Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation

Previous studies demonstrated that chronic systemic exposure to the pesticide and mitochondrial toxin rotenone through jugular vein cannulation reproduced many features of Parkinson's disease (PD) in rats, including nigrostriatal dopaminergic degeneration and formation of alpha-synuclein-positive cytoplasmic inclusions in nigral neurons (R. Betarbet et al., 2000, Nat. Neurosci. 3, 1301-1306). Although novel and conceptually important, the rotenone model of PD suffered from being extremely labor-intensive. The current paper demonstrates that these same features of PD can be reproduced by chronic, systemic exposure to rotenone following implantation of subcutaneous osmotic pumps. Chronic subcutaneous exposure to low doses of rotenone (2.0-3.0 mg/kg/day) caused highly selective nigrostriatal dopaminergic lesions. Striatal neurons containing DARPP-32 (dopamine and cAMP-regulated phosphoprotein) remained intact with normal morphology, and NeuN staining revealed normal neuronal nuclear morphology. Neurons of the globus pallidus and subthalamic nucleus were spared. Subcutaneous rotenone exposure caused alpha-synuclein-positive cytoplasmic aggregates in nigral neurons. This new protocol for chronic rotenone administration is a substantial improvement in terms of simplicity and throughput.     

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.     

Self‐Healing Polymer Networks Based on Reversible Michael Addition Reactions

A new polymeric material utilizing a highly efficient as well as reversible thiol‐ene click reaction is presented. For this purpose, a trithiol is reacted with a bisbenzylcyanoacetamide derivative resulting in the formation of a dynamic polymer network. The self‐healing ability of this novel material is tested by scratch healing experiments. Healing is found to take place from 60 °C onward. The underlying healing mechanism is studied in detail using temperature‐dependent Raman spectroscopy confirming the reversible opening of the thiol‐ene adducts. Additionally, the thermal and mechanical properties are investigated by differential scanning calorimetry, thermogravimetric analysis, and rheological measurements proving the network formation as well as its reversibility during the thermal treatment.

     

Lutein nanocrystals as antioxidant formulation for oral and dermal delivery

Lutein is a well known antioxidant and anti-free radical used in cosmetic, nutraceutical industry with potential application in pharmaceutics as supportive antioxidant in treatments. As lipophilic molecule it is poorly soluble in water and has a low bioavailability. Lutein nanosuspension was prepared to enhance dissolution velocity, saturation solubility (C_s), which are major factors determining oral bioavailability and penetration into the skin. High pressure homogenization (HPH) was used to prepare lutein nanosuspension. Particle size was determined by photon correlation spectroscopy (PCS) and laser diffractometry (LD). The lowest PCS diameter obtained was about 429 nm, the LD diameter 90% of 1.2 μm. The zeta potential was about −40 mV in water and −17 mV in the original dispersion medium. The 3 month storage study at different temperatures (4 °C, 25 °C, 40 °C) confirmed physical stability despite the low zeta potential of −17 mV in original surfactant solution. A pronounced increase in saturation solubility by 26.3 fold was obtained for lutein nanocrystals compared to coarse powder. The lutein nanosuspension was converted into pellets and filled into hard gelatin capsules for nutraceutical use, showed a superior in vitro release (factor of 3-4). Lyophilized nanosuspension was prepared for subsequent incorporation into creams and gels. The lyophilized nanosuspension was very well re-dispersible (435 nm). Using cellulose nitrate membranes as in vitro model, permeation through this barrier was 14× higher for lutein nanocrystals compared to coarse powder. However, pig ear skin did not allow lutein to permeate but supported localization of the lutein in the skin where it should act anti-oxidatively.     

Comparative distribution of protein components of the A20 ubiquitin-editing complex in normal human brain

Activation of innate and adaptive immune responses is tightly regulated, as insufficient activation could result in defective clearance of pathogens, while excessive activation might lead to lethal systemic inflammation or autoimmunity. A20 functions as a negative regulator of innate and adaptive immunity by inhibiting NF-κB activation. A20 mediates its inhibitory function in a complex with other proteins including RNF11 and Itch, both E3 ubiquitin ligases and TAX1BP1, an adaptor protein. Since NF-κB has been strongly implicated in various neuronal functions, we predict that its inhibitor, the A20 complex, is also present in the nervous system. In efforts to better understand the role of A20 complex and NF-κB signaling pathway, we determined regional distribution of A20 mRNA as well as protein expression levels and distribution of RNF11, TAX1BP1 and Itch, in different brain regions. The distribution of TRAF6 was also investigated since TRAF6, also an E3 ligase, has an important role in NF-κB signaling pathway. Our investigations, for the first time, describe and demonstrate that the essential components of the A20 ubiquitin-editing complex are present and mainly expressed in neurons. The A20 complex components are also differentially expressed throughout the human brain. This study provides useful information about region specific expression of the A20 complex components that will be invaluable while determining the role of NF-κB signaling pathway in neuronal development and degeneration.     

Fas-associated factor 1 and Parkinson's disease

Fas-associated factor 1 or FAF1 is a Fas-binding protein implicated in apoptosis. FAF1 is the product of a gene at PARK 10 locus on chromosome 1p32, a locus associated with late-onset PD [Hicks, A.A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H.S., Sainz, J., Frigge, M.L.et al., 2002. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol. 52, 549-555.]. In the present study we investigated the role of FAF1 in cell death and in Parkinson's disease (PD) pathogenesis. FAF1 levels were significantly increased in frontal cortex of PD as well as in PD cases with Alzheimer's disease (AD) pathology compared to control cases. Changes in FAF1 expression were specific to PD-related alpha-synuclein pathology and nigral cell loss. In addition, PD-related insults including, mitochondrial complex I inhibition, oxidative stress, and increased alpha-synuclein expression specifically increased endogenous FAF1 expression in vitro. Increased FAF1 levels induced cell death and significantly potentiated toxic effects of PD-related stressors including, oxidative stress, mitochondrial complex I inhibition and proteasomal inhibition. These studies, together with previous genetic linkage studies, highlight the potential significance of FAF1 in pathogenesis of idiopathic PD.     

Asian indians and insulin resistance syndrome: global perspective

Insulin resistance syndrome (IRS) is a crucial factor in causation of type 2 diabetes mellitus (T2DM) in Asian Indians. Approximately one-fifth of the migrant Asian Indians have evidence of metabolic syndrome. Furthermore, insulin resistance as estimated by homeostatic model assessment (HOMA-IR) was reported to be present in one-fifth of children and young adult Asian Indians with normal body mass index (BMI) and ~45-67% of those having high BMI. The cause(s) of such high prevalence of IRS in Asian Indians is not clear; however, inherent genetic predisposition, physical inactivity, excess regional body fat, and factors associated with migration may play an important role. It is important that lifestyle factor modification to prevent IRS and T2DM in Asian Indians should start in early childhood.     

Evaluation of existing and candidate measures of obesity for detection of insulin resistance and cardiometabolic risk among Asian Indians: Development of two clinically useful models

BackgroundThe optimal measure of obesity continues to be debated. The objective of this study was to evaluate existing and candidate measures of obesity for detecting the presence of cardiometabolic risk and insulin resistance among Asian Indians.MethodsAnthropometry, detailed body composition analysis, blood pressure, lipids, fasting blood glucose and fasting serum insulin were measured in a cross-sectional study involving 507 subjects from North India.ResultsIn females, all indices of obesity, except waist-to-hip ratio (WHR) and total body fat (TBF) to waist circumference (WC) ratio and in men, all indices of obesity including fat mass index and WHR, were significantly associated with insulin resistance and cardiovascular risk factors (p < 0.05). Using stepwise logistic regression, two models were developed excluding WC and WHR, respectively. In model 1, subscapular skinfold thickness, WHR and age in males, and waist circumference to square of height ratio (WS²R) and age in females; and in model 2, subscapular skinfold thickness, WS²R and visceral adiposity index in males, and TBF to WC ratio, WS²R and age in females showed strong and significant association with the presence of cardiovascular risk factors or insulin resistance.ConclusionsThe clinical models for measurement of obesity developed by us would help in detecting cardiometabolic risk in Asian Indians.