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Declining estrogen production in postmenopausal females causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. Although clinical drugs are currently available for the treatment of osteoporosis, sustained medication use is accompanied by serious side effects. Corydalis bungeana Herba, a famous traditional Chinese herb listed in the Chinese Pharmacopoeia Commission, constitutes various traditional Chinese Medicine prescriptions, which date back to thousands of years. One of the primary active components of C. bungeana Turcz. is Corynoline (Cor), a plant isoquinoline alkaloid derived from the Corydalis species, which possesses bone metabolism disease therapeutic potential. The study aimed at exploring the effects as well as mechanisms of Cor on osteoclast formation and bone resorption. TRAcP staining, F-actin belt formation, and pit formation were employed for assessing the osteoclast function. Western blot, qPCR, network pharmacology, and docking analyses were used for analyzing the expression of osteoclast-associated genes and related signaling pathways. The study focused on investigating how Cor affected OVX-induced trabecular bone loss by using a mouse model. Cor could weaken osteoclast formation and function by affecting the biological receptor activators of NF-κB and its ligand at various concentrations. Mechanistically, Cor inhibited the NF-κB activation, and the MAPKs pathway stimulated by RANKL. Besides, Cor enhanced the protein stability of the Nrf2, which effectively abolished the RANKL-stimulated ROS generation. According to an OVX mouse model, Cor functions in restoring bone mass, improving microarchitecture, and reducing the ROS levels in the distal femurs, which corroborated with its in vitro antiosteoclastogenic effect. The present study indicates that Cor may restrain osteoclast formation and bone loss by modulating NF-κB/MAPKs and Nrf2 signaling pathways. Cor was shown to be a potential drug candidate that can be utilized for the treatment of osteoporosis.
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Alcaloides de Berberina , Resorción Ósea , Osteoporosis , Femenino , Humanos , Osteogénesis , FN-kappa B/genética , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Osteoclastos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/genética , Resorción Ósea/metabolismo , Osteoporosis/tratamiento farmacológico , Osteoporosis/genética , Osteoporosis/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Diferenciación CelularRESUMEN
BACKGROUND: Type 2 diabetes is often linked with osteoporosis (T2DOP), a condition that accelerates bone degeneration and increases the risk of fractures. Unlike conventional menopausal osteoporosis, the diabetic milieu exacerbates the likelihood of fractures and osteonecrosis. In particular poliumoside (Pol), derived from Callicarpa kwangtungensis Chun, has shown promising anti-oxidant and anti-inflammatory effects. Yet, its influence on T2DOP remains to be elucidated. PURPOSE: The focus of this study was to elucidate the influence of Pol in HGHF-associated ferroptosis and its implications in T2DOP. STUDY DESIGN: A murine model of T2DOP was established using a minimal dosage of streptozotocin (STZ) through intraperitoneal infusion combined with a diet high in fat and sugar. Concurrently, to mimic the diabetic condition in a lab environment, bone mesenchymal stem cells (BMSCs) were maintained in a high-glucose and high-fat (HGHF) setting. METHODS: The impact of Pol on BMSCs in an HGHF setting was determined using methods, such as BODIPY-C11, FerroOrange staining, mitochondrial functionality evaluations, and Western blot methodologies, coupled with immunoblotting and immunofluorescence techniques. To understand the role of Pol in a murine T2DOP model, techniques including micro-CT, hematoxylin and eosin (H&E) staining, dual-labeling with calcein-alizarin red, and immunohistochemistry were employed for detailed imaging and histological insights. RESULTS: Our findings suggest that Pol acts against HGHF-induced bone degradation and ferroptosis, as evidenced by an elevation in glutathione (GSH) and a decline in malondialdehyde (MDA) levels, lipid peroxidation, and mitochondrial reactive oxygen species (ROS). Furthermore, Pol treatment led to increased bone density, enhanced GPX4 markers, and reduced ROS in the distal femur region. On investigating the underlying mechanism of action, it was observed that Pol triggers the Nrf2/GPX4 pathway, and the introduction of lentivirus-Nrf2 negates the beneficial effects of Pol in HGHF-treated BMSCs. CONCLUSION: Pol is effective in treating T2DOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.
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Ácidos Cafeicos , Diabetes Mellitus Tipo 2 , Ferroptosis , Glicósidos , Osteoporosis , Animales , Ratones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & controlRESUMEN
BACKGROUND: Osteoporosis is a prevalent bone metabolic disease in menopause, and long-term medication is accompanied by serious side effects. Estrogen deficiency-mediated hyperactivated osteoclasts is the initiating factor for bone loss, which is regulated by nuclear factor-κB (NF-κB) signaling. Safranal (Saf) is a monoterpene aldehyde produced from Saffron (Crocus sativus L.) and possesses multiple biological properties, particularly the anti-inflammatory property. However, Saf's role in osteoporosis remains unknown. PURPOSE: This study aims to validate the role of Saf in osteoporosis and explore the potential mechanism. STUDY DESIGN: The RANKL-exposed mouse BMM (bone marrow monocytes) and the castration-mediated osteoporosis model were applied to explore the effect and mechanism of Saf in vitro and in vivo. METHOD: The effect of Saf on osteoclast formation and function were assessed by TRAcP staining, bone-resorptive experiment, qPCR, immunoblotting and immunofluorescence, etc. Micro-CT, HE, TRAcP and immunohistochemical staining were performed to estimate the effects of Saf administration on OVX-mediated osteoporosis in mice at imaging and histological levels. RESULTS: Saf concentration-dependently inhibited RANKL-mediated osteoclast differentiation without affecting cellular viability. Meanwhile, Saf-mediated anti-osteolytic capacity and Sirt1 upregulation were also found in ovariectomized mice. Mechanistically, Saf interfered with NF-κB signaling by activating Sirt1 to increase p65 deacetylation and inactivating IKK to decrease IκBα degradation. CONCLUSION: Our results support the potential application of Saf as a therapeutic agent for osteoporosis.
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Osteoporosis , Animales , Ratones , Ratones Endogámicos C57BL , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Estrógenos/deficiencia , Estrógenos/metabolismo , Femenino , Osteoclastos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Ovariectomía , FN-kappa B/metabolismo , AcetilaciónRESUMEN
Curcumin, a polyphenolic compound extracted from curcuma longa, acts as a nontoxic matter with anti-oxidant and anti-inflammatory effects as well as antiproliferative activities. Here, our research aimed to explore the neuroprotective effects of curcumin both in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) in vivo and 6-OHDA-lesioned PC12 cells in vitro. In vitro, 6-OHDA caused a distinct decrease in cell viability of PC12 cells (150 µM). With the incubation of curcumin (1 µM), 6-OHDA-induced apoptosis was suppressed, increasing the autophagy markers (LC3-II/LC3-I, Beclin-1) and inhibiting phosphor-AKT/AKT, phosphor-mTOR/mTOR. In vivo, curcumin (50 mg/kg) reduced the accumulation of a-synuclein and led to higher parkinsonian disability scores in 6-OHDA-lesioned PD rats, contributing to induction of autophagy through inhibiting AKT/mTOR signal pathway. Moreover, treatment with autophagy inhibitors, such as 3-MA and chloroquine, abolished the neuroprotective effects of curcumin as evidence by compromised autophagy and declined motor behavior in PD rats. In conclusion, the present study demonstrated that curcumin repressed PC12 cell death in vitro and improved parkinsonian disability scores in vivo by inhibiting AKT/mTOR signaling pathway which mediated by autophagy, indicating a potential value of curcumin in the therapeutic intervention of Parkinson's disease.
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Curcumina , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Autofagia , Curcumina/farmacología , Curcumina/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , RatasRESUMEN
This study sought to investigate and evaluate a modified axial translaminar screw fixation for treating odontoid fractures. We performed a retrospective study at Wenzhou Medical University Affiliated Second Hospital between March 2016 and June 2018. We retrospectively collected and analyzed the medical records of 23 cases with odontoid fractures. All patients were identified as type II odontoid fractures without neurological deficiency and serious diseases following the classification of Anderson. The average age, gender ratio, and body mass index (BMI) were 54.3 ± 11.1 years, 12 men to 11 women, and 22.6 ± 2.4 kg/m2 , respectively. Patients in this study accepted screw fixation using our modified axial translaminar screw fixation combined with atlas pedicle or lateral mass screw fixation. Within the technique, a small cortical "window" was dug in the middle of the axial contralateral lamina, such that the screws in the lamina were visualized to prevent incorrectly implanting the posterior spinal canal through the visualized "window." A total of 46 bone screws were accurately inserted into the axial lamina without using fluoroscopy. The length of all translaminar screws ranged between 26 and 30 mm, while the diameter was 3.5 mm. During the follow-up survey, the visual analog scale (VAS) and neck disability index (NDI) were measured. We provide a simple modification of Wright's elegant technique with the addition of "visualized windows" at the middle of the axial lamina. In all patients, screws were inserted accurately without bony breach and the screw angle was 56.1 ± 3.0°. Mean operative time was 102 ± 28 min with an average blood loss of 50 ± 25 mL. Postoperative hemoglobin and mean length of hospital stay were 12.0 ± 1.4 g/dL and 10.4 ± 3.4 days, respectively. The average follow-up time of all cases was 14.7 months and no internal fixation displacement, loosening, or breakage was found. All patients with odontoid fractures reported being satisfied with the treatment during the recheck period and good clinical outcomes were observed. At 1, 6, and 12 months, NDI and VAS showed that the symptoms of neck pain and limitations of functional disability improved significantly during follow-up. Our results suggest that the modified translaminar screw fixation technique can efficiently treat Anderson type II odontoid fracture, followed by the benefits of less soft tissue dissection, simple operation, no fluoroscopy, and accurate placement of screws.
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Apófisis Odontoides , Fracturas de la Columna Vertebral , Fusión Vertebral , Adulto , Anciano , Tornillos Óseos , Femenino , Fijación Interna de Fracturas/métodos , Humanos , Masculino , Persona de Mediana Edad , Apófisis Odontoides/diagnóstico por imagen , Apófisis Odontoides/lesiones , Apófisis Odontoides/cirugía , Estudios Retrospectivos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer's disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients' phenotypes.
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Alzheimer's disease (AD) is the most common cause of dementia in elderly that serves to be a formidable socio-economic and healthcare challenge in the 21st century. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes contributing to the development of AD pathologies, namely amyloid-ß plaques (Aß) and neurofibrillary tangles (NFT). Here, we highlight the recent advances in the association between impaired mitophagy and AD, as well as delineate the potential underlying mechanisms. Furthermore, we conduct a systematic review the current status of mitophagy modulators and analyzed their relevant mechanisms, evaluating on their advantages, limitations and current applications in clinical trials for AD patients. Finally, we describe how deep learning may be a promising method to rapid and efficient discovery of mitophagy inducers as well as general guidance for the workflow of the process.
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BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) is a new type of administration that results in steadier levodopa plasma concentrations in advanced Parkinson's disease (PD) patients and effectively reduces poor mobility and dyskinesia. METHODS: Electronic databases were searched up to January 1, 2018. The inclusion criteria for this review were as follows: LCIG vs oral medication in advanced PD patients. RESULTS: Five trials, with a total of 198 patients, met all the inclusion criteria. The quality score of these studies ranged from 3 to 5. Two clinical trials showed that compared with oral medication, LCIG had a better treatment effect on on-time with troublesome dyskinesia (TSD) (p = 0.02) and on-time without TSD (p < 0.00001) in advanced PD patients. In addition, four of the 5 studies showed that the LCIG may have better efficacy than oral medication for improving the scores of the UPDRS, and two studies found that LCIG demonstrated better efficacy for improving the PDQ-39 scores. The video recording results indicated a potential decline in both dyskinesia and the "off" state in LCIG-treated patients. The incidence of adverse events was not significantly different between the LCIG and oral medication groups. CONCLUSION: Compared with oral treatment, LCIG exerts its effectiveness, mostly by reducing the time of on-time with TSD, increasing the time of on-time without TSD and scores of UPDRS and PDQ-39. It is suggesting that LCIG was likely to be a new type of administration used in clinical applications. However, due to methodological flaws, these findings should be viewed with caution, and more RCTs are needed in the field to complement our findings.
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Antiparkinsonianos/uso terapéutico , Carbidopa/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Administración Oral , Antiparkinsonianos/administración & dosificación , Carbidopa/administración & dosificación , Combinación de Medicamentos , Geles/administración & dosificación , Geles/uso terapéutico , Humanos , Levodopa/administración & dosificaciónRESUMEN
PURPOSE: Because of the complex cervical vertebral embryology and some normal variations, the atlantoadental interval (ADI) was not suitable for the evaluation of the anatomic relationship between the atlas and axial in children less than 2 years old. And the influence of the age and gender on the anatomic relationship between atlas and axial in children was still unclear. Two novel parameters, atlas-axis anteroposterior distance (AAAD) and atlas-axis lateral distance (AALD), were invented to evaluate the anatomic relationship between the atlas and axis in the children no more than 8 years old with different age and gender. METHODS: Cross-sectional computed tomography (CT) scans of the atlantoaxial joint for 140 randomly selected pediatric patients no more than 8 years old were analyzed. On the ideal CT reconstruction images, AAAD, AALD, atlantoaxial lateral bending angle (AALB), and atlantoaxial rotation angle (AARA) were measured. RESULTS: There was no statistically significant difference between the mean AAAD in different age and gender groups. The 99% confidence interval for AAAD was 7.12-7.82 mm. There was no significant correlation between AAAD and AALB/AARA and AALD and AALB/AARA. CONCLUSION: The AAAD was less than 7.12 mm or much than 7.82 mm that suggested a possible instability in the atlantoaxial joint and could help the diagnosis of the atlantoaxial instability in children no more than 8 years old. There was no difference between the mean AAAD of pediatric patients no more than 8 years old in different age and gender groups.
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Vértebra Cervical Axis/anatomía & histología , Atlas Cervical/anatomía & histología , Tomografía Computarizada por Rayos X , Factores de Edad , Puntos Anatómicos de Referencia , Vértebra Cervical Axis/diagnóstico por imagen , Atlas Cervical/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Factores SexualesRESUMEN
Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa-induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal ß-arrestin2 overexpression significantly reduces LID severity and have indicated that ß-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate ß-arrestin2. We found that striatal overexpression of AAV-mediated ß-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of ß-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of ß-arrestin2. Finally, overexpression of ß-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of ß-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of ß-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of ß-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats.
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Antiparkinsonianos , Discinesia Inducida por Medicamentos/terapia , Levodopa , Neostriado/metabolismo , Enfermedad de Parkinson Secundaria/terapia , Arrestina beta 2/biosíntesis , Arrestina beta 2/genética , Adenoviridae/genética , Animales , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Discinesia Inducida por Medicamentos/psicología , Eliminación de Gen , Terapia Genética , Vectores Genéticos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neostriado/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Fosfoproteínas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Factores de Transcripción/efectos de los fármacosRESUMEN
Prolonged pulsatile administration of Levodopa (L-dopa) can generate L-dopa-induced dyskinesia (LID). Numerous research has reported that continuous dopamine delivery (CDD) was useful in reducing the severity of LID. 6-OHDA lesioned rats were divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide) or Levodopa/benserazide PLGA microsphere (LBPM) for 3 weeks. rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablation of ß-arrestin2. We found that LBPM developed less AIM severity compared with standard L-dopa administration, whereas selective deletion of ß-arrestin2 in striatum neurons dramatically enhanced the severity of dyskinesia by LBPM. On the contrary, the effects of LBPM in terms of ALO AIM were further relieved by ß-arrestin2 overexpression. Furthermore, no significant change in motor behavior was seen either in inhibition or overexpression of ß-arrestin2. In short, our experiments provided evidence that LBPM's prevention of LID behavior was likely due to ß-arrestin2, suggesting that a therapy modulating ß-arrestin2 may offer a more efficient anti-dyskinetic method with a low risk of untoward effects.
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The cause of the L-dopa-induced dyskinesia (LID) has been ascribed to G-protein coupled receptor (GPCR) supersensitivity and uncontrolled downstream signaling. It is now supposed that ß-arrestin2 affects GPCR signaling through its ability to scaffold various intracellular molecules. We used the rAAV (recombinant adeno-associated virus) vectors to overexpress and ablation of ß-arrestin2. L-dopa-induced changes in expression of signaling molecules and other proteins in the striatum were examined by western blot and immunohistochemically. Our data demonstrated that via AAV-mediated overexpression of ß-arrestin2 attenuated LID performance in 6-OHDA-lesioned rodent models. ß-arrestin2 suppressed LID behavior without compromising the antiparkinsonian effects of L-dopa. Moreover, we also found that the anti-dyskinetic effect of ß-arrestin2 was reversed by SKF38393, a D1R agonist. On the contrary, the rat knockdown study demonstrated that reduced availability of ß-arrestin2 deteriorated LID performance, which was counteracted by SCH23390, a D1R antagonist. These data not only demonstrate a central role for ß-arrestin2/GPCR signaling in LID, but also show the D1R signal pathway changes occurring in response to dopaminergic denervation and pulsatile administration of L-dopa.
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Levodopa/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Receptores de Dopamina D1/metabolismo , Arrestina beta 2/metabolismo , Adenoviridae , Animales , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Masculino , Ratas , Arrestina beta 2/genéticaRESUMEN
Background: Modulation of Metabotropic glutamate receptor 5 (mGluR5) may be a novel therapeutic approach to manage Parkinson's disease (PD) Patients with L-dopa-induced dyskinesia (LID). Objectives: The objective of this meta-analysis was to evaluate the effects of mGluR5 antagonists for the treatment of LID patients. Methods: Several electronic databases were consulted up to July 30, 2017. Randomized clinical trials (RCTs) that compared mGluR5 antagonists vs. placebo in LID patients were included. Pooled weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using random-effects models. Results: Nine trials including 776 patients met all inclusion criteria. We pooled the whole data and found apparent difference between mGluR5 antagonists and placebo in terms of mAIMS (p = 0.010). However, there was no significant improvements on antidyskinetic in terms of LFADLDS (p = 0.42) and UPDRS Part IV (p = 0.20). Meanwhile, the effect size of UPDRS part III was similar in mGluR5 antagonist groups with in placebo groups (p = 0.25). Adverse events incidence was higher with mGluR5 antagonists than with placebo, especially at the expense of increased dizziness (16.3 vs. 4.3%), visual hallucination (10.1 vs. 1.1%), or fatigue (10.1 vs. 4.8%). Conclusions: mGluR5 antagonists had a greater treatment effect on the mAIMS in LID patients, however, there was no improvements on antidyskinetic in terms of LFADLDS and UPDRS Part IV compared with placebo. According to these results, we unable to recommend mGluR5 antagonists for the routine treatment of LID patients right now.
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Excessive extracellular matrix degradation and chondrocyte apoptosis are the pathological features of osteoarthritis (OA). The ability of flavonoid compounds isolated from Chinese hawthorn leaves to exert protective effects on several diseases, via inhibition of oxidative stress and inflammation, has been demonstrated in several studies. This study explored the effects of vitexin on chondrocytes, and the underlying mechanisms thereof. Vitexin, an active ingredient in hawthorn leaf extracts, was shown to exert protective effects on chondrocytes, by inhibiting the expression of GRP78 and PDI, and an apoptotic protein (CHOP) induced by interleukin-1ß. It also modulated thapsigargin-induced upregulation of GRP78 and PDI and subsequently an apoptotic protein (CHOP). Among rat chondrocytes, both the ER stress-activated nuclear factor kappa B (NF-κB) pathway and the induced expression of inflammatory cytokines (IL-6 and TNF-α) were significantly inhibited by vitexin. Finally, vitexin attenuated the progression of OA in vivo in rats. Taken together, all data demonstrate the relationship of ER stress and inflammation in the progression of OA, the ability of vitexin to protect chondrocytes and thus its therapeutic potential in patients with OA.
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Apigenina/farmacología , Apoptosis/efectos de los fármacos , Cartílago/efectos de los fármacos , Condrocitos/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Inflamación/tratamiento farmacológico , Animales , Cartílago/patología , Caspasa 3/genética , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Condrocitos/metabolismo , Modelos Animales de Enfermedad , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Interleucina-1beta/farmacología , Masculino , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Sincalida/genética , Sincalida/metabolismo , Tapsigargina/farmacología , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Long-term treatment with L-dopa leads to involuntary aimless movements called L-dopa-induced dyskinesia (LID) has hindered its use in Parkinson's disease (PD) patients. Emerging evidence suggests a possible role of CaMKIIa and its interacting partners in the development of LID. In this study, we found that CaMKIIa was found to form complexes with GluN2B after chronic administration of L-dopa in adult rat striatal neurons. Intrastriatal injection of KN-93 significantly reduced the level of GluN2B in CaMKIIa precipitates with a dose dependent response, as well as reduced the Global ALO AIM score without ablation of the therapeutic response to L-dopa. In parallel, intrastriatal injection of MK-801 significantly alleviated the level of CaMKIIa in GluN2B precipitates compared to LID group (p < 0.01), and this is accompanied by realizing improvement of the Global ALO AIM score also without affect the efï¬cacy of L-dopa. In summary, the present study indicated that CaMKIIa-GluN2B interaction had an important role in the development of LID. Disrupt of this link by intrastriatal infusion of KN-93 or MK-801 ameliorated dyskinesia in 6-OHDA-lesioned PD rats.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Bencilaminas/farmacología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Maleato de Dizocilpina/farmacología , Discinesia Inducida por Medicamentos/patología , Levodopa , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Ratas Sprague-Dawley , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: Acute Ischemic Stroke (AIS) is a common cause of death worldwide and the leading cause of long-term severe disability. Endovascular bridging therapies (EBT), including endovascular thrombectomy (ET) and intra-arterial thrombolytic (IAT), have been recommended to realize a favorable functional outcome for AIS patients. METHODS: An overview of meta-analyses of primary randomized controlled trial (RCT) studies was performed evaluating EBT for AIS patients compared with usual care. RESULTS: Ten meta-analyses were included in this overview. ET was associated with a higher incidence of achieving functional outcome improvement, defined as a modified Rankin scale of 0 to 1 (mRS, p = 0.003), 0 to 2 (p < 0.00001), and 0 to 3 (p = 0.005). The risk of symptomatic intracranial hemorrhage (sICH) rate and all-cause mortality were similar between the two groups. Moreover, IAT treatment was also related to significantly improved outcomes in terms of the mRS score (p < 0.05), but no significant difference in rates of sICH and mortality within 90 days. CONCLUSIONS: In conclusion, our analysis supports that EBT, regardless of format (e.g., ET or IAT), is superior to the best medical therapy alone (e.g., IVT) in terms of mRS score in patients with AIS. In addition, the safety of EBT is similar to IVT.
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Isquemia Encefálica/cirugía , Procedimientos Endovasculares/métodos , Trombolisis Mecánica/métodos , Accidente Cerebrovascular/cirugía , Trombectomía/métodos , Enfermedad Aguda , Isquemia Encefálica/mortalidad , Procedimientos Endovasculares/efectos adversos , Humanos , Trombolisis Mecánica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/mortalidad , Trombectomía/efectos adversosRESUMEN
BACKGROUND: Transpedicular screw fixation has a biomechanical advantage of improving fusion rates. In posterior thoracolumbar immobilization, a large number of screws cause perforation to the pedicle or vertebral body. Radiography and computed tomography (CT) have been used to minimize this complication. The ability of ultrasound (US) to detect the pedicle breach during placement of the screw is unknown. The aim of this study was to evaluate the sensitivity of US for detecting breaches. METHODS: A B-type transducer was used to scan 216 titanium pins inserted into cadaveric pedicles. Of the pins, 180 were intentionally misplaced: 90 pins breached the lateral wall of the pedicle, and 90 pins pierced the anterior wall of the vertebral body. US images were reviewed by 3 examiners blinded to both the procedure and the corresponding CT findings. The perforation length of pins was measured by 3 radiologists on CT images. RESULTS: CT data were divided into 2 groups. In group 1 (perforation length 0-2 mm), sensitivity of US for detecting lateral wall and anterior wall perforation was 80.95% and 76.42%, respectively; in group 2 (perforation length 2-4 mm), sensitivity was 94.79% and 91.93%. Overall sensitivity of US to detect lateral wall and anterior wall perforation was 89.63% and 86.30%, respectively. The sensitivity of US for detecting perforation was greater in the lateral wall than in the anterior wall. Sensitivity of US was greater in group 2 than group 1 for both lateral and anterior perforation. CONCLUSIONS: US can be applied to detect perforation of ≤4 mm. Use of US may improve patient safety.
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Vértebras Lumbares/cirugía , Tornillos Pediculares , Vértebras Torácicas/cirugía , Ultrasonografía , Cadáver , Humanos , Fijadores Internos , Masculino , Enfermedades de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Tomografía Computarizada por Rayos X , Ultrasonografía/métodosRESUMEN
BACKGROUND: Surgical wound closure directly influences spinal surgical efficiency and several postoperative complications. The traditional suture technique is time-consuming and associated with greater rates of complications. Bidirectional absorbable barbed sutures seem to compensate for some of the limitations of traditional suture; however, they rarely are reported in spinal surgery. We designed a novel suture technique for use in thoracolumbar spinal surgery. METHODS: The data of 189 patients with traumatic thoracolumbar fractures were analyzed between bidirectional barbed suture closure and traditional interrupted suture closure. Data of operative time, wound closure time, length of incision, intraoperative blood loss, complications of wound dehiscence and postoperative hematoma, cost, and neurologic status were collected. RESULTS: No significant differences were observed in the baseline demographics of included patients. Compared with the traditional suturing group, the barbed sutures decreased the mean operative time (P = 0.037), suture time (P < 0.01), and mean suturing time (P < 0.01) significantly, although no statistically significant differences were found in blood loss (P = 0.724) and neurologic functional scores (preoperative: P = 0.901; 3 months after surgery: P = 0.208; final follow-up assessments: P = 0.163), and no statistically significant differences were found in rates of postoperative infection, hematoma, and wound dehiscence. CONCLUSIONS: Our findings suggest that the novel knotless barbed suture has comparable strength to traditional sutures, with the advantage of less suturing time. It is an efficient, safe technique, and alternative choice for patients with thoracolumbar fracture after posterior surgery.
Asunto(s)
Vértebras Lumbares/cirugía , Tempo Operativo , Fracturas de la Columna Vertebral/cirugía , Técnicas de Sutura/tendencias , Vértebras Torácicas/cirugía , Adulto , Femenino , Estudios de Seguimiento , Humanos , Vértebras Lumbares/lesiones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Fracturas de la Columna Vertebral/diagnóstico , Técnicas de Sutura/normas , Vértebras Torácicas/lesionesRESUMEN
N-acetyl cysteine (NAC) has been extensively reported to exert neuroprotective effects on the central nervous system. Oxidative stress may contribute to the underlying mechanisms causing Alzheimer's disease (AD). The effect of NAC against oxidative stress injury was investigated in a cellular model of AD in the present study and the underlying mechanisms were revealed. The neuroprotective action of NAC (1, 10, 100 and 1,000 µmol/l) on a cellular model of AD [hydrogen peroxide (H2O2)induced (3, 30 and 300 µmol/l) toxicity in primary rat hippocampus neurons] demonstrated the underlying mechanisms. Cytotoxicity was measured using the MTT assay, and light microscopy and the dichloro-dihydro-fluorescein diacetate method were used to detect the reactive oxygen species (ROS) levels. Furthermore, the levels of mitogen-activated protein kinases (MAPKs) signal transduction and tau protein phosphorylation were measured via western blotting. NAC (100 µmol/l) protected hippocampus neurons against H2O2mediated toxicity, as evidenced by enhanced cell viability. Using MTT assay and light microscopy for the observation of cell death, NAC ameliorated cell viability, which was induced by H2O2 injury (P<0.05). NAC was found to mitigate the excessive production of ROS (P<0.05). Another mechanism involved in the neuroprotective action of NAC may be its ability to inhibit MAPK signal transduction following H2O2 exposure. In addition, NAC may protect cells against H2O2induced toxicity by attenuating increased tau phosphorylation. Thus, the protective ability of NAC is hypothesized to result from inhibition of oxidative stress and downregulation of MAPK signal transduction and tau phosphorylation.
Asunto(s)
Acetilcisteína/farmacología , Antioxidantes/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipocampo/lesiones , Peróxido de Hidrógeno/efectos adversos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neuronas/enzimología , Fármacos Neuroprotectores/farmacología , Animales , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/enzimología , Lesiones Encefálicas/patología , Hipocampo/enzimología , Hipocampo/patología , Peróxido de Hidrógeno/farmacología , Neuronas/patología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUNDS: Long non-coding RNA (LncRNA) have been reported to be involved in the pathogenesis of neurodegenerative diseases, but whether it can serve as a biomarker for Alzheimer disease (AD) is not yet known. METHODS: The present study selected four specific LncRNA (17A, 51A, BACE1 and BC200) as possible AD biomarker. RT-qPCR was performed to validate the LncRNA. Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were applied to study the potential of LncRNA as a biomarker in a population of 88 AD patients and 72 control individuals. RESULTS: We found that the plasma LncRNA BACE1 level of AD patients was significantly higher than that of healthy controls (p = 0.006). Plasma level of LncRNA 17A, 51A and BC200 did not show a significant difference between two groups (p = 0.098, p = 0.204 and p = 0.232, respectively). ROC curve analysis showed that LncRNA BACE1 was the best candidate of these LncRNA (95% CI: 0.553-0.781, p = 0.003). In addition, no correlation was found for expression of these LncRNA in both control and AD groups with age or MMSE scale (p > 0.05). CONCLUSIONS: Our present study compared the plasma level of four LncRNA between AD and non-AD patients, and found that the level of the BACE1 is increased in the plasma of AD patients and have a high specificity (88%) for AD, indicating BACE1 may be a potential candidate biomarker to predict AD.