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The adaptation of sponges to freshwater environments was a major event in the evolutionary history of this clade. The transition from a marine environment to freshwater ecosystems entailed a great number of adaptations to more unstable habitats, such as the ability to form resistance gemmules as a defense mechanism against environmental adversity. However, data on the parameters that modulate hatching and growth of these animals are scarce. In the present study, the growth response capacity of Ephydatia fluviatilis (Porifera: Spongillidae) has been evaluated in relation to both water alkalinity and light intensity. The results obtained revealed a positive association between the growth capacity of this freshwater sponge and high alkalinity values. On the other hand, exposure to light, regardless of its intensity, affected the development and distribution of the symbionts, which in turn, corresponds to a higher growth rate of the sponge. The obtained data suggest an explanation for the greater distribution of this species in alkaline environments. The results of this work also shed light on the importance of the symbiosis phenomenon in E. fluviatilis.

Phloroglucinol and derived compounds comprise a huge class of secondary metabolites widely distributed in plants and brown algae. A vast array of biological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer has been associated to this class of compounds. In this review, the available data on the antiviral and antibacterial capacity of phloroglucinols have been analyzed. Some of these compounds and derivatives show important antimicrobial properties

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events.

Ketamine is widely used in infants and young children for procedural sedation and anesthesia. The aim of this study was to evaluate the efficacy and safety of low dose oral ketamine to control pain and distress in children during intravenous (IV) cannulation.This is a prospective, randomized, double-blind study, including children aged between 3 and 6 years requiring a non-emergent IV-line placement. Children were randomly assigned to two groups, treated either with oral ketamine or a placebo. All patients were monitored for vital signs. Pain was assessed using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wong-Baker Faces Pain Rating Scale (WBFS) scales and sedation using a 5-point sedation score. The facility of IV-line placement was measured by a 3-point scale. Adverse effects were recorded after 1 and 24 hours.A total of 79 and 81 children were entered in the ketamine and placebo groups, respectively. The heart and respiratory rates increased significantly in the placebo group. The median CHEOPS 4 (95% confidence interval [CI]: 3, 4,Low dose oral ketamine effectively decreased the pain and distress during IV cannulation in children without any significant adverse reactions.

Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections. info:eu-repo/semantics/publishedVersion

In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this “doubleedged sword” in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.

Cancer is a leading cause of death worldwide and involves an oxidative stress mechanism. The transcription factor Nrf2 has a crucial role in cytoprotective response against oxidative stress, including cancer growth and progression and therapy resistance. For this reason, inhibitors of Nrf2 are new targets to be studied. Traditional plant-based remedies rich in phytochemicals have been used against human cancers and phenolic compounds are known for their chemopreventive properties. This comprehensive review offers an updated review of the role of phenolic compounds as anticancer agents due to their action on Nrf2 inhibition. In addition, the role of naturally-occurring bioactive anticancer agents are covered in the clinical applications of polyphenols as Nrf2 inhibitors.

Non-alcoholic fatty liver disease (NAFLD) shows liver fat depots without alcohol consumption. NAFLD does not have specific drug therapies, with a healthy lifestyle and weight loss being the main approaches to prevent and treat NAFLD. The aim was to assess the antioxidant and pro-inflammatory state in patients with NAFLD after 12-month-lifestyle intervention depending on the change in adherence to a Mediterranean diet (AMD). Antioxidant and inflammatory biomarkers were measured in 67 adults (aged 40–60 years old) diagnosed with NAFLD. Anthropometric parameters and dietary intake were measured by a validated semi-quantitative 143-item food frequency questionnaire. The nutritional intervention improved anthropometric and biochemical parameters after a 12-month follow-up. However, decreases in alanine aminotransferase (ALT) and C reactive protein (CRP) were higher in participants with high AMD, which also showed higher improvement in physical fitness (Chester step test) and intrahepatic fat contents. The intervention reduced plasma levels of malondialdehyde, myeloperoxidase, zonulin, and omentin, and increased resolvin D1 (RvD1), whereas the decrease in leptin, ectodysplasin-A (EDA), cytokeratin-18 (CK-18), interleukin-1ra (IL-1ra) and endotoxin was only significant in participants with higher AMD. The current study showed that a one-year nutritional intervention improved main NAFLD features such as body mass index, IFC, liver enzymes, and prooxidant and proinflammatory status. There was also a decrease in the concentration of plasmatic endotoxin, suggesting an improvement in intestinal permeability. These health benefits were more evident in participants that improved AMD to a greater extent. The trial was registered at ClinicalTrials.gov with registry number NCT04442620.

7 Pág., Xyricthys novacula is very popular fish species in the Balearic Islands and a main target for recreational fishing. Over the last years, spots were observed on many individuals, which seems to be progressively more common. The aim of the present study was to identify the parasite, determine its abundance in a marine protected area (MPA) and in a non-protected one with more anthropic influence, and to evaluate the antioxidant and immune responses to this parasite presence by studying biomarkers in both liver and epithelial mucus. Analysis of genetic sequences established with 98.6–98.4% certainty that the parasite is a digenean fluke Scaphanocephalus sp. An average abundance of 12.3 ± 11.3 and 1.3 ± 1.3 parasites per individual was found for the non-protected area and the MPA, respectively. The activities of lysozyme and superoxide dismutase and total immunoglobulin concentration were significantly higher in mucus of X. novacula with more parasites. Similarly, in liver, a higher parasite load is related to higher activities of catalase, glutathione peroxidase and glutathione S-transferase, whereas malondialdehyde remained similar. In conclusion, Scaphanocephalus sp. affects X. novacula, inducing an immune and antioxidant response in epithelial mucus and in liver. The potential influence of the environment on parasite transmission, prevalence and abundance require further research to determine whether it makes fish more susceptible to infections., This research was funded by Direccio ´ General de Política Universitaria ` i Recerca, Comunitat Autonoma ` de les Illes Balears AP_2021_012), by DG Pesca, Conselleria d'Agricultura i Pesca, Govern de les Illes Balears and, by the Biodibal project within the framework of the Collaboration Agreement between the University of the Balearic Islands and Red Electrica de Espana. ˜ A. Solomando was supported by an FPU contract with the Ministry of Science, Innovation and Universities from the Spanish Government (FPU18/04689). A. Sureda and S. Tejada were granted by the Programme of Promotion of Biomedical Research and Health Sciences, Instituto de Salud Carlos III (CIBEROBN CB12/03/30038).

Currently, the world is facing a pandemic of the new coronavirus SARS-CoV-2 that causes COVID-19. Identifying key targets in the viral infection lifecycle is urgently needed for designing therapeutic strategies to combat the virus. Furin is a subtilisin-like proprotein convertase with diverse cellular functions. Emerging evidence suggests that furin plays a critical role in the activation and/or infectivity of SARS-CoV-2. In this perspective, we discuss the potential role of furin in the entry SARS-CoV-2 into host cells. Furthermore, we evaluate available peptide and non-peptide furin inhibitors and potential outcomes, including immune responses.

Background:: Hypertension is a high prevalent chronic disease worldwide and a major cardiovascular risk factor. Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a wide distributed bioactive pentacyclic triterpenoid with diverse biological activities such as anti-inflammatory, hepaprotective anti-diabetic or anti-hypertensive. Objective:: The aim of this study was to review and highlight the available data about antihypertensive activity of oleanolic acid and the described mechanisms of action. Method:: Extensive searches were made in the available literature on oleanolic acid and the data investigating its antihypertensive effects were analysed. Results:: Most of research has been performed on animal models of hypertension, ex vivo studies with aortic ring and some in vitro tests with cell cultures, whereas clinical trials are still lacking. Treatment of hypertensive animals with oleanolic acid significantly ameliorated the rise in the systolic blood pressure. In addition, the hypotensive effects of oleanolic acid are also related to a potent diuretic-natriuretic activity and nephroprotection. In vitro studies have characterized the participation of various signalling pathways that modulate the release of vasodilation mediators. Conclusion:: In vitro and in vivo studies suggest that oleanolic acid effectively reduce blood pressure and could be an interesting co-adjuvant to conventional treatment of hypertension.

The western Mediterranean Sea is one of the most affected areas by the introduction of alien seaweed. Penicillus capitatus Lam. and the recently introduced Halimeda incrassata (J.Ellis) J.V.Lamour are tropical algae that invade native algae assemblies in the shallow sandy beds of Mallorca (Balearic Islands, western Mediterranean) where they are already settled. The aim of this study was to evaluate the effect of a potential competition between the invasive P. capitatus and H. incrassata and the native Padina pavonica (L.) Thivy, by means of biomarkers. P. pavonica samples were collected in their habitat without invasive species and areas where P. capitatus and H. incrassata cohabitated. P. pavonica densities were measured in the three investigated areas. The coexistence of the invasive algae and P. pavonica was related to a significant decrease in the densities of native algae when compared to the area without the invaders. Antioxidant enzymes, catalase and superoxide dismutase, and the reduced glutathione and polyphenols levels were significantly increased in P. pavonica in the presence of both invasive algae. Malondialdehyde, a marker of oxidative damage, and the reactive oxygen species production tended to increase in the presence of the alien species, but without significant differences. The obtained results show that the presence of P. capitatus and H. incrassata altered the normal vegetative growth of P. pavonica and caused an antioxidant response that led to a context of stress, but without evidence of oxidative damage. In conclusion, the presence of the alien H. incrassata and P. capitatus can be considered a source of competitive stress for P. pavonica, although further research regarding the increased water temperature is required.

Mitochondria are ubiquitous membrane-bound organelles that not only play a key role in maintaining cellular energy homeostasis and metabolism but also in signaling and apoptosis. Aryl hydrocarbons receptors (AhRs) are ligand-activated transcription factors that recognize a wide variety of xenobiotics, including polyaromatic hydrocarbons and dioxins, and activate diverse detoxification pathways. These receptors are also activated by natural dietary compounds and endogenous metabolites. In addition, AhRs can modulate the expression of a diverse array of genes related to mitochondrial biogenesis and function. The aim of the present review is to analyze scientific data available on the AhR signaling pathway and its interaction with the intracellular signaling pathways involved in mitochondrial functions, especially those related to cell cycle progression and apoptosis. Various evidence have reported the crosstalk between the AhR signaling pathway and the nuclear factor κB (NF-κB), tyrosine kinase receptor signaling and mitogen-activated protein kinases (MAPKs). The AhR signaling pathway seems to promote cell cycle progression in the absence of exogenous ligands, whereas the presence of exogenous ligands induces cell cycle arrest. However, its effects on apoptosis are controversial since activation or overexpression of AhR has been observed to induce or inhibit apoptosis depending on the cell type. Regarding the mitochondria, although activation by endogenous ligands is related to mitochondrial dysfunction, the effects of endogenous ligands are not well understood but point towards antiapoptotic effects and inducers of mitochondrial biogenesis.

Background T. vulgaris, commonly known as the thyme, is an aromatic plant belonging to the Lauraceae family. Six different chemotypes were described for T. vulgaris. The chemotypes are named after its dominant monoterpene: geraniol (G), α-terpineol (A), thuyanol-4 (U), linalool (L), carvacrol (C), and thymol (T). Scope and approach For this review, an extensive bibliographic research on Thymus vulgaris was carried out, including its main components both nutrients and bioactives. Botanical description, distribution and cultivation were also addressed as well as uses in folk medicine. Particular attention was given to biological activities, clinical studies, possible limitations and potential applications. Key findings and conclusions T. vulgaris L. is used as food and for medicinal purposes and it has a great economic importance due to its composition on monoterpene derivatives including p-cymene, thymol and carvacrol. The value of T. vulgaris has been recognized by the pharmaceutical industry, because it proved to have hepatoprotective properties and to have effectiveness as expectorant agent, anti-acne agent, and as fungicidal and antiviral drug. It has been also recognized by the industries of pests' repellents, foods, food packaging and cosmetics. This vast number of industrial applications is mainly due to its antioxidant, antimicrobial, anti-inflammatory and anticancer effects.

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide, directly related to the progressive increase in body weight and obesity. The accumulation of lipids in patients with NAFLD contributes to the development of insulin resistance, inflammatory response and oxidative stress in hepatocytes and alteration of the circulating lipid and glycaemic profile. However, to date, there are no effective pharmacological treatments for patients with NAFLD. Lifestyle changes and dietary modifications aimed at weight loss are the best current alternatives; therefore, new approaches should be considered. Resveratrol, a natural polyphenol of the stilbene group, is a potential candidate for the management of NAFLD for its anti-inflammatory, antioxidant properties, and calorie restriction-like effects. Methods: In this review, the available information on the potential therapeutic effects of resveratrol on NAFLD, found mainly in animal models and in some clinical trials, is summarizes. Results: In vitro and animal model studies have shown beneficial effects of resveratrol treatment on NAFLD. Resveratrol reduces the hepatic accumulation of lipids and improves lipid and glycaemic metabolism. Some of the mechanisms of action are the signalling pathways of AMP-activated protein kinase, sirtuin 1 and nuclear factor κB. However, the results obtained in clinical trials are inconclusive. Conclusion: Although preclinical trials have shown promising results of resveratrol against NALFD, the lack of clear results in clinical trials makes it necessary to conduct more studies with a larger number of patients and for a longer time.

Neurodegenerative disorders, particularly in the elderly population, represent one of the most pressing social and health-care problems in the world. Besides the well-established role of both oxidative stress and inflammation, alterations of the immune response have been found to be closely linked to the development of neurodegenerative diseases. Interestingly, various scientific evidence reported that an altered gut microbiota composition may contribute to the development of neuroinflammatory disorders. This leads to the proposal of the concept of the gut-brain-immune axis. In this scenario, polyphenols play a pivotal role due to their ability to exert neuroprotective, immunomodulatory and microbiota-remodeling activities. In the present review, we summarized the available literature to provide a scientific evidence regarding this neuroprotective and immunomodulatory effects and the interaction with gut microbiota of polyphenols and, the main signaling pathways involved that can explain their potential therapeutic application in neurodegenerative diseases.

Diabetes mellitus is one of the most common and complex problems in today's society and is responsible for many socio-economic problems. Type 1 diabetes is due to a defect in insulin secretion caused by a destruction of pancreatic β cells. In contrast, the pathogenesis of type 2 diabetes is associated with the development of insulin resistance in the liver and peripheral tissues, a decrease in β-cell mass, and a defect in insulin secretion. Various factors such as inflammation, stress, obesity, and lifestyle are involved in diabetes. Long-term or chronic increase in glucose in these patients is the leading causes of secondary disorders such as micro- and macro-angiopathy, weakness of the antioxidant defense system as well as metabolic disorders and altered lipid profile. The above conditions lead to short-term and long-term complications. These complications cause damage to the physical and physiological function of diverse organs of the body and threaten human health. Late complications of diabetes, including nephropathy, retinopathy, cardiovascular complications, neuropathy, hypertension, and weight gain are common and more research has been done on them. Numerous drugs such as Meglitinides, Biguanides, and Thiazolidinedione have been proposed to reduce high blood sugar, but due to the lack of complete cure of this disease with the use of existing drugs, the tendency to use alternative and traditional therapies has increased. In the meantime, the role of herbs with hypoglycemic properties in the treatment of diabetic patients cannot be ignored. The consumption of herbs by people with diabetes has become widespread even in Western countries. The use of herbs could be considered when conventional therapies cannot control the disease, and the patient needs to be prescribed insulin. The mammalian target of rapamycin, mTOR, plays a significant role in regulating cell growth, cellular metabolic status in response to nutrients, many extracellular cues and growth factors. Impaired insulin secretion can lead to altered mTOR signaling. The mTOR pathway has shown different behaviors depending on the situation. It has been shown that mTOR can regulate the adaptation of β cells to blood sugar but also chronic inhibition of the mTOR pathway can also induce diabetes. Here, we have reviewed recent findings on the role of mTOR in major metabolic organs, such as the liver, pancreas, brain, and adipose tissue and muscle, and discussed its potential as a diabetes-related drug target.

Macroautophagy (autophagy) has been a highly conserved process throughout evolution and allows cells to degrade aggregated/misfolded proteins, dysfunctional or superfluous organelles and damaged macromolecules, in order to recycle them for biosynthetic and/or energetic purposes to preserve cellular homeostasis and health. Changes in autophagy are indeed correlated with several pathological disorders such as neurodegenerative and cardiovascular diseases, infections, cancer and inflammatory diseases. Conversely, autophagy controls both apoptosis and the unfolded protein response (UPR) in the cells. Therefore, any changes in the autophagy pathway will affect both the UPR and apoptosis. Recent evidence has shown that several natural products can modulate (induce or inhibit) the autophagy pathway. Natural products may target different regulatory components of the autophagy pathway, including specific kinases or phosphatases. In this review, we evaluated ~100 natural compounds and plant species and their impact on different types of cancers via the autophagy pathway. We also discuss the impact of these compounds on the UPR and apoptosis via the autophagy pathway. A multitude of preclinical findings have shown the function of botanicals in regulating cell autophagy and its potential impact on cancer therapy; however, the number of related clinical trials to date remains low. In this regard, further pre-clinical and clinical studies are warranted to better clarify the utility of natural compounds and their modulatory effects on autophagy, as fine-tuning of autophagy could be translated into therapeutic applications for several cancers.

The global distribution and presence of plastic, at all levels of the water column, has made plastic debris one of today’s greatest environmental challenges. The ingestion and entanglement of plastic-containing marine debris has been documented in more than 60% of all cetacean species. In light of the increasing pressure on cetaceans, and the diversity of factors that they face, the aim of this work is to provide evidence of the impact of plastic debris on stranded cetaceans, in terms of ingestion and entanglement, in the Balearic Islands for the first-time. Detailed examinations, necropsies, and plastic debris analysis were performed on 30 of the 108 cetaceans stranded between 2019 and 2022. Specimens belonging to five different species, Stenella coeruleoalba, Tursiops truncatus, Grampus griseus, Balaenoptera physalus, and Physeter macrocephalus, were evaluated. Ten percent of the cetaceans (N = 3) presented plastic debris in their stomach, with one case of obstruction and perforation. Fishery gear fragments (ropes and nets) were found in two adults of T. truncatus, whereas packaging debris (plastic bag, packing straps, and plastic sheets) were found in a juvenile P. macrocephalus. Plastic items analysed by Fourier transform infrared spectroscopy (FT-IR) reported three polymer types: polypropylene, polyamide, and high-density polypropylene. A total of seven cases of entanglement were recorded during the study, affecting four different species (S. coeruleoalba, T. truncatus, P. macrocephalus, and Megaptera novaeangliae). Only two individuals were freed from the nets, although one died after a week, whereas the rest were already found dead. In conclusion, data collected in the present study provided evidence of plastic ingestion and entanglement in cetaceans of the Balearic Islands for the first-time, thus highlighting the need for the regular examination of stranded cetaceans (as they are top predators) in future research to better understand the effects of these pollutants.

Background: Triterpenes are a large group of secondary metabolites mainly produced by plants with a variety of biological activities, including potential antitumor effects. Hepatocellular carcinoma (HCC) is a very common primary liver disease spread worldwide. The treatment can consist of surgical intervention, radiotherapy, immunotherapy and chemotherapeutic drugs. These drugs mainly include tyrosine multikinase inhibitors, although their use is limited by the underlying liver disease and displays side effects. For that reason, the utility of natural compounds such as triterpenes to treat HCC is an interesting line of research. No clinical studies are reported in humans so far. Objective: The aim of the present work is to review the knowledge about the effects of triterpenes as a possible coadjuvant tool to treat HCC. Results: In vitro and xenograft models have pointed out the cytotoxic and anti-proliferative effects as well as improvements in tumor growth and development of many triterpenes. In addition, they have also shown to be chemosensitizing agents when co-administered with chemotherapeutic agents. The mechanisms of action are diverse and involve the participation of mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, and the survival-associated PI3K / Akt signaling pathway. However, no clinical studies are still reported in humans. Conclusion: Triterpenes could become a future strategy to address HCC or at least improve results when administered in combination with chemotherapeutic agents.

Propolis, a resinous substance produced by honeybees from various plant sources, has been used for thousands of years in traditional medicine for several purposes all over the world. The precise composition of propolis varies according to plant source, seasons harvesting, geography, type of bee flora, climate changes, and honeybee species at the site of collection. This apiary product has broad clinical applications such as antioxidant, anti-inflammatory, antimicrobial, anticancer, analgesic, antidepressant, and anxiolytic as well asimmunomodulatory effects. It is also well known from traditional uses in treating purulent disorders, improving the wound healing, and alleviating many of the related discomforts. Even if its use was already widespread since ancient times, after the First and Second World War, it has grown even more as well as the studies to identify its chemical and pharmacological features, allowing to discriminate the qualities of propolis in terms of the chemical profile and relative biological activity based on the geographic place of origin. Recently, several in vitro and in vivo studies have been carried out and new insights into the pharmaceutical prospects of this bee product in the management of different disorders, have been highlighted. Specifically, the available literature confirms the efficacy of propolis and its bioactive compounds in the reduction of cancer progression, inhibition of bacterial and viral infections as well as mitigation of parasitic-related symptoms, paving the way to the use of propolis as an alternative approach to improve the human health. However, a more conscious use of propolis in terms of standardized extracts as well as new clinical studies are needed to substantiate these health claims.

Pollution in the seas and oceans is a global problem, which highlights emerging pollutants and plastics, specifically microplastics (MPs), which are tiny (1 μm to 5 mm) ubiquitous plastic particles present in marine environments that can be ingested by a wide range of organisms. Holothurians are benthic organisms that feed on sediment; therefore, they can be exposed to contaminants present in the particles they ingest. The objective was to evaluate the effects of human activity on Holothuria tubulosa through the study of biomarkers. Specimens were collected in three different areas throughout the island of Eivissa, Spain: (1) a highly urbanized area, with tourist uses and a marina; (2) an urbanized area close to the mouth of a torrent; (3) an area devoid of human activity and considered clean. The results showed a higher presence of microplastics (MPs) in the sediments from the highly urbanized area in relation to the other two areas studied. Similarly, a higher number of MPs were observed in the digestive tract of H. tubulosa from the most affected area, decreasing with the degree of anthropic influence. Both in the sediment and in the holothurians, fibers predominated with more than 75% of the items. In the three areas, mesoplastics were analyzed by means of FTIR, showing that the main polymer was polypropylene (27%) followed by low-density polyethylene (17%) and polystyrene (16%). Regarding the biomarkers of oxidative stress, the intestine of H. tubulosa from the most impacted areas showed higher catalase, superoxide dismutase (SOD), glutathione reductase (GRd), and glutathione S-transferase (GST) activities and reduced glutathione (GSH) levels compared to the control area. The intermediate area only presented significant differences in GRd and GST with respect to the clean area. The activities of acetylcholinesterase and the levels and malondialdehyde presented similar values in all areas. In conclusion, human activity evaluated with the presence of MPs induced an antioxidant response in H. tubulosa, although without evidence of oxidative damage or neurotoxicity. H. tubulosa, due to its benthic animal characteristics and easy handling, can be a useful species for monitoring purposes.

The world population is progressively ageing, assuming an enormous social and health challenge. As the world ages, neurodegenerative diseases are on the rise. Regarding the progressive nature of these diseases, none of the neurodegenerative diseases are curable at date, and the existing treatments can only help relieve the symptoms or slow the progression. Recently, hormesis has increased attention in the treatment of age-related neurodegenerative diseases. The concept of hormesis refers to a biphasic dose-response phenomenon, where low levels of the drug or stress exert protective of beneficial effects and high doses deleterious or toxic effects. Neurohormesis, as the adaptive aspect of hormetic dose responses in neurons, has been shown to slow the onset of neurodegenerative diseases and reduce the damages caused by aging, stroke, and traumatic brain injury. Hormesis was also observed to modulate anxiety, stress, pain, and the severity of seizure. Thus, neurohormesis can be considered as a potentially innovative approach in the treatment of neurodegenerative and other neurologic disorders. Herbal medicinal products and supplements are often considered health resources with many applications. The hormesis phenomenon in medicinal plants is valuable and several studies have shown that hormetic mechanisms of bioactive compounds can prevent or ameliorate the neurodegenerative pathogenesis in animal models of Alzheimer’s and Parkinson’s diseases. Moreover, the hormesis activity of phytochemicals has been evaluated in other neurological disorders such as Autism and Huntington’s disease. In this review, the neurohormetic dose–response concept and the possible underlying neuroprotection mechanisms are discussed. Different neurohormetic phytochemicals used for the better management of neurodegenerative diseases, the rationale for using them, and the key findings of their studies are also reviewed.

Stressful situations induce an increase in the production of reactive oxygen species (ROS) which can lead to molecular damage and alteration of cell function. The introduction of new potential predators induces physiological stress in native fauna. However, behavioral responses have been reported in preys, demonstrating an induction of the defenses against alien species. Behavioral and antioxidant enzyme responses in the moorish gecko, Tarentola mauritanica, against the invasive predator horseshoe whip snake (Hemorrhois hippocrepis) were assessed. Behavior was recorded and a tissue sample from the tail was collected after placing the gecko in a terrarium with previous absence or presence of the snake in 'Control' and 'H. hippocrepis' groups, respectively. Fifteen behavioral variables were examined, including tongue flick (TF) and locomotion patterns. Antioxidant enzyme activities -catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR)-, and the levels of reduced (GSH) and oxidized glutathione (GSSG), glutathione/glutathione disulfide ratio (GSH/GSSG) and malondialdehyde (MDA) concentrations were measured in the tissue sampled. Geckos exposed to the snake's odor showed a higher number of TF, longer amounts of time remaining motionless or moving in slow motion and they spent less time on the ground in comparison to the 'Control' group. The presence of the snake produced a significant increase in the activities of CAT, SOD and GR and a decrease in the GSH/GSSG ratio in T. mauritanica individuals exposed to the snake's scent. Thus, both behavioral responses and oxidative stress biomarkers clearly showed that T. mauritanica is able to recognize H. hippocrepis as a potential predator, despite being a recently introduced snake at the Balearic Islands.

Background: A Mediterranean diet (MedDiet) is recommended as a therapy for non-alcoholic fatty liver disease (NAFLD) because there is no specific pharmacological treatment for this disease. Objective: To assess the relationship between the adherence to the Mediterranean diet and the intrahepatic fat content (IFC), levels of oxidative stress, and inflammation biomarkers after a 6-month lifestyle intervention in NAFLD patients. Methods: Patients diagnosed with NAFLD (n = 60 adults; 40–60 years old) living in the Balearic Islands, Spain, were classified into two groups, according to the adherence to the MedDiet after 6 months of lifestyle intervention. Anthropometry, blood pressure, IFC, maximal oxygen uptake, and pro/antioxidant and inflammatory biomarkers were measured in plasma and in PBMCs before and after the intervention. Results: Reductions in weight, body mass index, IFC, blood pressure levels, circulating glucose, glycosylated hemoglobin, and markers of liver damage—aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and cytokeratin 18 (CK-18)—were observed after the intervention. The highest reductions were observed in the group with the best adherence to the MedDiet. A significant improvement in cardiorespiratory fitness was also observed in the group with a higher adherence. The activities of catalase in plasma and catalase and superoxide dismutase in blood mononuclear cells increased only in the group with a higher adherence, as well as the catalase gene expression in the blood mononuclear cells. The plasma levels of malondialdehyde and myeloperoxidase decreased, and resolvin-D1 increased in both groups after the intervention, whereas interleukin-6 levels decreased only in the group with a higher adherence to the MedDiet. Conclusions: A greater adherence to the MedDiet is related to greater improvements in IFC, cardiorespiratory fitness, and pro-oxidative and proinflammatory status in NAFLD patients after a 6-month nutritional intervention based on the MedDiet.

Pollution in the seas and oceans is a global problem, which highlights emerging pollutants and plastics, specifically microplastics (MPs), which are tiny (1 μm to 5 mm) ubiquitous plastic particles present in marine environments that can be ingested by a wide range of organisms. Holothurians are benthic organisms that feed on sediment; therefore, they can be exposed to contaminants present in the particles they ingest. The objective was to evaluate the effects of human activity on

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a bioactive compound, a natural anthraquinone aglycone, present mainly in herbaceous species of the families Fabaceae, Polygonaceae and Rhamnaceae, with a physiological role in protection against abiotic stress in vegetative tissues. Emodin is mainly used in traditional Chinese medicine to treat sore throats, carbuncles, sores, blood stasis, and damp-heat jaundice. Pharmacological research in the last decade has revealed other potential therapeutic applications such as anticancer, neuroprotective, antidiabetic, antioxidant and anti-inflammatory. The present study aimed to summarize recent studies on bioavailability, preclinical pharmacological effects with evidence of molecular mechanisms, clinical trials and clinical pitfalls, respectively the therapeutic limitations of emodin. For this purpose, extensive searches were performed using the PubMed/Medline, Scopus, Google scholar, TRIP database, Springer link, Wiley and SciFinder databases as a search engines. The in vitro and in vivo studies included in this updated review highlighted the signaling pathways and molecular mechanisms of emodin. Because its bioavailability is low, there are limitations in clinical therapeutic use. In conclusion, for an increase in pharmacotherapeutic efficacy, future studies with carrier molecules to the target, thus opening up new therapeutic perspectives.

The aim of this study was to compare the 2 mouthwash solutions, including chlorhexidine (CHG) and ozonated water (OZW) to reduce the risk of ventilator-associated pneumonia (VAP) in patients on mechanical ventilation in intensive care unit (ICU).This randomized double-blind clinical trial was performed in ICU units of hospitals. Patients (n=73) were selected and divided into 2 groups of CHG (n=37) and OZW mouthwash (n=36). Mouthwash was performed by trained nurses. Chi-square test, independent t-test, paired t-test, Mann-Whitney U-test, and Repeated Measure ANOVA was used to evaluate the effect of CHG and OZW mouthwash on the risk of VAP occurrence by Clinical Pulmonary Infection Score (CPIS) checklists and swab culture.Both CHG and OZW mouthwash reduced the risk of VAP differ at different time points (the first, the third and the fifth days). There was also difference in the incidence of VAP in terms of culture of pulmonary secretions in the 2 groups. Incidence of VAP in the CHG mouthwash group was 45.9%, and also 25% in the OZW mouthwash group. Most pathogens, that found in the culture of pulmonary secretions in the CHG mouthwash was Acinetobacter baumannii; also, in the OZW mouthwash, A baumannii and Pseudomonas aeruginosa were the most frequent ones.OZW mouthwash was more effective than CHG mouthwash to reduce the risk of VAP.

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by the excessive accumulation of lipids in the liver parenchyma. To date, there is no effective pharmacological treatment against NAFLD. Objective: To assess the relationship between the improvement of the intrahepatic fat content (IFC) in patients with NAFLD and metabolic syndrome and biomarkers of oxidative stress and inflammation after 6 months of lifestyle intervention. Patients diagnosed with NAFLD (n = 60 adults; 40–60 years old) residing in the Balearic Islands, Spain, were distributed in tertiles attending the improvement of IFC calculated by magnetic resonance imaging (MRI). Anthropometrics, blood pressure, maximal oxygen uptake, and pro/antioxidant and inflammatory biomarkers were determined in plasma before and after the lifestyle intervention. The improvement in IFC levels was higher in tertile 3 with respect to tertiles 2 and 1. The greatest improvement in IFC is related to cardiorespiratory fitness and adherence to the Mediterranean diet (ADM). Higher reductions in weight, body mass index (BMI), and alanine aminotransferase (ALT) were observed in tertile 3 with respect to tertile 1 after 6 months of intervention. The improvement in catalase, irisin, and cytokeratin 18 plasma levels were higher in tertile 3, whereas no differences were observed in superoxide dismutase activity. Malondialdehyde and protein carbonyl levels, as biomarkers of oxidative damage, remained unchanged in all groups. The present data show that the reduction of IFC is associated with an improvement in pro/antioxidant and pro-inflammatory status and a better cardiorespiratory fitness in NAFLD patients.

Epigenetic alterations are one of the main factors that disrupt the expression of genes and consequently, they have an important role in the carcinogenicity and the progression of different cancers. Cancer stem cells (CSCs) are accountable for the recurrence, metastasis, and therapeutic failure of cancer. The noticeable and specific pathways in CSCs can be organized by epigenetic mechanisms such as DNA methylation, chromatin remodeling, regulatory RNAs, among others. Since epigenetics modifications can be changed and reversed, it is a possible tool for cancer control and treatment. Epigenetic therapies against CSCs are emerging as a very new strategy with a good future expectation to treat cancer patients. Phenolic compounds are a vast group of substances with anticarcinogenic functions, antiinflammatory, and antioxidative activities. It seems these characteristics are related to neutralizing CSCs development, their microenvironment, and metabolism through epigenetic mechanisms. In the current work, the types of epigenetic changes known in these cells are introduced. In addition, some studies about the use of polyphenols acting through a variety of epigenetic mechanisms to counteract these cells will be reviewed. The reported results seem to indicate that the use of these phenolic compounds may be useful for CSCs defeat.

The conventional therapies for cancer have a major concern of poor accessibility to tumor tissues. Furthermore, the requirement of higher doses and non-selective nature of therapeutic are associated with a range of adverse drug reactions (ADRs). However, flavonoids are documented to be effective against various types of cancer, but they are not evaluated for their safety profile and tumor site-specific action. Low solubility, rapid metabolism and poor absorption of dietary flavonoids in gastrointestinal tract hinder their pharmacological potential. Some studies have also suggested that flavonoids may act as pro-oxidant in some cases and may interact with other therapeutic agents, especially through biotransformation. Nanocarriers can alter pharmacokinetics and pharmacodynamic profile of incorporating drug. Moreover, nanocarriers are designed for targeted drug delivery, improving the bioavailability of poorly water-soluble drugs, delivery of macromolecules to site of action within the cell, combining therapeutic agents with imaging techniques which may visualize the site of drug delivery and co-delivery of two or more drugs. Combining two or more anti-cancer agents can reduce ADRs and nanotechnology played a pivotal role in this regard. In vitro and in vivo studies have shown the potential of flavonoids nano-formulations, especially quercetin, naringenin, apigenin, catechins and fisetin in the prevention and treatment of several types of cancer. Similarly, clinical trials have been conducted using flavonoids alone or in combination, however, the nano-formulations effect still needs to be elucidated. This review focuses on the impact of flavonoids nano-formulations on the improvement of their bioavailability, therapeutic and safety profile and will open new insights in the field of drug discovery for cancer therapeutics.

Troxerutin (TRX), a semi-synthetic bioflavonoid derived from rutin, has been reported to exert several pharmacological effects including antioxidant, anti-inflammatory, antihyperlipidemic, and nephroprotective. However, the related molecular details and its mechanisms remain poorly understood. In the present review, we presented evidences from the diversity in vitro and in vivo studies on the therapeutic potential of TRX against neurodegenerative, diabetes, cancer and cardiovascular diseases with the purpose to find molecular pathways related to the treatment efficacy. TRX has a beneficial role in many diseases through multiple mechanisms including, increasing antioxidant enzymes and reducing oxidative damage, decreasing in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and increasing the antiapoptotic BCL-2, increasing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and downregulating the nuclear factor κB (NFκ). TRX also reduces acetylcholinesterase activity and upregulates phosphoinositide 3- kinase/Akt signaling pathway in Alzheimer’s disease models. Natural products such as TRX may develop numerous and intracellular pathways at several steps in the treatment of many diseases. Molecular mechanisms of action are revealing novel, possible combinational beneficial approaches to treat multiple pathological conditions.

The accumulation of microplastics (MPs) is a growing problem in aquatic ecosystems. Despite increased research on MPs in the last decade, their potential threat to freshwater ecosystems remains an open question. In the present study, the negative impacts of MPs were investigated on blood biochemical parameters in the European pond turtle (Emys orbicularis). Pond turtles were distributed into three experimental groups (n = 9 for each group) and were fed diets containing 250, 500, and 1000 mg MPs (PE100 polyethylene) per kg of food for 30 days, and a control group fed with a standard uncontaminated diet. The results indicated that exposure to 500 and 1000 mg kg-1 MPs caused a significant increase in the activities of alanine and aspartate aminotransferases, and in the levels of cholesterol, glucose, creatinine, urea, and calcium (Ca+2) compared with the control group. On the contrary, the activity of gamma-glutamyl transferase and the levels of total protein, albumin, total immunoglobulins, and phosphorus were significantly reduced in E. orbicularis exposed to 500 and 1000 mg kg-1 MPs when compared with the controls. In all the MP-exposed groups, the activity of lactate dehydrogenase and globulin and magnesium (Mg+2) levels were significantly reduced; while creatine phosphokinase and alkaline phosphatase activities were increased with respect to the control turtles. A significant decrease in triglyceride levels was reported in E. orbicularis exposed to 1000 mg kg-1 MPs. MPs intake induced notable alterations in blood biochemical parameters of E. orbicularis. These results suggest that changes in the blood biochemical parameters could be an appropriate bio-indicator to evidence the existence of tissue damage in E. orbicularis.

Phytochemicals, especially polyphenols, are gaining more attention from both the scientific community and food, pharmaceutical, and cosmetics industries due to their implications in human health. In this line, lately new applications have emerged, and of great importance is the selection of accurate and reliable analytical methods for better evaluation of the quality of the end-products, which depends on diverse process variables as well as on the matrices and on the physicochemical properties of different polyphenols. The first of a two-part review on polyphenols will address the phytochemistry and biological activities of different classes of polyphenols including flavonoids, lignans and flavanolignans, stilbenoids, tannins, curcuminoids, and coumarins. Moreover, the possible interactions of polyphenols and current and potential industrial applications of polyphenols are discussed.

The concentrations of cadmium (Cd), mercury (Hg) and lead (Pb) were determined in muscular tissue of eleven loggerhead turtles (Caretta caretta) from the Balearic Islands (Spain, Western Mediterranean). The metal levels found in the present study were similar or lower than concentrations detected in Andalusia (mainland Spain), Italy, Canary Islands (Spain) or Japan. As the main source of metals in the loggerhead turtle is the diet, low metal burdens could be explained by its opportunistic feeding way. No significant differences were found in metal concentrations between juveniles and subadults in any of the heavy metals analysed. Furthermore, no significant correlation was detected between heavy metal concentrations and straight carapace length (SCL) of the studied individuals. These results could derive from the homogeneity in age and size of the turtles sampled, so further studies including adults are needed in order to assess the heavy metal accumulation with turtle growth.

Irrespective of sex and age, cancer is the leading cause of mortality around the globe. Therapeutic incompliance, unwanted effects, and economic burdens imparted by cancer treatments, are primary health challenges. The heritable features in gene expression that are propagated through cell division and contribute to cellular identity without a change in DNA sequence are considered epigenetic characteristics and agents that could interfere with these features and are regarded as potential therapeutic targets. The genetic modification accounts for the recurrence and uncontrolled changes in the physiology of cancer cells. This review focuses on plant-derived flavonoids as a therapeutic tool for cancer, attributed to their ability for epigenetic regulation of cancer pathogenesis. The epigenetic mechanisms of various classes of flavonoids including flavonols, flavones, isoflavones, flavanones, flavan-3-ols, and anthocyanidins, such as cyanidin, delphinidin, and pelargonidin, are discussed. The outstanding results of preclinical studies encourage researchers to design several clinical trials on various flavonoids to ascertain their clinical strength in the treatment of different cancers. The results of such studies will define the clinical fate of these agents in future.

Multiple Sclerosis (MS) is an inflammatory disorder wherein the myelin of nerve cells in the central nervous system is damaged. In the current study, we assessed the effect of Dapsone (DAP) on the improvement of behavioral dysfunction and preservation of myelin in the cuprizone (CPZ) induced demyelination model via targeting Nrf2 and IKB.MS was induced in C57BL/6 mice through diet supplementation of CPZ (0.2%) for 6 weeks, and DAP (12.5 mg/kg/day; IP) was administered for the last 2 weeks of treatment. Pole test and rotarod performance test, LFB and HE staining, and Immunohistochemistry (IHC) staining of p-Nrf2 and p-IKB were performed. Furthermore, superoxide dismutase (SOD) and nitrite were measured.DAP treatment prevented body loss induced by CPZ (These data support the suggestion that the beneficial properties of DAP on the CPZ-induced demyelination are mediated by targeting Nrf2 and NF-kB pathways.

Metabolic syndrome (MetS) is characterized by increased pro-oxidative stress and a pro-inflammatory state. Several studies emphasized the protective effect of the Mediterranean dietary pattern (MDP). To assess the oxidative and inflammatory state according to the adherence to MDP using biomarkers in patients with MetS. Antioxidant and pro-inflammatory biomarkers were determined in plasma, peripheral blood mononuclear cells (PBMCs), and neutrophils of adults (aged 55–75 years old; 60% women) with MetS living in Mallorca (Spain). Anthropometrics, dietary intake by a validated semi-quantitative 143-item food frequency questionnaire, and a Dietary Inflammatory Index were measured. Patients with low adherence to MDP showed higher levels of glycated haemoglobin A1c and triglycerides, and lower levels of HDL cholesterol. Plasma levels of interleukin-1β, IL-6, IL-15, tumour necrosis factor α, xanthine oxidase, and ghrelin, and activities of superoxide dismutase, and myeloperoxidase were higher in subjects with low adherence to the MDP. Reactive oxygen species production in PBMCs and neutrophils stimulated with lipopolysaccharide was higher in participants with low adherence to the MDP. Patients with MetS and higher adherence to the MDP showed less altered anthropometric parameters, blood biochemical profile, and better oxidative and inflammatory status.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, the prevalence of which has increased over the years. The management of this pathology is not clear, and a specific pharmacological drug that can treat NAFLD is not available. In this sense, efforts are focused on the potential use of compounds with a natural origin that can contribute to reversing hepatic steatosis. Supplementation with probiotics, live microorganisms, is a potential strategy for the management of NAFLD. Methods: In the present review, the available information on the potential therapeutic effects of probiotics in NAFLD, mainly in animal models and in some clinical trials, is summarized. Results: Studies carried out using animal models of NAFLD induced by a high-fat diet have shown the beneficial effects of probiotic supplementation in reducing liver steatosis and normalizing the blood lipid profile and liver enzyme activities. In addition, a decrease in lipogenesis and an increase in lipolysis have been observed, together with a reduction in the pro-oxidative and pro-inflammatory state and a normalization of intestinal dysbiosis. Clinical trials have reported a decrease in the serum transaminases and an improved lipid profile, as well as a reduction in inflammatory markers. Conclusions: In conclusion, probiotic supplementation can be used as a potential therapy for the management of NAFLD.

Hyperbaric oxygen therapy (HBOT) is the clinical application of oxygen at pressures higher than atmospheric pressure. HBOT has been effectively used to manage diverse clinical pathologies, such as non-healing diabetic ulcers. The aim of the present study was to analyse the effects of HBOT on the plasma oxidative and inflammation biomarkers and growth factors in patients with chronic diabetic wounds. The participants received 20 HBOT sessions (five sessions/week), and blood samples were obtained at sessions 1, 5 and 20, before and 2 h after the HBOT. An additional (control) blood sample was collected 28 days after wound recovery. No significant differences were evident in haematological parameters, whereas the biochemical parameters progressively decreased, which was significant for creatine phosphokinase (CPK) and aspartate aminotransferase (AST). The pro-inflammatory mediators, tumour necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β), progressively decreased throughout the treatments. Biomarkers of oxidative stress––plasma protein levels of catalase, extracellular superoxide dismutase, myeloperoxidase, xanthine oxidase, malondialdehyde (MDA) levels and protein carbonyls––were reduced in accordance with wound healing. Plasma levels of growth factors––platelet-derived growth factor (PDFG), transforming growth factor β (TGF-β) and hypoxia-inducible factor 1-alpha (HIF-1α)–– were increased as a consequence of HBOT and reduced 28 days after complete wound healing, whereas matrix metallopeptidase 9 (MMP9) progressively decreased with the HBOT. In conclusion, HBOT reduced oxidative and pro-inflammatory mediators, and may participate in activating healing, angiogenesis and vascular tone regulation by increasing the release of growth factors.

Plastic pollution in the oceans is a growing problem, with negative effects on exposed species and ecosystems. Xyrichtys novacula L. is a very important fish species both culturally and economically in the Balearic Islands. The aim of the present study was to detect and categorise the presence of microplastics (MPs) in the digestive tract of X. novacula, as well as the existence of oxidative stress in the liver. For this purpose, the fish were categorised into two groups based on the number of MPs observed in the digestive tracts: a group with no or low presence of MPs (0–3 items) and a group with a higher presence of MPs (4–28 items). MPs were found in 89% of the specimens analysed, with a dominance of fibre type and blue colour. Regarding the type of polymer, polycarbonate was the most abundant, followed by polypropylene and polyethylene. For the group with a greater presence of MPs, the activities of the antioxidant enzymes glutathione peroxidase and glutathione reductase, as well as the phase II detoxification enzyme glutathione s-transferase, were higher than the activities observed in fish with little to no presence of MPs. The activities of catalase and superoxide dismutase and the levels of malondialdehyde did not show significant differences between both groups. In conclusion, these results demonstrate the presence of MPs in the digestive tract of X. novacula and the existence of an antioxidant and detoxification response, mainly based on the glutathione-based enzymes.