RESUMO
PURPOSE: External snapping hip syndrome (ESHS) was historically attributed to isolated iliotibial band (ITB) contracture. However, the gluteus maximus complex (GMC) may also be involved. This study aimed to intraoperatively identify the ESHS origin and assess the outcomes of endoscopic treatment based on the identified aetiological type. METHODS: From 2008-2014, 30 consecutive patients (34 hips) with symptomatic ESHS cases refractory to conservative treatment underwent endoscopic stepwise "fan-like" release, gradually addressing all known reasons of ESHS: from the isolated ITB, through the fascial part of the GMC until a partial release of gluteus maximus femoral attachment occurred. Snapping was assessed intra-operatively after each surgical step and prospectively recorded. Functional outcomes were assessed via the MAHORN Hip Outcome Tool (MHOT-14). RESULTS: Twenty seven patients (31 hips) were available to follow-up at 24-56 months. In all cases, complete snapping resolution was achieved intra-operatively: in seven cases (22.6%) after isolated ITB release, in 22 cases (70.9%), after release of ITB + fascial part of the GMC, and in two cases (6.5%) after ITB + fascial GMC release + partial release of GM femoral insertion. At follow-up, there were no snapping recurrences and MHOT-14 score significantly increased from a pre-operative average of 46 to 93(p<0.001). CONCLUSION: Intraoperative identification and gradual addressing of all known causes of ESHS allows for maximum preservation of surrounding tissue during surgery while precisely targeting the directly involved structures. Endoscopic stepwise "fan-like" release of the ITB and GMC is an effective, tailor-made treatment option for ESHS regardless of the snapping origin in the patients with possibility to manually reproduce the snapping.
Assuntos
Contratura , Artropatias , Humanos , Articulação do Quadril/cirurgia , Artropatias/cirurgia , Endoscopia/efeitos adversos , Músculo Esquelético/cirurgia , Contratura/cirurgia , SíndromeRESUMO
BACKGROUND: Midcheek lift has been performed for cosmetic or reconstructive surgery of the lower eyelid. For midcheek lift through the subciliary incision, preperiosteal and subperiosteal dissections are the most often implemented, with good clinical outcomes. However, a comparative assessment of the effects of these 2 methods had not been conducted. OBJECTIVES: In this study we compared the effects of midcheek lift according to preperiosteal or subperiosteal plane and range of midfacial dissection. METHODS: Forty hemifaces of 20 fresh cadavers were dissected. One side of the hemiface underwent preperiosteal dissection, and the other side underwent subperiosteal dissection. After dissections of 5, 10, 15, 20, and 30â mm and all of the midcheek area from the inferior orbital rim, the length of the elevated lid-cheek junction was measured by placing upward traction on the lateral portion of the lower lid. RESULTS: In both methods, the length of the midcheek lift increased as the dissection progressed, and the length of the lift on the lateral side was greater than that on the medial side. The length of the pulled skin in the preperiosteal group was the greatest in most cases. However, in the full dissection cases, the midcheek lift length was not statistically different between the 2 surgical methods, especially on the lateral side. CONCLUSIONS: Flap elevation in lower blepharoplasty surgery can be predicted based on the surgical method and dissection range. Implementing a surgical plan that takes this into account can enhance both reconstruction and aesthetic surgery outcomes in the midcheek area.
Assuntos
Blefaroplastia , Ritidoplastia , Humanos , Ritidoplastia/efeitos adversos , Ritidoplastia/métodos , Blefaroplastia/efeitos adversos , Blefaroplastia/métodos , Pálpebras/cirurgia , Bochecha/cirurgia , DissecaçãoRESUMO
PTEN-induced kinase 1 (PINK1) is a well-known critical marker in the pathway for mitophagy regulation as well as mitochondrial dysfunction. Evidence suggests that mitochondrial dynamics and mitophagy flux play an important role in the development of brain damage from stroke pathogenesis. In this study, we propose a treatment strategy using nanoparticles that can control PINK1. We used a murine photothrombotic ischemic stroke (PTS) model in which clogging of blood vessels is induced with Rose Bengal (RB) to cause brain damage. We targeted PINK1 with poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles loaded with PINK1 siRNA (PINK1 NPs). After characterizing siRNA loading in the nanoparticles, we assessed the efficacy of PINK1 NPs in mice with PTS using immunohistochemistry, 1% 2,3,5-triphenyltetrazolium chloride staining, measurement of motor dysfunction, and Western blot. PINK1 was highly expressed in microglia 24 h after PTS induction. PINK1 siRNA treatment increased phagocytic activity, migration, and expression of an anti-inflammatory state in microglia. In addition, the PLGA nanoparticles were selectively taken up by microglia and specifically regulated PINK1 expression in those cells. Treatment with PINK1 NPs prior to stroke induction reduced expression of mitophagy-inducing factors, infarct volume, and motor dysfunction in mice with photothrombotic ischemia. Experiments with PINK1-knockout mice and microglia depletion with PLX3397 confirmed a decrease in stroke-induced infarct volume and behavioral dysfunction. Application of nanoparticles for PINK1 inhibition attenuates RB-induced photothrombotic ischemic injury by inhibiting microglia responses, suggesting that a nanomedical approach targeting the PINK1 pathway may provide a therapeutic avenue for stroke treatment.
Assuntos
AVC Isquêmico , Nanopartículas , Acidente Vascular Cerebral , Camundongos , Animais , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , RNA Interferente Pequeno/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Neuroproteção , Glicóis , Modelos Animais de Doenças , Isquemia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Camundongos Knockout , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Nanopartículas/uso terapêutico , InfartoRESUMO
PURPOSE: To assess if incomplete meniscal healing during second-look arthroscopy at six to eight weeks after all-inside suture hook meniscus repair results in longer-term failure of repair in patients with restored knee stability. METHODS: From 2008 to 2013, 41 patients with post-traumatic, longitudinal, vertical, complete meniscal tears with concomitant ACL injury were treated via a two-stage surgical procedure and prospectively evaluated. In the first stage, all-inside meniscus repair was performed using suture hook passers and non-absorbable sutures. In total, there were 26 medial and 16 lateral meniscus tears. A second-stage ACL reconstruction, performed six to eight weeks later, served as an early second-look arthroscopic evaluation of meniscal healing. Clinical follow-up was performed at a minimum of 24 months. RESULTS: Second-look arthroscopy revealed 31 cases (75.6%) of complete and ten cases (24.4%) of incomplete meniscal healing. Two patients were lost prior to follow-up, and three were excluded due to recurrent instability. Therefore, 36 patients were assessed at the final follow-up. All patients with complete meniscal healing during second-look arthroscopy achieved clinical success at follow-up. Six out of nine (66.7%) of patients with incomplete meniscal healing during second-look arthroscopy achieved clinical success at follow-up (p = 0.012). One saphenous neuropathy occurred (2.4%). CONCLUSION: Incomplete meniscal healing during early second-look arthroscopy after all-inside meniscal repair using suture hook passers and non-absorbable sutures did not necessarily result in longer-term failure in patients with restored knee stability. The described method of meniscal repair was associated with a low rate of symptomatic re-tears and complications.
Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Lesões do Menisco Tibial , Humanos , Artroscopia/efeitos adversos , Artroscopia/métodos , Lesões do Menisco Tibial/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , Lesões do Ligamento Cruzado Anterior/cirurgia , Meniscos Tibiais/cirurgiaRESUMO
Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells.
Assuntos
Neoplasias da Mama , Animais , Feminino , Humanos , Camundongos , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/metabolismo , Células MCF-7 , Monoéster Fosfórico Hidrolases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , RNA Interferente Pequeno/genética , Proteína Supressora de Tumor p53 , Polietilenoglicóis/química , NanopartículasRESUMO
PURPOSE: Accurate knowledge of greater palatine foramen (GPF) and greater palatine canal (GPC) anatomy is necessary to avoid injury to the greater palatine artery (GPA) when performing a variety of anesthesiologic, dental or surgical procedures. The aim of this paper was to perform a systematic review and meta-analysis of literature on the anatomy and localization of bony structures associated with the GPA, namely the GPF and GPC. METHODS: A systematic literature search was performed using PubMed, Embase, ScienceDirect, and Web of Science databases. Seventy-five studies were included in the meta-analysis (n = 22,202 subjects). RESULTS: The meta-analysis showed that the GPF is positioned 17.21 mm (95% CI = 16.34-18.09 mm) from the posterior nasal spine, 2.56 mm (95% CI = 1.90-3.22 mm) from the posterior border of the hard palate, 46.24 mm (95% CI = 44.30-48.18 mm) from the anterior nasal spine, 15.22 mm (95% CI = 15.00-15.43 mm) from the midline maxillary suture, 37.32 mm (95% CI = 36.19-38.45 mm) from the incisive foramen, and opposite the third maxillary molar (M3) in 64.9% (58.7-70.7%) of the total population. CONCLUSION: An up-to-date, comprehensive analysis of GPF and GPC clinical anatomy is presented. The results from this evidence-based anatomical study provides a unified set of data to aid clinicians in their practice.
Assuntos
Relevância Clínica , Maxila , Humanos , Maxila/anatomia & histologia , Palato Duro/anatomia & histologia , Artérias , Dente Molar/anatomia & histologiaRESUMO
A type of ultrathin films has been developed for suppressing capsule formation induced by medical silicone implants and hence reducing the inflammation response to such formation and the differentiation to myofibroblasts. The films were each fabricated from hyaluronic acid (HA) and modified ß-cyclodextrin (Mod-ß-CyD) polymer which was synthesized with a cyclodextrin with partially substituted quaternary amine. Ultrathin films comprising HA and Mod-ß-CyD or poly(allylamine hydrochloride) (PAH) were fabricated by using a layer-by-layer dipping method. The electrostatic interactions produced from the functional groups of Mod-ß-CyD and HA influenced the surface morphology, wettability, and bio-functional activity of the film. Notably, medical silicone implants coated with PAH/HA and Mod-ß-CyD multilayers under a low pH condition exhibited excellent biocompatibility and antibiofilm and anti-inflammation properties. Implantation of these nanoscale film-coated silicones showed a reduced capsular thickness as well as reduced TGFß-SMAD signaling, myofibroblast differentiation, biofilm formation, and inflammatory response levels. We expect our novel coating system to be considered a strong candidate for use in various medical implant applications in order to decrease implant-induced capsule formation.
Assuntos
Infecções Bacterianas , beta-Ciclodextrinas , Humanos , Ácido Hialurônico/química , Polímeros , Silicones/químicaRESUMO
Targeting microglial activation is emerging as a clinically promising drug target for neuropathic pain treatment. Fexofenadine, a histamine receptor 1 antagonist, is a clinical drug for the management of allergic reactions as well as pain and inflammation. However, the effect of fexofenadine on microglial activation and pain behaviors remains elucidated. Here, we investigated nanomedicinal approach that targets more preferentially microglia and long-term analgesics. Fexofenadine significantly abolished histamine-induced microglial activation. The fexofenadine-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Fexo NPs) injection reduced the pain sensitivity of spinal nerve ligation rats in a dose-dependent manner. This alleviation was sustained for 4 days, whereas the effective period by direct fexofenadine injection was 3 h. Moreover, Fexo NPs inhibited microglial activation, inflammatory signaling, cytokine release, and a macrophage phenotype shift towards the alternative activated state in the spinal cord. These results show that Fexo NPs exhibit drug repositioning promise as a long-term treatment modality for neuropathic pain.
Assuntos
Nanopartículas , Neuralgia , Animais , Microglia , Neuralgia/genética , Ratos , Medula Espinal , Nervos Espinhais , Terfenadina/análogos & derivadosRESUMO
With the global spread of severe acute respiratory syndrome coronavirus 2, several vaccines were developed; messenger RNA (mRNA) vaccines have recently been widely used worldwide. However, the incidence of myocarditis following mRNA vaccination is increasing; although the cause of myocarditis has not yet been clearly identified, it is presumed to be caused by a problem in the innate immune system. Immune-mediated thrombocytopenia (ITP) after vaccination is rare but has been reported and is also assumed to occur by the same mechanism. We report the first case of simultaneous myocarditis and ITP after mRNA vaccination. A 38-year-old woman presented with chest pain, mild dyspnea, and sweating after vaccination with mRNA-1273 vaccine (Moderna) 4 days prior to admission. Upon admission to the emergency department, cardiac enzymes were elevated; blood test performed 5 months ago showed normal platelet count, but severe thrombocytopenia was observed upon admission. After administration of intravenous immunoglobulin, the platelet count improved; subsequently, myocarditis was observed on endomyocardial biopsy. Thus, myocarditis and ITP were judged to have occurred simultaneously due to the expression of the innate immune system markers after mRNA vaccination. The patient was discharged on day 6 of admission.
Assuntos
COVID-19 , Miocardite , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Vacinas , Vacina de mRNA-1273 contra 2019-nCoV , Adulto , Vacinas contra COVID-19/efeitos adversos , Feminino , Humanos , Miocardite/complicações , Miocardite/etiologia , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/etiologia , RNA Mensageiro/genética , Trombocitopenia/complicações , Trombocitopenia/etiologia , Vacinação/efeitos adversosRESUMO
Oxygenated water (OW) contains more oxygen than normal drinking water. It may induce oxygen enrichment in the blood and reduce oxidative stress. Hypoxia and oxidative stress could be involved in epilepsy. We aimed to examine the effects of OW-treated vs. control on four rodent models of epilepsy: (1) prenatal betamethasone priming with postnatal N-methyl-D-aspartate (NMDA)-triggered spasm, (2) no prenatal betamethasone, (3) repetitive kainate injection, and (4) intraperitoneal pilocarpine. We evaluated, in (1) and (2), the latency to onset and the total number of spasms; (3) the number of kainate injections required to induce epileptic seizures; (4) spontaneous recurrent seizures (SRS) (numbers and duration). In model (1), the OW-treated group showed significantly increased latency to onset and a decreased total number of spasms; in (2), OW completely inhibited spasms; in (3), the OW-treated group showed a significantly decreased number of injections required to induce epileptic seizures; and in (4), in the OW-treated group, the duration of a single SRS was significantly reduced. In summary, OW may increase the seizure threshold. Although the underlying mechanism remains unclear, OW may provide an adjunctive alternative for patients with refractory epilepsy.
Assuntos
Epilepsia , Roedores , Animais , Ácido Caínico , Água , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Espasmo , Betametasona , OxigênioRESUMO
BACKGROUND: Prenatal stress increases the susceptibility of infants to seizures and is known to be associated with oxidative stress. Recent studies suggest that vitamin E has beneficial effects in various neurological diseases due to its antioxidant properties. In this study, we investigated the relationship between prenatal stress and vitamin E treatment on N-methyl-D-aspartate (NMDA)-induced spasms. METHODS: We used pregnant female Sprague Dawley rats and induced prenatal stress with an injection of betamethasone on G15. They were then treated orally with 200â¯mg/kg vitamin E or saline twice a day from G15-G21. On postnatal day 15, NMDA was administered to trigger spasms in offspring. The total number of spasms and latency to the first spasm were recorded. We also measured oxidative stress in the medial cortex using western blot, and calpain activity, thiobarbituric acid reactive substances (TBARS), glutathione (GSH)/GSH/glutathione disulfide (GSSG), superoxide dismutase (SOD) activity, catalase activity, and nitric oxide (NO) assays. RESULTS: We observed that rats treated with vitamin E while exposed to prenatal stress demonstrated reduced total number and frequency of spasms. Expression of glutamate decarboxylase 67 (GAD67) and K+/Cl- co-transporter (KCC2) were reduced after prenatal stress; this recovered in the vitamin E treated group. Further, expression of calpain 2 was decreased and various markers of oxidative stress (malondialdehyde (MDA), GSH/GSSG, SOD, catalase, and NO) were reduced in the vitamin E treated group. CONCLUSIONS: Our results provide evidence that vitamin E lowers oxidative stress and decreases seizure susceptibility in rat offspring exposed to prenatal stress. Given the well-known safety profile of vitamin E, these results indicate its potential as a strategy for preventing seizures.
Assuntos
Calpaína , Vitamina E , Animais , Antioxidantes , Catalase/metabolismo , Feminino , Glutationa/metabolismo , Estresse Oxidativo , Gravidez , Ratos , Ratos Sprague-Dawley , Espasmo , Superóxido Dismutase/metabolismo , Vitamina E/uso terapêuticoRESUMO
Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated n-methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.
Assuntos
Formaldeído/farmacologia , Inflamação/metabolismo , Dor/induzido quimicamente , Dor/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Medição da Dor/métodos , Ratos , Medula Espinal/metabolismo , Regulação para Cima/fisiologiaRESUMO
Activation of nuclear factor-kappa B (NF-κB) in microglia plays a decisive role in the progress of neuropathic pain, and the inhibitor of kappa B (IκB) is a protein that blocks the activation of NF-κB and is degraded by the inhibitor of NF-κB kinase subunit beta (IKBKB). The role of IKBKB is to break down IκB, which blocks the activity of NF-kB. Therefore, it prevents the activity of NK-kB. This study investigated whether neuropathic pain can be reduced in spinal nerve ligation (SNL) rats by reducing the activity of microglia by delivering IKBKB small interfering RNA (siRNA)-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles. PLGA nanoparticles, as a carrier for the delivery of IKBKB genes silencer, were used because they have shown potential to enhance microglial targeting. SNL rats were injected with IKBKB siRNA-encapsulated PLGA nanoparticles intrathecally for behavioral tests on pain response. IKBKB siRNA was delivered for suppressing the expression of IKBKB. In rats injected with IKBKB siRNA-encapsulated PLGA nanoparticles, allodynia caused by mechanical stimulation was reduced, and the secretion of pro-inflammatory mediators due to NF-κB was reduced. Delivering IKBKB siRNA through PLGA nanoparticles can effectively control the inflammatory response and is worth studying as a treatment for neuropathic pain.
Assuntos
Portadores de Fármacos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Nanopartículas/uso terapêutico , Neuralgia/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , RNA Interferente Pequeno/farmacologia , Animais , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Masculino , Microglia/patologia , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/patologia , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-DawleyRESUMO
Tonic extrasynaptic GABAA receptor (GABAA R) activation is under the tight control of tonic GABA release from astrocytes to maintain the brain's excitation/inhibition (E/I) balance; any slight E/I balance disturbance can cause serious pathological conditions including epileptic seizures. However, the pathophysiological role of tonic GABA release from astrocytes has not been tested in epileptic seizures. Here, we report that pharmacological or genetic intervention of the GABA-permeable Bestrophin-1 (Best1) channel prevented the generation of tonic GABA inhibition, disinhibiting CA1 pyramidal neuronal firing and augmenting seizure susceptibility in kainic acid (KA)-induced epileptic mice. Astrocyte-specific Best1 over-expression in KA-injected Best1 knockout mice fully restored the generation of tonic GABA inhibition and effectively suppressed seizure susceptibility. We demonstrate for the first time that tonic GABA from reactive astrocytes strongly contributes to the compensatory shift of E/I balance in epileptic hippocampi, serving as a good therapeutic target against altered E/I balance in epileptic seizures.
Assuntos
Astrócitos/metabolismo , Bestrofinas/metabolismo , Hipocampo/metabolismo , Inibição Neural/fisiologia , Convulsões/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Bestrofinas/genética , Ácido Caínico , Camundongos , Camundongos Knockout , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Convulsões/genéticaRESUMO
Neonatal ischemic stroke has a higher incidence than childhood stroke. Seizures are the first sign for the need for clinical assessment in neonates, but many questions remain regarding treatments and follow-up modalities. In the absence of a known pathophysiological mechanism, only supportive care is currently provided. Stroke-induced microglia activation and neuroinflammation are believed to play a central role in the pathological progression of neonatal ischemic stroke. We induced a photothrombotic infarction with Rose Bengal in neonatal rats to investigate the effects of pre- and post-treatment with Aspirin (ASA), Clopidogrel (Clop), and Coenzyme Q10 (CoQ10), which are known for their neuroprotective effects in adult stroke. Pre-stroke medication ameliorates cerebral ischemic injury and reduces infarct volume by reducing microglia activation, cellular reactive oxygen species (ROS) production, and cytokine release. Post-stroke administration of ASA, Clop, and CoQ10 increased motor function and reduced the volume of infarction, and the statistical evidence was stronger than that seen in the pre-stroke treatment. In this study, we demonstrated that ASA, Clop, and CoQ10 treatment before and after the stroke reduced the scope of stroke lesions and increased behavioral activity. It suggests that ASA, Clop, and CoQ10 medication could significantly have neuroprotective effects in the neonates who have suffered strokes.
Assuntos
Aspirina/uso terapêutico , Clopidogrel/uso terapêutico , Inflamação , Acidente Vascular Cerebral/prevenção & controle , Ubiquinona/análogos & derivados , Animais , Animais Recém-Nascidos , Aspirina/farmacologia , Isquemia Encefálica , Clopidogrel/farmacologia , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Rosa Bengala/toxicidade , Acidente Vascular Cerebral/induzido quimicamente , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.
Assuntos
Receptor 1 de Quimiocina CX3C/genética , Nanopartículas/química , Neuralgia/tratamento farmacológico , RNA Interferente Pequeno/farmacologia , Nervos Espinhais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C/antagonistas & inibidores , Humanos , Ligadura , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neuralgia/genética , Neuralgia/patologia , Manejo da Dor , Medição da Dor/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , RNA Interferente Pequeno/genética , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia , Nervos Espinhais/metabolismo , Nervos Espinhais/patologiaRESUMO
Several studies have shown that brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), an important molecule for maintaining circadian rhythms, inhibits the growth and metastasis of tumor cells in several types of cancer, including lung, colon, and breast cancer. However, its role in glioblastoma has not yet been established. Here, we addressed the function of BMAL1 in U87MG glioblastoma cells with two approaches-loss and gain of function. In the loss of function experiments, cell proliferation in U87MG cells transfected with small interfering RNA (siRNA) targeting BMAL1 was increased by approximately 24% (small interfering (si)-NC 0.91 ± 0.00 vs. si-BMAL1 1.129 ± 0.08) via upregulation of cyclin B1. In addition, cell migration and invasion of BMAL1 siRNA-treated glioblastoma cells were elevated by approximately 20% (si-NC 51.00 ± 1.53 vs. si-BMAL161.33 ± 0.88) and 209% (si-NC 21.28 ± 1.37 vs. si-BMAL1 44.47 ± 3.48), respectively, through the accumulation of phosphorylated-AKT (p-AKT) and matrix metalloproteinase (MMP)-9. Gain of function experiments revealed that adenovirus-mediated ectopic expression of BMAL1 in U87MG cells resulted in a 19% (Adenovirus (Ad)-vector 0.94± 0.03 vs. Ad-BMAL1 0.76 ± 0.03) decrease in cell proliferation compared with the control via downregulation of cyclin B1 and increased early and late apoptosis due to changes in the levels of BCL2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and cleaved caspase-3. Likewise, cell migration and invasion were attenuated by approximately 24% (Ad-vector 55.00 ± 0.00 vs. Ad-BMAL1 41.83 ± 2.90) and 49% (Ad-vector 70.01 ± 1.24 vs. Ad-BMAL1 35.55 ± 1.78), respectively, in BMAL1-overexpressing U87MG cells following downregulation of p-AKT and MMP-9. Taken together, our results suggest that BMAL1 acts as an anti-cancer gene by altering the proliferation, migration, and invasion of glioblastoma cells. Therefore, the BMAL1 gene could be a potential therapeutic target in the treatment of glioblastoma.
Assuntos
Fatores de Transcrição ARNTL/metabolismo , Neoplasias Encefálicas/metabolismo , Ciclina B1/metabolismo , Glioblastoma/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição ARNTL/análise , Fatores de Transcrição ARNTL/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina B1/análise , Regulação para Baixo , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Metaloproteinase 9 da Matriz/análise , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/análise , Interferência de RNARESUMO
INTRODUCTION: The aim of this study was to investigate the location and distribution patterns of neurovascular structures and determine the effective injection point in the tarsal tunnel for heel pain. METHODS: Fifteen adult non-embalmed cadavers with a mean age of 71.5 years were studied. The most inferior point of the medial malleolus of the tibia (MM) and the tuberosity of the calcaneus (TC) were identified before dissection. A line connecting the MM and TC was used as a reference line. The reference point was expressed in absolute distance along the reference line using the MM as the starting point. For measurements using MRI, the depth from the skin was measured to inferior at an interval of 1 cm from the MM. RESULTS: The posterior tibial artery, lateral plantar nerve, and medial plantar nerve were located from 29.0 to 37.3% of the reference line from the MM. The distribution frequencies of the medial calcaneal nerve on the reference line from the MM were 0%, 8.60%, 37.15%, 37.15%, and 17.10%, respectively. The mean depth of the neurovascular structures was 0.3 cm. DISCUSSION: This study recommended an effective injection site from 45.0 to 80.0% of the reference line.
Assuntos
Neuralgia/terapia , Manejo da Dor/métodos , Artérias da Tíbia/anatomia & histologia , Nervo Tibial/anatomia & histologia , Neuropatia Tibial/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cadáver , Calcâneo/anatomia & histologia , Calcâneo/diagnóstico por imagem , Dissecação , Feminino , Glucocorticoides/administração & dosagem , Calcanhar/anatomia & histologia , Calcanhar/diagnóstico por imagem , Humanos , Injeções Intralesionais/efeitos adversos , Injeções Intralesionais/métodos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuralgia/etiologia , Manejo da Dor/efeitos adversos , Artérias da Tíbia/diagnóstico por imagem , Artérias da Tíbia/lesões , Nervo Tibial/diagnóstico por imagem , Nervo Tibial/lesões , Neuropatia Tibial/complicações , Adulto JovemRESUMO
Microglia play a critical role in neuropathic pain. Since upregulated Foxp3 in microglia enhances tissue repair by resolving neuroinflammation in excitotoxin-induced neuronal death, it may attenuate neuropathic pain in a similar manner. Therefore, this study tests whether Foxp3 introduced with poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (Foxp3 NPs) can alleviate neuropathic pain by inhibiting microglia activity. The prepared Foxp3 NPs had an anti-inflammatory effect on lipopolysaccharide-stimulated BV2 cells in vitro, and localized to spinal microglia in vivo. Further, the Foxp3 NPs significantly attenuated pain behavior induced by spinal nerve ligation in rats for 7 days by suppressing microglial activity, followed by the downregulation of pro-nociceptive genes and the upregulation of anti-nociceptive genes in the spinal dorsal horn. Collectively, these data suggest that Foxp3 NPs effectively relieve neuropathic pain in animals by reducing microglia activity and subsequent modulation of neuroinflammation, and may be of therapeutic value in the treatment of neuropathic pain.
Assuntos
Comportamento Animal , Fatores de Transcrição Forkhead/metabolismo , Nanopartículas/química , Neuralgia/terapia , Plasmídeos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nervos Espinhais/patologia , Animais , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Ligadura , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuralgia/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1ß and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL.