Moderate-intensity constant or high-intensity interval training? Metabolic effects on candidates to undergo bariatric surgery.

BACKGROUND & AIMS: Bariatric surgery is highly effective against obesity. Pre-surgical exercise programs are recommended to prepare the candidate physically and metabolically for surgery-related rapid weight loss. However, the ideal exercise prescription in this population is unknown. This study aimed to compare the metabolic effects of moderate-intensity constant (MICT) vs. a high-intensity interval training (HIIT) program in candidates to undergo bariatric surgery. METHODS AND RESULTS: Twenty-five candidates (22 women) to undergo sleeve gastrectomy aged from 18 to 60 years old were recruited. At baseline, we measured body composition, physical activity levels, grip strength, and aerobic capacity. Further, we assessed metabolic function through glycemia and insulinemia (both fasting and after oral glucose tolerance test (OGTT)), homeostatic model assessment for insulin resistance (HOMA-IR), lipid profile, glycated haemoglobin (HbA1c), transaminases, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), apelin, and adiponectin. Afterward, participants were randomized into MICT (n = 14) or HIIT (n = 11). Both training programs consisted of 10 sessions (2-3 times/week, 30 min per session) distributed during 4 weeks before the surgery. After this, all outcomes were measured again at the end of the training programs and 1 month after the surgery (follow-up). A mixed effect with Tukey's post-hoc analysis was performed to compare values at baseline vs. post-training vs. postsurgical follow-up. Both training programs increased aerobic capacity after training (p < 0.05), but only after MICT these changes were kept at follow-up (p < 0.05). However, only MICT decreased fat mass and increased total muscle mass and physical activity levels (p < 0.05). Metabolically, MICT decreased insulinemia after OGTT (p < 0.05), whereas HIIT increased adiponectin after training and GDF15 at follow-up (both p < 0.05). CONCLUSIONS: Both MICT and HIIT conferred benefits in candidates to undergo bariatric surgery, however, several of those effects were program-specific, suggesting that exercise intensity should be considered when preparing these patients. Future studies should explore the potential benefits of prescribing MICT or HIIT in a customized fashion depending on a pretraining screening, along with possible summatory effects by combining these two exercise programs (MICT + HIIT). CLINICAL TRIAL REGISTRATION: International Traditional Medicine Clinical Trial Registry, N° ISRCTN42273422.

From gestational chronodisruption to noncommunicable diseases: Pathophysiological mechanisms of programming of adult diseases, and the potential therapeutic role of melatonin.

During gestation, the developing fetus relies on precise maternal circadian signals for optimal growth and preparation for extrauterine life. These signals regulate the daily delivery of oxygen, nutrients, hormones, and other biophysical factors while synchronizing fetal rhythms with the external photoperiod. However, modern lifestyle factors such as light pollution and shift work can induce gestational chronodisruption, leading to the desynchronization of maternal and fetal circadian rhythms. Such disruptions have been associated with adverse effects on cardiovascular, neurodevelopmental, metabolic, and endocrine functions in the fetus, increasing the susceptibility to noncommunicable diseases (NCDs) in adult life. This aligns with the Developmental Origins of Health and Disease theory, suggesting that early-life exposures can significantly influence health outcomes later in life. The consequences of gestational chronodisruption also extend into adulthood. Environmental factors like diet and stress can exacerbate the adverse effects of these disruptions, underscoring the importance of maintaining a healthy circadian rhythm across the lifespan to prevent NCDs and mitigate the impact of gestational chronodisruption on aging. Research efforts are currently aimed at identifying potential interventions to prevent or mitigate the effects of gestational chronodisruption. Melatonin supplementation during pregnancy emerges as a promising intervention, although further investigation is required to fully understand the precise mechanisms involved and to develop effective strategies for promoting health and preventing NCDs in individuals affected by gestational chronodisruption.

Minireview: functional roles of tissue kallikrein, kinins, and kallikrein-related peptidases in lung cancer.

Despite campaigns and improvements in detection and treatment, lung cancer continues to increase worldwide and represents a major public health problem. One approach to treating patients suffering from lung cancer is to target surface receptors overexpressed on tumor cells, such as GPCR-family kinin receptors, and proteases that control tumor progression, such as kallikrein-related peptidases (KLKs). These proteases have been visualized in recent years due to their contribution to the progression of cancers, such as prostate and ovarian cancer, facilitating the invasive and metastatic capacity of tumor cells in these tissues. In fact, KLK3 is the specific prostate antigen, the only tissue-specific biomarker used to diagnose this malignancy. In lung cancer to date, evidence indicates that KLK5, KLK6, KLK8, KLK11, and KLK14 are the major peptidases regulated and involved in its progression. The expression levels of KLKs in this neoplasm are modulated by the secretome of the different cell types present in the tumor microenvironment, the cancer subtype and the tumor stage, among others. Considering the multiple functions of kinin receptors and KLKs, this review highlights their roles, even considering the SARS-CoV-2 effects. Since lung cancer is often diagnosed in advanced stages, our efforts should focus on early diagnosis, validating for example specific KLKs, especially in high-risk populations such as smokers and people exposed to carcinogenic fumes, oil fields, and contaminated workplaces, unexplored fields to investigate. Furthermore, their modulation could be considered as a promising approach in lung cancer therapeutics.

Alpha-SNAP (M105I) mutation promotes neuronal differentiation of neural stem/progenitor cells through overactivation of AMPK.

Background: The M105I point mutation in α-SNAP (Soluble N-ethylmaleimide-sensitive factor attachment protein-alpha) leads in mice to a complex phenotype known as hyh (hydrocephalus with hop gait), characterized by cortical malformation and hydrocephalus, among other neuropathological features. Studies performed by our laboratory and others support that the hyh phenotype is triggered by a primary alteration in embryonic neural stem/progenitor cells (NSPCs) that leads to a disruption of the ventricular and subventricular zones (VZ/SVZ) during the neurogenic period. Besides the canonical role of α-SNAP in SNARE-mediated intracellular membrane fusion dynamics, it also negatively modulates AMP-activated protein kinase (AMPK) activity. AMPK is a conserved metabolic sensor associated with the proliferation/differentiation balance in NSPCs. Methods: Brain samples from hyh mutant mice (hydrocephalus with hop gait) (B6C3Fe-a/a-Napahyh/J) were analyzed by light microscopy, immunofluorescence, and Western blot at different developmental stages. In addition, NSPCs derived from WT and hyh mutant mice were cultured as neurospheres for in vitro characterization and pharmacological assays. BrdU labeling was used to assess proliferative activity in situ and in vitro. Pharmacological modulation of AMPK was performed using Compound C (AMPK inhibitor) and AICAR (AMPK activator). Results: α-SNAP was preferentially expressed in the brain, showing variations in the levels of α-SNAP protein in different brain regions and developmental stages. NSPCs from hyh mice (hyh-NSPCs) displayed reduced levels of α-SNAP and increased levels of phosphorylated AMPKα (pAMPKαThr172), which were associated with a reduction in their proliferative activity and a preferential commitment with the neuronal lineage. Interestingly, pharmacological inhibition of AMPK in hyh-NSPCs increased proliferative activity and completely abolished the increased generation of neurons. Conversely, AICAR-mediated activation of AMPK in WT-NSPCs reduced proliferation and boosted neuronal differentiation. Discussion: Our findings support that α-SNAP regulates AMPK signaling in NSPCs, further modulating their neurogenic capacity. The naturally occurring M105I mutation of α-SNAP provokes an AMPK overactivation in NSPCs, thus connecting the α-SNAP/AMPK axis with the etiopathogenesis and neuropathology of the hyh phenotype.

Diferencia en la expresión del ligando de receptor activador para el factor nuclear K B, en tejido tumoral frente a la infección por diferentes patógenos periodontales / Difference in receptor activator of nuclear factor K B expression in tumoral tissue by different periodontal pathogens

La enfermedad periodontal es una de las principales causas de pérdida dentaria. Clínicamente, esta patología, mediada por la desregulación del sistema inmune producto de una disbiosis ocurrida en el surco gingival, inicia con la inflamación de la encía y evoluciona con el daño irreversible de los tejidos que rodean el diente. El hueso alveolar es uno de los tejidos afectados esta patología, esto debido a la activación de osteoclastos por la sobreexpresión de la proteína RANKL en el huésped. El propósito de este trabajo es determinar el nivel de sobreexpresión de RANKL, en un modelo de células tumorales U2OS, frente a la infección con Porphyromonas gingivalis y Prevotella intermedia. Para identificar el nivel de RANKL, se definieron cuatro grupos: Un grupo control, no tratado; Grupo PG, tratado con P. gingivalis; Grupo PI, tratado con P. Intermedia; y un grupo PG+PI, tratado con ambas bacterias. El nivel relativo de la proteína RANKL fue determinado en el sobrenadante y en los extractos celulares de manera independiente, mediante la técnica Western blot. En sobrenadantes, el grupo PG mostró mayores niveles de RANKL comparados con PI (p < 0,05). En extractos celulares los niveles fueron mayores en el grupo PG+PI (p < 0,05). El grupo PI mostró los niveles más bajos de RANKL. La infección polimicrobiana resulta en una mayor expresión de RANKL en células tumorales U2OS, mientras que frente a la infección P. gingivalis, se observó mayor cantidad de RANKL soluble.

SUMMARY: Periodontal disease is one of the main causes of tooth loss. Clinically, this pathology, mediated by the deregulation of the immune system due to a dysbiosis occurred in the gingival sulcus, begins with the inflammation of the gum and evolves with the irreversible damage of the tissues that surround the tooth. Alveolar bone is one of the most affected tissues by this disease, due to the activation of osteoclasts by the upregulation of RANKL in the host. The aim of this study is to determine the increase of RANKL, in a U2OS tumor cells model, inoculated with Porphyromonas gingivalis and Prevotella intermedia. To identify the level of RANKL, four groups were defined: A control group, not treated; PG group, treated with P.gingivalis; PI group, treated with P. intermedia; and a PG+PI group, treated with both bacteria. The relative level of RANKL was determined in the supernatant and cell extracts independently, using the Western blot technique. In supernatants, the PG group showed higher RANKL levels compared to PI (p < 0.05). In cell extracts the levels were higher in the PG+PI group (p < 0.05.). The PI group showed the lowest levels of RANKL.Polymicrobial infection results in a greater expression of of soluble RANKL was observed.

Expression and distribution of kallikrein-related peptidases 5, 7, 8 and 10 in normal apocrine gland of canine skin / Expresión y distribución de péptidos relacionados con la calicreína 5, 7, 8 y 10 en glándula apocrina normal de piel canina

SUMMARY: Apocrine glands are sweat glands that are located in the skin of the dog. Anal sac apocrine, circunanal apocrine, and mammary glands are considered modified apocrine structures, and there are about nine possible types of neoplasms and other tumors in the apocrine glands of the dog and cat, including cysts, adenoma, carcinoma, and adenocarcinoma. Thus, it is important to provide new markers to characterize these glands to improve the histopathological diagnosis. In this article, we describe the distribution of kallikrein- related peptidases 5, 7, 8, and 10 in the normal apocrine glands of the dog's skin. These proteases have been shown to play a fundamental role in the homeostasis of the human skin barrier but have been scarcely studied in canine skin.

Las glándulas apocrinas son glándulas sudoríparas que se encuentran en la piel del perro. Las glándulas apocrinas del saco anal, apocrinas circunanales y mamarias se consideran estructuras apocrinas modificadas, y existen alrededor de nueve tipos posibles de neoplasias y otros tumores en las glándulas apocrinas del perro y el gato, incluidos quistes, adenoma, carcinoma y adenocarcinoma. Por lo tanto, es importante proporcionar nuevos marcadores para caracterizar estas glándulas para mejorar el diagnóstico histopatológico. En este artículo, describimos la distribución de las peptidasas 5, 7, 8 y 10 relacionadas con la calicreína en las glándulas apocrinas normales de la piel del perro. Se ha demostrado que estas proteasas desempeñan un papel fundamental en la homeostasis de la barrera de la piel humana, pero apenas se han estudiado en la piel canina.

Constant-moderate versus high-intensity interval training on heart adiponectin levels in high-fat fed mice: a preventive and treatment approach.

CONTEXT: Research has described that adiponectin plays a key role in cardiomyocytes metabolism, however, the effects of exercise during obesity on cardiac adiponectin levels is unclear. OBJECTIVE: To investigate the effects of constant-moderate endurance (END) and high-intensity interval training (HIIT), on heart adiponectin levels in mice. MATERIAL AND METHODS: Two experiments were conducted: (1) preventive (EX1): 10 week-old male mice were fed standard (CHOW) or high-fat diet (HFD;45% fat) and simultaneously trained with END and HIIT for 10 weeks; (2) Treatment (EX2): after 10 weeks of dietary intervention, another cohort of 10 week-old mice were trained by both programmes for 10 weeks. RESULTS: In EX1, END and HIIT decreased low-molecular weight adiponectin (∼0.5-fold; p < 0.05) and increased GLUT4 levels (∼2-fold; p < .05). In EX2, HFD significantly decreased high-molecular weight adiponectin (∼0.7-fold; p < .05), and END reversed this change.Discussion and conclusion: HFD and exercise influence heart adiponectin isoforms and therefore might impact cardiomyocyte metabolism.

Maternal melatonin treatment rescues endocrine, inflammatory, and transcriptional deregulation in the adult rat female offspring from gestational chronodisruption.

Introduction: Gestational chronodisruption impact maternal circadian rhythms, inhibiting the nocturnal increase of melatonin, a critical hormone that contributes to maternal changes adaptation, entrains circadian rhythms, and prepares the fetus for birth and successful health in adulthood. In rats, we know that gestational chronodisruption by maternal chronic photoperiod shifting (CPS) impaired maternal melatonin levels and resulted in long-term metabolic and cardiovascular effects in adult male offspring. Here, we investigated the consequences of CPS on mother and adult female offspring and explored the effects of melatonin maternal supplementation. Also, we tested whether maternal melatonin administration during gestational chronodisruption rescues maternal circadian rhythms, pregnancy outcomes, and transcriptional functions in adult female offspring. Methods: Female rats raised and maintained in photoperiod 12:12 light: dark were mated and separated into three groups: (a) Control photoperiod 12:12 (LD); (b) CPS photoperiod; and (c) CPS+Mel mothers supplemented with melatonin in the drinking water throughout gestation. In the mother, we evaluated maternal circadian rhythms by telemetry and pregnancy outcomes, in the long-term, we study adult female offspring by evaluating endocrine and inflammatory markers and the mRNA expression of functional genes involved in adrenal, cardiac, and renal function. Results: In the mothers, CPS disrupted circadian rhythms of locomotor activity, body temperature, and heart rate and increased gestational length by almost 12-h and birth weight by 12%, all of which were rescued by maternal melatonin administration. In the female offspring, we found blunted day/night differences in circulating levels of melatonin and corticosterone, abnormal patterns of pro-inflammatory cytokines Interleukin-1a (IL1a), Interleukin-6 (IL6), and Interleukin-10 (IL10); and differential expression in 18 out of 24 adrenal, cardiac, and renal mRNAs evaluated. Conclusion: Maternal melatonin contributed to maintaining the maternal circadian rhythms in mothers exposed to CPS, and the re-establishing the expression of 60% of the altered mRNAs to control levels in the female offspring. Although we did not analyze the effects on kidney, adrenal, and heart physiology, our results reinforce the idea that altered maternal circadian rhythms, resulting from exposure to light at night, should be a mechanism involved in the programming of Non-Communicable Diseases.

Recursos educativos digitales como herramientas de apoyo para la enseñanza de patología general en cursos de pregrado del área de la salud / Digital educational resources as support tools for teaching general pathology in undergraduate health courses

Los recursos educativos digitales se han transformado en un importante material de apoyo al proceso de enseñanza- aprendizaje, especialmente durante la pandemia por COVID-19. Estos corresponden a recursos de autoaprendizaje, generalmente en línea y de dominio público cuya disponibilidad inmediata a todo tipo de dispositivos electrónicos permite una rápida interacción del estudiante con materiales didácticos programados. El objetivo de este estudio fue evaluar el grado de satisfacción de cinco recursos educativos digitales, desarrollados como herramientas de apoyo para la enseñanza de la patología general, en estudiantes de carreras de pregrado del área de la salud de la Universidad Austral de Chile. Estudio descriptivo y exploratorio. Se desarrollaron cinco recursos educativos digitales donde se visualizan imágenes microscópicas correspondientes a procesos patológicos ocurridos en diferentes tejidos. Estos recursos fueron alojados en repositorios de la universidad y se encuentran actualmente disponibles en el canal de YouTube. Para conocer el grado de satisfacción, en sus aspectos pedagógicos y técnicos, se realizó una encuesta digital, anónima y voluntaria a estudiantes que cursaron asignaturas de patología, la que contempló cuatro dominios con sus respectivas preguntas: forma; control de usuario; contenido educativo y valoración global. El 94 % de los estudiantes calificaron el recurso de excelente o muy bueno y todos los dominios obtuvieron sobre el 80 % de satisfacción. Los contenidos representan lo que el recurso dice ofrecer, ayuda a resolver dudas y facilita la comprensión de la materia. El tamaño y color del texto es el adecuado y las imágenes presentan una excelente calidad y resolución. Los recursos cumplen con una alta calidad técnica y pedagógica, que asegura un gran potencial de uso para la enseñanza de la patología general, guiar el trabajo autónomo del estudiante y las actividades prácticas con el microscopio.

SUMMARY: Digital educational resources have become an important material to support the teaching-learning process, especially during the COVID-19 pandemic. These correspond to self-learning resources, generally online and the public domain, whose immediate availability to all types of electronic devices allows for rapid learner interaction with programmed didactic materials. The public domain and its immediate availability to all types of electronic devices allows a quick interaction of the student with self-explanatory didactic materials. The objective of this study was to evaluate the degree of satisfaction of five digital educational resources, developed as support tools for the teaching of general pathology, in undergraduate students of the health area of the Universidad Austral de Chile. Descriptive and exploratory study. Five digital educational resources have been developed where microscopic images corresponding to pathological processes occurring in different tissues are visualized these resources were hosted in university repositories and uploaded to the YouTube channel. To determine the degree of satisfaction, in their pedagogical and technical aspects, an anonymous and voluntary digital survey was carried out among students taking pathology courses, which included four domains with their respective questions: form; user control; educational content and overall assessment. The 94 % of the students evaluated the resource as excellent or very good and all domains obtained over 80 % satisfaction. The contents represent what the resource says it offers, helps to resolve doubts and facilitates the understanding of the subject. The size and color of the text is adequate, and the images present excellent quality and resolution. The resources developed offer a high technical and pedagogical quality, which guarantees a great potential for use in the teaching of general pathology, guiding the student's autonomous work and practical activities with the microscope.

Effects of exercise on irisin in subjects with overweight or obesity. A systematic review of clinical studies.

Introduction: Irisin is an adipomyokine involved in white adipose tissue browning, therefore, could be a key protein in metabolic health. However, exercise effects on irisin in subjects with overweight and/or obesity are conflicting. Therefore, this systematic review aims to search and analyse the literature available on this topic. From three databases: PubMed, ScienceDirect, and Medline, clinical studies published between 2010 and 2021 were considered. From 134 found, 14 studies were included. Only six reported plasma increases after exercise (~1.2 to 3-fold from pre-exercise levels). In addition, only 1 reported significant increases in skeletal muscle irisin mRNA levels (~2-fold). Also, irisin was measured from subcutaneous adipose tissue and saliva, where a ~2-fold increase in its protein levels was found in the latter. Exercise seems to increase the circulatory concentrations of irisin in subjects with overweight or obesity. However, this response is highly variable, therefore, a more integrative approach is urgently needed.

Introducción: La irisina es una adipomioquina relacionada a la transformación del tejido adiposo blanco a marrón, por tanto, podría ser una proteína clave para la salud metabólica. Sin embargo, los efectos del ejercicio sobre la irisina en personas con sobrepeso u obesidad son poco claros. Por lo anterior, esta revisión sistemática apunta a buscar y analizar la literatura disponible en este tema. Desde tres bases de datos: PubMed, ScienceDirect y Medline se buscaron estudios clínicos publicados entre el 2010 y 2021. De 134 estudios encontrados, 14 fueron incluidos. Solo 6 reportaron incrementos plasmáticos de irisina después del ejercicio (~1.2 a 3-veces respecto a niveles preejercicio). Además, solo 1 estudio describió incrementos significativos en el ARNm de irisina en el músculo esquelético (~2 veces sobre niveles preejercicio). La irisina también se medió desde tejido adiposo subcutáneo y saliva, encontrándose una elevación de (~2 veces sobre niveles preejercicio) en esta última. El ejercicio físico incrementaría las concentraciones circulatorias de irisina en personas con sobrepeso u obesidad. Sin embargo, esta respuesta es muy variable, por lo que se requiere una mirada más integrativa a la hora de estudiar este fenómeno.

Effects of exercise on irisin in subjects with overweight or obesity. A systematic review of clinical studies / Efectos del ejercicio sobre la irisina en personas con sobrepeso u obesidad. Una revisión sistemática de estudios clínicos

Irisin is an adipomyokine involved in white adipose tissue browning, therefore, could be a key protein in metabolic health. However, exercise effects on irisin in subjects with overweight and/or obesity are conflicting. Therefore, this systematic review aims to search and analyse the literature available on this topic. From three databases: PubMed, ScienceDirect, and Medline, clinical studies published between 2010 and 2021 were considered. From 134 found, 14 studies were included. Only six reported plasma increases after exercise (~1.2 to 3-fold from pre-exercise levels). In addition, only 1 reported significant increases in skeletal muscle irisin mRNA levels (~2-fold). Also, irisin was measured from subcutaneous adipose tissue and saliva, where a ~2-fold increase in its protein levels was found in the latter. Exercise seems to increase the circulatory concentrations of irisin in subjects with overweight or obesity. However, this response is highly variable, therefore, a more integrative approach is urgently needed. (AU)

La irisina es una adipomioquina relacionada a la transformación del tejido adiposo blanco a marrón, por tanto, podría ser una proteína clave para la salud metabólica. Sin embargo, los efectos del ejercicio sobre la irisina en personas con sobrepeso u obesidad son poco claros. Por lo anterior, esta revisión sistemática apunta a buscar y analizar la literatura disponible en este tema. Desde tres bases de datos: PubMed, ScienceDirect y Medline se buscaron estudios clínicos publicados entre el 2010 y 2021. De 134 estudios encontrados, 14 fueron incluidos. Solo 6 reportaron incrementos plasmáticos de irisina después del ejercicio (~1.2 a 3-veces respecto a niveles preejercicio). Además, solo 1 estudio describió incrementos significativos en el ARNm de irisina en el músculo esquelético (~2 veces sobre niveles preejercicio). La irisina también se medió desde tejido adiposo subcutáneo y saliva, encontrándose una elevación de (~2 veces sobre niveles preejercicio) en esta última. El ejercicio físico incrementaría las concentraciones circulatorias de irisina en personas con sobrepeso u obesidad. Sin embargo, esta respuesta es muy variable, por lo que se requiere una mirada más integrativa a la hora de estudiar este fenómeno. (AU)

The family of kallikrein-related peptidases and kinin peptides as modulators of epidermal homeostasis.

The epidermis is the outermost skin layer and is part of one of the largest organs in the body; it is supported by the dermis, a network of fibrils, blood vessels, pilosebaceous units, sweat glands, nerves, and cells. The skin as a whole is a protective shield against numerous noxious agents, including microorganisms and chemical and physical factors. These functions rely on the activity of multiple growth factors, peptide hormones, proteases, and specific signaling pathways that are triggered by the activation of distinct types of receptors sited in the cell membranes of the various cell types present in the skin. The human kallikrein family comprises a large group of 15 serine proteases synthesized and secreted by different types of epithelial cells throughout the body, including the skin. At this site, they initiate a proteolytic cascade that generates the active forms of the proteases, some of which regulate skin desquamation, activation of cytokines, and antimicrobial peptides. Kinin peptides are formed by the action of plasma and tissue kallikreins on kininogens, two plasma proteins produced in the liver and other organs. Although kinins are well known for their proinflammatory abilities, in the skin they are also considered important modulators of keratinocyte differentiation. In this review, we summarize the contributions of the kallikreins and kallikrein-related peptidases family and those of kinins and their receptors in skin homeostasis, with special emphasis on their pathophysiological role.

Effects of aerobic exercise on fibroblast growth factor 21 in overweight and obesity. A systematic review.

Fibroblast growth factor 21 (FGF21) has been suggested to improve metabolism during aerobic exercise in obesity. However, the variability of exercise interventions gives rise to discrepancies in the field. Therefore, we aimed to systematically review the available literature regarding the effects of aerobic exercise on FGF21 in the context of overweight and obesity. Our search included original articles published between 2009 and November 2021 found in PubMed, Science Direct, and Medline. Clinical and preclinical studies were included. Studies, where subjects or animals presented with other conditions (e.g., cancer, stroke), were excluded. From an initial 43 studies, 19 (clinical studies = 9; preclinical studies = 10) were eligible for inclusion in this review. The main findings were that acute exercise tended to increase circulatory levels of FGF21. In contrast, chronic exercise programs (≥4 weeks) had the opposite effect along with inducing mRNA and protein increases of FGF receptors and ß-klotho in adipose tissue, liver, and skeletal muscle. In conclusion, both clinical and preclinical studies showed that aerobic exercise exerts changes in circulatory and tissue FGF21, along with its receptors and co-receptor. Future research is needed to elucidate the mechanisms, along with the physiological and clinical implications of these changes.

Tamoxifen triggers the in vitro release of neutrophil extracellular traps in healthy horses.

Neutrophils display an array of biological functions including the formation of neutrophil extracellular traps (NETs), web-like structures specialized in trapping, neutralizing, killing and preventing microbial dissemination within the host. However, NETs contribute to a number of inflammatory pathologies, including severe equine asthma. Tamoxifen (TX) is a selective estrogen receptor modulator which belongs to the triphenylethyllenes group of molecules, and which is used as a treatment in all stages of estrogen-positive human breast cancer. Our previous results suggest that tamoxifen can modulate neutrophil functionality and promote resolution of inflammation; this would partly explain the clinical beneficial effect of this drug in horses with airway inflammation. Enhanced NETs production has been reported with tamoxifen use in humans, but minimal data exists regarding the drug's effect on NETs in horses. The aim of this study is to assess the in vitro effect of TX on NETs formation from peripheral blood of healthy horses. Five clinically healthy mixed-breed adult horses were enrolled in the study. For this, cellular free DNA quantification, immunofluorescence for the visualization of NETs, assessment of different types of NETs, and detection of mitochondrial superoxide. TX induced NETs formation at a concentration of 10 uM. Our results show that only two types of NETs were induced by TX: 95% spread NETs (sprNETs) and 5% aggregated NETs (aggNETs). Furthermore, induction of these NETs could be influenced by mitochondrial ROS. Future research should involve an In vivo study of horses with severe asthma and TX treatment, to evaluate BALF neutrophil NET formation. In conclusion, this in vitro study suggests that the resolution of inflammation by TX in horses with airway inflammation is due to inhibition of other neutrophilic functions but not to NET formation.

Combining Materials Obtained by 3D-Printing and Electrospinning from Commercial Polylactide Filament to Produce Biocompatible Composites.

The design of scaffolds to reach similar three-dimensional structures mimicking the natural and fibrous environment of some cells is a challenge for tissue engineering, and 3D-printing and electrospinning highlights from other techniques in the production of scaffolds. The former is a well-known additive manufacturing technique devoted to the production of custom-made structures with mechanical properties similar to tissues and bones found in the human body, but lacks the resolution to produce small and interconnected structures. The latter is a well-studied technique to produce materials possessing a fibrillar structure, having the advantage of producing materials with tuned composition compared with a 3D-print. Taking the advantage that commercial 3D-printers work with polylactide (PLA) based filaments, a biocompatible and biodegradable polymer, in this work we produce PLA-based composites by blending materials obtained by 3D-printing and electrospinning. Porous PLA fibers have been obtained by the electrospinning of recovered PLA from 3D-printer filaments, tuning the mechanical properties by blending PLA with small amounts of polyethylene glycol and hydroxyapatite. A composite has been obtained by blending two layers of 3D-printed pieces with a central mat of PLA fibers. The composite presented a reduced storage modulus as compared with a single 3D-print piece and possessing similar mechanical properties to bone tissues. Furthermore, the biocompatibility of the composites is assessed by a simulated body fluid assay and by culturing composites with 3T3 fibroblasts. We observed that all these composites induce the growing and attaching of fibroblast over the surface of a 3D-printed layer and in the fibrous layer, showing the potential of commercial 3D-printers and filaments to produce scaffolds to be used in bone tissue engineering.

TNF-α-activated eNOS signaling increases leukocyte adhesion through the S-nitrosylation pathway.

Nitric oxide (NO) is a key factor in inflammation. Endothelial nitric oxide synthase (eNOS), whose activity increases after stimulation with proinflammatory cytokines, produces NO in endothelium. NO activates two pathways: 1) soluble guanylate cyclase-protein kinase G and 2) S-nitrosylation (NO-induced modification of free-thiol cysteines in proteins). S-nitrosylation affects phosphorylation, localization, and protein interactions. NO is classically described as a negative regulator of leukocyte adhesion to endothelial cells. However, agonists activating NO production induce a fast leukocyte adhesion, which suggests that NO might positively regulate leukocyte adhesion. We tested the hypothesis that eNOS-induced NO promotes leukocyte adhesion through the S-nitrosylation pathway. We stimulated leukocyte adhesion to endothelium in vitro and in vivo using tumor necrosis factor-α (TNF-α) as proinflammatory agonist. ICAM-1 changes were evaluated by immunofluorescence, subcellular fractionation, immunoprecipitation, and fluorescence recovery after photobleaching (FRAP). Protein kinase Cζ (PKCζ) activity and S-nitrosylation were evaluated by Western blot analysis and biotin switch method, respectively. TNF-α, at short times of stimulation, activated the eNOS S-nitrosylation pathway and caused leukocyte adhesion to endothelial cells in vivo and in vitro. TNF-α-induced NO led to changes in ICAM-1 at the cell surface, which are characteristic of clustering. TNF-α-induced NO also produced S-nitrosylation and phosphorylation of PKCζ, association of PKCζ with ICAM-1, and ICAM-1 phosphorylation. The inhibition of PKCζ blocked leukocyte adhesion induced by TNF-α. Mass spectrometry analysis of purified PKCζ identified cysteine 503 as the only S-nitrosylated residue in the kinase domain of the protein. Our results reveal a new eNOS S-nitrosylation-dependent mechanism that induces leukocyte adhesion and suggests that S-nitrosylation of PKCζ may be an important regulatory step in early leukocyte adhesion in inflammation.NEW & NOTEWORTHY Contrary to the well-established inhibitory role of NO in leukocyte adhesion, we demonstrate a positive role of nitric oxide in this process. We demonstrate that NO induced by eNOS after TNF-α treatment induces early leukocyte adhesion activating the S-nitrosylation pathway. Our data suggest that PKCζ S-nitrosylation may be a key step in this process.

Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody.

Despite unprecedented global efforts to rapidly develop SARS-CoV-2 treatments, in order to reduce the burden placed on health systems, the situation remains critical. Effective diagnosis, treatment, and prophylactic measures are urgently required to meet global demand: recombinant antibodies fulfill these requirements and have marked clinical potential. Here, we describe the fast-tracked development of an alpaca Nanobody specific for the receptor-binding-domain (RBD) of the SARS-CoV-2 Spike protein with potential therapeutic applicability. We present a rapid method for nanobody isolation that includes an optimized immunization regimen coupled with VHH library E. coli surface display, which allows single-step selection of Nanobodies using a simple density gradient centrifugation of the bacterial library. The selected single and monomeric Nanobody, W25, binds to the SARS-CoV-2 S RBD with sub-nanomolar affinity and efficiently competes with ACE-2 receptor binding. Furthermore, W25 potently neutralizes SARS-CoV-2 wild type and the D614G variant with IC50 values in the nanomolar range, demonstrating its potential as antiviral agent.

[Relationship between fibroblast growth factor-21, muscle mass, and function outcomes in overweight and obese older adults living in the community. An exploratory study]. / Relación del factor de crecimiento de fibroblastos 21 con indicadores de masa y función muscular en personas mayores con sobrepeso u obesidad. Estudio exploratorio.

BACKGROUND: Age-related decreases in muscle mass and function are associated with the development of metabolic impairments, particularly in the context of obesity. Fibroblast growth factor21 (FGF-21) has been suggested as a common mediator of both processes. No known studies have examined the association between FGF-21 and muscle mass and function in overweight or obese older adults. With this in mind, this study aimed to investigate the association between plasma levels of FGF-21 and muscle mass and function outcomes in overweight or obese older adults. MATERIALS AND METHODS: Exploratory study, which included 39 adults of 60-70years old with body mass indexes >25kg/m2. As study outcomes, measurements were made of appendicular muscle mass (AMM), grip strength, 5 times sit-to-stand test (5xSTT), as well as plasma levels of FGF-21, fasting glucose, and insulin. The homeostatic model assessment index (HOMA-IR) was also calculated to determine the presence of insulin resistance. RESULTS: Significant relationships were found between plasma levels of FGF-21 vs 5xSTT (rho=0.49; P<.05). Moreover, FGF-21 levels were significantly higher in those with insulin resistance (P<.05), as well as with having lower levels of AMM (P<.05). CONCLUSION: There is a relationship between the plasma levels of FGF-21 and muscle function outcomes in overweight or obese older adults. Future studies should investigate the potential causalities between these relationships.

Antibacterial and cytotoxic evaluation of copper and zinc oxide nanoparticles as a potential disinfectant material of connections in implant provisional abutments: An in-vitro study.

OBJECTIVE: This study evaluates the antibacterial activity against mono and multispecies bacterial models and the cytotoxic effects of zinc oxide and copper nanoparticles(ZnO-NPs/Cu-NPs) in cell cultures of human gingival fibroblasts(HGFs). DESIGN: The antibacterial activities of ZnO-NPs and Cu-NPs against 4 bacteria species were tested according to their minimum inhibitory concentrations(MICs) and against mature multispecies anaerobic model by spectral confocal laser scanning microscopy. The viabilities and cytotoxic effects of ZnO-NPs and Cu-NPs to HGFs cell cultures were tested by MTT, LDH assays, production of ROS, and the activation of caspase-3. The results were analyzed using one-way ANOVA followed by Tukey tests, considering p < 0.05 as statistically significant. RESULTS: For all strains, MICs of ZnO-NPs and Cu-NPs were in the range of 78.3 µg/mL-3906 µg/mL and 125 µg/mL-625 ug/mL, respectively. In a multispecies model, a significant decrease in the total biomass volume(µ3) was observed in response to exposure to 125 µg/mL of each NPs for which there was bactericidal activity. Significant differences were found between the volumes of viable and nonviable biomass exposed to nanostructures with Cu-NPs compared to ZnO-NPs. Both NPs induced mitochondrial dose-dependent cytotoxicity, ZnO-NPs increases LDH release and intracellular ROS generation. Cu-NPs at a concentration of 50 µg/mL induced production of cleaved caspase-3, activating the apoptotic pathway early and at low doses. CONCLUSIONS: After 24 h, ZnO-NPs are biocompatible between 78-100 µg/mL and Cu-NPs below 50 µg/mL. Antibacterial activity in a monospecies model is strain dependent, and in a multispecies model was a lower doses after 10 min of exposure.

Impaired intracellular trafficking of sodium-dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a glutamine expansion at the first exon of the huntingtin gene. Huntingtin protein (Htt) is ubiquitously expressed and it is localized in several organelles, including endosomes. HD is associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. It is transported into neurons via the sodium-dependent vitamin C transporter 2 (SVCT2). During synaptic activity, ascorbic acid is released from glial reservoirs to the extracellular space, inducing an increase in SVCT2 localization at the plasma membrane. Here, we studied SVCT2 trafficking and localization in HD. SVCT2 is decreased at synaptic terminals in YAC128 male mice. Using cellular models for HD (STHdhQ7 and STHdhQ111 cells), we determined that SVCT2 trafficking through secretory and endosomal pathways is altered in resting conditions. We observed Golgi fragmentation and SVCT2/Htt-associated protein-1 mis-colocalization. Additionally, we observed altered ascorbic acid-induced calcium signaling that explains the reduced SVCT2 translocation to the plasma membrane in the presence of extracellular ascorbic acid (active conditions) described in our previous results. Therefore, SVCT2 trafficking to the plasma membrane is altered in resting and active conditions in HD, explaining the redox imbalance observed during early stages of the disease.