Modified Liuwei Dihuangtang Combined with Losartan Potassium Regulates ACE1/AngⅡ/AT1R Axis and Intestinal Flora in Rat Model of Diabetic Kidney Disease / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of modified Liuwei Dihuangtang in preventing and treating renal injury in diabetic kidney disease （DKD） via the angiotensin-converting enzyme 1 （ACE1）/angiotensin Ⅱ （AngⅡ）/angiotensin Ⅱ type 1 receptor （AT1R） axis. MethodFifty male SD rats were randomized into a normal group （n=8） and a modeling group （n=42）. The rats in the modeling group were fed with a high-sugar and high-fat diet for 6 weeks and intraperitoneally injected with 35 mg·kg-1 streptozotocin （STZ） to establish the model of DKD. After successful modeling， the rats were randomized into model， traditional Chinese medicine （modified Liuwei Dihuangtang granules 21 g·kg-1）， western medicine （losartan potassium， 33 mg·kg-1）， and integrated Chinese and western medicine （losartan potassium 33 mg·kg-1 combined with modified Liuwei Dihuangtang granules 21 g·kg-1） groups. The levels of fasting blood glucose （FBG）， urinary protein （Up）， blood urea nitrogen （Bun）， and serum creatinine （SCr） were measured in each group after 8 consecutive weeks of drug intervention. Enzyme-linked immunosorbent assay was employed to determine the serum levels of ACE1， AngⅡ， and AT1R. Western blot was employed to measure the protein levels of ACE1， AngⅡ， and AT1R in the renal tissue. The pathological and morphological changes of the renal tissue were observed after hematoxylin-eosin （HE） staining， Masson staining， and periodic acid Schiff 's （PAS） staining. The fecal samples of rats in each group were collected for 16S rDNA high-throughput sequencing. ResultCompared with the normal group， the model group showed elevated levels of Up， FBG， Bun， SCr， ACE1， AngⅡ， and AT1R （P<0.01）， serious lesions in the renal tissue， up-regulated protein levels of ACE1， AngⅡ， and AT1R （P<0.01）， increased Firmicutes/Bacteroidetes （F/B） ratio， decreased relative abundance of Lactobacillus， and increased relative abundance of Moralella and Bifidobacteria. Compared with the model group， drug intervention lowered the levels of Bun， SCr， ACE1， AngⅡ， and AT1R （P<0.01） and alleviated the pathological changes in the renal tissue. Chinese medicine and integrated Chinese and western medicine lowered the levels of Up and FBG （P<0.01）， and western medicine and integrated Chinese and western medicine down-regulated the protein levels of ACE1， AngⅡ， and AT1R. In addition， Chinese medicine down-regulated the protein levels of AngⅡ （P<0.01） as well as ACE1 and AT1R （P<0.05）. Chinese medicine and integrated Chinese and western medicine decreased the F/B ratio， and western medicine and Chinese medicine increased the relative abundance of Blautia. Chinese medicine and integrated Chinese and western medicine increased the relative abundance of Lactobacillus， Ruminococcus undetermined genera， and Bifidobacteria， decreased the relative abundance of Moralella， and increased the Chao 1 and Ace indexes （P<0.05）. Compared with the western medicine group， the integrated Chinese and western medicine group showed lowered levels of Up （P<0.01）， Bun （P<0.05）， and ACE1 and AT1R （P<0.01）， down-regulated protein levels of ACE1， AngⅡ， and AT1R （P<0.05）， alleviated pathological changes in the renal tissue， increased relative abundance of Bifidobacteria， and increased Chao 1 and Ace indexes （P<0.05）. ConclusionModified Liuwei Dihuangtang combined with losartan potassium can mitigate renal fibrosis by regulating the ACE1/AngⅡ/AT1R axis， increasing the relative abundance of Lactobacillus and Bifidobacterium， reducing the relative abundance of Moralella， improving the richness and evenness of intestinal flora， and alleviating pathological damage in the renal tissue.

Establishment of a rat model with aortic dissection induced by β-aminopropionitrile combined with angiotensin Ⅱ / 中国胸心血管外科临床杂志

@#Objective    To investigate the optimal administration combination of β-aminopropionitrile (BAPN) and Angiotensin Ⅱ (Ang-Ⅱ) in the establishment of SD rat aortic dissection (AD) model and the related complications. Methods    Forty-two three-week-old male SD rats were randomly divided into 7 groups: a group A (0.25% BAPN), a group B (0.40% BAPN), a group C (0.80% BAPN), a group D [1 g/(kg·d) BAPN], a group E [1 g/(kg·d) BAPN+ 1 μg/(kg·min) saline], a group F [1 g/(kg·d) BAPN+1 μg/(kg·min) Ang-Ⅱ] and a group G (control group). There were 6 rats in each group. The intervention period was 4 weeks (groups E and F were 4 weeks+5 days). Rats were dissected immediately if they died during the experiment. After the intervention, the surviving rats were sacrificed by pentobarbital sodium, and the whole aorta was separated and retained. Hematoxylin-eosin staining was used to observe the changes of aorta from the pathological morphology. Results    There was no statistical difference in the survival rate among the groups after 4 weeks of BAPN intervention (P>0.05). After 5 days of mini-osmotic pumps implantation, the survival rate of rats was higher in the group E than that in the group F (P=0.008), and the incidence of AD in the group E was lower than that in the group F (P=0.001). BAPN could affect the food and water intake of rats. After BAPN intervention for 4 weeks, the body weight of rats in the group G was higher than those in the intervention groups (P<0.05). BAPN combined with Ang-Ⅱ could make the aortic intima thick, elastic fiber breakage, arrangement disorder, and inflammatory cell infiltration in rats, which conformed to the pathological and morphological changes of AD. BAPN could also affect mental state and gastrointestinal tract. Conclusion    The combination of BAPN [1 g/(kg·d)] and Ang-Ⅱ [1 μg/(kg·min)] can stably establish AD model in rats, which will provide a stable carrier for further study of the pathogenesis and therapeutic targets of AD. However, the complications in this process are an unstable factor. How to balance the influence of BAPN on other tissues and organs in the process of AD model establishment remains to be further studied.

Angioedema por enalapril. Presentación de un caso

Los inhibidores de la enzima convertidora de angiotensina son utilizados por más de 40 millones de personas en todo el mundo para el tratamiento de enfermedades cardiovasculares. Son considerados seguros, aunque pueden producir angioedema severo en el 0,1 a 0, 5 % de los pacientes. Se presenta el caso de un paciente del sexo masculino, de 67 años de edad, con diagnóstico de diabetes mellitus e hipertensión arterial, tratado con metformina, hidroclorotiazida y enalapril desde hacía aproximadamente cuatro años, que ingresó en cuerpo de guardia con edema severo del tercio anterior de la lengua, sin compromiso respiratorio. Se indicó hidrocortisona y difenhidramina y evolucionó satisfactoriamente, por lo que fue dado de alta y se prescribió prednisona y difenhidramina por vía oral; se suspendió el enlapril y a las 48 horas se reevaluó y estaba asintomático. El mecanismo por el que estos medicamentos producen angioedema no está claro, pero probablemente sería por la acumulación tisular de bradiquinina y puede presentarse en cualquier momento del tratamiento. La correcta anamnesis, el diagnóstico precoz y el tratamiento inmediato con hidrocortisona por vía endovenosa son aspectos a considerar ante casos similares. El análisis del evento mediante la farmacovigilancia, permitió clasificarlo como severo, probablemente relacionado con el consumo de enalapril. Esto genera alertas para informar al personal de salud y tomar decisiones relacionadas con los medicamentos, que permitan la actuación inmediata con la finalidad de reducir la morbimortalidad.

Angiotensin converting enzyme inhibitors are used by more than 40 million people worldwide for the treatment of cardiovascular diseases. They are considered safe, although they can cause severe angioedema in 0.1 to 0.5% of patients. The case of a 67-years-old male patient diagnosed with diabetes mellitus and arterial hypertension, treated with metformin, hydrochlorothiazide and enalapril for approximately four years, who was admitted to the emergency room with severe edema of the third anterior of the tongue, without respiratory compromise is presented. Hydrocortisone and diphenhydramine were indicated and he evolved satisfactorily, for which he was discharged and prednisone and diphenhydramine were prescribed orally; he discontinued enlapril, 48 hours later he was reassessed and was asymptomatic. The mechanism by which these drugs produce angioedema is not clear, but it would probably be due to the tissue accumulation of bradykinin and can occur at any time during treatment. The correct history, early diagnosis and immediate treatment with intravenous hydrocortisone are aspects to consider in similar cases. Analysis of the event through pharmacovigilance allowed it to be classified as severe, probably related to the enalapril consumption. This generates alerts to inform health staff and make decisions related to medications, which allow immediate action in order to reduce morbidity and mortality.

Biomechanical Effects of Angiotensin 1-7 in Diabetes Rats Femur / Efectos Biomecánicos de la Angiotensina 1-7 en el Fémur de Ratas Diabéticas

SUMMARY: It is known that diabetes mellitus has late complications, including microvascular and macrovascular diseases. Diabetes can affect bones through biochemical markers of bone structure, density, and turnover. This study aimed to biomechanically investigate the bone-protective effects of angiotensin 1-7 (Ang 1-7), one of the active peptides in the renin-angiotensin system, in rats with diabetes. Thirty male Wistar albino rats, three months old and weighing 250-300 g, were divided into four groups: diabetes, Ang 1- 7, diabetes plus Ang 1-7, and control. One month later, diabetes developed in rats; the rats were sacrificed, and their right femur was removed. Three-point bending biomechanical tests were performed on the femurs. The diabetic group had significantly higher bone fragility than the other groups (Pr >.05). Bone fragility was lower, and bone flexibility was higher in the Ang 1-7 groups (Pr>F value 0.05). As a result of our study, the effect of Ang 1-7 on the bones of rats with diabetes was investigated biomechanically. Ang 1-7 has a protective impact on the bones of rats with diabetes.

Se sabe que la diabetes mellitus tiene complicaciones tardías, incluyendo enfermedades microvasculares y macrovasculares. La diabetes puede afectar los huesos a través de los marcadores bioquímicos de la estructura, la densidad y el recambio óseo. Este estudio tuvo como objetivo investigar biomecánicamente los efectos protectores en los huesos de la angiotensina 1-7 (Ang 1-7), uno de los péptidos activos en el sistema renina-angiotensina, en ratas con diabetes. Treinta ratas albinas Wistar macho, de tres meses de edad y con un peso de 250-300 g, se dividieron en cuatro grupos: diabetes, Ang 1-7, diabetes más Ang 1-7 y control. Un mes después, se desarrolló diabetes en ratas; se sacrificaron los animales y se extrajo su fémur derecho. Se realizaron pruebas biomecánicas de flexión de tres puntos en los fémures. El grupo diabéticos tenía una fragilidad ósea significativamente mayor que los otros grupos (Pr > 0,05). La fragilidad ósea fue menor y la flexibilidad ósea fue mayor en los grupos Ang 1-7 (valor Pr>F 0,05). Como resultado de nuestro estudio, se determinó biomecánicamente el efecto de Ang 1-7 en los huesos de ratas con diabetes. Se concluye que Ang 1-7 tiene un impacto protector en los huesos de ratas diabéticas.

Comparison of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors in the Management of Arterial Stiffness and Target Organ Damage in Patients with Hypertension

Abstract Background Arterial stiffness and hypertension are strong predictors of cardiovascular disease and mortality. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are first-line antihypertensive agents in reducing blood pressure and arterial stiffness. Objective The objective of this study was to compare the effects of ACEI and ARB in reducing arterial stiffness and preventing target organ damage in patients with hypertension. Methods This observational study included 654 participants who attend routine consultations at an outpatient hypertension clinic in 2 university hospitals. Patients were interviewed, and they underwent central and peripheral blood pressure measurements. Doppler echocardiography, carotid ultrasound, biochemical tests, and anthropometric parameters were carried out. Shapiro-Wilk, chi-square, and Fisher's exact test were used. A significance level of 5% was adopted. Results A total of 659 participants were evaluated in the study (398 from the ARB group and 256 from the ACEI group). Age, body mass index (BMI), central and peripheral blood pressure measurements, pulse wave velocity (PWV), left ventricular mass index, and carotid intima-media thickness did not show differences between the groups (p > 0.05). After linear regression analysis, the ACEI group had lower values of total vascular resistance (TVR) (p = 0.003) and augmentation pressure (p = 0.008), when compared to the ARB group. Conclusion This study showed that the ACEI group had a greater reduction in augmentation pressure and PWV. There were no differences between the groups regarding the improvement of outcomes related to central arterial pressure, PWV, and cardiac and vascular target organ damage.

Short-term Effects of Garlic-Based Diets on mRNA Expression of Angiotensinogen, Angiotensin-1 Converting Enzyme, and Atrial Natriuretic Peptide in Cyclosporine-Induced Prehypertensive Rats

The short-term effects of garlic, Allium sativum L., on the mRNA expression of angiotensin-1 converting enzyme (ACE), angiotensinogen (AGT), and atrial natriuretic peptide (ANP) in cyclosporine-induced prehypertensive rats were investigated in this work. Seven (7) groups of animals totaling n=7 were created. Prehypertensive (induced with 25mg/kg cyclosporine) and normal rats were given 10% and 20% diets based on garlic for 7 days. Alteration of Na+ and K+ levels, increased systolic and diastolic blood pressures, and ACE, AGT & ANP mRNA expressions were all associated with cyclosporin-induced prehypertension. In rats placed on garlic-based diets, these effects were reversed.

Bloqueo del eje renina angiontensina aldosterona (RAAS) en la enfermedad renal diabética. Más allá del control de la hipertensión arterial / Renin angiotensin aldosterone system (RAAS) and its suppression in diabetic kidney disease. Control of arterial hypertension and beyond

La enfermedad renal diabética (ERD) es una comorbilidad con alta prevalencia a nivel mundial, siendo una de las complicaciones más frecuentes de la diabetes mellitus (DM). La ERD se relaciona con complicaciones cardiovasculares y progresión de la enfermedad renal crónica (ERC), por ello la identificación de factores modificables, como el control de la presión arterial, es uno de los pilares más importantes en el manejo integral. En esta revisión hacemos un recorrido sobre el papel de la hipertensión y el bloqueo del eje renina angiotensina aldosterona (RAAS) en el curso de la ERD y las estrategias terapéuticas orientadas a la reducción de la presión arterial (PA), el bloqueo RAAS y el impacto en resultados renales y cardiovasculares. El objetivo de este artículo es hacer una revisión de las intervenciones más importantes que actúan bloqueando el eje renina angiotensina aldosterona (RAAS) y determinar si estas medidas en los pacientes con ERD, solo tienen impacto en el control de la presión arterial o si también son estrategias de nefro y cardio-protección. Conclusión: La ERD es una de las complicaciones más frecuentes de la diabetes mellitus (DM). El control de la PA sigue siendo un pilar fundamental para lograr estos objetivos. Los bloqueadores del RAAS (iECAS y BRAs) son los antihipertensivos de elección con efecto terapéutico por el bloqueo RAAS y esto les permite tener además del control de la PA, efectos nefroprotectores y cardioprotectores importantes en pacientes con ERD, sobre todo cuando hay la presencia de albuminuria. Evaluamos que además de los inhibidores de la enzima convertidora de angiotensina (iECAs) y los bloqueadores del receptor de angiotensina (BRAs), vienen tomando importancia los antagonistas selectivos del receptor mineralocorticoide (ARM) como Finerenona.

Diabetic kidney disease (DKD) is a comorbidity with a high worldwide prevalence, and one of the most frequent complications of diabetes mellitus (DM). CKD is related to cardiovascular complications and the progression of chronic kidney disease (CKD), therefore the identification of modifiable factors, such as blood pressure control, is one of the most important pillars in comprehensive management. In this review, we will analyze the role of hypertension and the renin-angiotensin-aldosterone system (RAAS) and its suppression in the course of CKD, and therapeutic strategies aimed at reducing blood pressure (BP), RAAS blockade, and the impact on renal and cardiovascular outcomes. The objective of this article is to review the most important interventions that act by blocking the renin-angiotensin-aldosterone system (RAAS) and to determine if these measures in patients with CKD only have an impact on blood pressure control or if they are also nephron and cardio-protective strategies. Conclusion: DKD is one of the most frequent complications of diabetes mellitus (DM). BP control continues to be a fundamental pillar to achieve these objectives. RAAS blockers (iECAS and ARBs) are the first-line antihypertensive with a therapeutic effect due to RAAS blockade and this allows them to have, in addition to BP control, important nephroprotective and cardioprotective effects in patients with CKD, especially when there is albuminuria. We evaluated that in addition to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), selective mineralocorticoid receptor antagonists (MRA) such as Finerenone are gaining importance.

Respiratory muscles: structure, function and relationship with the ACE gene: a brief morphofunctional communication / Músculos respiratorios: estructura, función y relación con el gen de la ECA: una breve comunicación morfofuncional

SUMMARY: Pulmonary ventilation is a mechanical process in which the respiratory muscles act in coordination to maintain the oxygenation of the organism. Any alteration in the performance of these muscles may reduce the effectiveness of the process. The respiratory muscles differ from the other skeletal muscles in the vital support that they provide through rhythmiccontractions. The structure and energy system of the muscles are specially adapted to perform this function. The composition of the respiratory muscles is exceptional; they are small, and present an abundant capillary network, endowing them with a high aerobic level and resistance to fatigue. Coordinated regulation of the local renin-angiotensin system provides proper blood flow and energy supply in the myofibrils of the skeletal muscle tissue. Specifically, this performance will depend to a large extent on blood flow and glucose consumption, regulated by the renin-angiotensin system. The angiotensin converting enzyme is responsible for degrading kinins, which finally regulate muscle bioenergy and glucose between the blood vessel and the skeletal muscle. The objective of this review is to describe the structure of the respiratory muscles and their association with the angiotensin converting enzyme gene.

La ventilación pulmonar es un proceso mecánico en el que los músculos respiratorios actúan coordinadamente para mantener la oxigenación en el organismo. Así, cualquier alteración en el desempeño de estos músculos puede reducir la efectividad del proceso. Los músculos respiratorios se diferencian de otros músculos esqueléticos, debido al apoyo vital que brindan a través de sus contracciones rítmicas. La estructura y el sistema energético de estos músculos están especialmente adaptados para realizar esta función. La composición de los músculos respiratorios es especial; son pequeñas y presentan una abundante red capilar, lo que les otorga un alto nivel aeróbico y resistencia a la fatiga. La regulación coordinada del sistema renina-angiotensina local, proporciona un adecuado flujo sanguíneo y suministro de energía a las miofibrillas del músculo esquelético. En concreto, este rendimiento dependerá en gran medida del flujo sanguíneo y del consumo de glucosa, regulado por el sistema renina-angiotensina. Aquí, la enzima convertidora de angiotensina es responsable de degradar las kininas, que finalmente regulan la bioenergía muscular y la glucosa entre el vaso sanguíneo y el músculo esquelético. El objetivo de esta breve comunicación es describir la estructura de los músculos respiratorios y su asociación con el gen de la enzima convertidora de angiotensina.

Influencia de la obesidad en la severidad de la infección por SARS-CoV-2

La obesidad es una enfermedad metabólica crónica asociada a un incremento de la morbimortalidad cuya prevalencia se ha incrementado a niveles pandémicos lo que la constituye como un factor de riesgo clínico típico de peor pronóstico en pacientes con COVID-19. El propósito de esta revisión fue categorizar los principales factores fisiopatológicos que influyen en la gravedad de COVID-19 en pacientes con obesidad, mediante la búsqueda sistemática de artículos publicados hasta el 11 de marzo de 2022 usando diferentes bases de datos (Scopus, Cochrane, PubMed, Web of Science y Medline). Los resultados indican que la presencia de angiotensina II permite el ingreso del virus SARS-CoV-2 en las células del tejido adiposo convirtiéndolo en un depósito importante del virus lo que causa una diseminación más rápida a órganos vecinos. Estos valores incrementados de angiotensina II en el pulmón pueden inducir a vasoconstricción que a su vez conduce a un desajuste de ventilación/perfusión e hipoxemia, así como a inflamación y daño oxidativo. El incremento de la angiotensina II en pacientes con obesidad puede exacerbar el aumento del nivel de angiotensina II inducido por COVID-19, lo que lleva a una lesión pulmonar más grave, además de la formación de microcoágulos que colapsan la irrigación a nivel capilar, sobre todo la del alveolo, causando fallo a este nivel con extravasación de líquidos y neumonía fulminante. Además, la obesidad produce una alteración del sistema inmune comprometiendo así su capacidad de respuesta ante la infección respiratoria y propiciando un empeoramiento de la enfermedad.

Obesity is a chronic metabolic disease associated with increased morbidity and mortality whose prevalence has increased to pandemic levels, making it a typical clinical risk factor for worse prognosis in patients with COVID-19. The purpose of this review was to categorize the main pathophysiological factors that influence the severity of COVID-19 in patients with obesity, through a systematic search for articles published up to March 11, 2022 using different databases (Scopus, Cochrane, PubMed, Web of Science and Medline). The results indicate that the presence of angiotensin II allows the SARS-CoV-2 virus to enter the adipose tissue cells, making it an important reservoir for the virus, which causes faster dissemination to neighboring organs. These increased values of angiotensin II in the lung can induce vasoconstriction which in turn leads to ventilation/perfusion mismatch and hypoxemia, as well as inflammation and oxidative damage. The increase in angiotensin II in the obese can exacerbate the increase in the level of angiotensin II induced by COVID-19, leading to more severe lung injury, in addition to the formation of microclots that collapse the irrigation at the capillary level, especially in the alveolus, causing failure at this level with fluid extravasation and fulminant pneumonia. In addition, obesity produces an alteration of the immune system, thus compromising its ability to respond to respiratory infection and leading to a worsening of the disease.

SARS-CoV-2 induced changes in the lungs based on autopsy cases

Context: Researchers throughout the world devote enormous efforts to reveal the peculiarities of the pathogenesis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, however, it continues to surprise and cause the death of millions of people. Aims: This article aims to study the molecular mechanisms provoked by SARS-CoV-2, the virus-induced changes in Angiotensin-converting enzyme 2 (ACE2) functionality, in the vascular homeostasis through CD34 expression, B-cell immunity through the expression of CD20 and CD79?, and adhesion molecules through E-cadherin. Settings and Design: This was a prospective, descriptive, and observational study. Methods and Material: A total of 15 autopsies of patients deceased by COVID-19 infection, confirmed by PCR, were performed. The lungs of all patients were examined histologically and immunohistochemically for ACE2, E-cadherin, CD34, CD20, and CD79?. Results: Immunohistological analysis showed increased ACE2 expression in all lung autopsy material affected by COVID-19 infection and we found a higher intensity of ACE2 expression than that of a healthy lung. CD20 examination reveals total deficiency of B-cells in the pulmonary parenchyma and CD79? is also absent. E-Cadherin is not expressed in the basal cellular sections where the contact elements are missing. CD34 demonstrates a desquamation of the endothelial cells, which indicates a direct damage of the vascular walls. Conclusions: We found that patients who died after severe COVID-19 had high immune deficiency and impaired intercellular communication in the parenchyma and endothelium of lung tissue, leading to severe thromboembolic complications in patients with multiple diseases.

Lung cancer in the older population: Interactive effects of angiotensin converting enzyme gene polymorphism (rs 4340 ID) and tobacco addiction in risk assessment

Background: rs4340ID polymorphism of angiotensin-converting enzyme (ACE) correlates with serum ACE levels in many known cancers. This study analyzed ACE rs4340 ID polymorphism in lung cancer (LC) in older patients of North India and correlated it with addiction status. Methods: The study enrolled all subjects aged 60 years and above with 154 LC and 205 healthy controls. Genotyping was done by polymerase chain reaction (PCR) and validated by sequencing of 10% of the sample. Statistical analysis was done by SPSS Statistics 21. Results: Genotype II was observed to have a significant 2.21-fold increased risk of LC as compared to the DD genotype and 3.43-folds enhanced risk with interaction of I allele with tobacco consumption habits as compared to D allele in LC was seen. Conclusion: The risk of LC was higher with II genotype as compared to DD genotype. Interactive effect showed that I allele with tobacco habits may increase the risk of LC.

Fast Skeletal Muscle Troponin and Tropomyosin as a Dietary Source of Antidiabetic and Antihypertensive Bioactive Peptides: An In Silico Study / Troponina y Tropomiosina de Músculo Esquelético como Fuente Alimentaria de Péptidos Bioactivos Antidiabéticos y Antihipertensivos: Estudio In Silico

Background: The nutraceutical properties of food hydrolysates rely on multiple biochemical interactions involving the modulation of enzymes and cellular receptors. Numerous bioactive peptides released from troponin and tropomyosin digestion have been identified. Their characterization has mostly been performed by hydrolysis catalyzed by proteases unrelated to the human digestive system. Objective: This study aimed to determine the bioactive profile of beef, pork, and chicken meat by analyzing the frequency and pharmacokinetics of biopeptides released from troponin and tropomyosin. Methods:In silico digestion and biopeptide release frequency were studied by three parameters; bioactive fragments release frequency (AE), frequency percentage (W), and mean occurrence (AS), all stated on the BIOPEP-UWM platform. Further on, hydrolysis end-products were screened based on gastrointestinal-absorption probability and pharmacokinetic profiling performed on SwissADME, SwissTargetPrediction, and ADME/Tlab bioinformatics web tools. Statistical analyses were performed using a one-way ANOVA test. Results: Dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibiting biopeptides exhibited the highest release frequency. Moreover, W and ASparameters showed no significant difference (p>0.05) between the myofibrillar isoforms assessed. Seven biopeptides were classified as highly absorbable and reported optimal drug-likeness compliance. Although biopeptides hold good pharmacokinetic properties, the therapeutic potency of biopeptides showed to be lower than those of DPP-IV and ACE-inhibiting drugs. Conclusions: Troponin and tropomyosin are rich dietary sources of bioactive peptides, mainly DPP-IV and ACE inhibitors. Digestion end-products are mainly dipeptides with optimal pharmacokinetic and drug-like properties, suggesting a potential therapeutic application in hypertensive and hyperglycemic disorders

Antecedentes: Las propiedades nutracéuticas de los hidrolizados de alimentos dependen de múltiples interacciones bioquímicos que involucran la modulación de enzimas y receptores celulares. Se han identificado numerosos péptidos bioactivos liberados de la digestión de troponina y tropomiosina, pero su caracterización se ha llevado a cabo principalmente por hidrólisis catalizada por proteasas ajenas al sistema digestivo humano. Objetivo: Este estudio tuvo como objetivo determinar el perfil bioactivo de la carne de res, cerdo y pollo mediante el análisis de la frecuencia y farmacocinética de los biopéptidos liberados de la troponina y la tropomiosina. Métodos: Se estudió la digestión in silico y la frecuencia de liberación de biopéptidos mediante dos parámetros; frecuencia de liberación de fragmentos bioactivos (AE), frecuencia porcentual (W) y ocurrencia media (AS), ambos indicados en la plataforma BIOPEP-UWM. Más adelante, los productos finales de la hidrólisis se examinaron en función de la probabilidad de absorción gastrointestinal y el perfil farmacocinético realizado en las herramientas bioinformáticas SwissADME, SwissTargetPrediction y ADME/Tlab. El análisis estadístico se llevó a cabo mediante una prueba ANOVA de una vía. Resultados: Los biopéptidos inhibidores de la dipeptidil peptidasa IV (DPP-IV) y la enzima convertidora de angiotensina (ECA) exhibieron la mayor frecuencia de liberación. Además, los parámetros W y ASno mostraron diferencias significativas (p> 0.05) entre las isoformas miofibrilares evaluadas. Siete biopéptidos se clasificaron como altamente absorbibles e informaron un cumplimiento óptimo de similitud con el fármaco. Aunque los biopéptidos tienen propiedades farmacocinéticas adecuadas, su potencia terapéutica demostró ser menor que la de los fármacos inhibidores de la DPP-IV y la ACE. Conclusiones: La troponina y la tropomiosina son una fuente dietética rica en péptidos bioactivos, principalmente DPP-IV e inhibidores de la ACE. Los productos finales de la digestión son principalmente dipéptidos con propiedades farmacocinéticas óptimas y similares a la de los fármacos, lo que sugiere una aplicación terapéutica factible en trastornos hipertensivos e hiperglicémicos

Efficacy and Safety of Fixed-Dose Combination of Efonidipine and Telmisartan in Stage II Hypertensive Patients: Results from Randomized Clinical Trial

Aim: The aim of this study was to evaluate the anti-hypertensive efficacy of a fixed-dose combination (FDC) of Efonidipine 40 mg and Telmisartan 40 mg in Stage II hypertensive patients. Study Design: Multicentric, randomized, double-blind, parallel, comparative Phase III clinical trial. Methodology: This clinical trial was conducted at six geographically distributed sites across India and enrolled 240 Stage II hypertensive patients. They were randomized into two groups in a ratio of 1:1 using computer-generated block randomization to receive E+T (FDC of Efonidipine 40 mg + Telmisartan 40mg) or C+T (FDC of Cilnidipine 10 mg + Telmisartan 40 mg) group intervention once daily for a period of 90 days. The study site staff, investigator and patients were blinded to the treatment allocation. The primary endpoint of the study evaluated the mean reduction in sitting systolic BP (SBP) and diastolic BP (DBP) from baseline to day 90 whereas the secondary endpoints assessed were mean reduction in BP from baseline to day 30 & 60, patients achieving target BP (<140/90 mmHg) and the safety and tolerability of the investigational products based on the incidences of adverse events (AEs) reported. Results: A total of 118 subjects were randomized to the E+T group wherein the mean (±SD) SBP and DBP at baseline was 167.25 ± 4.68/107.26 ± 5.19 mmHg. After 30 days of treatment with the E+T group, the mean reduction in SBP/DBP of 29.37/18.06 mmHg was observed whereas at Day 60 reduction of 38.55/22.69 mmHg was seen from the baseline. At Day 90, SBP/DBP decreased to 119.41±14.99/81.67±4.29 mmHg with a mean reduction of 47.94/25.89 mmHg in the E+T group. During the study period, the difference in systolic blood pressure between the treatments with E+T and C+T was -0.48 mmHg, with the two-sided 95% confidence interval (CI) ranging from -4.54 to 3.58?mmHg. The corresponding difference in diastolic blood pressure was -0.77 (95% CI: -2.60 to 1.06) mm?Hg. The upper boundary of the 95% CI was below the margin of 10?mmHg, confirming the non-inferiority of E+T to C+T. A total of 92% of patients who had been assigned to E+T treatment achieved their target BP goal. Only one patient reported an adverse event with E+T treatment. No unexpected AEs were reported in the E+T group suggesting its good safety and tolerability. Overall, the E+T treatment was effective, safe and well-tolerated by the patients for 90 days. Conclusion: It was concluded that the FDC of Efonidipine 40 mg and Telmisartan 40 mg was efficacious in the management of Stage II hypertension.

Kidney xenotransplantation: status quo and development trend of physiological research / 器官移植

Organ transplantation is the most effective treatment for all categories of end-stage organ diseases. To resolve the shortage of donors in organ transplantation, widespread attention has been diverted to xenotransplantation. At present, clinicians mainly highlight the problems related to xenotransplantation rejection and viral infection. The physiology of xenotransplantation has been rarely studied. Kidney performs endocrine function by producing erythropoietin (EPO), renin and activating vitamin D. Although these pathways are usually well preserved in allogeneic transplantation, species-specific differences, especially those between pigs and non-human primates, may still affect the physiological function of transplant organs. In this article, the changes of EPO, renin-angiotensin-aldosterone system (RAAS) and active vitamin D3 of pig and human after xenotransplantation were illustrated, aiming to provide reference for subclinical research of xenotransplantation.

Research progress of angiotensin converting enzyme 2 co-expression in non-small cell lung cancer and SARS-CoV-2 / 中国胸心血管外科临床杂志

@#Since the first case of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019, the virus has spread rapidly around the world and has become a global public health problem. In the process of this virus epidemic, compared with the general population, cancer patients are considered to be highly susceptible people, especially the lung cancer patients. Some studies have shown that angiotensin converting enzyme 2 (ACE2) may be the pathway for SARS-CoV-2 to infect the host. At the same time, ACE2 is often abnormally expressed in non-small cell lung cancer. Therefore, understanding the respective mechanisms of ACE2 in COVID-19 and non-small cell lung cancer has extremely important reference value for the study of vaccines and therapeutic drugs, and also provides meaningful guidance for the protection of patients with lung cancer during the epidemic. This article reviews the possible invasive mechanism of ACE2 in SARS-CoV-2 and its abnormal expression in non-small cell lung cancer.

The effects of high-intensity interval training on the renin-angiotensin system in spontaneously hypertensive rats / 中华物理医学与康复杂志

Objective:To observe any effect of high-intensity interval training on the blood pressure and renal function of Wistar-Kyoto rats modeling spontaneous hypertension (SHR) and to explore the mechanism of the renal renin-angiotensin system′s (RAS′s) role in this process.Methods:Twenty male SHR were randomly divided into a sedentary group and an exercise group, each of 10. Another 10 Wistar-Kyoto rats formed a normotensive control group. The rats in the normotensive and hypertensive sedentary groups were fed quietly in their cage, while the hypertensive exercise group performed high-intensity interval training for 8 weeks. After the last exercise, blood pressure, renal function, the kidney levels of nitric oxide and interleukin-6 (IL-6) and the protein expressions of angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R), AT2R and Mas receptor (MasR) were measured.Results:Compared with the normotensive group, the hypertensive sedentary group showed a significant increase in average blood pressure, IL-6, ACE and AT1R protein and the ratio of AT1R to AT2R. There was a significant decrease in the renal function, the average NO level and the expression of ACE2, AT2R and MasR protein. That group also showed a significant decrease in blood pressure, IL-6, ACE and AT1R protein expression and the AT1R: AT2R ratio compared with the hypertensive sedentary group, but a significant increase in renal function, average NO content and the expression of ACE2, AT2R and MasR protein.Conclusion:Eight weeks of high-intensity interval training has a protective effect on the kidneys by regulating the renin-angiotensin system, at least in rats.

Effect of ACE2 deletion on vasoconstriction reactivity of aortic segments in mice with tourniquet shock / 中国病理生理杂志

AIM:To observe the effect of angiotensin-converting enzyme 2(ACE2)deletion on vasoconstric-tion reactivity of aortic segments in ACE2 knockout(KO)mice with tourniquet shock(TS).METHODS:The 8-month-old male mice with C57BL/6 background were divided into wild-type(WT)control group,WT-TS group,KO group and KO-TS group,with 10 mice in each group,of which five were used for determination of vascular reactivity,and the other five for the other assays.The hindlimbs of the mice in WT-TS group and KO-TS group were ligated with tourniquet for 2 h and loosened for 4 h.The mice in WT group and KO group were subjected to the same treatment except for tourniquet liga-tion.The vasoconstriction reactivity of the aorta was measured on tensiometer.The morphological damage of the aorta was evaluated by vascular histopathology.Western blot was used to detect the expression of AT1,MAS,ACE and ACE2 pro-teins in aorta.The serum levels of angiotensin(Ang)Ⅱ and Ang-(1-7)were determined by enzyme-linked immunosorbent assay.RESULTS:Compared with WT group,the mice in WT-TS group had lower vascular reactivity to norepinephrine(NE)and obvious vascular lesions.The expression of ACE protein increased significantly(P＜0.01),while the expres-sion of ACE2 decreased(P＜0.05).The expression of AT1 protein in aorta decreased significantly,the expression of MAS protein increased significantly,and the AT1/MAS ratio decreased(P＜0.01).Serum Ang II level increased,serum Ang-(1-7)level decreased,and Ang Ⅱ/Ang-(1-7)ratio increased(P＜0.05).Compared with WT group,vascular reactivity in KO group increased at low concentration of NE(＜10-7 mol/L),and decreased at high concentration(＞10-7 mol/L)without vascular lesion.The expression levels of aortic AT1,MAS and ACE were all elevated(P＜0.05).The serum level of Ang Ⅱ increased(P＜0.05),but the level of Ang-(1-7)had no obvious change.Compared with KO and WT-TS groups,the aortic reactivity in KO-TS group subtracted apparently(P＜0.05),representing its curve shifting to the right obviously.The morphological damage aggravated slightly,and the expression of AT1 and ACE increased slightly in KO-TS group com-pared with WT-TS group(P＜0.05).However,the expression of MAS increased significantly in vascular tissue(P＜0.01).The serum levels of Ang Ⅱ and Ang-(1-7)further increased and decreased,respectively,and the Ang Ⅱ/Ang-(1-7)ratio increased(P＜0.01).CONCLUSION:Deficiency of ACE2 induces severe aortic hyporeactivity to NE during TS,which may be related to the increased imbalance of renin-angiotensin system in ACE2 gene knockout mice.

Correlation analysis between renin-angiotensin system and bone mineral density in children with glucocorticoid-induced osteoporosis / 中华内分泌外科杂志

Objective:To investigate the relationship between renin-angiotensin system (RAS) and bone mineral density in children with glucocorticoids-induced osteoporosis (GIOP) .Methods:From Apr. 2020 to May. 2021, 53 children with GIOP were recruited in the Children’s Hospital of Taiyuan Maternal and Child Health Hospital and included in the observation group, and 47 children who received glucocorticoid therapy but did not suffer from GIOP were included in the control group. The levels of serum RAS components and bone mineral density of the two groups of pediatric patients were detected and compared, and the risk clinical indicators affecting bone mineral density and GIOP were analyzed.Results:There were no significant differences between the observation group and the control group in terms of gender, age, BMI, disease type, type of glucocorticoid use, use of anti-osteoporosis (OP) drugs, expression levels of Angiotensin converting enzyme 2 (ACE2) or angiotensin II (Ang Ⅱ) (all P>0.05) . The bone density value of the observation group was lower than those of the control group, and the levels of angiotensin converting enzyme (ACE) (1.19±0.23) , angiotensin receptor 1 (AT1R) (1.24±0.24) , angiotensin receptor 2 (AT2R) (1.14±0.17) , and Mas receptor (MasR) (1.11±0.28) were significantly higher than those of the control group (1.00±0.23, 1.00±0.25, 1.00±0.21, 1.00±0.20) , and the differences were statistically significant (all P<0.05) . Pearson analysis showed that bone mineral density was negatively correlated with the levels of ACE ( r=-0.34, P=0.013) , AT1R ( r=-0.41, P=0.002) and AT2R ( r=-0.34, P=0.014) , and stepwise regression model showed that ACE ( t=-2.21, P=0.032) and AT1R ( t=-2.92, P=0.005) were the main factors affecting bone mineral density. Logistic regression model analysis showed that bone mineral density ( OR=0.85, P<0.001) , Ang Ⅱ ( OR=0.53, P=0.041) and AT2R ( OR=2.00, P=0.024) were independent clinical risk factors affecting GIOP (all P<0.05) . Conclusion:RAS components ACE and AT1R are independent risk factors affecting bone mineral density in children with GIOP, and are significantly correlated with bone mineral density in children.

Effect of fosinopril on angiotensin converting enzyme 2 and vascular endothelial growth factor in diabetic retinopathy mice / 解剖学报

Objective To explore the protective effect of fosinopril (Fos) on streptozotocin ( STZ) induced diabetic retinopatfry( DR) mice and on the expression of angiotensin converting enzyme 2(ACE2) and vascular endothelial growth factor (VEGF) in DR mice. Methods Totally forty-eight healthy male Kunming mice, thirty-six were randomly selected, and a diabetic mouse model induced by STZ was constructed after 6 weeks of high-fat diet. After the successful establishment of the model, the thirty-six mice were randomly divided into three groups: model group, Fos low concentration ( 5 mg/kg) group, and Fos high concentration ( 10 mg/kg) group. The remaining twelve mice were served as the control group. After 8 weeks administration, the bod)' weight and blood glucose level of mice in each group were determined. The change in the retinal structure was verified by HE staining. The serum level of VEGF was measured by ELISA. The expression of ACE2 in the retina tissue was verified by immunohistochemistry. The expression of ACE2 mRNA in diabetic retinopatlry was analyzed by Real-time PCR. The levels of ACE2 and VEGF protein in diabetic retinopatlry were detected by Western blotting. Results Fos ( 5 mg/kg, 10 mg/kg ) reduced significantly the proliferation of neovascularization in the inner boundaiy layer, down-regulated the expression of VEGF in the serum of diabetic mice and promoted the expression of ACE2 in the retina tissue of diabetic mice. In addition, the effect of the high concentration group of Fos had a stronger effect than the lower concentration group (P<0. 0 5 ) . Conclusion Fos has a protective effect on the retinopatlry of diabetic mice. This protective effect ma)' be mediated through the increased expression of ACE2 and the reduction of VEGF expression.

ZLY18 protects against angiotensin II-induced cardiac fibrosis via inhibiting TGF-β1/Smads pathway / 中国药理学通报

Aim To explore the effect of ZLY18 on angiotensin II-induced cardiac fibrosis and the underlying mechanism. Methods Ang II was used to induce cardiac fibrosis in vitro and in vivo. Cardiac fibroblasts were divided into blank control group, model group and medicine group. The medicine group was subdivided into ZLY18(L)group, ZLY18(M)group and ZLY18(H)group. Compound ZLY18 was given 1, 2, 5 μmol·L-1 respectively. C57BL/6 mice were randomly divided into control group, model group and medicine group. The medicine group were subdivided into ZLY18(L)group, ZLY18(M)group and ZLY18(H)group. Compound ZLY18 was given 10,20 and 50 mg·kg-1 respectively. Both the model group and the medicine group were given with Ang II to induce cardiac fibrosis. The changes of protein levels were detected by Western blot and immunofluorescence. The changes of cardiac function indexes in C57BL/6 mice were detected by small animal echocardiography. The morphology, cell arrangement and collagen fibers of cardiac fibroblasts were observed by tissue section staining and other methods. Results The model of Ang II-induced myocardial fibrosis was successfully established at the cell and animal levels, and ZLY18 treatment improved the elevated fibrosis-related protein caused by Ang II and abnormal cardiac function in mice. Moreover, ZLY18 was able to inhibit the increased phosphorylation of TGF-1 and Smad3 caused by Ang II and increased Smad2/3 nuclear entry, suggesting that the antifibrotic effect of ZLY18 might be related to the activation of TGF-1/Smads signaling pathway. Conclusions ZLY18 has a protective effect on Ang II-induced cardiac fibrosis. ZLY18 may inhibit TGF-β/Smads signaling pathway activation to exert anti-fibrotic effects.