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Cannabinoids are emerging as promising treatments for inflammatory diseases such as ulcerative colitis. Specifically, cannabinoid 2 (CB2) receptors, which are upregulated during inflammation, have been distinctively linked to anti-inflammatory and analgesic effects. HU308, a synthetic cannabinoid developed to activate CB2 receptors selectively, aims to minimize unwanted off-target side effects. This study evaluated the effectiveness of both cannabidiol (CBD) and HU308 in mouse models of dextran sodium sulphate (DSS)-induced colitis, which mimic the acute and chronic phases of ulcerative colitis. Mice were treated with DSS in drinking water (four percent for the acute model and one to two percent for the chronic model) to induce colitis, as indicated by increased disease activity index (DAI) scores and inflammatory markers. Treatment with 60 mg/kg of CBD, but not lower doses, significantly reduced colitis symptoms, such as inflammation, cytokine levels, and MPO activity, while also normalizing glucagon-like peptide-1 (GLP-1) levels. HU308 showed comparable efficacy to high-dose CBD (60 mg/kg) but at a much lower dose (2.5 mg/kg), without observable toxicity. HU308 effectively normalized DAI scores, colon inflammation, ammonia levels, and GLP-1 expression in both colitis models. These results suggest that both CBD and HU308 are promising treatments for ulcerative colitis. However, HU308 demonstrates enhanced therapeutic potential by achieving similar outcomes at a fraction of the dose required for CBD, reducing the risk of off-target side effects. The ability of HU308 to modulate GLP-1, a biomarker of gut endocrine function, further underscores its promise as a novel treatment option.

Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. In the present study, we first investigated the validity of a liver xenograft mouse model repopulated with primary hepatocytes using single-nucleus RNA sequencing (sn-RNA-seq) by studying the transcriptomic profile of human hepatocytes pre- and post-engraftment. Complementary immunofluorescence analyses performed in highly engrafted animals confirmed that the human hepatocytes organize and present appropriate patterns of zone-dependent enzyme expression in this model. Next, we tested a set of rationally designed HSPG de-targeted AAV-LK03 variants for relative transduction performance in human hepatocytes. We used immunofluorescence, next-generation sequencing, and single-nucleus transcriptomics data from highly engrafted FRG mice to demonstrate that the optimally HSPG de-targeted AAV-LK03 displayed a significantly improved lobular transduction profile in this model.

Abstract Background To verify the use of pain drawing to assess multisite pain in with primary dysmenorrhea (PD) and to assess its divergent validity, test–retest reliability, intra- and inter-rater reliability and measurement errors. Methods Cross-sectional study. Adult women with self-reported PD three months prior to the study. Women answered the Numerical Rating Scale (NRS) and the pain drawing during two consecutive menstruations. The pain drawings were digitalized and assessed for the calculation of total pain area (%). Intra- and inter-rater reliability and the test–retest reliability between the first and the second menstruations were assessed with the intraclass correlation coefficient (ICC). Measurement errors were calculated with the standard error of measurement (SEM), smallest detectable change (SDC) and the Bland–Altman plot. Spearman correlation (rho) was used to check the correlation between the total pain area and pain intensity of the two menstruations. Results Fifty-six women (24.1 ± 3.1 years old) participated of the study. Their average pain was 6.2 points and they presented pain in the abdomen (100%), low back (78.6%), head (55.4%) and lower limbs (50%). All reliability measures were considered excellent (ICC > 0.75) for the total pain area; test–retest SEM and SDC were 5.7% and 15.7%, respectively. Inter-rater SEM and SDC were 8% and 22.1%, respectively. Correlation between total pain area and pain intensity was moderate in the first (rho = 0.30; p = 0.021) and in the second menstruations (rho = 0.40; p = 0.002). Conclusion Women with PD presented multisite pain, which could be assessed with the pain drawing, considered a reliable measurement.

The aim of this study was to characterize the network structure of grief-related functional impairment symptoms as measured by The Grief Impairment Scale (GIS) in 520 Peruvian individuals who have experienced the death of a family member or loved one. A psychological network model was applied to evaluate the estimation, stability, and accuracy of the network during the analysis sequence. The results indicated that the inability to perform activities at work, school, or home was the most central symptom in the entire network. However, the presence of high instability in the centrality indices indicates that the central node may differ in other cultural contexts. The networks were invariant according to sex. The most influential node in the women's group was their inability to perform activities at work, school, or home. In men, the most central node was the presence of health problems due to bereavement. The results would help to better understand functional impairment due to bereavement [ABSTRACT FROM AUTHOR]

Cannabinoids are emerging as promising treatments for inflammatory diseases such as ulcerative colitis. Specifically, cannabinoid 2 (CB2) receptors, which are upregulated during inflammation, have been distinctively linked to anti-inflammatory and analgesic effects. HU308, a synthetic cannabinoid developed to activate CB2 receptors selectively, aims to minimize unwanted off-target side effects. This study evaluated the effectiveness of both cannabidiol (CBD) and HU308 in mouse models of dextran sodium sulphate (DSS)-induced colitis, which mimic the acute and chronic phases of ulcerative colitis. Mice were treated with DSS in drinking water (four percent for the acute model and one to two percent for the chronic model) to induce colitis, as indicated by increased disease activity index (DAI) scores and inflammatory markers. Treatment with 60 mg/kg of CBD, but not lower doses, significantly reduced colitis symptoms, such as inflammation, cytokine levels, and MPO activity, while also normalizing glucagon-like peptide-1 (GLP-1) levels. HU308 showed comparable efficacy to high-dose CBD (60 mg/kg) but at a much lower dose (2.5 mg/kg), without observable toxicity. HU308 effectively normalized DAI scores, colon inflammation, ammonia levels, and GLP-1 expression in both colitis models. These results suggest that both CBD and HU308 are promising treatments for ulcerative colitis. However, HU308 demonstrates enhanced therapeutic potential by achieving similar outcomes at a fraction of the dose required for CBD, reducing the risk of off-target side effects. The ability of HU308 to modulate GLP-1, a biomarker of gut endocrine function, further underscores its promise as a novel treatment option. [ABSTRACT FROM AUTHOR]

Antecedentes: La enfermedad por coronavirus 2019 (COVID-19) afecta al sistema cardiovascular, ya sea mediante la agresión directa viral o indirectamente por medio de la inflamación sistémica y afectación multiorgánica. Las troponinas son ampliamente utilizadas para determinar lesión cardiaca. La finalidad de este estudio es evaluar la prevalencia de afectación cardiaca (ACARD) en una población recuperada de COVID-19, derivada a resonancia magnética cardiaca (RMC), sin elevación de troponinas al momento del estudio. Métodos: Ciento cincuenta y seis pacientes que se recuperaron de COVID-19 y que no presentaron elevación de troponinas fueron derivados a RMC. Se consideró ACARD a la presencia de: realce tardío de gadolinio (RTG), edema, miocarditis, pericarditis, deterioro de la función sistólica del ventrículo izquierdo (DFSVI) y/o depresión de la función sistólica del ventrículo derecho (DFSVD). Resultados: La prevalencia de ACARD fue del 28.8%, siendo más frecuente en hombres (p = 0.002), en pacientes que requirieron hospitalización (p = 0.04) y en aquellos que cursaron cuadro no leve de infección (p = 0.007). La DFSVD (17.9%) y la DFSVI (13.4%) fueron las hallazgos más frecuentes. La frecuencia de miocarditis fue del 0.6%. El RTG se manifestó en el 7.1% de los pacientes y se relacionó con menor fracción de eyección del ventrículo izquierdo (FEVI) (p = 0.0001) y derecho (FEVD) (p = 0.04). Conclusión: La prevalencia de ACARD fue del 28.8%. Esta es más frecuente en hombres, en pacientes que requirieron internación y que cursaron cuadros de infección no leve. La miocarditis presentó una prevalencia muy baja. Los pacientes que presentaron RTG tuvieron menor FEVI y FSVD.

Abstract Iodine deficiency represents a public health problem worldwide. To increase the amount of iodine in the diet, biofortification strategies of plants have been tried. They rely on the exogenous administration of iodine to increase its absorption and accumulation. However, iodine is not stable in plants and can be volatilized as methyl iodide through the action of specific methyltransferases encoded by the HARMLESS TO OZONE LAYER (HOL) genes. The release of methyl iodide in the atmosphere represents a threat for the environment due to its ozone depletion potential. Rice paddies are among the strongest producers of methyl iodide. Thus, the agronomic approach of iodine biofortification is not appropriate for this crop, leading to further increases of iodine emissions. In this work, we used the genome editing CRISPR/Cas9 technology to knockout the rice HOL genes and investigate their function. OsHOL1 resulted a major player in methyl iodide production, since its knockout abolished the process. Moreover, its overexpression reinforced it. Conversely, knockout of OsHOL2 did not produce effects. Our experiments helped elucidating the function of the rice HOL genes, providing tools to develop new rice varieties with reduced iodine emissions and thus more suitable for biofortification programs without further impacting on the environment.

Resumen: Introducción: Promover la investigación en estudiantes de Medicina y elevar la producción científica en las universidades del Perú y de Latinoamérica es una prioridad y una necesidad. Objetivo: Describir el diseño y la aplicación del curso taller de titulación por tesis de pregrado y su eficacia en la producción de tesis. Métodos: Estudio descriptivo, comparativo, con componentes analíticos, que incluyó a estudiantes del pregrado de la Facultad de Medicina Humana de la Universidad Ricardo Palma, durante los años 2015, 2016 y 2017. Se tomaron como indicadores de eficacia del curso: número de proyectos aprobados, número de tesis de pregrado sustentadas y número de manuscritos de artículos finalizados. Resultados: Se incluyeron un total de 460 alumnos; el 55% fueron mujeres y el 45%, hombres. El 99% de los estudiantes no tenía experiencia previa en investigación. Las áreas elegidas por los estudiantes para las tesis fueron: clínica 50%, quirúrgica 30% y salud pública 20%. Pasamos de un promedio de 6 tesis por año a uno de 150 tesis anuales con la introducción de la nueva ley universitaria y la realización del curso taller. Los indicadores evaluados del curso mostraron una eficacia mayor al 95%, p = 0,000. Conclusión: El curso taller demostró ser un instrumento eficaz para contribuir a la producción de las tesis de pregrado en la Facultad de Medicina Humana de la Universidad Ricardo Palma. Abstract: Introduction: Promoting research in medical students and increasing scientific production in the universities of Peru and Latin America is a priority and a necessity. Objective: To describe the design and application of the undergraduate thesis workshop course and its effectiveness in thesis production. Methods: A descriptive, comparative study, with analytical components, which included undergraduate students of the Human Medicine Faculty of the Universidad Ricardo Palma (Peru), during the years 2015, 2016, and 2017. The effectiveness indicators of the course were taken as: number of completed projects, number of undergraduate thesis dissertations approved, and number of completed manuscripts of articles. Results: A total of 460 students were included; 55% were women and 45% were men. Almost all (99%) of the students had no previous experience in research. The areas chosen by the students for the theses were: clinical 50%, surgical 30%, and public health 20%. We passed from an average of 6 theses per year to one of 150 theses per year with the introduction of the new university law and the completion of the workshop course. The indicators evaluated of the course showed an efficiency greater than 95%, P = .000. Conclusion: The workshop course proved to be an effective tool for contributing to the production of undergraduate theses in the Faculty of Human Medicine of the Universidad Ricardo Palma. Palabras clave: Tesis de pregrado, Estudiantes de Medicina, Promoción de la investigación, Educación médica, Universidades, Investigación biomédica, Keywords: Undergraduate thesis, Medical students, Research promotion, Medical education, Universities, Biomedical research

Abstract Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of β-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1α) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.

Diabetes mellitus is widely recognised as one of the most serious metabolic diseases worldwide, and its incidence in Asian countries is growing at an alarming rate. Type 2 diabetes (T2DM) is closely associated with age, sedentary lifestyle and poor diet. In T2DM, [beta]-cell dysfunction will occur before hyperglycaemia develops. Excessive levels of glucose, lipid and various inflammatory factors interact at the level of the pancreatic islet to promote [beta]-cell dysfunction. Pancreatic [beta]-cell lines have been widely utilised since the early 1980s and have contributed a large volume of important information regarding molecular, metabolic and genetic mechanisms that regulate insulin secretion. The purpose of this review is to describe the origin and characteristics of the most commonly used [beta]-cell lines and their contribution to discovery of fundamental regulatory processes that control insulin production and release. Pancreatic islets obtained from rodents as well as other animals have additionally provided information on the architecture and three-dimensional design of this endocrine tissue that allows precise regulation of hormone release. Understanding the nature of failure of physiologic and metabolic processes leading to insufficient insulin release and subsequent diabetes has allowed development of novel anti-diabetic therapeutics, now in common use, worldwide., Author(s): R Carlessi [sup.1] , K N Keane [sup.1] , C Mamotte [sup.1] , P Newsholme [sup.1] Author Affiliations: (1) School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin [...]

The incretin hormone Glucagon-Like Peptide-1 (GLP-1) is best known for its “incretin effect” in restoring glucose homeostasis in diabetics, however, it is now apparent that it has a broader range of physiological effects in the body. Both in vitro and in vivo studies have demonstrated that GLP-1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic reprogramming, stimulate anti-inflammatory signaling, alter gene expression, and influence neuroprotective pathways. A substantial body of evidence has accumulated with respect to how GLP-1 and its analogs act to restore and maintain normal cellular functions. These findings have prompted several clinical trials which have reported GLP-1 analogs improve cardiac function, restore lung function and reduce mortality in patients with obstructive lung disease, influence blood pressure and lipid storage, and even prevent synaptic loss and neurodegeneration. Mechanistically, GLP-1 elicits its effects via acute elevation in cAMP levels, and subsequent protein kinase(s) activation, pathways well-defined in pancreatic β-cells which stimulate insulin secretion in conjunction with elevated Ca2+ and ATP. More recently, new studies have shed light on additional downstream pathways stimulated by chronic GLP-1 exposure, findings which have direct relevance to our understanding of the potential therapeutic effects of longer lasting analogs recently developed for clinical use. In this review, we provide a comprehensive description of the diverse roles for GLP-1 across multiple tissues, describe downstream pathways stimulated by acute and chronic exposure, and discuss novel pleiotropic applications of GLP-1 mimetics in the treatment of human disease.

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