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Introduction The NLR family pyrin domain containing 3 (NLRP3) signaling pathway has an important role in inflammation mediated by monosodium urate crystals in gout, and the characterization of single nucleotide polymorphisms (SNPs) have helped to recognize disease susceptibility. Objective The aim of this review is to provide an overview of the potential role of the inflammasome gene SNPs as a susceptibility factor for gout, discussing the current evidence available. Methods This review analyzes the relevant literature in the field of inflammasome SNPs and gout published in the last 10 years. The systematic research was performed in 16 articles, including both the SNPs associated and those not associated with gout, with the goal to have a complete overview. Results Sixty-nine SNPs from 10 different genes have been reported in the literature. Of these, 13 SNPs present association with gout susceptibility in different populations, while 56 have been established as not being associated with the disease. Conclusions This review is a summary of the potential role of inflammasome gene SNPs and their association with gout risk, all of them related with NLRP3 inflammasome signaling, suggesting these polymorphisms are susceptibility candidates and genetic markers for gout. From the 69 SNPs analyzed in the literature, 13 of them have been associated with gout as follows: NLRP3 (rs3806268 and rs10754558), CARD8 (rs2043211), TLR4 (rs2149356), CD14 (rs2569190), IL-1β (rs1143623), P2RX7 (rs2230911, rs1653624, rs7958316 and rs17525809) and PPARGC1B (rs45520937, rs10491360 and rs7712296) in different populations.

Rheumatoid arthritis (RA) is an autoimmune disease that affects approximately 1% of the worldwide population. In recent decades, oxidative stress (OS) has been shown to be involved in the progression of this disease through DNA, lipid and protein damage, resulting in synovial inflammation. There are many causes of OS; metabolism is involved in the production of reactive oxygen species (ROS) but pollution, diet and microbiota imbalances could lead to the overproduction of these ROS. A decade of research focused on understanding how OS is promoted by known RA risk factors is described herein. The use of antioxidants represents an integrative treatment for patients with rheumatoid arthritis, given the evidence of the damage caused by oxidative stress in this disease. Understanding the different factors that contribute to the development and progression of RA, such as OS, will pave the way not only for better pharmacological treatments but also for recommendations for dietary and health behaviours that will benefit patients with this disease.

Resumen Introduccion La enfermedad pulmonar intersticial (EPI) es una complicacion comun de la esclerosis sistemica (ES). El empleo de la tomografia computarizada de alta resolucion (TACAR) se ve muy limitado, y el ultrasonido pulmonar (USP) puede ser un instrumento alternativo para la evaluacion de la EPI. Objetivo Determinar la validez del USP en la deteccion temprana de la EPI en pacientes con ES. Metodos Se incluyeron 68 pacientes con ES ≥ 18 anos sin sintomas respiratorios. Un reumatologo valoro el estado respiratorio subclinico, otro reumatologo, cegado a la evaluacion clinica realizo el USP. Para determinar la validez concurrente se realizo una TACAR. Resultados Un 41,2% de pacientes mostro EPI por USP, a diferencia de los controles sanos (4,8%) (p = 0,0001). Las variables asociadas con los hallazgos de EPI al USP fueron anticuerpos anti-centromero (p = 0,005) y la puntuacion de piel RSS (p = 0,004). Se encontro una correlacion positiva entre los hallazgos de EPI por USP y TACAR (p = 0,001). La sensibilidad fue del 91,2% y la especificidad de 88,6%. Una buena confiabilidad entre observadores de los hallazgos por USP fue observada (k = 0,72). Conclusiones Al ser una herramienta alternativa valida, confiable y factible, consideramos que el USP puede ser implementado para la deteccion temprana de EPI en ES.

Background: The management of pain in patients with rheumatoid arthritis (RA) is a complex subject due to the autoimmune nature of the pathology. Studies have shown that chemical mediators play a fundamental role in the determination, susceptibility and modulation of pain at different levels of the central and peripheral nervous system, resulting in interesting novel molecular targets to mitigate pain in patients with RA. However, due to the complexity of pain physiology in RA cand the many chemical mediators, the results of several studies are controversial. Objective: The aim of this study was to identify the chemical mediators that are able to modulate pain in RA. Method: In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies that evaluated the expression of chemical mediators on the modulation of pain in RA. Results: Few studies have highlighted the importance of the expression of some chemical mediators that modulate pain in patients with rheumatoid arthritis. The expression of TRPV1, ASIC-3, and TDV8 encode ionic channels in RA and modulates pain, likewise, the transcription factors in RA, such as TNFα, TGF-β1, IL-6, IL-10, IFN-γ, IL-1b, mTOR, p21, caspase 3, EDNRB, CGRPCALCB, CGRP-CALCA, and TAC1 are also directly involved in pain perception. Conclusion: The expression of all chemical mediators is directly related to RA and the modulation of pain by a complex intra and extracellular signaling pathway, however, transcription factors are involved in modulating acute pain, while the ionic channels are involved in chronic pain in RA.

The nociceptive effect of Levetiracetam (LEV) on the expression of 5-HT1A and 5-HT7 receptors found in the thalamus was evaluated. Thirty-six male rats (Wistar) were randomized into six groups: in the Control group without treatment; LEV50 group LEV was administered in a single dose of 50 mg/kg i.g.; in the LEV300 group LEV dose of 300 mg/kg i.g.; in the FORMALIN group the formalin test was performed; in the LEV50/FORMALIN group LEV dose of 50 mg/kg i.g and the formalin test was performed; in the LEV300/FORMALIN group LEV dose of 300 mg/kg i.g and the formalin test was performed, subsequently the thalamus was dissected in all groups. In the formalin tests LEV exhibited an antinociceptive effect in the LEV300/FORMALIN group (p

Ultrasound (US) is a recognized imaging modality for the assessment of gout. Recently it is being explored for its potential role in the evaluation of subjects with asymptomatic hyperuricemia (AH). Preliminary reports demonstrated the presence of monosodium urate (MSU)-crystal deposits including aggregates, double contour sign and/or tophi in both intra-articular and periarticular tissues of AH individuals. Although these results are exciting, the value and potential application of US in AH remain to be clearly delineated. In this systematic literature review, we aim to summarise the recent publications regarding the role of US in the assessment of AH. We analyzed possible application of US in the daily clinical practice and its future clinical and research potential in the evaluation of AH individuals.

To investigate the potential role of US in the detection of ILD in a cohort of patients with RA.Patients with diagnosis of RA were consecutively enrolled. All patients underwent pulmonary examination, laboratory data, DLCO measure, chest HRCT and radiographs, and US examination. A healthy group was included as control group. US was performed according the 14-intercostal space scanning protocol using the following semiquantitative scale [0=normal (≤5 B-lines); 1=slight (≥6 and ≤15 B-lines); 2=moderate, (≤16 and ≥30 B-lines); 3=severe (≥30 B-lines)].A total of 74 RA patients and 74 healthy controls were included. Thirty of 74 patients (40.5%) showed US signs of ILD with respect to the healthy controls (3 subjects, 4.1%) (P0.001); whereas HRCT showed ILD in 27 (36.4%) of 74 patients. Among the 30 patients that showed US findings of ILD, 17 (56.6%) were asymptomatic from respiratory view-point. The sensitivity and specificity of US were 92% and 89% respectively. A positive correlation between US and HRCT findings were found (P0.001) whereas no correlation was found with chest radiographs and DLCO findings. Positive association between US findings and DAS28-ESR, anti-CCP and RF (P0.01 for each respectively) was found. Feasibility, represented by the mean time spent to perform the pulmonary US assessment was 7.8minutes (±SD 1.2, range 6 to 10minutes).Our results support the potential of US in detect accurately ILD in patients with RA and provide a rationale to consider it as a friendly screening tool to be implemented in early phases of the disease.

Articular cartilage is the target tissue of osteoarthritis (OA), and because it lacks capillary networks, the microenvironment is hypoxic. Hypoxia inducible factor-1 alpha (HIF-1α) regulates the homeostasis of this tissue. The aim of this study was to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA. We performed a case-control association study and genotyped 134 knee OA patients and 267 healthy controls. All participants were genotyped in order to evaluate 42 SNPs from 22 genes involved in the HIF-1α signaling pathway using the OpenArray technology. Gene-gene interactions (epistasis) were analyzed using the multifactor dimensionality reduction (MDR) method. The MDR analysis showed epistasis between AKT2 (rs8100018) and IGF1 (rs2288377), AKT2 (rs8100018) and IGF1 (rs35767), IGF1 (rs35767) and COL2A1 (rs1793953), and between GSK3B (rs6438552) and IGF1 (rs35767) polymorphisms, with information gain values of 21.24%, 8.37%, 9.93%, and 5.73%, respectively. Additionally, our model allowed us to identify high- and low-risk genotypes among COL2A1 rs1793953, GSK3B rs6438552, AKT2 rs8100018, and IGF1 rs35767 polymorphisms. Knowing the interactions of these polymorphisms involved in HIF-1α signaling pathway could provide a new diagnostic support tool to identify individuals at high risk of developing knee OA.

Nailfold capillaroscopy (NFC) has gained remarkable interest among rheumatologists because of its utility in both clinical practice and research activity. Nevertheless, there has been scarce attention on its potential in other rheumatic disorders such as vasculitis. We perform a systematic review of literature on NFC in noninfectious vasculitides, with the aim to provide an overview of the main NFC changes described, to discuss the current evidence supporting its clinical impact and applications in daily practice and to provide future research fields.

ObjectiveTo evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard.MethodsConsecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0–3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other’s findings.Results11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%—sensitivity of 91% (range 71%–87% in single sites) and specificity of 59% (range 68%–92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation.ConclusionUltrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.

The nociceptive effect of Levetiracetam (LEV) on the expression of 5-HT

Introduction and aim. Obesity is a worldwide epidemic problem, described as a risk factor for hepatic diseases, such as non-alcoholic fatty liver disease and other pathologies related to development of cholesterol crystals and cholesterol gallbladder stones. It has been reported that cholesterol overload may cause hepatic damage; however, little is known about the effects of an acute hypercholesterolemic diet on the gallbladder. The aim of this manuscript was to evaluate the impact of a cholesterol-rich diet on the gallbladder. Material and methods. The study included ten eight-week-old C57BL6 male mice, which were divided into two study groups and fed different diets for 48 h: a hypercholesterolemic diet and a balanced Chow diet. After 48 h, the mice were analyzed by US with a Siemens Acuson Antares equipment. Mice were subsequently sacrificed to carry out a cholesterol analysis with a Refloton System (Roche), a crystal analysis with a Carl Zeiss microscope with polarized light, and a histological analysis with Hematoxylin-eosin staining. Results. The hypercholesterolemic diet induced an increase in gallbladder size and total cholesterol content in the bile, along with important histological changes. Conclusion. Cholesterol overloads not only trigger hepatic damage, but also affect the gallbladder significantly.

Introduction and objectives It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. Materials and methods Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. Results Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-κB activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. Conclusion Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a wide-range of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor.

Background 9The OMERACT Ultrasound (US) in calcium pyrophosphate deposition disease (CPPD) sub-task force has been working on the assessment of the utility of US in CPPD since 2014 first creating definitions for CPPD identification and then demonstrating that US is a reliable tool[1]. Objectives Objective of this study is to assess the diagnostic accuracy of US in CPPD Methods This is a multicentre international diagnostic accuracy study involving 17 centres from 9 countries. We enrolled in this study consecutive patients waiting to undergo knee replacement surgery due to severe osteoarthritis. Each patient underwent US examination of the knee, focusing on the menisci and the hyaline cartilage, the day prior to surgery, scoring each site according to the presence/absence of CPP as defined by OMERACT[1]. After surgery, the menisci and the condyles were collected and examined microscopically. Six samples were collected, both from the surface and from the internal part of menisci and cartilage trying to cover a large part of the structure. All slides were observed under transmitted light microscopy and by compensated polarised microscopy. A dichotomous score was given for the presence/absence of CPP crystals. US and microscopic analysis were performed by blinded operators. Sensitivity and specificity of US were calculated using microscopic findings of the menisci and cartilage as the gold standard. Results These preliminary analyses include 30 patients. The mean age was 71yrs (SD±9.1), 19 (63%) were females. 17 patients were positive at US analysis and 12 at microscopic analysis. Diagnostic accuracy results of US at patient level, are presented in figure 1. Conclusion These preliminary results demonstrate that US is a sensitive exam for identification of CPPD with acceptable specificity. US is the first diagnostic technique with consistent reliability and validity to be applied for non-invasive screening for CPPD in clinical practice. References [1] Filippou G, Scire CA, Adinolfi A, et al. Identification of calcium pyrophosphate deposition disease (CPPD) by ultrasound: reliability of the OMERACT definitions in an extended set of joints—an international multiobserver study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force. Ann Rheum Dis 2018;:annrheumdis-2017-212542. doi:10.1136/annrheumdis-2017-212542 Disclosure of Interests Georgios Filippou Speakers bureau: Laborest, Abbvie, BMS, Sanofi, Anna Scanu: None declared, Antonella Adinolfi: None declared, Carmela Toscano: None declared, Raquel Largo-Carazo: None declared, Esperanza Naredo Consultant for: Abbvie, Speakers bureau: AbbVie, Roche, Bristol-Myers Squibb, Pfizer, UCB, Lilly, Novartis, Janssen, and Celgene GmbH, Emilio Calvo: None declared, Gabriel Herrero-Beaumont: None declared, Pascal Zufferey: None declared, Christel Madelaine-Bonjour: None declared, Daryl MacCarter: None declared, Stanley Makman: None declared, Zachary Weber: None declared, Ingrid Moller: None declared, Marwin Gutierrez: None declared, Carlos Pineda: None declared, Denise Clavijo Cornejo: None declared, Hector Garcia: None declared, Victor Ilizaliturri: None declared, Jaime Mendoza Torres: None declared, Raul Pichardo: None declared, Luis Carlos Rodriguez Delgado: None declared, Emilio Filippucci: None declared, Edoardo Cipolletta: None declared, Teodora Serban: None declared, Florentin Ananu Vreju Consultant for: abbvie and novartis, Speakers bureau: abbvie, novartis, pfizer, sandoz, eli lilly, ucb pharma, Gael Mouterde: None declared, Maria-Antonietta d’Agostino: None declared, Marcello Govoni: None declared, Leonardo Punzi Consultant for: BMS, Fidia, Grunenthal, Menarini, Speakers bureau: BMS, Fidia, Grunenthal, Menarini, Nemanja Damjanov Grant/research support from: AbbVie, Pfizer and Roche, Consultant for: Abbvie, Gedeon Richter, Merck, Novartis, Pfizer and Roche., Speakers bureau: Abbvie, Gedeon Richter, Merck, Novartis, Pfizer and Roche., Lene Terslev Speakers bureau: Speakers fee from : Roche, Novartis, Pfizer, MSD, BMS, Celgene, Irene Azzolin: None declared, Giulio Guerrini: None declared, Carlo Alberto Scire: None declared, Annamaria Iagnocco: None declared

Background: Nowadays, rheumatologists face challenges in finding an effective method to classify and treat patients with undifferentiated arthritis (UA). There is a need for new tools that could ensure accurate characterization of inflammatory processes in these patients. Objectives: To investigate if a characterization of UA patients using US may help to fulfill the 2010 ACR/EULAR RA classification criteria in a real-life cohort. Methods: We conducted a cross sectional study in two rheumatology care clinics. Patients not fulfilling the 2010 ACR/EULAR RA criteria were included. On the examination day, all patients underwent a physical examination, radiographs and US. The 7-joint US score (US 7) was adopted to scan all patients. US was performed according to EULAR criteria and interpreted by OMERACT definitions. Greyscale and power Doppler synovitis and tenosynovitis were scored. Bone erosions were also evaluated during the US examination. Results: A total of 204 patients were included. The diagnosis was modified from UA to RA in 86 (42.1%) patients. The greater proportion of synovitis detected by US was the main parameter that allowed changing the diagnosis from UA to RA, and modified the final score of the 2010 ACR/EULAR classification criteria, from a mean (±SD) of 4.6 (0.5), by clinical examination, to 6.5 (0.6) by US. The changes in the score of the 2010 ACR/EULAR classification criteria were from score 4 to score 6 in 6 (7%) patients; from 4 to 7 in 24 (27.9%) patients; from 5 to 6 in 42 (48.8%) patients; from 5 to 7 in 5 (5.8%) patients and from 5 to 8 in 5 (5.8%) patients. In addition to synovitis, a wide range of tenosynovitis and bone erosions were detected by US. Synovitis was more frequently detected in 2ndMCPj followed by 2ndMTPj and 5thMTPj. The tendons of the wrist, 2nd and 3th finger were the most affected. In relation to bone erosions, 2ndMCPj and 5thMTPj where the joints with more proportion of anatomical damage. Conclusion: US demonstrated to be useful to help accurately classify as RA, patients previously diagnosed with UA. Disclosure of Interests: Marwin Gutierrez: None declared, Chiara Bertolazzi: None declared, Edwin Castillo: None declared, Denise Clavijo Cornejo: None declared, Luis Carlos Rodriguez Delgado: None declared, Jaime Mendoza Torres: None declared, Carlos Pineda: None declared, Pedro Santos-Moreno Grant/research support from: Dr Santos has received research grants from Janssen, Abbvie and UCB, Speakers bureau: Dr Santos has received speaker fees from Sanofi, Lilly, Bristol, Pfizer, Abbvie, Janssen and UCB

Background Nowadays, rheumatologists face challenges in finding an effective method to classify and treat patients with undifferentiated arthritis (UA). There is a need for new tools that could ensure accurate characterization of inflammatory processes in these patients. Objective The aim of this study was to investigate if a characterization of UA patients using ultrasound (US) may help to fulfill the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) classification criteria in a real-life cohort. Methods We conducted a cross-sectional study in 2 rheumatology care clinics. Patients not fulfilling the 2010 ACR/EULAR RA criteria were included. On the examination day, all patients underwent a physical examination, radiography, and US. The 7-joint US score was adopted to scan all patients. The US was performed according to EULAR criteria and interpreted by Outcome Measures in Rheumatology definitions. Gray-scale and power Doppler synovitis and tenosynovitis were scored. Bone erosions were also evaluated during the US examination. Results A total of 204 patients were included. The diagnosis was modified from UA to RA in 86 patients (42.1%). Also, the final score of the 2010 ACR/EULAR RA classification criteria changed from a mean of 4.6 to 6.5 after the US examination. In addition to synovitis, a wide range of tenosynovitis and bone erosions were detected by US. Synovitis was more frequently detected in second metacarpophalangeal joint followed by second metatarsophalangeal joint (MTPj) and fifth MTPj. The tendons of the wrist and second and third fingers were the most affected. In relation to bone erosions, second metacarpophalangeal joint and fifth MTPj were the joints with more proportion of anatomical damage. Conclusions The US demonstrated to be useful to help accurately classify as RA patients previously diagnosed with UA.

Cholesterol overload in the liver has shown toxic effects by inducing the aggravation of nonalcoholic fatty liver disease to steatohepatitis and sensitizing to damage. Although the mechanism of damage is complex, it has been demonstrated that oxidative stress plays a prominent role in the process. In addition, we have proved that hepatocyte growth factor induces an antioxidant response in hepatic cells; in the present work we aimed to figure out the protective effect of this growth factor in hepatocytes overloaded with free cholesterol. Hepatocytes from mice fed with a high-cholesterol diet were treated or not with HGF, reactive oxygen species present in cholesterol overloaded hepatocytes significantly decreased, and this effect was particularly associated with the increase in glutathione and related enzymes, such asγ-gamma glutamyl cysteine synthetase, GSH peroxidase, and GSH-S-transferase. Our data clearly indicate that HGF displays an antioxidant response by inducing the glutathione-related protection system.

Osteoarthritis (OA) is the gradual loss of articular cartilage and decrease in subchondral space. One of the risk factors Exposure to cadmium (Cd) through tobacco smoke has been identified as a major OA risk factor. There are no reports addressing the role of Cd in OA progression at the molecular level. Our findings revealed that Cd can promote the activation of metalloproteinases (MMP1, MMP3, MMP9 y MMP13), affecting the expression of COL2A1 and ACAN, and decreasing the presence of glycosaminoglycans and proteoglycans through an inflammatory response related to IL-1β y a IL-6, as well as oxidative by producing ROS like O2−• and H2O2. In conclusion, our findings suggest a cytotoxic role of Cd in the articular cartilage, which could affect OA development.

Introduction Interstitial lung disease (ILD) is a common comorbidity present in patients with systemic sclerosis (SSc). Employment of high-resolution computed tomography (HRCT) is very limited and lung ultrasound (LUS) can be an alternative tool for the early evaluation of ILD. Objective To determine the validity of LUS in the early detection of ILD in patients with SSc. Materials and Methods Sixty-eight patients with SSc ≥18 years without respiratory symptoms were included. A rheumatologist rated the subclinical respiratory condition, another rheumatologist blinded to the clinical assessment performed the LUS. To determine validity HRCT was performed as well. Results Prevalence of LID in SSc patients was 41.2% in contrast to the 4.8% healthy controls (P = .0001). Variables associated with LUS and HRCT findings were anti-centromere antibodies (P = .005) and the Rodnan skin score (P = .004). A positive correlation was present between the findings of HRCT and LUS (P = .001). Sensitivity and specificity were 91.2% and 88.6% respectively. Good reliability in the LUS findings was found between observers (k = .72). Conclusion By proving to be a valid, trustworthy and feasible alternative tool, we consider that LUS can be implemented for the early detection of ILD in SSc.

The biotransformation of ethanol in hepatocytes leads to the production of acetaldehyde, an organic compound even more toxic than ethanol and responsible of practically all noxious effects associated to ethanol intake. Although the mechanism of acetaldehyde-induced cell injury remains partially characterized, it is well-known that cellular redox disruption is a key event in the process of damage. This multicomponent concern can be addressed by two main pathways; the first one is related to acetaldehyde targeting organelles, such as mitochondria and endoplasmic reticulum; and the second one impairing antioxidant systems, particularly the glutathione system in mitochondria and antioxidant enzymes. This chapter is focused to review the main knowledge regarding the acetaldehyde effects on cellular redox state and oxidative stress worsening the alcoholic liver disease.

Recent studies have identified AKNA as a potential susceptibility gene for several inflammatory diseases. Here, we aimed to assess the potential association of AKNA polymorphisms with knee osteoarthritis (KOA) susceptibility in a Mexican population, following STREGA recommendations. From a DNA bank of 181 KOA patients and 140 healthy controls, two AKNA SNPs were genotyped using TaqMan probes. The association between KOA susceptibility and AKNA polymorphisms genotypes was evaluated by multivariated logistic regression analysis. Information regarding patients’ inflammatory biomarkers levels was obtained and their association with AKNA polymorphisms genotypes was assessed by lineal regression. We found a positive association with the recessive inheritance model of both AKNA polymorphisms (A/A genotype for both) and KOA susceptibility adjusting by age, body mass index (BMI), gender and place of birth (OR = 2.48, 95% CI 1.09–5.65 for rs10817595 polymorphism; and OR = 4.96; 95% CI 2.421–10.2 for rs3748176 polymorphism). Additionally these associations were also seen after stratifying patients by KOA severity and age. Furthermore the total leukocyte count was positively associated with rs10817595 AKNA polymorphism (β = 1.39; 95% CI 0.44–2.34) adjusting by age, BMI, gender, place of birth and disease severity. We suggest that regulatory and coding polymorphisms of the inflammatory modulator gene AKNA can influence the development of KOA. Further structural and functional studies might reveal the role of AKNA in OA and other rheumatic diseases.

Osteoarthritis is characterized by the presence of proinflammatory cytokines and reactive oxygen species. We aimed to clarify the role of prooxidant enzyme content at the synovial membrane level and how it correlates with the inflammatory process in patients with knee osteoarthritis (KOA). In synovial membranes from KOA patients and control group, we analyzed the protein content of prooxidant enzymes such as Nox2, xanthine oxidase (XO), and prolidase as well as the proinflammatory NALP3. Results show that protein content of prolidase and Nox2 increased 4.8- and 8.4-fold, respectively, and XO showed an increasing trend, while the NALP3 inflammasome increased 5.4-fold with respect to control group. Levels of prolidase and XO had a positive correlation between the levels of NALP3 and Nox2. By principal component analysis the protein expression pattern by study groups was evaluated. Three clusters were identified; protein expression patterns were higher for clusters two (prolidase) and three (XO and Nox2) between KOA patients and controls. Data suggest that prooxidant enzymes increase in synovial membrane of KOA patients and may contribute to the inflammatory state and degradation of the articular cartilage.

Redox signaling is emerging as an essential mechanism in the regulation of biological activities of the cell. The HGF/c-Met signaling pathway has been implicated as a key regulator of the cellular redox homeostasis and oxidative stress. We previously demonstrated that genetic deletion of c-met in hepatocytes disrupts redox homeostasis by a mechanism involving NADPH oxidase. Here, we were focused to address the mechanism of NADPH oxidase regulation by HGF/c-Met signaling in primary mouse hepatocytes and its relevance. HGF induced a biphasic mechanism of NADPH oxidase regulation. The first phase employed the rapid increase in production of ROS as signaling effectors to activate the Nrf2-mediated protective response resulting in up-regulation of the antioxidant proteins, such as NAD(P)H quinone oxidoreductase and γ-glutamylcysteine synthetase. The second phase operated under a prolonged HGF exposure, caused a suppression of the NADPH oxidase components, including NOX2, NOX4, p22 and p67, and was able to abrogate the TGFβ-induced ROS production and improve cell viability. In conclusion, HGF/c-Met induces a Nrf2-mediated protective response by a double mechanism driven by NADPH oxidase.

Alcohol is undoubtedly, the main toxic agent that people consume by recreation and the abuse is associated with liver damage, mainly by the overproduction of reactive oxygen species and the toxic effects of its first metabolite acetaldehyde. It is known that acetaldehyde targets mitochondria inducing redox imbalance and oxidative stress. Mitochondrial superoxide dismutase transforms superoxide radical into hydrogen peroxide, which in addition, is transformed in water by other enzymes. In the present study we demonstrate that acetaldehyde transiently impairs SOD2 activity in HepG2 cells, the decrease in the enzyme activity was associated to a reduction in the protein content, which was rapidly recovered, to basal values, by synthesis de novo in a mechanism mediated by NF-κB and PKC. The SOD2 impairment was not associated with adduct formation. The recovery on SOD2 activity in HepG2 cells can represent survival advantage for cancer cells, the results shown that SOD2 could be considered a therapeutic target in liver cancer.

The worldwide increment of multidrug- and extensively drug-resistant tuberculosis has emphasized the importance of looking for new options in therapeutics. Long-time usage or higher doses of isoniazid and rifampicin have been considered for the treatment of multidrug-resistant tuberculosis; however, the risk of liver failure is proportionally increased. Hepatocyte growth factor (HGF) is a multitask growth factor that stimulates both antiapoptotic and antioxidant responses that counteract the toxic effects of drug metabolism in the liver. The present work was focused to address the antioxidant and antiapoptotic effects of HGF on isoniazid- and rifampicin-induced hepatotoxicity. BALB/c mice were subjected to rifampicin (150mg/kg, intragavage [ig]) plus isoniazid (75mg/kg, ig) for 7 days. Increments in alanine aminotransferase activity, steatosis, apoptosis, and oxidative stress markers were found in animals. Recombinant HGF (iv) prevented all the harmful effects by increasing the activation of Erk1/2 and PKCδ signaling pathways and glutathione (GSH) synthesis. Furthermore, inhibition of endogenous HGF with anti-HGF antibody (iv) enhanced the isoniazid- and rifampicin-induced oxidative stress damage and decreased the GSH content, aggravating liver damage. In conclusion, HGF demonstrated to be a good protective factor against antituberculosis drug-induced hepatotoxicity and could be considered a good adjuvant factor for the use of high doses of or the reintroduction of these antituberculosis drugs.

Resumen del poster presentado en The International Liver Congress – 48th Annual meeting of the European Association for the Study of the Liver celebrado en Paises Bajos en abril de 2013.-- et al.