Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
Display omitted
•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous ...production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.
Diabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a selective adrenoceptor ...agonist, on diabetic retinal neurodegeneration, recognizing the critical role of neurodegeneration in diabetic retinopathy.BACKGROUND/AIMDiabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a selective adrenoceptor agonist, on diabetic retinal neurodegeneration, recognizing the critical role of neurodegeneration in diabetic retinopathy.Streptozotocin-induced diabetes was established in adult male Sprague-Dawley rats to mimic diabetic retinopathy. Rats, except non-diabetic control rats, received topical applications of 0.15% brimonidine tartrate (treatment group) or balanced salt solution (diabetic control group) twice daily following diabetes induction. Each group comprised six randomly assigned animals. Retinal samples were analyzed using immunofluorescence staining, apoptosis assay, and western blot.MATERIALS AND METHODSStreptozotocin-induced diabetes was established in adult male Sprague-Dawley rats to mimic diabetic retinopathy. Rats, except non-diabetic control rats, received topical applications of 0.15% brimonidine tartrate (treatment group) or balanced salt solution (diabetic control group) twice daily following diabetes induction. Each group comprised six randomly assigned animals. Retinal samples were analyzed using immunofluorescence staining, apoptosis assay, and western blot.Topical brimonidine treatment reduced apoptosis of retinal ganglion cells at 8 weeks after induction of diabetes (p<0.05). Glial activation induced by diabetes was reduced by brimonidine treatment. Immunoblot and immunofluorescence assay revealed that the decrease in phospho- protein kinase B (AKT) level resulting from diabetes was also attenuated by brimonidine (p<0.05). Furthermore, brimonidine alleviated the decrease in anti-apoptotic proteins BCL2 apoptosis regulator (BCL2) and BCL-xl induced by diabetes (p<0.05). Elevation of phospho-p38 mitogen-activated protein kinase (p38MAPK) and p53 in diabetic rats were reduced by brimonidine (p<0.05). Additionally, brimonidine treatment attenuated the upregulation of the pro-apoptotic molecule BCL-2 associated X in retinas of diabetic rats (p<0.05).RESULTSTopical brimonidine treatment reduced apoptosis of retinal ganglion cells at 8 weeks after induction of diabetes (p<0.05). Glial activation induced by diabetes was reduced by brimonidine treatment. Immunoblot and immunofluorescence assay revealed that the decrease in phospho- protein kinase B (AKT) level resulting from diabetes was also attenuated by brimonidine (p<0.05). Furthermore, brimonidine alleviated the decrease in anti-apoptotic proteins BCL2 apoptosis regulator (BCL2) and BCL-xl induced by diabetes (p<0.05). Elevation of phospho-p38 mitogen-activated protein kinase (p38MAPK) and p53 in diabetic rats were reduced by brimonidine (p<0.05). Additionally, brimonidine treatment attenuated the upregulation of the pro-apoptotic molecule BCL-2 associated X in retinas of diabetic rats (p<0.05).These findings suggest that topical brimonidine treatment may protect retinal ganglion cells in experimental diabetes by modulating the AKT pathway and reducing pro-apoptotic p38MAPK levels. This presents a potential neuroprotective approach in diabetes, offering the advantage of localized treatment without the added burden of oral medication.CONCLUSIONThese findings suggest that topical brimonidine treatment may protect retinal ganglion cells in experimental diabetes by modulating the AKT pathway and reducing pro-apoptotic p38MAPK levels. This presents a potential neuroprotective approach in diabetes, offering the advantage of localized treatment without the added burden of oral medication.
Herein, we demonstrate three strategies of signal amplification for ultrasensitive detection of human immunoglobulin E (hIgE) based on poly(di-acetylene) supramolecules. To fabricate the ...ultrasensitive PDA biosensor, ethylenediamine as an interlinker and aptamer as a receptor were introduced into the chip fabrication process. Using the prepared PDA liposome biosensor, the hIgE could be detected up to below 1.0
ng/ml by a primary response. In order to accomplish more ultrasensitive detection of protein on a PDA biosensor, polyclonal hIgE antibody was employed as an external mechanical force for the inducement of a secondary response. As a result, a PDA liposome biosensor sensitivity as high as 0.01
ng/ml for the target hIgE was obtained, with a sensitivity which is one hundred times of that of the method without signal amplification. These results indicate that the proposed strategies were capable of ultrasensitive quantitative and qualitative analyses of biomolecules without non-specific binding of non-target proteins.
In order to discover a quercetin prodrug with improved bioavailability, we synthesized nine quercetin–amion acid conjugates and estimated their pharmacokinetic properties including water solubility, ...stability against chemical or enzymatic hydrolysis, and cell permeability. Among the synthesized quercetin prodrugs, quercetin–glutamic acid conjugate Qu-E (
4g/
5g) showed remarkable increases in water solubility, stability, and cell permeability compared with quercetin, which warrants further development as a quercetin prodrug.
We present a novel biosensor based on an electrical tracing-assisted silicon dual-microring resonator sensor system. The dual-microring system comprises one microring resonator as a sensing element ...and the other microring resonator integrated with an electrical controller as a tracing element. The resonance wavelength shift of the sensing microring induced by the refractive index change due to antigen–ligand bindings is traced and determined by direct voltage applied to the electrical tunable tracing microring. The sensor system enables the use of a low-cost broadband light source instead of a bulky and expensive tunable laser, which allows the development of cost-effective point-of-care diagnostic devices by significantly reducing the device cost and increasing its portability. The sensing capability of the developed dual-microring sensor was investigated using biotin–streptavidin binding as a model system. We have demonstrated the quantitative detection of streptavidin over a broad range of concentrations down to 190pM by monitoring the electrical power applied to the tracing ring. We have also validated the sensing principle of the dual-microring system by a direct comparison between the calculated and measured values for the resonance wavelength shift of the sensing microring. Furthermore, we have shown the quantitative and specific detection of a well-known breast cancer biomarker, human epidermal growth factor receptor 2 (HER2), in a bovine serum albumin solution using the antibody-modified dual-microring sensor system.
► A noble electrical tracing-assisted dual-microring system was developed. ► An inexpensive broadband light source was used instead of a tunable laser. ► Label-free and specific detection of HER2. ► The new platform opens new opportunities for applications in portable POC devices.
For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. ...Curcumin has a unique structure with phenolic hydroxyl group as well as β-diketone moiety in the same molecule, both of which are able to donate electrons to free radicals. However, due to the reactivity toward molecular oxygen, the carbon-centered radical derived from β-diketone moiety do not serve as radical-trapping antioxidants. In this study, we reasoned that stabilization of the carbon-centered radical through substitution with an electron-withdrawing group would enhance the radical-scavenging antioxidative activity of the resulting curcuminoids. Thus, various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) covering broad spectrum of the polar substituent effect were introduced to the central methylene position of both phenolic and non-phenolic curcuminoids. With the free phenolic hydroxyl groups present, the methylene-substituent did not exert significant effect on the antioxidant activity of the curcuminoids (EC
50
=
23.2–30.3
μM) with the exception of the acetoxy-substituted derivative (EC
50
=
8.7
μM) which showed more potent activity than curcumin (EC
50
=
22.6
μM). When substituted to the non-phenolic curcumin scaffold, however, the methylene-substituent enhanced antioxidant activity of the otherwise inactive curcuminoids in the increasing order of methyl
<
allyl
<
methoxy
<
xanthate
≪
acetoxy, which is well correlated with the polar inductive effects of the substituents.
Curcumin is a major component of Curcuma longa rhizome and has been used as a traditional medicine for centuries. In this study, we showed that curcumin induced cell cycle arrest followed by ...antiproliferation and apoptosis in human osteosarcoma (HOS) cells.
Antiproliferative activity was measured with the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Nuclear fragmentation was observed with a fluorescence microscope. Flow cytometry was performed to observe cell cycle distribution and apoptotic body appearance. Changes in cell cycle regulatory and apoptosis-related proteins were investigated by Western blot analysis.
The IC(50) value of curcumin was approximately 4.0 microg/ml. Induction of apoptosis was evidenced by apoptotic body appearance and chromosomal DNA degradation. Flow-cytometric analysis indicated that curcumin induced successive G(1)/S and G(2)/M phase arrest followed by apoptosis in HOS cells. The G(1)/S and G(2)/S phase arrest was accompanied by down-regulation of cyclin D1, cdc2 and cyclin B1, respectively. Apoptosis was induced by capspase-3 activation and poly(ADP-ribosyl)polymerase (PARP) cleavage.
Our results demonstrated that curcumin caused death of HOS cells by blocking cells successively in G(1)/S and G(2)/M phases and activating the caspase-3 pathway.
PDF
