Phytol from Scoparia dulcis prevents NF-κB-mediated inflammatory responses during macrophage polarization.

Macrophages are primary immune cells that mediate a wide range of inflammatory diseases through their polarization potential. In this study, phytol isolated from Scoparia dulcis has been explored against 7-ketocholesterol and bacterial lipopolysaccharide-induced macrophage polarization in IC-21 cells. Isolated phytol has been characterized using GC-MS, TLC, HPTLC, FTIR, 1H-NMR, and HPLC analyses. The immunomodulatory effects of viable concentrations of phytol were tested on oxidative stress, arginase activity, nuclear and mitochondrial membrane potentials in IC-21 cells in addition to the modulation of calcium and lipids. Further, gene and protein expression of atherogenic markers were studied. Results showed that the isolated phytol at a viable concentration of 400 µg/ml effectively reduced the production of nitric oxide, superoxide anion (ROS generation), calcium and lipid accumulation, stabilized nuclear and mitochondrial membranes, and increased arginase activity. The atherogenic markers including iNOS, COX-2, IL-6, IL-1ß, MMP-9, CD36, and NF-κB were significantly downregulated at the levels of gene and protein expression, while macrophage surface and nuclear receptor markers (CD206, CD163, and PPAR-γ) were significantly upregulated by phytol pre-treatment in macrophages. Therefore, the present pharmacognostic study supports the role of phytol isolated from Scoparia dulcis in preventing M2-M1 macrophage polarization under inflammatory conditions, making it a promising compound. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03924-9.

Interactions between macrophage membrane and lipid mediators during cardiovascular diseases with the implications of scavenger receptors.

The onset and progression of cardiovascular diseases with the major underlying cause being atherosclerosis, occur during chronic inflammatory persistence in the vascular system, especially within the arterial wall. Such prolonged maladaptive inflammation is driven by macrophages and their key mediators are generally attributed to a disparity in lipid metabolism. Macrophages are the primary cells of innate immunity, endowed with expansive membrane domains involved in immune responses with their signalling systems. During atherosclerosis, the membrane domains and receptors control various active organisations of macrophages. Their scavenger/endocytic receptors regulate the trafficking of intracellular and extracellular cargo. Corresponding influence on lipid metabolism is mediated by their dynamic interaction with scavenger membrane receptors and their integrated mechanisms such as pinocytosis, phagocytosis, cholesterol export/import, etc. This interaction not only results in the functional differentiation of macrophages but also modifies their structural configurations. Here, we reviewed the association of macrophage membrane biomechanics and their scavenger receptor families with lipid metabolites during the event of atherogenesis. In addition, the membrane structure of macrophages and the signalling pathways involved in endocytosis integrated with lipid metabolism are detailed. This article establishes future insights into the scavenger receptors as potential targets for cardiovascular disease prevention and treatment.

Sitosterol-rich Digera muricata against 7-ketocholesterol and lipopolysaccharide-mediated atherogenic responses by modulating NF-ΚB/iNOS signalling pathway in macrophages.

Digera muricata L., commonly known as Tartara, is an edible herb used as traditional medicine in many countries of Africa and Asia. This study aimed to elucidate the effect of a phytosterol-rich extract of D. muricata on 7-ketocholesterol-mediated atherosclerosis in macrophages. The extract was examined by phytochemical analyses, GC-MS, TLC, DPPH scavenging and hRBC membrane stabilization assays. Macrophage polarization was studied with experimental groups framed based on alamar blue cell viability and griess assays. Regulations of arginase enzyme activity, ROS generation, mitochondrial membrane potential, cell membrane integrity, pinocytosis, lipid uptake and peroxidation, as well as, intracellular calcium deposition were determined. In addition, expressions of atherogenic mediators were analysed using PCR, ELISA and immunocytochemistry techniques. Diverse phytochemicals with higher free radical scavenging activity and anti-inflammatory potential have been detected in the D. muricata. Co-treatment with D. muricata markedly reduced the atherogenic responses induced by 7KCh in the presence of LPS such as ROS, especially, NO and O2- along with lipid peroxidation. Furthermore, D. muricata significantly normalized mitochondrial membrane potential, cell membrane integrity, pinocytic activity, intracellular lipid accumulation and calcium deposition. These results provided us with the potentiality of D. muricata in ameliorating atherogenesis. Additionally, it decreased the expression of pro-atherogenic mediators (iNOS, COX-2, MMP9, IL-6, IL-1ß, CD36, CD163 and TGFß1) and increased anti-atherogenic mediators (MRC1 and PPARγ) with high cellular expressions of NF-κB and iNOS. Results showed the potential of sitosterol-rich D. muricata as a versatile biomedical therapeutic agent against abnormal macrophage polarization and its associated pathologies.

Dynamic Role of Macrophage Sub Types on Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy.

Atherosclerosis, a major contributor to cardiovascular disease, is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes the recruitment of monocytes to the inflammatory sites and subsides pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 have to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of pro-inflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage have atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

An insight on 7- ketocholesterol mediated inflammation in atherosclerosis and potential therapeutics.

7-ketocholesterol, a toxic oxidative product of oxysterol is a causative agent of several diseases and disabilities concomitant to aging including cardiovascular diseases like atherosclerosis. Auto-oxidation of cholesterol esters present in low-density lipoprotein (LDL) deposits lead to the formation of oxidized LDL (Ox-LDL) along with its byproducts, namely 7KCh. It is predominantly found in atherosclerotic plaque and also found to be more atherogenic than cholesterol by being cytotoxic, interfering with cellular homeostasis. This makes it a serious threat by being the foremost cause of morbidity and mortality worldwide and is likely to become more serious during forth coming years. It involves in mediating inflammatory mechanisms characterized by the advancement of fibroatheroma plaques. The atherosclerotic lesion is composed of Ox-LDL along with fibrotic mass consisting of immune cells and molecules. Macrophages being the specialized phagocytic cells, contribute to removal of detrimental contents of the lesion along with accumulated lipids leading to alteration of its biology and functionality due to its plasticity. Here, we have explored the known as well as proposed mechanisms involved with 7KCh associated atherogenesis along with potential therapeutic strategies for targeting 7KCh as a diagnostic and target in medicine.