Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 47
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Zhongguo Gu Shang ; 36(12): 1142-6, 2023 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-38130222

RESUMO

OBJECTIVE: To investigate CT values of cancellous bone in femoral neck in adults over 60 years with proximal femoral fractures. METHODS: From January 2020 to December 2020, a retrospective analysis was performed on 280 subjects aged 60 years or older who underwent bilateral hip CT examination, including 85 males and 195 females, 120 on the left side and 160 on the right side, aged 75 (66, 82) years old. One hundred thirty-six patients with proximal femoral fractures were included in study group and 144 patients without fractures were included in control group. GEOptima CT was used to scan and reconstruct horizontal, coronal and sagittal layers of proximal femur. CT values of cancellous bone in femoral neck were measured and compared between two groups. The relationship between CT values of cancellous bone of femoral neck and proximal femoral fracture was analyzed statistically. RESULTS: In terms of age, fracture group aged 79(73.3, 85.0) years old, non-fracture group aged 69.5 (64.0, 78.8) years old, and had significant difference in age between two groups (P<0.05). In terms of CT value, regional CT value in fracture group was 8.62(-3.62, 27.15) HU, which was lower than that in non-fracture group 34.31(-5.93, 71.74) HU(P<0.05). CT value on coronal view in fracture group was -8.48(-30.96, 17.46) HU, which was lower than that in non-fracture group 40.49(5.55, 80.71) HU (P<0.05). CT value on sagittal view in fracture group was -31.28(-54.91, -5.11) HU, which was lower than that in non-fracture group 7.74(-20.12, 44.54) HU (P<0.05). CT values on horizontal view in fracture group was 0.17(-23.13, 24.60) HU, which was lower than that in non-fracture group 46.40(10.42, 85.18) HU(P<0.05). The mean regional CT values among three planes in the fracture group were lower than those in the non-fracture group. Logistic regression analysis showed coronal CT value was influencing factors of proximal femoral fracture, and it could be written into regression equations that predict probability of fracture. CONCLUSION: In adults aged over 60 years old, CT values of cancellous bone of femoral neck decreased with increasing age. The smaller CT value of cancellous bone of femoral neck, the greater risk of proximal femoral fracture.


Assuntos
Fraturas do Quadril , Fraturas Proximais do Fêmur , Masculino , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Colo do Fêmur , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/cirurgia , Tomografia Computadorizada por Raios X , Densidade Óssea
2.
Front Microbiol ; 13: 1057284, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569088

RESUMO

Wickerhamomyces anomalus (W. anomalus) is widely reported in the brewing industry and has positive effects on the aromatic profiles of wines because of its unique physiological characteristics and metabolic features. However, the accumulation of ethanol during fermentation inhibits the growth of W. anomalus. Thiamine is involved in the response against various abiotic stresses in microorganisms. Therefore, we used transcriptomic and metabolomic analyses to study the effect of thiamine on ethanol-stressed W. anomalus. The results indicate that thiamine could alleviate the inhibitory effect of ethanol stress on the survival of W. anomalus. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) caused by the thiamine intervention were identified as oxidative phosphorylation through integrated transcriptomic and metabolomic analyses. In addition, ethanol treatment decreased the content of intracellular adenosine triphosphate (ATP), while thiamine partially alleviated this phenomenon. The present comprehensive transcriptional overview and metabolomic analysis provide insights about the mechanisms of thiamine protection on W. anomalus under ethanol stress and promote the potential applications of W. anomalus in the fermentation industry.

3.
Zhongguo Gu Shang ; 35(1): 20-5, 2022 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-35130594

RESUMO

OBJECTIVE: To investigate the clinical effect of porous tantalum Jumbo cup on acetabular reconstruction in revision of total hip arthroplasty. METHODS: From September 2014 to December 2017, 18 patients(18 hips) with acetabular defect were reconstructed by porous tantalum Jumbo cup technology, including 6 males and 12 females;the age ranged from 54 to 76 years old with an average of(63.8±15.3) years. There were 6 cases of paprosky typeⅡA, 8 cases of typeⅡB, 2 cases of typeⅡC and 2 cases of type Ⅲ a. Harris score and visual analogue scale (VAS) were performed before and after operation. Imaging examination was performed to evaluate the position of hip rotation center and prosthesis, and to judge whether acetabular loosening, displacement and complications existed. RESULTS: All cases were followed up for 13 to 49 months, with an average of 20.6 months. Harris score increased from 54.6±4.7 to 86.5±3.2 one year after operation(P<0.01), and VAS score decreased from 6.8±0.7 to 0.8±0.6 one year after operation (P<0.01). The transverse coordinate of hip rotation center was (3.52±0.72) cm before operation and (3.47±0.54) cm after operation (P>0.05). The longitudinal coordinate of hip rotation center was improved from (3.02±0.84) cm before operation to (2.35±0.53) cm after operation (P<0.01). During the follow-up period, the Jumbo cup was well fixed without loosening and displacement, the acetabular cup had bone ingrowth in varying degrees, and no light transmission line and osteolysis around the acetabular cup were found. No complications such as infection and nerve injury occurred. CONCLUSION: The method of reconstructing acetabular bone defect with porous tantalum Jumbo cup is simple and easy, the early stability of acetabulum is good, and the short-term follow-up effect is good.


Assuntos
Artroplastia de Quadril , Prótese de Quadril , Acetábulo/cirurgia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Porosidade , Falha de Prótese , Reoperação , Estudos Retrospectivos , Tantálio , Resultado do Tratamento
4.
J Orthop Surg Res ; 14(1): 279, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462276

RESUMO

INTRODUCTION: In this study, we described a positioner which allows a combination of preoperative plan and intraoperative insertion of the cup to improve the reconstruction of the rotation center of the hip. MATERIALS AND METHODS: A retrospective study was conducted on 32 consecutive patients (group A) using this positioner and 40 consecutive patients (group B) using conventional method; radiological parameters and clinical measurements before operation and at last follow-up were collected and evaluated. RESULTS: Group A had a reconstructed center of rotation (COR) that was 0.19 mm closer to the anatomic COR in height (P < 0.005), compared with group B with 3.45 mm vertical dislocation. There were no statistically significant differences in the horizontal displacement between the two groups. The accuracy of cup inclination was 42.14 ± 3.57 in the group A and 38.73 ± 7.65 in the group B (P = 0.015). The accuracy of cup anteversion was 14.82 ± 1.44 in the group A and 13.08 ± 5.95 in the group B (P = 0.082). All cups in the group A were radiologically stable, while one cup in the group B was radiologically unstable and was successfully treated with second-stage revision. Both of the groups obtained a higher mean postoperative Harris Hip Score. CONCLUSIONS: Utilizing this positioner helps to restore the COR position more precisely and provides satisfactory radiological and clinical outcomes in the short term, and more studies are required before its widespread adoption for complicated cases.


Assuntos
Acetábulo/diagnóstico por imagem , Acetábulo/cirurgia , Artroplastia de Quadril/instrumentação , Artroplastia de Quadril/normas , Prótese de Quadril/normas , Desenho de Prótese/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Mol Pain ; 15: 1744806918825044, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799685

RESUMO

BACKGROUND: The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation. RESULTS: After inflammation, GLT1 and KBBP showed an early upregulation and gradual transition to downregulation that lasted throughout the eight-week observation period. Nitration of GLT1 was reduced at 30 min and increased at eight weeks after inflammation, suggesting an initial increase and later decrease in transporter activity. Mechanical hyperalgesia and paw edema exhibited an initial developing phase with peak hyperalgesia at 4 to 24 h, a subsequent attenuating phase, followed by a late persistent phase that lasted for months. The downregulation of GLT1 occurred at a time when hyperalgesia transitioned into the persistent phase. In the rostral ventromedial medulla, pharmacological block with dihydrokainic acid and RNAi of GLT1 and KBBP increased nociception and overexpression of GLT1 reversed persistent hyperalgesia. Further, the initial upregulation of GLT1 and KBBP was blocked by local anesthetic block, and pretreatment with dihydrokainic acid facilitated the development of hyperalgesia. CONCLUSIONS: These results suggest that the initial increased GLT1 activity depends on injury input and serves to dampen the development of hyperalgesia. However, later downregulation of GLT1 fosters the net descending facilitation as injury persists, leading to the emergence of persistent pain.


Assuntos
Vias Aferentes/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Dor Crônica/patologia , Neuroglia/metabolismo , Sistema X-AG de Transporte de Aminoácidos/genética , Animais , Aprendizagem da Esquiva , Tronco Encefálico/fisiologia , Dor Crônica/induzido quimicamente , Modelos Animais de Doenças , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Adjuvante de Freund/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hiperalgesia/fisiopatologia , Imunoprecipitação , Masculino , Medição da Dor , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução Genética
6.
Physiol Behav ; 204: 129-139, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30797813

RESUMO

INTRODUCTION: Pain-related behavior secondary to masticatory function can be assessed with the rodent bite force model. A reduction of the bite force has been shown to be related to pain associated with the masseter muscle and jaw activity, while an increase in bite force suggests improvement of muscle function and less pain. To evaluate the usefulness of the bite force measure in studying long-lasting orofacial pain we analyzed biting parameters during prolonged myofascial pain induced by ligation injury of the masseter muscle tendon (TL) in mice. METHODS: C57Bl/6 mice were habituated to bite at a pair of aluminum plates attached to a force displacement transducer. The transduced voltage signals were amplified and converted to force through calibration with a standard weight set. Voluntary biting behavior was recorded for 100 s/session and those with bite forces ≥980 mN were analyzed. Nociception was also verified with von Frey, conditioned place avoidance (CPA) tests and mouse grimace scale. Persistent orofacial pain was induced with unilateral ligation of one tendon of the masseter muscle (TL). RESULTS: To reduce interference of random bites of smaller forces, the top 5 or 15 bite forces (BF5/15) were chosen as a measure of masticatory function and related to pain behavior. Both male and female mice exhibited similar BF5/15. For the first nascent test of all mice, mean bite force was significantly and positively correlated with the body weight. However, this correlation was less clear in the latter tests (2-8 w). TL induced a reduction of BF5/15 that peaked at 1 w and returned to the baseline within 3 w. The von Frey and CPA tests indicated that mechanical allodynia/hyperalgesia persisted at the time when the BF had returned to the pre-injury level. Infusion of pain-relieving bone marrow stromal cells improved biting behavior in both male and female mice as shown by significantly increased BF5/15, compared to vehicle-treated mice. CONCLUSIONS: Mouse voluntary biting behavior can be reliably measured and quantified with a simplified setup. The bite force showed an inverse relationship with the level of pain after TL and was improved by pain-relieving manipulations. However, the injury-induced reduction of bite force peaked early and did not parallel with other measures of nociception in the later phase of hyperalgesia. The results suggest that multiple factors such as the level of habituation, cognitive motive, physical status, and feeding drive may affect random voluntary biting and confound the biting parameters related to maintained hyperalgesia.


Assuntos
Força de Mordida , Dor Facial/psicologia , Animais , Aprendizagem da Esquiva , Fenômenos Biomecânicos , Peso Corporal , Eletromiografia , Expressão Facial , Feminino , Hiperalgesia/psicologia , Masculino , Músculo Masseter/fisiologia , Músculos da Mastigação/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor , Tendões/fisiologia
7.
J Neurochem ; 149(1): 98-110, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30674062

RESUMO

Myelin disruptions are frequently reported in human immunodeficiency virus (HIV)-infected individuals and can occur in the CNS very early in the disease process. Immature oligodendrocytes (OLs) are quite sensitive to toxic increases in [Ca2+ ]i caused by exposure to HIV-1 Tat (transactivator of transcription, a protein essential for HIV replication and gene expression), but sensitivity to Tat-induced [Ca2+ ]i is reduced in mature OLs. Tat exposure also increased the activity of Ca2+ /calmodulin-dependent kinase IIß (CaMKIIß), the major isoform of CaMKII expressed by OLs, in both immature and mature OLs. Since CaMKIIß is reported to interact with glycogen synthase kinase 3ß (GSK3ß), and GSK3ß activity is implicated in OL apoptosis as well as HIV neuropathology, we hypothesized that disparate effects of Tat on OL viability with maturity might be because of an altered balance of CaMKIIß-GSK3ß activities. Tat expression in vivo led to increased CaMKIIß and GSK3ß activity in multiple brain regions in transgenic mice. In vitro, immature murine OLs expressed higher levels of GSK3ß, but much lower levels of CaMKIIß, than did mature OLs. Exogenous Tat up-regulated GSK3ß activity in immature, but not mature, OLs. Tat-induced death of immature OLs was rescued by the GSK3ß inhibitors valproic acid or SB415286, supporting involvement of GSK3ß signaling. Pharmacologically inhibiting CaMKIIß increased GSK3ß activity in Tat-treated OLs, and genetically knocking down CaMKIIß promoted death in mature OL cultures treated with Tat. Together, these results suggest that the effects of Tat on OL viability are dependent on CaMKIIß-GSK3ß interactions, and that increasing CaMKIIß activity is a potential approach for limiting OL/myelin injury with HIV infection.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Infecções por HIV/metabolismo , Oligodendroglia/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Sobrevivência Celular , Infecções por HIV/patologia , HIV-1 , Camundongos , Camundongos Transgênicos , Oligodendroglia/patologia
8.
Front Integr Neurosci ; 12: 49, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459569

RESUMO

Bone marrow stromal cells (BMSCs) produce long-lasting attenuation of pain hypersensitivity. This effect involves BMSC's ability to interact with the immune system and activation of the endogenous opioid receptors in the pain modulatory circuitry. The nuclear factor kappa B (NF-κB) protein complex is a key transcription factor that regulates gene expression involved in immunity. We tested the hypothesis that the NF-κB signaling plays a role in BMSC-induced pain relief. We focused on the rostral ventromedial medulla (RVM), a key structure in the descending pain modulatory pathway, that has been shown to play an important role in BMSC-produced antihyperalgesia. In Sprague-Dawley rats with a ligation injury of the masseter muscle tendon (TL), BMSCs (1.5 M/rat) from donor rats were infused i.v. at 1 week post-TL. P65 exhibited predominant neuronal localization in the RVM with scattered distribution in glial cells. At 1 week, but not 8 weeks after BMSC infusion, western blot and immunostaining showed that p65 of NF-κB was significantly increased in the RVM. Given that chemokine signaling is critical to BMSCs' pain-relieving effect, we further evaluated a role of chemokine signaling in p65 upregulation. Prior to infusion of BMSCs, we transduced BMSCs with Ccl4 shRNA, incubated BMSCs with RS 102895, a CCR2b antagonist, or maraviroc, a CCR5 antagonist. The antagonism of chemokines significantly reduced BMSC-induced upregulation of p65, suggesting that upregulation of p65 was related to BMSCs' pain-relieving effect. We then tested the effect of a selective NF-κB activation inhibitor, BAY 11-7082. The mechanical hyperalgesia of the rat was assessed with the von Frey method. In the pre-treatment experiment, BAY 11-7082 (2.5 and 25 pmol) was injected into the RVM at 2 h prior to BMSC infusion. Pretreatment with BAY 11-7082 attenuated BMSCs' antihyperalgesia, but post-treatment at 5 weeks post-BMSC was not effective. On the contrary, in TL rats receiving BAY 11-7082 without BMSCs, TL-induced hyperalgesia was attenuated, consistent with dual roles of NF-κB in pain hypersensitivity and BMSC-produced pain relief. These results indicate that the NF-κB signaling pathway in the descending circuitry is involved in initiation of BMSC-produced behavioral antihyperalgesia.

9.
J Neuroinflammation ; 15(1): 285, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305110

RESUMO

BACKGROUND: The collective cognitive and motor deficits known as HIV-associated neurocognitive disorders (HAND) remain high even among HIV+ individuals whose antiretroviral therapy is optimized. HAND is worsened in the context of opiate abuse. The mechanism of exacerbation remains unclear but likely involves chronic immune activation of glial cells resulting from persistent, low-level exposure to the virus and viral proteins. We tested whether signaling through C-C chemokine receptor type 5 (CCR5) contributes to neurotoxic interactions between HIV-1 transactivator of transcription (Tat) and opiates and explored potential mechanisms. METHODS: Neuronal survival was tracked in neuronal and glial co-cultures over 72 h of treatment with HIV-1 Tat ± morphine using cells from CCR5-deficient and wild-type mice exposed to the CCR5 antagonist maraviroc or exogenously-added BDNF (analyzed by repeated measures ANOVA). Intracellular calcium changes in response to Tat ± morphine ± maraviroc were assessed by ratiometric Fura-2 imaging (analyzed by repeated measures ANOVA). Release of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF from CCR5-deficient and wild-type glia was measured by ELISA (analyzed by two-way ANOVA). Levels of CCR5 and µ-opioid receptor (MOR) were measured by immunoblotting (analyzed by Student's t test). RESULTS: HIV-1 Tat induces neurotoxicity, which is greatly exacerbated by morphine in wild-type cultures expressing CCR5. Loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions. Unexpectedly, when CCR5 was lost from glia, morphine appeared to entirely protect neurons from Tat-induced toxicity. Maraviroc pre-treatment similarly eliminated neurotoxicity and attenuated neuronal increases in [Ca2+]i caused by Tat ± morphine. proBDNF/BDNF ratios were increased in conditioned media from Tat ± morphine-treated wild-type glia compared to CCR5-deficient glia. Exogenous BDNF treatments mimicked the pro-survival effect of glial CCR5 deficiency against Tat ± morphine. CONCLUSIONS: Our results suggest a critical role for glial CCR5 in mediating neurotoxic effects of HIV-1 Tat and morphine interactions on neurons. A shift in the proBDNF/BDNF ratio that favors neurotrophic support may occur when glial CCR5 signaling is blocked. Some neuroprotection occurred only in the presence of morphine, suggesting that loss of CCR5 may fundamentally change signaling through the MOR in glia.


Assuntos
Analgésicos Opioides/farmacologia , Regulação da Expressão Gênica/genética , Neuroglia/metabolismo , Alcaloides Opiáceos/farmacologia , Receptores CCR5/deficiência , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Complexo AIDS Demência , Animais , Antagonistas dos Receptores CCR5/farmacologia , Corpo Estriado/citologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Maraviroc/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neuroglia/efeitos dos fármacos , Neurônios/fisiologia , Alcaloides Opiáceos/metabolismo , Receptores CCR5/genética , Receptores Opioides mu/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
10.
Sci Rep ; 7(1): 10107, 2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28860501

RESUMO

Systemic infusion of bone marrow stromal cells (BMSCs), a major type of multipotent stromal cells, produces pain relief (antihyperalgesia) that lasts for months. However, studies have shown that the majority of BMSCs are trapped in the lungs immediately after intravenous infusion and their survival time in the host is inconsistent with their lengthy antihyperalgesia. Here we show that long-lasting antihyperalgesia produced by BMSCs required their chemotactic factors such as CCL4 and CCR2, the integrations with the monocytes/macrophages population, and BMSC-induced monocyte CXCL1. The activation of central mu-opioid receptors related to CXCL1-CXCR2 signaling plays an important role in BMSC-produced antihyperalgesia. Our findings suggest that the maintenance of antihypergesia can be achieved by immune regulation without actual engraftment of BMSCs. In the capacity of therapeutic use of BMSCs other than structural repair and replacement, more attention should be directed to their role as immune modulators and subsequent alterations in the immune system.


Assuntos
Hiperalgesia/imunologia , Células-Tronco Mesenquimais/imunologia , Dor/imunologia , Animais , Quimiocina CCL4/metabolismo , Quimiocina CXCL1/metabolismo , Feminino , Macrófagos/imunologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores CCR2/metabolismo , Receptores Opioides mu/metabolismo , Transdução de Sinais
11.
ASN Neuro ; 8(5)2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27659560

RESUMO

White matter injury has been frequently reported in HIV+ patients. Previous studies showed that HIV-1 Tat (transactivator of transcription), a viral protein that is produced and secreted by HIV-infected cells, is toxic to young, immature oligodendrocytes (OLGs). Adding Tat to the culture medium reduced the viability of immature OLGs, and the surviving OLGs exhibited reduced process networks. OLGs produce and secrete autotaxin (ATX), an ecto-enzyme containing a lysophospholipase D (lysoPLD) activity that converts lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a lipid signaling molecule that stimulates OLG differentiation. We hypothesized that Tat affects OLG development by interfering with the ATX-LPA signaling pathway. Our data show that Tat treatment leads to changes in the expression of OLG differentiation genes and the area of OLG process networks, both of which can be rescued by LPA. Tat-treated OLGs showed no change in LPA receptor expression but significantly decreased extracellular ATX levels and lysoPLD activity. In Tat transgenic mice, expression of Tat in vivo leads to decreased OLG ATX secretion. Furthermore, co-immunoprecipitation experiments revealed a potential physical interaction between Tat and ATX. Together, these data strongly suggest two functional implications of Tat blocking ATX's lysoPLD activity. On one hand, it attenuates OLG differentiation, and on the other hand it interferes with the protective effects of LPA on OLG process morphology.

12.
Mol Pain ; 122016.
Artigo em Inglês | MEDLINE | ID: mdl-27329776

RESUMO

BACKGROUND: Bone marrow stromal cells (BMSCs) have shown potential to treat chronic pain, although much still needs to be learned about their efficacy and mechanisms of action under different pain conditions. Here, we provide further convergent evidence on the effects of BMSCs in rodent pain models. RESULTS: In an orofacial pain model involving injury of a tendon of the masseter muscle, BMSCs attenuated behavioral pain conditions assessed by von Frey filaments and a conditioned place avoidance test in female Sprague-Dawley rats. The antihyperalgesia of BMSCs in females lasted for <8 weeks, which is shorter than that seen in males. To relate preclinical findings to human clinical conditions, we used human BMSCs. Human BMSCs (1.5 M cells, i.v.) attenuated mechanical and thermal hyperalgesia induced by spinal nerve ligation and suppressed spinal nerve ligation-induced aversive behavior, and the effect persisted through the 8-week observation period. In a trigeminal slice preparation, BMSC-treated and nerve-injured C57B/L mice showed reduced amplitude and frequency of spontaneous excitatory postsynaptic currents, as well as excitatory synaptic currents evoked by electrical stimulation of the trigeminal nerve root, suggesting inhibition of trigeminal neuronal hyperexcitability and primary afferent input by BMSCs. Finally, we observed that GluN2A (N-methyl-D-aspartate receptor subunit 2A) tyrosine phosphorylation and protein kinase Cgamma (PKCg) immunoreactivity in rostral ventromedial medulla was suppressed at 8 weeks after BMSC in tendon-injured rats. CONCLUSIONS: Collectively, the present work adds convergent evidence supporting the use of BMSCs in pain control. As PKCg activity related to N-methyl-D-aspartate receptor activation is critical in opioid tolerance, these results help to understand the mechanisms of BMSC-produced long-term antihyperalgesia, which requires opioid receptors in rostral ventromedial medulla and apparently lacks the development of tolerance.


Assuntos
Comportamento Animal , Encéfalo/patologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Neuralgia/terapia , Animais , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Naloxona/farmacologia , Neuralgia/metabolismo , Neuralgia/patologia , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/patologia , Tendões/efeitos dos fármacos , Tendões/patologia , Nervo Trigêmeo/efeitos dos fármacos , Nervo Trigêmeo/patologia
13.
Brain Behav Immun ; 55: 202-214, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26774528

RESUMO

Human immunodeficiency virus (HIV) is associated with motor and mood disorders, likely influenced by reactive microgliosis and subsequent neural damage. We have recapitulated aspects of this pathology in mice that conditionally express the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat). Progestogens may attenuate Tat-related behavioral impairments and reduce neurotoxicity in vitro, perhaps via progesterone's 5α-reductase-dependent metabolism to the neuroprotective steroid, allopregnanolone. To test this, ovariectomized female mice that conditionally expressed (or did not express) central HIV-1 Tat were administered vehicle or progesterone (4mg/kg), with or without pretreatment of a 5α-reductase inhibitor (finasteride, 50mg/kg). Tat induction significantly increased anxiety-like behavior in an open field, elevated plus maze and a marble burying task concomitant with elevated protein oxidation in striatum. Progesterone administration attenuated anxiety-like effects in the open field and elevated plus maze, but not in conjunction with finasteride pretreatment. Progesterone also attenuated Tat-promoted protein oxidation in striatum, independent of finasteride pretreatment. Concurrent experiments in vitro revealed Tat (50nM)-mediated reductions in neuronal cell survival over 60h, as well as increased neuronal and microglial intracellular calcium, as assessed via fura-2 AM fluorescence. Co-treatment with allopregnanolone (100nM) attenuated neuronal death in time-lapse imaging and blocked the Tat-induced exacerbation of intracellular calcium in neurons and microglia. Lastly, neuronal-glial co-cultures were labeled for Iba-1 to reveal that Tat increased microglial numbers in vitro and co-treatment with allopregnanolone attenuated this effect. Together, these data support the notion that 5α-reduced pregnane steroids exert protection over the neurotoxic effects of HIV-1 Tat.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Pregnanolona/farmacologia , Progesterona/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Inibidores de 5-alfa Redutase/administração & dosagem , Animais , Ansiedade/induzido quimicamente , Técnicas de Cocultura , Feminino , Finasterida/administração & dosagem , Finasterida/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ovariectomia , Pregnanolona/administração & dosagem , Progesterona/administração & dosagem , Produtos do Gene tat do Vírus da Imunodeficiência Humana/efeitos dos fármacos
14.
J Neurosci ; 35(32): 11384-98, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26269645

RESUMO

Myelin pallor in HIV(+) individuals can occur very early during the disease process. While myelin damage might partly originate from HIV-induced vascular changes, the timing suggests that myelin and/or oligodendrocytes (OLs) may be directly affected. Histological (Golgi-Kopsch, electron microscopy) and biochemical studies have revealed an increased occurrence of abnormal OL/myelin morphology and dysregulated myelin protein expression in transgenic mice expressing the HIV-1 transactivator of transcription (Tat) protein. This suggests that viral proteins by themselves might cause OL injury. Since Tat interacts with NMDARs, we hypothesized that activation of NMDARs and subsequent disruption of cytoplasmic Ca(2+) ([Ca(2+)]i) homeostasis might be one cause of white matter injury after HIV infection. In culture, HIV-1 Tat caused concentration-dependent death of immature OLs, while more mature OLs remained alive but had reduced myelin-like membranes. Tat also induced [Ca(2+)]i increases and Thr-287 autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase II ß (CaMKIIß) in OLs. Tat-induced [Ca(2+)]i was attenuated by the NMDAR antagonist MK801, and also by the AMPA/kainate receptor antagonist CNQX. Importantly, both MK801 and CNQX blocked Tat-induced death of immature OLs, but only MK801 reversed Tat effects on myelin-like membranes. These results suggest that OLs can be direct targets of HIV proteins released from infected cells. Although viability and membrane production are both affected by glutamatergic receptor-mediated Ca(2+) influx, and possibly the ensuing CaMKIIß activation, the roles of AMPARs and NMDARs appear to be different and dependent on the stage of OL differentiation. SIGNIFICANCE STATEMENT: Over 33 million individuals are currently infected by HIV. Among these individuals, ∼60% develop HIV-associated neurocognitive disorders. Myelin damage and white matter injury have been frequently reported in HIV patients but not extensively studied. Clinical studies using combined antiretroviral therapy (cART) together with adjunctive "anti-inflammatory" drugs show no improvement over cART alone, suggesting existence of injury mechanisms in addition to inflammation. In our studies, oligodendrocytes exhibited rapid increases in intracellular Ca(2+) level upon HIV-1 transactivator of transcription (Tat) exposure. Thus, immature and mature oligodendrocytes can be direct targets of Tat. Since ionotropic glutamate receptor antagonists can partially or fully reverse the detrimental effects of Tat, glutamate receptors could be a potential therapeutic target for white matter damage in HIV patients.


Assuntos
Sobrevivência Celular/fisiologia , Oligodendroglia/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Camundongos , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Fosforilação , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
15.
J Neurosci ; 34(38): 12850-64, 2014 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-25232120

RESUMO

Synaptodendritic injury is thought to underlie HIV-associated neurocognitive disorders and contributes to exaggerated inflammation and cognitive impairment seen in opioid abusers with HIV-1. To examine events triggering combined transactivator of transcription (Tat)- and morphine-induced synaptodendritic injury systematically, striatal neuron imaging studies were conducted in vitro. These studies demonstrated nearly identical pathologic increases in dendritic varicosities as seen in Tat transgenic mice in vivo. Tat caused significant focal increases in intracellular sodium ([Na(+)]i) and calcium ([Ca(2+)]i) in dendrites that were accompanied by the emergence of dendritic varicosities. These effects were largely, but not entirely, attenuated by the NMDA and AMPA receptor antagonists MK-801 and CNQX, respectively. Concurrent morphine treatment accelerated Tat-induced focal varicosities, which were accompanied by localized increases in [Ca(2+)]i and exaggerated instability in mitochondrial inner membrane potential. Importantly, morphine's effects were prevented by the µ-opioid receptor antagonist CTAP and were not observed in neurons cultured from µ-opioid receptor knock-out mice. Combined Tat- and morphine-induced initial losses in ion homeostasis and increases in [Ca(2+)]i were attenuated by the ryanodine receptor inhibitor ryanodine, as well as pyruvate. In summary, Tat induced increases in [Na(+)]i, mitochondrial instability, excessive Ca(2+) influx through glutamatergic receptors, and swelling along dendrites. Morphine, acting via µ-opioid receptors, exacerbates these excitotoxic Tat effects at the same subcellular locations by mobilizing additional [Ca(2+)]i and by further disrupting [Ca(2+)]i homeostasis. We hypothesize that the spatiotemporal relationship of µ-opioid and aberrant AMPA/NMDA glutamate receptor signaling is critical in defining the location and degree to which opiates exacerbate the synaptodendritic injury commonly observed in neuroAIDS.


Assuntos
Cálcio/metabolismo , Dendritos/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Mitocôndrias/efeitos dos fármacos , Morfina/farmacologia , Sódio/metabolismo , Sinapses/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Nefropatia Associada a AIDS/induzido quimicamente , Nefropatia Associada a AIDS/metabolismo , Nefropatia Associada a AIDS/patologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dendritos/metabolismo , Dendritos/patologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/metabolismo , Morfina/antagonistas & inibidores , N-Metilaspartato/farmacologia , Cultura Primária de Células , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/genética , Rianodina/farmacologia , Sinapses/metabolismo , Sinapses/patologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/antagonistas & inibidores , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
16.
Neuropsychopharmacology ; 39(12): 2835-45, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24903651

RESUMO

Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Astrócitos/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Motivação , Núcleo Accumbens/efeitos dos fármacos , Recompensa , Consumo de Bebidas Alcoólicas/patologia , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Cálcio/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Citosol/efeitos dos fármacos , Citosol/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Núcleo Accumbens/patologia , Núcleo Accumbens/fisiopatologia , Ratos Sprague-Dawley , Ratos Wistar , Autoadministração
17.
Mol Pain ; 10: 35, 2014 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-24913307

RESUMO

BACKGROUND: It has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear. RESULTS: In the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1ß, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. CONCLUSIONS: These findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.


Assuntos
Hiperalgesia/patologia , Neuroglia/fisiologia , Neurônios/fisiologia , Percepção da Dor/fisiologia , Transdução de Sinais/fisiologia , Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Percepção da Dor/efeitos dos fármacos , Piperidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Nervos Espinhais/lesões
18.
Glia ; 62(9): 1543-1558, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24866099

RESUMO

Signaling via the major excitatory amino acid glutamate has been implicated in the regulation of various aspects of the biology of oligodendrocytes, the myelinating cells of the central nervous system (CNS). In this respect, cells of the oligodendrocyte lineage have been described to express a variety of glutamate-responsive transmembrane proteins including sodium-dependent glutamate transporters. The latter have been well characterized to mediate glutamate clearance from the extracellular space. However, there is increasing evidence that they also mediate glutamate-induced intracellular signaling events. Our data presented here show that the activation of oligodendrocyte expressed sodium-dependent glutamate transporters, in particular GLT-1 and GLAST, promotes the morphological aspects of oligodendrocyte maturation. This effect was found to be associated with a transient increase in intracellular calcium levels and a transient phosphorylation event at the serine (S)(371) site of the calcium sensor calcium/calmodulin-dependent kinase type IIß (CaMKIIß). The potential regulatory S(371) site is located within CaMKIIß's previously defined actin-binding/-stabilizing domain, and phosphorylation events within this domain were identified in our studies as a requirement for sodium-dependent glutamate transporter-mediated promotion of oligodendrocyte maturation. Furthermore, our data provide good evidence for a role of these phosphorylation events in mediating detachment of CaMKIIß from filamentous (F)-actin, and hence allowing a remodeling of the oligodendrocyte's actin cytoskeleton. Taken together with our recent findings, which demonstrated a crucial role of CaMKIIß in regulating CNS myelination in vivo, our data strongly suggest that a sodium-dependent glutamate transporter-CaMKIIß-actin cytoskeleton axis plays an important role in the regulation of oligodendrocyte maturation and CNS myelination.


Assuntos
Actinas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Oligodendroglia/citologia , Oligodendroglia/fisiologia , Citoesqueleto de Actina/fisiologia , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Células Cultivadas , Ácido Glutâmico/metabolismo , Espaço Intracelular/metabolismo , Fosforilação , Ratos Sprague-Dawley , Sódio/metabolismo
19.
AIDS ; 28(10): 1409-19, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24732776

RESUMO

OBJECTIVE: We explored the antiviral therapeutic potential of ibudilast (AV411, MN-166) and its amino analog, AV1013. METHODS: We analyzed whether Ibudilast, a nonselective cyclic AMP phosphodiesterase inhibitor that has been used clinically in Asia for bronchial asthma, poststroke dizziness, and ocular allergies, and AV1013, attenuate HIV-1 replication and the synergistic interactions seen with opiate abuse-HIV-1 comorbidity in neuronal death and inflammation. RESULTS: AV411 and AV1013 inhibited replication by HIV-1 in microglia and significantly suppressed Tat ± morphine-induced tumor necrosis factor-α and MIF production, the activation of the nuclear factor-kappa B subunit p65, and neuronal death. AV411 and AV1013 prevented HIV-1 replication, and attenuated tumor necrosis factor-α and MIF release at concentrations of 100  nmol/l and 1  µmol/l, which are likely achievable at clinical doses. More importantly, co-exposure with morphine did not negate the inhibitory actions of AV411. CONCLUSION: Collectively, our data suggest that AV411 and its amino analog, AV1013, may be useful neuroprotective agents counteracting neurotoxicity caused by infected and activated glia, and implicate them as potential therapies for the management of HIV-associated neurocognitive disorders in an opioid-abusing population.


Assuntos
Antivirais/farmacologia , HIV-1/fisiologia , Morfina/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piridinas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Camundongos , Neurônios/fisiologia
20.
Curr HIV Res ; 12(6): 424-34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25760046

RESUMO

Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca²âº]i, ROS, H2O2, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca²âº]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1ß, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca²âº]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca²âº]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.


Assuntos
Cálcio/metabolismo , Quimiocinas/metabolismo , Antagonistas de Entorpecentes/toxicidade , Neuroglia/efeitos dos fármacos , Neurônios/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Buprenorfina/metabolismo , Buprenorfina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Metadona/metabolismo , Metadona/toxicidade , Morfina/metabolismo , Morfina/toxicidade , Antagonistas de Entorpecentes/metabolismo , Entorpecentes/metabolismo , Entorpecentes/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA