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A methodology combining molecular structure represented by fragments, and artificial neural network (ANN) was applied for the prediction of a new acetylcholinesterase (AChE; EC 3.1.1.7) reactivator. We searched for a new structure of the AChE reactivator with the capability of reactivating AChE inhibited by almost all actual nerve agents. For this purpose, we have tested in vitro seventeen potential AChE reactivators for reactivation of AChE inhibited by sarin, cyclosarin, agent VX and tabun. The results obtained were used as input data for prediction by ANN. Using ANN we have predicted new AChE reactivators.

Owing to the threat of organophosphate exposures, not only to pesticides but also to nerve agents, it is very important to know the whole process of organophosphates-inhibited acetylcholinesterase (AChE, EC 3.1.1.7) reactivation. Although current antidotes against organophosphorus intoxications consist also of prophylactics, AChE reactivators are still needed especially in the case of intoxications with high doses of organophosphates, for which prophylactic treatment is not effective. For this reason, new AChE reactivators are still being developed. Our work summarizes accurately the whole reactivation process, and offers some help for scientists who are interested in the area of AChE reactivation.

The potency of a novel oxime K203 in reactivating soman-inhibited acetylcholinesterase and reducing acute toxicity of soman was compared with commonly used oximes (HI-6, obidoxime, trimedoxime, methoxime) using in vivo methods. The study determining percentage of reactivation of soman-inhibited blood and tissue acetylcholinesterase in rats showed that the potency of the oxime K203 to reactivate soman-inhibited acetycholinesterase in the peripheral compartment is slightly higher than obidoxime and trimedoxime, especially in the diaphragm, slightly lower than methoxime and markedly lower compared to the oxime HI-6. The reactivating efficacy of the oximes studied in the peripheral compartment roughly corresponds to their potency to reduce acute toxicity of soman in mice. Based on the obtained data, we can conclude that the oxime K203 is not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute soman poisoning due to its relatively low potency to counteract acute toxicity of soman.

This study was designed to investigate effects of insulin on fracture healing and expression of vascular endothelial growth factor (VEGF) in diabetic rats. Wister rats were randomly divided into diabetic control (n=66), diabetic insulin (=66) and non-diabetic control group (n=66). Diabetes was established by peritoneal injection of alloxan. Tibia fracture was surgically created and was allowed to heal. Radiological and biomechanical examinations were performed on the healing tibia. Immuohistochemistry was used to assess VEGF expression in the healing fracture tissues. Cortical reconstruction of the fracture sites in non-diabetic control and diabetic insulin groups was more rapid than in diabetic control group within 6 weeks of the fracture. Mechanical strength of the affected tibia in the diabetic insulin and non-diabetic control group was superior to diabetic control group. Histological examination of the fracture sites revealed a delay in chondrocyte maturation and hypertrophy in diabetic control group. VEGF expression was widely distributed in fracture sites within the first 4 weeks in control and diabetic insulin treatment group. However VEGF expression in the callus and periosteum in diabetic control group was much less than in diabetic insulin or non-diabetic control group. In conclusion, diabetes delays fracture healing and adversely affects callus formation with a reduced VEGF expression at the fracture sites. Insulin therapy improves fracture healing in diabetes rats, possibly through enhancing VEGF expression in the fractured bones.

To evaluate the in vitro effects of sunitinib malate and meloxicam in isolation, and to analyse the ability of meloxicam to enhance the cytotoxicity of sunitinib malate in three human bladder-cancer cell lines. Cell lines were treated with sunitinib malate and meloxicam, either in isolation or combined. Leishman staining, MTT method, comet assay, MDC staining and M30 CytoDEATH antibody were performed. The Chou and Talalay method was applied. Sunitinib malate and meloxicam supressed cell proliferation in bladder-cancer cells in isolation, in a concentration-dependent manner. Treatment of bladder-cancer cells with a combination of sunitinib malate and meloxicam showed a synergistic effect. When exploring the mechanism of this combination by means of comet assay, there is the suggestion that meloxicam increases sunitinib malate cytotoxicity through DNA damage. Autophagic and apoptotic studies show a greater incidence of autophagic vacuoles and early apoptotic cells when the combined treatment was put into use. In isolation, sunitinib malate and meloxicam demonstrated anti-tumour effects in our study. Furthermore, simultaneous exposure of cells to sunitinib malate and meloxicam provided a combinatorial beneficial effect. This hints at the possibility of a new combined therapeutic regimen, which could lead to improvements in the treatment of patients with bladder cancer.

Many advances in understanding colorectal cancer heterogeneity and its impact on the variability of treatment efficacy have been achieved in recent years. New methods have also been introduced in colorectal cancer diagnosis and early detection, including molecular biology techniques as well as newly developed or improved imaging techniques. We are currently aware of some aspects of colorectal cancer heterogeneity, such as alterations in the epidermal growth factor receptor signalling or the different behaviours of tumours belonging to different genetic and epigenetic subtypes. In the future, greater attention should also be focused on other signalling circuits with the goal to treat patients individually, based on the characteristics of their tumours. This so-called personalised medicine will bring more benefits to patients, without unnecessary adverse side effects. Therefore, all new information regarding colorectal cancer biology brings us one step closer to accomplishing this goal.

Tacrine is an inhibitor of enzyme acetylcholinesterase (AChE). In the past, it was used for the treatment of cognitive dysfunction during vascular dementia and Alzheimer disease. Some works have concluded that AChE inhibitors can modulate immune response, and for this reason, we decided to investigate the immune response to a model bacterial disease - tularemia - for which both innate and specific immunity are necessary to resolve the disease. We used 64 BALB/c mice divided into eight groups exposed variously to saline, tacrine in a dose of 20.0-500 μg/kg, infection with tularemia and infection with the contemporary application of tacrine. The mice were euthanized three days after the start of the experiment. We proved a significant reduction in the levels of interleukin-6 (IL-6) and interferon gamma (IFN-γ) in a dose response manner in the infected animals in the course of tularemia. Moreover, tacrine caused a significant increase of the bacterial burden in the liver and spleen. We can conclude that tacrine can aggravate tularemia: that it increases the accessibility of acetylcholine and in this way stimulates the cholinergic anti-inflammatory pathway. The results represent a substantial contribution to the field of inflammation control in the nervous system and it is an advancement of the inflammatory therapy issue.

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.

The content of nitrite admixture in preparations of dinitrosyl iron complexes (DNIC) with glutathione synthesized by treatment of aqueous solutions of Fe²⁺ + glutathione with gaseous NO (complex 1) or by mixing solutions of S-nitrosoglutathione (GS-NO) with solutions of Fe²⁺ + glutathione (complex 2) was determined using the Griess method and HPLC as well as from the level of HNO₂ formed upon interaction of gaseous NO with acidified distilled water. In both preparations, DNIC were predominantly represented by the binuclear form (B-DNIC). In complex 1, the appearance of nitrite in DNIC solutions was induced by nitrogen dioxide present in gaseous NO; its interaction with NO gives an adduct, which is further hydrolyzed to nitrite in aqueous solutions. In complex 2, the presence of nitrite admixture could appear in the presence of nitrite non-incorporated into GS-NO synthesized by mixing glutathione and nitrite in acid media. The per cent content of nitrite (with respect to the total content of complex 1) was 6%, whereas in complex 2 it was as low as 0.4%. Such a low level of nitrite contamination in the course of conventional synthesis of DNIC with glutathione does not make any significant contribution to their biomedical (e.g., hypotensive or vasodilator) activity.

The effects of acoustic waves on membrane structures, and any resulting consequences of this treatment on membrane subunit structures, remain poorly understood, as are the principals of related clinical effects. With a focus on morphological changes in the nuclear envelope, the current study presents detailed observations of membrane structures exposed to therapeutic ultrasound. Ultrasound treatment most commonly resulted in distinct changes in the distribution of nuclear pore complexes (NPCs) and mean NPC number per unit area after 30 min of repair, as well as alterations in NPC diameters on the protoplasmic face of fractured nuclear membranes after 10 min of repair. The greatest effects of ultrasound on nuclear envelope structure and NPCs were not to appear immediately, but became evident after repair processes were initiated. Results from the current study may contribute to the general view on the biophysical effects of therapeutic ultrasound on cell morphology and, particularly, the understanding of this effect in relation to the nuclear envelope.

The present study was carried out to investigate the hypoglycaemic effect of S-allyl cysteine (SAC), a garlic component, on some biochemical parameters of STZ induced diabetic rats. STZ induced diabetic rats were treated with SAC at two different doses (100 mg/kg b.w. and 150 mg/kg b.w.) for 45 days. Treatment with SAC significantly decreased the levels of blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum creatinine, and diminished activities of pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). The antihyperglycaemic nature of SAC is also evidenced from the improvement in the levels of plasma insulin and haemoglobin. Further, the results are comparable with glyclazide, an oral standard drug. A 150 mg/kg b.w. dose produced a better effect than a 100 mg dose. Thus, the present findings suggest that SAC may be considered as an effective therapeutic agent for the treatment of diabetes mellitus.

Radiation therapy occupies an important position in the treatment of malignant diseases in spite of the existence of radiation side effects on normal tissues. Thus, substances are being developed which are designed to reduce both the acute and long term radiation effects on healthy tissues. Currently a sulphur-containing compound amifostine (WR2721, ethyol) is used in clinical practice as a radioprotectant. However, it itself has considerable side effects including hypotension (found in 62% of patients), hypocalcaemia, diarrhoea, nausea, and vomiting. Carbon nanospheres, known as fullerenes, and their water soluble derivatives (e.g. C₆₀(OH)₂₄, dendrofullerene DF-1) exert anti-oxidative properties and reduce damage to the DNA in irradiated cells. Water soluble fullerenes are low-toxic substances and thus, are attractive in terms of their use as radioprotectants.

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.

Our present study aimed to investigate the effect of lentiviral-mediated RNAi using short hairpin RNA (shRNA) targeting Smad4 on TGF-β1 induced fibrosis. shRNAs targeting Smad4 were designed and the most efficient shRNA was screened. This shRNA was introduced into a lentiviral vector which was used to infect C2C12 myoblasts, and then the Smad4 expression was detected. Cells were divided into: C2C12 cells group, TGF-β1 induction group, transfection group, and transfection after TGF-β1 induction group. C2C12 myoblasts were transfected with lentivirus carrying Smad4-shRNA and treated with TGF-β1 to induce the differentiation into myofibroblasts. Fluorescence Real-time-PCR and the western blot assay were employed to detect the expressions of collagen I and α-SMA. The results showed that the protein and mRNA expression of Smad4 in the C2C12 cells transfected with Smad4-shRNA1 was significantly reduced when compared with C2C12 before transfection. In the TGF-β1 induction group, the mRNA expressions of α-SMA and collagen I were significantly increased as compared to the C2C12 cells group. In the transfection after TGF-β1 induction group, the mRNA expressions of α-SMA and collagen I were significantly increased compared to the transfection group, and the protein expressions significantly increased, respectively. In the transfection after TGF-β1 induction group, the mRNA expressions of α-SMA and collagen I were significantly decreased compared to the TGF-β1 induction group, and the protein expressions significantly reduced, respectively. The results indicate that suppression of Smad4 expression can efficiently inhibit the TGF-β1 induced fibrosis in myoblasts. The findings suggest Smad4 may become a novel target for the treatment of skeletal muscle fibrosis.

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.

Non-alcoholic steatohepatitis (NASH), an under- recognized hepatic ailment with increasing prevalence, is fast emerging as the dark horse of hepatic related morbidity and mortality. Though introduced as a hepatic condition as early as 1980, detailed exploration of its causes, underlying mechanisms and therapeutics has largely remained an ignored or neglected field. Only recently, the focus of attention has gravitated towards an understanding of NASH as a pathological manifestation of significance and a search for possible therapeutic interventions. Treatment schedules as of now involve life style management and usage of anti-diabetic or anti-obesity drugs and antioxidants. In the present review, we have focused on the available treatment schedules including herbal agents, plant extracts, polyherbal formulations and isolated phytocompounds. We present here a review of the available literature on pre-clinical and clinical evaluations of herbals including our recent findings on two plant extracts which can be used in mitigating NASH. This review attempts to provide a comprehensive account of NASH and the future of therapeutics and remediation by herbal principles, an aspect of the urgent need to target this important medical condition that contributes to many cases of silent morbidity and mortality.

Cilostazol is a phosphodiesterase-3 inhibitor that functions as a platelet aggregation inhibitor and is used for treating peripheral artery diseases and ischemic stroke. Dendritic cells (DCs) play an active role in the immunological processes related to atherosclerosis. Cilostazol has anti-atherogenic and anti-inflammatory effects, but the effects of cilostazol on DC maturation remain unknown. The purpose of this study was to determine the effects of cilostazol on lipopolysaccharide (LPS)-induced maturation of DCs. DC2.4 cells were treated with cilostazol for 12 h and subsequently stimulated with LPS to induce maturation. Cilostazol reduced the expression of maturation-associated markers induced by LPS, such as CD40, CD86, and MHCII, improved the endocytotic function, and decreased production of the tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) of these cells. To further elucidate the mechanisms responsible for the inhibition of DC2.4 maturation by cilostazol, we investigated the effect of cilostazol on LPS-stimulated nuclear factor-kappa B (NF-κB) activation. Our results indicated that cilostazol treatment decreased IκBα degradation and inhibited NF-κB p65 translocation, and the inhibitory effects of cilostazol were cAMP-independent. Therefore, inhibition of NF-κB by cilostazol might result in the suppression of DC maturation. In conclusion, cilostazol suppressed LPS-stimulated DC maturation, which might contribute to its anti-atherosclerosis effect.

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.

Free radicals are believed to play an important role in many pathological states. Consequently antioxidants are receiving increased attention in medicinal research. As part of studies of the biological effects of the antidotes against chemical warfare agents currently used in the Czech Armed Forces, eleven compounds were assayed for their free radical scavenging activity. An optimized PC-controlled sequential injection analysis (SIA) system with spectrophotometric detection was used for evaluation of the antioxidation activity of the antidotes. The automated method is based on the known reaction of 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH) with antioxidants. Only the radical scavenging activity of the tested compound 2,3-dimercaptopropanol (BAL) was found to be weaker compared to the reference antioxidant acidum ascorbicum. Other tested antidotes did not possess any DPPH radical scavenging activity. The results obtained show that a correlation between the required biological activity (prophylaxis or treatment of intoxications by warfare agents) and possible antioxidation activity of the tested antidotes is doubtful.

This study aimed to examine the effects of short and long term exposures to 81 mG EMF intensity. It focused on the roles of ROS, Ca²⁺ and calcium channel blocker (CCB) on the rat brain. Rats were exposed to 81 mG EMF intensity at the mobile phone base station for one and four weeks (2 hr/day, EMF exposed group). Another group of rats was pretreated with CCB (amlodipine 20 mg/kg) for four weeks and similarly exposed to EMF (EMF + amlodipine group). Sham exposed and amlodipine control groups were used. At the end of the study, Ca²⁺ as well as pro-inflammatory and oxidative stress markers were measured. Immunohistochemical staining for Bax in brain samples was carried out. Short term exposure evoked a cellular adaptation response. This was evident by a transient increase in brain levels of Ca²⁺, glutathione (GSH) and serum tumor necrosis factor alpha (TNFα). Long term exposure to EMF was lethal; progressive oxidative damage, and a prolonged increase in the Ca²⁺ level accompanied by a marked pro-inflammatory reaction (TNFα and CRP) were demonstrated. These alterations were ameliorated by pre- and con-comitant treatment with amlodipine. Furthermore, it restored the EMF induced apoptosis in brain to near normal. In conclusion, EMF is a stressor agent that induces an imbalance between ROS generation and antioxidant defense response. Calcium ions may play a pivotal role in enhancing oxidative stress, pro-inflammatory reactions and apoptosis associated with EMF exposure. Therefore calcium channel blockade seems to play a role in brain protection.

In the context of psychoneuroimmunology, which studies the complex interactions between the nervous system and the immune system, anxiety-causing situations affect the immune function leading to its impairment, whereas acupuncture provides the possibility of improving it via its action on the nervous system. Therefore, the aim of the present work was to study, in anxious adult women, the effect of an acupuncture treatment specifically designed to relieve their symptoms, on several parameters known to be altered in disturbed emotional situations. These include the release by blood leukocytes of the cytokines interleukin-2 (IL-2) and tumour necrosis factor-alfa (TNF-α), as well as the plasma cortisol levels and total antioxidant capacity. The results show regulation by acupuncture of all the studied parameters, as early as 72 hours after one single acupuncture session. Thus, the levels of IL-2, which were decreased in women with anxiety, increase following acupuncture, and the levels of TNF-α and cortisol, which were increased in these patients, decrease after the session. Therefore, acupuncture could exert its therapeutic action on anxiety by modulation of a number of parameters including those examined in the present work.

Originally a remembrance of an elderly physiologist, this paper illustrates the need for a standardized specification of certain experimental or survey conditions beyond those usually necessarily disclosed in conventional publications, namely calendar-dates, clock-times and geographic locations, to allow reference to helio-ionosphero-geomagnetics along with natural and artificial lighting and temperature. When possible, body times given by a marker rhythm also should be specified. A personalized chronobiologic cybercare can eventually include focus on infradians, beyond circadians. Benefits from longitudinal monitoring are:
1. Chronobiologically-interpreted blood pressure (BP) and heart rate (HR) monitoring enables the diagnosis and treatment of vascular variability anomalies (VVAs) or, if lasting in several 7-day records, disorders (VVDs), not yet screened for in practice, that increase cardiovascular disease risk independently of an elevated BP. 2. The optimal treatment time for the individual patient can be determined and potential harm avoided, since the same dose of the same medication for the same patient can help or harm depending only on when it is administered. 3. Benefit may be derived in cancer treatment timed according to marker rhythmometry. 4. The change from a spotcheck-based health care to one of internet-aided systematic self-surveillance by the automatic collection and analysis of time series stems from evidence that nonphotic and photic environmental influences affect biota, associations that may depend on geographic and temporal location. 5. Imaging in time includes formatting for time, globally and locally, for the mapping of a transdisciplinary spectrum of cycles involving "good" and "bad" strain in human physiology, versus sudden cardiac death, suicide and terrorism, all latter requiring rational countermeasures.

Ionising radiation (IR) is one of the main treatment modalities in oncology. However, we still search for substances which can radio-sensitize tumour cells. In this study we used caffeine, a non-specific ataxia-telangiectasia mutated kinase (ATM) inhibitor, and studied its effect on the activation of the proteins involved in cell cycle control and the induction of apoptosis in human T-lymphocyte leukaemic MOLT-4 cells (p53 wt). We evaluated the expression of the tumour-suppressor p53 (itself and phosphorylated on Ser¹⁵ and Ser³⁹²), the cell cycle regulator p21, and the anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1). After treatment with 2 mM caffeine, the cells were irradiated by 1 or 3 Gy, lysed and the proteins detected by Western-blotting. Apoptosis was determined by flow-cytometric annexin V/propidium iodine detection. Irradiation by 1 or 3 Gy induced p53 phosphorylation at Ser¹⁵ and Ser³⁹² after 2 h with maximum after 4 h. Adding caffeine significantly inhibited Ser¹⁵ phosphorylation, which is ATM-dependent but surprisingly also Ser³⁹² phosphorylation, which is ATM-independent, suggesting that caffeine might have another cellular target (protein kinase). Similarly, caffeine caused a substantial decrease in p21 in combination with both doses of IR and also Mcl-1 was down-regulated. Three days after irradiation, caffeine significantly increased induction of apoptosis. The ATM/p53 pathway was suppressed by caffeine, which led to increased apoptosis accompanied by a p53-independent decrease in Mcl-1. It also caused down-regulation of p21, which possibly contributed to the shortened cell cycle arrest necessary for effective DNA repair and thus impeded radio-resistance. Caffeine promotes the cytotoxic effect of ionising radiation and provides a possible platform for the development of new anti-cancer therapeutics known as radio-sensitizers.

Bone marrow mensenchyme cells (BMSCs) can differentiate into endothelial progenitor cells which then migrate to injured sites for the repair of neointima, and stromal cell-derived factor-1α (SDF-1α) can mediate the migration of CXCR4 expressing stem/progenitor cells to injured sites for pair. Protein and mRNA expression of SDF-1α and CXCR4 were determined by RT-PCR, Western blot and ELISA. Immediately after common carotid artery balloon injury, the mRNA expression of SDF-1α in vascular smooth muscle cells (VSMCs) first increased and then decreased 7 days later. VSMCs transfected with SDF-1α siRNA did not express SDF-1α mRNA, but after transfection with SDF-1α siRNA, the SDF-1α content in injured VSMCs gradually returned to the baseline level. Normal BMSCs rarely expressed CXCR4 mRNA, but the CXCR4 mRNA expression on BMSCs increased significantly 4 days after common carotid artery injury and was maintained. The migration of BMSCs after artery injury was enhanced when compared with normal BMSCs, but SDF-1α siRNA transfection of VSMCs and AMD3100 treatment remarkably decreased the chemotaxis of BMSCs to VSMCs and SDF-1α, respectively. We conclude that the SDF-1α/CXCR4 axis plays an important role in the migration of BMSCs after balloon injury and can ultimately cause abnormal proliferation of the intima.

Age related neurodegenerative disorders are becoming a serious public health problem. Alzheimer's disease (AD) is a progressive disease pathologically recognizable by deposition of neurofibrillary tangles and amyloid plaques. Oxidative stress probably plays a pivotal role in AD, but despite expectations, antioxidants such as vitamin E, vitamin C, β carotene, and flavonoids have failed as effective prophylaxis and/or treatment. Melatonin, a hormone controlling circadian rhythm, is a potent terminal antioxidant. In vitro tests and animal models have established that the application of melatonin could be beneficial for the amelioration of AD progression. Unfortunately, melatonin effects in human beings are not well understood and a lot of work has still to be done. The review summarizes the basic facts about melatonin and its prospects as a treatment for AD using its hormonal and antioxidant properties.

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.

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.

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.

Radiotherapy and chemotherapy are the basic approaches in cancer treatment, but these procedures are often associated with a number of undesirable side effects worsening the quality of life of the patient. In recent years a number of protective compounds capable of reducing or eliminating these side effects have been extensively investigated (for example: dexrazoxan, mesna, glutathion or N-acetylcystein). One of these compounds is amifostine (WR-2721), a broad-spectrum cytoprotective drug, selectively protecting normal tissues from the toxic effects of therapy, while the malignant tissues are subject to the anti-tumour effects of the treatment. In addition, several studies have revealed certain antimutagenic activities of amifostine making this agent potentially useful in the prevention of therapy-induced secondary malignancies. This article summarizes the information available on the antimutagenic and cytoprotective effects of amifostine and its effects also on the activity of the p53 tumour suppressor.

Hodgkin's Disease (HD) is one of the malignant diseases with good chances for a cure. The prognosis for cure depends on the initial stages and the outcome after initial treatment. Stages I or II at diagnosis, or a complete remission after initial treatment are good indicators for the best prognosis to patients.
A frequent problem faced by clinicians is met at the post-therapy stage because of the difficulty of distinguishing between dead tissue and disease activity in residual masses. Considering that these two situations include therapy options that run from treatment abstention to autologous stem cell transplantation, it is extremely important to distinguish them accurately.
Classical Tomography Scan (CT Scan), Gallium scintigraphy, Magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET) are used to investigate residual masses. In order to clarify the best way to confirm the post-treatment status of patients affected by HD, we describe in this paper our experience of using PET to solve those problem situations where a CT Scan or MRI were not conclusive and Gallium was negative.