Current Medicinal Chemistry - Volume 32, Issue 15, 2025

The purpose of this review is to revisit in detail the arguments supporting or disproving the hypothesis that oxidized low-density lipoprotein (LDL) plays a key role in atherosclerotic lesion development. The detection of oxidized LDL in vivo was extremely important for confirming its key role in atherogenesis. Indirect evidence of its existence included the presence of autoantibodies against malondialdehyde-treated LDL in human blood; however, the affinity of circulating antibodies to another LDL modification, such as desialylated LDL, was an order of magnitude stronger. At least 3 forms of atherogenic modified lipoproteins were isolated from the blood of atherosclerotic patients using different methods, namely, small dense, electronegative and desialylated. Their properties were so similar that it was suggested that the three types could be classified as the same multiple-modified LDL particle. It has been shown that when native (unmodified) LDL is incubated with autologous serum from patients with atherosclerosis, multiple modifications occur, which include desialylation, a decrease in the content of phospholipids and neutral lipids, a decrease in particle size, an increase in negative charge and other physical and chemical changes. Longer incubation also increased the susceptibility of LDL to oxidation. Thus, LDL oxidation is not the only, much less the most important, form of atherogenic modification of LDL since it occurs at the last stages of multiple modifications cascade and does not significantly increase the atherogenic potential of multiple-modified LDL. Finally, clinical trials did not support the oxidative hypothesis; however, research on oxidized LDL continues, influencing the future research. It is time to abandon the myth.

RNA modifications have recently gained great attention due to their extensive regulatory effects in a wide range of cellular networks and signaling pathways. In cardiovascular diseases (CVDs), several RNA changes, called “epitranscriptome” alterations, are found in all RNA molecules (tRNA, rRNA, mRNA, and ncRNAs). Unlike the epigenetic process, which influences the progression of atherosclerosis (AS), its transcriptional and post-transcriptional regulatory mechanisms are still unknown. Here, we described the main epitranscriptome signs to provide new insights into AS, including m⁶A, m⁵C, m1A, m⁷G, Ψ, and A-to-I editing. Moreover, we also included all current known RNA- modifier-targeting, including small molecular inhibitors or activators, mainly designed against m⁶A- and m⁵A-related enzymes, such as METTL3, FTO, and ALKBH5. Finally, since only a few drugs, such as azacitidine and tazemetostat, targeting the DNA epigenome, have been approved by the FDA, the next challenge would be to identify molecules for targeting the RNA epitranscriptome. To date, total Panax notoginseng total saponin could reduce vascular hyperplasia via Wilms’ tumor-associated protein-1 m⁶A-dependent. Indeed, a virtual screening allowed us to individuate a phytomolecule, the rhein, which acts as an FTO inhibitor by increasing mRNA m⁶A levels. In this review, we highlighted the RNA epitranscriptome pathways implicated in AS, describing their biological functions and their connections to the disease. The identification of epitranscriptome-sensitive pathways could provide novel opportunities to find predictive, diagnostic, and prognostic biomarkers for precision medicine.

Atherosclerotic cardiovascular disease represents the most common cause of death worldwide. Altered cholesterol metabolism and inflammation are major cardiovascular risk factors that underpin atherosclerotic plaque growth and destabilization. While initial evidence considered dyslipidemia and inflammation as independent atherogenic actors, growing evidence has revealed that several molecular mechanisms implicated in cholesterol metabolism participate in multiple inflammatory signalling pathways. In particular, proprotein convertase subtilisin/kexin type 9, adenosine monophosphate-activated protein kinase pathway, oxidized low-density lipoproteins, and lipoprotein (a) have been demonstrated to share concurrent atherogenic and inflammatory properties. Novel lipid-lowering therapies targeting these molecular pathways have been implemented. Mechanistic and clinical studies have addressed their hypolipidemic potential and explored their role in atherosclerosis-related vascular inflammation, and ongoing randomized clinical trials are investigating their prognostic role. The purpose of this review was to dive into the signalling pathways linking cholesterol metabolism and inflammation and outline the current evidence on the anti-inflammatory activities of the novel lipid-lowering drugs.

Atherosclerosis is the pathophysiological basis for major diseases, such as coronary heart disease, cerebral stroke, and peripheral arterial disease, which have become epidemic in modern Western society. Atherosclerosis has a complex nature that involves mutually related immune and metabolic mechanisms. Many cells of the vascular wall and peripheral bloodstream, including endothelial cells, monocytes and macrophages, platelets, and others, are involved in the development and progression of atherosclerosis. These cells perform a number of innate immune functions, disorders of which are associated with atherosclerosis. Furthermore, lipids are not only a morphological substrate but also important participants in the development of atherosclerosis. They are involved in the development and resolution of inflammation and mediate vascular cell function.

Metabolic syndrome (MetS) is a complex of serious pathologies with a high prevalence worldwide. Disruption of mitochondrial biogenesis and its interaction with other cell organelles plays an important role in the development of MetS. Studies have revealed the phenotypic and functional heterogeneity of mitochondria that exist within a single cell and can regulate metabolic signaling pathways, influencing the development of metabolic diseases. Excessive intake of fatty acids leads to changes in fatty acid metabolism that affect the biology of important cell organelles - the lipid droplets, whose specific biology is not fully understood. Perhaps targeted molecular genetic stimulation aimed at regulating the contact between mitochondria and lipids can break the vicious cycle of inflammation in MetS and restore normal cell function, reducing the risk of developing concomitant pathologies. The review describes potential (promising) therapeutic molecular targets associated with mitochondria and lipid droplets, focusing on the proteins involved in their contact and emphasizing their role in the pathogenesis of MetS.

Atherosclerosis is a complex vascular disease characterized by the buildup of lipids, inflammatory cells and fibrous components in arterial walls leading to plaque formation and potential thrombotic events like myocardial infarction and strokes. Recently, there has been research on the roles of various types of lipids such as low-density lipoprotein (LDL) cholesterol, oxidized LDL (oxLDL) cholesterol and small dense LDL (sdLDL) in the onset and progression of atherosclerosis. These lipoproteins contribute to dysfunction and inflammation processes that play a role in the development and instability of plaques. Moreover, certain enzymes and proteins linked to lipids have been associated with atherosclerosis highlighting the complex interplay between lipid metabolism and inflammation in this disease. This review delves into the mechanisms behind atherosclerosis focusing on the involvement of lipids, enzymes and regulatory proteins. Additionally, it will also discuss present treatments as well as new therapeutic approaches that target these molecular mechanisms with the goal of advancing our knowledge about atherosclerosis and guiding future treatment strategies.

Phytosomes are innovative compounds that enhance the bioavailability of plant-derived compounds, making them more effective in pharmaceuticals and nutraceuticals. By improving cellular absorption, phytosomes allow lower doses of plant extracts to achieve therapeutic effects, which may reduce both cost and the risk of potential side effects. The incorporation of phospholipids in phytosomes not only stabilizes the active compounds but also protects them from degradation in the gastrointestinal tract, potentially increasing their shelf life and efficacy. Despite their promise, more clinical trials are essential to fully validate the safety and therapeutic benefits of phytosomes. Ongoing research and developments may lead to a better understanding of their mechanisms of action and safety profiles and broaden their application in medicine.

Atherosclerotic cardiovascular disease (ASCVD) is an advanced chronic inflammatory disease and the leading cause of death worldwide. The pathological development of ASCVD begins with atherosclerosis, characterised by a pathological remodelling of the arterial wall, lipid accumulation and build-up of atheromatous plaque. As the disease advances, it narrows the vascular lumen and limits the blood, leading to ischaemic necrosis in coronary arteries. Exosomes are nano-sized lipid vesicles of different origins that can carry many bioactive molecules from their parental cells, thus playing an important role in intercellular communication. The roles of exosomes in atherosclerosis have recently been intensively studied, advancing our understanding of the underlying molecular mechanisms. In this review, we briefly introduce exosome biology and then focus on the roles of exosomes of different cellular origins in atherosclerosis development and progression, functional significance of their cargoes and physiological impact on recipient cells. Studies have demonstrated that exosomes originating from endothelial cells, vascular smooth muscle cells, macrophages, dendritic cells, platelets, stem cells, adipose tissue and other sources play an important role in the atherosclerosis development and progression by affecting cholesterol transport, inflammatory, apoptotic and other aspects of the recipient cells' metabolism. MicroRNAs are considered the most significant type of bioactive molecules transported by exosomes and involved in ASCVD development. Finally, we review the current achievements and limitations associated with the use of exosomes for the diagnosis and treatment of ASCVD.