Current Medicinal Chemistry - Volume 33, Issue 8, 2026

Atherosclerosis is a chronic disease characterized by the increased infiltration and retention of LDL particles in arterial walls. There are several mechanisms underlying atherogenesis, with the pro-atherogenic modifications of LDL playing a significant role. One such modification of native LDL is desialylation, which is characterized by the removal of terminal sialic acid from ApoB-100 glycans that induces critical changes in the overall functionality of the LDL particle.

The aim of this study was to model the desialylation of native LDL in mice, resembling a phenomenon previously observed in atherosclerotic patients.

LDL desialylation was induced in C57BL/6J mice via the injection of exogenous neuraminidase. The degree of LDL desialylation and its duration were assessed. The impact of LDL desialylation on blood lipid levels was evaluated. Furthermore, the morphological alterations in the aorta during LDL desialylation in the bloodstream were examined.

The control group of C57BL/6J mice received saline injections, while the experimental group underwent a single injection of IgG-conjugated Vibrio cholerae neuraminidase. The LDL sialic acid levels were assessed 1-7 days post-injection using the Warren method and normalized to total protein content measured via the Lowry method. A similar protocol was followed for the subchronic administration of the IgG-neuraminidase conjugate over a 6-week period. The blood lipid profiles were analyzed using commercial kits. The atherosclerotic plaque burden in the mouse aorta was quantified using Oil Red O and hematoxylin-eosin staining.

A single administration of 20 mU IgG-neuraminidase conjugate resulted in decreased LDL sialic acid levels for 5 days, gradually recovering by days 6-7. Subchronic administration maintained reduced LDL sialic acid levels for up to 2 months. Notably, sustained LDL desialylation was associated with elevated LDL cholesterol levels.

A sustained desialylation of LDL in C57BL/6J mice was achieved through subchronic administration of IgG-conjugated neuraminidase. This study provides an approach for sustained LDL desialylation in mice. Further studies using apolipoprotein E knockout mice and LDL desialylation will reveal the role of this process in the occurrence and development of atherosclerosis.

Mitochondria are the main sites of cellular aerobic energy production through conjugation of respiration and oxidative phosphorylation. We have recently discovered mutations (genome variants) of mitochondrial DNA (mtDNA) associated with atherosclerosis. We have then investigated the possible mechanisms underlying such association and the role of mitochondrial mutations in atherogenesis. Mitochondrial dysfunction is a known component of the pathogenesis of chronic human diseases, including atherosclerosis.

The aim of the study was to explore whether there is a relationship between cellular oxygen consumption and atherosclerosis-associated mitochondrial mutations. The study of mitochondrial respiration abnormalities can help to understand the role of mtDNA mutations in pathology.

By using the polarographic method with Clark electrode, we tested the possibility of respiration impairment in permeabilized cells carrying the tested mtDNA variants using the cybrid (cytoplasmic hybrid) lines. Mitochondria introduced in the cybrid lines were obtained from atherosclerotic patients that differed in the profile of mtDNA mutations, which made it possible to compare the degree of mtDNA mutation load with the rate of oxygen consumption by cybrid cells.

It was found that three of the studied mutations were individually associated with impaired respiration. Besides, some combinations of two specific mutations have a high probability of being associated with altered oxygen consumption. As a result, eight mutations were identified, individually or paired combinations of which were associated with high or low rates of cellular respiration, significantly different from control cells.

The observed effect may be involved in the pathogenesis of atherosclerosis. The study of mtDNA mutations associated with atherosclerosis can help reveal pharmacological targets for the development of novel therapies.

Geranyl acetate, a compound found in plant oils, has been studied for its potential effects on renal and cardiovascular ailments.

This study aimed to investigate the diuretic and anti-hyperuricemic properties of geranyl acetate in male Wistar rats using a hyperuricemia-induced rat model.

Molecular docking studies were conducted to assess geranyl acetate's interactions with various targets. In vitro studies were performed to evaluate its scavenging ability and inhibition of xanthine oxidase, urease, and acetylcholinesterase. Subsequently, we administered different doses of geranyl acetate (25, 50, and 100 mg/kg) and a reference drug (furosemide) to the rats to assess their acute and repeated dose diuretic effects over seven days. To understand the diuretic mechanism, we used inhibitors, such as L- NAME, indomethacin, and atropine, prior to administering geranyl acetate. We also tested the anti-hyperuricemic potential of geranyl acetate on hyperuricemic rats.

Molecular docking suggested strong binding between geranyl acetate and nitric oxide synthase. In vitro studies showed significant free radical scavenging activity and and inhibition of acetylcholinesterase, xanthine oxidase, and urease. The 100 mg/kg dose exhibited the most promising diuretic effects, with nitric oxide appearing to influence its action. Uric acid excretion increased at this dose, resembling allopurinol effects.

Geranyl acetate has demonstrated significant diuretic and anti-hyperuricemic effects, likely influenced by nitric oxide release and inhibition of enzymes, like xanthine oxidase and urease. The findings have suggested potential benefits for individuals with kidney ailments, hypertension, and gout.

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.

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.

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.

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.

Coronary atherosclerotic disease (CAD), clinically manifesting as progressive coronary atherosclerosis (As), involves endothelial cell (EC) dysfunction. HYMAI may contribute to atherogenesis by acting on ECs, but its regulation of endothelial injury and role in As pathogenesis remain unclear.

HYMAI expression was assessed via PCR array in blood samples from healthy individuals, patients with premature coronary atherosclerotic disease (PCAD), and patients with mature coronary atherosclerotic disease (MCAD) (each group consisting of 4 males and 2 females). Using male ApoE^−/− and LDLR^−/− mice fed with a high-fat diet (HFD) to model As, we evaluated the effects of endothelial-specific HYMAI overexpression on aortic lesions. Autophagy and apoptosis were analyzed in ox-LDL-treated human coronary artery endothelial cells (HCAECs).

HYMAI levels increased sequentially in healthy individuals, PCAD, and MCAD patients. In HFD-fed ApoE^−/− and LDLR^−/− mice, aortic atherosclerosis progressed with age, while HYMAI expression in aortic tissue declined. HYMAI overexpression in ECs promoted autophagy and attenuated atherosclerosis. In vitro, ox-LDL suppressed HYMAI, triggering autophagic inhibition and apoptotic activation in HCAECs. HYMAI overexpression rescued ox-LDL-impaired autophagy and suppressed apoptosis through the miR-19a-3p/ATG14 pathway. MiR-19a-3p overexpression reversed autophagic rescue and promoted apoptosis by repressing ATG14.

HYMAI upregulation counteracts ox-LDL-treated endothelial autophagic inhibition via the miR-19a-3p/ATG14 pathway, rescuing apoptosis and attenuating As in both in vivo and in vitro settings.

Our results demonstrated that HYMAI attenuated As progression in As mice and ox-LDL-treated HCAECs by enhancing endothelial autophagy through the miR-19a-3p/ATG14 axis. These findings establish HYMAI as a novel regulatory mechanism and provide a potential druggable target for As and CAD.