Current Medicinal Chemistry - Online First

Type 1 Diabetes Mellitus (T1DM) is characterized by the damage of pancreatic β-cells induced by autoimmune responses. Circular RNAs (circRNAs) play important regulatory roles in the pathogenesis of T1DM, but the underlying mechanisms require further substantiation.

This study focused on a novel circRNA, circ006029, to investigate its regulation on β-cell damage. The potential involvement of circ006029 in β-cell proliferation, apoptosis, autophagy, and inflammatory responses was investigated using CCK-8, qRT-PCR, and immunoblot assays. The utilization of a cytokine mixture, and specific molecular blockers Rapamycin and Capivasertib, was applied to investigate the pathway by which circ006029 regulates β-cell damage. Transcriptome sequencing and bioinformatics analysis were conducted to explore differentially expressed mRNAs related to circ006029 regulation.

The expression of circ006029 was observed to increase in damaged MIN6 cells. The inhibition of circ006029 serves a protective role in MIN6 β-cells by promoting β- cell proliferation and attenuating apoptosis. circ006029-knockdown could augment β- cell autophagy and attenuate apoptosis through the AKT/mTOR signaling pathway. Moreover, circ006029 might be involved in the inflammatory response of MIN6 cells.

The knockdown of circ006029 was demonstrated to alleviate β-cell inflammation and reduce cell apoptosis. The promotion of β-cell proliferation and heightened autophagy also substantiated the protective effects of circ006029 silence. Furthermore, we also proved that circ006029 might contribute to autophagy via the AKT/mTOR signaling pathway. All the results implied that the presence of circ006029 may drive a detrimental regulatory role in pancreatic β-cells. This may provide valuable evidence that circ006029 might be a potential target for alleviating β-cell damage in T1DM and rebuilding β-cell function.

These findings suggest that circ006029 may serve a detrimental role in β- cell damage, which provides new ideas for exploring the mechanism of β-cell damage in early insulitis in T1DM.

Respiratory syncytial virus (RSV) causes more than 30 million cases of lower respiratory tract infections (LRTIs) and approximately 3 million hospitalizations globally each year. Although RSV is particularly dangerous for young children, older adults and individuals with underlying health conditions or weakened immune systems are also at risk. Rapid diagnosis of RSV infection is crucial to ensure timely treatment and prevent disease spread. While conventional diagnostic techniques exist, many are time-consuming, expensive, or labor-intensive. Biosensors have recently emerged as a promising alternative.

This review involved gathering original articles published in English from various databases, including PubMed, Scopus, Web of Science, and Embase, between August and October, 2024. Additionally, reference lists from these articles were examined in Google Scholar for further relevant sources. Out of 147 electronically searched citations, 15 articles met the inclusion criteria.

Genosensors, particularly those employing Surface-Enhanced Raman Scattering (SERS) and electrochemical detection, demonstrated the most significant potential for RSV diagnosis. Biosensors are increasingly being applied for RSV detection due to their high sensitivity, accuracy, and rapid results. The most prevalent conventional techniques for RSV detection include immunofluorescence (IF), ELISA, cell culture, and RT-PCR (Real-time PCR). While molecular methods are fast and sensitive, they require advanced laboratory equipment and trained personnel. In contrast, biosensors offer a rapid, reliable, and cost-effective diagnostic approach.

Biosensors have emerged as a powerful diagnostic platform for RSV, providing faster, more sensitive, and cost-effective detection compared to conventional methods. Continued development and clinical validation of biosensor technologies could transform RSV surveillance and management, especially in low-resource or point-of-care settings.

Biosensors represent a significant advancement in RSV diagnostics, particularly in resource-limited settings. Enhancing biosensor technology could improve accessibility, speed, and accuracy in RSV detection, ultimately leading to better patient outcomes and reduced disease transmission.

An excessive inflammatory response plays a central role in the pathogenesis of ulcerative colitis (UC), but the specific cytokines involved remain unclear. This study aimed to identify inflammatory factors associated with UC and explore the possible mechanisms of the identified targets.

Protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) for inflammatory cytokines were obtained from a genome-wide pQTL study and the eQTL consortium, respectively. Summary data for UC from the exploration and validation cohorts were derived from a genome-wide association study and the Finngen cohort. MR and colocalization analyses were conducted to identify causal associations between inflammatory cytokines and UC. Bioinformatics analyses were employed to explore the involved biological processes of candidate targets. Immunohistochemistry was used to validate the expression of these candidate targets in colon tissues.

Among all inflammatory cytokines, a significant causal association was identified between C-X-C motif chemokine ligand 5 (CXCL5) and UC. Using eQTL data, a significant genetic association was established between the mRNA expression of CXCL5 and its receptor, C-X-C motif chemokine receptor 2 (CXCR2), with UC. Colocalization analysis further supported these identified links. Differential expression analysis confirmed the dysregulation of the CXCL5/CXCR2 axis in UC patients. Enrichment and immune infiltration analysis indicated that the CXCL5/CXCR2 axis was involved in neutrophil chemotaxis and immune activation in UC. Moreover, CXCL5 expression was found to correlate with neutrophil extracellular trap (NET) formation in UC. Immunohistochemistry further confirmed the dysregulation of the CXCL5/CXCR2 axis in colon tissues of UC patients.

The CXCL5/CXCR2 axis has been implicated to play a significant role within a broader inflammatory network that includes Interleukin (IL)-17, NF-κB, and Tumor Necrosis Factor (TNF) signaling pathways. Additionally, this axis interacts with macrophages and T cells, further contributing to the complexity of inflammatory responses in UC.

There is a significant association between CXCL5/CXCR2 and UC under the MR assumption, which is potentially linked with colonic chemotaxis and activation of neutrophils. These findings highlight the potential of CXCL5/CXCR2 as a therapeutic target for UC. However, future functional studies are needed to validate these findings and explore the exact mechanisms by which CXCL5/CXCR2 influences immune cell crosstalk in UC.

Spirooxindoles have been reported to be effective anticancer drug candidates by displaying promising pre-clinical results. Therefore, to find out a lead spirocyclic oxindole template, a series of spirooxindole derivatives bearing pyrrolizidine (14a-e) and N-methyl pyrrolidine (15a-e) were synthesized using an efficient multicomponent, one-pot, and stereoselective [3+2] cycloaddition reaction and evaluated in vitro against HT29 and HCT116 human colon cancer cell lines.

The pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives were synthesised in excellent regio- and stereoselectivity using previously optimized reaction conditions. They were evaluated in vitro against cell lines HT29 and HCT116. In silico ADME profiling, molecular docking, and dynamics simulation studies were performed to ascertain the probable mode of action of the lead derivative.

The spirooxindoles were characterized using FTIR, ESI-MS, ¹H and ¹³C NMR, purity was determined by RP-HPLC, and stereochemistry was confirmed by X-ray crystallography. Compound 14a produced the best anti-colon cancer activity with IC50 values of 62.66 and 9.55 µM against HT29 and HCT116 human colon cancer cell lines, respectively. The in silico studies revealed that MDM2 protein inhibition is a probable mode of anti-colon cancer activity, supported by the data obtained in the molecular docking and molecular dynamics study.

The described [3+2] cycloaddition reaction proved to be a highly efficient and catalyst-free reaction. The in vitro cell viability assays and in silico studies revealed that more spirooxindoles can be designed with a varied degree of substitution to target colon cancer.

Sarcomas are heterogeneous mesenchymal tumors with poor responses to systemic therapies. Ubiquitination is a post-translational modification that regulates various physiological processes and cancer growth.

We analyzed the transcriptomic data of 256 sarcoma patients from The Cancer Genome Atlas (TCGA) to define the network and prognostic value of predefined ubiquitination-related genes and performed subgroup analyses. Additionally, the role of TRIM21 in sarcoma progression was explored using cellular experiments.

We identified two ubiquitination-related clusters, and patients in the two clusters were characterized by different survival outcomes, enriched pathways, and characteristics of the tumor microenvironment. A ubiquitination-related signature involving LRRC41, RNF125, TRIM21, and UBE3D was identified to predict prognoses. The signature was associated with patient prognoses in the public sarcoma cohorts and our independent cohort. Immunohistochemistry analyses revealed that the risk score and CD8 could distinguish patients with different survival outcomes in our cohort. Mechanistically, different risk groups were also characterized by distinct enriched pathways and characteristics of the tumor microenvironment. Cellular experiments revealed that TRIM21 overexpression could suppress tumor progression in sarcomas.

This study provided a novel classification for sarcoma patients based on expressions of ubiquitination-related genes. The classification and the prognostic model may facilitate the understanding of sarcoma pathogenesis, the prediction of prognosis and immunotherapy response for sarcoma patients. Meanwhile, it was confirmed that TRIM21 suppressed sarcoma progression and identified it as a potential target for therapeutic interventions.

The classification and signature stratify sarcoma patients for prognosis and immunotherapy response, with TRIM21 representing a promising therapeutic target.

Ovarian cancer (OC), characterized by high mortality and lacking early diagnostic markers, poses a significant health threat. This study investigated the expression of metabolic reprogramming and circadian rhythm-related genes (MRCRRGs) in OC and their association with clinical features.

OC datasets and MRCRRG lists were sourced from TCGA, GEO, and GeneCards. Comprehensive bioinformatics analyses included calculating Metabolic Reprogramming and Circadian Rhythm Scores (MRCR.Score), identifying MRCR score-related genes (MRCRSRGs), building a Cox regression model, performing clustering for subtype identification, analyzing immune cell infiltration and immune checkpoint gene expression, conducting differential expression analysis, and performing Gene Set Enrichment Analysis (GSEA).

We identified 138 MRCRRGs. MRCR. Score differed significantly between OC and controls. Thirty-four MRCRSRGs were identified, and a Cox model based on four genes was developed. Clustering revealed two distinct OC subtypes with significant overall survival differences. Immune infiltration analysis showed significant expression differences in 26 immune cell types, and immune checkpoint genes differed between subtypes. Differential expression identified 89 genes (88 upregulated, 1 downregulated). A six-gene predictive model demonstrated moderate accuracy. GSEA revealed significant enrichment of key pathways, notably Fcgr3a-mediated IL-10 synthesis.

Findings demonstrate strong links between MRCRRGs, OC subtypes, patient survival, and the tumor immune microenvironment. Enrichment of pathways like Fcgr3a-mediated IL10 synthesis suggests novel OC mechanisms. Reliant on bioinformatics, the study provides insights into OC heterogeneity.

This study establishes a foundation for understanding MRCRRG molecular mechanisms in OC. The identified subtypes, prognostic model, immune landscape alterations, and enriched pathways offer valuable insights for future experimental validation and potential diagnostic/therapeutic strategies.

Malignant melanoma is a highly aggressive skin malignancy characterised by metastatic properties and resistance to conventional therapies. This indicates a necessity to explore novel, efficacious treatment modalities. Atranorin, a secondary metabolite derived from lichen, has demonstrated a diverse range of bioactivities. However, the antineoplastic mechanisms of atranorin in melanoma remain underexplored.

Human melanoma cancer cell lines (A-375, G-361, and MDA-MB-435) and normal human melanocytes were treated with various concentrations of atranorin. Cell viability and proliferation were evaluated by MTT assay, apoptosis was assessed using Annexin V-FITC/PI flow cytometry, and cell cycle distribution was determined by PI staining and flow cytometry. Gene expression of apoptosis-related markers was quantified by qRT-PCR, and protein levels were analyzed by Western blot. Cell migration was evaluated by the wound healing assay.

Atranorin demonstrated selective toxicity in human melanoma cancer cells, exhibiting minimal effect on normal human melanocytes. In a study on human malignant melanoma A-375 cells, it was found that atranorin, at an IC50 concentration of 12 μM, significantly increased the number of apoptotic cells by approximately 11-fold. Furthermore, the results of the study indicated that atranorin induced G1 phase arrest and inhibited migratory capacity by around 60%. Molecular profiling revealed the upregulation of the intrinsic (APAF1, BAX, and CASP9) and extrinsic (FAS, FADD and CASP10) apoptotic pathways, and the downregulation of the anti-apoptotic genes BCL2, MCL1, and BIRC5. In line with these observations, protein analyses revealed increased levels of cleaved caspase-3, caspase-9, and PARP, thereby providing evidence for the activation of apoptotic cascades.

In this study, the therapeutic effect of atranorin was comprehensively evaluated for the first time on A-375 melanoma cells, and it was highlighted as a natural compound with strong anti-cancer potential.

This study is the first to demonstrate the potent anti-melanoma effect of atranorin. This demonstrates the natural compounds' effects on cell proliferation, cell cycle progression, and the suppression of metastasis. These findings emphasize the potential of atranorin as a novel natural compound for use in adjunctive or targeted melanoma therapy, and highlight the need for further preclinical and clinical evaluation.