Antinociceptive effect of some extracts from Ajuga chamaecistus Ging. ssp. tomentella (Boiss.) Rech. f. aerial parts

Background

The genus Ajuga is used for the treatment of joint pain, gout, and jaundice in traditional Iranian medicine (TIM). Ajuga chamaecistus ssp. tomentella is an exclusive subspecies of Ajuga chamaecistus in the flora of Iran. The aim of this study was to evaluate antinociceptive properties of some extracts from aerial parts of A. chamaecistus ssp. tomentella.

Methods

Antinociceptive activities of total water and 80% methanol extracts, hexane, diethyl ether and n-butanolic partition fractions of the methanolic extract were analyzed using the formalin test in mice. Indomethacin (10 mg/kg) and normal saline were employed as positive and negative controls, respectively.

Results

Oral administration of all extracts (200, 400 and 600 mg/kg) 30 min before formalin injection had no effect against the acute phase (0–5 min after formalin injection) of the formalin-induced licking time, but hexane fraction (200 mg/kg) caused a significant effect (p < 0.001) on the chronic phase (15–60 min after formalin injection). Total water and diethyl ether extracts at a dose of 400 mg/kg showed a very significant analgesic activity on the chronic phase (p < 0.001 and p < 0.01, respectively).

Conclusions

The results of this study suggest that the extracts of A. chamaecistus ssp. tomentella have an analgesic property that supports traditional use of Ajuga genus for joint pain and other inflammatory diseases.     

Anti-hyperlipidemic and anti-atherosclerotic effects of Pinus eldarica Medw. nut in hypercholesterolemic rabbits

Background

Previous studies suggest that chemical constituents present in Pinus eldarica Medw (P. eldarica) nut possess antioxidant properties that may positively influence lipid profile.The present study was conducted to evaluate the efficacy of P. eldarica nut on the experimental atherosclerosis development in hypercholesterolemic rabbits.

Methods

Forty male 6 months old white New Zealand rabbits (1.8–2 kg) were randomly assigned into five equal groups. One group was kept as control (normal) group, fed on standard rabbit diet and other 4 groups were fed on high cholesterol diet (HCD). Out of four HCD groups one group was kept as control (HCD) and other three groups were treated with different doses (50, 100 and 200 mg/kg/day) of P. eldarica nut for 8 weeks. Percentage of aortic wall area changes as indication of atherosclerosis development and fasting blood cholesterol, LDL, HDL and triglyceride levels were determined in all groups.

Results

The results indicate that fasting blood cholesterol and aortic atherosclerotic involvements in 200 mg/kg/day and 100 mg/kg/day P. eldarica nut extract treated groups significantly decreased as compared to the high cholesterol-diet control group.

Conclusion

P. eldarica nut lowers blood cholesterol level and aortic atherosclerotic involvement in hypercholesterolemic rabbits.     

Cost–Consequence Analysis of Nitisinone for Treatment of Tyrosinemia Type I

Background:

Tyrosinemia type I is a rare but severe genetic metabolic disorder. Nitisinone combined with a diet low in tyrosine and phenylalanine became first-line therapy in 1994.

Objectives:

To estimate the direct medical costs of health care services related to the treatment of tyrosinemia type I, taking into consideration the real-life efficacy of nitisinone.

Methods:

A cost–consequence analysis was performed for all children with a confirmed diagnosis of tyrosinemia type I who were treated in Quebec between January 1, 1984, and January 1, 2009. The costs of care were compared for 3 consecutive historical groups: no nitisinone (1984 to 1994), late intervention with nitisinone (first dose received between 1994 and 1997), and early intervention with nitisinone (first dose received between 1997 and 2008). Data were derived from patient charts, hospital databases, and the Régie de l’assurance maladie du Québec and MED-ÉCHO administrative databases. Costs were reported in 2008 Canadian dollars.

Results:

Nitisinone treatment was associated with significant reductions in the number and duration of hospital admissions, the number of admissions to a pediatric intensive care unit, and the number of liver transplants. The cost of hospitalization per person-year was significantly lower in the 2 groups treated with nitisinone: $673 and $5 590 for the early-intervention and late-intervention groups, respectively, as compared to $12 980 for the no-nitisinone group (p < 0.001). Hospital costs per person-year for liver transplant were $3 198 for the late-intervention group and $5 044 for the no-nitisinone group: there were no transplants in the early-intervention group. The cost of nitisinone per person-year was $51 493 for the early-intervention group and $64 895 for the late-intervention group.

Conclusions:

Nitisinone treatment significantly improved the outcomes of patients with tyrosinemia type I, while decreasing utilization of health care resources, liver transplants, and associated costs.     

Mephedrone (4-methylmethcathinone) and d-methamphetamine improve visuospatial associative memory,but not spatial working memory,in rhesus macaques

BACKGROUND AND PURPOSE

The novel cathinone derivative 4-methylmethcathinone (4-MMC; mephedrone) is increasingly popular with recreational users. Little scientific information is available but users report both entactogen-like and classic stimulant-like subjective properties. A recent study in humans reported psychomotor speed improvement after intranasal 4-MMC suggesting classic stimulant properties. Limitations of the user group (which was impaired on some tasks) prompt controlled laboratory investigation.

EXPERIMENTAL APPROACH

Adult male rhesus monkeys were trained to perform tasks from the non-human primate Cambridge Neuropsychological Test Automated Battery, which assess spatial working memory, visuospatial associative memory, learning and motivation for food reward. Test of bimanual motor coordination and manual tracking were also included. The subjects were challenged with 0.178–0.56 mg·kg⁻¹ 4-MMC and 0.056–0.56 mg·kg⁻¹ d-methamphetamine (MA), i.m., in randomized order for behavioural evaluation.

KEY RESULTS

A pronounced improvement in visuospatial memory and learning was observed after the 0.32 mg·kg⁻¹ dose of each compound, this effect was confirmed with subsequent repetition of these conditions. Spatial working memory was not improved by either drug, and the progressive ratio, bimanual motor and rotating turntable tasks were all disrupted in a dose-dependent manner.

CONCLUSIONS AND IMPLICATIONS

These studies show that 4-MMC produces behavioural effects, including improvements in complex spatial memory and learning that are in large part similar to those of MA in non-human primates. Thus, the data suggest that the effects of 4-MMC in monkeys can be classified with classical psychomotor stimulants.     

Effect of myrtle fruit syrup on abnormal uterine bleeding: a randomized double-blind,placebo-controlled pilot study

Background

Myrtle (Myrtus communis L.) has been used in the Iranian Traditional Medicine as a treatment for abnormal uterine bleeding-menometrorrhagia. The main aim of this study is to evaluate the effect of myrtle fruit syrup on abnormal uterine bleeding-menometrorrhagia.

Methods

A randomized, double-blind, placebo-controlled pilot study was conducted on 30 women suffering from abnormal uterine bleeding-menometrorrhagia. Treatment comprised of giving 15 ml oral myrtle syrup daily (5 ml three times a day) for 7 days starting from the onset of bleeding. The myrtle syrup along with placebo was repeated for 3 consecutive menstrual periods. Menstrual duration and number of used pads were recorded by the Pictorial Blood loss Assessment Chart at the end of each menstrual period. The quality of life was also evaluated using the menorrhagia questionnaire.

Results

The mean number of bleeding days significantly declined from 10.6 ± 2.7 days to 8.2 ± 1.9 days after 3 months treatment with the syrup (p = 0.01) and consequently the participants in the intervention group used fewer pads after 3 months (16.4 ± 10.7) compared with the number of pads used at the beginning of the treatment (22.7 ± 12.0, p = 0.01). Bleeding days and number of pads used by the participants in the placebo group did not change significantly. Also significant changes of quality of life scores were observed in the intervention group after 3 months compared to the baseline.

Conclusion

Myrtle syrup is introduced as a potential remedy for abnormal uterine bleeding-menometrorrhagia.     

The hypoglycemic effect of Juglans regia leaves aqueous extract in diabetic patients: A first human trial

Background

Juglans regia L. (J. regia ) is one of the medicinal plants traditionally used for treatment of diabetes in Iranian medicine. The effect of this plant has already been investigated on animal models; however, this is the first study conducted on human subjects. The aim of this study is to investigate the hypoglycemic effect of J. regia leaves aqueous extract in type 2 diabetes patients. Fifty eight Iranian male and female patients with type 2 diabetes were enrolled. The patients were randomly allocated into two groups. One group (n = 30) received J. regia leaves extract while the other group (n = 28) received placebo. Fasting blood samples were collected at the beginning of the study and after two months for determination of HbA1c and blood glucose level as a main outcome and insulin, SGOT, SGPT, and ALP level as secondary outcome.

Results

Our analysis showed that serum fasting HbA1C and blood glucose levels were significantly decreased and the insulin level was increased in patients in the J. regia arm.

Conclusions

The results indicate that J. regia aqueous extract favorably affects blood levels of glucose, insulin and HbA1C in type 2 diabetic patients.     

Effect of Linum usitatissimum L. (linseed) oil on mild and moderate carpal tunnel syndrome: a randomized,double-blind,placebo-controlled clinical trial

Background

Carpal tunnel syndrome is known as the most common entrapment neuropathy. Conservative treatments cannot reduce the symptomatic severity satisfactorily; therefore, effectiveness of Linum usitatissimum L. (linseed) oil on carpal tunnel syndrome, as a complementary treatment, was evaluated in the current study. Linseed oil is a well-known preparation in Iranian traditional medicine and its analgesic, anti-inflammatory and anti-oxidative effects have been shown in previous studies.

Methods

A randomized, double-blind, placebo-controlled clinical trial was conducted. One hundred patients (155 hands) with idiopathic mild to moderate carpal tunnel syndrome aged between 18 and 65 years old were randomized in two parallel groups. These two groups were treated during 4 weeks with topical placebo and linseed oil. In addition, a night wrist splint was prescribed for both groups. Symptomatic severity and functional status were measured using Boston Carpal Tunnel Questionnaire. In addition, median sensory nerve conduction velocity, motor distal latency, sensory distal latency and compound latency as electrodiagnostic parameters were measured at baseline and after the intervention period.

Results

After the intervention, significant improvement was observed regarding Boston Carpal Tunnel Questionnaire symptomatic severity and functional status mean differences (p <0.001) in the linseed oil group compared with those in the placebo group. Also, regarding the mean differences of both groups, significant improvement of nerve conduction velocity of the median nerve was seen in the linseed oil group by a value of 2.38 m/sec (p < 0.05). However, motor distal latency and sensory distal latency of the median nerve showed no between-group significant changes (p = 0.14 for both items). Finally, compound latency was improved slightly in the case group, comparing mean differences between the groups (p <0.05). No significant adverse events were reported from using linseed oil.

Conclusions

It seems that linseed oil could be effective in the management of mild and moderate carpal tunnel syndrome, especially in improving the severity of symptoms and functional status. In addition, its effect on electerodiagnostic parameters, especially on the nerve conduction velocity, can be considered as a valuable point.     

Nebulized thiocyanate improves lung infection outcomes in mice

Background and Purpose

Nebulized saline solutions are used in the treatment of multiple pulmonary diseases including cystic fibrosis (CF), asthma and chronic obstructive pulmonary disease (COPD). The benefits of these therapies include improved lung function, phlegm clearance and fewer lung infections. The thiocyanate anion (SCN) is a normal component of the airway epithelial lining fluid (ELF) secreted by pulmonary epithelia with antioxidant and host defence functions. We sought to test if SCN could be nebulized to combat lung infection by bolstering innate immune defence and antioxidant capacity.

Experimental Approach

We established an effective antioxidant concentration of SCN in vitro using a bronchiolar epithelial cell line. We then developed a nebulization method of SCN in mice that increased ELF SCN above this concentration up to 12 h and used this method in a prolonged Pseudomonas aeruginosa infection model to test if increasing SCN improved host defence and infection outcomes.

Key Results

SCN protected against cytotoxicity in vitro from acute and sustained exposure to inflammation-associated oxidative stress. Nebulized SCN effectively reduced bacterial load, infection-mediated morbidity and airway inflammation in mice infected with P. aeruginosa. SCN also sustained adaptive increases in reduced GSH in infected mice.

Conclusions and Implications

SCN is a dually protective molecule able to both enhance host defence and decrease tissue injury and inflammation as an antioxidant. Nebulized SCN could be developed to combat lung infections and inflammatory lung disease.     

Bioactivity of enoxaparin in critically ill patients with normal renal function

Aim

In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls.

Methods

A prospective, controlled, open label study was performed on a medical intensive care unit (ICU) and a general medical ward. Fifteen ICU patients (male = 12, median age 52 years [IQR 40−65], with a median Simplified Acute Physiology Score of 30 [IQR 18−52]) and sex- and age-matched medical ward patients were included. The anti-FXa plasma activity was measured after a single subcutaneous dose of 40 mg enoxaparin. The thrombus size of a clot formed in an ex vivo perfusion chamber and endogenous thrombin potential (ETP) were measured.

Results

The anti-FXa plasma activity increased significantly after enoxaparin administration, with peak levels at 3 h after treatment, but was comparable between the ICU and medical ward groups (median 0.16 IU ml⁻¹[IQR 0−0.22 IU ml⁻¹]vs. 0.2 IU ml⁻¹[IQR 0.15−0.27 IU ml⁻¹], respectively, P= 0.13). The area under the anti-FXa activity curve from 0–12 h was similar between the groups (median 0.97 IU ml⁻¹ h [IQR 0.59−2.1] and 1.48 IU ml⁻¹ h¹[IQR 0.83−1.62], P= 0.42 for the ICU group compared with the control group, respectively). The ETP was lower in the ICU group (P < 0.05) at baseline, but it was comparable at 3 h between the groups. Thrombus size decreased at 3 h compared with predose (P= 0.029) and was not different between the groups.

Conclusion

Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function.     

Enhanced oxygen transfer rate and bioprocess yield by using magnetite nanoparticles in fermentation media of erythromycin

Background

Magnetite nanoparticles have widespread biomedical applications. In the aerobic bioprocesses, oxygen is a limiting factor for the microbial metabolic rate; hence a high availability of oxygen in the medium is crucial for high fermentation productivity. This study aimed to examine the effect of using magnetite nanoparticles on oxygen transfer rate in erythromycin fermentation culture.

Methods

Magnetite nanoparticles were synthetized through co-precipitation method. After observing the enhanced oxygen transfer rate in deionized water enriched with magnetite nanoparticles, these nanoparticles were used in the media of by Saccharopolyspora erythraea growth to explore their impact on erythromycin fermentation titer. Treatments comprised different concentrations of magnetite nanoparticles, (0, 0.005, 0.02 v/v).

Results

In the medium containing 0.02 v/v magnetite nanoparticles, KLa was determined to be 1.89 time higher than that in magnetite nanoparticle-free broth. An improved 2.25 time higher erythromycin titer was obtained in presence of 0.02 v/v nanoparticles.

Conclusions

Our results, demonstrate the potential of magnetite nanoparticles for enhancing the productivity of aerobic pharmaceutical bioprocesses.     

Alteration in brain-derived neurotrophic factor (BDNF) after treatment of mice with herbal mixture containing Euphoria longana,Houttuynia cordata and Dioscorea japonica

Background

Literature data indicate that brain-derived neurotrophic factor (BDNF), cyclic-AMP response element-binding protein (CREB) and phospho-CREB (pCREB) may have a place in depression. BDNF belongs to the neurotrophin family that plays an important role in proliferation, survival and differentiation of different cell populations in the mammalian nervous system. The herbal mixture used in the present study consists of Euphoria longana, Houttuynia cordata and Dioscorea japonica. The purpose of the present study was to determine the neuroprotective effect of herbal mixture. We also tested the hypothesis that administration of herbs reverses memory deficits and promotes the protein expression of BDNF in the mouse brain.

Methods

Mice were randomized into four different treatment groups (n = 10/group). Normal and stress groups received regular lab chow without stress and under stress conditions, respectively, for 3 weeks. The animals in the stress group were immobilized for 4 hours a day for 2 weeks. Different doses of herbal mixture (206 and 618 mg/kg) were administered for 3 weeks to those mice under stress conditions. Mice were analyzed by behavioral tests and immunoblotting examination in the hippocampus and cortex. An additional in vitro investigation was performed to examine whether herbs induce neurotoxicity in a human neuroblastoma cell line, SH-SY5Y cells.

Results

No significant toxicity of herbs on human neuroblastoma cells was observed. These herbs demonstrated an inductive effect on the expression of BDNF, pCREB and pAkt. For spatial working memory test, herbal mixture fed mice exhibited an increased level of spontaneous alternation (p < 0.01) compared to those in stress conditions. Moreover, herbal mixture produced highly significant (p < 0.01) reduction in the immobility time in the tail suspension test. Mice in the herbal mixture groups demonstrated lower serum corticosterone concentration than mice in the stress group (p < 0.05). Effects of the oral administration of herbal mixture on protein levels of BDNF in the hippocampi and cortices were significant.

Conclusions

Our study showed that herbal mixture administration has antidepressant effects in mice. It is proposed that adverse events such as stress and depression can modulate the expression of molecular players of cellular plasticity in the brain.     

Artemia salina as a model organism in toxicity assessment of nanoparticles

Background

Because of expanding presence of nanomaterials, there has been an increase in the exposure of humans to nanoparticles that is why nanotoxicology studies are important. A number of studies on the effects of nanomatrials in in vitro and in vivo systems have been published. Currently cytotoxicity of different nanoparticles is assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on different cell lines to determine cell viability, a tedious and expensive method. The aim of this study was to evaluate the Artemia salina test in comparison with the MTT assay in the assessment of cytotoxicity of nanostructures because the former method is more rapid and convenient and less expensive.

Methods

At the first stage, toxicity of different nanoparticles with different concentrations (1.56–400 μg/mL) was measured by means of the brine shrimp lethality test. At the second stage, the effect of nanoparticles on the viability of the L929 cell line was assessed using the MTT assay. Experiments were conducted with each concentration in triplicate.

Results

The results obtained from both tests (A. salina test and MTT assay) did not have statistically significant differences (P > 0.05).

Conclusions

These findings suggest that the A. salina test may expedite toxicity experiments and decrease costs, and therefore, may be considered an alternative to the in vitro cell culture assay.     

Immunomodulatory activity of methanolic fruit extract of Aegle marmelos in experimental animals

Aim

The aim of the present study was to investigate the immunomodulatory action of methanolic extract of Aegle marmelos fruit (FEAM) in experimental model of immunity.

Methods

Cellular immunity was carried out by neutrophil adhesion test and carbon clearance assay, whereas, humoral immunity was analyzed by mice lethality test and indirect haemagglutination assay. FEAM dose was selected by Stair case method (up and down) and administered at 100 and 500 mg/kg orally. The Ocimum sanctum (OSE, 100 mg/kg, p.o) was used as standard.

Results

FEAM at 100 and 500 mg/kg produced significant increases in adhesion of neutrophils and an increase in phagocytic index in carbon clearance assay. Both high and low doses of FEAM significantly prevented the mortality induced by bovine Pasteurella multocida in mice. Treatment of animals with FEAM and OSE significantly increased the circulating antibody titre in indirect haemagglunation test. Among the different doses, low one was more effective in cellular immunity models than the high. However, all the doses exhibited similar protection in humoral immunity procedures.

Conclusion

From the above findings, it is concluded that FEAM possesses potential for augmenting immune activity by cellular and humoral mediated mechanisms more at low dose (100 mg/kg) than high dose (500 mg/kg).     

Fungal transformation of androsta-1,4-diene-3,17-dione by Aspergillus brasiliensis

Background

The biotransformation of steroids by fungal biocatalysts has been recognized for many years. There are numerous fungi of the genus Aspergillus which have been shown to transform different steroid substances. The possibility of using filamentous fungi Aspergillus brasiliensis cells in the biotransformation of androsta-1,4-diene-3,17-dione, was evaluated.

Methods

The fungal strain was inoculated into the transformation medium which supplemented with androstadienedione as a substrate and fermentation continued for 5 days. The metabolites were extracted and isolated by thin layer chromatography. The structures of these metabolites were elucidated using ¹H-NMR, broadband decoupled ¹³C-NMR, EI Mass and IR spectroscopies.

Results

The fermentation yielded one reduced product: 17β-hydroxyandrost-1,4-dien-3-one and two hydroxylated metabolites: 11α-hydroxyandrost-1,4-diene-3,17-dione and 12β-hydroxyandrost-1,4-diene-3,17-dione.

Conclusions

The results obtained in this study show that A. brasiliendsis could be considered as a biocatalyst for producing important derivatives from androstadienedione.     

Liguzinediol improved the heart function and inhibited myocardial cell apoptosis in rats with heart failure

Aim:

Liguzinediol is a novel derivative of ligustrazine isolated from the traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franch), and produces significant positive inotropic effect in isolated rat hearts. In this study we investigated the effects of liguzinediol on a rat model of heart failure.

Methods:

To induce heart failure, male SD rats were injected with doxorubicin (DOX, 2 mg/kg, ip) once a week for 4 weeks. Then the rats were administered with liguzinediol (5, 10, 20 mg·kg⁻¹·d⁻¹, po) for 2 weeks. Hemodynamic examination was conducted to evaluate heart function. Myocardial cell apoptosis was examined morphologically. The expression of related genes and proteins were analyzed using immunohistochemical staining and Western blot assays, respectively.

Results:

Oral administration of liguzinediol dose-dependently improved the heart function in DOX-treated rats. Electron microscopy revealed that liguzinediol (10 mg·kg⁻¹·d⁻¹) markedly attenuated DOX-induced injury of cardiomyocytes, and decreased the number of apoptotic bodies in cardiomyocytes. Furthermore, liguzinediol significantly decreased Bax protein level, and increased Bcl-2 protein level in cardiomyocytes of DOX-treated rats, led to an increase in the ratio of Bcl-2/Bax. Moreover, liguzinediol significantly decreased the expression of both cleaved caspase-3 and NF-κB in cardiomyocytes of DOX-treated rats. Administration of digitalis (0.0225 mg·kg⁻¹·d⁻¹) also markedly improved the heart function and the morphology of cardiomyocytes in DOX-treated rats.

Conclusion:

Liguzinediol improves the heart function and inhibits myocardial cell apoptosis in the rat model of heart failure, which is associated with regulating Bcl-2, Bax, caspase-3 and NF-κB expression.     

Osteogenic potential of punica granatum through matrix mineralization,cell cycle progression and runx2 gene expression in primary rat osteoblasts

Background

Osteoporosis is one of the prevalent diseases in ageing populations. Due to side effects of many chemotherapeutic agents, there is always a need to search for herbal products to treat the disorder. Punica granatum (PG) represent a potent fruit-bearing medicinal herb which exerted valuable anti-osteoporotic activities. The present study was carried out to validate the in vitro osteogenic effects of the PG seed extract in primary calvarial osteoblast cultures harvested from neonatal rats.

Methods

The ethanolic extract of PG was subjected to evaluate cell proliferation, regeneration, mineralization and formation of collagen matrix using MTT, alkaline phosphatase, Alizarin Red-S staining and Sirius Red dye, respectively. Cell cycle progression and osteogenic gene Runx2 expression were carried out by flow cytometry and real time PCR, respectively.

Results

Exposure of different concentrations (10–100 μg/ml) of the extract on osteoblastic cells showed characteristic morphological changes and increment in cell number. A significant growth in cell proliferation, ALP activity, collagen contents and matrix mineralization of osteoblasts in a dose dependent manner (p < 0.05), suggested that PG has a stimulatory effect on osteoblastic bone formation or potential activity against osteoporosis. In addition, PG extract also enhanced DNA content in S phase of cell cycle and Runx2 gene expression level in osteoblasts.

Conclusion

The data clearly indicated that PG promoting bone cell proliferation and differentiation in primary osteoblasts might be due to elevating the osteogenic gene Runx2 expression. The present study provides an evidence for PG could be a promising herbal medicinal candidate that able to develop drugs for osteoporosis.     

The edaravone and 3-n-butylphthalide ring-opening derivative 10b effectively attenuates cerebral ischemia injury in rats

Aim:

Compound 10b is a hybrid molecule of edaravone and a ring-opening derivative of 3-n-butylphthalide (NBP). The aim of this study was to examine the effects of compound 10b on brain damage in rats after focal cerebral ischemia.

Methods:

SD rats were subjected to 2-h-middle cerebral artery occlusion (MCAO). At the onset of reperfusion, the rats were orally treated with NBP (60 mg/kg), edaravone (3 mg/kg), NBP (60 mg/kg)+edaravone (3 mg/kg), or compound 10b (70, 140 mg/kg). The infarct volume, motor behavior deficits, brain water content, histopathological alterations, and activity of GSH, SOD, and MDA were analyzed 24 h after reperfusion. The levels of relevant proteins in the ipsilateral striatum were examined using immunoblotting.

Results:

Administration of compound 10b (70 or 140 mg/kg) significantly reduced the infarct volume and neurological deficits in MCAO rats. The neuroprotective effects of compound 10b were more pronounced compared to NBP, edaravone or NBP+edaravone. Furthermore, compound 10b significantly upregulated the protein levels of the cytoprotective molecules Bcl-2, HO-1, Nrf2, Trx, P-NF-κB p65, and IκB-α, while decreasing the expression of Bax, caspase 3, caspase 9, Txnip, NF-κB p65, and P-IκB-α.

Conclusion:

Oral administration of compound 10b effectively attenuates rat cerebral ischemia injury.     

Insights into the preclinical treatment of blood-stage malaria by the antibiotic borrelidin

Background and Purpose

Blood-stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl-tRNA synthetases have been validated as antimalarial drug targets. We explored long-term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria.

Experimental Approach

Long-term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed.

Key Results

Borrelidin protected against lethal malaria at 0.25 mg·kg⁻¹·day⁻¹. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re-infection on further challenges, 75 and 340 days after the initial infection. This long-term immunity in borrelidin-treated mice resulted in negligible parasitaemia after re-infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long-term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts.

Conclusions and Implications

Low borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria.     

Association between eIF3α polymorphism and severe toxicity caused by platinum-based chemotherapy in non-small cell lung cancer patients

Aim

Platinum-induced toxicity severely impedes successful chemotherapy in lung cancer patients. The nucleotide excision repair (NER) pathway is considered as one of the major factors contributing to platinum effects. Furthermore, genetic variances of the NER pathway influence platinum toxicity. eIF3α, over expressed in many malignancies, is an up-stream gene of NER and could regulate its activity. The purpose of this study was to investigate whether eIF3α polymorphism is associated with severe platinum toxicity in patients with non-small cell lung cancer (NSCLC).

Methods

Two hundred and eighty-two incident NSCLC patients, from three different institutions, were enrolled and followed up. These patients were diagnosed and histologically confirmed with non-small cell lung cancer. All patients accepted platinum based chemotherapy for at least two cycles. Twenty-two SNPs of eIF3α were detected in these patients.

Results

eIF3α Arg803Lys C > T polymorphism was associated with cisplatin-induced toxicity in NSCLC patients (P = 0.02, OR = 0.54, 95% CI 0.32, 93). T-carrier subjects presented better tolerance to platinum nephrotoxicity, but poorer tolerance to ototoxicity.

Conclusion

eIF3α Arg803Lys was associated with platinum toxicity in NSCLC patients and could be considered as a predictor for pretreatment evaluation in lung cancer patients.     

The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients

Background

Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.

Methods

In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human β-Defensin 2 (HβD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.

Results

During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean ± SD 19.82 ± 19.55 days vs. 13.82 ± 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HβD2 levels were higher for NAC group (at day 3).

Conclusion

High dose of NAC administration not only did not improve patients’ outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.