The Central Theme of Parkinson’s Disease: α-Synuclein

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, defined by the presence of resting tremor, muscular rigidity, bradykinesia, and postural instability. PD is characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. The neuropathological hallmark of the disease is the presence of intracytoplasmic inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), containing α-synuclein, a small protein which is widely expressed in the brain. The α-synuclein gene, SNCA, is located on chromosome 4q22.1; SNCA-linked PD shows an autosomal dominant inheritance pattern with a relatively early onset age, and it usually progresses rapidly. Three missense mutations, A53T, A30P, and E46K, in addition to gene multiplications of the SNCA have been described so far. Although it is clear that LBs and LNs contain mainly the α-synuclein protein, the mechanism(s) which leads α-synuclein to accumulate needs to be elucidated. The primary question in the molecular pathology of PD is how wild-type α-synuclein aggregates in PD, and which interacting partner(s) plays role(s) in the aggregation process. It is known that dopamine synthesis is a stressfull event, and α-synuclein expression somehow affects the dopamine synthesis. The aberrant interactions of α-synuclein with the proteins in the dopamine synthesis pathway may cause disturbances in cellular mechanisms. The normal physiological folding state of α-synuclein is also important for the understanding of pathological aggregates. Recent studies on the α-synuclein protein and genome-wide association studies of the α-synuclein gene show that PD has a strong genetic component, and both familial and idiopathic PD have a common denominator, α-synuclein, at the molecular level. It is clear that the disease process in Parkinson’s disease, as in other neurodegenerative disorders, is very complicated; there can be several different molecular pathways which are responsible for diverse and possibly also unrelated functions inside the neuron, playing roles in PD pathogenesis.     

Human Peroxin PEX3 Is Co‐translationally Integrated into the ER and Exits the ER in Budding Vesicles

The long‐standing paradigm that all peroxisomal proteins are imported post‐translationally into pre‐existing peroxisomes has been challenged by the detection of peroxisomal membrane proteins (PMPs) inside the endoplasmic reticulum (ER). In mammals, the mechanisms of ER entry and exit of PMPs are completely unknown. We show that the human PMP PEX3 inserts co‐translationally into the mammalian ER via the Sec61 translocon. Photocrosslinking and fluorescence spectroscopy studies demonstrate that the N‐terminal transmembrane segment (TMS) of ribosome‐bound PEX3 is recognized by the signal recognition particle (SRP). Binding to SRP is a prerequisite for targeting of the PEX3‐containing ribosome?nascent chain complex (RNC) to the translocon, where an ordered multistep pathway integrates the nascent chain into the membrane adjacent to translocon proteins Sec61α and TRAM. This insertion of PEX3 into the ER is physiologically relevant because PEX3 then exits the ER via budding vesicles in an ATP‐dependent process. This study identifies early steps in human peroxisomal biogenesis by demonstrating sequential stages of PMP passage through the mammalian ER.      

Effect of ascorbic acid on production of nitric oxide by leukocytes

The effect of ascorbic acid on suspensions of blood formic elements was studied by the ESR method. It was shown that incubation of a suspension of formic blood elements in the presence of ascorbic acid leads to the appearance of nitric oxide, which is produced by leukocytes and partially probably by thrombocytes. The formation of nitric oxide is evidenced by the appearance of nitrosyl complexes heme-NO. In this case, hemoglobin of erythrocytes serves as a natural trap for nitric oxide.     

Anaerobic degradation of azo dye Drimaren blue HFRL in UASB reactor in the presence of yeast extract a source of carbon and redox mediator

This paper presents results on anaerobic degradation of the azo dye blue HFRL in a bench scale Upflow anaerobic sludge blanket (UASB) reactor operated at ambient temperature. The results show that the addition of yeast extract (500 mg/L) increased color removal (P < 0.05) from 62 to 93% despite the low chemical oxygen demand (COD) removal (~35%) which happened due to volatile fatty acids (VFA) accumulation. There were no differences in color removal (~91%) when yeast extract (500 mg/L) was used in the presence or absence of glucose, suggesting that yeast extract acted as source of redox mediator (riboflavin) and carbon. The specific rate of dye removal increased along the operational phases and depended on the presence of yeast extract, suggesting progressive biomass acclimatization. Analysis of bacterial diversity by Polymerase Chain Reaction-Denaturing Gradient Gel Electrophoresis (PCR–DGGE) method showed there was biomass selection along the bioreactor operation and no evidence of azo dye degrading bacteria predominance. This strengthens the hypothesis that color removal happens extracellularly by the reduction of azo bond by reduced redox mediators, such as riboflavin, which is present in high amount in the yeast extract.     

Effects of Bark Beetle Disturbance on Soil Nutrient Retention and Lake Chemistry in Glacial Catchment

Ecosystems - Forest ecosystems worldwide are subjected to human-induced stressors, including eutrophication and acidification, and to natural disturbances (for example, insect infestation,...     

Perceptual Learning of Interrupted Speech

The intelligibility of periodically interrupted speech improves once the silent gaps are filled with noise bursts. This improvement has been attributed to phonemic restoration, a top-down repair mechanism that helps intelligibility of degraded speech in daily life. Two hypotheses were investigated using perceptual learning of interrupted speech. If different cognitive processes played a role in restoring interrupted speech with and without filler noise, the two forms of speech would be learned at different rates and with different perceived mental effort. If the restoration benefit were an artificial outcome of using the ecologically invalid stimulus of speech with silent gaps, this benefit would diminish with training. Two groups of normal-hearing listeners were trained, one with interrupted sentences with the filler noise, and the other without. Feedback was provided with the auditory playback of the unprocessed and processed sentences, as well as the visual display of the sentence text. Training increased the overall performance significantly, however restoration benefit did not diminish. The increase in intelligibility and the decrease in perceived mental effort were relatively similar between the groups, implying similar cognitive mechanisms for the restoration of the two types of interruptions. Training effects were generalizable, as both groups improved their performance also with the other form of speech than that they were trained with, and retainable. Due to null results and relatively small number of participants (10 per group), further research is needed to more confidently draw conclusions. Nevertheless, training with interrupted speech seems to be effective, stimulating participants to more actively and efficiently use the top-down restoration. This finding further implies the potential of this training approach as a rehabilitative tool for hearing-impaired/elderly populations.     

Cardioprotective Effects of a Novel Hydrogen Sulfide Agent–Controlled Release Formulation of S-Propargyl-Cysteine on Heart Failure Rats and Molecular Mechanisms

Objective

Heart failure (HF) is one of the most serious diseases worldwide. S-propargyl-cysteine (SPRC), a novel modulator of endogenous hydrogen sulfide, is proved to be able to protect against acute myocardial ischemia. In order to produce more stable and sustainable hydrogen sulfide, we used controlled release formulation of SPRC (CR-SPRC) to elucidate possible cardioprotective effects on HF rats and investigate involved mechanisms on apoptosis and oxidation.

Methods

Left coronary artery was occluded to induce HF model of rat. The survival rats were randomly divided into 7 groups after 24 hours and treated with drugs for 6 weeks. Echocardiographic indexes were recorded to determine cardiac function. TTC staining was performed to determine infarct size. Plasmatic level of hydrogen sulfide was detected by modified sulfide electrode. Activity of enzyme and expression of protein were determined by colorimetry and Western blot, respectively.

Results

The cardioprotective effects of CR-SPRC on HF rats were confirmed by significant reduction of infarct size and improvement of cardiac function, with better effects compared to normal SPRC. CR-SPRC modulated antioxidant defenses by preserving levels of GSH, CAT and SOD and reducing CK leakage. In addition, CR-SPRC elevated ratio of Bcl-2/Bax and inhibited activity of caspases to protect against myocardial apoptosis. The cardioprotective effects of CR-SPRC were mediated by hydrogen sulfide.

Conclusions

All experiment data indicated cardioprotective effects of CR-SPRC on HF rats. More importantly, CR-SPRC exerted better effects than normal SPRC in all respects, providing a new perspective on hydrogen sulfide-mediated drug therapy.     

Chemical Composition and Biological Activity of Centaurea baseri: New Species from Turkey

The genus Centaurea L. is one of the largest and important genera of Asteraceae family. Centaurea species have been widely used as herbal remedies in folk medicine for their antidandruff, antidiarrheic, antirheumatic, anti‐inflammatory, choleretic, diuretic, digestive, stomachic, astringent, antipyretic, cytotoxic, and antibacterial properties. Centaurea baseri Kose & Alan is a recently described local endemic species in Turkey and this is the first study on the chemical composition and bioactivity of its hydrodistilled essential oil and the crude extract. According to chromatospectral analysis, hexadecanoic acid (42.3%), nonacosane (8.2%), and heptacosane (8.0%) were the main compounds of the essential oil, while 16 compounds were determined in the MeOH extract using LC/MS. Furthermore, antimicrobial, antioxidant, and cytotoxic effects of the essential oil and the extract were evaluated in comparison with the standard agents. The extract showed strong antifungal effect against Candida utilis at the concentration of 60 μg/ml (MIC) where the EO showed growth inhibition at the concentration of 47.00 μg/ml (MIC) against pathogen Bacillus cereus. Both the essential oil and the extract did not show any selective antioxidant properties. The extract showed remarkably selective cytotoxic properties against MCF‐7, PANC‐1, A549, and C6 glioma cells.