Current Molecular Medicine - Volume 22, Issue 3, 2022

Relaxin (recombinant human relaxin-2 hormone; RLX-2; serelaxin) had raised expectations as a new medication for fibrotic diseases. A plethora of in vitro and in vivo studies have offered convincing demonstrations that relaxin promotes remodeling of connective tissue extracellular matrix mediated by inhibition of multiple fibrogenic pathways, especially the downstream signaling of transforming growth factor (TGF)-β1, a major pro-fibrotic cytokine, and the recruitment and activation of myofibroblasts, the main fibrosis-generating cells. However, all clinical trials with relaxin in patients with fibrotic diseases gave inconclusive results. In this review, we have summarized the molecular mechanisms of fibrosis, highlighting those which can be effectively targeted by relaxin. Then, we have performed a critical reappraisal of the clinical trials performed to date with relaxin as an anti-fibrotic drug, in order to highlight their key points of strength and weakness and to identify some future opportunities for the therapeutic use of relaxin, or its analogues, in fibrotic diseases and pathologic scarring which, in our opinion, deserve to be investigated.

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disorder characterized by multisystem clinical manifestations resulting from immune dysregulation/autoimmunity, vasculopathy, and, most notably, progressive fibrosis of the skin and internal organs. In recent years, it has been observed that the main drivers of SSc-related tissue fibrosis are myofibroblasts, a type of mesenchymal cells with both the extracellular matrix-synthesizing features of fibroblasts and the cytoskeletal characteristics of contractile smooth muscle cells. The accumulation and persistent activation of pro-fibrotic myofibroblasts during SSc development and progression result in elevated mechanical stress and reduced matrix plasticity within the affected tissues and may be ascribed to a reduced susceptibility of these cells to pro-apoptotic stimuli, as well as their increased formation from tissue-resident fibroblasts or transition from different cell types. Given the crucial role of myofibroblasts in SSc pathogenesis, finding the way to inhibit myofibroblast differentiation and accumulation by targeting their formation, function, and survival may represent an effective approach to hamper the fibrotic process or even halt or reverse established fibrosis. In this review, we discuss the role of myofibroblasts in SSc-related fibrosis, with a special focus on their cellular origin and the signaling pathways implicated in their formation and persistent activation. Furthermore, we provide an overview of potential therapeutic strategies targeting myofibroblasts that may be able to counteract fibrosis in this pathological condition.

Inflammation and fibrosis are two interrelated disease pathologies with several overlapping components. Three specific cell types, namely macrophages, T helper cells, and myofibroblasts, play important roles in regulating both processes. Following tissue injury, an inflammatory stimulus is often necessary to initiate tissue repair, where cytokines released from infiltrating and resident immune and inflammatory cells stimulate the proliferation and activation of extracellular matrix-producing myofibroblasts. However, persistent tissue injury drives an inappropriate pro128;fibrotic response. Additionally, activated myofibroblasts can take on the role of traditional antigen-presenting cells, secrete pro-inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying the fibrotic response in a vicious cycle. Moreover, inflammatory cells have been shown to play contradictory roles in the initiation, amplification, and resolution of fibrotic disease processes. The central role of the inflammasome molecular platform in contributing to fibrosis is only beginning to be fully appreciated. In this review, we discuss the immune mechanisms that can lead to fibrosis, the inflammasomes that have been implicated in the fibrotic process in the context of the immune response to injury, and also discuss current and emerging therapies that target inflammasome-induced collagen deposition to treat organ fibrosis.

Atherosclerosis, a vascular disease, is characterized by narrowing the arteries and forming plaque inside arteries. There is a record of 17.5 million associated deaths recorded annually, representing 31% of global death. It has been noted that there is an association between vascular fibrosis and atherosclerosis. The thickening of the arterial wall and reduction of the lumen diameter may cause unwarranted deposition of extracellular matrix (ECM), and these conditions help in the progression of many clinical diseases and pathological conditions, such as atherosclerosis. Here, we reviewed the involvement of various circulating microRNAs (miRNAs) in the very early diagnosis of atherosclerosis. We have also tried to provide an insight into the advantages and validation of circulating miRNAs through different techniques. We have discussed different circulating miRNAs, such as miR-17, miR-17-5p, miR-29b, miR-30, miR-92a, miR-126, miR-143, miR-145, miR-146a, miR-212, miR-218, miR-221, miR-222 and miR- 361-5p as a biomarker for clinical diagnosis of atherosclerosis. The insightful demonstration in this review will offer a better opportunity for the researchers and technology developers in understanding the current scenario of circulating miRNA, which could facilitate them in improving the current diagnostic technologies of atherosclerosis in clinics.

Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway related to their clinical implications.

Objectives: Osteoporosis is the most prevalent metabolic bone disorder worldwide. This review was undertaken to compare the efficacies of bisphosphonates therapies for patient persistence and compliance for the treatment of osteoporosis. Methods: A systematic review was performed in accordance with the available reporting items. MEDLINE and Cochrane library databases were applied for literature searched up to January 2020. All major studies such as prospective, retrospective and review articles that examined patient persistence or compliance to bisphosphonates for osteoporosis were included. Results: The literature search found 656 relevant published reports, out of which 87 were included. The 10, 712, 176 osteoporotic patients were studied for patient persistence and 5, 875, 718 patients were studied for patient compliances. Analysis of all studied bisphosphonates showed almost similar patterns for patient persistence rates as it was decreased over the time following initial prescription, but persistence length was found to be significantly higher for alendronate therapy as compared to the other studied bisphosphonates (p<0.001), whereas the length of persistence of all other bisphosphonates (other than alendronate) were almost same (p>0.05). Analysis of patient compliances with etidronate therapy showed the highest percent medication possession ratio (MRP) at 12 months, followed by the MRPs of ibandronate, alendronate, risedronate, and clodronate. Conclusion: This is the first systematic review that shows the comparison of the efficiencies of bisphosphonates for patient persistence and compliance for the treatment of osteoporosis. The data showed that the length of patient persistence was highest for alendronate therapy, whereas patient compliance was highest for etidronate therapy for the treatment of osteoporosis.