The Role of Alarmins in the Pathogenesis of Rheumatoid Arthritis, Osteoarthritis, and Psoriasis.

Alarmins are immune-activating factors released after cellular injury or death. By secreting alarmins, cells can interact with immune cells and induce a variety of inflammatory responses. The broad family of alarmins involves several members, such as high-mobility group box 1, S100 proteins, interleukin-33, and heat shock proteins, among others. Studies have found that the concentrations and expression profiles of alarmins are altered in immune-mediated diseases. Furthermore, they are involved in the pathogenesis of inflammatory conditions. The aim of this narrative review is to present the current evidence on the role of alarmins in rheumatoid arthritis, osteoarthritis, and psoriasis. We discuss their potential involvement in mechanisms underlying the progression of these diseases and whether they could become therapeutic targets. Moreover, we summarize the impact of pharmacological agents used in the treatment of these diseases on the expression of alarmins.

The effect of plasma cytokines on the expression of adiponectin and its receptors in the synovial membrane of joints and the infrapatellar fat pad in patients with rheumatoid arthritis and osteoarthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA. OBJECTIVE: The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA). METHODS: Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR. RESULTS: In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1ß, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1ß. CONCLUSIONS: Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.

Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus.

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle-a well-balanced diet and physical activity. There is also a group of compounds-including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others-that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM.

The Role of Interleukin 6 in Periodontitis and Its Complications.

Interleukin 6 (IL-6) is a pleomorphic pro-inflammatory cytokine that is strongly associated with local as well as systemic inflammatory processes. Its role in physiological and pathogenic processes throughout the human body has been the subject of numerous studies in recent years. Measurements of the IL-6 levels in gingival crevicular fluid (GFC), as well as in serum, can be important diagnostic and prognostic factors in periodontal diseases (PD) and in assessing their impact on a range of related inflammatory diseases. This narrative review explores the significant role of IL-6 in patients with periodontitis and its association with other widespread inflammatory pathologies.

Recent Advances in the Use of Stem Cells in Tissue Engineering and Adjunct Therapies for Tendon Reconstruction and Future Perspectives.

Due to their function, tendons are exposed to acute injuries. This type of damage to the musculoskeletal system represents a challenge for clinicians when natural regeneration and treatment methods do not produce the expected results. Currently, treatment is long and associated with long-term complications. In this review, we discuss the use of stem cells in the treatment of tendons, including how to induce appropriate cell differentiation based on gene therapy, growth factors, tissue engineering, proteins involved in regenerative process, drugs and three-dimensional (3D) structures. A multidirectional approach as well as the incorporation of novel components of the therapy will improve the techniques used and benefit patients with tendon injuries in the future.

Immunotherapy Based on Immune Checkpoint Molecules and Immune Checkpoint Inhibitors in Gastric Cancer-Narrative Review.

Due to its rapid progression to advanced stages and highly metastatic properties, gastric cancer (GC) is one of the most aggressive malignancies and the fourth leading cause of cancer-related deaths worldwide. The metastatic process includes local invasion, metastasis initiation, migration with colonisation at distant sites, and evasion of the immune response. Tumour growth involves the activation of inhibitory signals associated with the immune response, also known as immune checkpoints, including PD-1/PD-L1 (programmed death 1/programmed death ligand 1), CTLA-4 (cytotoxic T cell antigen 4), TIGIT (T cell immunoreceptor with Ig and ITIM domains), and others. Immune checkpoint molecules (ICPMs) are proteins that modulate the innate and adaptive immune responses. While their expression is prominent on immune cells, mainly antigen-presenting cells (APC) and other types of cells, they are also expressed on tumour cells. The engagement of the receptor by the ligand is crucial for inhibiting or stimulating the immune cell, which is an extremely important aspect of cancer immunotherapy. This narrative review explores immunotherapy, focusing on ICPMs and immune checkpoint inhibitors in GC. We also summarise the current clinical trials that are evaluating ICPMs as a target for GC treatment.

The Role of MicroRNA in the Pathogenesis of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder associated with muscle wasting and degeneration. The disease is caused by mutations in the gene that encodes dystrophin, a protein that links the cytoskeleton with cell membrane proteins. The current treatment methods aim to relieve the symptoms of the disease or partially rescue muscle functionality. However, they are insufficient to suppress disease progression. In recent years, studies have uncovered an important role for non-coding RNAs (ncRNAs) in regulating the progression of numerous diseases. ncRNAs, such as micro-RNAs (miRNAs), bind to their target messenger RNAs (mRNAs) to suppress translation. Understanding the mechanisms involving dysregulated miRNAs can improve diagnosis and suggest novel treatment methods for patients with DMD. This review presents the available evidence on the role of altered expression of miRNAs in the pathogenesis of DMD. We discuss the involvement of these molecules in the processes associated with muscle physiology and DMD-associated cardiomyopathy.

The Role of Stem Cells in the Treatment of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death and include several vascular and cardiac disorders, such as atherosclerosis, coronary artery disease, cardiomyopathies, and heart failure. Multiple treatment strategies exist for CVDs, but there is a need for regenerative treatment of damaged heart. Stem cells are a broad variety of cells with a great differentiation potential that have regenerative and immunomodulatory properties. Multiple studies have evaluated the efficacy of stem cells in CVDs, such as mesenchymal stem cells and induced pluripotent stem cell-derived cardiomyocytes. These studies have demonstrated that stem cells can improve the left ventricle ejection fraction, reduce fibrosis, and decrease infarct size. Other studies have investigated potential methods to improve the survival, engraftment, and functionality of stem cells in the treatment of CVDs. The aim of the present review is to summarize the current evidence on the role of stem cells in the treatment of CVDs, and how to improve their efficacy.

The Role of Epigenetic Factors in the Pathogenesis of Psoriasis.

Psoriasis is a chronic inflammatory skin disease, the prevalence of which is increasing. Genetic, genomic, and epigenetic changes play a significant role in the pathogenesis of psoriasis. This review summarizes the impact of epigenetics on the development of psoriasis and highlights challenges for the future. The development of epigenetics provides a basis for the search for genetic markers associated with the major histocompatibility complex. Genome-wide association studies have made it possible to link psoriasis to genes and therefore to epigenetics. The acquired knowledge may in the future serve as a solid foundation for developing newer, increasingly effective methods of treating psoriasis. In this narrative review, we discuss the role of epigenetic factors in the pathogenesis of psoriasis.

Non-Coding RNA as Biomarkers and Their Role in the Pathogenesis of Gastric Cancer-A Narrative Review.

Non-coding RNAs (ncRNAs) represent a broad family of molecules that regulate gene expression, including microRNAs, long non-coding RNAs and circular RNAs, amongst others. Dysregulated expression of ncRNAs alters gene expression, which is implicated in the pathogenesis of several malignancies and inflammatory diseases. Gastric cancer is the fifth most frequently diagnosed cancer and the fourth most common cause of cancer-related death. Studies have found that altered expression of ncRNAs may contribute to tumourigenesis through regulating proliferation, apoptosis, drug resistance and metastasis. This review describes the potential use of ncRNAs as diagnostic and prognostic biomarkers. Moreover, we discuss the involvement of ncRNAs in the pathogenesis of gastric cancer, including their interactions with the members of major signalling pathways.

Follistatin and follistatin-like 3 in metabolic disorders.

Follistatin (FST) is a glycoprotein which main role is antagonizing activity of transforming growth factor ß superfamily members. Folistatin-related proteins such as follistatin-like 3 (FSTL3) also reveal these properties. The exact function of them has still not been established, but it can be bound to the pathogenesis of metabolic disorders. So far, there were performed a few studies about their role in type 2 diabetes, obesity or gestational diabetes and even less in type 1 diabetes. The outcomes are contradictory and do not allow to draw exact conclusions. In this article we summarize the available information about connections between follistatin, as well as follistatin-like 3, and metabolic disorders. We also emphasize the strong need of performing further research to explain their exact role, especially in the pathogenesis of diabetes and obesity.

Are SMAD2/4/7 genetic variants associated with rheumatoid arthritis susceptibility and severity?

OBJECTIVES: SMADs play one of the key roles in the TGFß signalling pathway. Therefore, through their involvement in the immune response as well as in the fibrosis process, these proteins appear to take on one of the essential functions in the pathogenesis of autoimmune connective tissue diseases such as RA. This study aimed to investigate the association of selected SNPs in SMAD2/4/7 with RA risk in the Caucasian population and disease course in RA patients. METHODS: The study was conducted on 647 patients with established RA and 496 unrelated healthy controls (HCs). All patients fulfilled the American College of Rheumatology Diagnostic classification criteria for RA (ACR 1987). The analysis has been conducted using TaqMan genotyping assay. Transcript-inferred pathogenicity score (TraP-score) has been evaluated by TrapScore. PredictSNP.2 has been used to predict the effect of amino acid substitutions. RESULTS: The present study revealed in SMAD4 a significantly higher frequency of AG rs12456284 (under codominant model OR=0.62 p=0.027 and overdominant model OR=0.59 p=0.016) and GA rs10502913 (under codominant model OR=0.65 p=0.050 and overdominant OR=0.64 p=0.033) genotypes in healthy subjects in comparison to RA patients. Additionally, very strong LD has been noted between these two genetic variants (D'=0.95 r2=0.90). Moreover, bioinformatic analysis classified rs12456284 as deleterious change with 94% prediction accuracy. SMAD2 rs1792666 and SMAD7 rs3736242 showed to have the highest association with disease course. SMAD4 rs10502913, SMAD7 rs3736242, and SMAD7 rs4464148 were associated with the concentration of creatinine. CONCLUSIONS: Our results suggested that rs12456284 and rs10502913 in SMAD4 may have a potential protective effect against RA. Particularly, SMAD2 rs1792666 and SMAD7 rs3736242 seem to be significantly associated with diseases course in RA patients in the Caucasian population.

The Role of the Oral Microbiome in the Development of Diseases.

Periodontal disease (PD) is a complex and infectious illness that begins with a disruption of bacterial homeostasis. This disease induces a host inflammatory response, leading to damage of the soft and connective tooth-supporting tissues. Moreover, in advanced cases, it can contribute to tooth loss. The aetiological factors of PDs have been widely researched, but the pathogenesis of PD has still not been totally clarified. There are a number of factors that have an effect on the aetiology and pathogenesis of PD. It is purported that microbiological, genetic susceptibility and lifestyle can determine the development and severity of the disease. The human body's defence response to the accumulation of plaque and its enzymes is known to be a major factor for PD. The oral cavity is colonised by a characteristic and complex microbiota that grows as diverse biofilms on all mucosal and dental surfaces. The aim of this review was to provide the latest updates in the literature regarding still-existing problems with PD and to highlight the role of the oral microbiome in periodontal health and disease. Better awareness and knowledge of the causes of dysbiosis, environmental risk factors and periodontal therapy can reduce the growing worldwide prevalence of PDs. The promotion of good oral hygiene, limiting smoking, alcohol consumption and exposure to stress and comprehensive treatment to decrease the pathogenicity of oral biofilm can help reduce PD as well as other diseases. Evidence linking disorders of the oral microbiome to various systemic diseases has increased the understanding of the importance of the oral microbiome in regulating many processes in the human body and, thus, its impact on the development of many diseases.

The Potential Role of Connexins in the Pathogenesis of Atherosclerosis.

Connexins (Cx) are members of a protein family which enable extracellular and intercellular communication through hemichannels and gap junctions (GJ), respectively. Cx take part in transporting important cell-cell messengers such as 3',5'-cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP), and inositol 1,4,5-trisphosphate (IP3), among others. Therefore, they play a significant role in regulating cell homeostasis, proliferation, and differentiation. Alterations in Cx distribution, degradation, and post-translational modifications have been correlated with cancers, as well as cardiovascular and neurological diseases. Depending on the isoform, Cx have been shown either to promote or suppress the development of atherosclerosis, a progressive inflammatory disease affecting large and medium-sized arteries. Cx might contribute to the progression of the disease by enhancing endothelial dysfunction, monocyte recruitment, vascular smooth muscle cell (VSMC) activation, or by inhibiting VSMC autophagy. Inhibition or modulation of the expression of specific isoforms could suppress atherosclerotic plaque formation and diminish pro-inflammatory conditions. A better understanding of the complexity of atherosclerosis pathophysiology linked with Cx could result in developing novel therapeutic strategies. This review aims to present the role of Cx in the pathogenesis of atherosclerosis and discusses whether they can become novel therapeutic targets.

Role of Sirtuins in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease leading to joint destruction. The causes of RA are not fully known. Most likely, the development of the disease depends on the coexistence of many factors, such as hereditary factors, immune system defects, gender, infectious agents, nicotine, and stress. Various epigenetic changes have been identified and correlated with the aggressive phenotype of RA, including the involvement of sirtuins, which are enzymes found in all living organisms. Their high content in the human body can slow down the aging processes, reduce cell death, counteract the appearance of inflammation, and regulate metabolic processes. Sirtuins can participate in several steps of RA pathogenesis. This narrative review presents, collects, and discusses the role of all sirtuins (1-7) in the pathogenesis of rheumatoid arthritis.

The Role of Sirtuins in the Pathogenesis of Psoriasis.

Psoriasis is the most common chronic inflammatory skin disease with a genetic basis. It is characterised by keratinocyte hyperproliferation, parakeratosis and inflammatory cell infiltration. Psoriasis negatively affects a patient's physical and emotional quality of life. Sirtuins (SIRTs; silent information regulators) are an evolutionarily conserved group of enzymes involved in the post-translational modification of proteins, including deacetylation, polyADP-ribosylation, demalonylation and lipoamidation. SIRTs are involved in a number of cellular pathways related to ageing, inflammation, oxidative stress, epigenetics, tumorigenesis, the cell cycle, DNA repair and cell proliferation, positioning them as an essential component in the pathogenesis of many diseases, including psoriasis. Activation of SIRT1 counteracts oxidative-stress-induced damage by inhibiting the mitogen-activated protein kinases (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways and may mitigate pathological events in psoriasis. There is a significant reduction in the expression of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 and an increase in the expression of SIRT6 and SIRT7 in psoriasis. The aim of the review is to draw the attention of physicians and scientists to the importance of SIRTs in dermatology and to provide a basis and impetus for future discussions, research and pharmacological discoveries to modulate SIRT activity. In light of the analysis of the mode of action of SIRTs in psoriasis, SIRT1-SIRT5 agonists and SIRT6 and SIRT7 inhibitors may represent new therapeutic options for the treatment of psoriasis.

The Role of Vitamin C and Vitamin D in the Pathogenesis and Therapy of Periodontitis-Narrative Review.

Periodontitis is a common disorder affecting the bone and soft tissues of the periodontal complex. When untreated, it may lead to severe mobility or even loss of teeth. The pathogenesis of periodontitis is complex, with crucial factors being chronic inflammation in gingival and periodontal tissues and oral microbiome alterations. However, recent studies highlight the alleged role of vitamins, such as vitamin C (VitC) and vitamin D (VitD), in the development of the disease. VitC regulates numerous biochemical reactions, but foremost, it is involved in synthesizing collagen. It was reported that VitC deficiency could lead to damage to the periodontal ligaments. VitC supplementation improves postoperative outcomes in patients with periodontitis. VitD is a steroid derivative that can be produced in the skin under ultraviolet radiation and later transformed into an active form in other tissues, such as the kidneys. VitD was established to decrease the expression of proinflammatory cytokines in gingiva and regulate the proper mineral density of teeth. Moreover, the supplementation of VitD was associated with better results in the nonsurgical treatment of periodontitis. In this review, we summarize recent knowledge on the role of vitamins C and D in the pathogenesis and treatment of periodontitis.

The Effect of the Gut Microbiota on Transplanted Kidney Function.

The intestinal microflora is extremely important, not only in the processes of absorption, digestion and biosynthesis of vitamins, but also in shaping the immune and cognitive functions of the human body. Several studies demonstrate a correlation between microbiota composition and such events as graft rejection, kidney interstitial fibrosis, urinary tract infections, and diarrhoea or graft tolerance. Some of those changes might be directly linked with pathologies such as colonization with pathogenic bacterial strains. Gut microbiota composition also plays an important role in metabolic complications and viral infections after transplantation. From the other side, gut microbiota might induce graft tolerance by promotion of T and B regulatory cells. Graft tolerance induction is still an extremely important issue regarding transplantology and might allow the reduction or even avoidance of immunosuppressive treatment. Although there is a rising evidence of the pivotal role of gut microbiota in aspects of kidney transplantation there is still a lack of knowledge on the direct mechanisms of microbiota action. Furthermore, some of those negative effects could be reversed by probiotics of faecal microbiota trapoinsplantation. While diabetes and hypertension as well as BKV and CMV viremia are common and important complications of transplantation, both worsening the graft function and causing systemic injuries, it opens up potential clinical treatment options. As has been also suggested in the current review, some bacterial subsets exhibit protective properties. However, currently, there is a lack of evidence on pro- and prebiotic supplementation in kidney transplant patients. In the current review, we describe the effect of the microbiota on the transplanted kidney in renal transplant recipients.

Genetic and Epigenetic Factors in Gestational Diabetes Mellitus Pathology.

Gestational diabetes (GDM) is the carbohydrate intolerance occurring during pregnancy. The risk factors of GDM include obesity, advanced maternal age, polycystic ovary syndrome, multigravidity, a sedentary lifestyle, and pre-existing hypertension. Additionally, complex genetic and epigenetic processes are also believed to play a crucial role in the development of GDM. In this narrative review, we discuss the role of genetic and epigenetic factors in gestational diabetes mellitus pathogenesis.

The Role of Genetics and Epigenetic Regulation in the Pathogenesis of Osteoarthritis.

Osteoarthritis (OA) is progressive disease characterised by cartilage degradation, subchondral bone remodelling and inflammation of the synovium. The disease is associated with obesity, mechanical load and age. However, multiple pro-inflammatory immune mediators regulate the expression of metalloproteinases, which take part in cartilage degradation. Furthermore, genetic factors also contribute to OA susceptibility. Recent studies have highlighted that epigenetic mechanisms may regulate the expression of OA-associated genes. This review aims to present the mechanisms of OA pathogenesis and summarise current evidence regarding the role of genetics and epigenetics in this process.