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Prolonged intermittent theta burst stimulation restores the balance between A_(2A)R-and A_(1)R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson's disease

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Neural Regeneration Research 2025年第7期20卷 2053-2067页

作者： Milica Zeljkovic Jovanovic Jelena Stanojevic Ivana Stevanovic Milica Ninkovic Tihomir V.Ilic Nadezda Nedeljkovic Milorad Dragic Laboratory for Neurobiology Department of General Physiology and BiophysicsFaculty of BiologyUniversity of BelgradeBelgradeSerbia Medical Faculty of Military Medical Academy University of DefenceBelgradeSerbia

An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's *** therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in *** transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's ***,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain *** purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated *** with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod ***,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate *** intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate *** with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor *** treatment with prolonged intermittent theta burst stimulation,complete motor recovery was *** improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst *** results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)***

关键词： A_(1)R A_(2A)R adenosine receptors adenosine ecto-5′-nucleotidase intermittent theta burst stimulation non-invasive brain stimulation Parkinson's disease purinergic signalling

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A-kinase anchoring protein-mediated compartmentalization of pro-survival signaling in the retina

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Neural Regeneration Research 2025年第2期20卷 479-480页

作者： Joanna Mackiewicz Tomasz Boczek department of molecular Neurochemistry Medical University of LodzLodzPoland

The retina plays a fundamental role in the process of vision,serving as the primary interface between external visual stimuli and the central nervous *** the retina is exposed to a variety of environmental stresses and deleterious insults,it is susceptible to a spectrum of pathological conditions that can detrimentally affect *** often leads to irreversible vision loss due to the injury of specific cell *** instance,inherited retinal degeneration and age-related macular degeneration can lead to the death of photoreceptors,while conditions like glaucoma and optic nerve injury can result in the loss of ganglion *** precise pathological mechanisms driving retinal degeneration remain largely elusive,although research utilizing mouse models suggests that disruptions in intracellular signal transduction pathways may play a pivotal *** pathways within the retina orchestrate various aspects of retinal physiology,including phototransduction,synaptic transmission,and neuronal survival.

关键词： degeneration utilizing irreversible

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Ryanodine receptors as pharmacological targets for heart disease

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Acta Pharmacologica Sinica 2007年第7期28卷 937-944页

作者： Marco SANTONASTAS Xander H T WEHRENS departments of molecular physiology and biophysics departments of molecular physiology and biophysics and Medieine(Cardiology) Baylor College of MedicineHoustonTexas 77030USA

Calcium release from intracellular stores plays an important role in the regulationof muscle contraction and electrical signals that determine the heart *** receptor （RyR） is the major calcium (Ca2+) release channel required forexcitation-contraction coupling in the *** studies have demonstratedthat RyR are macromolecular complexes comprising of 4 pore-forming channelsubunits,each of which is associated with regulatory *** andexperimental studies over the past 5 years have provided compelling evidencethat intracellular Ca2+release channels play a pivotal role in the development ofcardiac arrhythmias and heart *** in the channel regulation andsubunit composition are believed to cause diastolic calcium leakage from thesarcoplasmic reticulum,which could trigger arrhythmias and weaken ***,cardiac RyR have emerged as potential therapeutic tar-gets for the treatment of heart ***,there is a strong desire toidentify and/or develop novel pharmacological agents that may target these Ca2+signaling *** agents known to modulate RyR in the heart,and their potential application towards the treatment of heart disease are dis-cussed in this review.

关键词： arrhythmias calcium release channel heart failure pharmacology ryanodine receptor

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Olfactory receptors in neural regeneration in the central nervous system

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Neural Regeneration Research 2025年第9期20卷 2480-2494页

作者： Rafael Franco Claudia Garrigós Toni Capó Joan Serrano-Marín Rafael Rivas-Santisteban Jaume Lillo molecular Neurobiology Laboratory Department of Biochemistry and Molecular BiomedicineFacultat de BiologiaUniversitat de BarcelonaBarcelonaSpain CiberNed Network Center for Biomedical Research in Neurodegenerative Diseases Spanish National Health Institute Carlos ⅢMadridSpain School of Chemistry Universitat de BarcelonaBarcelonaSpain department of Biochemistry and physiology School of Pharmacy and Food SciencesUniversitat de BarcelonaBarcelonaSpain Laboratory of Computational Medicine Biostatistics UnitFaculty of MedicineAutonomous University of BarcelonaCampus BellaterraBarcelonaSpain

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional *** receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental *** ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous *** gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent *** the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's *** ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian *** ectopic expression provides insights into the chemical structures that can activate olfactory *** addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing *** analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation *** review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative *** suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous syste

关键词： adenosine receptors adrenergic receptors ectopic expression G proteincoupled receptors glia neurons

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Randomness in the Hybrid Modeling and Simulation of Insulin Secretion Pathways in Pancreatic Islets

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Tsinghua Science and Technology 2015年第5期20卷 441-452页

作者： Yang Pu David C.Samuels Layne T.Watson Yang Cao the department of Computer Science Virginia Polytechnic Institute and State University the department of molecular physiology and biophysics Vanderbilt University

Insulin secreted by pancreatic islet ˇ-cells is the principal regulating hormone of glucose *** of insulin secretion may cause glucose to accumulate in the blood, and result in diabetes *** deterministic models of the insulin secretion pathway have been developed, the stochastic aspect of this biological pathway has not been explored. The first step in this direction presented here is a hybrid model of the insulin secretion pathway, in which the delayed rectifying KCchannels are treated as stochastic events. This hybrid model can not only reproduce the oscillation dynamics as the deterministic model does, but can also capture stochastic dynamics that the deterministic model does not. To measure the insulin oscillation system behavior, a probability-based measure is proposed and applied to test the effectiveness of a new remedy.

关键词： insulin secretion mathematical modeling hybrid model and simulation stochastic dynamics

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DJ-1 as a deglycating enzyme:a unique function to explain a multifaceted protein?

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Neural Regeneration Research 2017年第11期12卷 1797-1798页

作者： Federica De Lazzari Marco Bisaglia molecular physiology and biophysics Unit Department of BiologyUniversity of PadovaPadovaItaly

The Parkinson＇s disease （PD）-associated protein DJ-1 is considered a multifunctional protein involved in oxidative stress responses. Although a large variety of functions has been attributed to DJ- 1, currently no consensus has been found on its effective cellular activity. Indeed, the protein has been described as a transcriptional modulator, a regulator of mitochondrial activity, a stabilizer of the nuclear factor erythroid 2-related factor （Nrf2）, a chaperone, a pro- tease, and a glutathione （GSH）-independent glyoxalase （Ariga et al., 2013）. Very recently, the additional participation of the protein to carbonvl stress defense has been emereing （Richarme et al., 2015）.

关键词： DJ-1 as a deglycating enzyme multifaceted protein

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E224G Regulation of the PIP2-Induced Gating Kinetics of Kir2.1 Channels

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Chinese Physics Letters 2017年第1期34卷 86-89页

作者：任树喜李军委张素花 D.E.Logothetis 安海龙展永 Key Laboratory of molecular biophysics of Hebei Province Institute of BiophysicsSchool of SciencesHebei University of TechnologyTianjin 300401 department of physiology and biophysics School of MedicineVirginia Commonwealth UniversityVirginiaUSA

As a member of the inwardly rectifying channel (Kir) family, Kir2.1 allows to influx the cell more easily than to efflux, a biophysical phenomenon named inward rectification. The function of Kir2.1 is to set the resting membrane potential and modulate membrane excitability. It has been reported that residue E224 plays a key role in regulating inward rectification. The mutant Kir2.1 (E224G) displays weaker inward rectification than the WT channel. Gating of Kir2.1 depends on the membrane lipid, PIP2, such that the channel gates are closed in the absence of PIP2. Here we perform electrophysiological and computational approaches, and demonstrate that E224 also plays an important role in the PIP2-dependent activation of Kir2.1 in addition to its influence on inward rectification. The E224G mutant takes 4.5 times longer to be activated by PIP2. To probe the mechanism by which E224G slows the channel opening kinetics, we perform targeted molecular dynamics simulations and find that the mutant weakens the interactions between CD-loop and C-linker (H221-R189) and the adjacent G-loops (R312-E303) which are thought to stabilize the open state of the channel in our previous work. These data provide new insights into the regulation of Kir2.1 channel activity and suggest that a common mechanism may be involved in the distinct biophysical processes, such as inward rectification and PIP2-induced gating.

关键词： WT PIP E224G Regulation of the PIP2-Induced Gating Kinetics of Kir2.1 Channels

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Oxidative stress in portal hypertension-induced rats with particular emphasis on nitric oxide and trace metals

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World Journal of Gastroenterology 2005年第23期11卷 3570-3573页

作者： Titiz Izzet Krand Osman Unal Ethem Yavuz Nihat Kusaslan Ramazan Dogan Mustafa Uzun Hafize Kiziler Ali Riza Aydemir Birsen Genc Habibe Aydin Seval Simsek Gonul department of Surgery department of Biochemistry department of biophysics department of physiology

AIM: To investigate the oxidative-stress-related changes in rats with portal hypertension with particular emphasis on nitric oxide (NO) and trace metals. METHODS: Cirrhosis was induced by partial portal vein ligation (PVL) in Wistar rats. The lipid peroxidation marker (malondialdehyde, MDA), antioxidant defense enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and agents known to have antioxidant features including nitric oxide (NO), zinc (Zn), copper (Cu) were determined both in serum and in liver tissue at 4 wk after surgery in PVL and sham-operated rats. Portal pressure of all experimental animals was measured. MDA was detected by thiobarbituric acid reactivity *** activity was determined by inhibition of nitroblue tetrazolium reduction with xanthine/xanthine oxidase used asa superoxide generator. CAT activity was determined by the breakdown of hydrogen peroxide. GSH concentrations were measured by using metaphosphoric acid for protein precipitation and 5'-5'-dithio-bis-2-nitrobenzoic acid for color development. NO was detected by the Griess method after reduction of nitrate to nitrite with nitrate reductase, and the concentrations of Zn and Cu were measured by a Shimadzu 680 AA atomic absorption spectrometer. Histopathological confirmation was done under light microscope. Statistical analyses were done by Student's t-test, and significance of the difference was tested by the unpaired Mann-Whitney test. P＜0.05 was considered statistically ***: Histopathological studies confirmed PVL induced cirrhotic changes. There was a statistically significant difference in portal pressure between PVL and control groups (P＜0.001). The results showed significant increases in the levels of MDA and NO in both tissue and serum (P＜0.05 and P＜0.001, respectively in tissue; P＜0.001 for each in serum), and Zn only in tissue (P＜0.001)in rats with PVL compared with sham-operated rats. Besides, PVL rats exhibited reduced plasma and tis

关键词： Portal hypertension Nitric oxide Lipid peroxidation Antioxidants Trace metals

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Exosomes in neurological disease, neuroprotection, repair and therapeutics: problems and perspectives

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Neural Regeneration Research 2015年第10期10卷 1565-1567页

作者： Anuradha Kalani Neetu Tyagi department of physiology and biophysics School of Medicine University of Louisville

Exosomes：Exosomes are a sub-population of micro-vesicles ranging from 40–100 nm that were earlier thought as artefacts under electron *** recently came into attention for their storage of biological information,cell-to-cell communication,serving as biomarkers and potential use in neural protection and regeneration （Kalani et al., 2013, 2014a）.

关键词： Exosomes in neurological disease neuroprotection problems and perspectives repair and therapeutics

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Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells

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Journal of molecular Cell Biology 2021年第6期13卷 433-444页

作者： Lei Duan Sarah Calhoun Daeun Shim Ricardo E.Perez Lothar A.Blatter Carl G.Maki department of Cell and molecular Medicine Rush University Medical CenterChicagoIL 60612USA department of molecular biophysics and physiology Rush University Medical CenterChicagoIL 60612USA

Tamoxifen(TAM)is the first-line endocrine therapy for estrogen receptor-positive(ER+)breast cancer(BC).However,acquired resistance occurs in∼50%***,although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients,complex signaling feedback loops exist,which can counter the effectiveness of inhibitors of this ***,we analyzed signaling pathways and metabolism in ER+MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting,quantitative polymerase chain reaction,and the Agilent Seahorse XF *** found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant ***,ERRα/PGC-1βand their target genes MCAD and CPT-1 were increased and regulated by AMPK,which coincided with increased fatty acid oxidation(FAO)and autophagy in TAM-resistant *** of AKT feedback-activates AMPK and ERRα/PGC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT ***,our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant *** inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

关键词： endoxifen fatty acid oxidation autophagy AMPK AKT

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