Standardized phytopreparations and cucurbitacin IIb from Ibervillea sonorae (S. Watson) greene induce apoptosis in cervical cancer cells by Nrf2 inhibition.

ETHNOPHARMACOLOGY RELEVANCE: Ibervillea sonorae (S. Watson) Greene is a plant from northwestern Mexico, known as "Wereke" or "Guareque", used by the Mayo ethnic group to treat diabetes and cancer. Cucurbitacin IIb (CIIb), isolated from I. sonorae has apoptotic and antitumor activity in a model of cervical cancer with the HeLa cell line. One pathway affected by cucurbitacins is Nrf2, a glutathione transferase (GST) transcription factor, important in the regulation of mitochondrial oxidative stress (MOS). A signal of MOS is the change in the mitochondrial membrane potential (ΔΨm), which has been detected in HeLa in the presence of CIIb. Fito-Ison-EtOH (Etanison) and Fito-Ison-EtOAc (Acetison) are phytopreparations from I. sonorae standardized according to their CIIb content (6.7 mg/g and 18.4 mg/g of CIIb, respectively). Etanison and Acetison have been reported to induce morphological changes in HeLa like those induced by CIIb. AIM OF THE STUDY: To evaluate the apoptotic and Nrf2 inhibition activity of the phytopreparations Acetison and Etanison from Ibervillea Sonorae in the HeLa cervical cancer cell line. MATERIALS AND METHODS: Antiproliferative activity was evaluated by the MTT method at 24, 48, and 72 h. For Acetison and Etanison, serial concentrations from 6.25 µg/mL to 100 µg/mL were tested, and for CIIb from 1.56 µg/mL to 50 µg/mL. The expression of Nrf2, caspase 3, and caspase 9 was evaluated by western blot, using concentrations of 30 µg/mL for Acetison, 50 µg/mL for Etanison, and 15 µg/mL for CIIb. Cisplatin was used as a positive control. RESULTS AND CONCLUSIONS: Apoptotic activity of Etanison and Acetison was demonstrated in HeLa, due to the presence of caspase-9 and caspase-3 in western blot assays. Likewise, both the phytopreparations and CIIb showed inhibition of Nrf2, associating apoptotic activity with the inhibition of the GST transcription factor. In this sense, the phytopreparations of I. sonorae, as well as their derivatives, have the potential to obtain and develop anticancer products.

The Beneficial Effects of Allicin in Chronic Kidney Disease Are Comparable to Losartan.

Recent studies suggest that allicin may play a role in chronic kidney disease (CKD), reducing hypertension and oxidative stress and improving renal dysfunction. In the present study, CKD was induced by 5/6 nephrectomy and the animals were divided into four treatment groups as follows: control (C), CKD, CKD+allicin (40 mg/kg pathway oral) (CKDA), and CKD+Losartan (20 mg/kg) (CKDL). After CKD induction, the rats developed hypertension from week 3 to the end of the study. This was associated with increased creatinine and blood urea nitrogen (BUN) levels in serum, increased albuminuria, increased urinary excretion of N-acetyl-ß-d-glucosaminidase (NAG), increased nephrin expression, and incrased histological alterations in the cortex. The levels of angiotensin receptors and endothelial nitric oxide synthase (eNOS) were decreased in the renal cortex from the CKD group. Otherwise, lipid and protein oxidation were higher in the CKD group than in the control group. A disturbance was observed in the expression levels of the nuclear factor erythroid 2-related factor 2/Kelch ECH associating protein 1 system (Nrf2/keap1) and the antioxidant enzymes catalase, superoxide dismutase, and heme oxygenase-1. Allicin or losartan treatments relieved renal dysfunction, hypertension, and oxidative stress. In addition, both treatments showed the same efficacy on the expression of angiotensin receptors, the nephrin, Nrf2/keap1 pathway, and eNOS. Further in silico analyses suggest that allicin and losartan could have a common mechanism involving interaction with AT1 receptors. Allicin showed antihypertensive, antioxidant, and nephroprotective effects. The beneficial effects showed by allicin are similar, or even better, than those of losartan. In fact, the effect of allicin on blood pressure and renal function is comparable to reductions seen with losartan, a prescription drug commonly used as a first-line therapy.

Anti-Inflammatory Therapy Modulates Nrf2-Keap1 in Kidney from Rats with Diabetes.

This study addressed the relationship of proinflammatory cytokines and Nrf2-Keap1 system in diabetic nephropathy. The experimental groups were control, diabetic, and diabetic treated with mycophenolate mofetil (MMF). The renal function, proinflammatory and profibrotic cytokines, oxidative stress, morphology, and nephrin expression were assessed. Diabetic group showed impaired renal function in association with oxidative stress and decreased Nrf2 nuclear translocation. These results were associated with increased mesangial matrix index, interstitial fibrosis, and increased nephrin expression in cortex and urine excretion. Additionally, interleukin-1ß, IL-6, and transforming growth factor-ß1 were increased in plasma and kidney. MMF treatment conserved renal function, prevented renal structural alterations, and partially prevented the proinflammatory and profibrotic cytokines overexpression. Despite that MMF treatment induced nephrin overexpression in renal tissue, preventing its urinary loss. MMF salutary effects were associated with a partial prevention of oxidative stress, increased Nrf2 nuclear translocation, and conservation of antioxidant enzymes in renal tissue. In conclusion, our results confirm that inflammation is a key factor in the progression of diabetic nephropathy and suggest that treatment with MMF protects the kidney by an antioxidant mechanism, possibly regulated at least in part by the Nrf2/Keap1 system, in addition to its well-known anti-inflammatory effects.

Urinary excretion of neutrophil gelatinase-associated lipocalin in diabetic rats.

UNLABELLED: Recent studies suggest that tubular damage precedes glomerular damage in the progression of diabetic nephropathy. Therefore, we evaluated oxidative stress and urinary excretion of tubular proteins as markers of tubular dysfunction. METHODS: Diabetes was induced in rats by streptozotocin administration (50 mg/kg). Oxidative stress was assessed by measuring the activity of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD); additionally, expression levels of 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), and oxidized protein (OP) were quantified. Whole glomerular filtration rate (GFR) was measured. Urinary excretion of neutrophil gelatinase-associated lipocalin (uNGAL), osteopontin (uOPN), and N-acetyl-ß-D-glucosaminidase (uNAG) was also determined. RESULTS: Diabetic rats showed an increase in uNGAL excretion 7 days following induction of diabetes. Diuresis, proteinuria, albuminuria, creatinine clearance, and GFR were significantly increased by 30 days after induction. Furthermore, there was an increase in both CAT and SOD activity, in addition to 3-NT, 4-HNE, and OP expression levels. However, GPx activity was lower. Serum levels of NGAL and OPN, as well as excretion levels of uNGAL, uOPN, and uNAG, were increased in diabetics. Tubular damage was observed by 7 days after diabetes induction and was further aggravated by 30 days after induction. CONCLUSION: The tubular dysfunction evidenced by urinary excretion of NGAL precedes oxidative stress during diabetes.

La ecocardiográfia transtorácica y transesofágica en el estudio de adultos con cardiopatía congénita y endocarditis infecciosa / The use of transthoracic and transesophageal echocardiography in patients with congenital heart disease and infective endocarditis

Se estudiaron 24 pacientes adultos (edad promedio 28 años) con cardiopatía congénita. En todos, el diagnóstico de endocarditis infecciosa se estableció con los criterios de Duke y en 18 se confirmó en cirugía y/o por anatomía patológica. Se dividieron en 2 grupos: el grupo A se formó con 13 pacientes que mostraban obstrucción al vaciamiento del ventrículo izquierdo, diez con válvula aórtica bicúspide. El grupo B se formó con 11 pacientes que tenían un cortocircuito aislado (PCA o CIV), o asociado a otras anomalías. Se demostró que las principales alteraciones asociadas con el proceso infeccioso fueron el trauma del endocardio o endotelio vascular por flujo turbulento acelerado (lesión jet) y las deformaciones valvulares. Los registros ecocardiográficos, principalmente transesofágicos, mostraron vegetaciones infecciosas en las cuatro válvulas cardíacas, endocarditis mural en ambos ventrículos y en la aurícula derecha, abscesos perivalvulares y trayectos fistulosos. La información ecocardiográfica ayudó en la selección del tipo de tratamiento en este grupo de pacientes con alta mortalidad hospitalaria(25 por ciento)

Endocarditis infecciosa mitral y/o aórtica. Correlación entre ecocardiografía transesofágica, cirugía y anotomía patológica / Mitral and/or aoertic infective endocarditis

El objetivo de este estudio fue correlacionar los hallazgos obtenidos por ecocardiografía transesofágica con los obtenidos durante la cirugía y el estudio de anatomía patológica en pacientes con endocarditis infecciosa (EI) en válvula mitral y/o aórtica. Se estudiaron 28 pacientes a quienes se les realizó historia clínica, estudio bacteriológico y ecocardiograma transesofágico (ETE). En el estudio bacteriológico se encontraron hemocultivos positivos en 15 casos, en 13 los hemocultivos fueron negativos. El ETE demostró vegetaciones infecciosas en válvula mitral en 11 casos y en 5 enfermos en ambas válvulas. Complicaciones relacionadas con el proceso infecciosos se encontraron en el 53 por ciento de los casos. La incidencia de eventos embólicos fue del 25 por ciento. La concordancia entre el ETE y la anatomía patológica, en relación a la presencia de vegetaciones, fue del 92.8 por ciento y entre el ETE y la cirugía, en relación a la presencia de vegetaciones y complicaciones, fue del 89.2 por ciento. El ETE es un método de gran utilidad no sólo para el diagnóstico, sino también para el pronóstico de la EI, por su alta concordancia con los estudios de anatomía patológica y cirugía