Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial.

Background and objectives: Oxidative stress (OS) participates in the pathophysiology of septic shock, which leads to multiple organ failure (MOF), ischemia-reperfusion injury, and acute respiratory distress syndrome. Therefore, antioxidants have been proposed as therapy. Here, we evaluated the effect of antioxidant treatments in patients with septic shock with MOF and determined levels OS before and after treatment. This study was a randomized, controlled, triple-masked, and with parallel assignment clinical trial with a control group without treatment. Materials and Methods: It included 97 patients of either sex with septic shock. 5 treatments were used each in an independent group of 18 patients. Group 1 received vitamin C (Vit C), group 2 vitamin E (Vit E), group 3 n-acetylcysteine (NAC), group 4 melatonin (MT), and group 5 served as control. All antioxidants were administered orally or through a nasogastric tube for five days as an adjuvant to the standard therapy. Results: The results showed that all patients presented MOF due to sepsis upon admission and that the treatment decreased it (p = 0.007). The antioxidant treatment with NAC increased the total antioxidant capacity (p < 0.05). The patients that received Vit C had decreased levels of the nitrate and nitrite ratio (p < 0.01) and C-reactive protein levels (p = 0.04). Procalcitonin levels were reduced by Vit E (p = 0.04), NAC (p = 0.001), and MT (p = 0.04). Lipid-peroxidation was reduced in patients that received MT (p = 0.04). Conclusions: In conclusion, antioxidant therapy associated with standard therapy reduces MOF, OS, and inflammation in patients with septic shock.

Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome.

BACKGROUND: Aortic dilatation in Marfan syndrome (MFS) is progressive. It is associated with oxidative stress and endothelial dysfunction that contribute to the early acute dissection of the vessel and can result in rupture of the aorta and sudden death. We evaluated the participation of the glutathione (GSH) system, which could be involved in the mechanisms that promote the formation and progression of the aortic aneurysms in MFS patients. PATIENTS AND METHODS: Aortic aneurysm tissue was obtained during chest surgery from eight control subjects and 14 MFS patients. Spectrophotometrical determination of activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO) index, carbonylation, total antioxidant capacity (TAC), and concentration of reduced and oxidized glutathione (GSH and GSSG respectively), was performed in the homogenate from aortic aneurysm tissue. RESULTS: LPO index, carbonylation, TGF-ß1, and GR activity were increased in MFS patients (p < 0.04), while TAC, GSH/GSSG ratio, GPx, and GST activity were significantly decreased (p < 0.04). CONCLUSIONS: The depletion of GSH, in spite of the elevated activity of GR, not only diminished the activity of GSH-depend GST and GPx, but increased LPO, carbonylation and decreased TAC. These changes could promote the structural and functional alterations in the thoracic aorta of MFS patients.

Dehydroepiandrosterone inhibits events related with the metastatic process in breast tumor cell lines.

Dehydroepiandrosterone (DHEA), an adrenal hormone, has a protective role against cancer. We previously shown that DHEA inhibits the proliferation and migration of cell lines derived from breast cancer; however, the role of DHEA in others events related with these effects are unknown. We hypothesized that DHEA inhibits the expression of proteins and some events related with cell migration and metastasis. We determined the migration in Boyden chambers, the invasion in matrigel, anchorage-independent growth and the formation of spheroids in 3 cell lines (MCF-7, MDA-MB-231, ZR-75-30) derived from breast cancer exposed to DHEA. The secretion of metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and several pro-inflammatory molecules in the secretome of these cells was also evaluated. DHEA inhibited the migration in transwells and the invasion in matrigel of MCF-7 and MDA-MB-231 cells. Besides, DHEA inhibited the anchorage-independent growth on agar and decreased the size of spheroids, and also reduced the secretion of IL-1α, IL-6, IL-8, and TNF-α in all cell lines. Metalloproteinase-1 (MMP-1) secretion was slightly decreased by DHEA treatment in MDA-MB-231 cells. Our results also showed that inhibition of migration and invasion induced by DHEA in breast cancer cells is correlated with the decrease of cytokine/chemokine secretion and the diminution of tumor cells growth. MCF-7 cells were the most responsive to the exposure to DHEA, whereas ZR-75-30 cells responded less to this hormone, suggesting that DHEA could be used in the treatment of breast cancer in early stages.

The interleukin-1 gene cluster polymorphisms are associated with Takayasu's arteritis in Mexican patients.

Takayasu's arteritis (TA) is a chronic inflammatory arteritis of unknown etiology involving mainly the aorta and its major branches. The interleukin (IL) 1ß and IL-1 receptor antagonist have been playing an important role as regulators of inflammation. We investigated whether the polymorphisms at the IL-1B and IL-1RN gene cluster were associated with the genetic susceptibility to develop TA. We analyzed the IL-1B, IL-1F10.3, and IL-1RN polymorphisms in a sample of 58 TA patients, and 248 clinically healthy unrelated Mexican individuals by 5' exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. We found increased frequencies of different polymorphisms (C allele and TC genotype of IL-1F10.3; TT genotype of IL-1RN.4; C allele and TC genotype of IL-1RN6.1; G allele of IL-1RN6.2 and haplotypes "1T" and "1C" of IL-RN VNTR and IL-1RN6.1) in the group of TA when compared to healthy controls. On the other hand, decreased frequency of IL-1-511 TC genotype was found in the TA group compared to controls. IL-1B and IL-1RN gene polymorphisms could be involved in the risk of developing TA in the Mexican population. These associations were independent of the affected vessels.

Association between PON1 genetic polymorphisms and miscarriage in Mexican women exposed to pesticides.

BACKGROUND: Placental oxidative stress has been involved in the pathogenesis of certain reproductive adverse effects, including miscarriage. Paraxonase 1 (PON1) is a high-density lipoprotein(HDL)-linked enzyme that prevents oxidation of low-density lipoproteins (LDL) and is involved in detoxification from organophosphate pesticides. OBJECTIVE: To assess the association between maternal PON1 polymorphisms (PON1192Q/R, PON155 L/M y PON1-108C/T) and the risk of miscarriage in women chronically exposed to organophosphate pesticides in Mexico. METHODS: In a cross-sectional study, socio-demographic data, reproductive history data, environmental exposures, and other variables of concern were collected by means of a questionnaire from 264 women (floriculturists and wives of floriculturists) who had been pregnant sometime during the 10 years preceding the study. Blood samples were also collected from them. PON1192 and PON155 genotypes were determined by PCR amplification, and PON1-108 genotypes, by a TaqMan real-time polymerase chain reaction assay. Complete information regarding the results of pregnancy and maternal genotype tests was obtained for 514 pregnancies (35 miscarriages and 479 controls). The association between PON1 genotypes and miscarriage was evaluate through GEE models. RESULTS: The risk of miscarriage by mothers with PON1192RR genotype was 2.2 higher than by mothers with PON1192QR/PON1192QQ genotype (95% CI 0.93-5.17). The risk was close to 4 times higher in mothers with PON155MM/PON155LM genotype than in mothers with PON155LL genotype (OR=3.9; 95% CI 1.38-11.0). No significant differences were found in risk of miscarriage based on the maternal PON1-108C/T genotype. No evidence was found of an interaction between the various PON1 genotypes and the mothers' floricultural activity during pregnancy. CONCLUSIONS: This study suggests that there is an effect of genetic maternal PON1 polymorphisms on miscarriage and provides additional evidence that combines with the growing information about the ways in which certain PON1 genotypes can affect the development of the fetus in utero.