Therapeutic effects of oral liothyronine on aluminum phosphide poisoning as an adjuvant therapy: A clinical trial.

BACKGROUND: In aluminum phosphide (AlP) poisoning, death is mainly due to cardiovascular failure and refractory acute heart failure. There is a lot of evidence showing thyroid hormones have cardioprotective effects. OBJECTIVE: The purpose of this study was to evaluate the effect of oral liothyronine in the treatment of AlP poisoning. METHODS: Twenty-four patients from intensive care unit of Baharloo Hospital, Tehran, Iran, were included based on the inclusion and exclusion criteria. They were randomly divided into two parallel groups of 12 cases and 12 controls. Intervention in the case group was administration of 50 µg liothyronine via nasogastric tube after gastric lavage, in the first 6 h of poisoning. In both groups, the routine treatment of AlP poisoning was performed. Blood samples were prepared at the beginning of the study and after 12 h. Patients were followed up till discharge from the hospital or death. RESULTS: The findings demonstrated that oral liothyronine was able to significantly improve systolic blood pressure, arterial blood pH, and total thiol molecules and also could decrease lipid peroxidation, increase catalase activity, and prevent further decline in total antioxidant capacity. CONCLUSION: Liothyronine administration is effective in controlling AlP poisoning and can improve patients' outcome.

A mechanistic approach for modulation of chlorpyrifos-induced toxicity in human lymphocytes by melatonin, coenzyme Q10, and vinpocetine.

BACKGROUND: Chlorpyrifos (CP) is an organophosphorus pesticide that induces oxidative stress through the production of free radicals and depletes intracellular antioxidant reserves. In this study, the efficacy of three antioxidants (melatonin, coenzyme Q10 (CoQ10), and vinpocetine) on alleviation of toxic effects of CP was evaluated. MATERIALS AND METHODS: Cytotoxicity of CP, in the presence or absence of effective doses of melatonin, CoQ10, and vinpocetine, was determined in human peripheral blood lymphocytes after 72-h exposure. The levels of acetylcholinesterase (AChE) activity along with tumor necrosis factor α (TNF-α), as inflammatory index, were measured. Further, the viability and oxidative stress markers including cellular mitochondrial activity, cell death modes (apoptosis vs. necrosis), total antioxidant power (TAP), total thiol molecules (TTM), lipid peroxidation (LPO), and myeloperoxidase (MPO) activity were measured. RESULTS: CoQ10 and also the combination of the three antioxidants were the most notable in opposing toxicity of CP and led to increasing TAP and TTM; improvement of AChE activity; and lowering LPO, MPO, TNF-α, and apoptosis compared to CP alone. CONCLUSION: CP toxicity overwhelms the intracellular antioxidant defense mechanisms. Exogenous supplementation with antioxidants, such as the ones we have investigated, seems to be effective in the prevention of cytotoxicity of CP.

Antiapoptotic effects of cerium oxide and yttrium oxide nanoparticles in isolated rat pancreatic islets.

Type I diabetes mellitus is a metabolic disease caused by the impairment of pancreatic ß-cells mainly mediated through oxidative stress and related apoptosis. Islets transplantation seems a promising treatment for these patients, but during islets transplant, various types of stresses related to the isolation and transplantation procedure compromise the function and viability of islets. We recently hypothesized that the combination of cerium oxide (CeO2) and yttrium oxide (Y2O3) nanoparticles with a potential free radical scavenger behavior should be useful to make isolated islets survive until transplanted. In the present study, oxidative stress-induced apoptosis in isolated rat pancreatic islets exposed to hydrogen peroxide (H2O2) and the protective effects of CeO2 and Y2O3 nanoparticles were investigated. Exposure of islets to H2O2 (50 µm, 2 h) increased intracellular oxidant formation such as reactive oxygen species and subsequently apoptosis and decreased viability, glucose-induced adenosine triphosphate (ATP) production and glucose-stimulated insulin secretion. Pretreatment with CeO2 and/or Y2O3 nanoparticles reduced the oxidant formation and apoptosis and increased viability, glucose-induced ATP production and glucose-stimulated insulin secretion. These results suggest that this combination may protect ß-cell apoptosis by improving the oxidative stress-mediated apoptotic pathway.

Molecular mechanisms of a novel selenium-based complementary medicine which confers protection against hyperandrogenism-induced polycystic ovary.

The objective was to evaluate ovarian functionality and oxidative response in hyperandrogenism-induced polycystic ovary (PCO) and the protective effects of immunomodulator drug (IMOD), an electromagnetically-treated, selenium-based, herbal medicine. Daily oral administration of letrozole (1 mg/kg) for 21 consecutive days induced ovarian cysts in female rats. An effective dose of IMOD (30 mg/kg per day) was given intraperitoneally for 21 days. Biomarkers of ovarian function, serum concentrations of estradiol, progesterone, testosterone, and ovarian prostaglandin-E (PGE), were analyzed. To determine the role of oxidative stress (OS) in hyperandrogenism-induced PCO, concentrations of cellular lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxynitrite (ONOO), and tumor necrosis factor (TNF)-α as a marker of inflammation and apoptosis were measured in serum and ovaries. Letrozole-induced PCO resulted in significant increases in concentrations of lipid peroxidation and peroxynitrite in serum and ovary, but significantly decreased superoxide dismutase, catalase, and glutathione peroxidase. Serum concentrations of testosterone and TNF-α, and ovarian prostaglandin-E were increased (P < 0.001) in animals with cysts versus control, whereas estradiol and progesterone were decreased (P < 0.01 and P < 0.001, respectively). When compared with controls, letrozole induced irregular cycles and PCO characterized by a high incidence of subcapsular ovarian cysts with a diminished granulosa cell layer, luteinized granulosa cells in the cyst wall, significantly more atretic preantral and antral follicles, and absence of CL. There were almost no intact primary, secondary, and tertiary follicles in PCO rats. All end points assessed were significantly improved by IMOD and reached close to normal levels. In conclusion, the present study provided evidence that toxic free radicals and TNF-α were involved in the pathogenesis of PCO; furthermore, IMOD prevented ovarian histopathologic, endocrine, and biochemical alterations induced by hyperandrogenism.

Mechanistic links between oxidative/nitrosative stress and tumor necrosis factor alpha in letrozole-induced murine polycystic ovary: biochemical and pathological evidences for beneficial effect of pioglitazone.

This study aimed to investigate the possible relationship between ovarian functionality and the oxidative response during cystogenesis induced by hyperandrogenization with letrozole and examine protective effect of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, pioglitazone (PIO), in polycystic ovary (PCO). Ovarian cysts were induced by oral administration of letrozol (1 mg/kg/day) for 21 consecutive days in the female rats. Effective dose of PIO (20 mg/kg/day) was administrated orally for 21 days. Serum estradiol (E), progesterone (P), testosterone (T), and the ovarian immunomodulator prostaglandin E (PGE) were analyzed as biomarkers of ovarian function. To determine the role of oxidative stress in PCO, the level of cellular lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and peroxynitrite (ONOO), and tumor necrosis factor alpha (TNF-α) as a marker of inflammation and apoptosis were measured in serum and the ovaries. Letrozole-induced PCO in rats exhibited a significant increase in LPO and ONOO in serum and ovary while significantly decreased serum and ovarian SOD, CAT, and GPx. Serum T and TNF-α, and ovarian PGE were increased in animals with cysts compared with healthy controls, while E and P diminished. When compared to control group, letrozole-treated group showed irregular sexual cycles, polycystic ovaries characterized by high incidence of sub-capsular ovarian cyst with diminished or scant granulosa cell layer, increased number of atretic pre-antral and antral follicles and absence of corpus luteum. There were almost no primary, secondary, and tertiary follicles observed in PCO rats. All measured parameters were improved by PIO and reached close to normal levels. The present study further supports the role of oxidative/nitrosative stress and infiammatory responses in the pathogenesis of letrozole-induced hyperandrogenic PCO rats. Results indicate that PIO is able to exert direct antioxidative and anti-inflammatory effects on the endocrine, biochemical, and pathological alterations independent of its possible effects mediated via increased insulin sensitivity in hyperandrogenized PCO.

On the benefit of whey-cultured Lactobacillus casei in murine colitis.

The objective of this study was to examine the prophylactic and therapeutic effect of whey-cultured Lactobacillus casei (L. casei) in a murine model of colitis. Colitis was induced by intracolonic administration of a mixture of 2,4,6-trinitrobenzenesulphonic acid (TNBS)/absolute ethanol in male Wistar rats. Animals were divided into 5 groups including sham (normal group), control (vehicle-treated), positive control (dexamethasone 1 mg/kg/day, orally), prevention (10(8) cfu L. casei/day, orally, 14 days before induction of colitis), and treatment (10(8) cfu L. casei/day, orally, 14 days after induction of colitis). After 14-days treatment, the animals were sacrificed on the day 15. Distal colons were removed for examining histological and biochemical assays. Biomarkers including TNF-α, myeloperoxidase (MPO), and lipid peroxidation (LPO) were measured in the homogenate of colon. Results indicated an apparent improvement in colon histopathology scores, TNF-α, MPO, and LPO in the treatment group, whereas prevention group did not demonstrate positive efficacy in prevention of colonic damage. It is concluded that L. casei grown in whey culture is very effective in ameliorating both biochemical and histopathological markers of colitis if used post induction of colitis but not if used before induction of colitis. The difference between effects of L. casei when used pre-colitis and post-colitis confirms its mechanism of action as an anti toxic stress agent. Further studies should be made in IBD patients.

Examination of Setarud (IMOD™) in the management of patients with severe sepsis.

BACKGROUND AND THE PURPOSE OF THE STUDY: Analysis of current immunomodulating strategies indicates that monovalent approaches are unlikely to restore immunostasis or achieve complete therapy of sepsis. Setarud (IMOD) as a mixture of urtica, carotenoids, urea, and selenium has been recently patented for its potential in reduction of Tumor Necrosis Factor alpha (TNF-α) and Interferon-γ and Interleukin-2 levels. The aim of this study was to examine efficacy of IMOD in the management of patients with severe sepsis. METHODS: Twenty patients with severe sepsis and acute physiology and chronic health evaluation (APACHE) score of more than 20 were randomized to receive standard treatment of severe sepsis (control group) or standard treatment plus IMOD (IMOD group). The group treated with IMOD for 14 days was according to the pilot study and regarding the stability of patient's conditions in the ICU. Of course patients in both groups received standard treatment and all were monitored for 28 days. Blood samples were analyzed for interleukins (IL-1, IL-2, IL-6), plasminogen activator inhibitor (PAI-1), TNF-α, total thiol molecules (TTM), nitric oxide (NO), total antioxidant power (TAP), and lipid peroxidation (LPO). Daily APACHE, Sequential Organ Failure Assessment (SOFA), and Simplified Acute Physiology Score (SAPS) were calculated. RESULTS AND MAJOR CONCLUSION: Comparing with controls, IMOD was significantly effective in improving SAPS, SOFA, and APACHE scores, and reduction of mortality rate. Among tested inflammatory biomarkers, IMOD significantly improved TTM and TNF-α values. It is concluded that IMOD might be added as a safe adjutant to standard treatment of severe sepsis.

Identification of enhanced cytokine generation following sepsis. Dream of magic bullet for mortality prediction and therapeutic evaluation.

BACKGROUND AND THE PURPOSE OF THE STUDY: sepsis is one of the most widespread and lethal disease in Intensive Care Units (ICU). Based on pathophisyology of sepsis, it seems that routine laboratory tests combined with analysis of pro-inflammatory cytokines plasma levels, help clinicians to have more information about disease progress and its correct management. METHODS: This was a prospective observational study to determine the predictive role of Tumor Necrosis Factor alpha (TNF-α), Interleukin (IL)-1ß and IL-6 as three main pro-inflammatory cytokines and Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) as two scoring systems in mortality of critically ill patients with severe sepsis. Fifty and five patients with criteria of severe sepsis were included in this study. An exclusion criterion was post Cardiopulmonary Resuscitation (CPR) status. Cytokines (TNF-α, IL-1ß and IL-6) were assayed in the first, third and seventh days in blood of patients. RESULTS AND MAJOR CONCLUSION: Among three measured cytokines, sequential levels of TNF-α and IL-6 showed significant differences between survivors and nonsurvivors. IL-6 had a good correlation with outcome and scoring systems during the period of this study. The areas under the receiver operating characteristic (AUROC) curve indicated that APACHE II (0.858, 0.848, 0.861) and IL-6 (0.797, 0.799, 0.899) had discriminative power in prediction of mortality during sequental measured days. Multiple logestic regression analysis identified that evaluation of APACHE II and TNF-α in the first day and APACHE II and IL-6 in the third and seventh days of severe septic patients are independent outcome predictors. Results of this study suggest that IL-6 and APACHE II are useful cytokine and scoring systems respectively in prediction of mortality and clinical evaluation of severe septic patients.

Effects of Angipars on oxidative inflammatory indices in a murine model of periodontitis.

BACKGROUND AND THE PURPOSE OF THE STUDY: There are strong evidences linking overproduction of reactive oxygen species and periodontal diseases. The aim of this study was to evaluate efficacy of Angipars a natural potent anti oxidative agent on markers of the oxidative damages and periodontal inflammation in the rat. METHODS: Periodontitis was induced by single injection of lipopolysaccharide (LPS) from E. coli (10 µg/µl saline) into rat mandibular gingiva. After 10 days, animals in the test group received Angipars (2.1 mg/kg) by gavage once a day and those of control group received same amount of vehicle. The amount of interleukin (IL)-1ß, lipid peroxidation (LPO), and 8-hydroxydeoxyguanosine (8-OHdG) were measured in gingival biopsy samples and the degree of apical migration of junctional epithelium (JE), alveolar bone resorption, and the number of polymorphonuclears (PMN) were evaluated by histological analysis of block samples of the left mandibular first molars. RESULTS: Periodontitis group showed a significant increase in periodontal IL-1ß, LPO, 8-OHdG, apical migration of JE, alveolar bone resorption and number of PMNs. Angipars treatment resulted in a significant decrease in gingival IL-1ß, LPO, 8-OHdG and the apical migration of JE; however, the reduction of alveolar bone resorption was not significant. The number of PMN increased significantly after treatment with Angipars. While intake of vehicle resulted in a significant decrease in gingival IL-1ß and LPO, the reduction of 8-OHdG, apical migration of JE, and alveolar bone resorption were not significant. Interestingly, PMNs were increased in groups received Angipars or the vehicle. CONCLUSION: From the results of this study, it seems that Angipars is beneficial in periodontitis by reduction of inflammatory and oxidative damage. Unexpected increase of PMN count by Angipars strengthens the hypothesis that chronic inflammatory disorders like periodontitis may need more time to get best advantage of anti oxidative drugs like Angipars. Regarding role of microbes in pathogenesis of periodontitis, further studies should be focused on antimicrobial effects of Angipars.