Silymarin improved 6-OHDA-induced motor impairment in hemi-parkisonian rats: behavioral and molecular study

Background

Neuroinflammation and oxidative stress has been shown to be associated with the development of Parkinson disease (PD). In the present study, we investigated the effect of intraperitoneal (i.p.) administration of silymarin, on 6-OHDA-induced motor-impairment, brain lipid per-oxidation and cerebrospinal fluid (CSF) levels of inflammatory cytokine in the rats.

Results

The results showed that silymarin is able to improve motor coordination significantly (p < 0.001) in a dose dependent manner. There was a significant (p < 0.001) increase in MDA levels of 6-OHDA-lesioned rats whereas; in silymarin (100, 200 and 300 mg/kg, i.p. for 5 days) pre-treated hemi-parkinsonian rats MDA levels was decreased markedly (p < 0.001). Furthermore the CSF levels of IL-1β was decreased (p < 0.001) in silymarin (100, 200 and 300 mg/kg) pre-treated rats up to the range of normal non-parkinsonian animals.

Conclusion

We found that pre-treatment with silymarin could improve 6-OHDA-induced motor imbalance by attenuating brain lipid per-oxidation as well as CSF level of IL-1β as a pro-inflammatory cytokine. We suggest a potential prophylactic effect for silymarin in PD. However, further clinical trial studies should be carried out to prove this hypothesis.     

N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: a randomized,double-blinded,placebo-controlled,clinical trial

Purpose

The aim of this study was to evaluate the effectiveness of oral n-acetyl cysteine, as a potential nephroprotective agent, in preventing and/or attenuating amphotericin B-induced electrolytes imbalances.

Methods

During a one year period, patients were to receive conventional amphotericin b for any indication for at least one week and were randomly allocated to receive either placebo or 600 mg oral n-acetyl cysteine twice daily during the treatment course of amphotericin b. Demographic and clinical data of the study population were gathered. Different aspects of amphotericin b nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, renal magnesium and potassium wasting were assessed. Each patient was monitored for any adverse reaction to n-acetyl cysteine. Sixteen and 14 patients in the n-acetyl cysteine and placebo groups completed the study, 3incidences of hypokalemia (75 % versus 70 %; P?=?0.724) and hypomagnesemia (30 % versus 20 %; P?=?0.468) did not differ significantly between placebo and NAC groups, respectively. Although the rate of AmB nephrotoxicity was higher in the placebo than in the NAC group (60 % versus 40 %), this difference was not statistically significant (P?=?0.209) even after adjusting for probable associated factors of amphotericin b nephrotoxicity (P?=?0.206). The incidence as well as time of onset of electrolyte abnormalities also did not differ significantly between placebo and n-acetyl cysteine groups. About 44 % of n-acetyl cysteine recipients experienced new onset nausea and a mild unpleasant taste during the study.

Conclusion

Oral n-acetyl cysteine during the amphotericin B treatment course was not significantly effective in preventing or mitigating different features of its nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, and renal potassium as well as magnesium wasting.     

Characterization of Plasmid-Mediated AmpC and Carbapenemases among Iranain Nosocomial Isolates of Klebsiella pneumoniae Using Phenotyping and Genotyping Methods

Objectives

Plasmid-mediated AmpC β-lactamases (PMABLs) and carbapenemases are emerging groups of antimicrobial-resistance determinants. The aims of the study were to evaluate the occurrence of PMABLs and carbapenemases in clinical isolates of Klebsiella pneumoniae and compare the test performance of various phenotypic methods for detection of these enzymes in Iran.

Methods

A total of 100 K. pneumoniae isolates were collected from clinical specimens obtained in Valiasr Hospital. AmpC production in all isolates was determined using the AmpC disk test, the cephamycin Hodge test, the AmpC Etest, and the boronic acid combined-disk test. In addition, carbapenemase production was determined using the modified Hodge test, the EDTA disk synergy test, and the boronic acid combined-disk test. The performances of various phenotypic methods were evaluated by the comparison of their results with polymerase chain reaction (PCR) method as the gold standard.

Results

Of the 100 isolates, 19 (19%) were demonstrated to harbor the PMABL-resistance gene by the multiplex PCR method. The PCR result indicated the presence of carbapenemase genes in 12 isolates. The performance of various phenotypic tests carried out for detection of carbapenemase-producing isolates varied widely, ranging in sensitivity from 30% to 100% and in specificity from 90.8% to 100%.

Conclusion

This is the first report of MOX-type AmpC β-lactamase and bla_GES in K. pneumoniae in Iran. A comparison of the phenotypic methods showed that a combination of cefoxitin plus boronic acid is optimal for detecting plasmid-mediated AmpC enzymes in K. pneumoniae, whereas the implementation of molecular methods is often complex, requires specially trained personnel, and is associated with higher costs.     

Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress

Background and Purpose

The hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Extracellular glutamate depletes cellular glutathione by blocking the glutamate/cystine antiporter system xc−. Glutathione depletion induces a well-defined programme of cell death characterized by an increase in reactive oxygen species and mitochondrial dysfunction.

Experimental Approach

We compared the mitochondrial shape, the abundance of mitochondrial complexes and the mitochondrial respiration of HT22 cells, selected based on their resistance to glutamate, with those of the glutamate-sensitive parental cell line.

Key Results

Glutamate-resistant mitochondria were less fragmented and displayed seemingly contradictory features: mitochondrial calcium and superoxide were increased while high-resolution respirometry suggested a reduction in mitochondrial respiration. This was interpreted as a reverse activity of the ATP synthase under oxidative stress, leading to hydrolysis of ATP to maintain or even elevate the mitochondrial membrane potential, suggesting these cells endure ineffective energy metabolism to protect their membrane potential. Glutamate-resistant cells were also resistant to oligomycin, an inhibitor of the ATP synthase, but sensitive to deoxyglucose, an inhibitor of hexokinases. Exchanging glucose with galactose rendered resistant cells 1000-fold more sensitive to oligomycin. These results, together with a strong increase in cytosolic hexokinase 1 and 2, a reduced lactate production and an increased activity of glucose-6-phosphate dehydrogenase, suggest that glutamate-resistant HT22 cells shuttle most available glucose towards the hexose monophosphate shunt to increase glutathione recovery.

Conclusions and Implications

These results indicate that mitochondrial and metabolic adaptations play an important role in the resistance of cells to oxidative stress.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Assessment of Demineralization Inhibition Effects of Dentin Desensitizers Using Swept-Source Optical Coherence Tomography

The purpose of this study was to evaluate the mechanism of action and the inhibiting effects of two types of desensitizers against dentin demineralization using pre-demineralized hypersensitivity tooth model in vitro. In this study, we confirmed that a hypersensitivity tooth model from our preliminary experiment could be prepared by immersing dentin discs in an acetic acid-based solution with pH 5.0 for three days. Dentin discs with three days of demineralization were prepared and applied by one of the desensitizers containing calcium fluoro-alumino-silicate glass (Nanoseal, NS) or fluoro-zinc-silicate glass (Caredyne Shield, CS), followed by an additional three days of demineralization. Dentin discs for three days of demineralization (de3) and six days of demineralization (de6) without the desensitizers were also prepared. The dentin discs after the experimental protocol were scanned using swept-source optical coherence tomography (SS-OCT) to image the cross-sectional (2D) view of the samples and evaluate the SS-OCT signal. The signal intensity profiles of SS-OCT from the region of interest of 300, 500, and 700 µm in depth were obtained to calculate the integrated signal intensity and signal attenuation coefficient. The morphological differences and remaining chemical elements of the dentin discs were also analyzed using scanning electron microscopy and energy-dispersive X-ray spectroscopy. SS-OCT images of CS and NS groups showed no obvious differences between the groups. However, SS-OCT signal profiles for both the CS and NS groups showed smaller attenuation coefficients and larger integrated signal intensities than those of the de6 group. Reactional deposits of the desensitizers even after the additional three days of demineralization were observed on the dentin surface in NS group, whereas remnants containing Zn were detected within the dentinal tubules in CS group. Consequently, both CS and NS groups showed inhibition effects against the additional three days of demineralization in this study. Our findings demonstrate that SS-OCT signal analysis can be used to monitor the dentin demineralization and inhibition effects of desensitizers against dentin demineralization in vitro.     

Evaluation of the efficacy of platelet-rich plasma on healing of clean diabetic foot ulcers: A randomized clinical trial in Tehran,Iran

Background and aimsDiabetic foot ulcers (DFUs) are among challenging hurdles both for the patient and the physician. There is a recent trend toward finding novel and clinically efficient modalities to treat this potentially hazardous complication of diabetes mellitus in a timely manner. Herein, we aim to appraise the efficacy of platelet-rich plasma (PRP) in healing of clean DFUs.Methods90 patients with clean DFUs consisting of 56 (62.2%) males and 34 (37.8%) females with mean age (±standard deviation) of 56.52 (±7.14) years were enrolled in this study between June 2017 and December 2018. They were randomly allocated into control group (47 patients who received conventional dressing along with silver sulfadiazine ointment twice daily), and case group (43 patients who received PRP gel twice weekly for 3 weeks). All the patients were followed up for 6 months.ResultsOur study showed that PRP significantly increased the healing rate of DFUs regardless of the age (p-value: 0.0), gender (p-value: 0.0), or smoking (p-value: 0.0) and blood pressure (p-value: 0.0) status of patients, but it did not have a significant impact on the need for amputation (p-value: 0.11), level of amputation (p-value: 0.16), or the need for further treatments such as graft or angioplasty (p-value: 0.52).ConclusionRegardless of the age, gender, or smoking and blood pressure status of patients, PRP can be efficiently used in diabetic patients to accelerate the healing rate of foot ulcers.     

Predictive role of PI-RADSv2 and ADC parameters in differentiating Gleason pattern 3 + 4 and 4 + 3 prostate cancer

Purpose

To compare the predictive roles of qualitative (PI-RADSv2) and quantitative assessment (ADC metrics), in differentiating Gleason pattern (GP) 3 + 4 from the more aggressive GP 4 + 3 prostate cancer (PCa) using radical prostatectomy (RP) specimen as the reference standard.

Methods

We retrospectively identified treatment-naïve peripheral (PZ) and transitional zone (TZ) Gleason Score 7 PCa patients who underwent multiparametric 3T prostate MRI (DWI with b value of 0,1400 and where unavailable, 0,500) and subsequent RP from 2011 to 2015. For each lesion identified on MRI, a PI-RADSv2 score was assigned by a radiologist blinded to pathology data. A PI-RADSv2 score ≤ 3 was defined as “low risk,” a PI-RADSv2 score ≥ 4 as “high risk” for clinically significant PCa. Mean tumor ADC (ADC_T), ADC of adjacent normal tissue (ADC_N), and ADC_ratio (ADC_T/ADC_N) were calculated. Stepwise regression analysis using tumor location, ADC_T and ADC_ratio, b value, low vs. high PI-RADSv2 score was performed to differentiate GP 3 + 4 from 4 + 3.

Results

119 out of 645 cases initially identified met eligibility requirements. 76 lesions were GP 3 + 4, 43 were 4 + 3. ADC_ratio was significantly different between the two GP groups (p = 0.001). PI-RADSv2 score (“low” vs. “high”) was not significantly different between the two GP groups (p = 0.17). Regression analysis selected ADC_T (p = 0.03) and ADC_ratio (p = 0.0007) as best predictors to differentiate GP 4 + 3 from 3 + 4. Estimated sensitivity, specificity, and accuracy of the predictive model in differentiating GP 4 + 3 from 3 + 4 were 37, 82, and 66%, respectively.

Conclusions

ADC metrics could differentiate GP 3 + 4 from 4 + 3 PCa with high specificity and moderate accuracy while PI-RADSv2, did not differentiate between these patterns.

     

Back Muscle Function in Older Women With Age-Related Hyperkyphosis: A Comparative Study

ObjectiveThe purpose of this study was to compare static maximal back extensor muscle force, endurance, and characteristics of flexion relaxation phenomenon (FRP) in older women with and without age-related hyperkyphosis.MethodsMaximum back extensor force and endurance measured in a sitting position with a designed load cell setup; appearance, onset, and offset angles of FRP; and extension relaxation ratio (ERR) during a dynamic flexion-extension task were compared between 24 older women with hyperkyphosis (thoracic kyphosis angle ≥50°), mean age 65 ± 4.4 years, and 24 older women without hyperkyphosis (thoracic kyphosis angle ?50°), mean age 63 ± 4.3 years. Variables of force, endurance, angles of FRP, and ERR were analyzed using an independent sample t test. A χ² test was used to identify differences between groups in FRP appearance.ResultsStatic back extensor force and endurance were significantly lower among those with versus those without hyperkyphosis (P ? .001). Although the 2 groups did not differ in FRP appearance and ERR in the superficial erector spinal muscles (P ? .05), FRP in the hyperkyphosis group started sooner and ended later than in the group without hyperkyphosis (P ? .05).ConclusionOur study indicates that women with age-related hyperkyphosis had decreased static maximal force and endurance of the back extensor muscles and prolonged myoelectrical silence of the superficial erector spinal muscles. Reduced endurance of the superficial erector spinal muscles may trigger early onset of FRP and prolonged relaxation of these muscles.