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During adolescence, a second period of central nervous system (CNS) plasticity that follows the fetal period, which involves sleep deprivation (SD), becomes apparent. SD during adolescence may result in abnormal development of neural circuits, causing imbalance in neuronal excitation and inhibition, which not only results in pain, but increases the chances of developing emotion disorders in adulthood, such as anxiety and depression. The quantity of surgeries during adolescence is also consistently on the rise, yet the impact and underlying mechanism of preoperative SD on postoperative pain remain unexplored. This study demonstrates that preoperative SD induces upregulation of the P2Y12 receptor, which is exclusively expressed on spinal microglia, and phosphorylation of its downstream signaling pathway p38Mitogen-activated protein/Nuclear transcription factor-κB (p38MAPK/NF-κB)in spinal microglia, thereby promoting microglia activation and microglial transformation into the proinflammatory M1 phenotype, resulting in increased expression of proinflammatory cytokines that exacerbate persisting postoperative incisional pain in adolescent mice. Both intrathecal minocycline (a microglia activation inhibitor) and MRS2395 (a P2Y12 receptor blocker) effectively suppressed microglial activation and proinflammatory cytokine expression. Interestingly, supplementation with dehydrocorydaline (DHC), an extract of Rhizoma Corydalis, inhibited the P2Y12/p38MAPK/NF-κB signaling pathway, microglia activation, and expression of pro-inflammatory cytokines in the model mice. Taken together, the results indicate that the P2Y12 receptor and microglial activation are important factors in persistent postoperative pain caused by preoperative SD in adolescent mice and that DHC has analgesic effects by acting on these targets.
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Microglia , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Privação do Sono/complicações , Privação do Sono/metabolismo , Medula Espinal/metabolismo , Transdução de Sinais , Citocinas/metabolismo , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/metabolismoRESUMO
Anxiety and depression induced by cancer-related pain disturb quality of life and willingness to survive. As a component of the limbic system, the basolateral amygdala (BLA) is critical for processing negative emotions. The reactive microglial engulfment of synapses may promote depression during adolescence. However, whether microglia phagocytose synapses to mediate cancer pain-induced depression remains unclear. The present study established a bone cancer-pain model to investigate the association between dendritic spine synapses and depressive-like behavior and explore the phagocytic function of microglia in the BLA. We found that tumor-bearing mice experienced postoperative pain-related depression, and their BLAs exhibited reactive microglia, as well as phagocytic synapses. The microglial inhibitor minocycline effectively mitigated depressive behavior, synaptic damage, and the phagocytic function of microglia. Our study implicates microglia-mediated synaptic loss in the BLA may act as the pathological basis of depressive-like behavior in bone cancer pain model.
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Complexo Nuclear Basolateral da Amígdala , Neoplasias Ósseas , Dor do Câncer , Animais , Neoplasias Ósseas/complicações , Camundongos , Microglia , Minociclina/farmacologia , Qualidade de VidaRESUMO
Sleep deprivation,the process and state of partial or complete lack of normal sleep caused by various factors,is prevalent at present.Seriously impairing the physical and mental health,sleep deprivation has become a public health problem that cannot be ignored.Studies have demonstrated that blood-brain barrier impairment is the key pathophysiological process of a variety of neurological diseases.Although clinical and basic studies have suggested that sleep deprivation can induce blood-brain barrier impairment,the underlying mechanisms remain to be elucidated.This review summarizes the advances in the mechanisms of blood-brain barrier impairment induced by sleep deprivation.
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Barreira Hematoencefálica , Privação do Sono , Humanos , Privação do Sono/complicações , EncéfaloRESUMO
Cancer immunotherapies, including immune checkpoint inhibitor (ICI)-based therapies, have revolutionized cancer treatment. However, patient response to ICIs is highly variable, necessitating the development of methods to quickly assess efficacy. In this study, an array of miniaturized bioreactors has been developed to model tumor-immune interactions. This immunotherapeutic high-throughput observation chamber (iHOC) is designed to test the effect of anti-PD-1 antibodies on cancer spheroid (MDA-MB-231, PD-L1+) and T cell (Jurkat) interactions. This system facilitates facile monitoring of T cell inhibition and reactivation using metrics such as tumor infiltration and interleukin-2 (IL-2) secretion. Status of the tumor-immune interactions can be easily captured within the iHOC by measuring IL-2 concentration using a micropillar array where sensitive, quantitative detection is allowed after antibody coating on the surface of array. The iHOC is a platform that can be used to model and monitor cancer-immune interactions in response to immunotherapy in a high-throughput manner.
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Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Imunoterapia , Dispositivos Lab-On-A-Chip , Neoplasias/tratamento farmacológicoRESUMO
The extraction of interstitial fluid (ISF) from skin using microneedles (MNs) has attracted growing interest in recent years due to its potential for minimally invasive diagnostics and biosensors. ISF collection by absorption into a hydrogel MN patch is a promising way that requires the materials to have outstanding swelling ability. Here, a gelatin methacryloyl (GelMA) patch is developed with an 11 × 11 array of MNs for minimally invasive sampling of ISF. The properties of the patch can be tuned by altering the concentration of the GelMA prepolymer and the crosslinking time; patches are created with swelling ratios between 293% and 423% and compressive moduli between 3.34 MPa and 7.23 MPa. The optimized GelMA MN patch demonstrates efficient extraction of ISF. Furthermore, it efficiently and quantitatively detects glucose and vancomycin in ISF in an in vivo study. This minimally invasive approach of extracting ISF with a GelMA MN patch has the potential to complement blood sampling for the monitoring of target molecules from patients.
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Líquido Extracelular , Gelatina , Hidrogéis , Agulhas/classificação , Pele , HumanosRESUMO
To investigate the inhibitory effects of chlorogenic acid on pulmonary fibrosis and the internal mechanisms in vivo and in vitro. 30 male BALB/C mice were randomized into 5 groups: control group, pulmonary fibrosis model group, low, middle and high dose of chlorogenic acid groups. Mice in pulmonary fibrosis model group were administered 5.0 mg/kg bleomycin with intracheal instillation and mice in 3 chlorogenic acid groups were treated with chlorogenic acid every day for 28 days after bleomycin administration. Lung tissue histology was observed using HE staining. Primary pulmonary fibroblasts were isolated and cultured. The expressions of fibrosis related factors (α-SMA and collagen I), as well as ER stress markers (CHOP and GRP78) were determined by both real-time PCR assay and Western blotting, while the expressions of other ER stress signaling pathway factors PERK, IRE-1, ATF-6 and protein levels of caspase-12, caspase-9, caspase-3, PARP were determined by Western blotting. RLE-6TN cell line induced by TGF-ß1 was also used to verify the amelioration effects in vitro study. In both in vivo and in vitro studies, TUNEL staining was used to evaluate cell apoptosis. Expressions of collagen I, α-SMA, GRP78, and CHOP were significantly inhibited by chlorogenic acid in dose-dependent manner. Similarly, decreasing levels of cleaved caspase-12, caspase-9, caspase-3 and increasing level of uncleaved PARP were observed in chlorogenic acid groups compared with those in the fibrosis group both in vivo and in vitro. Chlorogenic acid could also significantly down-regulate the level of phosphorylation of PERK and cleaved ATF-6 in vivo study. Moreover, MTT assay demonstrated chlorogenic acid could enhance proliferation of RLE-6TN cells induced by TGFß1 in vitro. And the apoptosis assays indicated that chlorogenic acid could significantly inhibit cell apoptosis both in vivo and in vitro studies. Chlorogenic acid could inhibit the pulmonary fibrosis through endoplasmic reticulum stress inhibition in vivo and in vitro.
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Bleomicina , Ácido Clorogênico/farmacologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Células Cultivadas , Chaperona BiP do Retículo Endoplasmático , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
We have successfully synthesized SiO2@(Y0.5Gd0.45Eu0.05)2O3 nanocomposites as a potential dual-modality nanoprobe for molecular imaging in vitro. However, their immunotoxicity assessment in vivo remains unknown. In this article, the in vitro biocompatibility of our dual-modality nanoprobes was assayed in terms of cell viability and apoptosis. In vivo immunotoxicity was investigated by monitoring the generation of reactive oxygen species (ROS), cluster of differentiation (CD) markers and cytokines in Balb/c mice. The data show that the in vitro biocompatibility was satisfactory. In addition, the immunotoxicity data revealed there are no significant changes in the expression levels of CD11b and CD71 between the nanoprobe group and the Gd in a diethylenetriaminepentaacetic acid (DTPA) chelator (Gd-DTPA) group 24 h after injection in Balb/c mice (p>0.05). Importantly, there are significant differences in the expression levels of CD206 and CD25 as well as the secretion of IL-4 and the generation of ROS 24 h after injection (p<0.05). Transmission electron microscopy (TEM) images showed that few nanoprobes were localized in the phagosomes of liver and lung. In conclusion, the toxic effects of our nanoprobes may mainly result from the aggregation of particles in phagosomes. This accumulation may damage the microstructure of the cells and generate oxidative stress reactions that further stimulate the immune response. Therefore, it is important to evaluate the in vivo immunotoxicity of these rare earth-based biomaterials at the molecular level before molecular imaging in vivo.
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Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/toxicidade , Nanocompostos/toxicidade , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Animais , Materiais Biocompatíveis/química , Linhagem Celular , Európio/química , Európio/metabolismo , Európio/toxicidade , Gadolínio/química , Gadolínio/metabolismo , Gadolínio/toxicidade , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/toxicidade , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Lectinas Tipo C/metabolismo , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Compostos Organometálicos/toxicidade , Óxidos/química , Óxidos/metabolismo , Óxidos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/metabolismo , Dióxido de Silício/metabolismo , Distribuição Tecidual , Ítrio/química , Ítrio/metabolismo , Ítrio/toxicidadeRESUMO
RATIONALE: Traumatic bronchial rupture in infants usually necessitates surgical intervention, with few reports documenting instances of multiple cardiac arrests occurring during surgery under conditions of severe hypoxemia. PATIENT CONCERNS: A 3-year-old boy after trauma presented with severe hypoxemia for 2 days and was urgently transferred to the operating room for surgery, 6 episodes of cardiac arrest happend during surgery. DIAGNOSES: The baby was diagnosed with bronchial rupture based on the history of trauma, clinica manifestations, and intraoperative findings. INTERVENTIONS: Intrathoracic cardiac compression and intravenous adrenaline were administrated. OUTCOMES: The normal sinus rhythm of the heart was successfully restored within 1 minute on each occasion, facilitating the smooth completion of the surgical procedure. By the end of surgery, SpO2 levels had rebounded to 95% and remained stable. LESSONS: Inadequate management of bronchial ruptures in infants frequently coincides with severe hypoxemia, necessitating immediate surgical intervention. Prompt identification and management of cardiac arrest by anesthetists during surgery is imperative to reduce mortality.
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Epinefrina , Parada Cardíaca , Masculino , Lactente , Humanos , Pré-Escolar , Parada Cardíaca/etiologia , Ruptura/cirurgia , Ruptura/complicações , Hipóxia/complicações , Salas CirúrgicasRESUMO
Preoperative stress has been recognized as an independent risk factor for chronic postsurgical pain (CPSP). However, the underlying mechanisms of CPSP influenced by preoperative stress remain elusive. Previous studies indicated that excessive stress could induce disruption of the blood-spinal cord barrier (BSCB). We wondered whether and how BSCB involves in CPSP by using a single prolonged stress (SPS) combining plantar incision model in male rats to mimic preoperative stress-related postsurgical pain. Here, we observed that preoperative SPS-exposed rats exhibited relentless incisional pain, which was accompanied by impairment of BSCB and persistent elevation of serum IL-6. Intraperitoneal injections of Tocilizumab (an IL-6 receptor monoclonal antibody) not only mitigated BSCB breakdown but also alleviated pain behaviors. In addition, intervening ß3-adrenoceptor (ADRB3) signaling in brown adipocytes by SR59230a (a specific ADRB3 antagonist) treatment or removal of brown adipose tissues could effectively decrease serum IL-6 levels, ameliorate BSCB disruption, and alleviate incisional pain. Further results displayed that SI-exposed rats also showed markedly spinal microglia activation. And exogenous His-tagged IL-6 could pass through the disrupted BSCB, which might contribute to microglia activation. Injection of SR59230a or ablation of brown adipose tissues could effectively reduce the activation of spinal microglia. Thus, our findings suggest that serum IL-6 induced by brown adipocyte ADRB3 signaling contributed to BSCB disruption and spinal microglia activation, which might be involved in preoperative stress mediated CPSP. This work indicates a promising treatment strategy for preoperative stress induced CPSP by blocking ADRB3.
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Adipócitos Marrons , Propanolaminas , Traumatismos da Medula Espinal , Animais , Masculino , Ratos , Adipócitos Marrons/metabolismo , Interleucina-6/metabolismo , Dor Pós-Operatória , Ratos Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Medula Espinal , Traumatismos da Medula Espinal/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMO
Continuous glucose monitoring systems (CGMs) are critical toward closed-loop diabetes management. The field's progress urges next-generation CGMs with enhanced antinoise ability, reliability, and wearability. Here, we propose a coin-sized, fully integrated, and wearable CGM, achieved by holistically synergizing state-of-the-art interdisciplinary technologies of biosensors, minimally invasive tools, and hydrogels. The proposed CGM consists of three major parts: (i) an emerging biochemical signal amplifier, the organic electrochemical transistor (OECT), improving the signal-to-noise ratio (SNR) beyond traditional electrochemical sensors; (ii) a microneedle array to facilitate subcutaneous glucose sampling with minimized pain; and (iii) a soft hydrogel to stabilize the skin-device interface. Compared to conventional CGMs, the OECT-CGM offers a high antinoise ability, tunable sensitivity and resolution, and comfort wearability, enabling personalized glucose sensing for future precision diabetes health care. Last, we discuss how OECT technology can help push the limit of detection of current wearable electrochemical biosensors, especially when operating in complicated conditions.
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Técnicas Biossensoriais , Diabetes Mellitus , Humanos , Automonitorização da Glicemia , Glicemia , Monitoramento Contínuo da Glicose , Reprodutibilidade dos Testes , Glucose , Diabetes Mellitus/diagnósticoRESUMO
OBJECT: The purpose of this study was to determine the incidence and outcomes of intraprocedural rupture (IPR) during endovascular coil embolization of intracranial aneurysm at a single center and to explore the technical reasons and put forward corresponding preventive measures for the feared event to serve as references for other endovascular specialists. METHODS: The aneurysm database in our series was retrospectively reviewed. From April 2005 to March 2009, 176 aneurysms were consecutively treated with coils in 161 patients and IPR occurred in 12 patients. The medical records for the 12 patients were seriously examined. RESULTS: Of the 12 patients (6.8 %), four were men and eight were women with a median age of 56 years. An emergency "rescue clipping" of the lesion was carried out in two patients, parent artery occlusion was performed in two cases, endovascular treatment was terminated in one case and aneurysm coiling was rapidly completed in the remaining seven cases. Complete occlusion was achieved in nine aneurysms and incomplete occlusion in one. One patient died, yielding a mortality rate of 8.3 %. The follow-up duration was 6-30 months (median 14 months) and the mean Glasgow Outcome Scale score at the last follow-up examination was 4.3. CONCLUSIONS: The rate of IPR during endovascular coiling of intracranial aneurysms is quite low and the clinical outcome from this complication need not be catastrophic if managed appropriately. Improved operation skill and practical experience exchange among neuroradiologists are essential to lower the incidence or better patient prognoses.
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Aneurisma Roto/terapia , Embolização Terapêutica/métodos , Aneurisma Intracraniano/terapia , Adulto , Idoso , Aneurisma Roto/etiologia , Artérias Cerebrais/cirurgia , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/mortalidade , Feminino , Humanos , Aneurisma Intracraniano/complicações , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Instrumentos Cirúrgicos , Resultado do TratamentoRESUMO
As a minimally invasive drug delivery platform, microneedles (MNs) overcome many drawbacks of the conventional transdermal drug delivery systems, therefore are favorable in biomedical applications. Microneedles with a combined burst and sustained release profile and maintained therapeutic molecular bioactivity could further broaden its applications as therapeutics. Here, we developed a double-network microneedles (DN MNs) based on gelatin methacrylate and acellular neural matrix (GelMA-ACNM). ACNM could function as an early drug release matrix, whereas the addition of GelMA facilitates sustained drug release. In particular, the double-network microneedles comprising GelMA-ACNM hydrogel has distinctive biological features in maintaining drug activity to meet the needs of application in treating different diseases. In this study, we prepared the double-network microneedles and evaluated its morphology, mechanical properties, drug release properties and biocompatibility, which shows great potential for delivery of therapeutic molecules that needs different release profiles in transdermal treatment.
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Ceftolozane/tazobactam (C/T) is approved in several countries to treat complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. There is a paucity of pharmacokinetics and safety data for C/T in Chinese participants. This study evaluated the pharmacokinetics, safety, and tolerability of C/T in 12 healthy Chinese participants after three single administrations of increasing doses (0.75 g, 1.5 g, and 3 g) and multiple administrations of 1.5 g C/T every 8 h for 3 days. After single doses, maximum concentrations of ceftolozane and tazobactam were reached by the end of the 1-h infusion and declined in a biphasic manner thereafter, with mean half-lives of 1.9-2.2 h and 0.74-0.95 h, respectively. Volume of distribution (Vd) and renal clearance (CL) were consistent across the three single-dose levels for ceftolozane (Vd, 15.8-19.5 L; CL, 5.68-6.09 L/h) and tazobactam (Vd, 23.3-28.6 L; CL, 20.8-23.5 L/h). Area under the concentration-time curve (AUC) extrapolated to infinity (ceftolozane, 88.1-328 hâµg/mL; tazobactam, 10.7-48.0 hâµg/mL) increased in a dose-dependent manner. After multiple doses over 3 days, AUC from time 0 to 8 h, and concentration at the end of infusion were similar to single-dose measurements (geometric mean ratios, 0.87-1.01 for both drugs). C/T was well tolerated, with no serious adverse events or discontinuations reported; all adverse events were mild. The pharmacokinetics and safety/tolerability of C/T in healthy Chinese participants was comparable to that in previous studies in other populations, supporting the use of C/T for the treatment of Chinese patients.
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Antibacterianos , Cefalosporinas , População do Leste Asiático , Tazobactam , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Cefalosporinas/administração & dosagem , Cefalosporinas/farmacocinéticaRESUMO
BACKGROUND AND OBJECTIVE: PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals. METHODS: Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed. RESULTS: Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials. CONCLUSIONS: PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.
Assuntos
População do Leste Asiático , Combinação Lidocaína e Prilocaína , Feminino , Humanos , Masculino , Método Duplo-Cego , Voluntários Saudáveis , Lidocaína/efeitos adversos , Combinação Lidocaína e Prilocaína/administração & dosagem , Combinação Lidocaína e Prilocaína/efeitos adversos , Combinação Lidocaína e Prilocaína/sangue , Combinação Lidocaína e Prilocaína/farmacocinética , Combinação Lidocaína e Prilocaína/uso terapêutico , Prilocaína , Ejaculação Precoce/sangue , Ejaculação Precoce/tratamento farmacológico , Administração Tópica , Pênis , Vagina , Colo do ÚteroRESUMO
OBJECTIVE: To assess the clinical applicability of focused transthoracic echocardiography (TTE) in intensive care unit (ICU) performed by intensivists and its impacts on clinical managements. METHODS: After 12-hour tutorials and initial cardiac clinical assessments, intensivists performed a focused TTE (2-4 views of 2D, without Doppler or M mode) examination in 88 patients to assess left ventricular function and left ventricular volume status, and rule out local ventricular wall motion abnormalities and significant pericardial effusions. Each investigation was immediately reviewed by an echocardiograph to determine the technical quality of the TTE and the accuracy of the intensivist's interpretation. RESULTS: Intensivists successfully performed a diagnostic focused TTE in 86 patients (97.7%) and interpreted correctly in 75 patients (85.2%). Management including fluid treatment, inotropic agent and vasoactive agent in 22.7% of patients were changed directly based on the focused TTE, 45.5% of patients were provided with valuable information, while 31.8% of them with non-valuable information. The mean focused TTE acquisition time of the intensivist was (11.2±5.2) minutes. CONCLUSIONS: After a brief standard training in using echocardiographic system, intensivists can successfully performed and correctly interpreted a focused TTE for critically ill patients. Our study demonstrates that new information can be provided by focused TTE, which can alter management in a significant number of patients. The present study supports incorporating bedside goal-directed, focused TTE into intensivists' training programs in China.
Assuntos
Ecocardiografia , Unidades de Terapia Intensiva , Sistemas Automatizados de Assistência Junto ao Leito , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Ecocardiografia Doppler , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Médicos , Estudos ProspectivosRESUMO
This study aims to explore the regulatory effect of S-ketamine on the mechanical allodynia, anxiety-like behaviors and microglia activation in adult male rats exposed to an animal model of post-traumatic stress disorder (PTSD). The rat PTSD model was established by the exposure to single-prolonged stress (SPS), and 1 day later, rats were intraperitoneally injected with 5 mg/kg S-ketamine or normal saline, respectively. Paw withdrawal mechanical threshold was measured 2 days before, and 1, 3, 5, 7, 10, 14, 21 and 28 days after injection to assess mechanical allodynia in the SPS-exposed rats. For anxiety-like behaviors, the open field test and elevated plus maze test were performed at 7 and 14 days after S-ketamine treatment in the SPS-exposed rats, respectively. SPS-induced rats presented pronounced mechanical allodynia and anxiety-like behaviors, which were alleviated by S-ketamine treatment. After behavioral tests, rats were sacrificed for collecting the anterior cingulate cortex (ACC), prefrontal cortex (PFC), dorsal striatum, and periaqueductal gray (PAG). Protein levels of TNF-α, IL-1ß, p-NF-κB, and NF-κB in brain regions were examined by Western blot. In addition, microglia activation in each brain region was determined by immunofluorescence staining of the microglia-specific biomarker Iba-1. Interestingly, pro-inflammatory cytokines were significantly upregulated in the dorsal striatum and PAG, rather than ACC and PFC. Activated microglia was observed in the dorsal striatum and PAG as well, and upregulated p-NF-κB was detected in the dorsal striatum. Inflammatory response, phosphorylation of NF-κB and microglia activation in certain brain regions were significantly alleviated by S-ketamine treatment. Collectively, S-ketamine is a promising drug in alleviating mechanical allodynia, anxiety-like behaviors, and pro-inflammatory responses in discrete brain regions in a model of PTSD.
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Post-traumatic stress disorder (PTSD)-associated cognitive dysfunction significantly disturbs patients' quality of life and will to live. However, its underlying mechanism is as yet unknown. Recent researches indicate that blood-brain barrier (BBB) breakdown is responsible for early cognitive dysfunction. Microglia might participate in remodeling of BBB-associated tight junction and regulating BBB integrity. Nevertheless, it is unclear whether microglia activation and BBB injury involve in PTSD-associated cognitive dysfunction. Hence, we established an animal model of PTSD, single prolonged stress (SPS), and investigated permeability changes in the hippocampus and further explored the effects of microglia on BBB remodeling. The Y maze was used to assess the changes of cognitive function. The sodium fluorescein (NaFlu) assay and western blotting analysis were employed to detect BBB integrity changes. Minocycline was administered to inhibit microglial activation. Immunofluorescence stains were used to assess the activation states in microglia. The results showed that SPS-exposed rats exhibited poorer cognitive performance, higher passage of NaFlu, and lower expression of tight junction proteins (occludin and claudin 5) in the hippocampus on the day after SPS, but no difference on the 7th day. Inhibition of microglial activation by minocycline attenuated poor cognitive performance and BBB impairment including the extravasation of NaFlu and protein levels of the tight junction. Taken together, the present study indicates that BBB impairment may underlie the shared pathological basis of PTSD and cognitive dysfunction. Microglial activation may involve in BBB remodeling at the early stage of SPS.
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Disfunção Cognitiva , Transtornos de Estresse Pós-Traumáticos , Animais , Barreira Hematoencefálica , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Hipocampo , Humanos , Microglia , Minociclina/farmacologia , Qualidade de Vida , RatosRESUMO
Neuroinflammation following peripheral surgery is a pivotal pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the key site of inflammation-mediated neural damage remains unclear. Impaired mitochondrial function is a vital feature of degenerated neurons. Dynamin-related protein 1 (DRP1), a crucial regulator of mitochondrial dynamics, has been shown to play an essential role in synapse formation. Here, we designed experiments to assess whether Drp1-regulated mitochondrial dynamics and function are involved in the pathological processes of POCD and elucidate its relationship with neuroinflammation. Aged mice were subjected to experimental laparotomy under isoflurane anesthesia. Primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF). We found an increase in Drp1 activation as well as mitochondrial fragmentation both in the hippocampus of mice after surgery and primary neurons after TNF exposure. Pretreatment with Mdivi-1, a Drp1 specific inhibitor, reduced this mitochondrial fragmentation. Drp1 knockdown with small interfering RNA blocked TNF-induced mitochondrial fragmentation in SH-SY5Y cells. However, the application of Mdivi-1 exhibited a negative impact on mitochondrial function and neurite growth in primary neurons. Calcineurin activity was increased in primary neurons after TNF exposure and contributed to the Drp1 activation. The calcineurin inhibitor FK506 exhibited a Drp1-independent function that mitigated mitochondrial dysfunction. Finally, we found that FK506 pretreatment ameliorated the neurite growth in neurons treated with TNF and the learning ability of mice after surgery. Overall, our research indicated a crucial role of mitochondrial function in the pathological processes of POCD, and neuronal metabolic modulation may represent a novel and important target for POCD.
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Complicações Cognitivas Pós-Operatórias , Animais , Dinaminas/genética , Dinaminas/metabolismo , Hipocampo/metabolismo , Camundongos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Doenças NeuroinflamatóriasRESUMO
Systemic administration of immune checkpoint blockade agents can activate the anticancer activity of immune cells; however, the response varies from patient to patient and presents potential off-target toxicities. Local administration of immune checkpoint inhibitors (ICIs) can maximize therapeutic efficacies while reducing side effects. This study demonstrates a minimally invasive strategy to locally deliver anti-programmed cell death protein 1 (anti-PD-1) with shear-thinning biomaterials (STBs). ICI can be injected into tumors when loaded in STBs (STB-ICI) composed of gelatin and silicate nanoplatelets (Laponite). The release of ICI from STB was mainly affected by the Laponite percentage in STBs and pH of the local microenvironment. Low Laponite content and acidic pH can induce ICI release. In a murine melanoma model, the injection of STB-ICI significantly reduced tumor growth and increased CD8+ T cell level in peripheral blood. STB-ICI also induced increased levels of tumor-infiltrating CD4+ helper T cells, CD8+ cytotoxic T cells, and tumor death. The STB-based minimally invasive strategy provides a simple and efficient approach to deliver ICIs locally.
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Inibidores de Checkpoint Imunológico , Melanoma , Animais , Materiais Biocompatíveis/farmacologia , Linfócitos T CD8-Positivos , Humanos , Camundongos , Linfócitos T Citotóxicos , Microambiente TumoralRESUMO
Electrical stimulation can facilitate wound healing with high efficiency and limited side effects. However, current electrical stimulation devices have poor conformability with wounds due to their bulky nature and the rigidity of electrodes utilized. Here, a flexible electrical patch (ePatch) made with conductive hydrogel as electrodes to improve wound management was reported. The conductive hydrogel was synthesized using silver nanowire (AgNW) and methacrylated alginate (MAA), with the former chosen as the electrode material considering its antibacterial properties, and the latter used due to its clinical suitability in wound healing. The composition of the hydrogel was optimized to enable printing on medical-grade patches for personalized wound treatment. The ePatch was shown to promote re-epithelization, enhance angiogenesis, mediate immune response, and prevent infection development in the wound microenvironment. In vitro studies indicated an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to electrical stimulation. An in vivo study in the Sprague-Dawley rat model revealed a rapid wound closure within 7 days compared to 20 days of usual healing process in rodents.