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To review the characteristics of the injuries among CrossFit® practitioners, including prevalence and incidence, nature, location, and risk factors.PubMed/MEDLINE, EMBASE, Web of Science, Scopus, and SPORTDiscus databases were searched from inception through August 2020, and English-language articles reporting on CrossFit®-related injuries were included. Data including sample (sex, age, and demographics) and injuries' characteristics (prevalence, incidence rate, nature, location, percentage of injuries requiring surgery and risk factors) were extracted.Overall, twenty-five studies involving a total of 12,079 CrossFit® practitioners met the inclusion criteria. The mean prevalence of injuries among the included studies was 35.3%, with an incidence rate varying between 0.2 and 18.9 per 1000 hours of training. The most injured areas were shoulder (26%), spine (24%), and knee (18%). Among the studies that reported the injuries requiring surgery, the mean percentage was 8.7%. Regarding the risk factors associated with injuries, older age, male sex, a greater body mass index, the existence of previous injuries, the lack of coach supervision, the experience on CrossFit® and the participation in competitions were reported by the studies.CrossFit® training has an injury incidence rate similar to weightlifting and powerlifting. Findings from the studies suggest that the most affected areas are shoulder, spine, and knee. The limited quality of the studies prevents us from drawing solid conclusions about injury risk factors.

Total hip replacement (THR) is a surgical procedure indicated for patients affected by severe hip osteoarthritis. Although this technique has proved to be effective in relieving pain and restoring function, gait limitations may persist following this procedure. The objective of this systematic review was to evaluate gait kinematics after THR and compare the results with those of the pre-operative state and with healthy control individuals. PubMed/MEDLINE, Embase, Web of Science, CENTRAL and Scopus databases were searched until December 2019. Methodological quality and internal validity score of each study were assessed using the PEDro and the Newcastle–Ottawa scales. In all, ten studies met our inclusion criteria. Following THR, statistically significant improvements were seen in dynamic hip and knee range of motion of both the affected and the contralateral limb, single-limb support time symmetry, step length, stride length, walking speed and gait pattern. However, deficits were observed in all the previous parameters, as well as in hip adduction angle in comparison with healthy subjects. In conclusion, gait patterns improve after THR in comparison with the pre-operative state, although there are deficits relative to healthy individuals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s43465-020-00101-x) contains supplementary material, which is available to authorized users.

Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit (ICU), to identify two transcriptomic clusters characterized by expression of either interferon-related or immune checkpoint genes, respectively. These profiles have different ICU outcome, in spite of no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding similar results. These findings reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19, aimed to ultimately personalize their therapies.

The lockdown due to the COVID-19 pandemic inherently changed people’s lifestyles. Forty-eight days of isolation led to worsening physical fitness in addition to the development of other unhealthy habits. The aim of this study was to describe sport-related injuries in the active general population. Physical therapy centres and sports medicine clinics were contacted via e-mail, seeking patients who had sustained an injury during or immediately (up to two weeks) after the lockdown. Patients who agreed to participate completed an online survey that followed the International Olympic Committee Statement. The questionnaire focused on physical exercise habits, type of injury, location and tissue affected. A total of 51 females and 67 males (30.5, SD = 8.8 years) participated in the study. Eighty percent of the participants performed aerobic training sessions, while the rest dedicated their workouts to strength training. Two in every three injuries were located in the lower limbs, and 80% affected the musculoskeletal tissue. Of all the injuries recorded, 67% occurred during the first week after lockdown. The number of aerobic exercise sessions was positively correlated with lower limb injuries (χ2 = 17.12, p < 0.05). Exercise habits should be considered when planning to return to a sport after a period of confinement to avoid injury.

Los nódulos tiroideos representan una causa común de consulta al especialista. El nódulo tiroideo tiene un riesgo de malignidad del 4-15%. El método citopatológico más utilizado para el diagnóstico del cáncer tiroideo es la toma de biopsia por aspiración con aguja fina (BAAF) de los nódulos tiroideos y la utilización del sistema Bethesda (SB) para su informe citopatológico. Realizamos el presente estudio para reportar nuestra experiencia utilizando el SB, y comparar los resultados obtenidos con este sistema con los resultados histopatológicos finales de las tiroidectomías realizadas.

Context: Determining the rate of injuries related to a certain sport is accepted as the primary step toward designing, implementing, and evaluating injury prevention programs. The aim of this study was to examine the injuries sustained by semiprofessional Spanish rink hockey players and to compare data per playing position. Design: Observational and retrospective. Methods: Athletes from 21 teams were surveyed via a self-reported questionnaire to screen for incidence, injury burden, location, tissue, and onset of injuries. Results: Overall, 101 time loss injuries were reported across 22,241 hours of exposure, giving rise to an incidence rate of 4.5/1000 hours. The main body regions injured were the hip/groin, shoulder, thigh, and head, accounting altogether for 47.5% of all injuries. Musculotendinous injuries were the most frequent, comprising 27.7% of all injuries. Incidence accounted for 3.1/1000 hours during training and 23/1000 hours during games (P Conclusion: The injury incidence in rink hockey is moderate, occurring mainly due to a contact mechanism. Preventative measurements should be implemented in rink hockey with a special concern for injuries affecting the hip/groin and head.

RationaleOutcomes in patients with severe SARS-CoV-2 infection (COVID-19) are conditioned by virus clearance and regulation of inflammation. Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections.ObjectiveTo characterize the impact of IFIH1 rs199076 variants on host response and outcomes after severe COVID-19.MethodsPatients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modelled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials.Measurements and Main Results227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to a MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids (N=14) survived their ICU stay (HR 2.49, 95% confidence interval 1.29–4.79). Patients with a TT variant treated with dexamethasone (N=50) showed an increased hospital mortality (HR 2.19, 95% confidence interval 1.01–4.87) and serum IL-6. In-silico clinical trials supported these findings.ConclusionsCOVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.

This systematic review evaluates the existing literature about medial tibial stress syndrome (MTSS) in novice and recreational runners. PubMed/MEDLINE, EMBASE, Web of Science, Scopus, SPORTDiscus and CINAHL databases were searched until July 2020. Studies covering risk factors, diagnostic procedures, treatment methods and time to recovery of MTSS in novice and recreational runners were selected. Eleven studies met the inclusion criteria and were included. The risk factors of MTSS are mainly intrinsic and include higher pelvic tilt in the frontal plane, peak internal rotation of the hip, navicular drop and foot pronation, among others. Computed tomography (CT) and pressure algometry may be valid instruments to corroborate the presence of this injury and confirm the diagnosis. Regarding treatment procedures, arch-support foot orthoses are able to increase contact time, normalize foot pressure distribution and similarly to shockwave therapy, reduce pain. However, it is important to take into account the biases and poor methodological quality of the included studies, more research is needed to confirm these results.

Report on socio -economic pilot activity at CERN since July 2019 to June 2020.&nbsp

A wide range of insults can trigger acute injury in the lungs, which eventually may lead to respiratory failure and death of patients. Current treatment relies mainly on supportive measures and mechanical ventilation. Even so, survivors frequently develop important sequels that compromise quality of life. In the search for new approaches to prevent and treat acute lung injury, many investigations have focused on molecular and cellular pathways which could exert a pathogenic role in this disease. Herein, we review recent findings in the literature suggesting that cellular senescence could be involved in lung injury and discuss the potential use of senotherapies to prevent disease progression.

BackgroundMechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumours have not been explored.MethodsTo characterise the influence of mechanical ventilation on the behaviour of lung tumours, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechanodependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of nonventilated patients.ResultsStretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro, leading to an increase in pro-protein convertase subtilisin/kexin type 9 (PCSK9) and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harbouring melanoma implants increased brain and kidney metastases 2 weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo. In patients, mechanical ventilation increased PCSK9 abundance in lung tumours and the incidence of metastasis, thus decreasing survival.ConclusionsOur results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.

There are studies that show preliminary evidence of the benefits of physical exercise for people with Attention Deficit Hyperactivity Disorder (ADHD). The objective of the research being reported here was to carry out a systematic review of articles relating to the effects that exercise sessions have on children and adolescents with this pathology.The total sample of studies considered was 1,723, of which only 11 met the eligibility criteria.The research included in this review showed that children with ADHD undertaking exercise experienced improvements in their characteristic symptoms, mainly attention deficit and hyperactivity, in comparison to other sedentary tasks such as watching a video. Five minutes of jumping or thirty minutes on a treadmill or static bicycle were enough to produce appreciable improvements in inhibitory control or in cognitive and executive functions. Benefits following exercise were also seen in other aspects such as reaction times and preparation for response, motor skills or brain activity.The findings make us optimistic that in the future physical exercise may become an alternative, or at least an effective complement, to the pharmacological treatments currently used for this pathology.

The haemorrhagic disease virus (RHDV) is a non‐cultivable virus that promotes in rabbits an acute disease which accomplishes many characteristics of an animal model of fulminant hepatic failure (FHF). Beneficial effects of melatonin have been reported in RHDV‐infected rabbits. This study investigated whether protection against viral‐derived liver injury by melatonin is associated with modulation of mitophagy, innate immunity and clock signalling. Rabbits were experimentally infected with 2 × 104 haemagglutination units of a RHDV isolate and killed at 18, 24 and 30 hours after infection (hpi). Melatonin (20 mg/kg body weight ip) was administered at 0, 12 and 24 hpi. RHDV infection induced mitophagy, with the presence of a high number of mitophagosomes in hepatocytes and increased expression of mitophagy genes. Greater expression of main innate immune intermediaries and inflammasome components was also found in livers with RHDV‐induced FHF. Both mitophagy and innate immunity activation was significantly hindered by melatonin. FHF induction also elicited an early dysregulation in clock signalling, and melatonin was able to prevent such circadian disruption. Our study discloses novel molecular routes contributing to RHDV‐induced damage progression and supports the potential of melatonin as a promising therapeutic option in human FHF.

Objective: To determine the effectiveness of respiratory muscle training in persons with Parkinson’s disease. Data sources: PubMed/MEDLINE, EMBASE, Web of Science, Scopus and PEDro electronic databases were searched until 15 November 2019. Reference lists of included studies were hand-searched. Methods: Randomized controlled trials assessing the effects of respiratory muscle training programmes (both inspiratory and expiratory) in patients with Parkinson’s disease were included. Two reviewers independently identified eligible studies and extracted data. Method quality was appraised with the PEDro scale. Results: Five papers including three randomized controlled trials with a total of 111 patients were identified. Method appraisal showed a mean score of 5 in the PEDro scale. One study analysed inspiratory muscle training, one expiratory muscle training and two established a comparison between both of them. Statistically positive results were found in maximal inspiratory pressure ( P Conclusions: Respiratory muscle training may be an effective alternative for improving respiratory muscle strength, swallowing function and phonatory parameters in subjects with Parkinson’s disease. Nevertheless, the lack of primary studies about this type of training prevents obtaining robust evidence.

Background and Aims: Abdominal radiotherapy (RT) causes harm to the mid gastrointestinal mucosa by release of pro-inflammatory cytokines and promotes autophagic changes in tumor cells. This study was aimed to measure the effect of glutamine administration on markers of inflammation and autophagy in cancer patients treated with RT. Methods: In this double-blind, randomized, controlled pilot trial 43 patients under abdominal RT diagnosed of pelvic or abdominal malignancies receiving glutamine (30 g/d) or placebo (casein, 30 g/d). Patient recruitment took place in the Complejo Asistencial Universitario of León (CAULE), Spain. Patient evaluation took place at three different time points during the study: before RT (pre-treatment), in the middle of the RT period (mid-treatment), and after finishing RT (post-treatment). Data were compared by analysis of variance and the Newmann Keuls test. Significance was accepted at p < 0.05. Results Abdominal RT increased whole blood mRNA levels of inflammatory and autophagic markers, but glutamine administration showed significantly lower expression of toll-like receptor 4 (TLR4), CD36, interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9). Moreover, glutamine reduced the expression of the transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). Glutamine also inhibited the autophagic response, with changes in expression of beclin-1, UV radiation resistance associated gene (UVRAG), autophagy-related protein-5 (Atg5), protein 1 light chain 3 (LC3), sequestosome 1 (p62/SQSTM1) and lysosome-associated membrane protein (LAMP)-1. Conclusions Findings provide evidence that glutamine decreases the inflammatory response and abolishes the changes of the autophagy machinery in patients receiving abdominal RT. The protective effect of glutamine must continue being investigated to disclose further molecular pathways.

The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl4 ) 5 μL g-1 body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg kg-1 day-1 i.p, beginning 2 weeks after the start of CCl4 administration. At both 4 and 6 weeks following CCl4 treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis. © 2016 BioFactors, 43(2):272-282, 2017.

Medical treatment of meningiomas is reserved for cases in which surgery and radiotherapy have failed. Given that a high percentage of meningiomas express somatostatin receptors, treatment with somatostatin analogues has been proposed. In addition, these medications have been shown to have an antiproliferative and antiangiogenic effect in vitro. To date, very few cases with clinical response and none with radiological response have been described. The case described here is the first to report a radiological response. A 76-year-old Caucasian male was first diagnosed with unresectable meningioma at age 47. The patient experienced multiple recurrences and underwent three surgeries and radiotherapy over the years from the initial diagnosis. Despite treatment, the disease continued its progression. Based on an Octreoscan positive for tumour uptake, therapy with extended-release somatostatin analogues was started. Although no clinical neurological improvement was observed, magnetic resonance imaging scans revealed a discreet but continuous radiological response over time. After >2 years of continuous administration of lanreotide, the patient remains progression free. In highly selected cases, somatostatin analogue treatment for meningioma may be beneficial. Based on our findings, treatment with somatostatin analogues should be maintained longer than previously described before evaluating treatment response.

25 p. The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in multiple biological processes, including liver diseases. This study investigate whether modulation of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2x104 hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0 hr, 12 hr and 24 hr postinfection. Liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased in RHDV-infected rabbits. S1P production and protein expression of the S1PR1 receptor were significantly elevated following RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits and phosphorylated inhibitor of kappa B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in this animal model of ALF, and supports the potential of melatonin as an antiviral agent

The current systematic review evaluated the effects of different pre-cooling techniques on sports performance in highly-trained athletes under high temperature conditions. PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL, Scopus, and SPORTDiscus databases were searched from inception to December 2019. Studies performing pre-cooling interventions in non-acclimatized highly-trained athletes (>55 mL/kg/min of maximal oxygen consumption) under heat conditions (≥30 °C) were included. The searched reported 26 articles. Pre-cooling techniques can be external (exposure to ice water, cold packs, or cooling clothes), internal (intake of cold water or ice), or mixed. Cooling prior to exercise concluded increases in distance covered (1.5–13.1%), mean power output (0.9–6.9%), time to exhaustion (19–31.9%), work (0.1–8.5%), and mean peak torque (10.4–22.6%), as well as reductions in completion time (0.6–6.5%). Mixed strategies followed by cold water immersion seem to be the most effective techniques, being directly related with the duration of cooling and showing the major effects in prolonged exercise protocols. The present review showed that pre-cooling methods are an effective strategy to increase sports performance in hot environments. This improvement is associated with the body surface exposed and its sensibility, as well as the time of application, obtaining the best results in prolonged physical exercise protocols.

This study aimed to investigate whether inhibition of autophagy and endoplasmic reticulum (ER stress) associates with the antifibrogenic effect of melatonin in mice treated with carbon tetrachloride (CCl4 ). Mice received CCl4 5 μL/g body wt i.p. twice a week for 4 wk or 6 wk. Melatonin was given at 5 or 10 mg/kg/day i.p, beginning 2 wk after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of α-smooth muscle actin (α-SMA)-positive cells. CCl4 induced an autophagic response measured as the presence of autophagic vesicles, protein 1 light chain 3 (LC3) staining, conversion of LC3-I to autophagosome-associated LC3-II, changes in expression of beclin-1, UV radiation resistance-associated gene (UVRAG), ubiquitin-like autophagy-related (Atg5), Atg12, Atg16L1, sequestosome 1 (p62/SQSTM1), and lysosome-associated membrane protein (LAMP)-2, and increased phosphorylation of the mammalian target of rapamycin (mTOR). There was an increase in the expression of the ER stress chaperones CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin-heavy-chain-binding protein (BiP/GRP78), and 94-kDa glucose-regulated protein (GRP94), and in the mRNA levels of pancreatic ER kinase (PERK), activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), and spliced X-box-binding protein-1 (XBP1). Phospho-IRE1, ATF6, and phospho-PERK protein concentration also increased significantly. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cells activation by melatonin. Furthermore, treatment with the indole resulted in significant inhibition of the autophagic flux and the unfolded protein response. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in fibrogenesis.

RIG-I-like receptors (RLRs) are cellular sensor proteins that detect certain RNA species produced during viral infections. RLRs activate a signaling cascade that results in the production of IFN-β as well as several other cytokines with antiviral and proinflammatory activities. We explored the potential of different constructs based on RLRs to induce the IFN-β pathway and create an antiviral state in type I IFN-unresponsive models. A chimeric construct composed of RIG-I 2CARD and the first 200 amino acids of MAVS (2CARD-MAVS200) showed an enhanced ability to induce IFN-β when compared to other stimulatory constructs. Furthermore, this human chimeric construct showed a superior ability to activate IFN-β expression in cells from various species. This construct was found to overcome the restrictions of blocking IFN-β induction or signaling by a number of viral IFN-antagonist proteins. Additionally, the antiviral activity of this chimera was demonstrated in influenza virus and HBV infection mouse models using adeno-associated virus (AAV) vectors as a delivery vehicle. We propose that AAV vectors expressing 2CARD-MAVS200 chimeric protein can reconstitute IFN-β induction and recover a partial antiviral state in different models that do not respond to recombinant IFN-β treatment.

(1) Background: The present study aimed to investigate whether beneficial effects of protocatechuic acid (PCA) are associated with inhibition of the SphK/S1P axis and related signaling pathways in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammatory bowel disease; (2) Methods: Colitis was induced in male Balb/c mice by intracolonic administration of 2 mg of TNBS. PCA (30 or 60 mg/kg body wt) was given intraperitoneally daily for five days; (3) Results: Administration of PCA prevented the macroscopic and microscopic damage to the colonic mucosa, the decrease in body weight gain and the increase in myeloperoxidase activity induced by TNBS. PCA-treated mice exhibited a lower oxidized/reduced glutathione ratio, increased expression of antioxidant enzymes and Nrf2 and reduced expression of proinflammatory cytokines. Following TNBS treatment mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production and expression of S1P receptor 1 and S1P phosphatase 2 were significantly elevated. However, there was a decreased expression of S1P lyase. Furthermore, TNBS-treated mice exhibited increased phosphorylation of AKT and ERK, and a higher expression of pSTAT3 and the NF-κB p65 subunit. PCA administration significantly prevented those changes; (4) Conclusions: Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the anti-inflammatory effect of PCA.

Autophagy is an important survival pathway and participates in the host response to infection. Beneficial effects of melatonin have been previously reported in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). This study was aimed to investigate whether melatonin protection against liver injury induced by the RHDV associates to modulation of autophagy. Rabbits were infected with 2 × 104 hemagglutination units of a RHDV isolate and received 20 mg/kg melatonin at 0, 12, and 24 hr postinfection. RHDV induced autophagy, with increased expression of beclin‐1, ubiquitin‐like autophagy‐related (Atg)5, Atg12, Atg16L1 and sequestrosome 1 (p62/SQSTM1), protein 1 light chain 3 (LC3) staining, and conversion of LC3‐I to autophagosome‐associated LC3‐II. These effects reached a maximum at 24 hr postinfection, in parallel to extensive colocalization of LC3 and lysosome‐associated membrane protein (LAMP)‐1. The autophagic response induced by RHDV infection was significantly inhibited by melatonin administration. Melatonin treatment also resulted in decreased immunoreactivity for RHDV viral VP60 antigen and a significantly reduction in RHDV VP60 mRNA levels, oxidized to reduced glutathione ratio (GSSG/GSH), caspase‐3 activity, and immunoglobulin‐heavy‐chain‐binding protein (BiP) and CCAAT/enhancer‐binding protein homologous protein (CHOP) expression. Results indicate that, in addition to its antioxidant and antiapoptotic effects, and the suppression of ER stress, melatonin induces a decrease in autophagy associated with RHDV infection and inhibits RHDV RNA replication. Results obtained reveal novel molecular pathways accounting for the protective effect of melatonin in this animal model of ALF.

The sphingosine kinase (SphK)/sphingosine1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma (HCC), but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer. We investigated effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p. beginning four weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30 or 40 weeks). Melatonin alleviated the distortion of normal hepatic architecture, lowered the incidence of preneoplastic/ neoplastic lesions and inhibited the expression of proliferative/cell-cycle regulatory proteins (Ki67, PCNA, cyclin D1, cyclin E, CDK4 and CDK6). S1P levels and expression of SphK1, SphK2 and S1P receptors (S1PR1/S1PR3) were significantly elevated in DEN-treated mice. However, there was a decreased expression of S1P lyase. These effects were significantly abrogated in a time- and dose-dependent manner by melatonin, which also increased S1PR2 expression. Following DEN treatment mice exhibited increased phosphorylation of PI3K, AKT, mTOR, STAT3, ERK and p38, and a higher expression of NF-κB p50 and p65 subunits. Melatonin administration significantly inhibited those changes. Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the protective effects of melatonin in hepatocarcinogenesis. This article is protected by copyright. All rights reserved.