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 [...].

Correction: Méndez-Blanco et al. Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells. Cancers 2019, 11, 1984.

In the original publication [...].

Influence of 12-Week Concurrent Training on Exosome Cargo and Its Relationship with Cardiometabolic Health Parameters in Men with Obesity.

Exosome release varies depending on the physiological state of the cell, so they could play a fundamental role in obesity, the biggest pandemic in today's societies. The beneficial effects that physical activity has both on weight and cardiovascular parameters may be mediated by exosomes released in response to exercise. Thus, we aimed (I) to study the influence of a 12-week CT intervention on exosome cargo modifications in men with obesity and (II) to determine whether changes in exosomes after the intervention were related to changes in cardiometabolic health parameters in our cohorts. An experimental, controlled design was performed in twelve (nine with valid data) adult male obese patients (mean values: 41.6 years old, 97.6 kg and 32.4 kg/m2) who were randomly divided into a control group (n = 4) and a training group (n = 5), which completed 36 sessions of CT (concurrent training) for 12 weeks. Before and after the training period, cardiometabolic health parameters were evaluated and blood samples to measure exosomes and proteins were drawn. No changes were observed in the levels of any exosomal markers and proteins; however, associations of changes between CD81 and both fat mass and weight, Flot-1 and VO2max, HSP70 and both CRP and left ventricle diastolic diameter or CD14 and leptin were found (all p ≤ 0.05). Although the current CT was not able to clearly modify the exosome cargo, a certain medium to large clinical effect was manifested considering the nature of this study. Moreover, the associations found between the promoted changes in cardiometabolic parameters and exosome-carried proteins could indicate a relationship to be considered for future treatments in patients with obesity.

Effects of submaximal and supramaximal accentuated eccentric loading on mass and function.

Introduction: Eccentric-overload (EO) resistance training emerges as an alternative to more optimally prescribe intensity relative to the force generation capabilities of the eccentric muscle contraction. Given the difficulties to individually prescribe absolute eccentric loads relative to each person's eccentric ability, setting the load relative to the concentric one-repetition maximum (1-RM) is the most used EO training approach. Therefore, we investigated the effects of submaximal and supramaximal (i.e., eccentric loads above 100% of 1-RM) accentuated eccentric training on changes in lean mass, anabolic hormonal responses and muscle function. Methods: Physically active university students (n = 27) were randomly assigned to two training groups. Participants in the training groups performed dominant leg isotonic training twice a week for 10 weeks (four sets of eight repetitions). Isotonic resistance was generated by an electric-motor device at two different percentages of 1-RM for the eccentric phase; 90% submaximal load, SUB group) and 120% (supramaximal load, SUPRA group). Concentric load was the same for both groups (30% of 1-RM). Changes in total thigh lean mass (TTLM), anabolic hormonal responses (growth hormone, IGF-1, IL-6, and total testosterone), unilateral leg-press 1-RM, maximal voluntary isometric contractions (MVIC), local muscle endurance (XRM), muscle power at 40 (PP40), 60 (PP60) and 80% (PP80) of the 1-RM, and unilateral vertical jump height before and after training were compared between groups. Results: After training, both SUB and SUPRA groups showed similar increases (p < 0.05) in MVIC (19.2% and 19.6%), XRM (53.8% and 23.8%), PP40 (16.2% and 15.7%), TTLM (2.5% and 4.2%), IGF-1 (10.0% and 14.1%) and IL-6 (58.6% and 28.6%). However, increases in 1-RM strength (16.3%) and unilateral vertical jump height (10.0%-13.4%) were observed for SUPRA only. Indeed, SUPRA was shown to be more favorable than SUB training for increasing 1-RM [ES = 0.77 (1.49-0.05)]. Unilateral muscle power at medium and high intensity (10.2% and 10.5%) also increased in SUB but without significant differences between groups. Discussion: Similar functional and structural effects were demonstrated after 10 weeks EO training with submaximal and supramaximal eccentric loads. Although supramaximal loading might be superior for increasing 1-RM, the use of this approach does not appear to be necessary in healthy, active individuals.

Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.

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.

Exercise Outcomes in Childhood Obesity-Related Inflammation and Oxidative Status.

Childhood obesity is identified as one of the major public health issues to increase the risk for cardiometabolic diseases and related complications in adulthood. The literature has supported inflammation and oxidative stress as the primary underlying mechanisms involved in the pathogenesis of obesity-related diseases. Epidemiological evidence consistently shows the benefits of physical activity in the improvement of obesity-mediated inflammation and oxidative stress status. In this narrative mini-review, the available scientific evidence on the potential effects of exercise in alleviating these susceptibilities in childhood obesity will be assessed.

Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies.

Neuropilin-1 (NRP1) is a transmembrane protein involved in numerous cellular functions which has had increasing interest from cancer researchers. Liver cancer and colorectal cancer (CRC) are two of the most frequent and deadly tumors with a complex pharmacological framework. Here, we assessed the prognostic, diagnostic and clinicopathological value of NRP1 in liver cancer and CRC patients. We searched PubMed, Scopus, Web of Science, Embase and Cochrane Library databases for articles evaluating the NRP1 correlation with survival parameters, tumor development or clinicopathological features. Hazard ratios and odds ratios with 95% confidence intervals were extracted or estimated by Parmar method and pooled to evaluate the overall effect size with STATA 16 software. Heterogeneity was analyzed by chi-square-based Q test and I2 statistic, along with meta-regression and subgroup analysis, and publication bias was assessed by funnel plot asymmetry and Egger's test. The study protocol was registered in PROSPERO (CRD42022307062). NRP1 overexpression was significantly correlated with lower survival in liver cancer patients and with tumor development in hepatocarcinoma patients, and was strongly correlated with an increased risk of vascular invasion in liver cancer and metastasis in CRC and liver tumors. These results support the role of NRP1 as a potential and useful biomarker in both types of cancer.

Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers.

Hepatobiliary, pancreatic, and gastrointestinal cancers account for 36% of the ten million deaths caused by cancer worldwide every year. The two main reasons for this high mortality are their late diagnosis and their high refractoriness to pharmacological treatments, regardless of whether these are based on classical chemotherapeutic agents, targeted drugs, or newer immunomodulators. Mechanisms of chemoresistance (MOC) defining the multidrug resistance (MDR) phenotype of each tumor depend on the synergic function of proteins encoded by more than one hundred genes classified into seven groups (MOC1-7). Among them, the efflux of active agents from cancer cells across the plasma membrane caused by members of the superfamily of ATP-binding cassette (ABC) proteins (MOC-1b) plays a crucial role in determining tumor MDR. Although seven families of human ABC proteins are known, only a few pumps (mainly MDR1, MRP1-6, and BCRP) have been associated with reducing drug content and hence inducing chemoresistance in hepatobiliary, pancreatic, and gastrointestinal cancer cells. The present descriptive review, which compiles the updated information on the expression of these ABC proteins, will be helpful because there is still some confusion on the actual relevance of these pumps in response to pharmacological regimens currently used in treating these cancers. Moreover, we aim to define the MOC pattern on a tumor-by-tumor basis, even in a dynamic way, because it can vary during tumor progression and in response to chemotherapy. This information is indispensable for developing novel strategies for sensitization.

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.

Cross-education effects of unilateral accentuated eccentric isoinertial resistance training on lean mass and function.

PURPOSE: We investigated the effects of three different unilateral isoinertial resistance training protocols with eccentric overload on changes in lean mass and muscle function of trained (TL) and contralateral non-trained (NTL) legs. METHODS: Physically active university students were randomly assigned to one of three training groups or a control group (n = 10/group). Participants in the training groups performed dominant leg isoinertial squat training twice a week for 6 weeks (4 sets of 7 repetitions) using either an electric-motor device with an eccentric phase velocity of 100% (EM100) or 150% (EM150) of concentric phase velocity or a conventional flywheel device (FW) with the same relative inertial load. Changes in thigh lean mass, unilateral leg-press one-repetition maximum (1-RM), muscle power at 40-80% 1-RM, and unilateral vertical jump height before and after training were compared between the groups and between TL and NTL. RESULTS: No changes in any variable were found for the control group. In TL, all training groups showed similar increases (p < 0.05) in 1-RM strength (22.4-30.2%), lean tissue mass (2.5-5.8%), muscle power (8.8-21.7%), and vertical jump height (9.1-32.9%). In NTL, 1-RM strength increased 22.0-27.8% without significant differences between groups; however, increases in lean mass (p < 0.001) were observed for EM150 (3.5%) and FW (3.8%) only. Unilateral vertical jump height (6.0-32.9%) and muscle power (6.8-17.5%) also increased in NTL without significant differences between training groups. CONCLUSION: The three eccentric-overload resistance training modalities produced similar neuromuscular changes in both the trained and non-trained legs, suggesting that strong cross-education effects were induced by the eccentric-overload training.

Comparison of Flywheel and Pneumatic Training on Hypertrophy, Strength, and Power in Professional Handball Players.

Purpose: The mechanical properties of resistance-training machines are a variable that may help to optimize sports performance and injury prevention protocols. The purpose of this study was to examine two non-gravity-dependent training modalities on muscle structure and function. Methods: Eighteen professional handball players were randomly divided into two experimental groups: 1) iso-inertial flywheel training (FW) and 2) pneumatic resistance training (PN). Participants in both groups completed twelve training sessions in six weeks consisting of three movements (lateral raise, internal and external rotation). Four sets of seven repetitions for each movement were performed during each session. Before and after training subscapularis and deltoid (anterior, middle, posterior) muscle thickness was measured. Isokinetic torque and power during internal and external rotation at 60, 180, and 240 deg·s-1 was measured as well. Throwing speed was assessed before and after training while both sitting and standing situations. Results: Both groups showed similar significant increases in throwing speed and internal and external rotation peak torque, average and peak power at all angular velocities. Anterior and middle deltoid muscle thickness changes were greater after training in FW (20 and 22%) in comparison to PN (14 and 7%, respectively). Conclusions: In summary, both flywheel and pneumatic training resulted in similar increases in shoulder strength and power and throwing speed. However, flywheel training appeared to possibly result in a slightly greater level of muscle hypertrophy of the anterior and middle deltoid. Non-gravity dependent training appears to induce changes that would be beneficial to sports performance and perhaps injury prevention.

The Synbiotic Combination of Akkermansia muciniphila and Quercetin Ameliorates Early Obesity and NAFLD through Gut Microbiota Reshaping and Bile Acid Metabolism Modulation.

Gut microbiota plays a key role in obesity and non-alcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. We aim to evaluate a nutritional intervention together with the administration of the bacteria Akkermansia muciniphila and the antioxidant quercetin in an in vivo model of early obesity and NAFLD. 21-day-old rats were fed with control or high-fat diet for six weeks. Then, all animals received control diet supplemented with/without quercetin and/or A. muciniphila for three weeks. Gut microbiota, NAFLD-related parameters, circulating bile acids (BAs) and liver gene expression were analyzed. The colonization with A. muciniphila was associated with less body fat, while synbiotic treatment caused a steatosis remission, linked to hepatic lipogenesis modulation. The synbiotic promoted higher abundance of Cyanobacteria and Oscillospira, and lower levels of Actinobacteria, Lactococcus, Lactobacillus and Roseburia. Moreover, it favored elevated unconjugated hydrophilic BAs plasma levels and enhanced hepatic expression of BA synthesis and transport genes. A. muciniphila correlated with circulating BAs and liver lipid and BA metabolism genes, suggesting a role of this bacterium in BA signaling. Beneficial effects of A. muciniphila and quercetin combination are driven by gut microbiota modulation, the shift in BAs and the gut-liver bile flow enhancement.

Association of FOXO3 Expression with Tumor Pathogenesis, Prognosis and Clinicopathological Features in Hepatocellular Carcinoma: A Systematic Review with Meta-Analysis.

Forkhead box O3 (FOXO3), an essential transcription factor related to liver disease, has been linked to cancer progression. The most frequent primary liver tumor, hepatocellular carcinoma (HCC), has an elevated mortality rate and patient outcomes remain very poor. Here, we examined the diagnostic, prognostic and clinicopathological significance of FOXO3 expression in HCC. We systematically searched Cochrane, Embase, PubMed, Scopus and Web of Science. Articles analyzing FOXO3 levels in HCC patient samples and its relationship with tumor development, survival or clinicopathological factors were selected. Hazard ratios, odds ratios and 95% confidence intervals were extracted, estimated by Parmar method or calculated and pooled across studies. Heterogeneity was evaluated by chi-square-based Q and I2 tests, while publication bias by funnel plots and Egger's test. Subgroup analysis was performed when heterogeneity was evident. The study protocol was registered in PROSPERO (CRD42021237321), and data were meta-analyzed employing STATA 16. Five studies involving 1059 HCC cases were finally included in this meta-analysis, finding that high FOXO3 levels significantly correlate with HCC development and shorter overall survival. Moreover, subgroup analysis revealed a significant association between positive FOXO3 expression and the risk of invasion. Thus, FOXO3 could function as a novel biomarker with diagnostic and prognostic value in HCC.

Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib.

Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.

Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics.

Aging involves progressive physiological and metabolic reprogramming to adapt to gradual deterioration of organs and functions. This includes mechanisms of defense against pre-malignant transformations. Thus, certain tumors are more prone to appear in elderly patients. This is the case of the two most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Accordingly, aging hallmarks, such as genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cell niches, impaired intracellular communication, and deregulated nutrient sensing can play an important role in liver carcinogenesis in the elders. In addition, increased liver fragility determines a worse response to risk factors, which more frequently affect the aged population. This, together with the difficulty to carry out an early detection of HCC and iCCA, accounts for the late diagnosis of these tumors, which usually occurs in patients with approximately 60 and 70 years, respectively. Furthermore, there has been a considerable controversy on what treatment should be used in the management of HCC and iCCA in elderly patients. The consensus reached by numerous studies that have investigated the feasibility and safety of different curative and palliative therapeutic approaches in elders with liver tumors is that advanced age itself is not a contraindication for specific treatments, although the frequent presence of comorbidities in these individuals should be taken into consideration for their management.

Diclofenac Administration after Physical Training Blunts Adaptations of Peripheral Systems and Leads to Losses in Exercise Performance: In Vivo and In Silico Analyses.

Recovery in athletes is hampered by soreness and fatigue. Consequently, nonsteroidal anti-inflammatory drugs are used as an effective strategy to maintain high performance. However, impact of these drugs on adaptations induced by training remains unknown. This study assessed the effects of diclofenac administration (10 mg/kg/day) on rats subjected to an exhaustive test, after six weeks of swimming training. Over the course of 10 days, three repeated swimming bouts were performed, and diclofenac or saline were administered once a day. Trained animals exhibited higher muscle citrate synthase and lower plasma creatinine kinase activities as compared to sedentary animals, wherein diclofenac had no impact. Training increased time to exhaustion, however, diclofenac blunted this effect. It also impaired the increase in plasma and liver interleukin-6 levels. The trained group exhibited augmented catalase, glutathione peroxidase, and glutathione reductase activities, and a higher ratio of reduced-to-oxidized glutathione in the liver. However, diclofenac treatment blunted all these effects. Systems biology analysis revealed a close relationship between diclofenac and liver catalase. These results confirmed that regular exercise induces inflammation and oxidative stress, which are crucial for tissue adaptations. Altogether, diclofenac treatment might be helpful in preventing pain and inflammation, but its use severely affects performance and tissue adaptation.