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Phototherapy is an emerging non-pharmacological treatment for depression, circadian rhythm disruptions, and neurodegeneration, as well as pain conditions including migraine and fibromyalgia. However, the mechanism of phototherapy-induced antinociception is not well understood. Here, using fiber photometry recordings of population-level neural activity combined with chemogenetics, we found that phototherapy elicits antinociception via regulation of the ventral lateral geniculate body (vLGN) located in the visual system. Specifically, both green and red lights caused an increase of c-fos in vLGN, with red light increased more. In vLGN, green light causes a large increase in glutamatergic neurons, whereas red light causes a large increase in GABAergic neurons. Green light preconditioning increases the sensitivity of glutamatergic neurons to noxious stimuli in vLGN of PSL mice. Green light produces antinociception by activating glutamatergic neurons in vLGN, and red light promotes nociception by activating GABAergic neurons in vLGN. Together, these results demonstrate that different colors of light exert different pain modulation effects by regulating glutamatergic and GABAergic subpopulations in the vLGN. This may provide potential new therapeutic strategies and new therapeutic targets for the precise clinical treatment of neuropathic pain.
Assuntos
Neuralgia , Nociceptividade , Camundongos , Animais , Nociceptividade/fisiologia , Neurônios GABAérgicos , Corpos Geniculados/fisiologia , Fototerapia , Neuralgia/terapiaRESUMO
Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 µM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.
Assuntos
Epilepsia , Excitação Neurológica , Camundongos , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Canfanos/uso terapêutico , Canfanos/farmacologia , Excitação Neurológica/fisiologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Modelos Animais de DoençasRESUMO
Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.
Assuntos
Disfunção Cognitiva , Epilepsia do Lobo Temporal , Masculino , Camundongos , Animais , Convulsões , Neurônios , Epilepsia do Lobo Temporal/psicologia , Hipocampo , CogniçãoRESUMO
Epilepsy is not well controlled by current anti-seizure drugs (ASDs). High mobility group box 1 (HMGB1) is a DNA-binding protein in the nucleus regulating transcriptional activity and maintaining chromatin structure and DNA repair. In epileptic brains, HMGB1 is released by activated glia and neurons, interacting with various receptors like Toll-like receptor 4 (TLR4) and downstream glutamatergic NMDA receptor, thus enhancing neural excitability. But there is a lack of small-molecule drugs targeting the HMGB1-related pathways. In this study we evaluated the therapeutic potential of inflachromene (ICM), an HMGB-targeting small-molecule inhibitor, in mouse epilepsy models. Pentylenetetrazol-, kainic acid- and kindling-induced epilepsy models were established in mice. The mice were pre-treated with ICM (3, 10 mg/kg, i.p.). We showed that ICM pretreatment significantly reduced the severity of epileptic seizures in all the three epilepsy models. ICM (10 mg/kg) exerted the most apparent anti-seizure effect in kainic acid-induced epileptic status (SE) model. By immunohistochemical analysis of brain sections from kainic acid-induced SE mice, we found that kainic acid greatly enhanced HMGB1 translocation in the hippocampus, which was attenuated by ICM pretreatment in subregion- and cell type-dependent manners. Notably, in CA1 region, the seizure focus, ICM pretreatment mainly inhibited HMGB1 translocation in microglia. Furthermore, the anti-seizure effect of ICM was related to HMGB1 targeting, as pre-injection of anti-HMGB1 monoclonal antibody (5 mg/kg, i.p.) blocked the seizure-suppressing effect of ICM in kainic acid-induced SE model. In addition, ICM pretreatment significantly alleviated pyramidal neuronal loss and granule cell dispersion in kainic acid-induced SE model. These results demonstrate that ICM is an HMGB-targeting small molecule with anti-seizure potential, which may help develop a potential drug for treating epilepsy.
Assuntos
Epilepsia , Proteína HMGB1 , Camundongos , Animais , Ácido Caínico/efeitos adversos , Ácido Caínico/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Hipocampo/metabolismo , Proteínas HMGB/metabolismo , Proteínas HMGB/farmacologia , Proteína HMGB1/metabolismo , Modelos Animais de DoençasRESUMO
Arabidopsis thaliana AKR2A plays an important role in plant responses to cold stress. However, its exact function in plant resistance to cold stress remains unclear. In the present study, we found that the contents of very long-chain fatty acids (VLCFAs) in akr2a mutants were decreased, and the expression level of KCS1 was also reduced. Overexpression of KCS1 in the akr2a mutants could enhance VLCFAs contents and chilling tolerance. Yeast-2-hybrid and bimolecular fluorescence complementation (BIFC) results showed that the transmembrane motif of KCS1 interacts with the PEST motif of AKR2A both in vitro and in vivo. Overexpression of KCS1 in akr2a mutants rescued akr2a mutant phenotypes, including chilling sensitivity and a decrease of VLCFAs contents. Moreover, the transgenic plants co-overexpressing AKR2A and KCS1 exhibited a greater chilling tolerance than the plants overexpressing AKR2A or KCS1 alone, as well as the wild-type. AKR2A knockdown and kcs1 knockout mutants showed the worst performance under chilling conditions. These results indicate that AKR2A is involved in chilling tolerance via an interaction with KCS1 to affect VLCFA biosynthesis in Arabidopsis.
Assuntos
Acetiltransferases/fisiologia , Proteínas de Arabidopsis/fisiologia , Ácidos Graxos/metabolismo , Chaperonas Moleculares/fisiologia , Acetiltransferases/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Temperatura Baixa/efeitos adversos , Resposta ao Choque Frio , Ácidos Graxos/fisiologia , Regulação da Expressão Gênica de Plantas , Técnicas de Silenciamento de Genes , Chaperonas Moleculares/genética , Fotossíntese , Plantas Geneticamente Modificadas , Técnicas do Sistema de Duplo-HíbridoRESUMO
The biosynthesis of very-long-chain fatty acids (VLCFAs) and their transport are required for fibre development. However, whether other regulatory factors are involved in this process is unknown. We report here that overexpression of an Arabidopsis gene ankyrin repeat-containing protein 2A (AKR2A) in cotton promotes fibre elongation. RNA-Seq analysis was employed to elucidate the mechanisms of AKR2A in regulating cotton fibre development. The VLCFA content and the ratio of VLCFAs to short-chain fatty acids increased in AKR2A transgenic lines. In addition, AKR2A promotes fibre elongation by regulating ethylene and synergizing with the accumulation of auxin and hydrogen peroxide. Analysis of RNA-Seq data indicates that AKR2A up-regulates transcript levels of genes involved in VLCFAs' biosynthesis, ethylene biosynthesis, auxin and hydrogen peroxide signalling, cell wall and cytoskeletal organization. Furthermore, AKR2A interacted with KCS1 in Arabidopsis both in vitro and in vivo. Moreover, the VLCFA content and the ratio of VLCFAs to short-chain fatty acids increased significantly in seeds of AKR2A-overexpressing lines and AKR2A/KCS1 co-overexpressing lines, while AKR2A mutants are the opposite trend. Our results uncover a novel cotton fibre growth mechanism by which the critical regulator AKR2A promotes fibre development via activating hormone signalling cascade by mediating VLCFA biosynthesis. This study provides a potential candidate gene for improving fibre yield and quality through genetic engineering.
Assuntos
Fibra de Algodão , Ácidos Graxos , Gossypium , Arabidopsis/genética , Ácidos Graxos/biossíntese , Ácidos Graxos/genética , Regulação da Expressão Gênica de Plantas/genética , Gossypium/genética , Gossypium/metabolismo , Chaperonas Moleculares/metabolismo , Transdução de Sinais/genéticaRESUMO
Acid rain (AR) impacts forest health by leaching calcium (Ca) away from soils and plants. Ca is an essential element and participates in various plant physiological responses. In the present study, the protective role of exogenous Ca in alleviating AR stress in Liquidambar formosana Hance at the physiological and proteomic levels was examined. Our results showed that low Ca condition resulted in the chlorophyll content and photosynthesis decreasing significantly in L. formosana leaves; however, these effects could be reversed by high Ca supplementation. Further proteomic analyses successfully identified 81 differentially expressed proteins in AR-treated L. formosana under different Ca levels. In particular, some of the proteins are involved in primary metabolism, photosynthesis, energy production, antioxidant defense, transcription, and translation. Moreover, quantitative real time polymerase chain reaction (qRT-PCR) results indicated that low Ca significantly increased the expression level of the investigated Ca-related genes, which can be reversed by high Ca supplementation under AR stress. Further, Western blotting analysis revealed that exogenous Ca supply reduced AR damage by elevating the expression of proteins involved in the Calvin cycle, reactive oxygen species (ROS) scavenging system. These findings allowed us to better understand how woody plants respond to AR stress at various Ca levels and the protective role of exogenous Ca against AR stress in forest tree species.
Assuntos
Cálcio/toxicidade , Liquidambar/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Proteoma/metabolismo , Chuva Ácida , Expressão Gênica , Liquidambar/efeitos dos fármacos , Redes e Vias Metabólicas , Folhas de Planta/efeitos dos fármacos , Proteínas de Plantas/genética , Proteoma/genética , Proteômica , Estresse FisiológicoRESUMO
The caseinolytic peptidase (Clp) core proteins are essential for plant growth and development, especially for chloroplast function. Antisense or overexpression of ClpP4, which is one of the Clp core subunits, causes chlorotic phenotypes in Arabidopsis. An E3 ligase gene, AtCHIP, has previously been found to ubiquitylate ClpP4 in vitro. ClpP4 antisense and overexpressing plants that also overexpressed AtCHIP were constructed to explore the effect of AtCHIP on ClpP4. Overexpression of AtCHIP was found to rescue the chlorotic phenotypes of both ClpP4 antisense and overexpressing plants. The unbalanced levels of Clp core proteins in ClpP4 antisense and overexpressing plants with overexpression of AtCHIP were similar to wild-type levels, suggesting that AtCHIP regulates Clp core proteins. The results also show that AtCHIP can interact with ClpP3 and ClpP5 in yeast and ubiquitylate ClpP3 and ClpP5 in vitro. This suggests that AtCHIP is directly related to ClpP3 and ClpP5. Given these results, the inference is that through selective degradation of Clp subunits, AtCHIP could positively regulate homeostasis of Clp proteolytic subunits and maximize the production of functional chloroplasts. Similar results were obtained from transgenic tobacco plants, suggesting that regulation of the Clp protease by AtCHIP is conserved.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Endopeptidase Clp/genética , Homeostase , Ubiquitina-Proteína Ligases/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Endopeptidase Clp/metabolismo , Proteólise , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons. An increasing body of evidence suggests that in the presence of inflammation and nerve damage, a significant number of satellite glial cells become activated, thus triggering a series of functional changes. This suggests that satellite glial cells are closely related to the occurrence of chronic pain. In this review, we first summarize the morphological structure, molecular markers, and physiological functions of satellite glial cells. Then, we clarify the multiple key roles of satellite glial cells in chronic pain, including gap junction hemichannel Cx43, membrane channel Pannexin1, K channel subunit 4.1, ATP, purinergic P2 receptors, and a series of additional factors and their receptors, including tumor necrosis factor, glutamate, endothelin, and bradykinin. Finally, we propose that future research should focus on the specific sorting of satellite glial cells, and identify genomic differences between physiological and pathological conditions. This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.
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Aim to provide practical clinical guidance for the treatment of implants in diabetic patients, this study investigated the corrosion mechanism of bionic coatings containing different Ca/P ratios in diabetic environments. The bionic coatings were prepared in ß-titanium alloys using micro-arc oxidation (MAO) technology and evaluated for corrosion mechanism, biocompatibility, and safety by cytotoxicity, electrochemical corrosion, and coating bonding force experiments. Ca and P from the electrolyte were integrated into the coating during MAO discharge process to form hydroxyapatite. The coating Ca/P ratio initially increased and then decreased with the electrolyte Ca/P ratio. In vitro cellular experiments demonstrated that increasing the porosity of HA-containing coatings would be beneficial to the growth of cells adhering to their surfaces. Corrosion tests revealed that the corrosion tendency of the coating at higher sugar content was more severe, and a proper elevation of the Ca/P ratio was better for the corrosion resistance of the coating. The bonding analysis of the coatings before and after corrosion showed that an increase in the Ca/P ratio would improve the bonding of the MAO coatings in higher glucose content environments, thus improving the safety of the implants in diabetic patients.
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Fear memory is essential for survival and adaptation, yet excessive fear memories can lead to emotional disabilities and mental disorders. Despite previous researches have indicated that histamine H1 receptor (H1R) exerts critical and intricate effects on fear memory, the role of H1R is still not clarified. Here, we show that deletion of H1R gene in medial septum (MS) but not other cholinergic neurons selectively enhances contextual fear memory without affecting cued memory by differentially activating the dentate gyrus (DG) neurons in mice. H1R in cholinergic neurons mediates the contextual fear retrieval rather than consolidation by decreasing acetylcholine release pattern in DG. Furthermore, selective knockdown of H1R in the MS is sufficient to enhance contextual fear memory by manipulating the retrieval-induced neurons in DG. Our results suggest that H1R in MS cholinergic neurons is critical for contextual fear retrieval, and could be a potential therapeutic target for individuals with fear-related disorders.
Assuntos
Neurônios Colinérgicos , Giro Denteado , Medo , Receptores Histamínicos H1 , Animais , Medo/fisiologia , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H1/genética , Giro Denteado/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Memória/fisiologia , Camundongos Knockout , Acetilcolina/metabolismo , Núcleos Septais/metabolismo , Núcleos Septais/fisiologia , Núcleos Septais/citologiaRESUMO
Importance: Early onset of myopia increases the risk of high myopia, which can lead to irreversible retinal damage and even loss of central vision. Objective: To investigate the efficacy and safety of naked-eye 3-dimensional vision training (NVT) in preventing the progression of myopia in children. Design, Setting, and Participants: This randomized clinical trial was conducted in 3 hospitals from May 25, 2022, to February 24, 2023. Participants were children (aged 6-18 years) who had a diagnosis of myopia with a spherical equivalent refraction of -0.75 to -6.00 diopters (D). Intervention: Children in the intervention group received 20 minutes of NVT treatment every day, whereas children in the control group lived as usual without vision training. Main Outcome and Measure: The primary outcome was the change in axial length at 6 months. Spherical equivalent refraction (SER) was included as a secondary outcome. Results: Among 263 participants, 125 (47.5%) were male and 138 (52.5%) were female; the mean (SD) age was 10.3 (1.9) years (range, 6.1-15.6 years). A total of 227 patients (86.3%) completed the 6-month follow-up, including 102 in the intervention group and 125 in the control group. In the intervention group, the changes in axial length and SER at 6 months were 0.18 mm (95% CI, 0.16 to 0.20 mm) and -0.25 D (95% CI, -0.31 to -0.19 D), respectively. In the control group, the changes in axial length and SER at 6 months were 0.23 mm (95% CI, 0.21 to 0.25 mm) and -0.35 D (95% CI, -0.41 to -0.30 D), respectively. The differences in AL and SER between the 2 groups were significant (AL difference: -0.06 mm; 95% CI, -0.09 to -0.03; P < .001; SER difference: 0.10 D; 95% CI, 0.02 to 0.19; P = .02). No study-related adverse reactions were reported during follow-up. Conclusions and Relevance: NVT is a safe and promising means to control myopia progression in children with good adherence. Trial Registration: ClinicalTrials.gov Identifier: NCT05468775.
Assuntos
Miopia , Refração Ocular , Humanos , Criança , Feminino , Masculino , Adolescente , Miopia/prevenção & controle , Miopia/terapia , Refração Ocular/fisiologia , Progressão da Doença , Resultado do TratamentoRESUMO
Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.
Assuntos
Epilepsia do Lobo Temporal , Hipocampo , Excitação Neurológica , Animais , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/terapia , Excitação Neurológica/fisiologia , Masculino , Hipocampo/fisiopatologia , Camundongos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Estimulação Elétrica/métodos , Córtex Entorrinal/fisiopatologia , Convulsões/etiologia , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Terapia por Estimulação Elétrica/métodosRESUMO
Arabidopsis thaliana ANKYRIN REPEAT-CONTAINING PROTEIN 2A (AKR2A) interacts with peroxisomal membrane-bound ASCORBATE PEROXIDASE3 (APX3). This interaction involves the C-terminal sequence of APX3 (i.e., a transmembrane domain plus a few basic amino acid residues). The specificity of the AKR2A-APX3 interaction suggests that AKR2A may function as a molecular chaperone for APX3 because binding of AKR2A to the transmembrane domain can prevent APX3 from forming aggregates after translation. Analysis of three akr2a mutants indicates that these mutant plants have reduced steady state levels of APX3. Reduced expression of AKR2A using RNA interference also leads to reduced steady state levels of APX3 and reduced targeting of APX3 to peroxisomes in plant cells. Since AKR2A also binds specifically to the chloroplast OUTER ENVELOPE PROTEIN7 (OEP7) and is required for the biogenesis of OEP7, AKR2A may serve as a molecular chaperone for OEP7 as well. The pleiotropic phenotype of akr2a mutants indicates that AKR2A plays many important roles in plant cellular metabolism and is essential for plant growth and development.
Assuntos
Repetição de Anquirina , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Chaperonas Moleculares/metabolismo , Peroxidases/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Ascorbato Peroxidases , Regulação da Expressão Gênica de Plantas , Proteínas de Membrana , Chaperonas Moleculares/genética , Peroxidases/genética , Peroxissomos/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Mapeamento de Interação de Proteínas , Interferência de RNARESUMO
A novel crosslinking agent, suberoyl chloride, was used to crosslink N-phthaloyl acylated chitosan and improves the properties of chitosan membranes. Membranes with different crosslinking degrees were synthesized. The derivatives were characterized by Fourier transform infrared spectroscopy and ¹³C solid state nuclear magnetic resonance spectroscopy, which indicated that the crosslinking degrees ranged from 0 to 7.4%. The permeabilities of various plant nutrients, including macroelements (N, P, K), microelements (Zn²âº and Cu²âº), and a plant growth regulator (naphthylacetic acid), were varied by moderate changes in crosslinking degree, indicating that the controlled-release properties can be regulated in this way. The film-forming ability of native chitosan was maintained, whilst mechanical properties, hydrophobicity and controlled permeability were improved. These dramatic improvements occurred with a small amount of added suberoyl chloride; excessive crosslinking led to membranes with unwanted poor permeability. Thus, both the mechanical properties and permeability of the crosslinked membrane can be optimized.
Assuntos
Quitosana/química , Cloretos/química , Preparações de Ação Retardada/química , Membranas Artificiais , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Ácidos Naftalenoacéticos/química , Ressonância Magnética Nuclear Biomolecular , Permeabilidade , Reguladores de Crescimento de Plantas/química , Resistência à TraçãoRESUMO
Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery, likely due to the widespread seizure network. Previous studies have primarily focused on the disruption of dysplastic lesions, rather than remote regions such as the hippocampus. Here, we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia. We further investigated the cellular substrates leading to the epileptic hippocampus, using multiscale tools including calcium imaging, optogenetics, immunohistochemistry and electrophysiology. For the first time, we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures. Somatostatin-positive were recruited during cortical dysplasia-related seizures. Interestingly, optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization. By contrast, parvalbumin-positive interneurons retained an inhibitory role as in controls. Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus. Taken together, our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.
Assuntos
Interneurônios , Convulsões , Humanos , Interneurônios/metabolismo , Hipocampo , Somatostatina/genética , Somatostatina/metabolismo , Giro Denteado/metabolismoRESUMO
Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.
Assuntos
Claustrum , Receptores Opioides kappa , Masculino , Camundongos , Animais , Receptores Opioides kappa/metabolismo , Dinorfinas , Depressão/etiologia , Claustrum/metabolismo , Transdução de Sinais/fisiologia , Camundongos Endogâmicos C57BLRESUMO
Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein-coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed GPR177/WNT5A coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes.
Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Peptídeos e Proteínas de Sinalização Intracelular , Neuralgia , Receptores Acoplados a Proteínas G , Canais de Cátion TRPV , Proteína Wnt-5a , Animais , Diabetes Mellitus/metabolismo , Neuropatias Diabéticas/metabolismo , Gânglios Espinais/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Neuralgia/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/metabolismo , Proteína Wnt-5a/metabolismoRESUMO
The Arabidopsis gene AVP1 encodes a vacuolar pyrophosphatase that functions as a proton pump on the vacuolar membrane. Overexpression of AVP1 in Arabidopsis, tomato and rice enhances plant performance under salt and drought stress conditions, because up-regulation of the type I H+-PPase from Arabidopsis may result in a higher proton electrochemical gradient, which facilitates enhanced sequestering of ions and sugars into the vacuole, reducing water potential and resulting in increased drought- and salt tolerance when compared to wild-type plants. Furthermore, overexpression of AVP1 stimulates auxin transport in the root system and leads to larger root systems, which helps transgenic plants absorb water more efficiently under drought conditions. Using the same approach, AVP1-expressing cotton plants were created and tested for their performance under high-salt and reduced irrigation conditions. The AVP1-expressing cotton plants showed more vigorous growth than wild-type plants in the presence of 200 mM NaCl under hydroponic growth conditions. The soil-grown AVP1-expressing cotton plants also displayed significantly improved tolerance to both drought and salt stresses in greenhouse conditions. Furthermore, the fibre yield of AVP1-expressing cotton plants is at least 20% higher than that of wild-type plants under dry-land conditions in the field. This research indicates that AVP1 has the potential to be used for improving crop's drought- and salt tolerance in areas where water and salinity are limiting factors for agricultural productivity.
Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/fisiologia , Arabidopsis/fisiologia , Gossypium/genética , Gossypium/fisiologia , Pirofosfatase Inorgânica/genética , Pirofosfatase Inorgânica/fisiologia , Plantas Geneticamente Modificadas , Arabidopsis/genética , Fibra de Algodão , Secas , Regulação da Expressão Gênica de Plantas , Tolerância ao Sal , Estresse Fisiológico , Vacúolos/metabolismoRESUMO
One of the hallmarks of the Gram-negative bacterium Pseudomonas aeruginosa is its ability to thrive in diverse environments that includes humans with a variety of debilitating diseases or immune deficiencies. Here we report the complete sequence and comparative analysis of the genomes of two representative P. aeruginosa strains isolated from cystic fibrosis (CF) patients whose genetic disorder predisposes them to infections by this pathogen. The comparison of the genomes of the two CF strains with those of other P. aeruginosa presents a picture of a mosaic genome, consisting of a conserved core component, interrupted in each strain by combinations of specific blocks of genes. These strain-specific segments of the genome are found in limited chromosomal locations, referred to as regions of genomic plasticity. The ability of P. aeruginosa to shape its genomic composition to favor survival in the widest range of environmental reservoirs, with corresponding enhancement of its metabolic capacity is supported by the identification of a genomic island in one of the sequenced CF isolates, encoding enzymes capable of degrading terpenoids produced by trees. This work suggests that niche adaptation is a major evolutionary force influencing the composition of bacterial genomes. Unlike genome reduction seen in host-adapted bacterial pathogens, the genetic capacity of P. aeruginosa is determined by the ability of individual strains to acquire or discard genomic segments, giving rise to strains with customized genomic repertoires. Consequently, this organism can survive in a wide range of environmental reservoirs that can serve as sources of the infecting organisms.