Current Medicinal Chemistry - Online First

This study aims to elucidate the mechanisms contributing to the transition from acute to chronic inflammation, particularly in the context of atherosclerosis, by investigating the pro-inflammatory responses of cybrid cell lines derived from patients with coronary heart disease.

Acute inflammatory reactions are essential components of the innate immune response, typically resolving within hours or days. However, disruptions in this process can lead to chronic inflammation, which is linked to significant morbidity and mortality. Atherosclerosis, characterized by chronic vascular inflammation, poses a major health threat, underscoring the need for understanding its underlying mechanisms.

The primary objective is to analyze the pro-inflammatory cytokine responses of 14 cellular lines, including 13 cybrids and one maternal line (THP-1), to identify intolerant and tolerant responses to key cytokines associated with inflammation.

We utilized cybrid cell lines created by fusing THP-1 monocytic cells with platelets from patients diagnosed with atherosclerosis. Cytokine responses were assessed through quantitative analysis of IL-1β, IL-6, MPC-1, IL-8, and TNF-α secretion. Gene expression profiles were analyzed to correlate cytokine secretion with specific gene regulation patterns, focusing on epigenetic mechanisms influencing immune responses.

Distinct intolerant and tolerant responses were observed across the cellular lines for key cytokines. Specifically, TC-HSMAM1 and TCP-521 were intolerant to IL-1β, TC-HSMAM1, TC-LSM2, and TC-522 were intolerant to IL-6, six lines exhibited intolerance to MPC-1, and eight lines were intolerant to IL-8. No intolerant responses were noted for TNF-α. Gene expression analysis revealed that at least ten genes correlated with increased cytokine secretion in intolerant reactions, while 23 genes showed higher expression during these intolerant responses, indicating significant roles for DNA modification and chromatin remodeling. An important finding emerged from the study of agents affecting histone modification. Specifically, unlike other agents, sodium butyrate not only exhibited a stronger suppression of the inflammatory response in cells but also eliminated their intolerance to inflammatory stimulation. Therefore, in the near future, sodium butyrate could be regarded as a fundamentally new anti-inflammatory preventive and therapeutic agent, with its mechanism of action rooted in the prevention and suppression of chronic inflammation.

In chronic non-infectious diseases like atherosclerosis the intolerant response or trained immunity can worsen inflammation. This study shows that both genetic and epigenetic regulation contribute to this intolerant response. It was also found that sodium butyrate can prevent the intolerant response, suggesting it may become a new anti-inflammatory agent that suppresses chronic inflammation.

Our findings have suggested that the interplay between pro-inflammatory cytokine responses and epigenetic regulation mechanisms is critical in determining whether a cell exhibits a normal or intolerant immune response. Understanding these dynamics may provide insights into the chronic inflammatory processes associated with atherosclerosis and other related conditions.

Coronavirus disease (COVID-19) is a highly infective disease caused by SARS-CoV-2. The SARS-CoV-2 spike protein binds with the human ACE2 receptor to facilitate viral entry into the host cell; therefore, spike protein serves as a potential target for drug development.

Keeping in view the significance of SARS-CoV-2 spike protein for viral replications, in the current study, we identified the potent inhibitors against SARS-CoV-2 spike protein in order to combat the viral infection.

In the current study, we screened an in-house library of ~900 natural and synthesized compounds against the spike protein receptor binding domain (RBD) using a structure-based virtual approach, followed by an in-vitro inhibition bioassay.

Seven (C1-C7) potent compounds were identified with docking scores ≥ −6.66 Kcal/mol; their drug-likeness, pharmacokinetic, and pharmacodynamic characteristics were excellent with no toxic effect. Those molecules were subjected to a triplicate simulation for 200 ns, which further confirmed their stable binding with RBD. This tight packing of complexes was reflected by calculated binding free energy, which disclosed higher binding free energy of C4, C7 and C6 than C1-C3, while predicted entropic energy demonstrates higher values for C4, C7 and C1 than the rest of the compounds, indicating more thermodynamic stability in protein due to conformational changes in spike protein induced by binding of C4, C7 and C1. These computational analyses were later validated through in-vitro bioassay. Remarkably, C2-C7 displayed significant inhibitory potential with >76 to 89% inhibition and C3, C4, C6 and C7 demonstrated the highest inhibition of RBD.

The current findings suggest that compounds C3 and C6 effectively disrupt the function of RBD of SARS-CoV-2 spike protein and can serve as potential drug candidates for spike protein.

GLP-1 receptor peptide agonists have revolutionized type 2 diabetes mellitus and obesity treatment, primarily through injection-based therapies. Small-molecule GLP-1 receptor agonists allow oral administration, but none are clinically established. Pfizer's danuglipron and lotiglipron, presented in 2018-2019, were “first-in-class” drug candidates, becoming prototypes for “next-in-class” drug development.

This review summarizes “next-in-class” GLP-1 receptor agonists developed, identifying different relationships between the molecular structure and functional activity of agonists.

Patents containing danuglipron- and lotiglipron-like agonists from January 2021 to July 2024 were browsed in databases, such as Espacenet and Google Patents, using specified keywords. Over 5,000 compounds from 67 patent publications were analyzed.

Our analysis identified some key general SAR trends. The presence of a carboxyl group leads to highly active agonists, but replacing it with bioisosteric analogs may improve the ADME profile of the target compounds. The introduction of specific privileged fragments, as well as the replacement of 1H-benzo[d]imidazole nucleus or (S)-oxetan-2-ylmethyl substituent in the prototype structure with bioisosteric heterocycles, may be viable approaches. The replacement of 1,4-disubstituted piperidine linker with its (S)-2-methyl-substituted homologue or O, N-disubstituted piperidin-4-ol may also result in highly potent agonists. Additionally, the classic 2,4-EWG-disubstituted benzyl alcohol residue allows significant variability.

Despite the limited clinical success of danuglipron and lotiglipron, as well as the inherent problems associated with the complex nature of GLP-1R signaling, the current state of research and the abundance of novel, promising chemotypes of highly potent compounds suggest that approved GLP-1R agonists may emerge in the coming years.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are major gynecological malignancies, causing significant cancer-related deaths in women. Current treatments yield poor outcomes, with a 5-year survival rate of only 17%. Identifying new biomarkers and therapeutic targets is crucial for improving prognosis and guiding personalized treatments.

We analyzed TCEAL2 expression using data from The Cancer Genome Atlas (TCGA) across various cancers, including CESC. We explored its correlation with clinical features, prognosis, immune infiltration, MSI, mRNAsi, and drug sensitivity. TCEAL2 expression was validated in GSE9750 datasets and CESC cell lines using qRT-PCR.

TCEAL2 expression was significantly dysregulated in CESC. Elevated TCEAL2 levels correlated with poor clinical outcomes, including advanced pathological M stage (p = 0.009), initial treatment failure (p = 0.0098), and reduced overall survival (OS) (p = 0.013). TCEAL2 was an independent predictor of unfavorable OS (p = 0.032). It was associated with key pathways such as calcium signaling, oxidative phosphorylation, and Wnt signaling. TCEAL2 also correlated with immune cell infiltration, MSI, and mRNAsi. Notably, TCEAL2 levels inversely correlated with sensitivity to several drugs, including CAY10603 and SB-223133.

The results suggest that TCEAL2 plays a significant role in CESC progression and its tumor microenvironment. Its correlation with immune infiltration and drug sensitivity highlights its potential as a prognostic biomarker and therapeutic target. Future studies should focus on elucidating the molecular mechanisms and validating their clinical utility.

TCEAL2 is a potential prognostic biomarker and therapeutic target in CESC. Further research is needed to explore its role and clinical applications.

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.