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PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.
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This article aimed to study the global consensus problem of high-order multi-agent systems with a saturation constraint and communication delay. Among them, all agents are described by discrete-time systems. Firstly, in order to compensate for the communication delay, a networked predictive control method is adopted and a predictive-based control protocol is designed. Secondly, for the neutrally stable agent model, leaderless and leader-following situations are considered and it is proven that, under a fixed communication topology, adopting the prediction-based control protocol makes the multi-agent systems with saturation constraint and communication delay achieve a global consensus. Finally, the results are illustrated via numerical simulation.
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Cadmium ion (Cd2+) is a common environmental pollutant with high biotoxicity. Interestingly, the Cd2+ biotoxicity can be alleviated by the coexisting selenite (SeO32-), which induces the formation of cadmium selenide-rich nanoparticles (CdSe NPs) under the function of thiol-capping peptides. However, the detailed biochemical mechanisms by which Cd and Se are synergistically transformed into CdSe NPs in living organisms remain unclear so far. Here, we shed light on the molecular basis of such biotransformation processes in Caenorhabditis elegans by focusing on the roles of several key thiol-capping peptides. By monitoring the compositional and structural changes of the Cd and Se species and the genetic-level responses of nematodes, we revealed the specific roles of glutathione (GSH) and phytochelatins (PCs) in mediating the CdSe NP formation. With the aid of in vitro bioassembly assay and density functional theory calculations, the detailed Cd-Se interaction pathways were further deciphered: the ingested Cd binds predominantly to GSH and PCs in sequence, then further interacts with selenocysteine to form tetrahedral-structured PC2-Cd2-Sec2 complex, and ultimately grows into CdSe NPs. This work provides molecular-level insights into the Cd-Se interaction in C. elegans and lays a basis for controlling the ecological and health risks of heavy metals in polluted environment.
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Cádmio , Selênio , Animais , Biotransformação , Caenorhabditis elegans , Glutationa/metabolismo , Fitoquelatinas/metabolismo , Compostos de SulfidrilaRESUMO
OBJECTIVES: Subbranches of Y-chromosome haplogroup C2a-L1373 are founding paternal lineages in northern Asia and Native American populations. Our objective was to investigate C2a-L1373 differentiation in northern Asia and its implications for Native American origins. MATERIALS AND METHODS: Sequences of rare subbranches (n = 43) and ancient individuals (n = 37) of C2a-L1373 (including P39 and MPB373), were used to construct phylogenetic trees with age estimation by BEAST software. RESULTS: C2a-L1373 expanded rapidly approximately 17.7,000-14.3,000 years ago (kya) after the last glacial maximum (LGM), generating numerous sublineages which became founding paternal lineages of modern northern Asian and Native American populations (C2a-P39 and C2a-MPB373). The divergence pattern supports possible initiation of differentiation in low latitude regions of northern Asia and northward diffusion after the LGM. There is a substantial gap between the divergence times of C2a-MPB373 (approximately 22.4 or 17.7 kya) and C2a-P39 (approximately 14.3 kya), indicating two possible migration waves. DISCUSSION: We discussed the decreasing time interval of "Beringian standstill" (2.5 ky or smaller) and its reduced significance. We also discussed the multiple possibilities for the peopling of the Americas: the "Long-term Beringian standstill model," the "Short-term Beringian standstill model," and the "Multiple waves of migration model." Our results support the argument from ancient DNA analyses that the direct ancestor group of Native Americans is an admixture of "Ancient Northern Siberians" and Paleolithic communities from the Amur region, which appeared during the post-LGM era, rather than ancient populations in greater Beringia, or an adjacent region, before the LGM.
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Indígena Americano ou Nativo do Alasca , Povo Asiático , Cromossomos Humanos Y/genética , Migração Humana/história , Antropologia Física , Ásia Setentrional , Povo Asiático/classificação , Povo Asiático/genética , Povo Asiático/história , História Antiga , Humanos , Masculino , América do Norte , Filogenia , Indígena Americano ou Nativo do Alasca/classificação , Indígena Americano ou Nativo do Alasca/genética , Indígena Americano ou Nativo do Alasca/históriaRESUMO
Epilepsy is the most common childhood neurologic disorder. Status epilepticus (SE), which refers to continuous epileptic seizures, occurs more frequently in children than in adults, and approximately 40-50% of all cases occur in children under 2 years of age. Conventional antiepileptic drugs currently used in clinical practice have a number of adverse side effects. Drug-resistant epilepsy (DRE) can progressively develop in children with persistent SE, necessitating the development of novel therapeutic drugs. During SE, the persistent activation of neurons leads to decreased glutamate clearance with corresponding glutamate accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Our previous study demonstrated that after developmental seizures in rats, E-64d exerts a neuroprotective effect on the seizure-induced brain damage by modulating lipid metabolism enzymes, especially ApoE and ApoJ/clusterin. In this study, we investigated the impact and mechanisms of E-64d administration on neuronal excitotoxicity. To test our hypothesis that E-64d confers neuroprotective effects by regulating autophagy and mitochondrial pathway activity, we simulated neuronal excitotoxicity in vitro using an immortalized hippocampal neuron cell line (HT22). We found that E-64d improved cell viability while reducing oxidative stress and neuronal apoptosis. In addition, E-64d treatment regulated mitochondrial pathway activity and inhibited chaperone-mediated autophagy in HT22 cells. Our findings indicate that E-64d may alleviate glutamate-induced damage via regulation of mitochondrial fission and apoptosis, as well as inhibition of chaperone-mediated autophagy. Thus, E-64d may be a promising therapeutic treatment for hippocampal injury associated with SE.
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Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Glutâmico/toxicidade , Hipocampo/efeitos dos fármacos , Leucina/análogos & derivados , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Hipocampo/fisiologia , Leucina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologiaRESUMO
Membrane bioreactor (MBR) technology has been paid extensive attention for wastewater treatment because of its advantages of high effluent quality and minimized occupation space and sludge production. However, the membrane fouling is always an inevitable problem, which causes high operation and maintenance costs and prevents the wide use of MBR technology. The membrane biofouling is the most complicated and has relatively slow progress among all types of fouling. In recent years, many membrane biofouling control methods have been developed. Different from the physical or chemical methods, the biological-based strategies are not only more effective for membrane biofouling control, but also milder and more environment-friendly and, therefore, have been increasingly employed. This paper mainly focuses on the mechanism, unique advantages and development of biological-based control strategies for MBR membrane biofouling such as quorum quenching, uncoupling, flocculants and so on. The paper summarizes the up-to-date development of membrane biofouling control strategies, emphasizes the advantages and promising potential of biological-based ones, and points out the direction for future studies.
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Incrustação Biológica , Purificação da Água , Incrustação Biológica/prevenção & controle , Reatores Biológicos , Membranas Artificiais , Esgotos , Águas ResiduáriasRESUMO
Antagonism between heavy metal and selenium (Se) could significantly affect their biotoxicity, but little is known about the mechanisms underlying such microbial-mediated antagonistic processes as well as the formed products. In this work, we examined the cadmium (Cd)-Se interactions and their fates in Caenorhabditis elegans through in vivo and in vitro analysis and elucidated the machinery of Se-stimulated Cd detoxification. Although the Se introduction induced up to 3-fold higher bioaccumulation of Cd in C. elegans than the Cd-only group, the nematode viability remained at a similar level to the Cd-only group. The relatively lower level of reactive oxygen species in the Se & Cd group confirms a significantly enhanced Cd detoxification by Se. The Cd-Se interaction, mediated by multiple thiols, including glutathione and phytochelatin, resulted in the formation of less toxic cadmium selenide (CdSe)/cadmium sulfide (CdS) nanoparticles. The CdSe/CdS nanoparticles were mainly distributed in the pharynx and intestine of the nematodes, and continuously excreted from the body, which also benefitted the C. elegans survival. Our findings shed new light on the microbial-mediated Cd-Se interactions and may facilitate an improved understanding and control of Cd biotoxicity in complicated coexposure environments.
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Nanopartículas , Selênio , Animais , Cádmio , Caenorhabditis elegans , Compostos de SulfidrilaRESUMO
Quantum dots (QDs) are recognized as the excellent fluorescence and photochemical materials to be applied in bioimaging, biomedical, and solar cell fields. Biosynthesized QDs (bio-QDs) have attracted attention due to their simple, eco-friendly, and excellent biocompatible traits. Moreover, bio-QDs could not be replaced by chemically fabricated QDs in many fields. Bio-QDs synthesized by different microorganisms have diverse characteristics. In this work, the biosynthesis of QDs by Tetrahymena pyriformis, a typical protozoa in aquatic environments, was achieved for the first time. The synthesized materials by T. pyriformis emitted yellow fluorescence and had an average diameter of 8.27 ± 0.77 nm. Spectral characterization results demonstrated that the synthesized QDs were CdS1-XSeX. Meanwhile, the fluorescence intensities of the synthesized bio-QDs showed a linear relationship with Cd2+ dosage ranging from 20 to 80 µM. The fluorescence enhancement of the synthesized QDs was highly selective to Cd2+ compared to other metal ions. The bio-QDs were demonstrated to have a great potential to be applied for Cd2+ detection. This work provides valuable information about the transformation of heavy metal ions in protozoan and is useful to accelerate the applications of the synthesized QDs.
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Cádmio/análise , Engenharia Metabólica/métodos , Redes e Vias Metabólicas/genética , Pontos Quânticos/metabolismo , Tetrahymena pyriformis/metabolismo , Cátions Bivalentes/análise , Fluorescência , Química Verde/métodos , Metais Pesados/análise , Pontos Quânticos/química , Análise Espectral , Tetrahymena pyriformis/genéticaRESUMO
Purpose/Aim of the study In this study, we sought to observe the effects of Ca2+/calmodulin-dependent protein kinase II (CaMKII) on neuropathic pain and fear memory in a rat model of chronic constriction injury (CCI). Materials and methods Rats were randomly divided into the Sham, Control, CCI and m-AIP groups. In the m-AIP group, an intrathecal injection of m-AIP, the specific antagonist of CaMKII, was given either pretreatment or posttreatment in rats. Mechanical allodynia and thermal hyperalgesia tests were used to test pain behavior, and the passive avoidance test was used to measure fear memory in rats. Results The right side of hippocampus tissues were taken at varying time points. The expression levels of CaMKII-α, pCaMKII-α, CaMKII-ß, pCaMKII-ß, NR2A, pNR2A, NR2B and pNR2B were detected by Western blot analysis. Significant pain behaviors and impaired cognitive function were shown after CCI surgery, accompanied by the upregulation of proteins in the hippocampus. Pretreatment with m-AIP appeared to provide a temporary improvement in pain and fear memory and decreased the expression of the above proteins in the hippocampus seven days after surgery. Furthermore, postoperative treatment with m-AIP provided relief for pain behavior and protein expression but did not affect fear memory. Conclusions These data suggested that CaMKII played an important role in the crosstalk between neuropathic pain and fear memory, indicating that CaMKII may be a potential therapeutic target for neuropathic pain treatment.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Neuralgia/metabolismo , Animais , Constrição , Hiperalgesia/metabolismo , Masculino , Neuralgia/psicologia , Fosforilação , Ratos Sprague-Dawley , Nervo Isquiático/lesõesRESUMO
Reduction of calcaneal fractures via a small incision approach at the sinus tarsi is technically difficult. This study was undertaken to determine if preoperative virtual simulation based on computed tomographic data improves reduction and reduces complications. Fifty-five patients with calcaneal fractures were treated via the sinus tarsi approach with minimally invasive plates between February 2013 and December 2015. DICOM files obtained from computed tomographic imaging preoperatively were imported into Superimage software, and virtual surgery was performed. Preoperative planning time, operative time, and complications were recorded. Clinical function was analyzed with radiology and with the American Orthopaedic Foot and Ankle Society and visual analogue scale scores. As a result, preoperative planning time was 30.7 ± 4.1 minutes, which increased with the severity of the fracture (Sanders III vs Sanders II: 34.2 ± 2.5 minutes vs 27.8 ± 2.7 minutes), which was in line with the real surgery, with a mean operative time of 86.7 ± 4.5 minutes (Sanders III vs Sanders II: 89.5 ± 2.7 minutes vs 84.3 ± 4.4 minutes). Radiologic results indicated that the calcaneal width, length, height, Böhler angle, and Gissane angle were significantly corrected from preoperatively to postoperatively. After a mean follow-up of 21.5 ± 6.1 months, no complications were observed. The mean American Orthopaedic Foot and Ankle Society score was 88.7 ± 4.0, with an excellent/good rate of 94.5% (52 of 55). The mean visual analogue scale score was 0.8 ± 0.9. In conclusion, preoperative virtual simulation may be efficient to promote accomplishment of sinus tarsi surgery, and this step may help improve outcomes for calcaneal fractures.
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Calcâneo/lesões , Simulação por Computador , Fixação Interna de Fraturas/métodos , Fraturas Intra-Articulares/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Calcâneo/cirurgia , China , Estudos de Coortes , Feminino , Seguimentos , Traumatismos do Pé/diagnóstico por imagem , Traumatismos do Pé/cirurgia , Consolidação da Fratura/fisiologia , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/cirurgia , Humanos , Imageamento Tridimensional , Escala de Gravidade do Ferimento , Fraturas Intra-Articulares/cirurgia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Medição de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Chronic social defeat stress induces depression and anxiety-like behaviors in rodents and also responsible for differentiating defeated animals into stress susceptible and resilient groups. The present study investigated the effects of social defeat stress on a variety of behavioral parameters like social behavior, spatial learning and memory and anxiety like behaviors. Additionally, the levels of various dopaminergic markers, including the long and short form of the D2 receptor, and total and phosphorylated dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32, and proteins involved in intracellular trafficking were assessed in several key brain regions in young adult mice. METHODS: Mouse model of chronic social defeat was established by resident-intruder paradigm, and to evaluate the effect of chronic social defeat, mice were subjected to behavioral tests like spontaneous locomotor activity, elevated plus maze (EPM), social interaction and Morris water maze tests. RESULTS: Mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. The susceptible group exhibited greater decreases in time spent in the open and closed arms compared to the control group on the EPM. In the social interaction test, the susceptible group showed greater increases in submissive and neutral behaviors and greater decreases in social behaviors relative to baseline compared to the control group. Furthermore, increased expression of D2L, D2S, Rab4, and G protein-coupled receptor associated sorting protein-1 was observed in the amygdala of the susceptible group compared to the control group. CONCLUSION: These findings suggest that social defeat stress induce anxiety-like and altered social interacting behaviors, and changes in dopaminergic markers and intracellular trafficking-related proteins.
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Encéfalo/metabolismo , Relações Interpessoais , Líquido Intracelular/metabolismo , Receptores de Dopamina D2/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Animais , Aprendizagem da Esquiva/fisiologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Isoformas de Proteínas/metabolismo , Transporte Proteico/fisiologiaRESUMO
Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aß) within extracellular spaces of the brain. Aggregation of Aß has been shown to trigger oxidative stress, inflammation, and neurotoxicity resulting in cognitive dysfunction. In this study, we use models of cerebral Aß amyloidosis to investigate anti-amyloidogenic effects of scutellarin in vitro and in vivo. Our results show that scutellarin, through binding to Aß42, efficiently inhibits oligomerization as well as fibril formation and reduces Aß oligomer-induced neuronal toxicity in cell line SH-SY5Y. After nine months of treatment in APP/PS1 double-transgenic mice, scutellarin significantly improves behavior, reduces soluble and insoluble Aß levels in the brain and plasma, decreases Aß plaque associated gliosis and levels of proinflammatory cytokines TNF-α and IL-6, attenuates neuroinflammation, displays anti-amyloidogenic effects, and highlights the beneficial effects of intervention on development or progression of AD-like neuropathology.
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Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Apigenina/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Glucuronatos/administração & dosagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/sangue , Precursor de Proteína beta-Amiloide/genética , Animais , Apigenina/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Feminino , Glucuronatos/farmacologia , Humanos , Masculino , Camundongos , Resultado do TratamentoRESUMO
Background Accumulating evidence has shown that the signal from spinal brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl- cotransporter-2 plays a critical role in the process of pain hypersensitivity. The activation of alpha-7 nicotinic acetylcholine receptors could have an analgesic effect on remifentanil-induced postoperative hyperalgesia. Nevertheless, whether intrathecal administration of PNU-120596, an alpha-7 nicotinic acetylcholine receptors selective type II positive allosteric modulator, before surgery could affect the duration of remifentanil-induced postoperative hyperalgesia remains unknown, and the effects of alpha-7 nicotinic acetylcholine receptors activation on the brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl- cotransporter-2 signal in the spinal dorsal horn of rats with remifentanil-induced postoperative hyperalgesia is still enigmatic. Results We demonstrated that the brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl- cotransporter-2 signal played a critical role in the development of remifentanil-induced postoperative hyperalgesia. Intrathecal administration of PNU-120596 (8 µg/kg, 15 min before surgery) was associated with earlier signs of recovery from remifentanil-induced postoperative hyperalgesia. Simultaneously, remifentanil-induced postoperative hyperalgesia-induced K+-Cl- cotransporter-2 downregulation was partly reversed and coincided with a decreased expression of brain-derived neurotrophic factor/tyrosine receptor kinase B in the spinal dorsal horn, approximately correlating with the time course of the nociceptive behavior. Moreover, intrathecal administration of the K+-Cl- cotransporter-2 inhibitor VU0240551 significantly reduced the analgesic effect of PNU-120596 on remifentanil-induced postoperative hyperalgesia. Conclusions The activation of alpha-7 nicotinic acetylcholine receptors induced a shorter duration of remifentanil-induced postoperative hyperalgesia by restoring the brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl- cotransporter-2 signal in the spinal dorsal horn of rats, which provides new insight into treatment in clinical postoperative pain management.
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Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Piperidinas/farmacologia , Corno Dorsal da Medula Espinal/metabolismo , Simportadores/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Isoxazóis/farmacologia , Masculino , Compostos de Fenilureia/farmacologia , Ratos , Ratos Sprague-Dawley , Remifentanil , Simportadores/antagonistas & inibidores , Tiazóis/farmacologia , Tioglicolatos/farmacologia , Cotransportadores de K e Cl-RESUMO
BACKGROUND: Chronic pain is a debilitating threat to human health, and its molecular mechanism remains undefined. Previous studies have illustrated a key role of cAMP response element-binding protein (CREB) in pain regulation; CREB-regulated transcription coactivator 1 (CRTC1) and microRNA212/132 (miR212/132) are also vital in synaptic plasticity. However, little is known about the interaction among these factors in pain condition. We conducted this experiment mainly to determine the crosstalk between CREB, CRTC1, and miR212/132 in vitro. Moreover, we explored the changes in hyperalgesia on chronic constrictive injury (CCI) mouse in vivo when given CREB-related adenovirus vectors, CRTC1-related adenovirus vectors, and miR212/132-locked nucleic acid (LNA). METHODS: We cultured primary neurons in the spinal cord of mouse embryos. Exogenous glutamate was added to cultured neurons to simulate in vivo pain process. Real-time quantitative polymerase chain reaction was used to determine changes of NR2B, CRTC1, CREB, and miR212/132 at the mRNA level; Western blot was used to detect p-NR2B, p-CREB, and CRTC1 at protein level. Von Frey cilia were used to study mechanical hyperalgesia in a murine model of CCI. CREB-miR (adenovirus vector interfering CREB gene), CREB-AD (adenovirus vector overexpressing CREB gene); CRTC1-miR (adenovirus vector interfering CRTC1 gene), CRTC1-AD (adenovirus vector overexpressing CRTC1 gene), and miR212/132-LNA were injected intrathecally. RESULTS: In vitro, 100 µmol/L glutamate induced p-CREB and miR212/132-LNA. CRTC1 protein was downregulated by CREB-miR and miR212/132-LNA. CRTC1 mRNA was upregulated by CREB-AD and downregulated by CREB-miR and miR212-LNA. P-CREB was upregulated by CRTC1-AD and downregulated by miR212/132. CREB mRNA was upregulated by CRTC1-AD and downregulated by CRTC1-miR. MiR212/132 was upregulated by CRTC1-AD and CREB-AD; downregulated by CREB-miR. In vivo, CRTC1-miR, CREB-miR, and miR212/132-LNA increased paw withdrawal mechanical threshold in various degrees. CONCLUSIONS: The NR2B-CREB-miR212/132-CRTC1-CREB signal network plays an important role in the regulation of pain. Intervening with any molecule in this signal network would reduce pain perception.
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Dor Crônica/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hiperalgesia/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Dor Crônica/genética , Dor Crônica/fisiopatologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Limiar da Dor , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transdução de Sinais , Medula Espinal/embriologia , Medula Espinal/fisiopatologia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Numerous clinical investigations have revealed the circadian rhythm changes in the perception of chronic pain, and most clinical chronic pain types peak in the night. However, it is still undiscovered whether circadian rhythm of pain exists in rodents and the specific mechanism that may underlie it. Our study was conducted to investigate the rhythmic changes of hyperalgesia behavior in a chronic constrictive injury (CCI) model of rodents and to explore the role of the N-methyl-d-aspartate receptor 2B (NR2B)-cAMP response element binding protein (CREB)-CREB-regulated transcription coactivator 1 (CRTC1) signaling pathway in this pain rhythm. METHODS: A CCI operation was performed to mimic clinical chronic pain. Paw mechanical withdrawal threshold and paw withdrawal thermal latency were used to test pain behavior in rats; a von Frey cilia test was used to test mechanical hyperalgesia in mice at Zeitgeber time (ZT) 4, ZT10, ZT16, and ZT22 for 14 contiguous days. The relative mRNA and protein expression of NR2B, CREB and CRTC1 in the suprachiasmatic nuclei and the dorsal horn were measured by real-time polymerase chain reaction and Western blot. CRTC1 and CREB interference adenovirus vectors were injected intrathecally at 2 time points, respectively (ZT12 and ZT0), to further explore the proper time point for pain treatment. RESULTS: During the period of chronic pain state, the pain behavior of CCI rodents showed a circadian rhythm with the peak at ZT4 or ZT10 daily. The pain thresholds were significantly different between the activity period and the rest period. The expressions of NR2B, CRTC1, and CREB at the spinal level were consistent with the pain rhythm. The intrathecal treatment with CRTC1 or CREB interference adenovirus from day 7 to day 9 after CCI surgery markedly improved pain behaviors. Nevertheless, when given at ZT0, they were both more effective at relieving peak pain than drugs given at ZT12. CONCLUSIONS: Pain behavior in the chronic pain of CCI displayed circadian rhythm and was associated with circadian secretion of pain-related receptors. The NR2B-CREB-CRTC1 signaling pathway may play a crucial role in this rhythm. Moreover, our results suggest that measures to relieve pain should be taken before pain reaches its peak.
Assuntos
Constrição Patológica/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Dor/fisiopatologia , Receptores de N-Metil-D-Aspartato/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Animais , Comportamento Animal , Doença Crônica , Ritmo Circadiano/genética , Temperatura Alta , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Limiar da Dor , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Acute compartment syndrome (ACS) is the result of increased intracompartmental pressure (ICP), and to avoid a delay in diagnosis requires ICP measurement. This study was designed to compare 2 available methods with Bland-Altman analysis for measuring ICP in experimental animal models, healthy volunteers, and patients with suspected ACS to evaluate their agreement and interchangeability. METHODS: In 20 New Zealand White rabbits, we inflated a tourniquet to stop arterial blood flow to establish ACS rabbit models, of which ICP was measured and recorded by the Whitesides apparatus and the invasive arterial blood pressure monitor system (IABPMS) before and after modeling. The same 2 measurements were applied to the tibialis anterior compartment's ICP of 30 healthy volunteers. The experimental data were analyzed using the Bland-Altman method. Once it was considered to be a substitute for the Whitesides apparatus based on statistical analysis, we used IABPMS to measure the ICP of the patients suspected of having ACS to estimate its clinical prospect. RESULTS: The rabbit models' ICP estimated by the Whitesides apparatus and IABPMS were 9.60±2.74 and 9.55±2.33 mm Hg, with an increase to 30.20±4.44 and 30.05±4.58 mm Hg after modeling, respectively. The limits of agreement for the ICP were -2.01/2.11 and -2.41/2.71 mm Hg before and after model establishment. The healthy volunteers' ICP were 10.92±6.06 and 10.85±5.87 mm Hg; the limits of agreement for the ICP were -2.53/2.66 mm Hg. With IABPMS to continuously monitor the ICP increasing (40.45±10.42 vs 13.82±4.94 mm Hg) and ΔP (34.54±11.77 mm Hg) to guide the diagnosis of ACS, 5 of 11 patients underwent the emergency fasciotomy for decompression. CONCLUSION: The invasive pressure monitoring via IABPMS can be used as an alternative to the Whitesides method, thanks to the sufficient agreement between the 2 methods in ICP measurement, and also for its advantages recommended as a novel diagnostic approach to ACS in experimental and clinical applications.
Assuntos
Síndrome do Compartimento Anterior/diagnóstico , Pressão Arterial , Monitores de Pressão Arterial , Adulto , Animais , Síndrome do Compartimento Anterior/cirurgia , Síndromes Compartimentais/diagnóstico , Síndromes Compartimentais/etiologia , Síndromes Compartimentais/cirurgia , Descompressão Cirúrgica , Fasciotomia , Feminino , Traumatismos do Antebraço/complicações , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Animais , Pressão , Coelhos , Coxa da Perna , Torniquetes , Adulto JovemRESUMO
The use of a multidisciplinary team approach is essential for increasing the likelihood of recovery among individuals with early psychosis. The aim of the present study was to investigate the effects of community-based mental health services on the symptoms and socio-occupational functioning of subjects with early psychosis. The study included participants who were referred to our Mental Health Promotion Center and who agreed to participate in diverse individual and group programs. During the 1-year follow-up, the medication adherence rate remained high, the recovery rate substantially increased, and the scores on the Positive and Negative Syndrome Scale, Psychotic Symptom Rating Scale-Delusion and Auditory Hallucinations subscales, Global Assessment of Functioning, Interpersonal Sensitivity Measure, and Social Functioning Questionnaire significantly improved over time. The findings suggest that the 1-year outcome of subjects with early psychosis can be improved by diverse community-based psychosocial interventions.
Assuntos
Serviços Comunitários de Saúde Mental , Transtornos Psicóticos/terapia , Adulto , Antipsicóticos/uso terapêutico , Serviços Comunitários de Saúde Mental/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Adesão à Medicação/psicologia , Adesão à Medicação/estatística & dados numéricos , Prognóstico , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologia , Ajustamento Social , Resultado do TratamentoRESUMO
Xinjiang is at the crossroads between East and West Eurasia, and it harbors a relatively complex genetic history. In order to better understand the population movements and interactions in this region, mitochondrial and Y chromosome analyses on 40 ancient human remains from the Tianshanbeilu site in eastern Xinjiang were performed. Twenty-nine samples were successfully assigned to specific mtDNA haplogroups, including the west Eurasian maternal lineages of U and W and the east Eurasian maternal lineages of A, C, D, F, G, Z, M7, and M10. In the male samples, two Y chromosome haplogroups, C* and N1 (xN1a, N1c), were successfully assigned. Our mitochondrial and Y-chromosomal DNA analyses combined with the archaeological studies revealed that the Di-qiang populations from the Hexi Corridor had migrated to eastern Xinjiang and admixed with the Eurasian steppe populations in the early Bronze Age.
Assuntos
Povo Asiático/genética , Cromossomos Humanos Y/genética , DNA Mitocondrial/genética , Migração Humana , Antropologia Física , China , Feminino , Humanos , Masculino , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2), DRD3, and dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32 (DARPP-32) in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR) and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS) and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS) in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls.
Assuntos
Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Transtornos Psicóticos/diagnóstico , RNA Mensageiro/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Esquizofrenia/diagnóstico , Linfócitos T/metabolismo , Adolescente , Adulto , Idade de Início , Biomarcadores/metabolismo , Estudos de Casos e Controles , Diagnóstico Diferencial , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Linfócitos T/citologiaRESUMO
BACKGROUND: The NR2B subunit (N-methyl-D-aspartate receptor 2B subunit) regulates the source of pain, and it participates in the formation of central sensitization. Palmitoylation was shown to be involved in the regulation of N-methyl-D-aspartate receptor internalization. In the present study, we investigated the effects of NR2B subunit palmitoylation in a chronic dorsal root ganglia compression (CCD) rat model. METHODS: Paw mechanical withdrawal threshold and paw withdrawal thermal latency were used to assess mechanical allodynia and thermal hyperalgesia after a CCD operation and an intrathecal injection of the inhibitor of palmitoylation (2-bromopalmitate [2-BP]). The acyl-biotinyl exchange method, Western blotting, and coimmunoprecipitation were used to investigate the effects of pain processing and the expression of levels of NR2B palmitoylation and phosphorylation at the spinal level. RESULTS: CCD rats had long-lasting thermal hyperalgesia and mechanical allodynia, leading to upregulation of the level of NR2B palmitoylation and phosphorylation at the spinal level. An intrathecal treatment with 2-BP on day 14 after CCD surgery markedly improved pain behaviors and downregulated the expression of NR2B palmitoylation and phosphorylation. CONCLUSIONS: These data suggest that upregulated NR2B palmitoylation in CCD-induced neuropathic pain and intrathecal injection of 2-BP could reduce pain behaviors and NR2B phosphorylation. Our findings indicate that spinal NR2B palmitoylation is an important component of CCD-induced neuropathic pain, and it might be a potential target for chronic pain therapy.