Screening of Microalgae for Bioactivity with Antiviral, Antibacterial, Anti-Inflammatory and Anti-Cancer Assays.

Marine microalgae are a rich reservoir of natural compounds, including bioactives. Nonetheless, these organisms remain fairly unexplored despite their potential biotechnological applications. Culture collections with diverse taxonomic groups and lifestyles are a good source to unlock this potential and discover new molecules for multiple applications such as the treatment of human pathologies or the production of aquaculture species. In the present work extracts from thirty-three strains (including twenty dinoflagellates, four diatoms and nine strains from seven other algal classes), cultivated under identical conditions, were examined for their antiviral, antibacterial, anti-inflammatory and anti-cancer activities. Among these, antiviral and anti-inflammatory activities were detected in a few strains while the antibacterial tests showed positive results in most assays. In turn, most trials did not show any anti-cancer activity. Significant differences were observed between species within the same class, in particular dinoflagellates, which were better represented in this study. These preliminary findings pave the way for an in-depth characterization of the extracts with highest signals in each test, the identification of the compounds responsible for the biological activities found and a further screening of the CCVIEO culture collection.

EDA2R reflects the acute brain response to cranial irradiation in liquid biopsies.

BACKGROUND: Cranial radiotherapy is standard of care for high-grade brain tumors and metastases; however, it induces debilitating neurocognitive impairments in cancer survivors, especially children. As the numbers of pediatric brain cancer survivors continue improving, the numbers of individuals developing life-long neurocognitive sequalae are consequently expected to rise. Yet, there are no established biomarkers estimating the degree of the irradiation-induced brain injury at completion of radiotherapy to predict the severity of the expected neurocognitive complications. We aimed to identify sensitive biomarkers associated with brain response to irradiation that can be measured in easily accessible clinical materials, such as liquid biopsies. METHODS: Juvenile mice were subjected to cranial irradiation with 0.5, 1, 2, 4 and 8 Gy. Cerebrospinal fluid (CSF), plasma and brains were collected at acute, subacute, and subchronic phases after irradiation, and processed for proteomic screens, molecular and histological analyses. RESULTS: We found that the levels of ectodysplasin A2 receptor (EDA2R), member of tumor necrosis factor receptor superfamily, increased significantly in the CSF after cranial irradiation, even at lower irradiation doses. The levels of EDA2R were increased globally in the brain acutely after irradiation and decreased over time. EDA2R was predominantly expressed by neurons, and the temporal dynamics of EDA2R in the brain was reflected in the plasma samples. CONCLUSIONS: We propose EDA2R as a promising potential biomarker reflecting irradiation-induced brain injury in liquid biopsies. The levels of EDA2R upon completion of radiotherapy may aid in predicting the severity of IR-induced neurocognitive sequalae at a very early stage after treatment.

Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review.

The purpose of this systematic review is to provide an overview of the existing knowledge on the therapeutic potential of melatonin to counteract the undesirable effects of chemotherapy in breast cancer patients. To this aim, we summarized and critically reviewed preclinical- and clinical-related evidence according to the PRISMA guidelines. Additionally, we developed an extrapolation of melatonin doses in animal studies to the human equivalent doses (HEDs) for randomized clinical trials (RCTs) with breast cancer patients. For the revision, 341 primary records were screened, which were reduced to 8 selected RCTs that met the inclusion criteria. We assembled the evidence drawn from these studies by analyzing the remaining gaps and treatment efficacy and suggested future translational research and clinical trials. Overall, the selected RCTs allow us to conclude that melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients. Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates. Accordingly, this systematic review leads us to draw attention to the need for more RCTs to provide a comprehensive view of the promising actions of melatonin in breast cancer and, given the safety profile of this molecule, adequate translational doses should be established in further RCTs.

Potential of melatonin to reverse epigenetic aberrations in oral cancer: new findings.

It is now an accepted principle that epigenetic alterations cause cellular dyshomeostasis and functional changes, both of which are essential for the initiation and completion of the tumor cycle. Oral carcinogenesis is no exception in this regard, as most of the tumors in the different subsites of the oral cavity arise from the cross-reaction between (epi)genetic inheritance and the huge challenge of environmental stressors. Currently, the biochemical machinery is put at the service of the tumor program, halting the cell cycle, triggering uncontrolled proliferation, driving angiogenesis and resistance to apoptosis, until the archetypes of the tumor phenotype are reached. Melatonin has the ability to dynamically affect the epigenetic code. It has become accepted that melatonin can reverse (epi)genetic aberrations present in oral and other cancers, suggesting the possibility of enhancing the oncostatic capacity of standard multimodal treatments by incorporating this indolamine as an adjuvant. First steps in this direction confirm the potential of melatonin as a countermeasure to mitigate the detrimental side effects of conventional first-line radiochemotherapy. This single effect could produce synergies of extraordinary clinical importance, allowing doses to be increased and treatments not to be interrupted, ultimately improving patients' quality of life and prognosis. Motivated by the urgency of improving the medical management of oral cancer, many authors advocate moving from in vitro and preclinical research, where the bulk of melatonin cancer research is concentrated, to systematic randomized clinical trials on large cohorts. Recognizing the challenge to improve the clinical management of cancer, our motivation is to encourage comprehensive and robust research to reveal the clinical potential of melatonin in oral cancer control. To improve the outcome and quality of life of patients with oral cancer, here we provide the latest evidence of the oncolytic activity that melatonin can achieve by manipulating epigenetic patterns in oronasopharyngeal tissue.

In Vitro and In Vivo Characteristics of Olive Oil as Excipient for Topical Administration.

Oily excipients are vital components of dermatological products. In this study, the in vitro and in vivo characteristics of Wild Olive Oil (WOO) were compared with two other types of olive oils: Extra Virgin Olive Oil (EVOO) and Virgin Olive Oil (VOO). This work has also included Liquid Paraffin (LP) and Rosehip Oil (RO) as reference oils. Melatonin was used in the study as a model drug to demonstrate the antioxidant capacity of the oils. The melatonin carrier capacity and antioxidant performance was related to the degree of unsaturation of the oils and was highest for RO and WOO and lowest for LP. However, the most stable oil to oxidation was LP. The in vivo performance of the oils in the skin of eight healthy volunteers was investigated with a dermoanalyser. The highest increment of oil and hydration in the skin was obtained with RO. The lowest perception of oiliness was described for WOO, which produced the highest increase in elasticity of the skin area where it was applied. An in vitro-in vivo correlation was therefore performed through multivariable analysis (MVA).

Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout.

NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel N-sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1ß release in vitro. The greatest effect was observed for compound 4b, which was similar to MCC950. Moreover, compound 4b was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1ß processing. Additional in silico predictions confirmed the safety profile of compound 4b, and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound 4b, which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.

Influence of the extraction method on the recovery of bioactive phenolic compounds from food industry by-products.

Agro-foodindustries generate colossal amounts of non-edible waste and by-products, easily accessible as raw materials for up-cycling active phytochemicals. Phenolic compounds are particularly relevant in this field given their abundance in plant residues and the market interest of their functionalities (e.g. natural antioxidant activity) as part of nutraceutical, cosmetological and biomedical formulations. In "bench-to-bedside" achievements, sample extraction is essential because valorization benefits from matrix desorption and solubilization of targeted phytocompounds. Specifically, the composition and polarity of the extractant, the optimal sample particle size and sample:solvent ratio, as well as pH, pressure and temperature are strategic for the release and stability of mobilized species. On the other hand, current green chemistry environmental rules require extraction approaches that eliminate polluting consumables and reduce energy needs. Thus, the following pages provide an update on advanced technologies for the sustainable and efficient recovery of phenolics from plant matrices.

In Silico Prediction of the Toxic Potential of Neuroprotective Bifunctional Molecules Based on Chiral N-Propargyl-1,2-amino Alcohol Derivatives.

N-Propargylamines are useful synthetic scaffolds for the synthesis of bioactive molecules, and in addition, they possess important pharmacological activities. We obtained several neuroprotective molecules, chiral 1,2-amino alcohols and 1,2-diamines, able to reduce by almost 70% the rotenone and oligomycin A-induced damage in SH-SY5Y cells. Furthermore, some molecules assessed also counteracted the toxicity evoked by the Ser/Thr phosphatase inhibitor okadaic acid. Before extrapolating these data to preclinical studies, we analyze the molecules through an in silico prediction system to detect carcinogenicity risk or other toxic effects. In light of these promising results, these molecules may be considered as a lead family of neuroprotective and relatively safe compounds.

Melatonin Reduces NLRP3 Inflammasome Activation by Increasing α7 nAChR-Mediated Autophagic Flux.

Microglia controls the immune system response in the brain. Specifically, the activation and dysregulation of the NLRP3 inflammasome is responsible for the initiation of the inflammatory process through IL-1ß and IL-18 release. In this work, we have focused on studying the effect of melatonin on the regulation of the NLRP3 inflammasome through α7 nicotinic receptor (nAChR) and its relationship with autophagy. For this purpose, we have used pharmacological and genetic approaches in lipopolysaccharide (LPS)-induced inflammation models in both in vitro and in vivo models. In the BV2 cell line, LPS inhibited autophagy, which increased NLRP3 protein levels. However, melatonin promoted an increase in the autophagic flux. Treatment of glial cultures from wild-type (WT) mice with LPS followed by extracellular adenosine triphosphate (ATP) produced the release of IL-1ß, which was reversed by melatonin pretreatment. In cultures from α7 nAChR knock-out (KO) mice, melatonin did not reduce IL-1ß release. Furthermore, melatonin decreased the expression of inflammasome components and reactive oxygen species (ROS) induced by LPS; co-incubation of melatonin with α-bungarotoxin (α-bgt) or luzindole abolished the anti-inflammatory and antioxidant effects. In vivo, melatonin reverted LPS-induced cognitive decline, reduced NLRP3 levels and promoted autophagic flux in the hippocampi of WT mice, whereas in α7 nAChR KO mice melatonin effect was not observed. These results suggest that melatonin may modulate the complex interplay between α7 nAChR and autophagy signaling.

Morphometry and meristics of two species of Ictalurus (Siluriformes: Ictaluridae), native catfishes of Sierra Madre Occidental, Mexico

Introduction: Morphotypes of native catfish of the genus Ictalurus (Siluriformes: Ictaluridae) are known to occur in allopatry in the northern Sierra Madre Occidental of Mexico, with only the Yaqui catfish (Ictalurus pricei) taxonomically described. Recent genetic analysis of these morphotypes has revealed the monophyly of the I. pricei complex, which indicates Ictalurus sp. from the Culiacán River and San Lorenzo River basins as its nearest genetic relative and recognizes as an evolutionarily significant unit the Culiacán River and San Lorenzo River morphotypes. Objective: To compare the meristic and morphometric characteristics of the catfish of the Culiacán River basin with its nearest genetic relative, the Yaqui catfish, in order to determine the presence of distinctive morphological characters that support genetic evidence previously reported for these morphotypes. Methods: Catfish specimens were collected during various field expeditions (1990-2012) to remote sites of the Sierra Madre Occidental and conducted in the Yaqui River and Culiacán River basins with the purpose of morphological comparison. Forty-five morphological characters (40 morphometric and five meristic) were examined in 76 adult specimens - 52 Ictalurus sp. and 24 Ictalurus pricei. Three groups were subject to a discriminant function analysis (DFA), including two Ictalurus sp. groups from the Humaya River and Tamazula River sub-basins, representing the Culiacán River basin, and one I. pricei group representing the Yaqui River basin. The standardized measurements and meristic data of the catfish morphotypes were compared by means of DFA. Results: The DFA revealed 12 characters to be significantly different (P< 0.01) among the groups compared. The morphological characters separating the Ictalurus sp. (Culiacán River basin) from the Yaqui catfish were associated with lower anal, pelvic and pectoral fin ray numbers, shorter head and predorsal lengths, shorter longest lateral barbel and longest dorsal ray lengths and a narrower premaxilar dentary plate; and finally longer distances in Ictalurus sp. for dorsal-fin origin to last anal-fin ray base and dorsal-fin origin to posterior end of the adipose fin base. The standardized coefficients for canonical variables 1 and 2 accounted for 85.6 % and 14.4 % of the total variation, respectively. Conclusions: The distinctive morphological characters of the Ictalurus sp. found in the Culiacán River basin, combined with the known mitochondrial evidence for this morphotype, identify it as an evolutionarily significant unit that requires description as a new species based on taxonomical protocols.

Introducción: Morfotipos de bagres nativos del género Ictalurus (Siluriformes: Ictaluridae) se distribuyen de manera alopátrica en el norte de la Sierra Madre Occidental, de los cuales solo el bagre Yaqui (Ictalurus pricei) ha sido taxonómicamente descrito. Análisis genéticos recientes de esos morfotipos han revelado la monofilia del complejo I. pricei, que incluyó a Ictalurus sp. de las cuencas de los ríos Culiacán y San Lorenzo como su pariente genético más cercano, además del reconocimiento de los morfotipos de los ríos Culiacán and San Lorenzo como una unidad evolutivamente significativa. Objetivo: Comparar características merísticas y morfométricas del bagre de la cuenca del río Culiacán con su pariente genético más cercano, el bagre Yaqui, con el propósito de determinar la presencia de caracteres morfológicos distintivos en apoyo a evidencia genética previamente reportada para esos morfotipos. Métodos: Especímenes de bagres fueron recolectados durante varias expediciones de campo (1990-2012) en sitios remotos de la Sierra Madre Occidental en las cuencas de los ríos Yaqui y Culiacán para comparación morfológica. Cuarenta y cinco caracteres morfológicos (40 morfométricos y cinco merísticos) fueron examinados en 76 especímenes adultos (52 de Ictalurus sp. y 24 de Ictalurus pricei). Medidas corporales estandarizadas y datos merísticos de los morfotipos de bagres estudiados fueron comparados por medio de un análisis de función discriminante (AFD). Resultados: El AFD arrojó 12 caracteres significativamente diferentes (P< 0.01) entre los grupos comparados. Los caracteres morfológicos que distinguen al bagre del río Culiacán del bagre Yaqui, estuvieron asociados con un menor número de radios anales, pélvicos y pectorales, así como dimensiones más pequeñas para la longitud de la cabeza, longitud predorsal, longitud de la barbilla lateral más larga, longitud del radio dorsal más largo y una menor anchura de la placa dentaria premaxilar; y finalmente, dimensiones mayores en Ictalurus sp. (cuenca del río Culiacán) para distancias como origen de aleta dorsal a la base del último radio anal y origen de aleta dorsal a conexión posterior de aleta adiposa. Los coeficientes estandarizados para las variables canónicas 1 y 2 explicaron el 85.6 y 14.4 % de la variación total, respectivamente. Conclusiones: Los caracteres morfológicos distintivos de Ictalurus sp. de la cuenca del río Culiacán, en combinación con la evidencia mitocondrial conocida para este mismo morfotipo, permite reconocerlo como una unidad evolutivamente significativa y que requiere ser descrita como una especie nueva bajo los protocolos taxonómicos.

Capillary and wet techniques. A pilot study comparing two tissue sampling methods guided by endoscopic ultrasound.

BACKGROUND: There are different techniques for obtaining tissue using a fine needle guided by endoscopic ultrasound (EUS); all aim to obtain the most appropriate material, free of defects, of good quality and in sufficient quantity. OBJECTIVE: The objective of the study was to determine which of the two EUS-guided techniques (capillary and wet) provides better quality samples for cytopathological analysis and which should be used for obtaining tissue from pancreatic, bile duct, liver, and lymph node tumors. MATERIAL AND METHODS: We conducted a pilot prospective study that included 26 patients with evidence of pancreatic tumor, liver tumor, and/or lymph node metastasis of primary tumor. All patients were subjected to two different tissue sampling techniques, the capillary technique and the wet technique, during the same procedure. Both techniques relied on EUS guidance. The samples obtained for the cytopathological analysis were evaluated in blinded manner by two different pathologists. RESULTS: Pathologist A was able to make a diagnosis using the capillary technique in 96.15% of the cases and in 88.46% of the cases using the wet technique. Pathologist B was able to make a diagnosis using the capillary technique in 96.15% of the cases and in 92.30% of the cases using the wet technique. The kappa coefficient between observers for histopathological diagnosis was 1 for capillarity and 0.948 for wet technique. CONCLUSION: The capillary technique yielded better results than the wet technique in terms of sample quality and cellularity.

ANTECEDENTES: Existen diferentes técnicas para la obtención de tejido usando la aguja fina guiada por ultrasonido endoscópico. Todas ellas pretenden obtener el tejido mas apropiado, libre de defectos, con una buena calidad y una cantidad suficiente. OBJETIVO: Determinar cuál de las dos técnicas guiadas por ultrasonido endoscópico (capilar y húmeda) proporciona mejor calidad de la muestra para análisis citopatológico y biopsia de tejido pancreático, vías biliares, hígado y tumores de nodos linfáticos. MÉTODO: Estudio piloto, prospectivo, que incluyó 26 pacientes con evidencia de tumor pancreático, hepático o metástasis de nodos linfáticos. Durante el mismo procedimiento, los pacientes fueron sometidos a las dos técnicas de obtención de muestra tisular guiadas por ultrasonido endoscópico. Las muestras para el análisis citopatológico fueron evaluadas de forma cegada por dos patólogos diferentes. RESULTADOS: El patólogo A pudo hacer el diagnóstico usando la técnica de capilaridad en el 96.15% de los casos y en el 88.46% cuando se usó la técnica húmeda; el patólogo B realizó el diagnóstico en el 96.15% y el 92.30% de los casos, respectivamente. El coeficiente kappa entre los observadores para el diagnóstico histopatológico fue de 1 para la técnica de capilaridad y de 0.948 para la técnica húmeda. CONCLUSIÓN: La técnica de capilaridad mostró mejores resultados en términos de calidad de la muestra y celularidad.

Total Laparoscopic Inferior Mesenteric Artery Ligation and Direct Sac Puncture Embolization Technique for Treatment of Type II Endoleak.

Type II endoleak relates to aneurysm perfusion through a patent branch vessel. Reintervention for type II endoleak should be considered in the presence of significant aneurysm growth. Recurrences and subsequent reinterventions are frequent by occult type II endoleaks through feeder arterial branches. We report a case of a patient with a type II endoleak due to inferior mesenteric artery (IMA) patency associated with aneurysm sac growth after an unsuccessfully attempt of transarterial embolization. Laparoscopic ligation of the IMA with direct sac puncture embolization was performed. The postoperative and 1-year follow-up computed tomography angiography scan demonstrated no endoleak signs and aneurysm sac shrinkage. The proposed modification of this technique constitutes a novel approach to this entity. Total laparoscopic IMA ligation and direct sac puncture embolization technique may increase the success rate for the treatment of endoleaks type II by excluding the recurrences. This technique may offer a safe, feasible, and minimally invasive approach for type II endoleaks when other endovascular techniques are unsuccessful.

Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics.

The wide variety of epigenetic controls available is rapidly expanding the knowledge of molecular biology even overflowing it. At the same time, it can illuminate unsuspected ways of understanding the etiology of cancer. New emerging therapeutic horizons, then, promise to overcome the current antitumor strategies need. The translational utility of this complexity is particularly welcome in oral cancer (OC), in which natural history is alarmingly disappointing due to the invasive and mutilating surgery, the high relapsing rate, the poor quality of life and the reduced survival after diagnosis. Melatonin activates protective receptor-dependent and receptor-independent processes that prevent tissue cancerisation and inhibit progressive tumor malignancy and metastasis. Related evidence has shown that melatonin pleiotropy encompasses gene expression regulation through all the three best-characterized epigenetic mechanisms: DNA methylation, chromatin modification, and non-coding RNA. OC has received less attention than other cancers despite prognosis is usually negative and there are no significant therapy improvements recorded in the past decade. However, a large research effort is being carried out to elucidate how melatonin´s machinery can prevent epigenetic insults that lead to cancer. In the light of recent findings, a comprehensive examination of biochemistry through which melatonin may reverse epigenetic aberrations in OC is an extraordinary opportunity to take a step forward in the clinical management of patients.

Laparoscopic treatment of median arcuate ligament syndrome: a systematic review.

INTRODUCTION: Median arcuate ligament syndrome (MALS) is an uncommon condition caused by the extrinsic compression of the celiac trunk (CT) and celiac ganglion, secondary to an anatomical abnormality of the median arcuate ligament fibers. It is characterized by postprandial epigastric pain, chronic abdominal pain, weight loss, nausea and vomiting. MALS is typically diagnosed after the exclusion of other, more common conditions; however, a variety of imaging and diagnostic modalities, including Duplex ultrasonography, computed tomography angiography, magnetic resonance angiography, gastric tonometry and angiography can suggest findings consistent with MALS. EVIDENCE ACQUISITION: Laparoscopic approach has been proposed as the option of choice for the treatment of these patients. A systematic review of the international literature regarding this modality of treatment is presented here. EVIDENCE SYNTHESIS: The review included 504 cases, and several principles are suggested to improve the management. The advantages of this minimally invasive technique include short operative time (136.0 minutes, range 70-242), shorter hospital stay (3.8 days, range 0.5-7) and low rate of conversion to open surgery (4.2%). CONCLUSIONS: Various treatment modalities are available to decompress the celiac trunk. Although open surgery has been traditionally accepted as the gold standard, laparoscopic division of the MALS has proven equal results. Others have described different treatment modalities, including bypass surgery and endovascular procedures (angioplasty or stent placement). Laparoscopic approaches to correct MALS are feasible and safe. It may be the preferred modality of treatment in view of its lack of morbidity, shorter hospital stay and good results.