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1.
J Neurotrauma ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33297828

RESUMO

Traumatic spinal cord injury (SCI) often causes micturition dysfunction. We recently discovered a low level of spinally-derived dopamine (DA) that regulates recovered bladder and sphincter reflexes in SCI female rats. Considering substantial sexual dimorphic features in the lower urinary tract, it is unknown if the DA-ergic mechanisms act in the male. Histological analysis showed a similar distribution of tyrosine hydroxylase (TH)+ neurons in the lower cord of male rats and the number increased following thoracic SCI. Subsequently, focal electrical stimulation in slices obtained from L6/S1 spinal segments of SCI rats elicited detectable DA release with fast scan cyclic voltammetry. Using bladder cystometrogram and external urethral sphincter (EUS) electromyography in SCI male rats, intravenous (i.v.) administration of SCH 23390, a D1-like receptor (DR1) antagonist, induced significantly increased tonic EUS activity and a trend of increased residual volume, whereas activation of these receptors with SKF 38393 did not influence the reflex. Meanwhile, blocking spinal D2-like receptors (DR2) with remoxipride had no effect but stimulating these receptors with quinpirole elicited EUS bursting to increase voiding volume. Furthermore, intrathecal (i.t.) delivery of SCH 23390 and quinpirole resulted in similar responses to those with i.v. delivery, respectively, which indicates the central action regardless of delivery route. In addition, metabolic cage assays showed that quinpirole increased the voiding frequency and total voiding volume in spontaneous micturition. Collectively, spinal DA-ergic machinery regulates recovered micturition reflex following SCI in male rats; spinal DR1 tonically suppress tonic EUS activity to enable voiding and activation of DR2 facilitates voiding.

2.
Chempluschem ; 85(8): 1737-1746, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32790226

RESUMO

A facile approach is reported for the preparation of dirhodium coordination polymers [Rh2 (L1)2 ]n (Rh2 -L1) and [Rh2 (L2)2 ]n (Rh2 -L2; L1=N,N'-(pyromellitoyl)-bis-L-phenylalanine diacid anion, L2=bis-N,N'-(L-phenylalanyl) naphthalene-1,4,5,8-tetracarboxylate diimide) from chiral dicarboxylic acids by ligand exchange. Multiple techniques including FTIR, XPS, and 1 H→13 C CP MAS NMR spectroscopy reveal the formation of the coordination polymers. 19 F MAS NMR was utilized to investigate the remaining TFA groups in the obtained coordination polymers, and demonstrated near-quantitative ligand exchange. DR-UV-vis and XPS confirm the oxidation state of the Rh center and that the Rh-single bond in the dirhodium node is maintained in the synthesis of Rh2 -L1 and Rh2 -L2. Both coordination polymers exhibit excellent catalytic performance in the asymmetric cyclopropanation reaction between styrene and diazooxindole. The catalysts can be easily recycled and reused without significant reduction in their catalytic efficiency.

3.
Biomed Res Int ; 2020: 8143754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733956

RESUMO

The proteasome inhibitor bortezomib (BTZ) is a potent first-line anticancer drug for multiple myeloma; nonetheless, it induced peripheral neuropathy. It has been suggested that many cytokines may play a role in mediating neuropathic pain, but the underlying molecular mechanism is not fully understood. Recent studies have shown that neuropathic pain is closely related to the purinergic ligand-gated ion channel 7 receptor (P2X7R), one of the P2X receptors, which is richly expressed in glial cells. P2X7-p38 pathway is correlated with microglia- and satellite glial cell- (SGC-) mediated neuropathic pain. However, the association of P2X7R and p38MAPK in mediating BTZ-induced neuropathic pain remains unclear. In this study, the relationship between P2X7R activation and p38 phosphorylation in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) in the development and maintenance of BTZ-induced neuropathic pain was elucidated. The results showed that BTZ increased mechanical thresholds in rats, accompanied with upregulation of P2X7R expression and p38MAPK phosphorylation, indicating that P2X7R and p38MAPK are key molecules in the development and maintenance of BTZ-induced neuropathic pain. Inhibiting p38MAPK phosphorylation with SB203580 resulted in downregulation of P2X7R expression levels. Inhibition of P2X7R with Brilliant Blue G (BBG) reversed neuropathic pain might decrease through the expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 via inhibiting p38MAPK phosphorylation. The P2X7R/p38MAPK signaling pathway in SGCs of DRG and microglia of SDH might be a potential pharmacological target behind this mechanism as an opportunity to relieve BTZ-induced neuropathic pain.

4.
Neurosci Res ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32593591

RESUMO

The pathogenesis of diabetic peripheral neuropathy (DPN) is complex and not well understood. Recently, oxidative stress and endoplasmic reticulum (ER) stress induced by hyperglycemia have been demonstrated to play a critical role in neuronal apoptosis, which then contributing to DPN. However, the specific molecular mechanism that underlies the hyperglycemia-induced neuronal stresses and apoptosis remains largely unknown. In this study, we demonstrated for the first time that Pim1 kinase is a positive modulator of dorsal root ganglion (DRG) neuron survival in vitro. Hyperglycemia causes compensatory upregulation of Pim1 kinase in the DRG neurons, which provides protection against high glucose-induced oxidative stress and ER stress. Pharmacological inhibition of Pim1 not only sensitizes the stress response to high glucose in the DRG neurons, but also accelerates the apoptosis of DRG neurons in vitro. Therefore, our work provides experimental evidence for the prevention of high glucose-induced neuronal stress and apoptosis by targeting Pim1 kinase.

5.
Exp Mol Pathol ; 114: 104416, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32165091

RESUMO

Mesenchymal stromal injection is a promising therapy for traumatic brain injury (TBI). The aim of this study was to explore the effects of the HIF-1α/SDF-1/CXCR4 axis on neuron repair in TBI rats through improving the bone marrow-derived mesenchymalstromal cells (BMSCs) migration. TBI rat models were established. The rats were treated with exogenous SDF-1, and then the neuronal apoptosis in TBI rats was measured. BMSCs from rats were collected, and the roles of NF-κB p65 expression in nuclei, overexpression of SDF-1 and HIF-1α, as well as downregulation of CXCR4 in BMSC migration were identified. HIF-1α- and SDF-1- treated BMSCs were transplanted into TBI rats, after which the neuronal apoptosis and activity of the HIF-1α/SDF-1/CXCR4 axis were detected. Consequently, we found SDF-1 elevated the HIF-1α/SDF-1/CXCR4 activity and presented protective roles in TBI rat hippocampal neurons with reduced neuronal apoptosis. SDF-1 promoted BMSC migration in vitro, and co-effects of SDF-1 and HIF-1α showed strong promotion, while CXCR4 inhibition suppressed BMSC migration. BMSC transplantation activated the HIF-1α/SDF-1/CXCR4 axis and reduced neuronal apoptosis in TBI rats. To conclude, our study demonstrated that the HIF-1α/SDF-1/CXCR4 axis could enhance BMSC migration and alleviate neuronal damage and apoptosis in TBI rats. This study provided novel options for TBI therapy.


Assuntos
Lesões Encefálicas Traumáticas/genética , Quimiocina CXCL12/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Receptores CXCR4/genética , Animais , Apoptose/genética , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Movimento Celular/genética , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos , Transdução de Sinais/genética , Células Estromais/metabolismo , Células Estromais/patologia
6.
J Cell Mol Med ; 24(8): 4677-4686, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32181582

RESUMO

Glioma is a brain tumour that is often diagnosed, and temozolomide (TMZ) is a common chemotherapeutic drug used in glioma. Yet, resistance to TMZ is a chief hurdle towards curing the malignancy. The current work explores the pathways and involvement of miR-3116 in the TMZ resistance. miR-3116 and FGFR1 mRNA were quantified by real-time PCR in malignant samples and cell lines. Appropriate assays were designed for apoptosis, viability, the ability to form colonies and reporter assays to study the effects of the miR-3116 or FGFR1. The involvement of PI3K/AKT signalling was assessed using Western blotting. Tumorigenesis was evaluated in an appropriate xenograft mouse model in vivo. This work revealed that the levels of miR-3116 dipped in samples resistant to TMZ, while increased miR-3116 caused an inhibition of the tumour features mentioned above to hence augment TMZ sensitivity. miR-3116 was found to target FGFR1. When FGFR1 was overexpressed, resistance to TMZ was augmented and reversed the sensitivity caused by miR-3116. Our findings further confirmed PI3K/AKT signalling pathway is involved in this action. In conclusion, miR-3116 sensitizes glioma cells to TMZ through FGFR1 downregulation and the PI3K/AKT pathway inactivation. Our results provide a strategy to overcome TMZ resistance in glioma treatment.

7.
Brain Behav ; 9(12): e01471, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743631

RESUMO

BACKGROUND: Hypertensive cerebral hemorrhage (HCH) is a potentially life-threatening neurological condition with an extremely high morbidity and mortality. In recent years, neuroendoscopy has been used to treat intracerebral hemorrhage (ICH). However, the choice of neuroendoscopic surgery versus craniotomy for patients with intracerebral hemorrhages is controversial. AIM: We conducted this meta-analysis to assess the efficacy of neuroendoscopic surgery compared with craniotomy in patients with supratentorial hypertensive ICH. METHODS: A systematic electronic search was conducted of online electronic databases: PubMed, Embase, and the Cochrane Library updated on December 2017. The meta-analysis only included randomized controlled studies. RESULTS: Three randomized controlled trials met our inclusion criteria. The pooled analysis of death showed that neuroendoscopic surgery decreased the rate of death when compared with craniotomy (RR = 0.58, 95% CI 0.26-1.29; p = .18). The pooled result of complications indicated that neuroendoscopic surgery has a tendency toward lower complications (RR = 0.37, 95% CI 0.28-0.49; p < .001). CONCLUSIONS: Our results suggested that neuroendoscopic surgery has lower complications, but no superior advantages in morbidity rates. Since the advantage of neuroendoscopic surgery has been performed in some area, the continuation of multi-center comparative investigation with craniotomy may be necessary. Moreover, some efforts need to be taken in selecting appropriate patients with different treatments.


Assuntos
Craniotomia , Hemorragia Intracraniana Hipertensiva/cirurgia , Neuroendoscopia , Complicações Pós-Operatórias , Craniotomia/efeitos adversos , Craniotomia/métodos , Humanos , Neuroendoscopia/efeitos adversos , Neuroendoscopia/métodos , Avaliação de Processos e Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Cell Death Dis ; 10(10): 773, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601787

RESUMO

Adult skeletal muscle regeneration after injury depends on normal myoblast function. However, the intrinsic mechanisms for the control of myoblast behaviors are not well defined. Herein, we identified Pim1 kinase as a novel positive regulator of myoblast behaviors in vitro and muscle regeneration in vivo. Specifically, knockdown of Pim1 significantly restrains the proliferation and accelerates the apoptosis of myoblasts in vitro, indicating that Pim1 is critical for myoblast survival and amplification. Meanwhile, we found that Pim1 kinase is increased and translocated from cytoplasm into nucleus during myogenic differentiation. By using Pim1 kinase inhibitor, we proved that inhibition of Pim1 activity prevents myoblast differentiation and fusion, suggesting the necessity of Pim1 kinase activity for proper myogenesis. Mechanistic studies demonstrated that Pim1 kinase interacts with myogenic regulator MyoD and controls its transcriptional activity, inducing the expression of muscle-specific genes, which consequently promotes myogenic differentiation. Additionally, in skeletal muscle injury mouse model, deletion of Pim1 hinders the regeneration of muscle fibers and the recovery of muscle strength. Taken together, our study provides a potential target for the manipulation of myoblast behaviors in vitro and the myoblast-based therapeutics of skeletal muscle injury.


Assuntos
Desenvolvimento Muscular/genética , Músculo Esquelético/fisiologia , Mioblastos/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Regeneração/genética , Animais , Apoptose/genética , Linhagem Celular , Núcleo Celular/enzimologia , Núcleo Celular/metabolismo , Proliferação de Células/genética , Sobrevivência Celular/ética , Bases de Dados Genéticas , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/enzimologia , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Proteína MyoD/metabolismo , Mioblastos/enzimologia , Fosforilação , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/genética , Regulação para Cima
9.
J Neuroimmune Pharmacol ; 14(4): 688-696, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31321663

RESUMO

Oxidant toxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), an insidiously progressive neurodegenerative disorder involving upper and lower motor neurons. Here, we investigated the cellular and molecular mechanisms underlying the neuroprotective effects of an anti-oxidant genistein in SOD1-G93A transgenic mouse model of ALS. Rotarod test, hanging wire test and hindlimb clasping test were used to determined disease onset and assess motor performance. Immunostaining together with neuronal size measurement were used to count viable motor neurons. In addition, immunostaining procedure and ELISA kit were used to assess the inflammatory response in the spinal cord. Our results showed that Genistein administration suppressed the production of pro-inflammatory cytokines and alleviated gliosis in the spinal cord of SOD1-G93A mice. In addition, genistein administration induced autophagic processes and enhanced the viability of spinal motor neurons. As a result, genistein alleviated ALS-related symptoms and slightly prolonged the lifespan of SOD1-G93A mice. Taken together, our results indicate that genistein is neuroprotective in SOD1-G93A mice, suggesting genistein could be a promising treatment for human ALS. Graphical Abstract Genistein protects impariments in SOD1-G93A transgenic mouse model.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/prevenção & controle , Modelos Animais de Doenças , Genisteína/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Superóxido Dismutase/genética , Esclerose Amiotrófica Lateral/tratamento farmacológico , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fitoestrógenos/uso terapêutico
10.
Spine (Phila Pa 1976) ; 44(15): E865-E872, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30817738

RESUMO

STUDY DESIGN: Animal experiment: a rat model of lumbar disc herniation (LDH) induced painful radiculopathies. OBJECTIVE: To investigate the role and mechanism of AMP-activated protein kinase (AMPK) in dorsal root ganglia (DRG) neurons in LDH-induced painful radiculopathies. SUMMARY OF BACKGROUND DATA: Overactivation of multiple pain signals in DRG neurons triggered by LDH is crucial to the development of radicular pain. AMPK is recognized as a cellular energy sensor, as well as a pain sensation modulator, but its function in LDH-induced pain hypersensitivity remains largely unknown. METHODS: The LDH rat model was established by autologous nucleus pulposus transplantation into the right lumbar 5 (L5) nerve root. At different time points after AMPK agonist metformin (250 mg/kg/d) or mammalian target of rapamycin (mTOR) inhibitor rapamycin (5 mg/kg) intraperitoneal administration, thermal and mechanical sensitivity were evaluated by measuring paw withdrawal latency (PWL) and 50% paw withdrawal thresholds (PWT). The levels of AMPK, mTOR, and p70S6K phosphorylation were determined by Western blot. We also investigated the proportion of p-AMPK positive neurons in the right L5 DRG neurons using immunofluorescence. RESULTS: LDH evoked persistent thermal hyperalgesia and mechanical allodynia on the ipsilateral paw, as indicated by the decreased PWL and 50% PWT. These pain hypersensitive behaviors were accompanied with significant inhibition of AMPK and activation of mTOR in the associated DRG neurons. Pharmacological activation of AMPK in the DRG neurons not only suppressed mTOR/p70S6K signaling, but also alleviated LDH-induced pain hypersensitive behaviors. CONCLUSION: We provide a molecular mechanism for the activation of pain signals based on AMPK-mTOR axis, as well as an intervention strategy by targeting AMPK-mTOR axis in LDH-induced painful radiculopathies. LEVEL OF EVIDENCE: N/A.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Deslocamento do Disco Intervertebral/metabolismo , Radiculopatia/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Gânglios Espinais/enzimologia , Hiperalgesia/enzimologia , Degeneração do Disco Intervertebral/enzimologia , Deslocamento do Disco Intervertebral/enzimologia , Masculino , Metformina/farmacologia , Neurônios/enzimologia , Neurônios/metabolismo , Núcleo Pulposo/enzimologia , Núcleo Pulposo/metabolismo , Dor/enzimologia , Dor/metabolismo , Fosforilação , Radiculopatia/enzimologia , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Raízes Nervosas Espinhais/enzimologia , Raízes Nervosas Espinhais/metabolismo , Serina-Treonina Quinases TOR/metabolismo
11.
Exp Cell Res ; 374(1): 198-209, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500392

RESUMO

Coactivator-associated arginine methyltransferase 1 (CARM1) is involved in a variety of biological processes in different cell types and disease conditions, including myogenesis. However, the specific function of CARM1 in skeletal muscle wasting under pathologic conditions remains unclear. Here, we identify CARM1 as a novel participant in muscular atrophy. Increases in CARM1 protein levels correlated positively with the loss of muscle mass upon denervation in mice. Notably, the knockdown of CARM1 represses the progression of muscle wasting and the expression of the atrophy-related genes Atrogin-1 and MuRF1 in vivo and in vitro. With respect to the underlying mechanism, we show that CARM1 interacts with and asymmetrically dimethylates FoxO3 (a specific transcription factor that controls atrophy-related gene expression). This methylation modification by CARM1 is required for FoxO3-dependent transcription. Accordingly, a CARM1 methyltransferase inhibitor also restrains the expression of Atrogin-1 and MuRF1 and myotube atrophy. Furthermore, CARM1 knockdown induces a remarkable myofiber autophagic deficit during the atrophy process. Altogether, our study identifies a crucial regulator of skeletal muscle atrophy and suggests that CARM1 is a potential target for the prevention of muscle atrophy.


Assuntos
Autofagia , Proteína Forkhead Box O3/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Linhagem Celular , Dexametasona , Masculino , Metilação , Camundongos Endogâmicos C57BL , Modelos Biológicos , Denervação Muscular , Atrofia Muscular/patologia , Tamanho do Órgão , Ligação Proteica
12.
J Muscle Res Cell Motil ; 39(3-4): 117-134, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30209718

RESUMO

The communication between primary afferent neuron and skeletal muscle (SKM) is one of the important factors on maintaining the structure and function of SKM cells. Neuregulin-1ß (NRG-1ß) signaling is essential for regulating synaptic neurotransmission. Here, we established a neuromuscular coculture model of dorsal root ganglion (DRG) sensory neurons and SKM cells to explore the nerve-muscle communication in the presence of exogenous NRG-1ß. The expression of three distinct subtypes (TrkA, TrkB, and TrkC) of tyrosine kinase receptors was monitored for the phenotypical alterations of the neurons. The aggregation extent of acetylcholine receptor (AChR) represents the specific changes of SKM cells after NRG-1ß incubation in this neuromuscular coculture model. The results showed that NRG-1ß not only enhanced neurite outgrowth of DRG neurons but also increased the length and branches of SKM cells. NRG-1ß treatment not only induced expression of all the three subtypes of Trk receptors in neurons but also promoted AChR aggregation on the surface of SKM cells. The effects of NRG-1ß could be blocked by administration of ERK1/2 inhibitor PD98059, PI3K inhibitor LY294002, and JAK2 inhibitor AG490, respectively. These data imply that NRG-1ß is essential for the nerve-muscle communication by enhancing growth and modifying phenotypes of the two different kinds of cells. The specific effects produced by NRG-1ß add novel interpretation for nerve-muscle communication between sensory neurons and SKM cells.


Assuntos
Gânglios Espinais/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Neuregulina-1/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Cromonas/farmacologia , Técnicas de Cocultura , Flavonoides/farmacologia , Gânglios Espinais/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Músculo Esquelético/citologia , Ratos , Ratos Wistar , Células Receptoras Sensoriais/citologia , Tirfostinas/farmacologia
13.
Skelet Muscle ; 8(1): 29, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219099

RESUMO

BACKGROUND: The formation of intrafusal muscle (IM) fibers and their contact with afferent proprioceptive axons is critical for construction, function, and maintenance of the stretch reflex. Many factors affect the formation of IM fibers. Finding new factors and mechanisms of IM fiber formation is essential for the reconstruction of stretch reflex arc after injury. METHODS: We established a coculture system of organotypic dorsal root ganglion (DRG) explants and dissociated skeletal muscle (SKM) cells. The formation of IM fibers was observed in this coculture system after neuregulin-1ß (NRG-1ß) incubation. RESULTS: We found that NRG-1ß promoted outgrowth of neurites and migration of neurons from the organotypic DRG explants and that this correlated with an induction of growth-associated protein 43 (GAP-43) expression. NRG-1ß also increased the amount of nuclear bag fibers and nuclear chain fibers by elevating the proportion of tyrosine kinase receptor C (TrkC) phenotypic DRG neurons. In addition, we found that the effects of NRG-1ß could be blocked by inhibiting ERK1/2, PI3K/Akt, and JAK2/STAT3 signaling pathways. CONCLUSION: These data imply that NRG-1ß promoted neurite outgrowth and neuronal migration from the organotypic DRG explants and that this correlated with an induction of GAP-43 expression. The modulating effects of NRG-1ß on TrkC DRG neuronal phenotype may link to promote IM fiber formation. The effects produced by NRG-1ß in this neuromuscular coculture system provide new data for the therapeutic potential on IM fiber formation after muscle injury.


Assuntos
Gânglios Espinais/citologia , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/citologia , Neuregulina-1/farmacologia , Animais , Células Cultivadas , Técnicas de Cocultura , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Sistema de Sinalização das MAP Quinases , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Crescimento Neuronal , Ratos , Receptor trkC/genética , Receptor trkC/metabolismo
14.
Mol Pain ; 14: 1744806918793229, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30027794

RESUMO

Background Diabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study. Methods The mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively. Results The mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats. Conclusion The findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.


Assuntos
Neuropatias Diabéticas/patologia , Gânglios Espinais/patologia , Canais de Potássio KCNQ/metabolismo , Neurônios/metabolismo , Animais , Antracenos/farmacologia , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Células Cultivadas , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Canais de Potássio KCNQ/genética , Moduladores de Transporte de Membrana/farmacologia , Moduladores de Transporte de Membrana/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Técnicas de Patch-Clamp , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , RNA Mensageiro/metabolismo , Ratos , Estreptozocina/toxicidade , Canais de Cátion TRPV/metabolismo
15.
ACS Appl Mater Interfaces ; 10(16): 13914-13923, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29617104

RESUMO

Heterogeneous organometallic catalysts with well-defined active sites and hierarchical pores hold tremendous promise for efficient and eco-friendly chemical processes. However, the simple and scalable preparation of these materials remains difficult to date, which has hampered a more broad application scope. Herein, we reported a low-cost, rapid, and scalable aerosol-assisted assembly approach for the synthesis of a well-defined PdDPP (PdCl2(PPh2(CH2)2))_ complex-containing benzene-bridged organosilica-based catalyst with a hierarchical bimodal micro-macroporous structure. This novel material was realized by using Pd(II) organometallic silane (Pd[PPh2(CH2)2Si(OEt)3]2Cl2) as the active species, organosilane 1,4-bis(triethoxysilyl)benzene (Ph[Si(OEt)3]2) as the silicate scaffold and the surfactant cetyltrimethylammonium bromide and the inorganic salt NaCl as the dual templates on a home-built aerosol spraying-instrument. Multiple techniques including X-ray photoelectron spectroscopy and solid-state NMR spectra revealed that the organopalladium complex with a well-defined molecular configuration of major trans model and minor cis model existed in the phenyl-functionalized silica material. As expected, it efficiently promoted a variety of important carbon-carbon cross-coupling transformations including Tsuji-Trost, Sonogashira, and Suzuki reactions in pure water without the assistance of any additives. In comparison with the homogeneous catalyst PdCl2(PPh2CH3)2, it even exhibited enhanced activity and selectivity in some cases owing to the unique confinement effect and the shape selectivity generated from the hierarchical porous structure. Meanwhile, it was easily recycled and reused eight times without the loss of its activity.

16.
Quant Imaging Med Surg ; 7(5): 532-536, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29184765

RESUMO

Background: DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke, and may play a neuroprotective role by acting on multiple active targets. The aim of this study was to predict the target proteins of NBP in mammalian cells. Methods: The similarity ensemble approach search tool (SEArch), one of the commonly used public bioinformatics tools for target prediction, was employed in the experiment. The molecular docking of NBP to target proteins was performed by using the three-dimensional (3-D) crystal structure, substrate free. The software AutoDock Vina was used for all dockings. The binding targets of NBP were illustrated as 3-D and 2-D diagrams. Results: Firstly, the results showed that NBP bounded to the same binding site on NAD(P)H quinone oxidoreductases (NQO1) as the substrate FAD, leading to competitive inhibition for the catalytic site with -7.2 kcal/mol. This might break the 3-D structure of NQO1 and bring about P53 degradation, resulting in a decrease of p53-mediated apoptosis in ischemic brain cells. Secondly, NBP might exert its therapeutic effect on acute ischemic stroke via modulating indoleamine 2,3-dioxygenase (IDO) bioactivity after associating with it. NBP could alleviate the depression following ischemic stroke by inhibiting IDO. Thirdly, NBP might modulate the function of NADH-ubiquinone oxidoreductase by competitively embedding itself into this complex, further affecting mitochondrial respiration in cerebrovascular diseases as an anti-oxidant agent. Conclusions: Three potential target proteins of NBP were identified, which may provide a novel aspect for better understanding the protective effects of NBP on the nervous system at the molecular level.

17.
Int J Biol Macromol ; 105(Pt 1): 346-353, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28720546

RESUMO

Long non-coding RNAs play a significant role in cancer metastasis. Studies have demonstrated that LncRNA NEAT1 promotes cancer progression. We aimed to explore whether NEAT1 regulated growth and invasion in breast cancer cells. We provided evidence that lncRNA NEAT1 was up-regulated in breast cancer cell lines and tissues. NEAT1 promoted invasion through inducing Epithelial-mesenchymal transition (EMT) and NEAT1 played a role in 5-fluorouracil (5-FU) resistance. In addition, we revealed a reciprocal repression between NEAT1 and miR-211. Furthermore, the EMT-inducer HMGA2 was identified as a down-stream target of miR-211. LncRNA NEAT1 induced EMT and 5-FU resistance through the miR-211/HMGA2 axis. Our findings suggest that lncRNA NEAT1 could be a new diagnostic biomarker and therapy target for breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína HMGA2/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Neoplasias da Mama/diagnóstico , Linhagem Celular Tumoral , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Prognóstico , Regulação para Cima
18.
Luminescence ; 32(8): 1411-1416, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28569403

RESUMO

A novel ultra-sensitive fluorescent sensor for monitoring microRNA (miRNA) in living cells was constructed by utilizing a hybridization chain reaction (HCR) as the signal amplification with a carbon nitride nanosheet (CNNS) as a carrier. The Cy5-labeled hairpin DNA could be adsorbed onto the surface of CNNS, resulting in fluorescence quenching of Cy5. When treated with complementary miRNA, the fluorescence was recovered because miRNA could efficiently trigger an HCR, which led to the release of the HCR products from the CNNS. This intracellular HCR strategy can be used for ultra-sensitive monitoring of intracellular miRNA. The main advantages of the proposed method are its simplicity, high sensitivity, high specificity and low toxicity for monitoring low-level biomarkers.


Assuntos
Corantes Fluorescentes/química , MicroRNAs/análise , Nanoestruturas/química , Nitrilos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Corantes Fluorescentes/farmacologia , Nitrilos/farmacologia , Hibridização de Ácido Nucleico , Células PC12 , Ratos , Espectrometria de Fluorescência , Relação Estrutura-Atividade
19.
Nat Commun ; 8: 14828, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28425483

RESUMO

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.


Assuntos
Colangite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Doenças Autoimunes/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Adulto Jovem
20.
Sci Rep ; 7: 43949, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276453

RESUMO

Restoring the contractile function of long-term denervated skeletal muscle (SKM) cells is difficult due to the long period of denervation, which causes a loss of contractility. Although sensory innervation is considered a promising protective approach, its effect is still restricted. In this study, we introduced insulin-like growth factor-1 (IGF-1) as an efficient protective agent and observed that IGF-1 potentiated the effects of sensory protection by preventing denervated muscle atrophy and improving the condition of denervated muscle cells in vivo and in vitro. IGF-1-induced Akt phosphorylation suppressed the mitochondrial outer-membrane protein Mul1 expression, which is a key step on preserving contractile property of sensory innervated SKM cells. Mul1 overexpression interfered with the balance between mitochondrial fusion and fission and was a key node for blocking the effects of IGF-1 that preserved the contractility of sensory-innervated SKM cells. Activation of AMP-activated protein kinase α (AMPKα), a mitochondrial downstream target, could block the effects of IGF-1. These data provide novel evidence that might be applied when searching for new approaches to improve the functional condition of long-term denervated SKM cells by increasing sensory protection using the IGF-1 signalling system to modulate the balance between mitochondrial fusion and fission.


Assuntos
Gânglios Espinais/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Dinâmica Mitocondrial , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Atrofia , Linhagem Celular , DNA Mitocondrial/metabolismo , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Proteínas Musculares , Músculo Esquelético/patologia , Proteínas Proto-Oncogênicas c-akt , Ratos Wistar , Proteínas Ligases SKP Culina F-Box , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo
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