Current Medicinal Chemistry - Online First

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.