Two-photon dual-channel fluorogenic probe for in situ imaging the mitochondrial H2S/viscosity in the brain of drosophila Parkinson’s disease model

H₂S is an essential gas signal molecule in cells, and viscosity is a key internal environmental parameter. Recent studies have shown that H₂S acts as a cytoarchitecture agent and gas transmitter in many tissues, e.g., as a regulator of neuroendocrine in the brain for mediating vascular tone in blood vessels. Mitochondrial viscosity is an important parameter for judging whether mitochondrial function is normal. It has been reported that oxidative stress and mitochondrial dysfunction are connected with Parkinson’s disease (PD), and the protective role of H₂S in PD models has been extensively demonstrated. Herein, Mito-HS, a new two-photon fluorescent probe was demonstrated to detect cross-talk between the two channels of mitochondrial viscosity and H₂S content. Moreover, this probe could detect the relative amount of and changes in mitochondrial H₂S in situ due to the reduced mitochondrial targeting ability after reaction with H₂S. The results show that H₂S in mitochondria is inversely related to viscosity. The PD model has a lower H₂S in mitochondria and a higher mitochondrial viscosity than did the normal. This result is important for our deep understanding of PD and its causes.     

L-cysteine-regulated in situ formation of Prussian blue/Turnbull’s blue nanoparticles as the colorimetric probe for the detection of copper ion

A fast, simple, sensitive, and selective colorimetric method for the detection of Cu²⁺ was developed using Prussian blue/Turnbull’s blue nanoparticles (PBNPs/TBNPs) as the probe. The colorimetric sensor is based on the following principle. Cu²⁺ can induce the aggregation of L-cysteine (L-cys) modified-PBNPs/TBNPs (L-cys-PBNPs/TBNPs), resulting in an obvious red shift of its maximum absorption peak. Thus, the concentration of Cu²⁺ can be determined based on the peak shift in the UV–Vis spectra. The optimal pH, concentration of L-cys, reaction temperature between L-cys-PBNPs/TBNPs and Cu²⁺, the formation time of L-cys-PBNPs/TBNPs, and the reaction time between L-cys-PBNPs/TBNPs and Cu²⁺ of the method were determined to be pH 4.5, 2.0 mM, 20 °C, 5.0 min, and 2.0 min, respectively. A good linearity for the colorimetric determination of Cu²⁺ at the range of 0.25–2.5 μM (R² = 0.986) was obtained, with a limit of detection (LOD) of 0.12 μM. Moreover, the negligible response of other metal ions demonstrates good selectivity and specificity of the sensor. In addition, the method was employed in the detection of Cu²⁺ in lake water samples, and the spiked recoveries are in the range of 96.7–106.6% with a relative standard deviation less than 7.4%. Therefore, the colorimetric method is applicable for Cu²⁺ detection in real water samples of high sensitivity and selectivity.     

Chemometric modeling of PET imaging agents for diagnosis of Parkinson’s disease: a QSAR approach

Structural Chemistry - Recently, adenosine A2A receptor antagonists have been identified as an interesting drug target for the treatment of Parkinson’s disease (PD). Radiolabelled molecular...     

A thiol-selective fluorogenic probe based on the cleavage of 4-methylumbelliferyl-2’,4’,6’-trinitropheyl ether

A new fluorescent probe 1,4-methylumbelliferyl-2′,4′,6′-trinitropheyl ether (Probe 1) was designed and synthesized. Probe 1 was a nonfluorescent compound and was synthesized via the one-step reaction of 4-methylumbelliferone (4-MU) with 1-chloro-2,4,6-trinitrobenzene. Upon mixing with biothiols under neutral aqueous conditions, the 2,4,6-trinitrophenyl group of 1 was efficiently removed, and the emissive free dye 4-MU was released, hence leading to a dramatic increase in fluorescence emission of the reaction mixture. A good linear relationship was obtained from 0.1 to 4.0 μmol L⁻¹ for cysteine (Cys), from 0.1 to 3.0 μmol L⁻¹ for homocysteine (Hcy), and from 0.2 to 3.0 μmol L⁻¹ for glutathione (GSH), respectively. The detection limits of Cys, Hcy, and GSH were 24.3, 35.6, and 26.8 nmol L⁻¹, respectively. Furthermore, probe 1 was highly selective for biothiols without the interference of some biologically relevant analytes and has been applied to detecting biothiols in human serum samples.     

Quantum dots protect against MPP+-induced neurotoxicity in a cell model of Parkinson’s disease through autophagy induction

Autophagy is a basic cellular process that decomposes damaged organelles and aberrant proteins. Dysregulation of autophagy is implicated in pathogenesis of neurodegenerative disorders, including Parkinson's disease(PD). Pharmacological compounds that stimulate autophagy can provide neuroprotection in models of PD. Nanoparticles have emerged as regulators of autophagy and have been tested in adjuvant therapy for diseases. In this present study, we explore the effects of quantum dots(QDs) that can induce autophagy in a cellular model of Parkinson's disease. Cd Te/Cd S/Zn S QDs protect differentiated rat pheochromocytoma PC12 cells from MPP+-induced cell damage, including reduced viability, apoptosis and accumulation of α-Synuclein, a characteristic protein of PD. The protective function of QDs is autophagy-dependent. In addition, we investigate the interaction between quantum dots and autophagic pathways and identify beclin1 as an essential factor for QDs-induced autophagy. Our results reveal new promise of QDs in the theranostic of neurodegenerative diseases.     

The role of metal ions in dopaminergic neuron degeneration in Parkinsonism and Parkinson’s disease

Abstract  

Parkinson’s disease is characterized by the selective degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra and locus coeruleus. Although the cause of this disease remains unknown, several transition metals, including manganese and copper, have been associated with the development of the atypical form of Parkinsonism, and iron accumulation has been associated with the development of Parkinson’s disease. Manganese³⁺ is a strong oxidizing agent, which oxidizes dopamine to aminochrome (dopaminochrome), the precursor of neuromelanin. Aminochrome formation in cell culture medium induces acute cell death in cells that uptake aminochrome, explaining the role of manganese in the development of atypical Parkinsonism. Copper accumulation in Wilson’s disease also induces Parkinsonism as one of the main symptoms, and an atypical Parkinsonism has also been observed in young copper miners. Interestingly, copper is able to complex with dopamine, which can be taken up by cells expressing the dopamine transporter, inducing caspase-independent cell death with formation of autophagic vacuoles. Iron is also able to form a complex with dopamine, the neurotoxic action of which also depends on the cellular expression of the dopamine transporter. The neurotoxicities of these transition metals to cells expressing the dopamine transporter all involve dopamine oxidation to quinones and require the inhibition of DT-diaphorase.     

Neuroprotective effects of Cassia tora against paraquat-induced neurodegeneration: relevance for Parkinson’s disease

The aim of the present study was to determine whether Cassia tora extracts could reverse the oxidative stress-induced neurodegeneration in a Parkinson’s disease in vitro model. The leaves were treated with ethyl acetate (CtEA) or methanol (CtME). The extracts were first analysed by HPLC for their phenolic content and then tested for their neuroprotective effects in human SK-N-SH neuroblastoma cells. Cells were pre-treated with various concentrations of extracts followed by incubation with paraquat (14 μM). Firstly, pre-treatment of SK-N-SH cells with 100 μg/mL of CtEA or CtME significantly reduced the paraquat-induced production of reactive oxygen species. Furthermore, both CtEA and CtME reduced the paraquat-induced apoptosis. Moreover, there was a significant reduction of paraquat-induced DNA damage in SK-N-SH cells pre-treated with CtEA or CtME. Finally, both extracts significantly inhibited paraquat-dependent lipid peroxidation. Altogether, these in vitro data establish C. tora as a possible anti-Parkinson natural remedy.     

A multiscale study on photophysical properties of a novel fluorescent probe for imaging amyloid-β in Alzheimer's disease

Detection of amyloid-β deposition in the brain region is of significant importance for early diagnosis of Alzheimer's disease (AD). In the last few decades, the fluorescent imaging technique has been considered an effective tool for detecting amyloid-β plaques due to its safety, sensitivity, and operability. Thus, numerous fluorescent probes for amyloid-β have been developed. The design of a probe with high selectivity and improved sensing performance requires knowledge about the potential binding sites for the probe in amyloid-β and local microstructure of the probe in different sites. In this study, amyloid-β-specific photophysical properties of a novel fluorescent probe (cis-PAD-1) are theoretically investigated by using multiscale simulations, including molecular docking and quantum mechanics/molecular mechanics calculations. Binding profile of cis-PAD-1 in amyloid-β has been simulated, and binding affinity of the probe in various sites is calculated. An excited-state property study on cis-PAD-1 illustrates that the probe shows remarkable fluorescence enhancement in amyloid-β due to the influence of the microenvironment, which is consistent with the experimental observation. Most importantly, two-photon absorption cross section of the probe is greatly increased in the near-infrared region when targeting with amyloid-β owing to the enhanced transition dipole moment. Therefore, one can propose the usage of cis-PAD-1 as an excellent candidate in two-photon fluorescent imaging for amyloid-β. The detailed investigations provide information on the development and design strategy of a new fluorescent probe for amyloid-β imaging in AD.     

Application of multilayered strategy for variable selection in QSAR modeling of PET and SPECT imaging agents as diagnostic agents for Alzheimer’s disease

Structural Chemistry - Non-invasive imaging of amyloid beta (Aβ) and tau fibrils in the brain may support an early and precise diagnosis of Alzheimer’s disease. Molecular imaging...     

Kinetics of H2S destruction in the radiolysis of CH4−H2S gas mixtures

The kinetics of H₂S destruction in the radiolysis of CH₄–H₂S and CH₄–H₂S–O₂ mixtures has been studied. It has been shown that G(–H₂S) depends on amounts of hydrogen sulfide and the presence of oxygen in the starting mixture and is within the range of 5–13 mol/100 eV. G(H₂) decreases with the increases of O₂ content and amounts to the constant value of 2.     

Coronarin D attenuates MPTP-induced Parkinson’s disease in mice by inhibition of oxidative stress and apoptosis

Parkinson’s disease (PD) is a brain-related disease condition, globally it is the second most common neurodegenerative disease that mostly disturbs the brain motor control and action of the aged populations. It involves a tiny, dark portion of the brain denoted as substantia nigra. Dopamine is produced in the substantia nigra for the usage of the brain. This dopamine communicates messages among nerves and controls muscle movements. Coronarin D is a diterpenoid with exclusive pharmacological possessions and its effectiveness over a few neurogenerative diseases exposed to some intense properties. The present study was intended to exhibit the neuroprotective efficacy of Coronarin D over MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced animals. Oral management of Coronarin D (10 and 20 mg/kg body wt.) protects the MPTP-induced nigrostriatal dopamine (DA) depletion and its intermediate substances. Behavioral studies like narrow beam walk test, open field test and hang test were conducted to study the movement and actions of Coronarin D treated MPTP induced experimental animals, in which Coronarin D treated group III & IV animals showed better behavioral alterations. Our compound as well attenuated MPTP persuaded oxidative pressure in experimental animals. Apoptotic marker studies displayed that management with Coronarin D upturned MPTP induced programmed cell death, which might be its anti-apoptotic properties. Ultimately to conclude, Coronarin D recovered oxidative pressure, neurochemical alterations, apoptosis, and functional irregularities in investigational mice and propose a potential approach to disease management of neurodegenerative and its related disease.     

Pd–Fe/TiO2 catalysts for phenol degradation with in situ generated H2O2

This study deals with the degradation of phenol over Pd–Fe/TiO₂ catalysts at mild conditions in the presence of in situ generated H₂O₂ from oxygen and formic acid. This catalytic system demonstrated interesting ability to oxidize phenol by Fenton process in a one-pot reaction without the addition of ferrous ion. Lower Pd content catalysts, despite producing a higher hydrogen peroxide amount for bulk purposes, did not reach the same efficiency as the 5Pd–5Fe catalyst in phenol degradation. A close interaction between Pd and iron oxide species is necessary to obtain high active catalysts. These results highlight the advantage of in situ generation of H₂O₂, for oxidation reactions with respect to conventional Fenton process.     

Synthesis and evaluation of a phenylbenzothiazole-based 99mTc(CO)3-radiotracer for possible application in imaging of β-amyloid plaques in Alzheimer’s disease

The 2-phenyl benzothiazole pharmacophore is known to have high affinity for amyloid beta (Aβ) and is therefore derivatized, to [N-(4′-benzothiazol-pyridin-2-yl-methyl-amino)-acetic acid (BTPAA)] for radiolabeling with [^99mTc(CO)₃(H₂O)₃]⁺ precursor. The radiotracer, ^99mTc(CO)₃–BTPAA is evaluated in vitro and in vivo to determine its binding with the Aβ and ability to cross the blood brain barrier. The radiotracer prepared in >95 % radiochemical yield, showed ~25 % inhibition in presence of thioflavin-T, indicating its specificity towards aggregated Aβ protein. The radiotracer also showed brain uptake of 0.25 ± 0.04 % injected dose/g at 2 min post injection, indicating its ability to cross the blood brain barrier.     

A simple in situ characterization technique for the onset of the chemical degradation of PEM fuel cells’ fluorinated membranes

The onset of the chemical degradation of the fluorinated PEM fuel cells’ membranes is characterized using an in situ novel technique. It is based upon measuring the pH of the water drained out from the cathode and the anode compartments using a flow pH meter connected to these outlets. It was found that the acidity of water increases significantly as the load increases if the cell operates at low temperature–low relative humidity (RH) condition after it was working at high temperature–high RH condition previously. Degradation rates were calculated from the pH measurements.     

Description of the system HCl/H2O with a ‘local composition’ equation for the activity coefficient and a suitable dissociation model

The establishment of a dissociation model makes the application of a ‘local composition’ equation to electrolyte solutions possible. The model states, that only water is in the immediate neighbourhood of ions. This is considered by establishing an equilibrium reaction for the formation of complexes, which consist of water and ions. Only similar species are in the solution if the ion and its ‘water cloud’ are conceived as one component in the mixture.     

Analytic calculation of second-order perturbatior energy for the one-dimensional Hubbard model in the Hückel limit

The study of the Hückel limit for the one-dimensional Hubbard model is very complicated. It is necessary to prepare the Lieb-Wu system of equations for expansion and then to initialize the variables which appear in the system, which is not straightforward. However, it is remarkable that, for the second-order contribution to the energy in this limit, it is possible to obtain, after complicated manipulations, quite transparent expressions. The analytical solution is obtained order by order for the variables to ^–2 which appear in the Lieb-Wu solution and the ^–1 coefficient in the energy is calculated using these expansions. The energy can be calculated numerically using these analytic results for the variables for increasing values ofN.     

Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer's disease mitigates Aβ pathology and improves cognitive function

The plant viral protease, NIa, has a strict substrate specificity for the consensus sequence of Val-Xaa-His-Gln, with a scissoring property after Gln. We recently reported that NIa efficiently cleaved the amyloid-β (Aβ) peptide, which contains the sequence Val-His-His-Gln in the vicinity of the cleavage site by α-secretase, and that the expression of NIa using a lentiviral system in the brain of AD mouse model reduced plaque deposition levels. In the present study, we investigated whether exogenous expression of NIa in the brain of AD mouse model is beneficial to the improvement of cognitive deficits. To address this question, Lenti-NIa was intracerebrally injected into the brain of Tg-APPswe/PS1dE9 (Tg-APP/PS1) mice at 7 months of age and behavioral tests were performed 15-30 days afterwards. The results of the water maze test indicated that Tg-APP/PS1 mice which had been injected with Lenti-GFP showed an increased latency in finding the hidden-platform and markedly enhanced navigation near the maze-wall, and that such behavioral deficits were significantly reversed in Tg-APP/PS1 mice injected with Lenti-NIa. In the passive avoidance test, Tg-APP/PS1 mice exhibited a severe deficit in their contextual memory retention, which was reversed by NIa expression. In the marble burying test, Tg-APP/PS1 mice buried marbles fewer than non-transgenic mice, which was also significantly improved by NIa. After behavioral tests, it was verified that the Tg-APP/PS1 mice with Lenti-NIa injection had reduced Aβ levels and plaque deposition when compared to Tg-APP/PS1 mice. These results showed that the plant viral protease, NIa, not only reduces Aβ pathology, but also improves behavioral deficits.