Assessment of associations of nailfold videocapillaroscopy (NVC) scleroderma patterns ('early', 'active' and 'late') with future severe clinical involvement in a systemic sclerosis (SSc) population.
...Sixty-six consecutive patients with SSc according to the LeRoy and Medsger criteria underwent NVC assessment at baseline. Videocapillaroscopic images were classified into 'normal', 'early', 'active' or 'late' NVC pattern. Clinical evaluation was performed for nine organ systems (general, peripheral vascular, skin, joint, muscle, gastrointestinal tract, lung, heart and kidney) according to the disease severity scale of Medsger (DSS) at 18-24 months of follow-up. Severe clinical involvement was defined as category 2-4 per organ of the DSS.
NVC patterns were significantly associated with future severe, peripheral vascular/lung involvement at 18-24 months. The OR rose steadily throughout the patterns. The OR for future severe peripheral disease based on simple/multiple (correcting for disease duration, subset and medication) logistic regression was 2.49/2.52 (95% CI 1.33 to 5.43, p=0.003/1.11 to 7.07, p=0.026) for early, 6.18/6.37 for active and 15.35/16.07 for late NVC scleroderma patterns versus the normal NVC pattern. The OR for future severe lung involvement based on simple/multiple regression was 2.54/2.33 (95% CI 1.40 to 5.22, p=0.001/1.13 to 5.52, p=0.021) for early, 6.43/5.44 for active and 16.30/12.68 for late NVC patterns.
This pilot study is the first demonstrating an association between baseline NVC patterns and future severe, peripheral vascular and lung involvement with stronger odds according to worsening scleroderma patterns. This may indicate a putative role of capillaroscopy as a biomarker.
From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of ...different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.
Sex hormones play an active role in inflammatory responses, with androgens being anti‐inflammatory, whereas estrogens have both pro‐ and anti‐inflammatory effects. In rheumatoid arthritis (RA) ...patients, low levels of androgens and high levels of estrone are found in the synovial fluid. Aromatase is the key enzyme for the conversion of androgens into estrogens. Proinflammatory cytokines stimulate aromatase activity so that the inflammatory milieu can induce conversion of androgens to estrogens. Moreover, testosterone inhibits aromatase activity. As local androgen levels are low in RA, this can contribute to high aromatase activity in the synovium. Importantly, aromatase‐converted estrogens are converted into proproliferative and proinflammatory 16‐hydroxylated estrogens. A hormone involved in aromatase activity is vitamin D, which downregulates aromatase in human RA macrophages. Collectively, evidence suggests a key role of aromatase in sex hormone balance during chronic inflammation and points to the importance of vitamin D as a possible new tool for aromatase modulation.
Vitamin D, steroid hormones, and autoimmunity Cutolo, Maurizio; Paolino, Sabrina; Sulli, Alberto ...
Annals of the New York Academy of Sciences,
20/May , Letnik:
1317, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The endogenous serum metabolite of vitamin D (calcitriol, 1,25(OH)2D3) is considered a true steroid hormone (D hormone), and like glucocorticoids (GCs) and gonadal hormones, may exert several ...immunomodulatory activities. Serum vitamin D deficiency (25(OH) D), and therefore reduced 1,25(OH)2D3 availability, is considered a risk factor for several chronic/inflammatory or autoimmune conditions, including infectious diseases, type 1 diabetes, multiple sclerosis, and especially autoimmune rheumatic diseases (ARD). In ARD in particular, 1,25(OH)2D3 regulates both innate and adaptive immunity, potentiating the innate response (antimicrobial activity) but reducing adaptive immunity (antigen presentation, T and B cell activities). Regarding a possible synergism between vitamin D and GCs, several studies show that 1,25(OH)2D3 has significant additive effects on dexamethasone‐mediated inhibition of human lymphocyte and monocyte proliferation. Conversely, vitamin D deficiency seems to play a role in increasing autoantibody production by B cells, and seasonal vitamin D declines may trigger flares in ARD, as recently shown. Finally, 1,25(OH)2D3 seems to reduce aromatase activity and limit the negative effects related to increased peripheral estrogen metabolism (cell proliferation, B cell overactivity).
Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the ...main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.
Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients' informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.
Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells).
In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.
Circadian rhythms (Nobel prize for Medicine 2017) regulate, under action of biological clocks located both at the level of central nervous system and inside peripheral cells, several daily ...activities, embracing sleep, feeding times, energy metabolism, endocrine and immune functions with related pathological conditions, including rheumatoid arthritis (RA).
In RA the circadian rhythms impact on cellular functions, involving night synthesis and release of pro-inflammatory cytokines and chemokines, cell migration to inflamed tissues, phagocytosis, proliferative cell response and all are peaking at late night. In chronic inflammatory conditions such as RA, the amplitude of the circadian rhythm of the anti-inflammatory endogenous cortisol availability is not increased as expected and requested, which indicate a reduced night cortisol secretion under the adrenal chronic stress induced by the disease. Therefore, the prevention/treatment of the immune cell night hyperactivity, with related flare of cytokine synthesis and morning RA clinical symptoms, has been shown more effective when the availability of the exogenous glucocorticoids is obtained in the middle of the night (night release). The impressive positive results observed in RA patients treated with modified-night release prednisone with a low-dose chronotherapy, seem applicable even for other agents such as conventional NSAIDs and DMARDs, including the positive experimental and clinical results obtained by the night time daily administration of methotrexate. Interestingly, a very recent study showed that methotrexate upregulates important cell circadian genes, resulting in induction of apoptosis in synovial fibroblasts. The link between the circadian rhythms of the disease and the chronotherapy of RA is promising.
Objective
To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6‐month period in patients with systemic sclerosis (SSc).
Methods
In ...this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses.
Results
Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow‐up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval 95% CI 0.681–0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510–0.756).
Conclusion
This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs.
Circulating fibrocytes are an important source of fibroblasts and myofibroblasts, which are involved in fibrotic processes, including systemic sclerosis (SSc). The study aimed to investigate the ...effect of nintedanib (a tyrosine kinase inhibitor) in inhibiting the in vitro transition of circulating SSc fibrocytes into myofibroblasts and their pro-fibrotic activity.
Circulating fibrocytes were obtained from 18 SSc patients and 5 healthy subjects (HSs). Cultured SSc fibrocytes were maintained in growth medium (untreated cells) or treated with nintedanib 0.1 and 1 μM for 3 and 24 h. Fibroblast-specific protein-1 (S100A4) and α-smooth muscle actin (αSMA), as markers of fibroblast/myofibroblast phenotype, together with type I collagen (COL1) and fibronectin (FN), were investigated by qRT-PCR and Western blotting. Non-parametric tests were used for statistical analysis.
Significantly elevated gene and protein expressions of αSMA, S100A4, COL1, and FN were observed in SSc fibrocytes compared to HS fibrocytes (gene: αSMA p < 0.001; others p < 0.0001; protein: all p < 0.05). Interestingly, an increased gene and protein expression of αSMA and S100A4 was found in fibrocytes from SSc patients positive for anti-Scl70 and with interstitial lung disease (ILD) (Scl70
ILD
) compared to Scl70
ILD
patients (S100A4: gene: p < 0.01; protein: p < 0.05), whereas no differences were observed for COL1 and FN. Nintedanib reduced gene and protein expression of αSMA, S100A4, COL1, and FN in SSc fibrocytes compared to untreated ones with different statistical significance. Noteworthy, nintedanib significantly downregulated gene and protein expression of αSMA, S100A4, COL1, and FN in Scl70
ILD
fibrocytes (all p < 0.05), whereas only that of S100A4 and FN was significantly downregulated (p < 0.05) in Scl70
ILD
fibrocytes compared to the related untreated cells.
Nintedanib seems to downregulate in vitro the transition of fibrocytes into myofibroblasts and their pro-fibrotic activity, particularly in cells isolated from Scl70
ILD
SSc patients.
Alternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 ...(CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB). The study investigated the possible role of ET-1 in inducing the transition from cultured human macrophages into M2 cells.
Cultured human monocytes (THP-1 cell line) were activated into macrophages (M0 macrophages) with phorbol myristate acetate and subsequently maintained in growth medium (M0-controls) or treated with either ET-1 (100nM) or interleukin-4 (IL-4, 10ng/mL, M2 inducer) for 72 hours. Similarly, primary cultures of human peripheral blood monocyte (PBM)-derived macrophages obtained from healthy subjects, were maintained in growth medium (untreated cells) or treated with ET-1 or IL-4 for 6 days. Both M0 and PBM-derived macrophages were pre-treated with ET receptor antagonist (ETA/BRA, bosentan 10-5M) for 1 hour before ET-1 stimulation. Protein and gene expression of CD204, CD206, CD163, TGFbeta1 were analysed by immunocytochemistry, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Gene expression of interleukin(IL)-10 and macrophage derived chemokine (CCL-22) was evaluated by qRT-PCR. MMP-9 production was investigated by gel zymography.
ET-1 significantly increased the expression of M2 phenotype markers CD204, CD206, CD163, IL-10 and CCL-22, and the production of MMP-9 in both cultures of M0 and PBM-derived macrophages compared to M0-controls and untreated cells. In cultured PBM-derived macrophages, ET-1 increased TGFbeta1 protein and gene expression compared to untreated cells. The ET-1-mediated effects were contrasted by ETA/BRA treatment in both cultured cell types.
ET-1 seems to induce the M2 phenotype in cultured human macrophages, a process apparently contrasted by the action of the ETA/BRA, suggesting possible clinical implications in those fibrotic diseases characterized by increased ET-1 concentrations, such as systemic sclerosis but also type 2 diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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