Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model

BACKGROUND: Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS: The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS: The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION: benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.

Utilidad del índice de fibrosis hepática (IFH) medido durante la ultrasonografía endoscópica en la evaluación del parénquima pancreático / Usefulness of the Liver Fibrosis Index (LFI) Measured during Endoscopic Ultrasonography in Evaluating the Pancreatic Parenchyma

El ultrasonido endoscópico ha cambiado la evaluación de las enfermedades pancreáticas y ha logrado un diagnóstico histopatológico (cuando se asocia con la punción); sin embargo, este procedimiento requiere de entrenamiento, no está libre de complicaciones y alrededor de 25% de los pacientes puede tener falsos negativos. Por esto se ha implementado el uso de la elastografía cuantitativa con el strain ratio, el cual permite diferenciar las masas benignas de las malignas. Existe evidencia creciente, pero aún no conclusiva, dada la heterogeneidad de los resultados (sin consenso para su realización), por lo que es necesario desarrollar otros métodos, que permitan una mayor certeza diagnóstica, como el índice de fibrosis hepática (IFH) medido por ultrasonografía endoscópica, el cual tienen como base la inteligencia artificial, validado para el diagnóstico y el seguimiento de la fibrosis hepática. Nuestro grupo considera que se podría usar de la misma forma para valorar el parénquima pancreático. Objetivo: evaluar si el IFH puede diferenciar tres tipos diferentes de tejidos pancreáticos: páncreas normal, páncreas graso y cáncer de páncreas. Metodología: estudio prospectivo de corte transversal en un solo centro. Se incluyeron 66 pacientes mayores de 18 años, con indicación de ultrasonografía endoscópica. El grupo 1 fue de pacientes con indicación diferente a la enfermedad biliopancreática (55 pacientes). En este grupo se aplicó la escala de clasificación de páncreas graso por ultrasonografía endoscópica (USE), utilizando como referencia la ecogenicidad del bazo (previamente validada); este grupo se subdividió en uno con parénquima pancreático normal y en otro con páncreas graso. En el grupo 2 (11 pacientes) se incluyeron los pacientes llevados para el estudio de lesión sólida pancreática, con diagnóstico citológico positivo para carcinoma de páncreas. Como herramienta de recolección de datos se utilizó un formulario virtual de Google Drive, disponible con dirección acortada: shorturl.at/pIMWX, diligenciado antes y después del procedimiento por fellows de Gastroenterología, previamente entrenados para este fin. El IFH se tomó en el páncreas en tiempo real mediante un software suministrado por el fabricante (Hitachi-Noblus), en un período comprendido entre enero de 2019 y enero 2020. A todos los pacientes se les realizó una ecoendoscopia biliopancreática completa, con un ecoendoscopio Pentax lineal y procesador Hitachi-Noblus; luego se efectuó una elastografía cualitativa y una cuantitativa, la cual incluyó la medición del IFH. Resultados: en total se incluyeron 66 pacientes: 11 pacientes con diagnóstico confirmado por citología de cáncer de páncreas y 55 pacientes que se enviaron para ecoendoscopia por evaluación de otras patologías diferentes a la biliopancreática. El rango de edad fue de 23-89, media de 56,75 años. El antecedente más frecuente fue la esteatosis o esteatohepatitis (n = 14) (25,45%). La indicación para la realización del procedimiento más frecuente fue la lesión subepitelial (n = 29) (52,73 %). Los porcentajes de pacientes según los grados de ecogenicidad del páncreas fueron de grado I (n = 29) (52,73 %); grado II (n = 5) (9,09 %); grado III (n = 18) (32,73 %); grado IV (n = 3) (5,45 %). Se tomaron los grados I y II como páncreas normal, y los grado III y IV como páncreas graso. Estos se dividieron en n = 34 pacientes (61,82 %) para páncreas normal y n = 21 (38 %) para páncreas graso; es decir, que de acuerdo con la escala utilizada hay una prevalencia para páncreas graso de 38,18 %. Se realizó el IFH en los tres subgrupos diferentes: los considerados como ecoendoscópicamente normales, los clasificados como páncreas graso y los pacientes con diagnóstico de cáncer de páncreas confirmado por citología, tomado en el páncreas. El IFH para los tres diferentes grupos fueron, respectivamente, normal: IFH 2,60, rango 0,97-3,47 (IC 95 % 2,17-3,02); páncreas graso: IFH 3,87, rango 2-5,5 (IC 95 % 3,44-4,29); cáncer de páncreas: IFH 6,35, rango 5,8-7,8 (IC 95 % 5,92-6,77). Conclusiones: este es el primer estudio piloto que usa el IFH aplicado al parénquima pancreático, y se sugiere su utilidad para diferenciar, de manera no invasiva, el páncreas normal, el graso y el carcinoma de páncreas. Este hallazgo se debe confirmar en poblaciones más amplias y heterogéneas, con el fin de ser validado.

Abstract Endoscopic ultrasound has changed the evaluation of pancreatic diseases and has achieved a histopathological diagnosis (when associated with a puncture); however, this procedure requires training, is not free of complications, and around 25 % of patients may have false negatives. Therefore, quantitative elastography with the strain ratio has been implemented to differentiate benign masses from malignant ones. There is growing but not yet conclusive evidence, given the heterogeneity of the results (without consensus on its performance). It is necessary to develop other methods that allow for greater diagnostic certainty, such as the liver fibrosis index (LFI) measured by endoscopic ultrasonography. This method is based on artificial intelligence and validated for diagnosing and monitoring liver fibrosis. Our group considers that it could also be used to assess the pancreatic parenchyma. Aim: To evaluate whether the LFI can differentiate three types of pancreatic tissues: normal pancreas, fatty pancreas, and pancreatic cancer. Materials and methods: Prospective cross-sectional single-center study. We included sixty-six patients over 18 years of age with an indication for endoscopic ultrasonography. Group 1 consisted of patients with an indication other than the biliopancreatic disease (55 patients). The endoscopic ultrasonography (EUS) fatty pancreas classification scale was applied to this group, taking the echogenicity of the spleen (previously validated) as a reference; this group was subdivided into normal pancreatic parenchyma and fatty pancreas. Group 2 (11 patients) included those examined for solid pancreatic lesions with a positive cytological diagnosis of pancreatic carcinoma. We used a Google Form as a data collection tool, available with a shortened address (shorturl.at/pIMWX). It was filled out before and after the procedure by Gastroenterology fellows, previously trained for this purpose. The LFI was measured in the pancreas in real-time using software supplied by the manufacturer (Hitachi Noblus) between January 2019 and January 2020. All patients underwent a complete biliopancreatic echoendoscopy, with a linear Pentax echoendoscope and Hitachi Noblus processor. Then, qualitative and quantitative elastography was performed, including LFI measurement. Results: We included a total of 66 patients: 11 with a diagnosis of pancreatic cancer confirmed by cytology and 55 sent for ultrasound endoscopy due to pathologies other than the biliopancreatic disease. The age range was 23-89, with a mean of 56.75 years. The most frequent history was steatosis or steatohepatitis (n = 14) (25.45 %). The most frequent indication for performing the procedure was subepithelial lesion (n = 29) (52.73 %). The percentages of patients according to pancreatic echogenicity were Grade I (n = 29) (52.73 %); Grade II (n = 5) (9.09 %); Grade III (n = 18) (32.73 %); Grade IV (n = 3) (5.45 %). Grades I and II were taken as a normal pancreas and Grades III and IV as a fatty pancreas, divided into n = 34 patients (61.82 %) for a normal pancreas and n = 21 (38 %) for a fatty pancreas. According to the scale used, there is a fatty pancreas prevalence of 38.18 %. The LFI was measured in three subgroups: those considered endoscopically normal, those classified as fatty pancreas, and patients diagnosed with pancreatic cancer confirmed by cytology taken from the pancreas. The LFI for these groups were, respectively, normal pancreas: LFI 2.60, range 0.97-3.47 (95 % CI 2.17-3.02); fatty pancreas: LFI 3.87, range 2-5.5 (95 % CI 3.44-4.29); pancreatic cancer: LFI 6.35, range 5.8-7.8 (95 % CI 5.92-6.77). Conclusions: This is the first pilot study that applies the LFI to the pancreatic parenchyma. It is useful in differentiating a normal pancreas, a fatty pancreas, and pancreatic carcinoma non-invasively. This finding must be validated in larger and more heterogeneous populations.

Fatty Pancreas: Disease or Finding?

Despite a growing number of investigative studies on pancreatic fat deposition, there remains no clear indication regarding the clinical relevance of fat infiltration in the pancreas, also called fatty pancreas (FP). An individual's body weight is correlated with their pancreatic weight. Moreover, lipid infiltration causes disorders that compromise not only morphology but also metabolic functions. Fat infiltration leads to insulin resistance, type II diabetes mellitus, and pancreatic cancer; however, knowledge about pancreatic fat content and aspects related to the clinical profile remains unclear in the literature. The present review describes the current knowledge of FP, including its pathophysiology and clinical implications, as well as lifestyle changes in FP.

Correlation of Clinical and Histopathologic Parameters with Ultrasonographic Grades in Pediatric Non-Alcoholic Fatty Liver Disease

5). Higher body mass index (BMI) percentile, waist circumference, hematocrit, insulin resistance, and lower insulin sensitivity index were significantly positively correlated with the grade of fatty liver. NAFLD activity score, amount of steatosis, and fibrosis significantly worsened as the fatty liver grade increased. Higher BMI, lower insulin sensitivity index, and boy were significantly positively correlated with the fatty pancreas grade.CONCLUSION: Altogether, ultrasonographic severity of fatty liver shows good correlation with that of clinical parameters and hepatic pathology.

Prediabetes and type 2 diabetes are independent risk factors for computed tomography-estimated nonalcoholic fatty pancreas disease

OBJECTIVES: Nonalcoholic fatty pancreas disease (NAFPD) is characterized by excessive fat deposition in the pancreas in the absence of alcohol consumption. In this study, we aimed to detect a possible relationship between adipose tissue accumulation, prediabetes and diabetes. METHODS: This cross-sectional and retrospective study included 110 patients. Three groups were classified as controls, patients with prediabetes and patients with type 2 diabetes. The abdominal computed tomography (CT) attenuation measurement results of the pancreas were evaluated independently by two experienced radiologists. CT measurements and biochemical parameters were compared between study groups. The relationship between continuous variables was assessed by using one-way ANOVA. To determine the changes in the dependent variable for the effects on study groups, the independent variable was adjusted using ANCOVA. A p-value less than 0.05 was considered statistically significant. RESULTS: The presence of prediabetes and type 2 diabetes was correlated with a decrease in the mean Hounsfield Unit (HU) value of the pancreas (p=0.002). Age was determined to be an independent risk factor and was correlated with NAFPD (p=0.0001). When compared to the controls (p=0.041), 71% of patients with prediabetes and 67% of patients with type 2 diabetes were observed to have an increased incidence of NAFPD. Decreased serum amylase was found to be correlated with the mean HU value of the pancreas (p=0.043). CONCLUSION: NAFPD was independently correlated with both prediabetes and type 2 diabetes adjusted for age (p=0.0001) in this study. Additionally, age was determined to be an independent risk factor and was correlated with NAFPD.

Remodelamento do fígado, pâncreas e tecido adiposo em modelo experimental de 'síndrome metabólica' tratado com telmisartana, sitagliptina e metformina / Remodeling of the liver, pancreas and adipose tissue in an experimental model of metabolic syndrome treated with telmisartan, sitagliptin and metformin

A intervenção farmacológica pode minimizar ou até mesmo reverter o remodelamento adverso em órgãos num modelo de síndrome metabólica. Este trabalho teve como objetivo avaliar os efeitos das monoterapias e associações medicamentosas sobre a morfologia do tecido adiposo, remodelamento hepático e pancreático em camundongos C57b1/6 alimentados com dieta very high-fat. Camundongos C57b1/6 machos foram alimentados com dieta very high-fat (HF, 60% de lipídios) ou dieta padrão (SC, 10% de lipídios) por 10 semanas, quando foram iniciados os tratamentos: HF-T (HF + Telmisartana, 5.2mg/Kg/dia), HF-S (HF + Sitagliptina, 1.08g/Kg/dia), HF-M (HF + Metformina, 310.0mg/Kg/dia) e as associações medicamentosas HF-TM, HF-TS e HF-SM. Os grupos tratados também tiveram livre acesso à dieta high fat e os tratamentos duraram 6 semanas. Técnicas morfométricas, estereológicas, imunohistoquímicas, ELISA, western blotting e microscopia eletrônica foram utilizadas. A dieta high-fat causou sobrepeso, intolerância oral à glucose, hiperinsulinemia, hipertrofia de ilhotas e adipócitos, grau 2 de esteatose hepatica (<33%) redução da expressão de PPAR-alfa e de GLUT-2, concomitante com aumento da expressão de SREBP-1 no grupo HF (P<0.0001). Por outro lado, todos os tratamentos resultaram resultaram em perda de peso significativa, reversão da resistência à insulina, hipertrofia de ilhotas e adipócitos e alívio da esteatose hepática. Somente os grupos HF-T e HF-TS apresentaram massa corporal similar ao grupo SC ao final do experimento, sendo que o último também apresentou reversão da esteatose hepática. O aumento da expressão do PPAR-alfa paralelamente ao decréscimo da expressão do SREBP-1 explica os achados favoráveis para o fígado. A normalização do tamanho do adipócito foi consistente com os níveis maiores de adiponectina e com a redução dos níveis de TNT-alfa (P<0.0001) nos grupos tratados. Todos os tratamentos foram eficazes para controlar a síndrome metabólica. Os melhores resultados ...

Pharmacological intervention can minimize or even reverse remodeling due to metabolic syndrome. This work sought to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, pancreatic and hepatic remodeling in C57BL/6 mice fed a high-fat diet. Male C57BL/6 mice were fed a very high-fat diet (HF, 60% lipids) or standard chow (SC, 10% lipids) over 10 weeks, after which drug treatments began: HF-T (HF + Telmisartan, 5.2mg/Kg/day), HF-S (HF + Sitagliptin, 1.08g/Kg/day), HF-M (HF + Metformin, 310.0mg/Kg/day) and the drug combinations HF-TM, HF-TS and HF-SM. Treated groups also had free access to HF diet and treatments lasted 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blotting and electron microscopy were used. The HF diet yielded an overweight phenotype, oral glucose intolerance, hyperinsulinemia, hypertrophied islets and adipocytes, stage 2 steatosis (<33%) and reduced liver PPAR-alpha and GLUT-2, concomitant with enhanced SREBP-1 expression, in the HF group (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, reversed insulin resistance, islet and adipocyte hypertrophy and alleviated hepatic steatosis. Only HF-T and HF-TS presented body weights similar to SC mice at the end of the experiment and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining parallel to higher GLUT-2 and reduced SREBP-1 expression explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha levels (P<0.0001) in treated groups. In conclusion, all treatments were effective in controlling metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action

Patrones sonográficos y ubicación topográfica de la esteatosis pancreática por ecoendoscopia

Introducción: El reemplazo graso del páncreas se conoce que ocurre bajo ciertas condiciones pero esta patogénesis no está bien establecida. El diagnóstico requiere la demostración del reemplazo graso y a pesar del desarrollo reciente de imágenes diagnósticas, es difícil distinguir de otras anormalidades. Objetivo: evaluar por ecoendoscopia los patrones sonográficos de la glándula pancreática y establecer un diagnóstico de Esteatosis Pancreática. Materiales y Pacientes: Estudio retrospectivo cuyos datos fueron obtenidos de 1764 historias de pacientes referidos al Centro de Investigaciones Tecnológicas Ecoendoscópicas (CITE), para realizarse una EE superior, en el período comprendido entre abril del 2000 y junio del 2004. El estudio dinámico del páncreas evaluó dos elementos: primero se realizaron comparaciones del patrón ecográfico de la glándula en estudio con evaluaciones de páncreas normales por ecoendoscopia y segundo se utilizaron las características sonográficas del hígado. Los diferentes patrones fueron descritos desde el punto de vista topográfico ubicándose según la anatomía de la glándula pancreática en: proceso uncinado, cabeza, istmo, cuerpo y cola. Los patrones sonográficos fueros evaluados por separados dependiendo de su distribución en la glándula Resultados: Un total de 45 pacientes fueron estudiados, 28 mujeres y 17 hombres, con una media de 55 +/- 11 años. Las alteraciones del páncreas fueron divididas en esteatosis difusa n=43: leve, moderada y severa, y esteatosis heterogénea n=2. El estado general de acuerdo al grado de esteatosis pancreática fue: leve en 24 casos, moderado 17 casos y severo en 4 casos. Se observo un patrón en parches leve y otro moteado moderado, ambos ubicados en el istmo, el cuerpo y la cola. Las zonas más afectadas fueron cuerpo y cola 98% y 96% respectivamente. Las zonas menos afectadas fueron cabeza y proceso uncinado con 58% y 47% respectivamente. En las diferentes topografías se muestran tres patrones predominantes. Fueron más evidentes los siguientes tres patrones: afectación igual en todo el páncreas 42%, en cuerpo y cola 22% y cuerpo, cola e istmo con eventual aparición de afectación en proceso uncinado y cabeza 33%. Conclusiones: la ecoendoscopia permite evaluar en forma rigurosa los cambios de ecogenicidad del páncreas al igual que la topografía de este, siendo más compleja de lo antes expuesto en la literatura requiriendo de trabajos prospectivos que enfoquen el tema de la esteatosis pancreática y la ecoendoscopia.

Introduction: The fatty replacement of the pancreas occurs under certain conditions but the pancreatic pathogenesis is not well understood. Even though, there are new imaging techniques available fatty pancreas replacement is difficult to differentiate from other pancreatic abnormalities. Aim of the study: assessment of the different sonographic patterns of the pancreatic gland using endoscopic ultrasound in other to diagnose pancreatic steatosis. Patients and Methods: Between April 2000 an June 2004 1764 endoscopic ultrasound were review at the Centro de Investigaciones Tecnológicas Ecoendoscópicas (CITE). The dynamic sonography of the pancreas assess two elements, first it made a relation between normal pancreatic sonographic parenchyma and the evaluated gland, and second the sonographic features of the liver were used. All patterns where described topographically and divided according to the different anatomic parts of the pancreas: uncinated process, head, neck, body and tail. Separated analysis of the pancreatic patterns was performed according to the pancreatic distribution. Results: 45 patients were evaluated, 28 females and 17 males, with a mean of 55 +/- 11 years. Pancreatic patterns were divided in diffused steatosis n=43 mild, moderated and severe, and heterogeneous steatosis n=2. According to severity we found 24 mild, 17 moderated and 4 severs. One pattern was mild patch in and the other one was moderated spots both located at the neck, body and tail. The body and tail were the most affected location with a 98% and 96% respectively; the less affected locations were the head and the uncinated process with 58% and 47% respectively. Three patterns were the most frequents: 42% had global steatosis, 22% had the body and tail and 33% had body, tail and neck with sporadic changes in head and uncinated process. Conclusions: pancreatic echogenecity is well defined by endoscopic ultrasound. Pancreatic steatosis should be address in future prospective protocols due to a complexity of his topography in the pancreas.