Effect of multi-glycosides of Tripterygium wilfordii on renal injury in diabetic kidney disease rats through NLRP3/caspase-1/GSDMD pyroptosis pathway / 中国中药杂志

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1β(IL-1β) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.

Sacubitril/valsartan attenuates left ventricular remodeling and improve cardiac function by upregulating apelin/APJ pathway in rats with heart failure / 中华心血管病杂志

Objective: To investigate the effect and mechanism of sacubitril/valsartan on left ventricular remodeling and cardiac function in rats with heart failure. Methods: A total of 46 SPF-grade male Wistar rats weighed 300-350 g were acclimatized to the laboratory for 7 days. Rats were then divided into 4 groups: the heart failure group (n=12, intraperitoneal injection of adriamycin hydrochloride 2.5 mg/kg once a week for 6 consecutive weeks, establishing a model of heart failure); heart failure+sacubitril/valsartan group (treatment group, n=12, intragastric administration with sacubitril/valsartan 1 week before the first injection of adriamycin, at a dose of 60 mg·kg-1·d-1 for 7 weeks); heart failure+sacubitril/valsartan+APJ antagonist F13A group (F13A group, n=12, adriamycin and sacubitril/valsartan, intraperitoneal injection of 100 μg·kg-1·d-1 APJ antagonist F13A for 7 weeks) and control group (n=10, intraperitoneal injection of equal volume of normal saline). One week after the last injection of adriamycin or saline, transthoracic echocardiography was performed to detect the cardiac structure and function, and then the rats were executed, blood and left ventricular specimens were obtained for further analysis. Hematoxylin-eosin staining and Masson trichrome staining were performed to analyze the left ventricular pathological change and myocardial fibrosis. TUNEL staining was performed to detect cardiomyocyte apoptosis. mRNA expression of left ventricular myocardial apelin and APJ was detected by RT-qRCR. ELISA was performed to detect plasma apelin-12 concentration. The protein expression of left ventricular myocardial apelin and APJ was detected by Western blot. Results: Seven rats survived in the heart failure group, 10 in the treatment group, and 8 in the F13A group. Echocardiography showed that the left ventricular end-diastolic diameter (LVEDD) and the left ventricular end-systolic diameter (LVESD) were higher (both P<0.05), while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower in the heart failure group than in the control group (both P<0.05). Compared with the heart failure group, rats in the treatment group were featured with lower LVEDD and LVESD (both P<0.05), higher LVEF and LVFS (both P<0.05), these beneficial effects were reversed in rats assigned to F13A group (all P<0.05 vs. treatment group). The results of HE staining showed that the cardiomyocytes of rats in the control group were arranged neatly and densely structured, the cardiomyocytes in the heart failure group were arranged in disorder, distorted and the gap between cells was increased, the cardiomyocytes in the treatment group were slightly neat and dense, and cardiomyocytes in the F13A group were featured similarly as the heart failure group. Masson staining showed that there were small amount of collagen fibers in the left ventricular myocardial interstitium of the control group, while left ventricular myocardial fibrosis was significantly increased, and collagen volume fraction (CVF) was significantly higher in the heart failure group than that of the control group (P<0.05). Compared with the heart failure group, the left ventricular myocardial fibrosis and the CVF were reduced in the treatment group (both P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). TUNEL staining showed that the apoptosis index (AI) of cardiomyocytes in rats was higher in the heart failure group compared with the control group (P<0.05), which was reduced in the treatment group (P<0.05 vs. heart failure group), this effect again was reversed in the F13A group (P<0.05 vs. treatment group). The results of RT-qPCR and Western blot showed that the mRNA and protein levels of apelin and APJ in left ventricular myocardial tissue of rats were downregulated in heart failure group (all P<0.05) compared with the control group. Compared with the heart failure group, the mRNA and protein levels of apelin and APJ were upregulated in the treatment group (all P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). ELISA test showed that the plasma apelin concentration of rats was lower in the heart failure group compared with the control group (P<0.05); compared with the heart failure group, the plasma apelin concentration of rats was higher in the treatment group (P<0.05), this effect was reversed in the F13A group (P<0.05 vs. treatment group). Conclusion: Sacubitril/valsartan can partially reverse left ventricular remodeling and improve cardiac function in rats with heart failure through modulating Apelin/APJ pathways.

Efficacy and safety of valsartan as an antiproteinuric agent in children aged 3 to 18 years with minimal change nephrotic syndrome

Background: Nephrotic syndrome is primarily a pediatric disorder which causes heavy proteinuria hypoalbuminemia, edema, and hyperlipidemia. Most children [90%] with nephrotic syndrome have idiopathic nephrotic syndrome caused in 85% of the patients by minimal change glomerular disease. Valsartan is an angiotensin II receptor blocker approved in adults for the treatment of hypertension, heart failure and it may also reduce proteinuria in nephritic syndrome

Objective: The aims of this study are to assess antiproteinuric effect of valsartan in nephrotic syndrome in comparison with propranolol and captopril, and to assess safety of valsartan in pediatric age

Patients and Methods: A case control study was done for 104 patients who attended three pediatric hospitals [The Central Pediatric Hospital, Al- Elwyia Pediatric Hospital and lbn Al-Baladi Hospital] where they were newly diagnosed with minimal change nephrotic syndrome and 38 of them [36.5%] were diagnosed with hypertension from 2006 to 2013 and they were followed up for six months [course of disease treatment]. Data collected in this study included: age, sex, time of diagnosis and blood pressure was measured. Laboratory tests were done which include: measurement of blood urea, serum creatinine, serum potassium, serum cholesterol, serum albumin, hemoglobin level, liver enzymes [serum glutamate pyruvate transaminase, serum glutamic-oxaloacetic transaminase and serum alkaline phosphatase] and albumin in urine

Result: Despite comparable reduction in blood pressure among the 3 groups, angiotensin receptor blockertreated group showed statistically more significant reduction in proteinuria [amount and onset after initiation of therapy] than other groups. Drug-related adverse events were minor and infrequent, no patient developed dangerous increase in serum potassium, renal function and liver function parameters nor dangerous decrease in mean hemoglobin level

Conclusion: Valsartan is an effective and safe drug to be used in childhood minimal chang nephrotic syndrom with rapid and consistent antiproteinuric effect even beyond its antihypertensive effect

Compatibility and stability of valsartan in a solid pharmaceutical formulation

Valsartan (VAL) is a highly selective blocker of the angiotensin II receptor that has been widely used in the treatment of hypertension. Active pharmaceutical ingredient compatibility with excipients (crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose and titanium dioxide) is usually evaluated in solid pharmaceutical development. Compatibility and stability can be evaluated by liquid chromatography. Studies were performed using binary mixtures of 1:1 (w/w) VAL/excipient; samples were stored under accelerated stability test conditions (40 ºC at 75% relative humidity). The results indicate that VAL is incompatible with crospovidone and hypromellose, which reduced the VAL content and gave rise to new peaks in the chromatogram due to degradation products.

Valsartana (VAL) é um bloqueador altamente seletivo do receptor da angiotensina II, que tem sido amplamente utilizado para o tratamento da hipertensão. Testes de compatibilidade com excipientes usualmente empregados em formulações sólidas são utilizados no desenvolvimento de formulações sólidas. Neste trabalho, realizaram-se testes utilizando misturas binárias na proporção 1:1 (m/m) de VAL/excipiente e as amostras foram armazenadas em condições de estabilidade acelerada (40 ºC em 75% de umidade relativa). Os resultados obtidos indicam a incompatibilidade de VAL com crospovidona e hipromelose, através da redução do teor de VAL e a presença de novos picos no cromatograma provenientes de produtos de degradação.

Efecto de los antagonistas de los receptores AT1 de la angiotensina II sobre la enfermedad periodontal inducida por inyecciones de lipopolisacáridos en ratas / Effect of ang II AT1 receptor antagonists, on periodontal disease induced by injections of lipopolysaccharide in rats

La Enfermedad Periodontal (EP) es una condición inflamatoria progresiva que afecta los tejidos que soportan y rodean a los dientes. Las endotoxinas bacterianas como los lipopolisacáridos (LPS), inducen una cascada inflamatoria causando resorción ósea mediante la producción y modulación de la red de citoquinas del tejido periodontal, del sistema RANK-RANKL-OPG y de la producción de especies reactivas del oxígeno (ERO). Siendo la vía final la activación del factor de transcripción NFκB para el control de la infección. Se sabe que el Sistema Renina Angiotensina (SRA) esta involucrado en la inflamación. Estas acciones pro-inflamatorias de la Ang II son producidas por la activación de NFkB mediante los receptores AT1, y por la generación de ERO. Nuestro objetivo fue determinar si la inhibición del receptor AT1 con el uso del valsartán reduciría la respuesta inmunitaria innata inflamatoria en un modelo de EP inducida por las inyecciones de LPS en la encía de las ratas. Nuestros resultados demuestran que el Valsartán disminuyó la leucocitosis sistémica, la movilidad dentaria, atenuó la pérdida de peso corporal de las ratas, disminuyó la formación de enzimas antioxidantes y NOS, redujo la producción y liberación de citocinas pro inflamatorias y aumentó las citocinas antinflamatorias, disminuyó la activación de p-p38, p-NFkB y la expresión de los receptores TLR4. El Valsartán también revirtió los efectos del LPS sobre la resorción ósea ya que disminuyó el número de osteoclastos, la expresión de los receptores RANK/RANKL/OPG y la relación RANKL/OPG y aumentó los depósitos de calcio y colágeno. Los mecanismos por los cuales el Valsartán reduce los efectos inflamatorios producidos por el LPS no están claras, pero la interferencia del ensamblaje de la NAD(P)H oxidasa con apocinina y el Tempol, indica que el Valsartán puede interferir con los pasos para el reconocimiento de LPS y su asociación con TLR4. Concluyéndose que las ERO participan en la señalización intracelular de la ANG II, vía el AT1R. Este estudio ayuda a dilucidar el papel del SRA en procesos inflamatorios. Además contribuye con sus resultados a ofrecer una alternativa terapéutica en el tratamiento de la EP.