Mitochondrial Dysfunction in Systemic Lupus Erythematosus: Insights and Therapeutic Potential.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the presence of various serum autoantibodies and multi-system effects, predominantly affecting young female patients. The pathogenesis of SLE involves a combination of genetic factors, environmental triggers, and pathogen invasions that disrupt immune cell activation, leading to the release of autoantibodies and chronic inflammation. Mitochondria, as the primary cellular powerhouses, play a crucial role in SLE development through their control of energy generation, reactive oxygen species (ROS) production, and cellular apoptotic pathways. Dysregulation of mitochondrial structure and function can contribute to the immune dysregulation, oxidative stress, and inflammation seen in SLE. Recent research has highlighted the impact of mitochondrial dysfunction on various immune cells involved in SLE pathogenesis, such as T-lymphocytes, B-lymphocytes, neutrophils, and plasmacytoid dendritic cells. Mitochondrial dysfunction in these immune cells leads to increased ROS production, disrupted mitophagy, and alterations in energy metabolism, contributing to immune dysregulation and inflammation. Moreover, genetic variations in mitochondrial DNA (mtDNA) and abnormalities in mitochondrial dynamics have been linked to the pathogenesis of SLE, exacerbating oxidative stress and immune abnormalities. Targeting mitochondrial function has emerged as a promising therapeutic approach for SLE. Drugs such as sirolimus, N-acetylcysteine, coenzyme Q10, and metformin have shown potential in restoring mitochondrial homeostasis, reducing oxidative stress, and modulating immune responses in SLE. These agents have demonstrated efficacy in preclinical models and clinical studies by improving disease activity, reducing autoantibody titers, and ameliorating organ damage in SLE patients. In conclusion, this review underscores the critical role of mitochondria in the pathogenesis of SLE and the potential of targeting mitochondrial dysfunction as a novel therapeutic strategy for improving outcomes in SLE patients. Further investigation into the mechanisms underlying mitochondrial involvement in SLE and the development of targeted mitochondrial therapies hold promise for advancing SLE treatment and enhancing patient care.

Vitamin D in Primary Sjogren's Syndrome (pSS) and the Identification of Novel Single-Nucleotide Polymorphisms Involved in the Development of pSS-Associated Diseases.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterised by lymphocytic infiltration of the exocrine glands, which leads to dryness of the eyes and mouth; systemic manifestations such as arthritis, vasculitis, and interstitial lung disease; and increased risks of lymphoma and cardiovascular diseases. SS predominantly affects women, with a strong genetic component linked to sex chromosomes. Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with primary SS (pSS), revealing insights into its pathogenesis. The adaptive and innate immune systems are crucial to SS's development, with viral infections implicated as environmental triggers that exacerbate autoimmune responses in genetically susceptible individuals. Moreover, recent research has highlighted the role of vitamin D in modulating immune responses in pSS patients, suggesting its potential therapeutic implications. In this review, we focus on the recently identified SNPs in genes like OAS1, NUDT15, LINC00243, TNXB, and THBS1, which have been associated with increased risks of developing more severe symptoms and other diseases such as fatigue, lymphoma, neuromyelitis optica spectrum disorder (NMOSD), dry eye syndrome (DES), and adverse drug reactions. Future studies should focus on larger, multi-ethnic cohorts with standardised protocols to validate findings and identify new associations. Integrating genetic testing into clinical practise holds promise for improving SS management and treatment strategies, enabling personalised interventions based on comprehensive genetic profiles. By focusing on specific SNPs, vitamin D, and their implications, future research can lead to more effective and personalised approaches for managing pSS and its complications.

Foam Cells: The Origin of Formation and Target for Plant-derived Bioactive Compounds.

Foam cells play a crucial role in the initiation and progression of atherosclerosis, a condition marked by the development and growth of plaques that narrow blood vessel lumens. This narrowing can prevent normal blood flow and, in severe cases, lead to plaque rupture and blood clot formation, which can cause stroke or myocardial infarction. The origin of foam cells is diverse, arising from monocytes, vascular smooth muscle cells, stem/progenitor cells, and dendritic and endothelial cells. In their attempt to eliminate excess lipoproteins and cholesterol, foam cells inadvertently contribute to plaque development and rupture. Cholesterol uptake, efflux, and esterification are the major processes regulating foam cell formation. Advances in technology, such as the identification of cell-surface markers for lineage tracing and single-cell RNA sequencing, have unveiled diverse molecular mechanisms involved in the formation of foam cells from different origins, offering new insights into plaque formation and potential targets for anti-foam cell therapies. In this review, we focus on recent studies exploringthe inhibitory effects of medicinal plants and their bioactive components on foam cell formation. Various mechanisms are explored, including the inhibition of cholesterol uptake and the up-regulation of cholesterol efflux, as well as the suppression of inflammatory and adhesion activities. Emphasizing a cellular target-based therapeutic approach, this review envisions the development of innovative plant-based medications for atherosclerosis treatment.

Exosomes in Atherosclerosis: Role in the Pathogenesis and Targets for Therapy.

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.

Role of ABCA1 in Atherosclerosis: Novel Mutations and Potential Plant-derived Therapies.

ATP-binding cassette transporter A1 (ABCA1) is one of the key proteins regulating cholesterol homeostasis and playing a crucial role in atherosclerosis development. ABCA1 regulates the rate-limiting step of reverse cholesterol transport, facilitates the efflux of surplus intracellular cholesterol and phospholipids, and suppresses inflammation through several signalling pathways. At the same time, many mutations and Single Nucleotide Polymorphisms (SNPs) have been identified in the ABCA1 gene, which affects its biological function and is associated with several hereditary diseases (such as familial hypo-alpha-lipoproteinaemia and Tangier disease) and increased risk of cardiovascular diseases (CVDs). This review summarises recently identified mutations and SNPs in their connection to atherosclerosis and associated CVDs. Also, we discuss the recently described application of various plant-derived compounds to modulate ABCA1 expression in different in vitro and in vivo models. Herein, we present a comprehensive overview of the association of ABCA1 mutations and SNPs with CVDs and as a pharmacological target for different natural-derived compounds and highlight the potential application of these phytochemicals for treating atherosclerosis through modulation of ABCA1 expression.

Cholesteryl Ester Transfer Protein (CETP) Variations in Relation to Lipid Profiles and Cardiovascular Diseases: An Update.

Lipid metabolism plays an essential role in the pathogenesis of cardiovascular and metabolic diseases. Cholesteryl ester transfer protein (CETP) is a crucial glycoprotein involved in lipid metabolism by transferring cholesteryl esters (CE) and triglycerides (TG) between plasma lipoproteins. CETP activity results in reduced HDL-C and increased VLDL- and LDL-C concentrations, thus increasing the risk of cardiovascular and metabolic diseases. In this review, we discuss the structure of CETP and its mechanism of action. Furthermore, we focus on recent experiments on animal CETP-expressing models, deciphering the regulation and functions of CETP in various genetic backgrounds and interaction with different external factors. Finally, we discuss recent publications revealing the association of CETP single nucleotide polymorphisms (SNPs) with the risk of cardiovascular and metabolic diseases, lifestyle factors, diet and therapeutic interventions. While CETP SNPs can be used as effective diagnostic markers, diet, lifestyle, gender and ethnic specificity should also be considered for effective treatment.

Glycation of LDL: AGEs, impact on lipoprotein function, and involvement in atherosclerosis.

Atherosclerosis is a complex disease, and there are many factors that influence its development and the course of the disease. A deep understanding of the pathological mechanisms underlying atherogenesis is needed to develop optimal therapeutic strategies and treatments. In this review, we have focused on low density lipoproteins. According to multiple studies, their atherogenic properties are associated with multiple modifications of lipid particles. One of these modifications is Glycation. We considered aspects related to the formation of modified particles, as well as the influence of modification on their functioning. We paid special attention to atherogenicity and the role of glycated low-density lipoprotein (LDL) in atherosclerosis.

Modulating mTOR Signaling as a Promising Therapeutic Strategy for Atherosclerosis.

For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of gaps remain in our understanding of the pathogenesis of atherosclerosis, and only their closure will bring us closer to understanding the causes of the disease at the cellular and molecular levels and, accordingly, to the development of an effective treatment. One of the seemingly well-studied elements of atherogenesis is the mTOR signaling pathway. However, more and more new details are still being clarified. Therapeutic strategies associated with rapamycin have worked well in a number of different diseases, and there is every reason to believe that targeting components of the mTOR pathway may pay off in atherosclerosis as well.

Role of the mtDNA Mutations and Mitophagy in Inflammaging.

Ageing is an unavoidable multi-factorial process, characterised by a gradual decrease in physiological functionality and increasing vulnerability of the organism to environmental factors and pathogens, ending, eventually, in death. One of the most elaborated ageing theories implies a direct connection between ROS-mediated mtDNA damage and mutations. In this review, we focus on the role of mitochondrial metabolism, mitochondria generated ROS, mitochondrial dynamics and mitophagy in normal ageing and pathological conditions, such as inflammation. Also, a chronic form of inflammation, which could change the long-term status of the immune system in an age-dependent way, is discussed. Finally, the role of inflammaging in the most common neurodegenerative diseases, such as Alzheimer's and Parkinson's, is also discussed.

Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing.

Cardiovascular diseases (CVDs) are the leading cause of death globally, representing approximately 32% of all deaths worldwide. Molecular chaperones are involved in heart protection against stresses and age-mediated accumulation of toxic misfolded proteins by regulation of the protein synthesis/degradation balance and refolding of misfolded proteins, thus supporting the high metabolic demand of the heart cells. Heat shock protein 90 (HSP90) is one of the main cardioprotective chaperones, represented by cytosolic HSP90a and HSP90b, mitochondrial TRAP1 and ER-localised Grp94 isoforms. Currently, the main way to study the functional role of HSPs is the application of HSP inhibitors, which could have a different way of action. In this review, we discussed the recently investigated role of HSP90 proteins in cardioprotection, atherosclerosis, CVDs development and the involvements of HSP90 clients in the activation of different molecular pathways and signalling mechanisms, related to heart ageing.

The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment.

Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria-primarily, the regulation of mitochondria-mediated apoptosis, Ca2+ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.