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The hallmarks of Parkinson's disease (PD) include the loss of dopaminergic neurons and formation of Lewy bodies, whereas multiple sclerosis (MS) is an autoimmune disorder with damaged myelin sheaths and axonal loss. Despite their distinct etiologies, mounting evidence in recent years suggests that neuroinflammation, oxidative stress, and infiltration of the blood-brain barrier (BBB) all play crucial roles in both diseases. It is also recognized that therapeutic advances against one neurodegenerative disorder are likely useful in targeting the other. As current drugs in clinical settings exhibit low efficacy and toxic side effects with long-term usages, the use of natural products (NPs) as treatment modalities has attracted growing attention. This mini-review summarizes the applications of natural compounds to targeting diverse cellular processes inherent in PD and MS, with the emphasis placed on their neuroprotective and immune-regulating potentials in cellular and animal models. By reviewing the many similarities between PD and MS and NPs according to their functions, it becomes evident that some NPs studied for one disease are likely repurposable for the other. A review from this perspective can provide insights into the search for and utilization of NPs in treating the similar cellular processes common in major neurodegenerative diseases.

t‐Darpp (truncated isoform of dopamine‐ and cAMP‐regulated phosphoprotein) is a protein encoded by the PPP1R1B gene and is expressed in breast, colon, esophageal, gastric, and prostate cancers, as well as in normal adult brain striatal cells. Overexpression of t‐Darpp in cultured cells leads to increased protein kinase A activity and increased phosphorylation of AKT (protein kinase B). In HER2+ breast cancer cells, t‐Darpp confers resistance to the chemotherapeutic agent trastuzumab. To shed light on t‐Darpp function, we studied its secondary structure, oligomerization status, metal‐binding properties, and phosphorylation by cyclin‐dependent kinases 1 and 5. t‐Darpp exhibits 12% alpha helix, 29% beta strand, 24% beta turn, and 35% random coil structures. It binds calcium, but not other metals commonly found in biological systems. The T39 site, critical for t‐Darpp activation of the AKT signaling pathway, is a substrate for phosphorylation by cyclin‐dependent kinase 1 and cyclin‐dependent kinase 5. Gel filtration chromatography, sedimentation equilibrium analysis, blue native gel electrophoresis, and glutaraldehyde‐mediated cross‐linking experiments demonstrate that the majority of t‐Darpp exists as a monomer, but forms low levels (

Early treatment of Alzheimer's disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer's disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology.We recruited adults with probable Alzheimer's disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer's disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer's disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04-0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study.Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer's disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach.

The hallmarks of Parkinson's disease (PD) include the loss of dopaminergic neurons and formation of Lewy bodies, whereas multiple sclerosis (MS) is an autoimmune disorder with damaged myelin sheaths and axonal loss. Despite their distinct etiologies, mounting evidence in recent years suggests that neuroinflammation, oxidative stress, and infiltration of the blood-brain barrier (BBB) all play crucial roles in both diseases. It is also recognized that therapeutic advances against one neurodegenerative disorder are likely useful in targeting the other. As current drugs in clinical settings exhibit low efficacy and toxic side effects with long-term usages, the use of natural products (NPs) as treatment modalities has attracted growing attention. This mini-review summarizes the applications of natural compounds to targeting diverse cellular processes inherent in PD and MS, with the emphasis placed on their neuroprotective and immune-regulating potentials in cellular and animal models. By reviewing the many similarities between PD and MS and NPs according to their functions, it becomes evident that some NPs studied for one disease are likely repurposable for the other. A review from this perspective can provide insights into the search for and utilization of NPs in treating the similar cellular processes common in major neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Electrospray-mass spectrometry (ES?MS) was employed to confirm the formation of the [Cu.sup.2+] complex with [alpha]-syn or with an N-terminal peptide, [alpha]-synuclein which play an important role in neuropathology in ParkinsonEs disease (PD). The results provide insight into partial role of oxidative stress for the loss of dopaminergic cells in PD brain and the multifaceted role of the [alpha]-syn-[Cu.sup.2+] complex in oxidative stress associated with PD symptoms.

The complexation of Cu(II) by amyloid-[beta] (A[beta]) is examined through the tandem use of fluorescence and electron paramagnetic resonance (EPR) spectroscopies. With the help of tyrosine fluorescence spectroscopy has provided mechanistic insights into the oxidation state of copper ions bound to A[beta], the binding heterogeneity and the impact of solution conditions on complex formation.

The redox reactions of copper complexes and the binding stoichiometry between Cu(II) and the full-length [beta]-amyloid A[beta](1-42) was determined. A stoichiometric ratio of 1:1 was observed which remains the same in the presence of more than 10--fold excess of Cu(II) and the A[beta]-Cu(II) complex could be involved in the consumption of antioxidants causing their depletion in neurons and damaging the neuronal defense system.

Electrochemical surface plasmon resonance (EC-SPR) and electrochemical quartz crystal microbalance (EQCM) are employed to study the redox-induced orientation change of 11-ferrocenylundecanethiol self-assembled monolayers (FcC11SH) (SAM) in two electrolyte solutions. It is seen that the tandem use of EC-SPR and EQCM is an attractive approach for delineating the various redox-triggered surface processes of FcF11SH SAMs.

Two six-port injector valves and one selector valve commonly used in flow injection analysis are combined with a surface plasmon resonance (SPR) instrument wherein solutions introduced from the two inlets counter-flow inside the flow cell. The system is versatile as the same or different solutions can be rapidly and repeatedly introduced to the two fluidic channels in series or in parallel. Unlike most commercial SPR instruments employing a single injector valve, solutions separately injected from the two injector valves can be readily exchanged (<1 s) between the two channels. This new method, referred to as the alternate injection mode, not only saves analysis time but also facilitates efficient and facile surface reactions for ligand immobilization and prevents immobilized species from desorbing. These advantages are demonstrated with the measurements of binding of acetazolamide (222.2 Da) to histidine-tagged human carbonic anhydrase II (his-tagged HCA). Amine-containing residues of his-tagged HCA molecules tethered at Ni-nitrilotriacetic acid (NTA) sensors were rapidly cross-linked to the underlying carboxymethylated dextran. The higher ligand densities and more stable surfaces are essential for SPR detection of small molecule binding. In a different application, microglobulin solutions of increasing concentrations were introduced for continuous binding to the preimmobilized antibody. The kinetic and affinity measurements can be conducted without performing repeated dissociation and surface regeneration reactions. [ABSTRACT FROM AUTHOR]

Pyrene derivatives are among the most widely used organic fluorescent photoprobes. Many of them are photosensitizers for hole injection. Pyrenes, however, are mostly UV absorbers, limiting their utility for photonic applications. Nitration of pyrene shifts its absorption to the visible region. Conversely, nitration of pyrene that is already derivatized for covalent labeling, produces mixtures of isomers that are challenging to separate. We present a robust procedure for attaining isomerically pure nitropyrenes. NMR analysis provides unequivocal assignments of the regioisomers and of the structures of the disubstituted nitropyrenes. The added substituents negligibly affect the electronic properties of the nitropyrenes. Photoexcited nitropyrenes undergo efficient triplet formation, making them an attractive choice for triplet sensitizers and photooxidants. Hence, facile and reliable preparation of disubstituted nitropyrenes provides venues for exploring their electronic and photonic utility. [ABSTRACT FROM AUTHOR]

Antimicrobial polypeptides, including lysozymes, have membrane perturbing activity and are well-documented effector molecules of innate immunity. In cystic fibrosis, a hereditary disease with frequent lung infection with Pseudomonas aeruginosa, the non-esterified fatty acid DA (docosahexaenoic acid), but not OA (oleic acid), is decreased, and DA supplementation has been shown to improve the clinical condition in these patients. We hypothesized that DA may, either alone or in conjunction with lysozyme, exert antibacterial action against Ps. aeruginosa. We found that DA and lysozyme synergistically inhibit the metabolic activity of Ps. aeruginosa, in contrast with OA. Electron microscopy and equilibrium dialysis suggest that DA accumulates in the bacterial membrane in the presence of lysozyme. Surface plasmon resonance with live bacteria and differential scanning calorimetry studies with bacterial model membranes reveal that, initially, DA facilitates lysozyme incorporation into the membrane, which in turn allows influx of more DA, leading to bacterial cell death. The present study elucidates a molecular basis for the synergistic action of non-esterified fatty acids and antimicrobial polypeptides, which may be dysfunctional in cystic fibrosis. [ABSTRACT FROM AUTHOR]

The combination of high-performance liquid chromatography (HPLC) with surface plasmon resonance (SPR) for continuous separation and label-free detection of protein samples is described. The detection was realized by electrostatic adsorption of proteins bearing positive and negative charges onto chemically modified SPR sensors in two separate SPR channels. One SPR channel is coated with carboxymethylated dextran which facilitates the detection of positively charged proteins, whereas the other, devoted to the monitoring of negatively charged proteins, is covered with ethylenediamine molecules attached onto a dextran surface. Renewal of the sensor surface in the channels can be accomplished by introducing regeneration solutions through two six-port valves. The coupled technique (HPLC-SPR) was assessed for its analytical figures of merit and applied to the quantification of lysozyme in human milk samples. Unlike the SPR detection of bulk solution refractive index changes during chromatographic peak elutions, the highest sensitivity of SPR is retained in this work since the measurement is performed at the SPR sensor surface where the evanescent field is the strongest. The renewable SPR detection of continuous separations is reproducible and versatile and does not require the separated proteins to contain chromophores or to be prelabeled with a tag (e.g., a redoxactive or fluorescent molecule). Such generality makes SPR complementary to other types of chromatographic detectors. [ABSTRACT FROM AUTHOR]

Scanning electrochemical microscopy (SECM) has been employed in the imaging of DNA microarrays fabricated on gold substrates using methylene blue (MB) as a redox-active intercalator and ferrocyanide as the SECM mediator in solution. MB intercalated between base pairs of immobilized ds-DNA is electrochemically reduced via electron transfer from the underlying gold substrate, and the product is reoxidized in solution by SECM tip-generated ferricyanide. The resulting feedback current allows a heterogeneous electron-transfer rate constant for the MB-intercalated DNA to be deduced. Moreover, DNA microarray spots can be imaged at a detection level of 14 fmol/spot for ds-DNA consisting of 15 base pairs. Microarrays prepared using 20 M DNA solutions are easily visualized, and the feasibility of detecting base pair mismatches is also demonstrated. [ABSTRACT FROM AUTHOR]