of fructosylated insulin close to the native conformer. The Rh values of native, fructosylated insulin and insulin incubated with fructose and metformin were found to be 2.65 ± 0.28, 307.6 ± 24.19 nm, and 110.1 ± 4.08 nm, respectively. This study also identified metformin as an antioxidant by protecting critical amino acid residues of the insulin domain.

The study reports the protective effects of metformin on insulin structure, conformation, and function. The findings suggest a potential role for metformin in improving the risk profile associated with insulin resistance due to altered structure or the accumulation of protein aggregates. Interaction studies between insulin and metformin presented here are due to the chemical effect; hence, further in-depth studies are required to identify the molecular mechanism of insulin sensitivity and changes in cellular processes and pathways.

The results suggest that metformin safeguards against fructosylation-induced structural, conformational, morphological, and amyloidogenic aggregating tendencies of insulin. Protein aggregation has been linked to several neurological and metabolic diseases. Hence, metformin may be crucial in preserving the biological activity of insulin by maintaining and protecting its structural integrity and minimizing the associated comorbidities. The study may further be extended to identify the role of metformin in controlling the gradual insulin resistance in T2DM at the molecular level.

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.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. The aim of this study was to explore the possibility of OS hypoxia subtype for anti-OS mRNA vaccine development and select suitable patients for precision therapy.

We comprehensively explored hypoxia-related genes (HRGs) as potential sources of tumor neoantigens in OS patients. Gene set enrichment analysis algorithm and consensus clustering analysis were used to determine immune subtypes and evaluate tumor microenvironment. Estimation of stromal and immune cells in malignant tumour tissues using expression data algorithm was used to assess tumour immune activity. The OS hypoxia landscape was visualized using dimensionality reduction analysis based on the DDRTree algorithm. Assessment of clinical samples and molecular experiments were performed to verify the determined tumor antigens.

Four overexpressed and mutated tumor antigens associated with prognosis and infiltration of antigen-presenting cells were identified and verified by clinical samples and molecular experiments. Furthermore, OS patients were stratified into two OS hypoxia subtypes. Interestingly, patients with the OS hypoxia subtype 1 tumor had a superior survival than those with the OS hypoxia subtype 2 tumor. Distinct expressions of immune checkpoint proteins (ICPs) and immunogenic cell death (ICD) modulators were observed in different immune subtype tumors. Finally, the immune landscape of OS showed a high degree of heterogeneity between individual patients.

This study identified potential antigens for the anti-OS mRNA vaccine as well as different OS hypoxia subtypes, guiding more effective immunotherapeutic strategies and selecting appropriate patients for tumor vaccine therapy.

This study aimed to investigate the target sites, core pathways, and mechanisms of action of melittin in treating ovarian cancer through network pharmacology, molecular docking, and experimental verification.

Potential targets for melittin in ovarian cancer treatment were predicted using databases, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The binding of the drug to these targets was confirmed through molecular docking. The core targets and pathways were experimentally validated. A tumor-bearing nude mouse model was established, with the mice randomly divided into treatment and control groups. The treatment group received 5 mg/kg of melittin by intraperitoneal injection, whereas the control group received saline injections. Changes in mouse weight and tumor volume were monitored, and protein expression in mouse tumor tissues was assessed via immunohistochemistry and Western blotting at the end of the experiment.

Fifty-three common targets between melittin and ovarian cancer were identified in the SEA and GeneCards databases. The Protein-Protein Interaction (PPI) analysis highlighted core targets, including MMP9, STAT3, MMP2, STAT6, FURIN, and BRCA1. The GO enrichment results were related mainly to the metabolic processes of collagen degradation, extracellular matrix disassembly, external encapsulating structures, and phospholipase C-activated G-protein-coupled receptor signaling pathways. The KEGG pathway analysis revealed the enrichment of genes related to estrogen signaling, necroptotic apoptosis, the FoxO signaling pathway, microRNAs in cancer, the JAK-STAT signaling pathway, proteoglycans in cancer, and receptor-mediated carcinogenesis. Cell Counting Kit-8 (CCK8) assays, scratch wound healing tests, and Transwell invasion assays demonstrated that melittin significantly inhibited the proliferation, migration, and invasion of ovarian cancer cells. The Western blot results indicated that melittin downregulated the levels of p-JAK2, p-STAT3, and MMP9 in ovarian cancer cells. Molecular docking demonstrated that melittin bound stably to MMP9 and STAT3. The results of animal experiments indicated that melittin suppressed the growth of ovarian tumors in nude mice and significantly downregulated the expression of MMP9, p-JAK2, and p-STAT3 in tumor tissues (p<0.05).

Melittin may inhibit the growth of ovarian cancer cells by downregulating MMP9 expression via the JAK2-STAT3 signaling pathway, thus exerting a therapeutic effect.

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.

Type 2 diabetes (T2D) is a disease of high prevalence that is expected to continue increasing despite the pharmacological treatments available; in most cases, it is difficult to control. Therefore, more research on experimental drugs is necessary to propose better treatments.

This study aimed to identify the molecular alterations of pancreatic islets in type 2 diabetes through multi-omics data integration and possible pharmacological targets using bioinformatics methods.

In this study, the OmicsNet tool was used to integrate the multi-omics data associated with T2D, and the protein-protein interaction was visualized. Then, gene ontology and KEGG pathways analyses were carried out. Using the DrugRep server, the hub genes obtained underwent a virtual screening with experimental drugs, and twelve experimental drugs were selected to execute the molecular docking by CB-Dock2. Finally, the interactions were displayed in BIOVIA software.

Our results showed that the main molecular alterations of pancreatic islets in T2D were enzyme binding, mitochondrial metabolism, transcription factors, etc. They were involved in glucose uptake, receptor insulin signaling, and secretion. The molecular docking showed that SRC, AKT1, CREBBP, and HSP90AA1 were therapeutic targets for DB02729, DB04877, DB07970, DB07789, and DB03373.

We identified some alterations in the pancreas of patients with T2D, ten hub genes, and five experimental drugs that could potentially correct gene expression abnormalities. However, further studies are required to validate these results.

The rise of drug-resistant strains of Mycobacterium tuberculosis (Mtb) represents a substantial public health challenge. Current TB treatments involve the combination of several antibiotics and other agents. However, the development of drug resistance, reduced bioavailability, and elevated toxicity have rendered most of the drugs less effective.

To resolve this problem, the identification of novel anti-tuberculosis agents with novel mechanisms of action is the need of the hour. HsaA monooxygenase is an enzyme involved in cholesterol metabolism, particularly in certain strains of Mycobacterium bacteria. This research focuses on discovering new inhibitors for HsaA from a pool of 40 compounds using computational techniques like molecular docking and Molecular Dynamics (MD) simulations along with comparing it with GSK2556286.

Docking studies revealed that AK05 and AK13 showed good binding affinity as compared to GSK2556286. The docking scores of AK05, AK13, and GSK2556286 are -9.4, -9.0, and -8.9 kcal/mol, respectively. ADMET studies showed that these thiadiazole derivatives can be investigated as lead molecules for the development of novel antituberculosis drugs. MD simulation studies showed that both of the compounds AK05 and AK13 were stable at the binding site with RMSD below 0.25 nm.

All these findings demonstrated that AK05 and AK13 could be used as potent compounds for the development of HsaA monooxygenase inhibitors.

As the leading cause of cancer-related deaths globally, colorectal cancer (CRC) ranks third in prevalence. Gene Expression Omnibus (GEO) offers clinicians and bioinformaticians an accessible platform for genomic research across various cancer types, with a particular emphasis on CRC.

We aim to uncover key genes and pathways in the Chinese CRC population.

We identified differentially expressed genes (DEGs) in CRC utilizing four microarray datasets sourced from the GEO database, all specifically from the Chinese population. Functional enrichment analysis was conducted to uncover the molecular mechanisms at play in CRC. The PPI network and CytoHubba tools were employed to identify key genes linked to CRC, with further validation through databases such as Gene Expression Profiling Interactive Analysis (GEPIA), ONCOMINE, and the Human Protein Atlas (HPA).

Our analysis identified 188 DEGs with overlapping significance, comprising 97 up-regulated and 91 down-regulated genes. Gene Ontology (GO) analysis indicated that up-regulated DEGs were predominantly involved in the extracellular space. In contrast, the down-regulated ones were linked to bicarbonate transport and extracellular exosomes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted the involvement of up-regulated DEGs in cytokine-cytokine receptor interactions and the TNF signaling pathway. In contrast, the down-regulated genes were associated with nitrogen metabolism and bicarbonate reclamation in the proximal tubule. Notably, the transcriptional levels of CCL20, CDC20, CXCL1, CXCL2, CXCL5, NEK2, and PPBP were elevated in CRC tissues compared to normal tissues. In addition, CXCL12 showed a decreased expression. Additionally, the translational levels of CDC20 and PPBP were found to be higher in CRC tissues.

Eight genes (CCL20, CDC20, CXCL1, CXCL12, CXCL2, CXCL5, NEK2, and PPBP) were identified as potential diagnostic indicators for CRC. The identified pathways, such as cytokine-cytokine receptor interactions and TNF signaling, along with nitrogen metabolism and bicarbonate reclamation in the proximal tubule, are hypothesized to have a role in the genesis and progression of CRC. This study provides unique insights into the etiology and progression of CRC within the Chinese population.

Intellectual disability (ID) is characterized by impairments in cognitive functioning and adaptive behavior. Globally, it affects 1-3% of the general population, with an increased prevalence in consanguineous families. It is a clinically heterogeneous disorder that can manifest as a variable phenotype. Intellectual developmental disorder and retinitis pigmentosa (IDDRP) is a rare syndrome in which patients present with both ID and retinitis pigmentosa.

This study examined a consanguineous family to identify disease-associated pathogenic mutations and elucidate their potential functional impact in patients with IDDRP.

Clinical assessment of the patients revealed characteristics consistent with both intellectual disability (ID) and retinitis pigmentosa. Individuals affected by IDDRP were subjected to whole exome sequencing (WES), and the identified candidate pathogenic variants were validated by Sanger sequencing. Computational analyses were conducted to evaluate the impact of these mutations on the protein structure and function.

WES identified a protein-truncating variant, c.2605A>T (p.Lys869Ter), in the S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) gene. SCAPER has previously been reported to cause IDDRP. In silico analyses revealed structural and interactional alterations in the SCAPER protein. This variant is novel in the Pakistani population and has not been previously reported. This variant exhibits an autosomal recessive mode of inheritance and segregates among the investigated affected and unaffected family members.

The present study expands the spectrum of disease-causing variants in SCAPER and will contribute to a better understanding of the genetic etiology of IDDRP.

Renal cancer presents a significant global health challenge due to its rising incidence and mortality rates. Often undetected in early stages, it complicates diagnosis and treatment. Current therapies face resistance and limited effectiveness, especially in advanced stages. The diverse subtypes of renal cancer highlight the need for new biomarkers and risk assessment tools for targeted treatments.

This study aims to assess the prognostic significance of global DNA methylation (GM) levels in renal cancer, identify new biomarkers, and evaluate the therapeutic potential of the DNA methyltransferase inhibitor decitabine.

Data on RNA sequencing, gene mutations, DNA methylation, and clinical outcomes were collected from TCGA and GEO databases. We calculated global DNA methylation scores (GMS) and categorized patients into high, intermediate, and low GMS groups. Survival analysis and genomic analyses were conducted to explore the relationships between GMS, clinical outcomes, and tumor characteristics.

Higher GMS was identified as an independent prognostic factor associated with worse outcomes in renal cancer. Patients with elevated GMS showed increased mutations, copy number variations, and a more aggressive tumor phenotype. Treatment with decitabine was observed to reduce tumor hypermethylation and downregulate cell cycle pathway activity, indicating potential therapeutic benefits.

Global DNA methylation plays a significant role in renal cancer prognosis. GMS may serve as valuable biomarkers for prognosis and personalized treatment strategies. Decitabine shows potential efficacy for high GMS patients, particularly through its impact on cell cycle regulation, underscoring the importance of personalized approaches in cancer treatment.

Endothelial dysfunction (ED) results from impaired vascular endothelial cell function, disrupting key processes such as hemostasis, vascular tone regulation, vasculogenesis, angiogenesis, and inflammation. These processes are mediated by a complex signaling network involving hormones, cytokines, and chemokines. ED is recognized as a major contributor to the onset and progression of several micro- and macrovascular diseases, including diabetes. Our previous study demonstrated that the polyphenol Rosolic acid (RA) protects against endoplasmic reticulum (ER) stress-induced ED in vitro by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, RA enhanced the proliferation and survival of pancreatic β-cells in a co-culture model with endothelial cells under ER stress conditions.

In this study, we investigated RA's protective effects against diabetes-induced ED using high-fat diet (HFD)-fed and streptozotocin-induced type-2 diabetic rat models. We evaluated RA’s impact on vascular function and metabolic parameters in these models.

RA significantly mitigated diabetes-induced ED in the aortic tissues of HFD-fed diabetic Wistar rats. RA treatment improved glucose tolerance and reduced hyperlipidemia, showing efficacy comparable to the anti-diabetic drug Gliclazide. Moreover, RA elevated Nrf2 levels and its downstream target genes in aortic tissues while reducing ED markers such as Intercellular Adhesion Molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and endothelin-1.

These findings highlight RA as a promising therapeutic agent for diabetes and its associated vascular complications, with potential for broader clinical applications.

The precise function of DDX59 Antisense RNA 1 (DDX59-AS1) in lung adenocarcinoma (LUAD) has yet to be fully elucidated.

This study uses bioinformatics analysis and experimental validation to investigate the association between DDX59-AS1 and LUAD.

This study uses statistical analysis and database interrogation to investigate the potential association between DDX59-AS1 expression and various clinical characteristics, prognostic factors, regulatory networks, and immune infiltration in LUAD. The quantification of DDX59-AS1 expression in LUAD cell lines is conducted through the use of quantitative real-time polymerase chain reaction (qRT-PCR).

DDX59-AS1 showed significantly elevated levels of expression in patients with LUAD. High levels of DDX59-AS1 expression were found to be significantly associated with poorer overall survival (OS) in patients with LUAD (p = 0.024). Furthermore, an independent correlation was observed between high DDX59-AS1 expression (p = 0.037) and OS in LUAD patients. DDX59-AS1 was found to be involved in various pathways, including glutathione metabolism, proteasome function, and the cytosolic DNA sensing pathway, among others. A significant correlation was observed between the expression levels of DDX59-AS1 and immune cell infiltration in the context of LUAD. Notably, elevated expression of DDX59-AS1 was observed in LUAD cell lines compared to the non-cancerous Beas-2B cell line.

A significant correlation was observed between elevated DDX59-AS1 expression in patients with LUAD and adverse prognosis, alongside increased immune infiltration. These results indicate that DDX59-AS1 may function as a prognostic marker for LUAD and a potential predictor of immunotherapy response.

We aimed to develop Ferroptosis-Related Gene (FRG) signatures to predict overall survival (OS) along with disease-free survival (DFS) in individuals with colorectal cancer (CRC).

Prediction of CRC prognosis is challenging. Ferroptosis constitutes a newly reported kind of cell death, and its association with CRC prognosis remains unexplored.

This research endeavored to establish a prognostic risk signature for colorectal cancer by leveraging ferroptosis-related genes (FRGs), with the objective of refining prognostic precision in clinical settings.

The clinical data and mRNA expression profiles were obtained from The Cancer Genome Atlas (TCGA) colorectal cancer cohorts. The Lasso algorithm was employed to develop the overall survival (OS) and disease-free survival (DFS) prediction models. These models were subsequently validated using independent data from GSE38832.

Our research unveiled a significant difference in the expression levels of 85% of ferroptosis-related genes (FRGs) between CRC tissues and paracancer tissues. Out of these, 11 prognostic genes were pinpointed through univariate Cox analysis. By employing two models, patients were stratified into low- and high-risk groups based on predicted risk scores, which were subsequently validated as independent prognostic factors via multivariate Cox analysis. The robustness of these models was further confirmed through Receiver Operating Characteristic (ROC) curve analysis. Functional enrichment analysis indicated a predominance of cancer-associated pathways in the high-risk group, including WNT signaling, along with variations in immune status between the two risk categories. Leveraging the Connectivity Map (CMap) database, a total of sixteen potential therapeutic drugs were identified. Additionally, in vitro experiments corroborated that Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1) was underexpressed in CRC and exhibited tumor suppressive properties. More specifically, FDFT1 may augment ferroptosis in CRC by modulating the expression of the Iron-Sulfur Cluster Assembly Enzyme (ISCU).

Our study highlighted the significance of ferroptosis-related genes in the pathogenesis of CRC and underscored the potential of ferroptosis-related gene-based risk signatures as valuable tools for improving prognostic accuracy and tailoring therapeutic strategies. However, the validity of these predictive models required further validation through real-world studies to ensure their reliability and applicability.

G-quadruplexes (G4s) are non-classical high-level structures that are formed by DNA/RNA sequences and have been a promising target for developing antitumor drugs. However, it is still a challenge to find a ligand that binds to a particular G4 with selectivity. Telomeric multimeric G4s are more accessible for screening for specific ligands due to their higher-order structure compared with telomeric monomeric G4s.

In this study, the natural product berberine was found to exhibit a higher selectivity for telomeric multimeric G4 in comparison with other G4s. The mechanism of interaction between telomeric G4s and berberine was further investigated by fluorescence spectra measurements, job plot analysis, and UV titrations. We found that there are three binding sites for berberine on telomeric dimeric G-quadruplex Tel45, which are located at the 5' and 3' terminal G-quartet surfaces and the pocket between the two quadruplex units of Tel45. It was worth noting that the berberine preferred to interact within the interfacial cavity between two G4 units.

Moreover, via dynamic light scattering (DLS) and native polyacrylamide gel electrophoresis (Native-PAGE) assays, it was found that the particle size of the telomeric multimeric G4s conformation was significantly increased by the addition of berberine. In contrast, the particle sizes of Tel21 did not change significantly after the addition of berberine. An immunofluorescence assay indicated that berberine induced the formation of endogenous telomeric G4 structures along with the related telomeric DNA damage response.

This study provides a hypothetical basis for the development of natural products targeting telomeric G4 as antitumor drugs.

Escherichia coli strains are known to cause various gastrointestinal disorders, with Shiga toxin 2, a potent cytotoxin, being a key virulence factor contributing to disease severity. Targeting Shiga toxin 2 presents a promising approach for therapeutic intervention in controlling E. coli O157 infections. This study aims to explore natural and synthetic inhibitors as potential therapeutic agents against Shiga toxin 2 through in-silico molecular docking and drug-likeness predictions.

An in-silico molecular docking study was conducted using AutoDock Vina and Chimera to assess the binding affinity of various natural and synthetic inhibitors against Shiga toxin 2. The selected inhibitors were evaluated for their drug-likeness based on adsorption, distribution, metabolism, and excretion (ADME) properties, applying Lipinski's rule of five and the Boiled-Egg technique to predict their suitability as potential drugs in biological systems.

During the screening process, luteolin, a natural flavonoid, exhibited the highest binding affinity to Shiga toxin 2, with a notable negative binding energy of -8.7 kcal/mol, indicating strong interaction potential.

The findings suggest that luteolin holds promise as a lead molecule for further development as a therapeutic agent against E. coli infections, warranting additional studies to validate its efficacy and safety.

Hyperuricemia (HUA) is a condition characterized by excessive uric acid production and/or inadequate uric acid excretion due to abnormal purine metabolism in the human body. Uric acid deposits resulting from HUA can lead to complications such as renal damage. Currently, drugs used to treat HUA lack specificity and often come with specific toxic side effects.

This study aimed to investigate the renal protective effects of an optimized tea polyphenol formula and allopurinol in a rat model of hyperuricemia following renal resection. The goal was to explore the mechanisms underlying these effects.

Initially, a blend was formulated based on the distinctive functions of catechins, thearubigins, tea polysaccharides, and theanine. Orthogonal experiments were then employed to select a rational combination. A 5/6 renal resection rat model was successfully established, and the animals were fed a 2% oxonic acid diet to induce hyperuricemia. Urinary protein content was measured using the biuret method, and serum levels of uric acid, creatinine, and urea nitrogen were determined biochemically. Kidney pathology was examined through HE staining and renal tubulointerstitial pathological scoring. The expression of α-SMA, CD34, PCNA, and TGF-β in renal tissue was detected using immunohistochemistry. Apoptosis of renal tubular epithelial cells was assessed using the TUNEL method.

Hyperuricemia markedly worsens renal damage in rats following nephrectomy, while tea polyphenols demonstrate the ability to reduce levels of blood uric acid, urea nitrogen, creatinine, and urinary protein. Additionally, tea polyphenols enhance smooth muscle proliferation in renal glomerular arterioles, prevent the loss of interstitial capillaries, alleviate apoptosis of renal tubular epithelial cells, promote their proliferation, and reduce interstitial fibrosis. A significant improvement in the severity of renal damage is observed in rats subjected to nephrectomy combined with hyperuricemia, and this effect surpasses that of allopurinol.

Tea polyphenols could effectively alleviate renal damage in rats with nephrectomy combined with hyperuricemia. They demonstrate high cost-effectiveness and minimal side effects, positioning them as a promising new therapeutic option for hyperuricemia-induced renal damage.

To build an innovative telomere-associated scoring model to predict prognosis and treatment responsiveness in acute myeloid leukemia (AML).

AML is a highly heterogeneous malignant hematologic disorder with a poor prognosis. While telomere maintenance is frequently observed in tumors, investigations into telomere-related genes (TRGs) in AML remain limited.

This study aimed to identify prognostic TRGs using the least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression, evaluate their predictive value, explore the association between TRG scores and immune cell infiltration, and assess the sensitivity of high-scoring AML patients to chemotherapeutic agents.

Univariate Cox regression analysis was conducted on the TCGA cohort to identify prognostic TRGs and to develop the TRG scoring model using LASSO-Cox and multivariate Cox regression. Validation was performed on the GSE37642 cohort. Immune cell infiltration patterns were assessed through computational analysis, and the sensitivity to chemotherapeutic agents was evaluated.

Thirteen prognostic TRGs were identified, and a seven-TRG scoring model (including NOP10, OBFC1, PINX1, RPA2, SMG5, MAPKAPK5, and SMN1) was developed. Higher TRG scores were associated with a poorer prognosis, as confirmed in the GSE37642 cohort, and remained an independent prognostic factor even after adjusting for other clinical characteristics. The high-score group was characterized by elevated infiltration of B cells, T helper cells, natural killer cells, tumor-infiltrating lymphocytes, regulatory T (Treg) cells, M2 macrophages, neutrophils, and monocytes, along with reduced infiltration of gamma delta T cells, CD4- T cells, and resting mast cells. Moreover, high infiltration of M2 macrophages and Tregs was associated with poor overall survival compared to low infiltration. Notably, high-risk AML patients were resistant to Erlotinib, Parthenolide, and Nutlin-3a, but sensitive to AC220, Midostaurin, and Tipifarnib. Additionally, using RT-qPCR, we observed significantly higher expression of two model genes, OBFC1 and SMN1, in AML tissues compared to control tissues.

This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.

Astaxanthin (AXT), a natural antioxidant recognized for its therapeutic potential in cancer and cardiovascular diseases, holds promise in mitigating adriamycin-induced cardiotoxicity (AIC). Nevertheless, the underlying mechanisms of AXT in AIC mitigation remain to be elucidated. Consequently, this study endeavors to elucidate the mechanism of AXT against AIC, employing an integrated approach.

Network pharmacology, molecular docking, and molecular dynamics simulations were harnessed to explore the molecular mechanism underlying AXT's action against AIC. Furthermore, the in-vitro AIC model was established with the H9c2 cell to generate transcriptome data for validation.

A total of 533 putative AXT targets and 1478 AIC-related genes were initially screened by database retrieval and bioinformatics analysis. A total of 248 potential targets of AXT against AIC and several signaling pathways were identified by network pharmacology and enrichment analysis. Two core genes (CCL2 and NOS3) and the AGE-RAGE signaling pathway in diabetic complications were further highlighted by transcriptome validation based on the AIC in-vitro model. Additionally, molecular docking and dynamics analyses supported the robust binding affinity of AXT with the core targets.

The study suggested that AXT might ameliorate AIC through the inhibition of CCL2 and NOS3 as well as AGE-RAGE signaling, which provide a theoretical basis for the development of a strategy against AIC.

Prosopis juliflora has been employed in many traditional treatments. As evidenced by our earlier research, Prosopis juliflora leaf methanol extract (PJME) has a promising future in the fight against lung cancer. It may also be used in conjunction with other treatments to effectively manage lung cancer. Aims and objective: The main objective of this study was to explore the potential of PJME to inhibit lung cancer in A549 cells, along with its underlying mechanisms of action.

The antiproliferative effects were determined using MTT and LDH tests. Apoptosis-inducing capacity was evaluated using the DAPI staining, caspase-3 test, cytochrome C assay, PARP cleavage, and qRT-PCR. To investigate the mechanism of action of PJME in lung cancer, the levels of ROS, MMP, GSH, MDA, and specific ferroptosis indicators were measured.

The experimental data of the current study indicated that exposure of A549 cells to PJME reduced cell viability and increased cellular cytotoxicity. The apoptosis-inducing ability of PJME in A549 cells was validated by enhanced nuclear condensation, level of the caspase-3, cytochrome C, and PARP release. In addition, qRT-PCR investigations verified that the administration of PJME led to a decrease in the expression of anti-apoptotic gene Bcl2 while enhancing the mRNA level of pro-apoptotic genes, such as Bax and caspase-3, in A549 cells.

The study also found that PJME has the ability to activate ferroptosis pathways, as evidenced by elevated reactive oxygen species (ROS) generation, changes in the levels of antioxidant markers (MDA and GSH), and decreased expression of SLC7A11 and GPX4. The results of the present study clearly showed that PJME inhibited the proliferation of A549 cells and induced ferroptosis by reducing the expression of the important targets SLC7A11 and GPX4. Further research is necessary to fully understand the clinical efficacy of PJME before it can be investigated as supplemental or adjuvant therapy for lung cancer.

Menopause symptoms may be distressing, especially when they appear at a time when women are expected to play significant responsibilities in society. Numerous biological systems are influenced by the hormonal changes that start during the menopausal transition. This review attempts to decipher the complex relationship between obesity, menopause, and depression, citing some recent longitudinal and cross-sectional studies. Additionally, this study provides a summary of the different phytoestrogens, their sources, and probable mechanisms of action in addition to available therapeutic alternatives.

For this review purpose, the authors have gone through a vast number of articles from various scientific databases like PubMed, Google Scholar, and Web of Science.

It is becoming clear that the physiological basis for these menopausal symptoms is complicated and connected to estrogen deficiency, but not alone. Other hormones like FSH, LH, progesterone, and inhibin B are the major ones that are both directly and indirectly responsible for most of the menopausal symptoms. Numerous longitudinal and cross-sectional studies have found a direct relationship between the incidence of menopause and depression as well as obesity. Phytoestrogens like stilbene, lignans, isoflavone, and coumestan have been reported to be the alternatives to synthetic estrogen with lesser side effects, as reported in various studies.

The complex relationship between depression, menopause, and obesity presents a complex obstacle to women's health and overall well-being. There might be a lot of promising prospects for revolutionary advancements in women's health during the menopausal stage in the future. Promising drug development that targets not just one but also the three conditions -obesity, menopause, and depression - as well as more thorough research are needed to improve the healthcare system for women who suffer from these conditions.

Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health.

This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-like cells.

Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry.

The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing.

The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

Aspergillus fumigatus, a significant fungal pathogen, poses a threat to human health, especially in immunocompromised individuals. Addressing the need for novel antifungal strategies, this study employs virtual screening to identify potential inhibitors of Fructosamine oxidase, also known as Amadoriase II, a crucial enzyme in A. fumigatus (PDB ID: 3DJE).

Virtual screening of 81,197 triazole derivatives was subjected to computational analysis, aiming to pinpoint molecules with high binding affinity to the active site of Fructosamine oxidase. Subsequently, an in-depth ADMET analysis assessed the pharmacokinetic properties of lead compounds, ensuring their viability for further development. Molecular dynamics simulations were performed to evaluate the stability of top-ranked compounds over time.

The results unveil a subset of triazole derivatives displaying promising interactions, suggesting their potential as inhibitors for further investigation.

This approach contributes to the development of targeted antifungal agents, offering a rational starting point for experimental validation and drug development against Aspergillus fumigatus infections.