Efficacy of various exercise interventions for migraine treatment: A systematic review and network meta-analysis.

OBJECTIVE: To compare various exercise modalities' efficacy on migraine frequency, intensity, duration, and disability. BACKGROUND: Exercise has been shown to be an effective intervention to reduce migraine symptoms and disability; however, no clear evidence exists regarding the most effective exercise modalities for migraine treatment. METHODS: A systematic review was performed in PubMed, PEDro, Web of Science, and Google Scholar. Clinical trials that analyzed the efficacy of various exercise modalities in addressing the frequency, intensity, duration, and disability of patients with migraine were included. Eight network meta-analyses based on frequentist (F) and Bayesian (B) models were developed to estimate the direct and indirect evidence of various exercise modalities. Standardized mean difference (SMD) and 95% confidence (CI) and credible intervals (CrI) were calculated for each treatment effect based on Hedge's g and p scores to rank the modalities. RESULTS: We included 28 studies with 1501 migraine participants. Yoga (F: SMD -1.30; 95% CI -2.09, -0.51; B: SMD -1.33; 95% CrI -2.21, -0.45), high-intensity aerobic exercise (F: SMD -1.30; 95% CI -2.21, -0.39; B: SMD -1.17; 95% CrI -2.20, -0.20) and moderate-intensity continuous aerobic exercise (F: SMD -1.01; 95% CI -1.63, -0.39; B: SMD -1.06; 95% CrI -1.74, -0.38) were significantly superior to pharmacological treatment alone for decreasing migraine frequency based on both models. Only yoga (F: SMD -1.40; 95% CI -2.41, -0.39; B: SMD -1.41; 95% CrI -2.54, -0.27) was significantly superior to pharmacological treatment alone for reducing migraine intensity. For diminishing migraine duration, high-intensity aerobic exercise (F: SMD -1.64; 95% CI -2.43, -0.85; B: SMD -1.56; 95% CrI -2.59, -0.63) and moderate-intensity continuous aerobic exercise (SMD -0.96; 95% CI -1.50, -0.41; B: SMD -1.00; 95% CrI -1.71, -0.31) were superior to pharmacological treatment alone. CONCLUSION: Very low-quality evidence showed that yoga, high- and moderate-intensity aerobic exercises were the best interventions for reducing migraine frequency and intensity; high- and moderate-intensity aerobic exercises were best for decreasing migraine duration; and moderate-intensity aerobic exercise was best for diminishing disability.

Description of conformational ensembles of disordered proteins by residue-local probabilities.

The study of proteins with intrinsically disordered regions (IDRs) has emerged as an active field of research due to their intriguing nature. Although IDRs lack a well-defined folded structure, they play important functional roles in cells, following biological mechanisms different from those of the traditional structured proteins. Consequently, it has been necessary to re-design experimental and theoretical methods in order to face the challenges introduced by the dynamic nature of IDRs. In this work, we present an accurate and cost-effective method to study the conformational dynamics of IDRs based on the use of residue-local probabilistic expressions that characterize the conformational ensembles obtained from finite-temperature molecular dynamics (MD) simulations. It is shown that the good performance and the high convergence rates achieved with our method are independent of the IDR lengths, since the method takes advantage of the major influence of the identity and conformation of the nearest residue neighbors on the amino-acid conformational preferences to evaluate the IDR conformational ensembles. This allows us to characterize the conformational space of IDRs using a reduced number of probabilities which can be obtained from comparatively short MD simulations or experimental databases. To exemplify the usefulness of our approach, we present an application to directly detect Molecular Recognition Features (MoRFs) in an IDR domain of the protein p53, and to follow the time evolution of the thermodynamic magnitudes of this system during its exploration of the conformational space.

Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation.

Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence.

Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N-acetyl-5-methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti-inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti-inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma.

Melatonin modulates mitophagy, innate immunity and circadian clocks in a model of viral-induced fulminant hepatic failure.

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.

On the Role of Entropy in the Stabilization of α-Helices.

Protein folding evolves by exploring the conformational space with a subtle balance between enthalpy and entropy changes which eventually leads to a decrease of free energy upon reaching the folded structure. A complete understanding of this process requires, therefore, a deep insight into both contributions to free energy. In this work, we clarify the role of entropy in favoring the stabilization of folded structures in polyalanine peptides with up to 12 residues. We use a novel method referred to as K2V that allows us to obtain the potential-energy landscapes in terms of residue conformations extracted from molecular dynamics simulations at conformational equilibrium and yields folding thermodynamic magnitudes, which are in agreement with the experimental data available. Our results demonstrate that the folded structures of the larger polyalanine chains are stabilized with respect to the folded structures of the shorter chains by both an energetic contribution coming from the formation of the intramolecular hydrogen bonds and an entropic contribution coming from an increase of the entropy of the solvent with approximate weights of 60 and 40%, respectively, thus unveiling a key piece in the puzzle of protein folding. In addition, the ability of the K2V method to provide the enthalpic and entropic contributions for individual residues along the peptide chain makes it clear that the energetic and entropic stabilizations are basically governed by the nearest neighbor residue conformations, with the folding propensity being rationalized in terms of triads of residues.

Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine-induced hepatocellular carcinoma.

Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg-1 d-1 ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev-erbα, and Rev-erbß decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia-inducible factors Hif-1α and Hif-2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl-2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin-treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV-ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro-apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.

Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1-phosphate signaling pathway in a mouse model of diethylnitrosamine-induced hepatocellular carcinoma.

The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma, 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 the 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 4 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.

Effects Of Oral Glutamine on Inflammatory and Autophagy Responses in Cancer Patients Treated With Abdominal Radiotherapy: A Pilot Randomized Trial.

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-1ß (IL-1ß), 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.

Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin.

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 2 × 10(4) hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0, 12, and 24 hr postinfection. Liver mRNA levels, protein concentration, and immunohistochemical labeling 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.

Relaxation pathways of the OD stretch fundamental of HOD in liquid H2O.

The molecular dynamics with quantum transitions method is used to study the vibrational relaxation of the OD stretching mode of HOD dissolved in liquid H2O water at 303 K. All the vibrational modes of the solute and solvent molecules that participate in the relaxation process are described by quantum mechanics, while the rotational and translational degrees of freedom are treated classically. A modification of the water intramolecular SPC/E (Simple Point Charge/Extended) force field providing vibrational frequencies in solution closer to the experimental values is proposed to analyze the influence of the vibrational energy gaps on the relaxation channels. The relaxation times obtained are in satisfactory agreement with experimental values. The energy transfer during the relaxation process alters significantly the H-bond network around the HOD molecule. The analysis of the vibrational transitions during the relaxation process reveals a complex mechanism which involves the participation of both intra- and intermolecular channels and provides a compromise for the different interpretations of the experimental data reported for this system in recent years.

Assessment of dietary lutein, zeaxanthin and lycopene intakes and sources in the Spanish survey of dietary intake (2009-2010).

We assessed the intake and major dietary sources of lutein, zeaxanthin and lycopene (non-provitamin A carotenoids) in Spain using food consumption data from the Spanish National Dietary Intake Survey (2009-2010). Three-day diaries and one 24-h recall were used to collect dietary data and a software application that includes HPLC data was used. Average intake of those carotenoids was 4290.8 µg/d (67.1% total carotenoid intake), mainly from vegetables (3414.0 µg/d), followed by fruits (393.5 µg/d), oils/fats (204.0 µg/d) and eggs/egg products (170.0 µg/d). Main sources of lutein and zeaxanthin were vegetables (62.9% total diet, 1235.2 µg/person/d). Lycopene intake was 3055.6 µg/d (71.2% of non-provitamin A carotenoids), mainly from tomato and by-products (86.3%) and watermelon. Red- and orange-colored fruits and vegetables were the major contributors of non-provitamin carotenoids (3219.0 µg/person/d). Balanced diets should favor fruits and vegetables over other dietary sources (oils, eggs, processed foods) that contain components to be consumed with moderation.

Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis.

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.

Assessment of dietary vitamin A intake (retinol, α-carotene, ß-carotene, ß-cryptoxanthin) and its sources in the National Survey of Dietary Intake in Spain (2009-2010).

The aim of this study is to assess the intake of the individual components of vitamin A and major dietary sources in the Spaniards using data on food consumption from Spanish National Dietary Intake Survey (2009-2010). A 24-h dietary recall, 3-day diet diary and a software application that includes HPLC analytical data were used. Average dietary vitamin A intake is 716.4 µg retinol equivalents (RE), which is supplied as retinol (57.9%RE) and as provitamin-A carotenoids (42.1%RE). ß-Carotene represents 71.9% of provitamin-A carotenoids, ß-cryptoxanthin 15.3%, α-carotene 12.8%. Red- and orange-colored fruits and vegetables are major contributors of provitamin-A (1587 µg/day). Spanish diet covers the dietary reference on the intake for vitamin A, provided mainly by foods of animal origin. The main contributors to the intake of provitamin-A carotenoids are carrots, tomatoes, spinach and oranges. Data on the intake of individual components of vitamin A contribute to improving our understanding of the relationship between diet and health.

Autophagic response in the Rabbit Hemorrhagic Disease, an animal model of virally-induced fulminant hepatic failure.

The Rabbit Hemorrhagic Disease Virus (RHDV) induces a severe disease that fulfils many requirements of an animal model of fulminant hepatic failure. However, a better knowledge of molecular mechanisms contributing to liver damage is required, and it is unknown whether the RHDV induces liver autophagy and how it relates to apoptosis. In this study, we attempted to explore which signalling pathways were involved in the autophagic response induced by the RHDV and to characterize their role in the context of RHDV pathogenesis. Rabbits were infected with 2 × 104 hemmaglutination units of a RHDV isolate. The autophagic response was measured as presence of autophagic vesicles, LC3 staining, conversion of LC3-I to autophagosome-associated LC3-II and changes in expression of beclin-1, UVRAG, Atg5, Atg12, Atg16L1 and p62/SQSTM1. RHDV-triggered autophagy reached a maximum at 24 hours post-infection (hpi) and declined at 30 and 36 hpi. Phosphorylation of mTOR also augmented in early periods of infection and there was an increase in the expression of the endoplasmic reticulum chaperones BiP/GRP78, CHOP and GRP94. Apoptosis, measured as caspase-3 activity and expression of PARP-1, increased significantly at 30 and 36 hpi in parallel to the maximal expression of the RHDV capsid protein VP60. These data indicate that RHDV infection initiates a rapid autophagic response, perhaps in an attempt to protect liver, which associates to ER stress development and is independent from downregulation of the major autophagy suppressor mTOR. As the infection continues and the autophagic response declines, cells begin to exhibit apoptosis.

Melatonin modulates the autophagic response in acute liver failure induced by the rabbit hemorrhagic disease virus.

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 × 10(4) 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.

Markers of lutein and zeaxanthin status in two age groups of men and women: dietary intake, serum concentrations, lipid profile and macular pigment optical density.

BACKGROUND & AIMS: Lutein and zeaxanthin accumulate in retina (macular pigment). Their nutritional status can be assessed using dietary or biochemical markers and both have been associated with macular pigment optical density. We proposed to assess dietary and status markers of lutein and zeaxanthin in a group of healthy Spanish volunteers, considering the potential influence of age, gender and serum lipids to investigate the predictors of the macular pigment optical density. METHODS: Serum lutein and zeaxanthin concentrations, dietary intake and macular pigment optical density were determined in 108 healthy men and women (20-35 and 45-65 years), using high-performance liquid chromatography, 3-day food records and heterochromic flicker photometry, respectively. Mann-Whitney U-test, Spearman correlation coefficient and multivariate regression analysis were used for the statistical study. RESULTS: Serum concentrations and dietary intake of lutein plus zeaxanthin (p < 0.0001 and p = 0.001, respectively) were higher in older vs younger subjects, whereas macular pigment optical density was lower (p = 0.038). The highest correlation coefficients between intake and serum were for fruit and serum lutein (ρ = 0.452, p < 0.0001) and for fruit and lutein + zeaxanthin (ρ = 0.431, p < 0.0001) in the younger group. Macular pigment optical density correlated with serum xanthophylls (ρ = 0.223, p = 0.02) and fruit and vegetable intake (ρ = 0.350, p = 0.0002), showing highest correlations when lutein and zeaxanthin were expressed in relation to serum lipids in older subjects (ρ = 0.262, p = 0.006). Multivariate regression analysis identified age and serum lutein as major predictors of macular pigment optical density (total sample), and a coefficient of determination of 29.7% for the model including lutein + zeaxathin/cholesterol + triglycerides, sex and fruit + vegetables in the older group. CONCLUSIONS: The establishment of normal/reference ranges for serum lutein and zeaxanthin should consider age ranges and be expressed in relation to lipid concentrations, at least in subjects over 45 years, as this could influence macular pigment optical density. The macular pigment optical density showed age-specific correlations with lutein plus zeaxanthin expressed in relation to serum lipid concentrations as well as with the fruit and vegetable intake.

Efficiency, Kinetics and Mechanism of 4-Nitroaniline Removal from Aqueous Solutions by Emulsion Liquid Membranes Using Type 1 Facilitated Transport.

4-Nitroaniline (4NA) is a common organic pollutant that is released into the environment during the manufacture and processing of a wide variety of industrial products. This article describes the use of an emulsion liquid membrane process to remove 4NA from aqueous solutions using a type 1 facilitated transport mechanism. Optimization of the removal process was carried out by analyzing the efficiency of 4NA removal from the feed phase and the initial apparent feed/membrane fluxes and permeabilities under different experimental conditions. The kinetics of the removal process was analyzed using a simplified mass transfer model involving an empirical mass transfer coefficient calculated from experimental data, assuming that the concentrations of 4NA in the external aqueous phase and in the internal w/o emulsion are uniform. The results show that there is a very good fit between the experimental and model data and that the variation in the values of the overall mass transfer coefficients with the experimental conditions coincides with that of the removal efficiency mentioned above. The transport mechanism was studied by identifying the rate-controlling step of the removal process, using models described for adsorption processes, due to the strong parallelism between the transport mechanisms in adsorption and emulsion liquid membrane processes.

Correction: Crespo et al. Protective Effect of Protocatechuic Acid on TNBS-Induced Colitis in Mice Is Associated with Modulation of the SphK/S1P Signaling Pathway. Nutrients 2017, 9, 288.

In the original publication [...].

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.