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Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.
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Córtex Auditivo , Camundongos , Animais , Córtex Auditivo/metabolismo , Tálamo/fisiologia , Neurônios/metabolismo , Corpos Geniculados , Interneurônios/fisiologia , Parvalbuminas/metabolismoRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000â m for 4â h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.
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Transtorno do Espectro Autista , Transtorno Autístico , Camundongos , Masculino , Animais , Transtorno Autístico/genética , Transtorno Autístico/terapia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/terapia , Núcleo Dorsal da Rafe , Neurônios Serotoninérgicos/fisiologia , Hipóxia , Fenótipo , Proteína do X Frágil da Deficiência IntelectualRESUMO
We present the results for the complete next-to-leading order electroweak corrections to ppâHH at the Large Hadron Collider, focusing on the dominant gluon-gluon fusion process. While the corrections at the total cross-section level are approximately -4%, those near the energy of HH production threshold exceed +15%, and corrections at the high-energy region are around -10%, leading to a shape distortion for the differential distributions. Our findings substantially diminish the theoretical uncertainties associated with this pivotal process, providing valuable input for understanding the shape of the Higgs boson potential upon comparison with experimental measurements.
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A novel doubly interpenetrated indium-organic framework of 1 has been assembled by In3+ ions and highly conjugated biquinoline carboxylate-based bitopic connectors (H2L). The isolated 1 exhibits an anionic framework possessing channel-type apertures repleted with exposed quinoline N atoms and carboxyl O atoms. Owing to the unique architecture, 1 displays a durable photoluminescence effect and fluorescence quenching sensing toward CrO42-, Cr2O72-, and Cu2+ ions with reliable selectivity and anti-interference properties, fairly high detection sensitivity, and rather low detection limits. Ligand-to-ligand charge transition (LLCT) was identified as the essential cause of luminescence by modeling the ground state and excited states of 1 using DFT and TD-DFT. In addition, the negatively charged framework has the ability to rapidly capture single cationic MB, BR14, or BY24 and their mixture, including the talent to trap MB from the (MB + MO) system with high selectivity. Moreover, intrinsic light absorption capacity and band structure feature endow 1 with effective photocatalytic decomposition ability toward reactive dyes RR2 and RB13 under ultraviolet light. Notably, after further polishing the band structure state of 1 by constructing the S-scheme heterojunction of In2S3/1, highly efficient photocatalytic detoxification of Cr(VI) and degradation of reactive dyes have been fully achieved under visible light. This finding may open a new avenue for designing novel multifunctional MOF-based platforms to address some intractable environmental issues, i.e., detection of heavy metal ions, physical capture of pony-sized dyes, and photochemical decontamination of ultrastubborn reactive dyes and highly toxic Cr(VI) ions from water.
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BACKGROUND: circRNAs have been shown to participate in diverse diseases; however, their role in oral submucous fibrosis (OSF), a potentially malignant disorder, remains obscure. Our preliminary experiments detected the expression of circRNA mitochondrial translation optimization 1 homologue (circMTO1) in OSF tissues (n = 20) and normal mucosa tissues (n = 20) collected from Hunan Xiangya Stomatological Hospital, and a significant decrease of circMTO1 expression was showed in OSF tissues. Therefore, we further explored circMTO1 expression in OSF. METHODS: Target molecule expression was detected using RT-qPCR and western blotting. The migration and invasion of buccal mucosal fibroblasts (BMFs) were assessed using wound healing and Transwell assays. The interaction between miR-30c-5p, circMTO1, and SOCS3 was evaluated using dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down assays. The colocalisation of circMTO1 and miR-30c-5p was observed using fluorescence in situ hybridisation (FISH). RESULTS: circMTO1 and SOCS3 expression decreased, whereas miR-30c-5p expression increased in patients with OSF and arecoline-stimulated BMFs. Overexpression of circMTO1 effectively restrained the fibroblast-myofibroblast transition (FMT), as evidenced by the increase in expression of Coll I, α-SMA, Vimentin, and the weakened migration and invasion functions in BMFs. Mechanistic studies have shown that circMTO1 suppresses FMT by enhancing SOCS3 expression by sponging miR-30c-5p and subsequently inactivating the FAK/PI3K/AKT pathway. FMT induced by SOCS3 silencing was reversed by the FAK inhibitor TAE226 or the PI3K inhibitor LY294002. CONCLUSION: circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF.
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Fibroblastos , MicroRNAs , Fibrose Oral Submucosa , RNA Circular , Proteína 3 Supressora da Sinalização de Citocinas , Humanos , MicroRNAs/metabolismo , Fibrose Oral Submucosa/patologia , Fibrose Oral Submucosa/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fibroblastos/metabolismo , RNA Circular/genética , Miofibroblastos , Masculino , Movimento Celular , Mucosa Bucal/metabolismo , Mucosa Bucal/citologia , Mucosa Bucal/patologia , Transdução de Sinais , Feminino , Células CultivadasRESUMO
The coordination of complex behavior requires knowledge of both neural dynamics and the mechanics of the periphery. The feeding system of Aplysia californica is an excellent model for investigating questions in soft body systems' neuromechanics because of its experimental tractability. Prior work has attempted to elucidate the mechanical properties of the periphery by using a Hill-type muscle model to characterize the force generation capabilities of the key protractor muscle responsible for moving Aplysia's grasper anteriorly, the I2 muscle. However, the I1/I3 muscle, which is the main driver of retractions of Aplysia's grasper, has not been characterized. Because of the importance of the musculature's properties in generating functional behavior, understanding the properties of muscles like the I1/I3 complex may help to create more realistic simulations of the feeding behavior of Aplysia, which can aid in greater understanding of the neuromechanics of soft-bodied systems. To bridge this gap, in this work, the I1/I3 muscle complex was characterized using force-frequency, length-tension, and force-velocity experiments and showed that a Hill-type model can accurately predict its force-generation properties. Furthermore, the muscle's peak isometric force and stiffness were found to exceed those of the I2 muscle, and these results were analyzed in the context of prior studies on the I1/I3 complex's kinematics in vivo.
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Aplysia , Aplysia/fisiologia , Animais , Fenômenos Biomecânicos/fisiologia , Modelos Biológicos , Comportamento Alimentar/fisiologia , Contração Muscular/fisiologia , Músculos/fisiologia , Músculo Esquelético/fisiologiaRESUMO
OBJECTIVES: Porphyromonas gingivalis-LPS regulated bone metabolism by triggering dysfunction of osteoblasts directly, and affecting activity of osteoclasts through intracellular communication. Exosome, as the mediator of intercellular communication, was important vesicle to regulate osteogenesis and osteoclastogenesis. This research was designed for investigating the mechanism of BMSCs-EXO in modulating osteoclastic activity under the P. gingivalis-LPS. MATERIALS AND METHODS: The cytotoxicity and osteogenic effects of P. gingivalis-LPS on BMSCs was evaluated, and then osteoclastic activity of RAW264.7 co-cultured with exosomes was detected. Besides, Affymetrix miRNA array and luciferase reporter assay were used to identify the target exosomal miRNA signal pathway. RESULTS: BMSCs' osteogenic differentiation and proliferation were decreased under 1 and 10 µg/mL P. gingivalis-LPS. Osteoclastic-related genes and proteins levels were promoted by P. gingivalis-LPS-stimulated BMSCs-EXO. Based on the miRNA microarray analysis, exosomal miR-151-3p was lessened in BMExo-LPS group, which facilitated osteoclastic differentiation through miR-151-3p/PAFAH1B1. CONCLUSIONS: Porphyromonas gingivalis-LPS could regulated bone metabolism by inhibiting proliferation and osteogenesis of BMSCs directly. Also, P. gingivalis-LPS-stimulated BMSCs-EXO promoted osteoclastogenesis via activating miR-151-3p/PAFAH1B1 signal pathway.
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It is desirable to obtain high levels of viable Lacticaseibacillus paracasei, a widely used food probiotic whose antibacterial activity and potential application in milk remain largely uninvestigated. Here, we isolated and purified the L. paracasei strain XLK 401 from food-grade blueberry ferments and found that it exhibited strong antibacterial activity against both gram-positive and gram-negative foodborne pathogens, including Staphylococcus aureus, Salmonella paratyphi B, Escherichia coli O157, and Shigella flexneri. Then, we applied alternating tangential flow (ATF) technology to produce viable L. paracasei XLK 401 cells and its cell-free supernatant (CFS). Compared with the conventional fed-batch method, 22 h of ATF-based processing markedly increased the number of viable cells of L. paracasei XLK 401 to 12.14 ± 0.13 log cfu/mL. Additionally, the CFS exhibited good thermal stability and pH tolerance, inhibiting biofilm formation in the abovementioned foodborne pathogens. According to liquid chromatography-mass spectrometry analysis, organic acids were the main antibacterial components of XLK 401 CFS, accounting for its inhibition activity. Moreover, the CFS of L. paracasei XLK 401 effectively inhibited the growth of multidrug-resistant gram-positive Staph. aureus and gram-negative E. coli O157 pathogens in milk, and caused a reduction in the pathogenic cell counts by 6 to 7 log cfu/mL compared with untreated control, thus considerably maintaining the safety of milk samples. For the first time to our knowledge, ATF-based technology was employed to obtain viable L. paracasei on a large scale, and its CFS could serve as a broad-spectrum biopreservative for potential application against foodborne pathogens in milk products.
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Escherichia coli O157 , Lacticaseibacillus paracasei , Animais , Leite , Antibacterianos/farmacologia , Contagem de Células/veterináriaRESUMO
BACKGROUND: Studies has suggested that receiving social support improves the professional identity of health professional students. According to the two-way social support theory, social support includes receiving social support and giving social support. However, the effect of the two-way social support on health professional students' professional identity has not been clarified yet. METHODS: To explore the mechanism of how two-way social support affects health professional students' professional identity, an observational, cross-sectional study was conducted among a convenience and cluster sample of 1449 health professional students from two medical schools in western China. Measures included a short version of the two-way social support scale, a health professional students' professional identity questionnaire, an achievement motivation scale, and a meaning in life scale. Data were analyzed by use of SPSS26.0 software and PROCESSv4.0 plug-in. RESULTS: Receiving social support, giving social support, achievement motivation, meaning in life, and professional identity were positively correlated with each other. Receiving and giving social support not only directly predicted health professional students' professional identity, but also indirectly predicted health professional students' professional identity through the mediating roles of achievement motivation and meaning in life, and the chain mediating roles of achievement motivation and meaning in life, respectively. The effectiveness of predicting health professional students' professional identity varied among different types of two-way social support, which could be depicted as two-way social support > mainly giving social support > mainly receiving social support > low two-way social support. CONCLUSION: In the medical education, the awareness and ability of health professional students to receive and give social support should be strengthened. More attention should be drawn on the chain mediating effect of achievement motivation and meaning in life between two-way social support and professional identity. The current results shed new light on exploring effective ways of improving health professional students' professional identity, which suggested that more attention should be paid to the positive effects of mainly giving social support and two-way social support rather than only on the effects of receiving social support.
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Motivação , Identificação Social , Apoio Social , Humanos , Estudos Transversais , Masculino , Feminino , Adulto Jovem , China , Estudantes de Medicina/psicologia , Adulto , Inquéritos e Questionários , Estudantes de Ciências da Saúde/psicologiaRESUMO
BACKGROUND: Hydrocephalus following a ruptured aneurysm portends a poor prognosis. The authors aimed to establish a nomogram to predict the risk of hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A total of 421 patients with aSAH who were diagnosed by digital subtraction angiography in The General Hospital of Northern Theater Command center from January 2020 to June 2021 were screened to establish the training cohort. An additional 135 patients who enrolled between July 2021 and May 2022 were used for the validation cohort. Variate difference analysis and stepwise logistic regression (model A) and univariate and multivariate logistic regressions (model B) were respectively used to construct two models. Then, the net reclassification improvement (NRI), integrated discrimination improvement (IDI), and receiver operating characteristic (ROC) curve were used to compare the predictive abilities of the two models. Finally, two nomograms were constructed and externally validated. RESULTS: After screening, 556 patients were included. The area under the ROC curve of models A and B in the training cohort were respectively 0.884 (95 % confidence interval [CI]: 0.847-0.921) and 0.834 (95 % CI: 0.787-0.881). The prediction ability of the model A was superior to model B (NRI > 0, IDI > 0, p < 0.05). The C-index of models A and B was 0.8835 and 0.8392, respectively. Regarding clinical usefulness, the two models offered a net benefit with a threshold probability of between 0.12 and 1 in the decision curve analysis, suggesting that the two models can accurately predict hydrocephalus events. CONCLUSIONS: Both models have good prediction accuracy. Compared with model B, model A has better discrimination and calibration. Further, the easy-to-use nomogram can help neurosurgeons to make rapid clinical decisions and apply early treatment measures in high-risk groups, which ultimately benefits patients.
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Hidrocefalia , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/diagnóstico por imagem , Nomogramas , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Estudos Retrospectivos , PrognósticoRESUMO
Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.
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Dor Crônica , Metilação de DNA , Epigênese Genética , Humanos , Dor Crônica/genética , Dor Crônica/metabolismo , AnimaisRESUMO
BACKGROUND: Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological states, leading to daily function impairment and increased disability. However, the neural circuit mechanisms by which pain disrupts attention are incompletely understood. METHODS: We used a three-choice serial reaction time task (3CSRTT) to construct a sustained-attention task model in male C57BL/6J mice. Formalin or complete Freund's adjuvant was injected into a paw to establish an inflammatory pain model. We measured changes in 3CSRTT performance in the two inflammatory pain models, and investigated the neural circuit mechanisms of pain-induced attentional deficits. RESULTS: Acute inflammatory pain impaired 3CSRTT performance, while chronic inflammatory pain had no effect. Either inhibition of the ascending pain pathway by blockade of the conduction of nociceptive signals in the sciatic nerve using the local anesthetic lidocaine or chemogenetic inhibition of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) neurons in the lateral parabrachial nucleus (LPBN) attenuated the acute inflammatory pain-induced impairment of 3CSRTT performance, while chemogenetic activation of CaMKIIα neurons in the LPBN disrupted the 3CSRTT. Furthermore, the activity of CaMKIIα neurons in the LPBN was significantly lower on Day 2 after complete Freund's adjuvant injection than on the day of injection, which correlated with the recovery of 3CSRTT performance during chronic inflammatory pain. CONCLUSIONS: Activation of excitatory neurons in the LPBN is a mechanism by which acute inflammatory pain disrupts sustained attention. This finding has implications for the treatment of pain and its cognitive comorbidities.
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Dor Crônica , Núcleos Parabraquiais , Camundongos , Animais , Masculino , Núcleos Parabraquiais/fisiologia , Adjuvante de Freund/metabolismo , Adjuvante de Freund/farmacologia , Camundongos Endogâmicos C57BL , Neurônios , AtençãoRESUMO
Marine phytoplankton fuel the oceanic biotic chain, determine the carbon sequestration levels, and are crucial for the global carbon cycle and climate change. In the present study, we show a near-two-decadal (2002-2022) spatiotemporal distribution of global phytoplankton abundance, proxy as dominant phytoplankton taxonomic groups (PTGs), with a newly developed remote sensing model. Globally, six chief PTGs, namely chlorophytes (~26%), diatoms (~24%), haptophytes (~15%), cryptophytes (~10%), cyanobacteria (~8%), and dinoflagellates (~3%), explain most of the variation (~86%) in phytoplankton assemblages. Spatially, diatoms generally dominate high latitudes, marginal seas, and coastal upwelling zones, whereas chlorophytes and haptophytes control the open oceans. Satellite observations reveal a gentle multi-annual trend of the PTGs in the major oceans, indicative of roughly "unchanged" conditions on the total biomass or compositions of the phytoplankton community. Jointly, "changed" status applies to a short-term (seasonal) timescale: (1) Fluctuations of PTGs exhibit different amplitudes among different subregions, together with a general rule-more intense vibration in the Northern Hemisphere and polar oceans than other zones; (2) diatoms and haptophytes vary more dramatically than other PTGs in a global-scale scope. These findings provide a clear picture of the global phytoplankton community composition and can improve our understanding of their state and further analysis of marine biological processes.
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Cianobactérias , Diatomáceas , Dinoflagellida , Fitoplâncton , Oceanos e MaresRESUMO
Atherosclerotic diseases remain the leading cause of adult mortality and impose heavy burdens on health systems globally. Our previous study found that disturbed flow enhanced YAP activity to provoke endothelial activation and atherosclerosis, and targeting YAP alleviated endothelial inflammation and atherogenesis. Therefore, we established a luciferase reporter assay-based drug screening platform to seek out new YAP inhibitors for anti-atherosclerotic treatment. By screening the FDA-approved drug library, we identified that an anti-psychotic drug thioridazine markedly suppressed YAP activity in human endothelial cells. Thioridazine inhibited disturbed flow-induced endothelial inflammatory response in vivo and in vitro. We verified that the anti-inflammatory effects of thioridazine were mediated by inhibition of YAP. Thioridazine regulated YAP activity via restraining RhoA. Moreover, administration of thioridazine attenuated partial carotid ligation- and western diet-induced atherosclerosis in two mouse models. Overall, this work opens up the possibility of repurposing thioridazine for intervention of atherosclerotic diseases. This study also shed light on the underlying mechanisms that thioridazine inhibited endothelial activation and atherogenesis via repression of RhoA-YAP axis. As a new YAP inhibitor, thioridazine might need further investigation and development for the treatment of atherosclerotic diseases in clinical practice.
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Aterosclerose , Células Endoteliais , Tioridazina , Animais , Humanos , Camundongos , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Inflamação/etiologia , Proteína rhoA de Ligação ao GTP/efeitos dos fármacos , Tioridazina/uso terapêutico , Proteínas de Sinalização YAP/efeitos dos fármacosRESUMO
Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.
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Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , CicatrizaçãoRESUMO
BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.
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Limiar da Dor , Estimulação Transcraniana por Corrente Contínua , Adolescente , Adulto , Feminino , Humanos , Adulto Jovem , Analgésicos , Giro do Cíngulo , Dor , Limiar da Dor/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodosRESUMO
Extracellular vesicles (EVs) derived from living cells play important roles in donor cell-induced recipient tissue regeneration. Although numerous studies have found that cells undergo apoptosis after implantation in an ischemic-hypoxic environment, the roles played by the EVs released by apoptotic cells are largely unknown. In this study, we obtained apoptotic vesicles (apoVs) derived from human deciduous pulp stem cells and explored their effects on the dental pulp regeneration process. Our work showed that apoVs were ingested by endothelial cells (ECs) and elevated the expression of angiogenesis-related genes, leading to pulp revascularization and tissue regeneration. Furthermore, we found that, at the molecular level, apoV-carried mitochondrial Tu translation elongation factor was transported and regulated the angiogenic activation of ECs via the transcription factor EB-autophagy pathway. In a beagle model of dental pulp regeneration in situ, apoVs recruited endogenous ECs and facilitated the formation of dental-pulp-like tissue rich in blood vessels. These findings revealed the significance of apoptosis in tissue regeneration and demonstrated the potential of using apoVs to promote angiogenesis in clinical applications.
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Polpa Dentária , Vesículas Extracelulares , Animais , Autofagia , Cães , Células Endoteliais , Humanos , Fatores de Alongamento de Peptídeos , Regeneração , Fatores de TranscriçãoRESUMO
PURPOSE: Hyperoxia-induced apoptosis in alveolar epithelial type II cells (AECIIs) plays a critical role in the development of bronchopulmonary dysplasia (BPD). Melatonin has been shown to improve BPD. However, the protective effect of melatonin on hyperoxia-induced apoptosis in AECIIs and the precise mechanisms involved remain unclear. METHODS: Human alveolar epithelial type II A549 cells were treated with hyperoxia as an in vitro model to investigate the antiapoptotic mechanism of melatonin. CCK-8 assays were performed to investigate the viability of A549 cells. Hoechst 33,258 staining was carried out to quantify apoptosis in A549 cells. The protein expression levels of E26 oncogene homolog 1 (ETS1), Bcl-2, Bax, Bim, Wnt, ß-catenin, AKT and phosphorylated AKT were measured by western blotting. LY294002, SC79 and the downregulation of ETS1, melatonin receptor 1 (MT1) and MT2 with specific siRNAs were used to investigate the role of the PI3K/AKT pathway, ETS1, MT1 and MT2 in hyperoxia-induced apoptosis in A549 cells. RESULTS: Melatonin prevented hyperoxia-induced apoptosis in A549 cells, and the upregulation of E26 oncogene homolog 1 (ETS1) contributed to the antiapoptotic effect of melatonin. Melatonin activated the PI3K/AKT axis, which led to ETS1 upregulation and inhibited apoptosis in hyperoxia-exposed A549 cells. Furthermore, melatonin-induced activation of the PI3K/AKT axis, upregulation of ETS1 and inhibition of apoptosis were reversed by melatonin receptor 2 (MT2) siRNA in hyperoxia-exposed A549 cells. CONCLUSION: Melatonin prevents hyperoxia-induced apoptosis by activating the MT2/PI3K/AKT/ETS1 axis in alveolar epithelial cells.
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Displasia Broncopulmonar , Hiperóxia , Melatonina , Recém-Nascido , Humanos , Células Epiteliais Alveolares , Hiperóxia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Melatonina/farmacologia , Melatonina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Receptores de Melatonina/metabolismo , Transdução de Sinais , Apoptose , Displasia Broncopulmonar/metabolismo , Células Epiteliais/metabolismo , Proteína Proto-Oncogênica c-ets-1RESUMO
Some of the statins have been shown to have antidepressant effects, but whether atorvastatin (AV) has antidepressant effects is unknown. This study was to investigate the effect of AV treatment on depressive behaviors. Herein, we show that AV treatment had antidepressant-like effect in physiological conditions and antidepressant effect in depressive state which depended on α7 nicotinic acetylcholine receptor (α7nAChR) expression in the ventral hippocampus (vHPC), but not α4ß2 nicotinic acetylcholine receptor (α4ß2nAchR) expression in vHPC, nor the α7nAChR and α4ß2nAchR expression in dorsal hippocampus (dHPC). By using MLA, a selective α7nAChR antagonist, we investigated the role of α7nAChR in AV treatment. Behavior tests demonstrated that MLA abolished the antidepressant effect of AV. Besides, our data showed that AV treatment increased Akt phosphorylation, brain-derived neurotrophic factor (BDNF), synaptic related protein synapsin and spinophilin expression. The phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 reversed AV-induced increase of BDNF expression, newborn neurons and antidepressant behavior effects. Our study suggests that AV plays an antidepressant role by regulating synaptic plasticity of vHPC through PI3K/Akt-BDNF signaling pathway, which may be a good choice for depression treatment.
Assuntos
Antidepressivos/farmacologia , Atorvastatina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo/etiologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
BACKGROUND: Inflammation induced by intracerebral hemorrhage (ICH) is one of the main causes of the high mortality and poor prognosis of patients with ICH. A1 astrocytes are closely associated with neuroinflammation and neurotoxicity, whereas A2 astrocytes are neuroprotective. Homer scaffolding protein 1 (Homer1) plays a protective role in ischemic encephalopathy and neurodegenerative diseases. However, the role of Homer1 in ICH-induced inflammation and the effect of Homer1 on the phenotypic conversion of astrocytes remain unknown. METHODS: Femoral artery autologous blood from C57BL/6 mice was used to create an ICH model. We use the A1 phenotype marker C3 and A2 phenotype marker S100A10 to detect astrocyte conversion after ICH. Homer1 overexpression/knock-down mice were constructed by adeno-associated virus (AAV) infection to explore the role of Homer1 and its mechanism of action after ICH. Finally, Homer1 protein and selumetinib were injected into in situ hemorrhage sites in the brains of Homer1flox/flox/Nestin-Cre+/- mice to study the efficacy of Homer1 in the treatment of ICH by using a mouse cytokine array to explore the potential mechanism. RESULTS: The expression of Homer1 peaked on the third day after ICH and colocalized with astrocytes. Homer1 promotes A1 phenotypic conversion in astrocytes in vivo and in vitro. Overexpression of Homer1 inhibits the activation of MAPK signaling, whereas Homer1 knock-down increases the expression of pathway-related proteins. The Homer1 protein and selumetinib, a non-ATP competitive MEK1/2 inhibitor, improved the outcome in ICH in Homer1flox/flox/Nestin-Cre+/- mice. The efficacy of Homer1 in the treatment of ICH is associated with reduced expression of the inflammatory factor TNFSF10 and increased expression of the anti-inflammatory factors activin A, persephin, and TWEAK. CONCLUSIONS: Homer1 plays an important role in inhibiting inflammation after ICH by suppressing the A1 phenotype conversion in astrocytes. In situ injection of Homer1 protein may be a novel and effective method for the treatment of inflammation after ICH.