Search

Wnt-1 inducible signaling pathway protein 2 (WISP-2/CCN5) is a recently identified adipokine that has been described as an important mediator of canonical Wnt activation in adipogenic precursor cells. In osteoarthritis (OA), the most common form of arthritis, chondrocytes exhibit aberrant and increased production of pro-inflammatory mediators and matrix degrading enzymes such as IL-1β and MMP-13. Although recent evidence suggests a role for Wnt signaling in OA physiopathology, little is known about the involvement of WISP-2 in cartilage degradation. In the present study, we determined the expression of WISP-2 in healthy and OA human chondrocytes. WISP-2 expression is modulated along chondrocyte differentiation and downregulated at the onset of hypertrophy by inflammatory mediators. We also investigated the effect of WISP-2 on cartilage catabolism and performed WISP-2 loss-of-function experiments using RNA interference technology in human T/C-28a2 immortalized chondrocytes. We demonstrated that recombinant human WISP-2 protein reduced IL-1β-mediated chondrocyte catabolism, that IL-1β and WNT/b-catenin signaling pathways are involved in rhWISP-2 protein and IL-1β effects in human chondrocytes, and that WISP-2 has a regulatory role in attenuating the catabolic effects of IL-1β in chondrocytes. Gene silencing of WISP-2 increased the induction of the catabolic markers MMP-13 and ADAMTS-5 and the inflammatory mediators IL-6 and IL-8 triggered by IL-1β in human primary OA chondrocytes in a Wnt/β-catenin dependent manner. In conclusion, here we have shown for the first time that WISP-2 may have relevant roles in modulating the turnover of extracellular matrix in the cartilage and that its downregulation may detrimentally alter the inflammatory environment in OA cartilage. We also proved the participation of Wnt/β-catenin signaling pathway in these processes. Thus, targeting WISP-2 might represent a potential therapeutical approach for degenerative and/or inflammatory diseases of musculoskeletal system, such as osteoarthritis.

Despite the benefits of current therapeutic options for treating inflammatory bowel disease (IBD), there are still patients who are refractory to these therapies. Moreover, the relapses caused by incomplete intestinal mucosa healing are frequent. Therefore, there is a need for novel pharmacological targets that can improve the existing IBD therapeutic armamentarium. Chemokine and chemokine receptors have emerged as appealing options to this end. As well as controlling leukocyte trafficking to inflamed tissues, these proteins regulate many other processes related to the development of intestinal inflammation. In this review, we summarise the most recent preclinical studies, along with the putative application of chemokine-based therapies in patients with IBD.

C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytes. This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA). We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target. We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes. We concluded that mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.

We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was supported by European Union FEDER funds and `Fondo de Investigaciones Sanitarias (Grant PI18/00042) from 'Instituto de Salud Carlos III' (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Rio Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future) (Grant Number CM20/00006). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, co-funded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). BA-M is a recipient of a `Lopez Albo Post-Residency Programme funded by Servicio Cantabro de Salud. LL-G is supported by funds from IDIVAL (INNVAL20/06). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (Grant Numbers RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899-Olive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by ESF (`Investing in your future) (Grant Number CP16/00033)., Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between, European Commission, 'Instituto de Salud Carlos III' (ISCIII, Health Ministry, Spain) PI18/00042 Instituto de Salud Carlos III, European Social Fund (ESF) CM20/00006, RETICS Program (ISCIII) RD16/0012/0009, European Commission IDIVAL 18/01 INNVAL20/06, Servicio Cantabro de Salud, European Union FEDER fund RD16/0012/0014 PI17/00409, European Commission 734899 CP16/00033

We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was supported by European Union FEDER funds and `Fondo de Investigaciones Sanitarias´ (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) (grant number CM20/00006). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, co-funded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud. LL-G is supported by funds from IDIVAL (INNVAL20/06). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (grant numbers RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899—Olive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by ESF (`Investing in your future´) (grant number CP16/00033)., Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598- 021- 91055-z, BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immunemediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV., European Union FEDER fund RD16/0012/0014, H2020 Programme 734899, Health Ministry, Servicio Cántabro de Salud, Servizo Galego de Saude, European Commission PI18/00042 EC, Research Executive Agency REA, Instituto de Salud Carlos III CP16/00033,PI17/00409 ISCIII, European Social Fund CM20/00006,RD16/0012/0009 ESF, European Regional Development Fund ERDF, Instituto de Investigación Marqués de Valdecilla PREVAL 18/01 IDIVAL, Servicio Gallego de Salud SERGAS

Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxonethalidomide repurpose to treat OA-associated inflammatory responses.

Introduction: Patients with axial spondyloarthritis (axSpA) have a high disease burden mainly due to the rheumatic disease itself, and also exhibit accelerated atherosclerosis, that leads to a higher incidence of cardiovascular (CV) disease. Accordingly, the identification of biomarkers of CV risk and inflammation in axSpA patients is clinically relevant. In this sense, given the beneficial functions exerted by the adipomyokine irisin in processes related to CV disease and inflammation, our aim was to assess, for the first time, the role of irisin as a genetic and serological biomarker of subclinical atherosclerosis, CV risk and disease severity in axSpA patients. Methods: A large cohort of 725 Spanish patients with axSpA was included. Subclinical atherosclerosis (presence of plaques and abnormal carotid intima-media thickness values) was evaluated by carotid ultrasound. Four irisin polymorphisms (rs16835198 G/T, rs3480 A/G, rs726344 G/A, and rs1570569 G/T) were genotyped by TaqMan probes. Additionally, serum irisin levels were determined by ELISA. Results: Low irisin levels were linked to the presence of plaques (p=0.002) and atherogenic index values ?4 (p=0.01). Serum irisin were positively correlated with C-peptide levels (p2.1 (Odds Ratio (OR): 0.48 [0.28-0.83] and OR: 0.73 [0.57-0.92], respectively, p=0.01 in both cases). Additionally, the frequency of rs1570569 T allele was higher in these patients (OR: 1.46 [1.08-1.97], p=0.01). Furthermore, the GGGT haplotype was more frequent in patients with ASDAS values >2.1 (OR: 1.73 [1.13-2.66], p=0.01). Conclusions: Our results indicate that low serum irisin levels could be indicators of the presence of subclinical atherosclerosis, high CV risk and more severe disease in axSpA patients. In addition, irisin may also constitute a genetic biomarker of disease activity in axSpA. FUNDING: This work was partially supported by grants from Instituto de Investigación Sanitaria IDIVAL (NVAL17/10) and from the ‘Asociación Cántabra de Reumatologıá ’ awarded to FG. FG and JR-G are beneficiaries of a grant funded by ‘Instituto de Salud Carlos III’ (ISCIII) (PI20/00059). FG is supported by funds of the RICORS Program (RD21/0002/0025) from ISCIII, co-funded by the European Union. SR-M and VP-C are supported by funds of the RETICS Program (RD16/0012/0009) from ISCIII, co-funded by the European Regional Development Fund. RL-M is a recipient of a Miguel Servet type II Program fellowship from ISCIII, co-funded by the European Social Fund, `Investing in your future´ (CPII21/00004). ACKNOWLEDGMENTS: We are indebted to the patients for their essential collaboration to this study.

White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key molecule with pleiotropic functions. It is primarily recognized for its role in regulating energy homeostasis and food intake. Currently, further evidence suggests its potent role in reproduction, glucose metabolism, hematopoiesis, and interaction with the immune system. It is implicated in both innate and adaptive immunity, and it is reported to contribute, with other adipokines, in the cross-talking networks involved in the pathogenesis of chronic inflammation and immune-related diseases of the musculoskeletal system such as osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the most recent findings concerning the involvement of leptin in immunity and inflammatory responses in OA and RA. O.G. and F.L. are staff personnel (I3SNS stable researchers) of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff contract (ISCIII/SERGAS). C.R.F. is a predoctoral research scholar funded by ISCIII and FEDER (Exp.18/00188). M.G.R. is a recipient of a pre-doctoral contract funded by Xunta de Galicia (IN606A-2020/010). A.C.B. is a recipient of a pre-doctoral contract funded by Secretaría de Estado de Universidades, Investigación, Desarrollo e Innovación, Ministerio de Universidades (FPU2018-04165). O.G. and MAGG are members of the RICORS Programme, RD21/0002/0025 via ISCIII and FEDER. F.L. is a member of Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). The work of O.G. and J.P. (PI17/00409 and PI20/00902), and F.L. (PI18/00821, PI21/01145) is funded by ISCIII and FEDER. O.G. is a beneficiary of a project funded by the Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (project number 734899). O.G. is beneficiary of a grant funded by Xunta de Galicia, Conselleriá de Educación, Universidade e Formación Profesional, and Conselleriá de Economia, Emprego e Industria (GAIN), GPC IN607B2019/10.

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.

BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGTA a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGTA, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.

Osteoarthritis, a major cause of disability in developed countries does not have effective treatment. Activation of TLR4 and innate immune response factors contribute to osteoarthritis progressive cartilage degradation. There are no clinically available TLR4 inhibitors. Interestingly, the antidepressant amitriptyline could block this receptor. Thus, we evaluated amitriptyline anti-TLR4 effects on human osteoarthritis chondrocytes in order to repurpose it as an inhibitor of innate immune response in joint inflammatory pathologies.Using in silico docking analysis, RT-PCR, siRNA, elisa, proteomics and clinical data mining of drug consumption, we explored the clinical relevance of amitriptyline blockade of TLR4-mediated innate immune responses in human osteoarthritis chondrocytes.Amitriptyline bound TLR4 but not IL-1 receptor. Interestingly, amitriptyline binding to TLR4 inhibited TLR4- and IL-1 receptor-mediated innate immune responses in human osteoarthritis chondrocytes, synoviocytes and osteoblasts cells. Amitriptyline reduced basal innate immune responses and promoted anabolic effects in human osteoarthritis chondrocytes. Supporting its anti-innate immune response effects, amitriptyline down-regulated basal and induced expression of NLRP3, an inflammasome member from IL-1 receptor signalling linked to osteoarthritis and gout pathologies. Accordingly, mining of dissociated and aggregated drug consumption data from 107,172 elderly patients (65 years) revealed that amitriptyline consumption was significantly associated with lower colchicine consumption associated with inflammatory gout flare treatment.Amitriptyline blocks TLR4-, IL-1 receptor and NLRP3-dependent innate immune responses. This together with clinical data amitriptyline could be repurposed for systemic or local innate immune response management in diverse joint inflammatory pathologies.

OBJECTIVES: To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). METHODS: VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. CONCLUSIONS: VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.

Relaxin is an insulin-like hormone with pleiotropic protective effects in several organs, including the liver. We aimed to characterize its role in the control of hepatic metabolism in healthy rats. Sprague-Dawley rats were treated with human recombinant relaxin-2 for 2 weeks. The hepatic metabolic profile was analyzed using UHPLC-MS platforms. Hepatic gene expression of key enzymes of desaturation (Fads1/Fads2) of n-6 and n-3 polyunsaturated fatty acids (PUFAs), of phosphatidylethanolamine (PE) N-methyltransferase (Pemt), of fatty acid translocase Cd36, and of glucose-6-phosphate isomerase (Gpi) were quantified by Real Time-PCR. Activation of 5'AMP-activated protein kinase (AMPK) was analyzed by Western Blot. Relaxin-2 significantly modified the hepatic levels of 19 glycerophospholipids, 2 saturated (SFA) and 1 monounsaturated (MUFA) fatty acids (FA), 3 diglycerides, 1 sphingomyelin, 2 aminoacids, 5 nucleosides, 2 nucleotides, 1 carboxylic acid, 1 redox electron carrier, and 1 vitamin. The most noteworthy changes corresponded to the substantially decreased lysoglycerophospholipids, and to the clearly increased FA (16:1n-7/16:0) and MUFA + PUFA/SFA ratios, suggesting enhanced desaturase activity. Hepatic gene expression of Fads1, Fads2, and Pemt, which mediates lipid balance and liver health, was increased by relaxin-2, while mRNA levels of the main regulator of hepatic FA uptake Cd36, and of the essential glycolysis enzyme Gpi, were decreased. Relaxin-2 augmented the hepatic activation of the hepatoprotector and master regulator of energy homeostasis AMPK. Relaxin-2 treatment also rised FADS1, FADS2, and PEMT gene expression in cultured Hep G2 cells. Our results bring to light the hepatic metabolic features stimulated by relaxin, a promising hepatoprotective molecule.

PURPOSE OF REVIEW: This review focuses on the molecular taxonomy of osteoarthritis from the perspective of molecular biomarkers. We discuss how wet biochemical markers may be used to understand disease pathogenesis and progression and define molecular endotypes of osteoarthritis and how these correspond to clinical phenotypes. RECENT FINDINGS: Emerging evidence suggests that osteoarthritis is a heterogeneous and multifaceted disease with multiple causes, molecular endotypes and corresponding clinical phenotypes. Biomarkers may be employed as tools for patient stratification in clinical trials, enhanced disease management in the primary care centres of the future and for directing more rational and targeted osteoarthritis drug development. Proximal molecular biomarkers (e.g synovial fluid) are more likely to distinguish between molecular endotypes because there is less interference from systemic sources of biomarker noise, including comorbidities. SUMMARY: In this review, we have focused on the molecular biomarkers of four distinct osteoarthritis subtypes including inflammatory, subchondral bone remodelling, metabolic syndrome and senescent age-related endotypes, which have corresponding phenotypes. Progress in the field of osteoarthritis endotype and phenotype research requires a better understanding of molecular biomarkers that may be used in conjunction with imaging, pain and functional assessments for the design of more effective, stratified and individualized osteoarthritis treatments.

Adiponectin is an adipokine that plays a relevant role in the development of metabolic syndrome (MetS), a complication that increases the risk of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). Accordingly, we assessed for the first time the short-term effect of anti-IL-6 receptor tocilizumab (TCZ) administration on adiponectin serum levels in RA patients and explored the potential association of adiponectin levels with MetS features, other CV risk factors and demographic and clinical characteristics of these patients.Adiponectin serum levels were evaluated in 50 non-diabetic RA patients, undergoing TCZ treatment, immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion).No significant differences in adiponectin levels pre- and post-TCZ infusion were found in RA patients (p=0.69). Patients with obesity exhibited decreased basal levels of adiponectin with respect to those non-obese (p=0.03). Additionally, a negative association of adiponectin basal levels with body mass index, insulin, insulin/glucose index, C-peptide and leptin levels (p0.01; p=0.02; p=0.03; p=0.03 and p=0.01, respectively), as well as a positive correlation with HDL-cholesterol levels (p0.001) was seen.Our results support the claim that low adiponectin may contribute to the development of MetS and, consequently, CV disease in RA. Anti-IL-6 therapy does not seem to exert a short-term effect on adiponectin levels.

Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view.

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p, This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from ‘‘Instituto de Salud Carlos III’’ (ISCIII) (Spain). However, this research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors.

Objective To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions Our results support the association of the HLA complex with the susceptibility to ASSD.

Virola is the largest genus of Myristicaceae in America, comprising about 60 species of medium-sized trees geographically spread from Mexico to southern Brazil. The plant species of this genus have been widely used in folk medicine for the treatment of several ailments, such as rheumatic pain, bronchial asthma, tumors in the joints, intestinal worms, halitosis, ulcers, and multiple infections, due to their pharmacological activity. This review presents an updated and comprehensive summary of Virola species, particularly their ethnomedicinal uses, phytochemistry, and biological activity, to support the safe medicinal use of plant extracts and provide guidance for future research. The Virola spp.’s ethnopharmacology, including in the treatment of stomach pain and gastric ulcers, as well as antimicrobial and tryponosomicidal activities, is attributable to the presence of a myriad of phytoconstituents, such as flavonoids, tannins, phenolic acids, lignans, arylalkanones, and sitosterol. Hence, such species yield potential leads or molecular scaffolds for the development of new pharmaceutical formulations, encouraging the elucidation of not-yet-understood action mechanisms and ascertaining their safety for humans.

Ethnopharmacological relevance Virola oleifera (Schott) A.C. Smith, Myristicaceae, has been widely used in traditional medicine in Brazil to treat rheumatic pain, joint tumours, skin diseases, halitosis, bronchial asthma, haemorrhoids, and intestinal worms. Recently, research data showed the antioxidant properties in several oxidative stress-related models. However, there is no experimental evidence supporting its potential use in managing rheumatic diseases and bone malignancies. Aims of the study To evaluate the therapeutic potential of the resin from Virola oleifera in joint and bone diseases, namely arthritis, osteosarcoma, chondrosarcoma, and multiple myeloma. Materials and methods To determine Virola oleifera resin (VO) effects on arthritis-associated inflammation and cartilage degradation, the LPS-induced NO production, and mRNA and protein expression of ADAMTS5, MMP13, COL2, and ACAN, were evaluated in chondrocytes (ATDC5 and TC28 cell lines). The cytotoxic effects of VO (0.05–50 μg/ml) on multiple myeloma (ARH-77), osteosarcoma (SAOS-2), and chondrosarcoma (SW-1353) cell lines were analysed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The VO effects, combined with dexamethasone or bortezomib, were evaluated in a multiple myeloma cell line. The mechanisms of VO, alone or in combination with bortezomib, were determined by cell cycle analysis through flow cytometry, while expression levels of p-Akt/Akt, p-ERK/ERK, p-p38/p38 MAPK, Bax, Bcl-2, and cleaved-caspase-3/caspase-3 proteins by Western blot. Results VO had no significant effect on LPS-induced NO production in chondrocytes at non-cytotoxic concentrations. VO treatment diminished the mRNA levels of metalloproteinases and ECM components; however, any significant effect was observed on the protein expression levels. The cell viability of a multiple myeloma cell line was strongly reduced by VO treatment in a dose- and time-dependent manner, while osteosarcoma and chondrosarcoma cell lines viability was significantly affected only by the highest dose assessed. In multiple myeloma cells, VO leads to G2/M cell cycle arrest. Furthermore, it synergizes with dexamethasone by increasing cell toxicity. Finally, VO reverts bortezomib activity by counteracting ERK1/2, Bax, and caspase-3 activation. Conclusions The current work supports the ethnopharmacological use of Virola oleifera (Schott) A.C. Smith in bone and joint diseases, but there is no evidence for the amelioration of arthritis-associated inflammatory or catabolic processes. Our data also supports the potential use of Virola oleifera as adjuvant therapy to optimize the pharmacologic effects of current chemotherapeutic drugs. However, possible herb-drug interactions should be considered before clinical application.

It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of cardiovascular diseases, mainly due to a low grade of inflammation and the excessive fat accumulation produced in this state. The adipose tissue dysfunction in obesity leads to an aberrant release of adipokines, some of them with direct cardiovascular and inflammatory regulatory functions. Inflammation is a common link between obesity and cardiovascular diseases, so this review will summarise the role of the main adipokines implicated in the regulation of the inflammatory processes occurring under the scenario of cardiovascular diseases.

Objective: To determine whether giant cell arteritis (GCA) patients with the typical pattern of cranial ischemic manifestations and those with the extracranial large-vessel-vasculitis (LW)-GCA phenotype exhibit different HLA-DRB1 association. Methods: 178 biopsy-proven GCA patients who had cranial ischemic features but no LW manifestations, 100 patients with LVV-GCA without cranial ischemic manifestations and 486 ethnically matched healthy controls were recruited. All patients and controls were Spanish of European ancestry. We compared HLA-DRB1 phenotype frequencies between the three groups. Results: Both GCA subgroups had well-differentiated clinical features. Patients with LVV-GCA were younger (68.0 +/- 10.0 years versus 74.0 +/- 10.4 years; p < 0.01) and presented more commonly with polymyalgia rheumatica symptoms (81% versus 39.3%; p < 0.01) than those with the classic cranial GCA phenotype. HLA-DRB1*04 phenotype frequency was significantly increased in patients with classic cranial GCA compared to controls (42.1% versus 23.5%, respectively; p < 0.01; odds ratio-OR [95% confidence interval-CI] = 2.38 [1.62-3.47]). This association was mainly due to the HLA-DRB1*04:01 allele (20.8% versus 5.3%, respectively; p < 0.01; OR [95% CI] = 4.64 [2.63-8.26]). HLA-DRB1*04 association was also observed in LW-GCA patients when compared to controls (46.0% versus 23.5%, respectively; p < 0.01; OR [95% CI] = 2.78 [1.73-4.44]). Similar to cranial GCA, the association was also mainly due to the HLA-DRB1*04:01 allele (19.0% versus 5.3%, respectively; p < 0.01; OR [95% CI] = 4.15 [2.06-8.19]). Cranial and LW-GCA patients did not exhibit HLA-DRB1 allele differences. Conclusion: Cranial and extracranial LVV-GCA share similar HLA-DRB1 association. (C) 2020 Elsevier Inc. All rights reserved.

Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1 , MIP1 , MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.

Cardiovascular (CV) disease is the main cause of mortality in axial spondyloarthritis (axSpA). CV risk is enhanced by dysregulation of adipokines. Low omentin levels were associated with metabolic dysfunction and CV disease in conditions different from axSpA. Accordingly, we evaluated the genetic and functional implication of omentin in CV risk and subclinical atherosclerosis in a cohort of 385 axSpA patients. Subclinical atherosclerosis was evaluated by carotid ultrasound. Omentin rs12409609, in linkage disequilibrium with a polymorphism associated with CV risk, was genotyped in 385 patients and 84 controls. Serum omentin levels were also determined. omentin mRNA expression was assessed in a subgroup of individuals. Serum and mRNA omentin levels were lower in axSpA compared to controls. Low serum omentin levels were related to male sex, obesity, inflammatory bowel disease (IBD) and high atherogenic index. rs12409609 minor allele was associated with low omentin mRNA expression in axSpA. No association was observed with subclinical atherosclerosis at the genetic or functional level. In conclusion, in our study low omentin serum levels were associated with CV risk factors in axSpA. Furthermore, rs12409609 minor allele may be downregulating the expression of omentin. These data support a role of omentin as a CV risk biomarker in axSpA. We wish to thank all the patients and controls that participated in this study. This work was supported by funds of a NEXT-VAL grant (NVAL17/10) (Instituto de Investigación Sanitaria IDIVAL) awarded to FG. SR-M is supported by funds of the RETICS Program (RD16/0012/0009) from the ‘Instituto de Salud Carlos III´ (ISCIII), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by the European Social Fund (ESF)). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the ESF (grant CP16/00033).

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD, This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ‘Instituto de Salud Carlos III’ (ISCIII), cofunded by the European Social Fund (ESF, ‘Investing in your future’) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ESF). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). OG,is member of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG (PI17/00409), was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10

Calprotectin (CPT) is released during inflammation, also in the context of atherosclerosis. The link between CPT and the atherosclerotic process was evaluated in several diseases. However, studies in axial spondyloarthritis (axSpA), associated with a high incidence of subclinical atherosclerosis, are scarce. Therefore, we assessed the association of CPT with subclinical atherosclerosis and metabolic risk factors in axSpA. CPT serum levels were measured by enzyme-linked immunosorbent assay in 163 axSpA patients and 63 controls. Subclinical atherosclerosis was determined in patients by carotid ultrasonography (assessing the presence/absence of carotid plaques and carotid intima-media thickness [cIMT]). Data on inflammation, disease activity, lipid profile and treatment were collected to evaluate its relationship with CPT. axSpA patients evidenced lower CPT levels than controls. CPT showed no association with plaques or cIMT in axSpA. CPT and HDL-cholesterol negatively correlated, while a positive association of CPT with the atherogenic index was disclosed. Additionally, axSpA patients with C-reactive protein values at diagnosis higher than 3?mg/L displayed higher CPT levels. Our study shows no relationship between CPT and markers of subclinical atherosclerosis in axSpA. Nevertheless, it demonstrates an association of CPT with adverse lipid profiles and inflammatory biomarkers, which could further influence on the development of atherosclerosis. We wish to thank all the patients and controls that participated in this study and Begoña Ubilla for technical assistance. FG is a recipient of a Sara Borrell post-doctoral fellowship from the Instituto de Salud Carlos III (ISCIII) (Spain), co-funded by the European Social Fund (ESF, “Investing in your future”) (grant CD15/00095). SR-M is supported by funds of the RETICS Program (RIER) RD16/0012/0009 (ISCIII, co-funded by the European Regional Development Fund, ERDF). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ERDF). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the ESF (grant CP16/00033). This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Leptin is an adipokine that participates in the regulation of the immune and inflammatory response. Chronic systemic inflammation contributes to the development of cardiovascular (CV) disease in rheumatoid arthritis (RA). In this study, we aimed to assess the short-term effect of the anti-IL-6 receptor tocilizumab (TCZ) administration on circulating leptin concentrations in patients with RA, as well as the potential association of leptin with CV risk factors and demographic and clinical characteristics of these patients.We recruited 50 consecutive non-diabetic patients with RA undergoing periodic treatment with TCZ. Leptin serum levels were determined by a commercial immunoassay kit in samples obtained immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion).A significant reduction of leptin levels was observed following the TCZ infusion (9.24±7.98 ng/mL vs. 7.92±7.32 ng/mL, pre- and post-infusion, respectively, p=0.002). Additionally, there was a strong positive correlation between body mass index of RA patients and basal levels of leptin (r=0.56; p=0.0001). Moreover, high basal levels of leptin in RA patients were associated with female sex (p=0.006), obesity (p0.001) and rheumatoid factor negative status (p=0.006).Our study disclosed a short-term effect of anti-IL-6 therapy on leptin serum levels in RA patients. Decreased leptin levels may explain the beneficial effect of anti-IL-6 blockade on CV disease associated to RA.

Background/Aims: The E74-like factor 3 (ELF3) is an inflammatory mediator that participates in cartilage destruction in osteoarthritis. Leptin and other adipokines negatively impact articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated whether leptin induces ELF3 expression in chondrocytes and the signaling pathway involved in this process. Methods: We determined mRNA and protein levels of ELF3 by RT-qPCR and Western blotting using cultured human primary chondrocytes and the human T/C-28a2 chondrocyte cell line. Further, we measured luciferase activities of different reporter constructs, and we assessed the contribution of leptin to the induction of ELF3 mRNA by knocking down hLEPR gene expression using siRNA technology. Results: Leptin synergizes with IL-1β in inducing ELF3 expression in chondrocytes. We also found that PI3K, p38, and JAK2 signaling pathways are at play in the leptin-driven induction of ELF3. Moreover, we confirm the participation of NFΚB in the leptin/IL-1β synergistic induction of ELF3. Conclusion: Here we show, for the first time, the regulation of ELF3 expression by leptin, suggesting that this transcription factor likely mediates the inflammatory responses triggered by leptin in articular chondrocytes.

Osteoarthritis (OA) is the most common form of joint disease. This presents the OA research community and pharmaceutical companies developing disease-modifying osteoarthritis drugs (DMOADs) with great opportunities.. The different OA subtypes complicates the traditional approaches for developing new treatments. If we can identify new markers that can distinguish different subtypes this can greatly facilitate drug development from early discovery to late clinical development. Nevertheless, the current approaches result in poorly targeted treatments and the inability to recruit the right patients for clinical trials. Thus, there is an urgent medical need for objective biomarker tools for patient phenotyping.

Intervertebral disc degeneration (IVDD) is a chronic, expensive, and high-incidence musculoskeletal disorder largely responsible for back/neck and radicular-related pain. It is characterized by progressive degenerative damage of intervertebral tissues along with metabolic alterations of all other vertebral tissues. Despite the high socio-economic impact of IVDD, little is known about its etiology and pathogenesis, and currently, no cure or specific treatments are available. Recent evidence indicates that besides abnormal and excessive mechanical loading, inflammation may be a crucial player in IVDD. Furthermore, obese adipose tissue is characterized by a persistent and low-grade production of systemic pro-inflammatory factors. In this context, chronic low-grade inflammation associated with obesity has been hypothesized as an important contributor to IVDD through different, but still unknown, mechanisms. Adipokines, such as leptin, produced prevalently by white adipose tissues, but also by other cells of mesenchymal origin, particularly cartilage and bone, are cytokine-like hormones involved in important physiologic and pathophysiological processes. Although initially restricted to metabolic functions, adipokines are now viewed as key players of the innate and adaptative immune system and active modulators of the acute and chronic inflammatory response. The goal of this review is to summarize the most recent findings regarding the interrelationships among inflammation, obesity and the pathogenic mechanisms involved in the IVDD, with particular emphasis on the contribution of adipokines and their potential as future therapeutic targets.

Extra virgin olive oil (EVOO) is the main source of fat in the Mediterranean diet. Phenolic compounds of EVOO, in particular, secoiridoids, are minor components that have generated special interest due to their positive effects on human health, supported by several clinical trials. This review summarizes the most recent findings on the pharmacological properties and action's mechanisms of secoiridoid oleocanthal, focusing attention on inflammation, oxidative stress, cancer, neurodegenerative processes, and rheumatic diseases. Being of relevance to the clinical effects of EVOO intake, the bioavailability and biotransformation of EVOO polyphenols are addressed. Moreover, this review summarizes the factors that may influence the oleocanthal concentration in EVOO. With the growing incidence of age- and lifestyle-related diseases, the current data indicated that the administration of EVOO rich in secoiridoids may be helpful in the prevention or treatment of different pathologies with an inflammatory component. Although promising, the future raises several questions and challenges, which are discussed here. The real beneficial effects of olive oil phenols on human health need to be clarified in new, well-designed clinical studies.

Background and Purpose: Recombinant human relaxin-2, serelaxin, is being proved as a novel drug with therapeutic efficacy in some cardiovascular diseases, especially heart failure, a disease whose physiopathology and course are firmly correlated with important alterations in cardiac metabolism. The aim of our present work was to investigate changes in the cardiac metabolome following relaxin-2 treatment. Experimental Approach: Sprague-Dawley rats were treated with human recombinant relaxin-2 using osmotic minipumps at a dose of 0.4 mg/kg/day for 2 weeks. Body composition was measured with a nuclear magnetic resonance imaging system seven days after surgery and on the final day of the experiment. The last two days of treatment, respiratory quotient, locomotor activity and energy expenditure were measured with a calorimetric system. The plasma levels of relaxin-2, total cholesterol, high- and low- density lipoproteins (HDL, LDL), triglycerides and the hepatic enzymes glutamic-pyruvic transaminase (GTP) and gamma-glutamyltransferase (GGT) levels were analyzed. The metabolic profiling of both atria from relaxin-2-treated and control rats was carried out using two separate ultra-high performance liquid chromatography (UHPLC)-Time of Flight-MS based platforms analyzing methanol and chloroform/methanol extracts combined with a UHPLC-single quadrupole-MS based platform used to analyze aminoacids and with a methanol/water extract platform that covered polar metabolites. Identified ion features in the methanol extract platform included fatty acids, acyl carnitines, bile acids, monoacylglycerophospholipids, monoetherglycerophospholipids, free sphingoid bases, and oxidized fatty acids. The chloroform / methanol extract platform provided coverage over glycerolipids, cholesterol esters, sphingolipids, diacylglycerophospholipids, and acyl-ether-glycerophospholipids. Gene expression levels of the adipokines adiponectin, leptin and nesfatin-1 in visceral adipose tissue and cardiac gene expression levels of key enzymes of desaturation and elongation of n-6 and n-3 PUFAs were assessed by Real Time-PCR. Key Results: Twenty-eight metabolites out of three hundred sixty-two were significantly altered by human relaxin-2. These included fifteen glycerophospholipids: three phosphatidylethanolamines (PE) and twelve phosphatidylcholines (PC); eight sphingolipids: three ceramides (Cer) and five sphingomyelins (SM); and also five aminoacids and one carboxylic acid. Interestingly, the majority of changes correspond to lipid classes, twelve of them polyunsaturated diacylglycerophosphatidylcholines with long acyl chains, containing mainly docosahexaenoic acid (22:6) and arachidonic acid (20:4). Atrial levels of Elovl5 (Elongation of very long chain fatty acids protein 5), Fads1 (Delta 5-fatty acid desaturase) and Fads2 (Delta 6-fatty acid desaturase), key enzymes of elongation and desaturation of n-6 and n-3 PUFAs like arachidonic acid and DHA, respectively, were significantly increased by relaxin-2 treatment. Atrial tissues from rats treated with relaxin-2 showed a significant increase in the mRNA levels of Srebf1, a transcription factor that activates the gene expression of Elovl5, Fads1 and Fads2. The treatment with relaxin-2 significantly decreased the visceral fat mRNA expression levels of adiponectin, leptin and nesfatin-1, adipokines known to exert an important influence on the regulation of cardiovascular function. Conclusion and Implications: Serelaxin (human recombinant relaxin-2) treatment induces significant changes in cardiac major components of the membrane lipid bilayer such as glycerophospholipids and sphingolipids, known to have structural roles but also very relevant regulatory effects in cardiac function. Serelaxin induced also modifications in several aminoacids of high influence in cardiac energy metabolism regulation. Our results highlight the need to further understand the role of relaxin-2 in the regulation of cardiac energy metabolism, in the context of the therapeutic strategies for the treatment of cardiometabolic pathologies as heart failure.

Giant cell arteritis (GCA) is the most common form of vasculitis in adults. Cranial manifestations are typical clinical features of this vasculitis. Sometimes the presenting symptoms are nonspecific and, in some cases, large-vessel involvement may prevail. Polymyalgia rheumatica is a frequent manifestation that in some cases may be the presenting symptom of GCA. Visual complications, in particular the risk of blindness, constitute the most feared manifestations of GCA. Prompt recognition of this vasculitis is required to avoid irreversible complications. Prednisone/prednisolone at a dose of 40–60 mg/day is the cornerstone therapy in GCA. Glucocorticoids lead to rapid improvement of symptoms and may reduce the risk of irreversible visual loss. However, relapses are common when the prednisone dose is tapered. Therefore, additional therapies are required in relapsing GCA or when a rapid reduction of glucocorticoids is needed. The most widely used conventional immunosuppressive drug is methotrexate Adjunctive treatment with methotrexate may decrease the risk of relapses and reduce glucocorticoid exposure. However, comprehensive reviews indicate that the efficacy of methotrexate in GCA is modest. The experience with other conventional immunosuppressive drugs in GCA patients is scarce. In some cases, the new biologic agents are required. Among them, the most frequently used is the recombinant humanized anti-IL-6 receptor antibody tocilizumab. It improves clinical symptoms, reduce the cumulative prednisone dose and the frequency of relapses in GCA patients. However, anti-tumor necrosis factor-α therapy is not useful in GCA. Promising results on other biologic agents, such as abatacept, ustekinumab or anakinra, require further confirmatory studies.

Objective To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). Methods We performed a genome-wide association study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima-media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals. Results A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome-wide level of significance (minor allele [G] beta coefficient 0.142, P = 1.86 x 10(-8)). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate-adjusted P = 4.01 x 10(-3)). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 x 10(-4), P = 5.94 x 10(-4), and P = 2.46 x 10(-4), respectively). Conclusion The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA., Supported in part by the European Union FEDER fund and the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigacion Sanitaria grants PI06/0024, PS09/00748, PI12/00060, PI15/00525, and CP16/00033), the ISCIII RETICS programs (RD12/0009 and RD16/0012), the European IMI BTCure Program. Dr. Lopez-Mejias is recipient of the Miguel Servet type I Program Fellowship from the ISCIII and the European Social Fund (ESF) (grant CP16/00033). Dr. Carmona's work was supported by the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal Program grant RYC-2014-16458). Dr. Genre is recipient of a Sara Borrell postdoctoral fellowship from the ISCIII and ESF (grant CD15/00095). Dr. Remuzgo-Martinez' work was supported by the ISCIII and European Regional Development Fund (ERDF) (RETICS Program RD16/0012/0009). Ms Pulito-Cueto's work was supported by a predoctoral grant from the Instituto de Investigacion Sanitaria Valdecilla (PREVAL 18/01). Ms Mijares' work was supported by the Miguel Servet type I Program from the ISCIII and ESF (grant CP16/00033). Dr. Gualillo is staff personnel of Xunta de Galicia (Servizo Galego de Saude [SERGAS]) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and FEDER (grants RD16/0012/0014 [RIER] and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899-Olive-Net.

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration. Acknowledgments: This work was supported by Xunta de Galicia (Servizo Galego de Saude, SERGAS), through a research-staff contract (ISCIII/SERGAS) to OG and FL, which are Staff Personnel (I3SNS stable Researcher), by Instituto de Salud Carlos III (ISCIII) and by FEDER through a predoctoral research scholar to CR-F (Exp.18/00188), and “Miguel Servet” Researcher contract to RG and JC. MG is a recipient of pre-doctoral contract funded by Xunta de Galicia (IN606A-2020/010). AC is a recipient of a pre-doctoral contract funded by Secretaría de Estado de Universidades, Investigación, Desarrollo e Innovación, Ministerio de Universidades (FPU2018-04165). OG is member of RETICS Programme, [RD16/0012/0014] (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via ISCIII and FEDER. FL is a member of CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares). ISCIII and FEDER also support OG and JP [PI17/00409 and PI20/00902]. This work was supported by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme [Project number 734899], and Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN) [GPC IN607B2019/10] to OG. A.M. has received funding from the following sources: The European Commission Framework 7 program (EU FP7; HEALTH.2012.2.4.5-2, project number 305815; Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases). The Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. A.M. also wishes to acknowledge funding from the European Commission through a Marie Curie Intra-European Fellowship for Career Development grant (Project number 625746; acronym: CHONDRION; FP7-PEOPLE-2013-IEF). A.M. also wishes to acknowledge financial support from the European Structural and Social Funds (ES Strukt ¯ urin˙ es Paramos) through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity “Improvement of researchers” qualification by implementing world-class R&D projects’ of Measure No. 09.3.3-LMTK-712 (grant application code: 09.3.3-LMT-K-712-01-0157, agreement No. DOTSUT-215) and the new funding program: Attracting Foreign Researchers for Research Implementation (2018-2022).

Objective Vitamin D deficiency is a public health problem that occurs more frequently than expected. The aim of this study is to evaluate the vitamin D levels of children attending the paediatrics unit of the Bertamiráns primary care centre (A Coruña NW Spain). This is an observational study carried out during 1 year on a random sample of the pediatric population aged between 5 and 15 years. The levels of vitamin D (25(OH)D) were determined by immunoassay (ADVIA Centaur Vitamin D®). The results were classified as sufficient (> 20 ng/ml), insufficient (10–20 ng/ml) and deficient (

Background/Aims: Oleocanthal (OC), a phenolic compound present in extra virgin olive oil (EVOO), has attracted attention since its discovery for its relevant pharmacological properties in different pathogenic processes, including inflammation. Here, we investigated the involvement of OC in LPS-activated osteoarthritis (OA) human primary chondrocytes. Methods: Human primary chondrocytes were harvested from articular cartilage samples obtained from OA patients. The effects of OC on the viability of chondrocytes were tested by MTT assay. Protein and mRNA expression of several catabolic and pro-inflammatory factors after OC treatment were measured by RT-qPCR and western blot respectively. Moreover, we analysed the NO production by Griess reaction. Finally, several pathways mediators were analysed by western blot. Results: We demonstrated that OC did not have any cytotoxic effect. Oleocanthal inhibited NO production and strongly decreased NOS2 and COX-2 protein and mRNA expression in LPS-activated human primary OA chondrocytes. Interestingly, OC also inhibits MMP-13 and ADAMTS-5. In addition, OC downregulates several pro-inflammatory factors, such as IL-6, IL-8, CCL3, LCN2 and TNF-α induced by LPS in human primary OA chondrocytes. Finally, we demonstrated that OC exerts its effects through the MAPK/P38/NF-kB pathways. Conclusion: These data show that OC is able to block LPS-mediated inflammatory response and MMP-13 and ADAMTS-5 induction in human primary OA chondrocytes via MAPKs/NF-kB pathways, suggesting that OC may be a promising agent for the treatment of inflammation in cartilage and a potential molecule to prevent disease progression by inhibiting metalloproteases and aggrecanases.

Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability. Recent work suggests that the global burden of OA is increasing, and costs associated with treatment are expected to increase dramatically as the aging human population expands. OA is currently diagnosed using radiography, but this technique is an indirect and insensitive measure of alterations in articular cartilage and fails to measure dynamic inflammatory processes in the joint. Radiographic changes detected overtime are small and occur in only a subset (progressors) of patients with OA. Therefore, we diagnose patients with OA on the basis of a diagnostic classification that is outdated. We also use the same tools and approaches for assessing the efficacy of new pharmacological and nonpharmacological interventions. In this review, we discuss the utility of soluble biochemical markers as biomarkers of OA and discuss whether we are close to using them in clinical practice. Combining patient information, functional imaging and carefully selected panels of biomarkers can help in achieving enhanced patient stratification and lead to better designed clinical trials. Biomarkers can be used for molecular endotyping and for developing more effective and more personalized treatments that will enhance clinical care for patients with OA.

Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders.

Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the most ancient known foods and has long been associated with health benefits. Many phenolic compounds extracted from Olea europea L. have attracted attention since their discovery. Among these phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for different diseases, showing relevant pharmacological properties in various pathogenic processes, including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention on its anti-inflammatory and chemotherapeutic roles.

Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint-space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs).

Osteoarthritis is a high-incidence painful and debilitating disease characterized by progressive degeneration of articular joints, which indicates a breakdown in joint homeostasis favoring catabolic processes. Biomechanical loading, associated with inflammatory and metabolic imbalances of joint, strongly contributes to the initiation and progression of the disease. Obesity is a primary risk factor for disease onset, and mechanical factors increased the risk for disease progression. Moreover, inflammatory mediators, in particular, adipose tissue-derived cytokines (better known as adipokines) play a critical role linking obesity and osteoarthritis. The present article summarizes the knowledge about the role of adipokines in cartilage and bone function, highlighting their contribution to the imbalance of joint homeostasis and, consequently, pathogenesis of osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:594-604, 2018.

Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases.

Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.

Contains fulltext : 174687.pdf (Publisher’s version ) (Closed access) Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.

Until the discovery of leptin 20 years ago, adipose tissue was considered only as a fat storage organ, involved in the regulation of energy homeostasis. At present, it is well known that adipokines, being leptin the forerunner of this superfamily, may act in different biological processes, including inflammation and immunity. In this review, we have explored the recent evidence about the relationship between leptin and immune system, summarizing the most important findings related to the involvement of leptin in both innate and adaptive immune response.

Nesfatin-1, a satiety-inducing peptide identified in hypothalamic regions that regulate energy balance, is an integral regulator of energy homeostasis and a putative glucose-dependent insulin coadjuvant. We investigated its production by human cardiomyocytes and its effects on glucose uptake, in the main cardiac glucose transporter GLUT-4 and in intracellular signaling. Quantitative RT-PCR, Western blots, confocal immunofluorescence microscopy, and ELISA of human and murine cardiomyocytes and/or cardiac tissue showed that cardiomyocytes can synthesize and secrete nesfatin-1. Confocal microscopy of cultured cardiomyocytes after GLUT-4 labeling showed that nesfatin-1 mobilizes this glucose transporter to cell peripherals. The rate of 2-deoxy-d-[3H]glucose incorporation demonstrated that nesfatin-1 induces glucose uptake by HL-1 cells and cultured cardiomyocytes. Nesfatin-1 induced dose- and time-dependent increases in the phosphorylation of ERK1/2, AKT, and AS160. In murine and human cardiac tissue, nesfatin-1 levels varied with diet and coronary health. In conclusion, human and murine cardiomyocytes can synthesize and secrete nesfatin-1, which is able to induce glucose uptake and the mobilization of the glucose transporter GLUT-4 in these cells. Nesfatin-1 cardiac levels are regulated by diet and coronary health.