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Ginger and turmeric rhizomes are used in folk medicine for the treatment of several cerebrovascular diseases with limited scientific basis for their action. Hence, in this study, we investigate the effects of two Zingiberaceae varieties (ginger and turmeric) on ectonucleotidases (NTPDase and 5'-nucleotidase), adenosine deaminase (ADA) and acetylcholinesterase (AChE) activities in synaptosomes of cerebral cortex from l-NAME induced hypertensive rats. The animals were divided into seven groups (n = 10): normotensive control rats; hypertensive rats; hypertensive rats treated with atenolol; normotensive and hypertensive rats treated with 4% supplementation of turmeric and ginger rhizomes, respectively. After 14 days of pre-treatment with both rhizomes the animals were induced with hypertension by oral administration of l-NAME. The results revealed an increase of ATP and AMP hydrolysis as well as ADA and AChE activities of cerebral cortex synaptosomes in induced rats when compared with the control. The supplementation of both rhizomes prevented these alterations by decreasing ATP and AMP hydrolysis and ADA and AChE activities in cerebral cortex. In conclusion, this study demonstrated that both rhizomes interfere with the purinergic and cholinergic neurotransmission in cerebral cortex of hypertensive rats. Therefore, we can suggest that both rhizomes exert neuroprotective potential under hypertensive state.

Effects of atorvastatin on the expression of Cytochrome P450 3A2 and its enzymatic activity in the kidney of diabetic rats were investigated. Diabetes was induced by injection of streptozotocine (50 mg/kg, b.w., i.p.) in male Wistar rats. The animals were assigned into four groups including control (C), non-treated diabetic (D), atorvastatin-treated diabetic (AD) and atorvastatin-treated non-diabetic (A) groups. Metabolism of testosterone was examined in the presence of renal microsomes. The expression of CYP 3A2 at mRNA level was examined by means of PCR technique. The atorvastatin administration resulted in a remarkable improvement of diabetes-induced nephropathy and oxidative stress. Enzyme kinetics analyses showed that both diabetic groups produced significantly (P < 0.05) more 6β-hydroxytestosterone (V_max for D = 34.7 ± 1.3 and for AD = 45.1 ± 2.3 pM/min/mg) than that of the control group (V_max = 21.6 ± 1.5 pM/min/mg). Both diabetes and atorvastatin administration resulted in a significant up regulation of CYP 3A2 mRNA level in the kidney. Our data suggest that due to profound influence of diabetes and atorvastatin on renal metabolism of CYP 3A2 substrate and up-regulation of this gene, there should be adjusted dose regimen for medications which are classified as CYP 3A2 substrates.

Aims: Diabetic neuropathy has been identified as a common complication caused by diabetes. However, its pathophysiological mechanisms are not fully understood yet. Statins, also known as HMG-CoA reductase inhibitors, alleviate the production of cholesterol. Despite this cholesterol-reducing effect of statins, several reports have demonstrated their beneficial properties in neuropathic pain. In this study, we used streptozotocin (STZ)-induced diabetic model to investigate the possible role of nitric oxide (NO) in the antineuropathic-like effect of atorvastatin. Methods: Diabetes was induced by a single injection of STZ. Male rats orally received different doses of atorvastatin for 21 days. To access the neuropathy process, the thermal threshold of rats was assessed using hot plate and tail-flick tests. Moreover, sciatic motor nerve conduction velocity (MNCV) studies were performed. To assess the role of nitric oxide, N(G)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG), and 7-nitroindazole (7NI) were intraperitoneally administered along with some specific doses of atorvastatin.

Key findings: Atorvastatin significantly reduced the hyperalgesia in diabetic rats. L-NAME pretreatment with atorvastatin showed the antihyperalgesic effect, suggesting the possible involvement of the NO pathway in atorvastatin protective action. Furthermore, co-administration of atorvastatin with AG and 7NI resulted in a significant increase in pain threshold in diabetic rats.

Significance: Our results reveal that the atorvastatin protective effect on diabetic neuropathy is mediated at least in a part via the nitric oxide system.

The influence of iron, copper and nitrate ions on free-radical processes in rats and the dependence between dose and effect of pro-oxidants were studied. Rats were divided into 14 groups and administered differing concentrations and combinations of chemicals with drinking water. Concentrations of iron, copper and nitrate in the water were 1, 0.5 and 0.33 of maximum permissible concentrations (MPCs) for every chemical. The action of the investigated pollutants on the intensity of free-radical processes was estimated by the determination of conjugated dienes in liver homogenate and the intensity of Fe²⁺-induced chemiluminescence of the blood serum. It is estimated that chemicals entering the organism in doses that do not exceed their MPC lead to an increase in free-radical oxidation in comparison to the controls. A maximal effect of iron on the concentration of conjugated dienes was observed in a dose equal to 0.33 MPC, while copper and nitrate possess maximal activity in concentrations of 0.5 MPCs. Fast flash amplitude of chemiluminescence in serum was not dose-dependent in rats obtaining iron and copper, while nitrate had a reverse dose-dependent effect. Total luminosity was maximal in doses of chemicals equal to 0.33 MPCs. The combined action of pollutants was more evident in comparison to isolated chemicals in doses equal to 1 MPC.

The aqueous extract of Cichorium intybus (CIE) leaves have shown the properties of protecting against pancreatic β-cell damage by streptozotocin (STZ), but the molecular mechanisms of its protection are not completely elucidated yet. Our current study focuses on elucidating the mechanisms of these preventive effects of CIE in MIN6 cells and an in-vivo model of Wistar rats. CIE offers protection against STZ in MIN6 cells by reducing the pro-oxidants and increasing the activity of the antioxidant enzymes. In vitro results also indicated that CIE inhibited cytotoxicity, reduced Reactive oxygen species (ROS), maintained glucose-stimulated insulin secretion and reduced NF-κB p65 translocation into the nucleus. The group administered with a 250 mg/kg dose of CIE in vivo has shown an ability to maintain blood glucose level and also to preserve the number and morphology of pancreatic islets when compared to the diabetic group treated with STZ. Probably, active compounds like quercetin, rutin, and catechin present in CIE, preserve the integrity of pancreatic islets thereby protecting β-cells from the adverse effects of STZ.

Tong Luo Jiu Nao (TLJN), a modern formula of traditional Chinese medicine, has proven to be clinically efficacious in several vascular cerebral diseases but its specific effect is not known. In the present study we investigated the acute and persisting effects of TLJN on anxiety model in Wistar male rats. TLJN was administered intragastrically during three successive days (Days 1-3) and then, the double TLJN dose was given on Day 7. For the evaluation of anxiety-related behavior of animals, we used the open field (OF) and elevated plus maze (EPM) paradigms. Testing in the OF was performed on Days 1, 2, 3, 4, 8, 14 and 22; in the EPM on the Day 23.
Two-way repeated-measures ANOVA revealed significant differences between control and TLJN treated animals in the open field model where TLJN induced increased exploratory activity, indicating reduced anxiety-like behavior. The effect persisted for several days after the treatment and was still present on Days 14 and 22. Reduced anxiety-like behavior was also observed on EPM 16 days after the last TLJN administration.
The results demonstrate behavioral effects of intragastric administered TLJN, which indicate reduced anxiety. Persistence of the induced behavioral changes suggests prolonged duration of action.

The ability of two novel oximes K378 and K348 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. Both new potential oxime reactivators were chosen for this study based on the data obtained during the extensive work on oximes development, from structure-activity relationship studies and in vitro evaluation of their ability to reactivate acetylcholinesterase inhibited by organophosphorus compounds. In vivo determined percentage of reactivation of sarin-inhibited rat blood and brain acetylcholinesterase showed that the potency of both novel oximes K378 and K458 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to low reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be efficient reactivator of sarin-inhibited acetylcholinesterase in the peripheral compartment. While the oxime HI-6 was able to reduce the acute toxicity of sarin more than three times, both novel oximes decreased the acute toxicity of sarin less than two times. Based on the results, we can conclude that reactivating and therapeutic efficacy of both novel oximes K378 and K458 are significantly lower compared to the oxime HI-6 and, therefore, it is not suitable to replace the oxime HI-6 for the antidotal treatment of acute sarin poisoning.

The potency of three nerve agents (sarin, soman, tabun) to induce oxidative damage of DNA in lymphocytes, liver and brain during lethal or sublethal poisoning was investigated. The single strand breaks or oxidative base DNA damage was evaluated with the help of Comet assay and a specific enzyme able to detect oxidative bases of DNA (endonuclease III). While sarin and soman administered at sublethal doses corresponding to 50% of their LD50 values were not able to induce oxidative damage of DNA, their lethal dose (LD50) induced the significant increase of the number of oxidative bases in DNA of hepatocytes. In addition, tabun administered at lethal dose (LD50) induced significant increase of the number of single strand breaks and oxidative bases of DNA in glial cells isolated from pontomedullar brain region. Thus, some nerve agents were able to induce oxidative damage in the peripheral as well as central compartment but only in the case of severe poisoning caused by lethal doses of nerve agents. This non-cholinergic effect of nerve agents has probably consequences with nerve agents-induced hypoxic status during acute cholinergic crisis and it can contribute to their long-term toxic effects.

Cholinesterase inhibitors are beneficial in the treatment of Alzheimer's disease via indirect increase of cholinergic neuro-transmission. The aim of the present study was to evaluate the potency of inhibitors tacrine, rivastigmine and donepezil to reverse cholinergic depletion induced by 3-quinuclidinyl benzilate (QNB, 2 mg kg^-1) in Wistar rats performing the multiple T-maze test. The effect of QNB on retention was compared to the effect of standard amnesic drug, scopolamine, at the dose of 0.3 mg kg^-1. Well-trained rats were treated intra-peritoneally with QNB, followed by another injection containing saline or tacrine (10 mg kg^-1) or rivastigmine (1.2 mg kg^-1) or donepezil (2.65 mg kg^-1) 15 min later. Rats were subjected to the T-maze task 30 min and 24 h following QNB administration. The passage time and number of errors were observed. QNB significantly impaired the performance of rats in both tested times in contrast to short-lasting effect of scopolamine (30 min only). The inhibitors rivastigmine and donepezil significantly attenuated QNB-induced behavioural impairment in the 30 min tests, whereas tacrine failed to have the same effect. Moreover, the performance of tacrine-treated rats was worse due to cholinergic over-stimulation. Beneficial effects of all tested inhibitors including tacrine were evident in the 24 h test.

Brain ischemia is a leading cause of death and disability worldwide that occurs when blood supply of the brain is disrupted. Brain-derived neurotrophic factor (BDNF) is a protective factor in neurodegenerative conditions. Nevertheless, there are some problems when exogenous BDNF is to be used in the clinic. 14-3-3ζ is a pro-survival highly-expressed protein in the brain that protects neurons against death. This study evaluates 14-3-3ζ effects on BDNF transcription at early time point after ischemia and its possible protective effects against ischemia damage. Human 14-3-3ζ protein was purified after expression. Rats were assigned into four groups, including sham, ischemia, and two treatment groups. Stereotaxic cannula implantation was carried out in the right cerebral ventricle. After one week, rats underwent middle cerebral artery occlusion (MCAO) surgery and received 14-3-3ζ (produced in our laboratory or standard form as control) in the middle of ischemia time. At 6 h of reperfusion after ischemia, brain parts containing the hippocampus, the cortex, the piriform cortex-amygdala and the striatum were collected for real time PCR analysis. At 24 h of reperfusion after ischemia, neurological function evaluation and infarction volume measurement were performed. The present study showed that 14-3-3ζ could up-regulate BDNF mRNA at early time point after ischemia in the hippocampus, in the cortex and in the piriform cortex-amygdala and could also improve neurological outcome and reduce infarct volume. It seems that 14-3-3ζ could be a candidate factor for increasing endogenous BDNF in the brain and a potential therapeutic factor against brain ischemia.

Dose-limiting nephrotoxicity restricts Cisplatin use in high therapeutic doses. Empagliflozin showed a reno-protective effect in diabetic nephropathy. We investigated if Empagliflozin can ameliorate Cisplatin nephrotoxicity whether used prophylactically or therapeutically. Forty male Wistar rats were divided into 5 groups: (1) control; (2) Cisplatin-induced nephrotoxicity by single intraperitoneal dose; (3) Empagliflozin was given for 10 days before a single dose of Cisplatin; (4) a single dose of Cisplatin followed by Empagliflozin for 10 days; (5) received Empagliflozin only. Regular assessment of weight was done, biochemical evaluation for serum urea, creatinine, uric acid, albumin, and glucose was performed, kidney tissue nerve growth factor-β (NGF-β) and oxidative stress parameters were measured, kidneys were evaluated histopathologically and immunostained for caspase 3. Cisplatin significantly reduced body weight, NGF-β, and reduced glutathione, elevated urea, creatinine, and malondialdehyde with no effect on other serum biochemical parameters. Histopathologically, there was high acute tubular necrosis (ATN) score with strong immunostaining of caspase 3. The use of Empagliflozin significantly reduced urea and creatinine in both prophylactic and therapeutic, reduced ATN score in the prophylactic group associated with minimal staining of caspase 3 and elevated reduced glutathione. In conclusion, prophylactic Empagliflozin protected against Cisplatin-induced acute kidney injury mainly via anti-apoptotic effect.

PPARδ-dependent maintenance of inotropic function is mentioned as crucial for cardiomyocytes. However, change of PPARδ in endotoxins-induced cardiac dysfunction is still unclear. The present study is then designed to investigate the changes of PPARδ in rats showing LPS-induced cardiac dysfunction. In the in vivo experiments, adult Wistar rats were treated with intravenous injection of 10 mg/kg LPS for 6 h. The isolated heart determined in Langendorff apparatus and the hemodynamic analysis of rats used to measure the changes of cardiac function extra vivo and in vivo. We found that LPS decreased the cardiac contractility in isolated heart and lowered the hemodynamic dP/dt_max in rats. Also, this action of LPS was reversed by PPARδ agonist. In cultured neonatal rat cardiac cells incubated with LPS, the intracellular calcium concentration and troponin I phosphorylation were both reduced after the detection of intracellular calcium level and Western blotting analysis. PPARδ agonist also reversed both actions of LPS in cardiomyocyte. The obtained results suggest that LPS induced decreases in PPARδ expression and troponin I phosphorylation to result in acute heart failure similar to cardiac dysfunction in endotoxemia.

The ability of the oxime HI-6 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) using a functional observational battery. Tabun-induced neurotoxicity and the neuroprotective effects of HI-6 alone, and HI-6 combined with trimedoxime or K203, in rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 80% of LD₅₀ value), were monitored by the functional observational battery at 24 hours following tabun challenge. The results indicate that both oxime mixtures tested, combined with atropine are able to allow tabun-poisoned rats to survive for 24 hours following tabun challenge, while one non-treated tabun poisoned rat and one tabun-poisoned rat treated with the oxime HI-6 alone combined with atropine, died within 24 hours following tabun challenge. The oxime HI-6 alone, as well as both oxime mixtures combined with atropine, were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings, but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to reduce tabun-induced acute neurotoxcicity was almost the same, regardless of type of antidotal treatment. Thus, the tested combinations of oximes were not able to increase the neuroprotective effectiveness of the antidotal treatment of acute tabun poisonings compared to the individual oxime.

Because of biological rhythms, drug efficiency and toxicity vary according to the time of administration of the drug. This study investigates whether the haematological toxicity of the immunosuppressive agent Mycophenolate Mofetil varies according to the circadian dosing-time in rats. 300 mg/kg of Mycophenolate Mofetil was injected by i.p. route to different groups of animals at six different circadian stages (1, 7, 13, and 19 hours after light onset, i.e., HALO). Mycophenolate Mofetil treatment induced a significant decrease at 7 HALO in red blood cells (-18%), in haemoglobin rate (-15%) and in white blood cells (-54%). These parameters followed a circadian rhythm with an acrophase located at the end of the light-rest phase. A significant thrombocytopenia was observed according to Mycophenolate Mofetil the circadian dosing-time. In the controls, the number of platelets followed a circadian rhythm. Mycophenolate Mofetil modified this rhythm which became an 8-h ultradian rhythm. The data indicate that, the Mycophenolate Mofetil-induced haematological toxicity was maximum when the drug was administered in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.

The aim of this study was to investigate the protective effect of naringenin on oxidative stress, on pro-inflammatory cytokines like TGF-β1, IL-1β and on programmed cell death in the testicular damage resulting from streptozotocin (STZ) induced diabetes in rats. Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg), and the rats were treated with naringenin (5 mg/kg and 10 mg/kg) administered once a day orally for 10 weeks, starting 3 days after the STZ injection. At the end of the study, all animals were sacrificed. Testis tissue and blood samples were collected for the assessment of sperm parameters, and for biochemical and histopathological analysis. Naringenin treatment significantly decreased the levels of elevated tissue TBARS (thio-barbituric acid) and increased the superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) enzyme activities in the testis tissues. The naringenin-treated rats in the diabetic group showed an improved histological appearance, sperm parameters, and serum testosterone levels, along with a decrement of terminal dUTP nick end-labeling (TUNEL) detected program cell death and a reduced over expression of TGF-β1, IL-1β in Sertoli cells and Leydig cells. These results suggest that naringenin is a food supplement potentially beneficial in reducing testicular damage in diabetic rats by decreasing the oxidative stress related to programmed cell death.

This study aimed to investigate the effect of stress during spermatogenesis and oogenesis on reproductive performance in adult rats and sex ratio in offspring. The rats were subjected to predatory stress (exposed to a cat) twice a day for 50 (male) and 15 (female) consecutive days. At the end of the stress procedure, a number of control and stressed rats were considered to examine reproductive parameters and the rest was coupled as follows: both male and female control, male stressed/female control, male control/female stressed, and both male and female stressed. After parturition, the pups were counted, weighed, and gendered. Stress significantly increased the number of female pups in each litter (P= 0.034). In parents, stress reduced sperm quality (mobility, number, and morphology), testicular parameters (SI, STET, sloughing, and detachment), and thickness of vaginal epithelium in all phases of the estrous cycle. Serum testosterone and 17-B estradiol levels decreased significantly in stressed parents. These results emphasize the suppressive influence of stress during spermatogenesis and oogenesis on the performance of the organs of the reproductive system in parents and its consequence on sex ratio in offspring.

The effect of moderate and overtraining exercise on Th1/Th2 balance was evaluated in rat splenocytes. Male Wistar rats were divided into sedentary control (C), moderately trained (MT; V = 20 m/min, 30 min/day, 8 weeks), overtrained (OT; V = 25 m/min, 60 min/day, 11 weeks) and recovered after overtraining (OR) (OT plus 2 weeks recovery) groups. At the end of study, cell viability, proliferation, interleukin 4 (IL-4) and interferon-γ (IFN-γ) secretion were evaluated in non-stimulated, phytohemagglutinin (PHA) and concavaline A (Con A)-stimulated splenocytes. Cell viability increased in MT and OR groups compared to control. Cell proliferation was higher in OR group than other groups. IL-4 concentration in PHA-stimulated cells from MT and OT groups, and IL-4 concentration in Con A-stimulated cells from OR and OT groups, were higher than the control group, but not for IFN-γ. In non-stimulated cells, IFN-γ/ IL-4 ratio was higher than MT and OT groups. In PHA and Con A-stimulated cells, IFN-γ/ IL-4 ratio was lower in exercise groups than control. We previously showed that moderate exercise increases Th1 cytokines in serum, but in splenocytes, Th2 or Th1 response may increase depending on the type of mitogen stimulation. Two-week recovery restored Th1/Th2 balance, only in non-stimulated splenocytes of overtrained animals.

Sarin is a potent inhibitor of acetylcholinesterase (AChE). It is known as an agent of chemical warfare and is one of a number of nerve agents misused for chemical terrorism, e.g. on the Tokyo subway attacks. Though effect of sarin on the cholinergic system is well-known, long-term adverse effects and the role of oxidative stress in sarin toxicity remain unknown. The experiment reported here was carried out on laboratory Wistar rats intramuscularly exposed to 0.5-50% of sarin LD₅₀ for one hour. A complex biochemical examination of plasma samples and an assessment of oxidative stress in the liver, kidney, spleen, cerebellum and frontal lobe were performed after euthanasia of the animals. By means of these biochemical markers, we were able to observe the induction of hyperglycaemia in a dose-dependent manner. Other biochemical markers such as transaminases were influenced in a non-standard manner as sarin probably acted as an inhibitor of these markers. Oxidative stress markers and an assessment of AChE activity showed an unequal impact of sarin on different tissues. Significant inhibition of AChE was found in the cerebellum and frontal lobe. Besides this, alterations in reduced glutathione, ferric reducing antioxidant power (FRAP) and thiobarbituric acid reactive substances (TBARS) were proven. In particular, an accumulation occurred of reduced glutathione in the frontal lobe, whereas depletion of FRAP was found in the kidney and spleen, and a strong increase in TBARS occurred in the spleen in a dose-dependent manner. We infer that sarin extensively influences oxidative homeostasis. Surprisingly, the central nervous system seems to be more resistant than the other organs.

Sporadic Alzheimer's disease is characterised by cognitive impairments and associated with cerebrometabolic anomaly and dementia which are burdensome for the old age population and their caregivers worldwide. A safe and effective treatment is essentially required for its prevention and cure. γ-Oryzanol (OZ) is reported for anti-oxidative, anti-inflammatory, anticancer, anti-hyperlipidemic, and anti-diabetic effects in various preclinical studies. In silico studies showed similar binding interactions with acetylcholinisterase like Donepezil (DONO). In vitro DPPH assay, AchE activity inhibition assay and cell viability assay on SH-SY5Y cell line confirmed that OZ has good free radical scavenging and cholinesterase inhibitory activity as well as safety profile. OZ was evaluated in vivo for its effect in streptozotocin (STZ) induced sporadic Alzheimer's disease in rats. Maze tests reflected improvement in spatial cognitive behavior indicated by reduction in working memory and reference memory error. OZ showed anti-AchE, anti-inflammatory and antioxidative effects. OZ showed effective anti-proinflammatory effects in cerebral milieu as indicated by significant reduction in active glial cells and found to improve synaptic connectivity. Thereby OZ reflected protection of the cerebral architecture against STZ induced damage. Thus, OZ exhibits its candidature as a therapeutic moiety to improve cognitive behavior in neurodegenerative disorders.

The effect of hydro-alcoholic extract of Curculigo orchoides on hexavalent chromium (Cr VI) induced toxicity in rats was investigated. Sub-acute toxicity studies were performed by OECD guidelines. K₂Cr₂O₇ (30 mg/kg) was administered to all groups except control group for a period of 28 days by oral gavage. Control group received distilled water; treatment groups received C. orchoides (25, 50 and 100 mg/kg). Cr(VI) administration resulted in up-regulation of serum biochemical parameters such as alanine transaminase, aspartate transaminase, alkaline phosphatase, and tissue biochemical markers viz. lipid peroxidation and protein carbonyl content. C. orchioides (100 mg/kg) significantly decreased these enzyme levels. The activities of anti-oxidant enzymes like superoxide dismutase, catalase and glutathione S-transferase were significantly decreased by Cr(VI) administration (50.7%, 43.7% and 37.9%, respectively). Further, mRNA expression studies and histopathology studies confirmed Cr(VI) toxicity. In all cases, C. orchioides promoted significant restoration of enzyme levels in a dose dependent manner. These results suggest the ameliorating effect of C. orchoides on Cr(VI) induced oxidative stress is probably via, modulation of cytokines, transcription factors and apoptotic genes.

We aimed this study to evaluate histopathology of heart, lung, liver, kidney, small and large intestine in the context of clinical biochemistry, mitotic (intestine only) and apoptotic activity and morphometric analysis (intestine and lung only). Male Wistar rats were poisoned by soman (i.m., 52 μg kg^-1; 70% LD₅₀). Samples were taken 1, 3 and 7days following soman exposure. Biochemistry was evaluated in blood. Hematoxylin-eosin staining, Mallory's PTAH method, immunohistochemical detection of activated-caspase-3, TUNEL, and morphometric computer analysis were performed. We found increased AST and CK in blood, areas ranging from acute myolysis and necrosis to areas undergoing resolution in heart, a biphasic response consisting of hyperaemia, edema and bleeding leading to decreased airiness (day 1) and delayed inflammatory response with increased apoptosis (day 7) in lung, lymphangiectasis in small intestine (day 1) and subepithelial edema in large intestine (day 3) after soman intoxication. In intestine, mitotic activity decreased in crypts 1 and 7days after the intoxication. Apoptotic activity decreased in the superficial compartment on the day 1, whereas it increased in the same compartment 3days after the poisoning. Soman intoxication at the sublethal dose induced significant biochemical changes in blood and histopathological changes in heart, lung and intestine.

This study compares the abilities of the newly developed bispyridinium oxime K203 with currently available oximes (HI-6, obidoxime, and trimedoxime) in the reactivation of sarin-inhibited acetylcholinesterase and the reduction of the acute toxicity of sarin. The percentage of reactivation of sarin-inhibited rat blood and tissue acetylcholinesterase was determined in vivo and it was shown that the potency of bispyridinium oxime K203 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the relatively low reactivating efficacy of obidoxime and trimedoxime except in the diaphragm where K203 was not effective. On the other hand, the oxime HI-6 was found to be a very efficient reactivator of sarin-inhibited acetylcholinesterase in the peripheral as well as central compartment. The oxime HI-6 was able to reduce the acute toxicity of sarin by more than four times, but the other oximes studied, including K203, decreased the acute toxicity of sarin by less than three times. Based on these results, we can conclude that the reactivating and therapeutic efficacy of the oxime K203 is significantly lower compared to the oxime HI-6 and, therefore, it is not a suitable replacement for the oxime HI-6 in the antidotal treatment of acute sarin poisoning.

Ageing is commonly accompanied by a chronic subclinical inflammatory status that coexists with immune dysfunction. Consumption of foods rich in antioxidants is associated with a lower incidence of chronic diseases. The aim of this study was to evaluate the effect of the consumption of a Jerte Valley cherry-based beverage on the inflammatory load in two different animal species: rats and ringdoves (Streptopelia risoria); each divided into two age groups. To this purpose, circulating levels of both pro-inflammatory (IL-1β and TNF-α) and anti-inflammatory (IL-4 and IL-2) cytokines were measured before and after a 10-day treatment with the Jerte Valley cherry-based beverage. Our results suggest that the 10-day treatment with the Jerte Valley cherry-based beverage modulated the balance of pro- and anti-inflammatory cytokines in both rats and ringdoves by down-regulating the levels of pro-inflammatory (IL-1β and TNF-α) cytokines and up-regulating the levels of anti-inflammatory (IL-4 and IL-2) cytokines. Moreover, old animals showed imbalanced levels of inflammatory markers towards a pro-inflammatory status, thereby underlining the fact that ageing is usually accompanied by systemic inflammation and inflammation-related chronic diseases. In conclusion, since an increased dietary intake of vegetable-derived bioactive compounds may retard age-related immune dysfunctions and prolong life-span, supplementing diets with the cherry-based beverage may reduce the inflammatory load by modulating the serum concentrations of some markers of inflammation.

Recently, oxidative stress has been identified as a pivotal pathological factor inducing bone osteoporosis. This phenomenon is responsible for low bone density. It alters bone quality and generates bone fractures. Strontium is found to induce osteoblast activity by stimulating bone formation and reducing bone resorption by restraining osteoclasts. Bioglass (BG) has been used to repair bone defects, and, in combination with strontium (BG-Sr), offers an opportunity to treat this disease. This study investigated the potential role of BG-Sr in improving antioxidant activity and regenerative bone capacity, The effects of both BG-Sr and BG were tested on osteoblast SaOS2 and endothelial EAhy926 cell proliferation in vitro. In vivo, BG-Sr and BG were implanted in the femoral condyles of Wistar rats and compared to that of control groups. Cell proliferation increased significantly by 120% at SaOS2 and 127% at EAhy926. Superoxide Dismutase (SOD), Catalase (CAT) and Glutathione Peroxidase (GPx) were significantly enhanced in BG-Sr treated rats compared to other groups. Moreover, a significant decrease of thiobarbituric acid-reactive substances (TBARs) was observed. The Ca/P ratio increase improved progressive bone mineralization. According to these results, BG-Sr ameliorated cell proliferation and developed an antioxidative defense against ROS. The histological findings highlight the BG-Sr implications in the osteoporosis treatment confirmed by bone construction. The development of BG-Sr as a therapeutic biomaterial protecting against oxidative stress might make an effective choice for application in tissue engineering.

The primary aim of this study was to investigate the effects of ortanique peel polymethoxylated flavones extract (PMF^ort) on antioxidant enzymes activities and lipid peroxide levels in organs of hypercholesterolemic and normal rats. Thirty Sprague-Dawley rats were fed high cholesterol diets supplemented with 1.5% PMF^ort and niacin respectively for 49 days. Hypercholesterolemic rats fed PMF^ort had significant reductions in malondialdehyde levels in the liver and brain compared to untreated hypercholesterolemic control rats. This reduction also occurred in the brain of the rats fed niacin. The activities of catalase, glutathione reductase, transferase and peroxidase were significantly reduced in the spleen, brain and liver of hypercholesterolemic rats fed PMF^ort compared to control. The activities of these enzymes were only reduced in the brain and liver of rats fed niacin. The results would suggest that PMF^ort modulates hypercholesterolemia-associated organ injury and oxidative stress in rat organs. PMF^ort could therefore be a suitable candidate of natural origin for prophylactic and therapeutic treatment of hypercholesterolemia-associated oxidative stress and organ injury.

The purpose of our study is to evaluate the protective effect of diphenyl dimethyl bicarboxylate (DDB) in combination with some antioxidants, namely vitamin C (V.C), vitamin E (V.E), and selenium (Se), in liver damage induced by carbon tetrachloride (0.2 ml/kg body weight). This was done by monitoring the liver total and fractional lactate dehydrogenase (LDH) activities. The results revealed a significant increase in the activity of liver total LDH activity in CCl4 - intoxicated rats with a significant increase in both LDH3 and 4 and a significant decrease in LDH5. LDH2 disappeared after CCl4 treatment and neither DDB nor its combinations could restore this permanent change. DDB alone significantly decreased the CCl4-raised total LDH and LDH4, but still far from the control and failed to correct LDH3 and 5 variations. A combination of DDB and V.C, V.E and Se showed the best corrective potential in both total LDH and LDH3 activities, without correcting the increased LDH4, nor the decreased LDH5 isoenzyme. Although this combination was previously reported to correct liver function disturbances, it seems that CCl4 and consequently hepatitis C may induce some irreversible, non-curable changes by DDB or even by additional antioxidants. Its clinical usefulness seems to be through different metabolic pathways, not including correction of LDH disturbances, which necessitates additional investigation for other adjunct medicines for treating liver fibrosis in clinical practice.

The present study aimed to investigate the roles of fibrin deposition and protease activated receptor-1 (PAR-1) in renal cytokine/chemokine production and inflammatory cell infiltration in rats of different ages. Acute inflammation was induced by lipopolysaccharide (LPS) in rats which were then treated with tranexamic acid (TA), TA+urokinase (UK) or TA+low-molecular-weight heparin (HP). Fibrin deposition, inflammatory cells and expressions of PAR-1, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) were detected. A reduction in fibrin deposition and PAR-1 expression in the LPS+TA+HP group was associated with decreased infiltration of inflammatory cells and down-regulated expressions of MCP-1 and ICAM-1. In the LPS+TA+UK group, the fibrin deposition, but not the PAR-1 expression, was reduced, However, the infiltration of inflammatory cells decreased and the expressions of MCP-1 and ICAM-1 down-regulated. There were significant differences in the fibrin deposition, infiltration of inflammatory cells and expression of PAR-1, MCP-1 and ICAM-1 between young and old rats undergoing the same treatment. These findings demonstrated that fibrin deposition plays more important roles than PAR-1 dose in cytokine/chemokine production and inflammatory cell infiltration in vivo, and ageing may deteriorate the fibrin deposition-induced production of cytokines/chemokines and infiltration of inflammatory cells.

Lymphocytes are among the most radiosensitive cells. After exposure of the organism to ionizing radiation, they promptly die by apoptosis at a rate proportional to the dose received. Because of this, they are frequently used in biodosimetry. We demonstrated that one hour after whole-body irradiation of rats, histone H2AX in the lymphocyte nuclei was quickly phosphorylated on serine 139, the phosphorylation process being directly dependent on the gamma radiation dose. In the work presented here, we studied the kinetics of lymphocyte depletion in the peripheral blood and phosphorylation of histone H2AX in the peripheral blood lymphocytes after local (thoracic) irradiation of rats. Twenty-four hours after whole-body irradiation of the rats at a dose of 5 Gy, the lymphocyte count declined to almost zero values, whereas after local irradiation of the thorax area, the counts of lymphocytes in the peripheral blood remained unaltered.
The authors employed two methods (flow-cytometric and microscopic) for the γH2AX determination in the peripheral blood lymphocytes, 1 h after thoracic irradiation of rats. Flow cytometry revealed a dose dependence on the increase in γH2AX in a dose range of 10-30 Gy. The microscopic method was more sensitive in the case of lower radiation doses, the dependence on the dose being obvious from a dose as low as 5 Gy. The methods are able, in the dose range 5-30 Gy, to differentiate between the type of irradiation, i.e. the whole-body or local.

Recent years have seen mounting evidence for the role of melatonin in mediating programmed cell death, with a protective, anti-apoptotic effect in healthy cells, but an anti-tumoural, pro-apoptotic action in many tumour cells. In this study, we evaluated the effect of melatonin on the programmed cell death induced by thapsigargin (TG), on lymphocytes and neutrophils, and on various tissues obtained from rats injected with human promyelocytic leukæmia cells (HL-60), treated with melatonin in their drinking water (20 μm), and fed ad libitum. Melatonin treatment significantly reduced caspase-3 and -9 activity, and caused the proportions of lymphocytes, neutrophils, and eosinophils to revert to their basal values. No histological differences were observed. In conclusion, melatonin has anti-apoptotic effects on lymphocytes and neutrophils obtained from rats injected with HL-60 leukæmia cells.

Fullerenol C₆₀(OH)₂₄ nanoparticles (FNP) are promising radioprotectors in prevention of early and late ionizing radiation injury. The aim of this study was to compare the efficacy of FNP and amifostine (AMI) in protection of rats exposed to whole-body X-ray irradiation (7 or 8 Gy). Both compounds (FNP, 100 mg/kg ip; AMI, 300 mg/kg ip) were given 30 min before irradiation throughout the study. The general radioprotective efficacy of FNP and AMI were evaluated in rats irradiated with an absolutely lethal dose of X-rays (8 Gy) and their survival were monitored during the period of 30 days after irradiation. Both compounds were of comparable efficacy. Tissue-protective effects of tested compounds were assessed in rats irradiated with an sublethal dose of X-rays (7 Gy). For this purpose, the animals were sacrificed on the 7th and 28th day after irradiation. Their lung, heart, liver, kidney, small intestine and spleen were taken for histopathological and semiquantitative analysis. Careful examination of established tissue and vascular alteration revealed better radioprotective effects of FNP compared to those of AMI on the small intestine, lung and spleen, while AMI had better radioprotective effects than FNP in protection of the heart, liver and kidney. Results of this study confirmed high radioprotective efficacy of FNP in irradiated rats that was comparable to that of AMI, a well-known radioprotector.