Standardized Centella asiatica extract ECa 233 alleviates pain hypersensitivity by modulating P2X3 in trigeminal neuropathic pain

Abstract During oral surgery and temporomandibular joint repositioning, pain hypersensitivity often occurs due to irritation or inflammation of the nerve endings in the orofacial region. Objective: This study aimed to investigate the effects of ECa 233, a Centella asiatica-standardized extract, on the development of mechanical hyperalgesia and allodynia induced by chronic constriction injury of the infraorbital nerve in mice. Methodology: The right infraorbital nerves of the mice were ligated. Oral carbamazepine (20 mg/kg) or ECa 233 (30, 100, or 300 mg/kg) was administered daily for 21 days. Von Frey and air-puff tests were performed on both sides of the whisker pad on days 0, 7, 14, and 21. Thereafter, the expression of purinergic receptor subtype 3 (P2X3) and voltage-gated sodium channel 1.7 (NaV1.7), a transmembrane protein, in the trigeminal ganglion and c-fos immunoreactivity-positive neurons in the trigeminal nucleus caudalis was assessed. Results: After 21 days of infraorbital nerve ligation, the mice showed allodynia- and hyperalgesia-like behavior, P2X3 and NaV1.7 were upregulated in the trigeminal ganglion, and nociceptive activity increased in the trigeminal nucleus caudalis. However, the oral administration of carbamazepine (20 mg/kg), ECa 233 (100 mg/kg), or ECa 233 (300 mg/kg) mitigated these effects. Nevertheless, ECa 233 failed to affect NaV1.7 protein expression. Conclusion: Carbamazepine and ECa 233 can prevent pain hypersensitivity in mice. Considering the side effects of the long-term use of carbamazepine, ECa 233 monotherapy or combined ECa 233 and carbamazepine therapy can be used as an alternative for regulating the development of hypersensitivity in trigeminal pain. However, further detailed clinical studies should be conducted to provide comprehensive information on the use of ECa 233.

Enzima convertidora de angiotensina homóloga (ECA2) y actividad de ROCK en la falla cardíaca experimental

Antecedentes: La ECA2 ha mostrado ser un regulador esencial de la funcionalidad cardíaca. En un modelo experimental de insuficiencia cardíaca (IC) con Fier, modelo de coartación de aorta (COA), se encontró activación de la vía Rho-kinasa. La inhibición de esta vía con fasudil no mejoró el remodelado cardíaco ni la disfunción sistólica. Se desconoce en este modelo, si el deterioro de la función cardíaca y activación de la vía rho-kinasa se asocia con una disminución de la ECA2 cardíaca y si la inhibición de Rho-kinasa tiene un efecto sobre la expresión de ECA2. Objetivo: Nuestro objetivo es determinar si en la falla cardaca experimental por coartación aórtica, los niveles proteicos de ECA2 en el miocardio se asocian a disfunción sistólica y cual es su interacción con la actividad de ROCK en el miocardio. Métodos: Ratones C57BL6J machos de 7-8 semanas se randomizaron en 3 grupos experimentales. Grupo COA por anudación de la aorta + vehículo; Grupo COA + Fasudil (100 mg/Kg día) por bomba osmótica desde la semana 5 post-cirugía; y grupo control o Sham. Se determinaron las dimensiones y función cardíaca por ecocardiografía. Posterior a la eutanasia, se determinaron los niveles de ECA2 del VI por Western-blot y actividad de la Rho-kinasa Resultados: En los grupos COA+vehículo y COA-FAS hubo deterioro de la función cardíaca, reflejada por la reducción de la FE (47,9 ± 1,53 y 45,5 ± 2,10, p < 0,05, respectivamente) versus SHAM (68,6 ± 1,19). Además, aumentaron las dimensiones cardíacas y hubo desarrollo de hipertrofia (0,53 ± 0,02 / 0,53 ± 0,01, p < 0,05) medida por aumento de la masa cardíaca relativa respecto del grupo SHAM (0,40 ± 0,01). En los grupos COA+vehículo y COA-FAS se encontró una disminución significativa del 35% en la expresión de ECA2 cardíaca respecto al grupo control. Conclusiones: La disfunción sistólica por coartación aórtica se asocia con aumento de la actividad de Rho-kinasa y significativa disminución de la expresión de ECA2. La inhibición de Rho-kinasa no mejoró el remodelado cardíaco, la disfunción sistólica y tampoco modificó los niveles de ECA2 cardíaca.

Background: ACE2 has been described as an essential regulator of cardiac function. In an experimental model of heart failure (HF) and heart failure reduced ejection fraction (HFrEF), the aortic coarctation (COA) model, activation of the Rho-kinase pathway of cardiac remodeling was found. Inhibition of this pathway did not improve cardiac remodeling or systolic ventricular dysfunction. It is unknown in this model whether the impairment of cardiac function and activation of the rho-kinase pathway is associated with a decrease in ACE2 and whether rho-kinase inhibition has an effect on ACE2 expression. Objective: To determine if in experimental heart failure due to aortic coarctation, ACE2 protein levels in the myocardium are associated with systolic dysfunction and what is its interaction with ROCK activity in the myocardium. Methods: Male C57BL6J mice aged 7-8 weeks were divided into 3 groups and anesthetized: One group underwent COA+ vehicle; A second group COA + Fasudil (100 mg/Kg/d) by osmotic pump from week 5 post-surgery and; the third group, control(SHAM). Echocardiograms were performed to determine cardiac dimensions and systolic function. Rats were then euthanized. Ventricular expression of ACE2, activity of the Rho-kinase pathway by MYPT-1 phosphorylation, relative cardiac mass, area and perimeter of cardiomyocytes were determined by Western blot. Results: In both COA+vehicle and COA+FAS groups there was deterioration of cardiac function, reflected in the reduction of EF (47.9 ± 1.53 and 45.5 ± 2.10, p < 0.05, respectively) versus the SHAM group (68.6 ± 1.19). In addition, cardiac dimensions and hypertrophy increased (0.53 ± 0.02 / 0.53 ± 0.01, p < 0.05) due to increased relative cardiac mass compared to the SHAM group (0.40 ± 0.01). In the COA+vehicle and COA+FAS groups a significant decrease of 35% in cardiac ACE2 expression was found compared to the control group. Conclusions: Systolic dysfunction due to aortic coarctation is associated with increased Rhokinase activity and a significant decrease in ACE2 expression. Rho-kinase inhibition did not improve cardiac remodeling, systolic dysfunction, nor did it change cardiac ACE2 levels.

Telmisartán y losartán: las marcadas diferencias entre sus propiedades químicas y farmacológicas pueden explicar la diferencia en la eficacia terapéutica en pacientes hospitalizados con covid-19 / Telmisartan and losartan: marked differences in chemical and pharmacological properties may explain differences in therapeutic efficacy in hospitalized patients with COVID-19

El objetivo de este artículo es comparar las propiedades químicas y farmacológicas del telmisartán y el losartán, y su metabolito activo EXP3174, con el fin de entender por qué el telmisartán es efectivo en pacientes hospitalizados con Covid-19 mientras que el losartán no lo es. Se llevó a cabo una revisión bibliográfica exhaustiva de las propiedades químicas, farmacocinéticas y farmacodinámicas de ambos fármacos y se destacaron las diferencias más importantes que podrían estar relacionadas con su efectividad en pacientes con Covid-19. Se concluyó que las propiedades farmacológicas del telmisartán, como su mayor afinidad por el receptor AT1, su duración de acción prolongada y su capacidad para modular la inflamación podrían explicar su efectividad en pacientes con Covid-19. Por otro lado, las propiedades farmacológicas del losartán, como su menor afinidad por el receptor AT1 y su rápido metabolismo, pueden limitar su efectividad en pacientes con Covid-19. Estos resultados resaltan la importancia de comprender las propiedades químicas y farmacológicas de los medicamentos para identificar posibles candidatos terapéuticos efectivos en el tratamiento de Covid-19. (AU)

The objective of this article is to compare the chemical and pharmacological properties of telmisartan and losartan and their active metabolite EXP3174 to understand why telmisartan is effective in hospitalized patients with COVID-19 while losartan is not. A comprehensive literature review of the chemical, pharmacokinetic and pharmacodynamic properties of both drugs was done to highlight the most important differences that may be related to their efficacy in patients with COVID-19. It was concluded that the pharmacological properties of telmisartan, such as its higher affinity for the AT1 receptor, its long duration of action and its ability to modulate inflammation, could explain its efficacy in patients with COVID-19. On the other hand, the pharmacological properties of losartan, such as its lower affinity for the AT1 receptor and its rapid metabolism, may limit its efficacy in patients with COVID-19. These results highlight the importance of understanding the chemical and pharmacological properties of drugs to identify potential effective therapeutic candidates for the treatment of COVID-19. (AU)

Sesamol regulates autophagy and apoptosis of esophageal squamous cell carcinoma Eca109 cells through AMPK/SIRT1/NF-κB signal pathway / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨芝麻酚（SEM）通过腺苷酸活化蛋白激酶（AMPK）/沉默信息调节因子1（SIRT1）/核因子κB（NF-κB）通路影响食管鳞状细胞癌（ESCC）Eca109细胞自噬和凋亡的机制。方法: 用不同浓度的SEM（0、1.562 5、3.125、6.25、12.5、25、50、100、200、400 μmol/L）分别处理Eca109细胞、人食管上皮细胞HEEpiC 48 h，CCK-8法检测细胞增殖率，筛选适宜的SEM浓度用于后续实验。将Eca109细胞分为对照组（CK组，0 µmol/L）、低剂量SEM组（SEM-L组，25 µmol/L）、中剂量SEM组（SEM-M组，50 µmol/L）、高剂量SEM组（SEM-H组，100 µmol/L）、高剂量SEM+Compound C（AMPK抑制剂）组（SEM-H+Compound C组，100 µmol/L+10 µmol/L），所有各组Eca109细胞在对应的药物浓度下处理48 h后，CCK-8法检测Eca109细胞增殖，流式细胞术检测细胞凋亡，透射电镜观察Eca109细胞内自噬小体，WB法检测Eca109细胞中微管相关蛋白1轻链3（LC3）-Ⅱ/LC3-Ⅰ、Beclin-1、B淋巴细胞瘤2（Bcl2）、Bcl2相关X蛋白（BAX）、p-AMPK、SIRT1、p-NF-κB p65的表达。结果: 通过预实验选择SEM实验浓度为25、50、100 μmol/L用于正式研究。在SEM处理下，与CK组比较，SEM-L组、SEM-M组、SEM-H组Eca109细胞的增殖水平（24、48 h）和Bcl2、p-NF-κB p65蛋白表达均显著降低，细胞凋亡率和自噬小体数量、LC3-Ⅱ/LC3-Ⅰ、Beclin-1、BAX、p-AMPK、SIRT1蛋白表达显著升高，且呈剂量依赖性（均P<0.05）；与SEM-H组比较，SEM-H+Compound C组Eca109细胞增殖水平（24、48 h）和Bcl2、p-NF-κB p65蛋白表达均显著升高，细胞凋亡率和自噬小体数量、LC3-Ⅱ/LC3-Ⅰ、Beclin-1、BAX、p-AMPK、SIRT1蛋白表达均显著降低（均P<0.05）。结论:SEM可能通过激活AMPK/SIRT1信号通路而抑制NF-κB活性来促进Eca109细胞自噬与凋亡。

miR-216b-5p mediates autophagy to reverses cisplatin resistance of esophageal cancer Eca109 cells by targeting ATG5 / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨miR-216b-5p对食管癌Eca109细胞顺铂（DDP）耐药性的影响及其作用机制。方法:采用qPCR法检测miR-216b-5p在食管癌细胞TE-1、KYSE-150、Eca109和耐药细胞Eca109/DDP中的表达水平。利用脂质体转染技术分别将miR-216b-5p mimic及mimic NC、自噬相关蛋白5（ATG5）过表达质粒转染到Eca109/DDP细胞中，用CCK-8、EdU法和FCM分别检测转染后细胞的增殖和凋亡；mRFP-eGFP-LC3双荧光标记实验检测mRFP-eGFP-LC3慢病毒感染后各组细胞自噬发生情况，WB法检测自噬相关蛋白LC3、Beclin 1和P62表达。用荧光素酶报告基因实验验证miR-216b-5p与ATG5的靶向关系，WB法检测ATG5的表达。建立裸鼠Eca109/DDP细胞移植瘤模型，观察miR-216b-5p过表达对移植瘤生长的影响。结果：miR-216b-5p在TE-1、KYSE-150、Eca109和Eca109/DDP细胞中均呈低表达（均P<0.05）。过表达miR-216b-5p可显著抑制Eca109/DDP细胞的增殖并诱导凋亡（均P<0.05），减少细胞中自噬小体数量（P<0.05），下调LC3Ⅱ/LC3Ⅰ比值和Beclin 1蛋白水平、上调P62蛋白水平（均P<0.05）。双荧光素酶报告基因实验证实miR-216b-5p靶向并负调控ATG5的表达（P<0.05），过表达ATG5可使miR-216b-5p mimic对Eca109/DDP细胞增殖、自噬的抑制作用和凋亡的诱导作用明显减弱（均P<0.05），自噬相关蛋白P62表达降低、LC3Ⅱ/LC3Ⅰ比值和Beclin 1表达升高（均P<0.05）。荷瘤实验结果表明，miR-216b-5p过表达可显著抑制裸鼠移植瘤的生长（P<0.05）。结论：miR-216b-5p过表达可逆转食管癌Eca109/DDP细胞对DDP的耐药性，其机制可能与靶向负调控ATG5表达并影响细胞自噬有关。

Tratamientos y bioterapias para COVID-19 / Therapeutics and biotherapies for covid-19

INTRODUCCIÓN: Un nuevo brote de coronavirus surgió en 2019 en Wuhan, China, causando conmoción en el sistema sanitario de todo el mundo; el Comité Internacional de Taxonomía de Virus lo denominó SARS-CoV-2, agente causante de la enfermedad COVID-19.El espectro de gravedad de la enfermedad es muy amplio: la mayoría de los pacientes no presentan gravedad, pero otros pueden desarrollar neumonías, y la insuficiencia respiratoria aguda es la causa más frecuente de mortalidad. Objetivo: analizar y desarrollar las distintas alternativas terapéuticas aportadas por la Biotecnología para tratar los síntomas de aquellos pacientes con COVID-19. Metodología: se realizó una revisión de la bibliografía disponible, a partir de enero de 2020 en PubMed, acerca de los tratamientos que se encuentran aún en ensayos clínicos y aquellos que cuentan con aprobación bajo uso de emergencia para la enfermedad COVID-19. También se realizaron búsquedas a través de Google y Google Académico para publicaciones de organismos de Salud en referencia a políticas de salud establecidas para la terapéutica durante dicha pandemia. Resultados: este trabajo aborda las nuevas alternativas terapéuticas para COVID-19 derivadas de la Biotecnología, que se encuentran tanto en uso como en etapas de ensayos clínicos comprendidos dentro del segmento de los biofármacos y las bioterapias. Se incluye un breve resumen del estatus regulatorio de entidades de salud, el mecanismo de acción de dichas terapias y características generales de cada uno. Se incluyen novedosas bioterapias que se empezaron a implementar para afrontar la pandemia. Conclusiones: la pandemia de coronavirus está poniendo a prueba el sistema sanitario internacional, para brindar soluciones tanto desde el diagnóstico y prevención como para el tratamiento de la población a fin de disminuir la mortalidad. Esto incluyó, obviamente también, al área de la Biotecnología aplicada a la salud, que ha aportado en los tres aspectos mencionados; el presente trabajo se centra en las respuestas de tipo terapéutico que ha brindado y que están comercializadas o en fases clínicas. (AU)

INTRODUCTION: A new coronavirus outbreak emerged in 2019 in Wuhan, China, causing a shock to the healthcare system around the world; the International Committee on Taxonomy of Viruses named it SARS-CoV- 2, the infectious agent of the COVID-19 disease. The spectrum of severity of the disease is very wide, most patients are not serious, but others can develop pneumonia, with acute respiratory failure being the most frequent cause of mortality. Objective: to analyze and develop the different therapeutic alternatives provided by Biotechnology dedicated to Health, to treat the symptoms of those COVID-19 patients who require it, and thus reduce mortality.Methodology: a review of the available literature from January 2020 in PubMed of the treatments that are still in clinical trials and those that have been approved under emergency use for the disease COVID-19 was performed. Searches were also carried out through Google and Google Scholar for publications of Health organizations in reference to health policies established for therapeutics during the mentioned pandemic. Results: this work addresses the new therapeutic alternatives derived from Biotechnology, which are both in use and in stages of clinical trials, to treat patients who developed COVID-19 included within the segment of biopharmaceuticals and biotherapies. A brief summary of the regulatory status of health entities, the mechanism of action of said therapies and general characteristics of each one is included. Innovative biotherapies that began to be implemented to face the pandemic are included. Conclusions: The coronavirus pandemic has driven the international health system to the test, to provide solutions both from the diagnosis, prevention and treatment of the population to reduce the mortality of patients. This obviously also included the area of Biotechnology applied to health, which has contributed in the three aspects mentioned. The present work focuses on the therapeutic responses that it has provided and that are commercialized or in clinical phases. (AU)

Uso de anticorpos monoclonais por pacientes com covid-19 interfere na concentração sérica de angiotensina II? / Does the use of monoclonal drugs by patients with COVID-19 interfere with the serum concentration of angiotensin II? / ¿El uso de fármacos monoclonales por pacientes con COVID-19 interfiere con la concentración sérica de angiotensina II?

Introdução:uma vez conhecidos os mecanismos de patogênese do SARS-CoV-2, vários métodos de tratamento para a COVID-19 foram desenvolvidos, dentre eles destaca-se o uso dos anticorpos monoclonais para o contexto de pacientes em estágios graves da doença. Objetivo: compreender se o uso dos anticorpos monoclonais para tratamento da COVID-19 grave interfere nos níveis séricos da angiotensina II. Metodologia:Para a realização dessa pesquisa foram selecionados através do DeCS e MeSH os descritores "COVID-19", "Angiotensin II" e "Antibodies, Monoclonal" e seus respectivos "entry terms" sugeridos pela base MeSH. Posteriormente,utilizando-se os operadores booleanos OR e AND, foi montada uma estratégia de busca, a qual foi utilizada nas bases de dados PUBMED, EMBASE, Web of Science, Cochrane Library e Scopus, sem restrição dedata de publicação ou idioma. Resultados:ao final do processo de seleção dos artigos, 29 foram selecionados para a leitura e análise completa. Nesta revisão, foram abordados diferentes tipos de anticorpos monoclonais, os quais foram oportunamente agrupados de acordo com o seu mecanismo de ação. Conclusão: foi possível concluir que das cinco classes de anticorpos monoclonais tratadas neste trabalho, três potencialmente podem causar alterações nos níveis séricos de angiotensina II (AU).

Introduction:once the mechanisms of pathogenesis of SARS-CoV-2 are known, several methods of treatment for COVID-19 have been developed, among them the use of monoclonal antibodies for the context of patients in severe stages of the disease. Purpose:to understand whether the use of monoclonal antibodies for the treatment of severe COVID-19 interferes with serum angiotensin II levels. Methodology:For this research were selected through DeCS and MeSH the descriptors "COVID-19", "Angiotensin II" and "Antibodies, Monoclonal" and their respective entry "Terms" suggested by the MeSH database. Subsequently, using the boolean operators OR and AND, a search strategy was set up, which was used in the databases PUBMED, EMBASE, Web of Science, Cochrane Library and Scopus, without restriction of publication date or language. Results:at the end of the article selection process, 29 were selected for reading and full analysis. In this review, different types of monoclonal antibodies were addressed, which were opportunely grouped according to their mechanism of action. Conclusion:it was possible to conclude that of the five classes of monoclonal antibodies treated in this study, three potentially can cause changes in serum levels of angiotensin II (AU).

Introducción:Una vez conocidos los mecanismos de patogénesis del SARSCoV-2, se desarrollaron variosmétodos de tratamiento para el COVID-19, entre ellos, el uso de anticuerpos monoclonales para el contexto de pacientes en fases graves de la enfermedad. Objetivo:Comprender si el uso de anticuerpos monoclonales para el tratamiento de la COVID-19 grave interfiere en los niveles séricos de angiotensina II. Metodología:Los descriptores "COVID-19", "Angiotensina II", "Anticuerpos, Monoclonales" y sus respectivos "entry terms" (términos de entrada) sugeridos por el MeSH fueron seleccionados a través de DeCS yMeSH. Posteriormente, utilizando los operadores booleanos OR y AND, se estableció una estrategia de búsqueda que se utilizó en las bases de datos PUBMED, EMBASE, Web of Science, Cochrane Library y Scopus, sin restricción de fecha de publicación ni de idioma. Resultados:Al final del proceso de selección de artículos, se seleccionaron 29 artículos para su lectura y análisis completos. En esta revisión se han abordado diferentes tipos de anticuerpos monoclonales, que se han agrupado oportunamente según su mecanismo de acción. Conclusión:Se pudo concluir que de las cinco clases de anticuerpos monoclonales tratados en este trabajo, tres pueden potencialmente causar alteraciones en los niveles séricos de angiotensina II (AU).

Essential oil from Saussurea costus inhibits proliferation and migration of Eca109 cells via mitochondrial apoptosis and STAT3 signaling

Objective: To investigate the effect and its underlying molecular mechanisms of essential oil from Saussurea costus in esophageal cancer cell line Eca109. Methods: The chemical composition of essential oil from Saussurea costus was investigated by gas chromatography-mass spectrometry (GC-MS). The anti-proliferative, anti-migrative, and apoptotic effects of essential oil from Saussurea costus against Eca109 cells were analyzed. Moreover, the expression of proteins associated with cell cycle, metastasis, and apoptosis was determined. Results: GC-MS analysis showed that essential oil from Saussurea costus was predominantly comprised of sesquiterpenes. Saussurea costus essential oil inhibited the viability of Eca109 cells in a dose-and time-dependent manner with IC 50 values of (24.29±1.49), (19.16±2.27) and (6.97±0.86) μg/mL at 12, 24, and 48 h, respectively. The expression levels of target proteins in the cell cycle (phase G 1 /S), including cyclin D1, p21, and p53, were affected by Saussurea costus essential oil. The essential oil also downregulated the expression of metastasis-related proteins MMP-9 and MMP-2. Moreover, it induced apoptosis of Eca109 cells through the mitochondrial pathway, as well as inhibition of STAT3 phosphorylation. Conclusions: The essential oil from Saussurea costus exhibited anti-proliferative, anti-migrative, and apoptotic effects on Eca109 cells, and could be further explored as a potential anti-esophageal cancer agent.

Implicações da COVID-19 no Sistema Cardiovascular: uma Revisão de Literatura / Implications of COVID-19 on the Cardiovascular System: a Literature Review

Introdução: O novo coronavírus da Síndrome Respiratória Aguda Grave 2 (SARS-CoV-2), responsável pela Doença do Coronavírus 2019 (COVID-19), é um vírus capaz de causar pneumonia viral, além de complicações extrapulmonares. Revisou-se conceitos básicos sobre a COVID-19, focando nos seus efeitos sobre o sistema cardiovascular. Métodos: Realizou-se revisão de literatura a partir de buscas nas bases de dados PUBMED, Scielo e LILACS entre Janeiro de 2019 a Maio de 2020, com as palavras chaves: "COVID-19" AND "Cardiovascular" e seus correlatos em português e inglês. Foram excluídos estudos repetidos, relatos de caso, estudos experimentais em animais, cartas ao editor, comentários, estudos não disponíveis em inglês ou português e os que limitavam-se à terapêutica da doença. Selecionaram-se estudos observacionais, estudos descritivos, revisões de literatura e revisões sistemáticas. Resultados: A ligação entre a injúria miocárdica e a infecção pelo novo coronavírus é consequência, em grande parte, da sua relação fisiopatológica com o receptor ECA-2, interação capaz de desequilibrar os sistemas imune e cardiovascular. As complicações mais comuns incluem arritmia, lesão cardíaca, miocardite fulminante, insuficiência cardíaca, embolia pulmonar e Coagulação Intravascular Disseminada (CIVD). Ademais, pacientes com condições cardíacas prévias possuem risco aumentado, inclusive para morbimortalidade hospitalar. Conclusão: Conclui-se que a COVID-19 é uma doença com tropismo por vários órgãos, capaz de gerar agressões em diversos sistemas, entre eles, o cardiovascular, cujos danos se devem a mecanismos que afetam tanto a estrutura do miocárdio quanto dos vasos, podendo levar ao óbito. Desta forma, há necessidade de avaliação precoce e monitoramento contínuo dos danos cardíacos.

SARS-CoV-2 impact on oral health: a general view / Impacto del SARS-CoV-2 en la salud oral: una visión general

Abstract Coronavirus disease 2019 (COVID-19) is a new disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. China reported the first case of COVID-19 in December 2019, and a few months later, the World Health Organization declared it as a pandemic. Oral ulcers in adult patients have been associated with COVID-19. However, no cases have yet been documented in children. The angiotensin-converting enzyme-2 (ACE2) receptor has been identified in tissues of the oral cavity. Studies have identified the tongue as the site with the highest expression of ACE2, and the oral epithelium, gingival epithelium, and salivary glands as sites of lesser extent expression. ACE2 expression is lower in children and varies with age. SARS-CoV-2 in saliva has been identified in various studies, which suggests that this could be a useful sample for diagnosis. However, its presence in saliva would indicate the high risk of contagion of this fluid.

Resumen La COVID-19 es una nueva enfermedad causada por el SARS-CoV-2 (coronavirus tipo 2 del síndrome respiratorio agudo grave). El primer caso de COVID-19 se reportó en China en diciembre de 2019, y unos meses después la Organización Mundial de la Salud la declaró como una pandemia. En pacientes adultos se han asociado úlceras orales a la COVID-19; en niños aún no se han documentado casos. El receptor de la enzima convertidora de la angiotensina 2 (ECA2) se ha identificado en tejidos de la cavidad oral. Los estudios han identificado que la lengua es el sitio con mayor expresión del receptor de la ECA2, y el epitelio bucal, el epitelio gingival y las glándulas salivales lo son en menor medida. La expresión de la ECA2 es menor en los niños y va aumentando con la edad. En diversos estudios se ha identificado el SARS-CoV-2 en la saliva, lo que sugiere que podría ser una muestra útil para el diagnóstico de este virus. Sin embargo, su presencia en saliva indicaría un alto riesgo de contagio de este fluido.

Na covid-19 é real a não suspensão dos inibidores do sistema renina angiotensina aldosterona? / In covid-19, the non-suspension of inhibitors of the renina angiotensin aldosterone system is real?

A interação dos bloqueadores do sistema renina angiotensina com o SARS-CoV-2 permanece obscura. Os inibidores do sistema renina angiotensina aldosterona (IECAs) e os bloqueadores do receptor AT1 da angiotensina 2 (BRAs) são fármacos com evidências robustas para terapia farmacológica de pacientes portadores, principalmente de hipertensão arterial e insuficiência cardíaca, além de outras comorbidades cardiovasculares. Os pacientes que se beneficiam desta terapêutica são considerados grupos de risco para má evolução desta virose e não há na literatura um consenso a respeito desta questão, em vista do vírus utilizar a expressão da ECA2 para penetração no ser humano. Apesar destas considerações fisiopatológicas da biologia do vírus, as principais diretrizes recomendam não suspender a terapia dos pacientes em uso dos bloqueadores do sistema renina angiotensina aldosterona no curso da infecção com o COVID-19. Aditivamente, o estudo BRACE-CORONA trouxe evidências mais consistentes para não suspensão desses fármacos

The interaction of blockers of the renin angiotensin system with SARS-COV-2 remains unclear. Inhibitors of the renin angiotensin aldosterone system (ACE inhibitors) and angiotensin 2 AT1 receptor blockers (BRAs) are drugs with robust evidence for pharmacological therapy for patients with mainly arterial hypertension and heart failure, and other cardiovascular comorbidities. Patients who benefit from this therapy are considered groups at risk for poor evolution of this virus and the literature still does not have a consensus on this issue, in view of the virus using the expression of ECA2 to penetrate in humans. Despite these athophysiological considerations of the biology of the virus, the main guidelines recommend not to suspend therapy for patients using blockers of the renin angiotensin aldosterone system in the course of infection with COVID-19. In addition, the BRACE corona study has more consistent evidence for not suspending these drugs.

LINC01140 regulates the proliferation and invasion of esophageal squamous cell carcinoma Eca109 cells via miR-452-5p/Wnt/β-catenin axis / 中国肿瘤生物治疗杂志

@# [摘 要] 目的： 探讨长链非编码RNA（lncRNA）LINC01140在食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）组织及细胞中的表达及其对Eca109细胞增殖与侵袭的影响及其分子机制。方法：选取2012年3月至2015年5月河北医科大学第四医院收治的133例ESCC患者的临床资料和GEPIA数据库中收集的182例ESCC组织及286例食管正常黏膜组织的LINC01140表达数据，以及ESCC细胞系Kyse150、Eca109和TE13。用qPCR法检测癌组织和细胞中LINC01140的表达水平，分析其表达水平与患者临床病理特征及预后的关系。分别将pcDNA3.1-LINC01140、阴性对照（pcDNA3.1-NC）或miR-452-5p mimic及阴性对照（miR-NC）转染到Eca109细胞，MTS、Transwell实验分别检测细胞的增殖与侵袭能力。用双荧光报告基因实验及TOP/FOP报告基因系统检测LINC01140与miR-452-5p的靶向结合作用及LINC01140对Wnt/β-catenin通路活化水平的影响。结果：LINC01140在ESCC组织和细胞中表达均显著下调（均P<0.01），LINC01140低表达与ESCC患者年龄、淋巴结转移、TNM分期及OS密切相关（均P<0.05）。LINC01140过表达明显抑制Eca109细胞的增殖及侵袭能力（均P<0.01）。机制研究表明，LINC01140可能通过竞争结合miR-452-5p影响Wnt/β-catenin信号通路的活化水平继而调控Eca109细胞的恶性生物学行为。结论：LINC01140通过靶向miR-452-5p/Wnt/β-catenin轴促进ESCC细胞的增殖与侵袭能力，其有望成为ESCC患者靶向治疗的潜在靶点及预后评估的标志物。

Advances in the research of enterobacterial common antigen / 生物工程学报

The enterobacterial common antigen (ECA) is a polysaccharide composed of polysaccharide repeats that are located in the outer membrane of almost all Enterobacteriaceae bacteria and has diverse biological functions. ECA is synthesized by the synergistic action of multiple genes that are present in clusters on the genome of Enterobacteriaceae bacteria, forming the ECA antigen gene cluster, an important virulence factor that plays a role in host invasion and survival of Enterobacteriaceae in vivo. ECA also plays an important role in the maintenance of the bacterial outer membrane permeability barrier, flagella gene expression, swarming motility, and bile salts resistance. In addition, ECALPS, anchored in the core region of bacterial lipopolysaccharide, is an important surface antigen for bacteria, stimulating high levels of antibody production in the host and could be a target for vaccine research. This review summarizes ECA purification, genes involved in ECA biosynthesis, its immunological characteristics, biological functions and clinical applications.

A standardized extract of Centella asiatica (ECa 233) prevents temporomandibular joint osteoarthritis by modulating the expression of local inflammatory mediators in mice

Abstract Objectives To investigate the effect of a standardized extract of Centella asiatica (ECa 233), which has anti-inflammatory properties, on the local expression of the transient receptor potential vanilloid 1 (TRPV1), the acid-sensing ion channel subunit 3 (ASIC3), and the calcitonin gene-related peptide (CGRP) in the temporomandibular joint (TMJ) structure 21 days after injecting the TMJ with complete Freund's adjuvant (CFA). Methodology A mouse model was induced by analyzing the CFA-injected TMJ on days 7, 14, and 21. We assessed TMJ histology by the osteoarthritis cartilage grade score. Then, we observed the effect of different ECa 233 concentrations (30, 100, and 300 mg/kg) and of 140 mg/kg ibuprofen doses on TRPV1, ASIC3, and CGRP local expression on day 21. Results Osteoarthritis cartilage scores were 1.17±0.37 and 3.83±0.68 on days 14 and 21, respectively, in the CFA group (n=5). On day 21, TRPV1, ASIC3, and CGRP expression significantly increased in the CFA group. In the ibuprofen-treated group, TRPV1 expression significantly decreased, but ASIC3 and CGRP showed no significant difference. All ECa 233 doses reduced TRPV1 expression, but the 100 mg/kg ECa 233 dose significantly decreased ASIC3 expression. Conclusions TRPV1, ASIC3, and CGRP expression increased in mice with TMJ-OA on day 21. All ECa 233 and ibuprofen doses inhibited pathogenesis by modulating the local expression of TRPV1 and ASIC3. Therefore, ECa 233 was more effective than ibuprofen.

Enfermedad cardiovascular, oncológica y reumatológica, su comportamiento en pacientes COVID-19: Factores pronósticos, complicaciones y tratamiento

La infección por SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) puede presentar manifestaciones propias, pero también, puede exacerbar las de enfermedades preexistentes o provocar manifestaciones que simulen dichas patologías. Las enfermedades cardiovasculares, neoplásicas o reumatológicas son ejemplos de ello. Este tipo de patologías comparten factores de riesgo de mal pronóstico y de muerte por la infección, la posibilidad de desarrollar complicaciones a largo plazo, e implican un desafío al momento de instaurar medidas de seguimiento y tratamiento con requerimiento de valoración multidisciplinaria. Por ello, nuestro objetivo fue plantear las dificultades en el seguimiento a corto y largo plazo de este tipo de pacientes y evaluar cómo la pandemia afecta su tratamiento. La pandemia ha cambiado la práctica médica habitual, promoviendo nuevas formas de seguimiento de los pacientes, como la telemedicina, imponiendo jerarquizar la necesidad de atención y procedimientos presenciales, obligando a reasignar las partidas presupuestarias para poder hacer frente a la misma, con consecuencias que probablemente habrá que analizar a largo plazo.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection clinical course can present its own manifestations, but it can also exacerbate those of pre-existing diseases or cause manifestations that simulate said pathologies. Cardiovascular, cancer or rheumatological diseases are examples of this. These types of pathologies share risk factors for poor prognosis and death due to infection, the possibility of developing long-term complications, and they imply a challenge when establishing follow-up and treatment measures requiring multidisciplinary assessment. Therefore, our objective was to raise the difficulties in the short and long-term follow-up of this type of patients and to evaluate how the pandemic affects their treatment. The pandemic has changed the usual medical practice, promoting new forms of patient follow-up, such as telemedicine, imposing a hierarchy of the need for face-to-face care and procedures, forcing budget items to be reallocated to be able to deal with it, with consequences that are likely to it will have to be analyzed in the long term.

A infecção por SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pode apresentar manifestações próprias, mas também pode exacerbar aquelas de doenças pré-existentes ou causar manifestações que simulam essas patologias. Doenças cardiovasculares, neoplásicas ou reumatológicas são exemplos disso. Esses tipos de patologias compartilham fatores de risco para mau prognóstico e óbito por infecção, possibilidade de desenvolvimento de complicações em longo prazo, e representam um desafio no estabelecimento de medidas de acompanhamento e tratamento que requerem avaliação multidisciplinar. Portanto, nosso objetivo foi levantar as dificuldades no acompanhamento a curto e longo prazo desse tipo de paciente e avaliar como a pandemia afeta seu tratamento. A pandemia alterou a prática médica usual, promovendo novas formas de acompanhamento do paciente, como a telemedicina, impondo uma hierarquia da necessidade de atendimento e procedimentos presenciais, obrigando a realocação de itens orçamentários para poderem lidar com ela, com consequências que provavelmente terá que ser analisado a longo prazo.

Expresión génica de receptores ECA2 en cavidad bucal y glándulas salivales y su papel en la infección por SARS CoV2. Revisión de la literatura / Gene Expression of ECA2 Receptors in the Oral Cavity and Salivary Glands and Its Role in SARS CoV2 Infection. Literature Review

Resumen Los receptores ECA2 presentan una expresión génica importante en las células escamosas de la lengua y glándulas salivales, mecanismo que es conveniente para la inoculación de SARS CoV2 toda vez que busca hacer el complejo de ensamblaje mediante su glicoproteína o proteína espiga hacia el receptor ECA2 de la mucosa bucal. Una vez inoculado y favorecido por las proteasas es la llave que permite la entrada del virión en la célula huésped para su posterior replicación, aumento de carga viral y potencial desaminación e infección; los estomatólogos deben estar alerta de los mecanismos de infección en cavidad bucal para protección propia y de los pacientes que son atendidos por este personal de salud.

Abstract ECA2 receptors have an important gene expression in the squamous cells of the tongue and salivary glands, a mechanism that is convenient for the inoculation of SARS CoV2 since it seeks to make the assembly complex through its glycoprotein or spike protein towards the ECA2 receptor of the oral mucosa. Once inoculated and favored by proteases, it is the key that allows the entry of the virion into the host cell for its subsequent replication, increase of viral load and potential deamination and infection; dental professionals must be alert to the mechanisms of infection in the oral cavity for their own protection and that of the patients who are treated by this health personnel.

Eje Renina Angiotensina, Enzima Convertidora de Angiotensina 2 y Coronavirus / Renin Angiotensin Axis, Angiotensin Converting Enzyme 2 and Coronavirus

Resumen: El sistema renina angiotensina aldosterona (SRAA) es el principal regulador del volumen plasmático, manteniendo la homeostasis cardiovascular e hidrosalina. En la vía clásica, la enzima convertidora de angiotensina (ECA) genera Angiotensina II (AngII), de potente efecto inflamatorio y vasoconstrictor. Esta vía clásica es a su vez regulada por la ECA2, que convierte AngII a Ang 1-7, cuyas acciones vaso dilatadoras y antiinflamatorias dan balance a los efectos de AngII. La ECA2 se ha relacionado con la patogenia de infecciones respiratorias como el virus respiratorio sincicial y el síndrome respiratorio agudo grave por coronavirus (SARS-CoV y SARS-CoV-2). Estudios recientes han demostrado que la ECA2 corresponde al principal receptor del SARS-CoV-2, que en conjunto con otros receptores como la serin proteasa TMPRSS2, permiten la fijación, fusión y entrada del virus a la célula huésped. En animales infectados por SARS-CoV se produce una caída de la concentración tisular de ECA2 y Ang 1-7, con la consiguiente sobreexpresión de AngII, y sus efectos vasoconstrictores e inflamatorios. Experimentos con ECA2 recombinante han mostrado un efecto protector frente a la sobreexpresión del SRAA en animales infectados por SARS-CoV, efecto similar al demostrado con el uso de bloquea- dores del receptor de AngII, AT1. La evidencia sobre el rol protector de ECA2 parece respaldar las recomendaciones respecto a no suspender estos medicamentos en la infección SARS-CoV-2. En este artículo presentamos el conocimiento actual sobre el rol del SRAA en la infección por SARS-CoV, a partir de conceptos fisiopatológicos, bases moleculares, y evidencia experimental y clínica.

Abstract: The renin-angiotensin-aldosterone system (RAAS) is the main plasma volume regulator, which maintains cardiovascular and hydrosaline homeostasis. In the classical pathway, the angiotensin converting enzyme (ACE) generates Angiotensin II (AngII), which is powerfully inflammatory and vasoconstrictive. This classical pathway is also regulated by ACE2, which converts AngI to Ang 1-9, and degrades AngII to Ang 1-7, whose vasodilatory and anti-inflammatory functions balance out the effects of AngII. ACE2 has been associated with the pathogenesis of respiratory infections such as RSV and severe acute respiratory syndrome coronavirus (SARS-CoV and SARS-CoV-2). Recent studies have shown that ACE2 corresponds to the main SARS-CoV-2 receptor, which together with other receptors such as the TMPRSS2, allows the virus to attach, fuse, and enter the host cell. These studies have shown that in animals infected with coronavirus there is a drop in tissue concentration of ACE2 and Ang 1-7, leading to overexpression of AngII and its vasoconstrictive and inflammatory effects. Experiments with recombinant ACE2 have shown a protective effect against overexpression of RAAS in coronavirus-infected animals, which is similar to that demonstrated with the use of AnglI receptor blockers (AT1). Evidence on the protective role of ACE2 seems to support the recommendations re garding not discontinuing these drugs in COVID-19 infection. In this article, we present the current knowledge about the role of RAAS in coronavirus infection, based on physiopathological concepts, molecular bases, and experimental and clinical evidence.

lncRNA LINC00886 over-expression inhibits malignant biological behaviors of esophageal squamous cell carcinoma Eca109 cells / 中国肿瘤生物治疗杂志

@#Objective: To investigate the expression of lncRNA LINC00886 in human esophageal squamous cell carcinoma (ESCC) tissues and cell lines, and its effects on proliferation, migration and invasion of Eca109 cells. Methods: The cancer tissues and corresponding para-cancerous tissues of 69 ESCC patients were collected in the biological specimen bank of the Fourth Hospital of Hebei Medical University from June 2014 to December 2016; the ESCC cell lines Eca109, TE13, TE1, Kyse150, Yes-2 and Kyse170 were also collected. LINC00886 gene expression in ESCC tissues and cell lines was detected by qPCR. Eca109 cells were transfected with pIRES2-LINC00886 and pIRES2-NC, respectively, and the overexpression efficiency of LINC00886 gene in Eca109 cells was detected by qPCR; MTS, clone formation assay, wound-healing assay and Transwell invasion assay were respectively used to detect the effect of LINC00886 over-expression on proliferation, migration and invasion ability of Eca109 cells. Results: The expression of LINC00886 gene in ESCC tissues was significantly lower than that in para-cancerous tissues (P<0.01), and its expression level was associated with tumor TNM stage and lymph node metastasis (both P<0.05). The expression level of LINC00886 gene in ESCC cell lines was also lower than that of the control group (all P<0.01). Compared with control group, the expression level of LINC00886 gene was significantly higher in Eca109 cells transfected with pIRES2-LINC00886 (both P<0.05). Compared with the control group, LINC00886 overexpression significantly inhibited the proliferation, migration and invasion abilities of Eca109 cells (all P<0.01). Conclusion: The decreased expression of LINC00886 gene may be related to the occurrence and development of ESCC. Over-expression of LINC00886 gene inhibits the proliferation, migration and invasion abilities of ESCC cells.

Expression of lncRNA01296 in esophageal carcinoma tissues and its effect on proliferation and migration of TE-2 cells / 中国肿瘤生物治疗杂志

@#Objective: To investigate the expression of lncRNA01296 in esophageal cancer (EC) tissues and its effect on the proliferation and migration of EC TE-2 cells. Methods:Atotal of 36 pairs of esophageal cancer tissues and corresponding para-cancerous tissues were collected from EC patients admitted to the Department of Thoracic Surgery,Affiliated Hospital of Chengde Medical College from January 2017 to September 2018. The human normal esophageal epithelial (HEEC) cells and human esophageal cancer cell lines ECA109, TE-1 and TE-2 were cultured. qPCR was used to detect the mRNAexpressions of lincRNA01296, SNRPA(small nuclear ribonucleoproteinA) and NGF (nerve growth factor) in EC tissues and cells. Recombinant lentiviral interference vectoror control vector were used to transfect EC cell lines, as sh-lncRNA01296#1,#2 and Mock groups. WB was used to detect the protein expressions of SNRPAand NGF in transfected cells. MTS assay was used to detect cell proliferation, and Transwell assays were used to detect cell invasion and migration of TE-2 cells after transfection. Results: The mRNAexpressions of lncRNA01296, SNRPAand NGF were significantly increased in esophageal cancer tissues and cell lines (all P<0.01), and these expressions in poorly differentiated TE-2 cells were higher than those in highly differentiated ECA109 and TE-1 cells (all P<0.05). The mRNAexpressions of lncRNA01296 and NGF in sh-lncRNA01296#1 and sh-lncRNA01296#2 groups were significantly lower than those in Mock group (all P<0.01), while the mRNAexpression of SNRPAshowed no statistical difference among three groups (P>0.05). The protein expressions of lncRNA01296 and NGF in sh-lncRNA01296#1 and sh-lncRNA01296#2 groups were significantly lower than those in Mock group (all P<0.01). The relative proliferation ability of cells in sh-lncRNA01296#1 and shlncRNA01296#2 groups was significantly lower than that of Mock group at 48 and 72 h after transfection (P<0.05 or P<0.01). The number of invasive cells was (72.0±6.3), (36.6±4.3) and (33.9±3.7) in Mock, sh-lncRNA01296#1 and sh-lncRNA01296#2 groups, respectively; and the number of migrated cells was (85.2±9.9), (47.5±8.1) and (43.8±6.5), respectively, indicating that the numbers of invasive and migrated cells in sh-lncRNA01296#1 and sh-lncRNA01296#2 groups were significantly less than those in Mock group(all P<0.01). Conclusion: lncRNA01296 can up-regulate SNRPAexpression to promote NGF-mediated proliferation and metastasis of EC cells, which may provide new target for the diagnosis and treatment of esophagealcancer.

Effects of cinnamaldehyde on apoptosis of oesophageal squamous cell carcinoma Eca109 cells and its mechanism / 中草药

Objective: To investigate effects of cinnamaldehyde (CA) on the proliferation and apoptosis of oesophageal squamous cell carcinoma Eca109 cells and to explore its mechanism. Methods: The effects of different concentrations (1.88, 3.75, 7.50, 15.00, 30.00 μg/mL) of CA on the proliferation of Eca109 cells were detected by MTS assay; Morphological changes were observed by phase contrast microscope; Flow cytometry was used to detect cell cycle distribution and apoptosis rate of Eca109 at different concentrations of CA; The expression of apoptosis-related protein Caspase-3/Caspase-9, pro-apoptosis protein Bax and anti-apoptosis protein Bcl-2 and Mcl-1 in ECA109 cells treated with different concentrations of CA for 24 h was detected by Western blotting. Results: After treated by CA with a concentration of 15.00, 30.00 μg/mL for 24 h, compared with the control group, the cell proliferation of Eca109 cells was significantly inhibited [(42.91 ± 2.15)%, (36.04 ± 2.97)% vs (100.00 ± 0.00)%, P < 0.05]; After treated by CA, Eca109 cells showed obvious apoptotic morphological changes; After treated with different concentrations of CA for 24 h, the proportion of cells in G0/G1 phase was decreased significantly (P < 0.05), while the proportion of cells in G2/M phase was increased significantly (P < 0.05); After treated by CA for 24 h, the apoptosis rate of Eca109 cells was increased significantly [(4.3 ± 0.11)%, (4.8 ± 0.07)%, (9.1 ± 0.13)% vs (1.0 ± 0.03)%, P < 0.05]; Compared with the control group, the fragment of protein Caspase-3 and Caspase-9 was significantly cleaved in Eca109 cells treated with different concentrations of CA for 24 h (P < 0.05); The expression levels of anti-apoptotic protein Bcl-2 and Mcl-1 were significantly decreased (P < 0.05), while the pro-apoptotic protein Bax expression was significantly up-regulated (P < 0.05). Conclusion: Cinnamaldehyde can inhibit the proliferation of oesophageal squamous cell carcinoma Eca109 cells and promote its apoptosis. The mechanism may be associated with the up-regulation of Caspase-3, Caspase-9, pro-apoptotic protein Bax and down-regulation of anti-apoptotic protein Bcl-2 and Mcl-1.