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1.
Exp Cell Res ; 426(1): 113552, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36914061

RESUMEN

It is recognized that the cerebral ischemia/reperfusion (I/R) injury triggers inflammatory activation of microglia and supports microglia-driven neuronal damage. Our previous studies have shown that ginsenoside Rg1 had a significant protective effect on focal cerebral I/R injury in middle cerebral artery occlusion (MCAO) rats. However, the mechanism still needs further clarification. Here, we firstly reported that ginsenoside Rg1 effectively suppressed the inflammatory activation of brain microglia cells under I/R conditions depending on the inhibition of Toll-likereceptor4 (TLR4) proteins. In vivo experiments showed that the ginsenoside Rg1 administration could significantly improve the cognitive function of MCAO rats, and in vitro experimental data showed that ginsenoside Rg1 significantly alleviated neuronal damage via inhibiting the inflammatory response in microglia cells co-cultured under oxygen and glucose deprivation/reoxygenation (OGD/R) condition in gradient dependent. The mechanism study showed that the effect of ginsenoside Rg1 depends on the suppression of TLR4/MyD88/NF-κB and TLR4/TRIF/IRF-3 pathways in microglia cells. In a word, our research shows that ginsenoside Rg1 has great application potential in attenuating the cerebral I/R injury by targeting TLR4 protein in the microglia cells.


Asunto(s)
Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Microglía/metabolismo , Receptor Toll-Like 4/metabolismo , Fármacos Neuroprotectores/farmacología , Isquemia Encefálica/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo
2.
Exp Brain Res ; 240(1): 97-111, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34661743

RESUMEN

This study aimed to establish the role of miR-129 and miR-384-5p in cerebral ischemia-induced apoptosis. Using PC12 cells transfected with miR-129 or miR-384-5p mimics or inhibitors, oxygen glucose deprivation (OGD) conditions were applied for 4 h to simulate transient cerebral ischemia. Apoptotic phenotypes were assessed via lactate dehydrogenase (LDH) assay, MTT cell metabolism assay, and fluorescence-activated cell sorting (FACS). The effect of miR overexpression and inhibition was evaluated by protein and mRNA detection of bcl-2 and caspase-3, critical apoptosis factors. Finally, the direct relationship of miR-129 and bcl-2 and miR-384-5p and caspase-3 was measured by luciferase reporter assay. The overexpression of miR-384-5p and miR-129 deficiency significantly enhanced cell viability, reduced LDH release, and inhibited apoptosis. By contrast, overexpression of miR-129 and miR-384-5p deficiency aggravated hypoxia-induced apoptosis and cell injury. miR-129 overexpression significantly reduced mRNA and protein levels of bcl-2 and miR-129 inhibition significantly increased mRNA and protein levels of bcl-2 in hypoxic cells.miR-384-5p overexpression significantly reduced protein levels of caspase-3 while miR-384-5p deficiency significantly increased protein levels of caspase-3. However, no changes were observed in caspase-3 mRNA in either transfection paradigm. Finally, luciferase reporter assay confirmed caspase-3 to be a direct target of miR-384-5p; however, no binding activity was detected between bcl-2 and miR-129.Transient cerebral ischemia induces differential expression of miR-129 and miR-384-5p which influences apoptosis by regulating apoptotic factors caspase-3 and bcl-2, thereby participating in the pathological mechanism of cerebral ischemia, and becoming potential targets for the treatment of ischemic cerebral injury in the future.


Asunto(s)
Glucosa , MicroARNs , Animales , Apoptosis/genética , MicroARNs/genética , Oxígeno , Células PC12 , Ratas
3.
Pharm Biol ; 60(1): 909-914, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35575436

RESUMEN

CONTEXT: Red ginseng polysaccharide (RGP) is an active component of the widely used medicinal plant Panax ginseng C. A. Meyer (Araliaceae), which has displayed promising activities against cancer cells. However, the detailed molecular mechanism of RGP in ferroptosis is still unknown. OBJECTIVE: This study evaluates the effects of RGP in cancer cells. MATERIALS AND METHODS: A549 and MDA-MB-231 cells were used. Cell proliferation was measured by CCK-8 assay after being treated with RGP at concentrations of 0, 50, 100, 200, 400, 800 and 1600 µg/mL at 0, 12, 24 and 48 h. Lipid reactive oxygen species (ROS) levels were assessed by C11-BODIPY assay. The control group was treated with PBS. RESULTS: RGP inhibited human A549 (IC50: 376.2 µg/mL) or MDA-MB-231(IC50: 311.3 µg/mL) proliferation and induced lactate dehydrogenase (LDH) release, promoted ferroptosis and suppressed the expression of GPX4. Moreover, the effects of RGP were enhanced by the ferroptosis inducer erastin, while abolished by ferroptosis inhibitor ferrostatin-1. DISCUSSION AND CONCLUSIONS: Our study is the first to demonstrate (1) the anticancer activity of RGP in human lung cancer and breast cancer. (2) RGP presented the anti-ferroptosis effects in lung and breast cancer cells via targeting GPX4.


Asunto(s)
Neoplasias de la Mama , Ferroptosis , Panax , Neoplasias de la Mama/tratamiento farmacológico , Regulación hacia Abajo , Femenino , Humanos , Polisacáridos/farmacología
4.
Neural Plast ; 2017: 1621629, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28884027

RESUMEN

DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7. In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced. In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7-9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.


Asunto(s)
Axones/fisiología , Factores de Transcripción de Tipo Kruppel/genética , Regeneración Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración Nerviosa/genética , Plasticidad Neuronal/genética , Ratas , Recuperación de la Función/genética , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Sinapsis/fisiología
5.
Neural Regen Res ; 18(5): 933-939, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36254971

RESUMEN

Chx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci.

6.
Artículo en Inglés | MEDLINE | ID: mdl-21869897

RESUMEN

Previously, we demonstrated acupuncture at acupoint HT7 (Shen-Men) attenuated ethanol withdrawal syndrome by normalizing the dopamine release in nucleus accumbens shell. In the present study, we investigated the effect of acupuncture on anxiety-like behavior in rats and its relevant mechanism by studying neuro-endocrine parameters during ethanol withdrawal. Rats were treated with 3 g kg(-1)day(-1) of ethanol (20%, w/v) or saline by intraperitoneal injections for 28 days. The rats undergoing ethanol withdrawal exhibited anxiety-like behavior 72 h after the last dose of ethanol characterized by the decrease of time spent in the open arms of the elevated plus maze compared with the saline-treated rats (P < .05). Radioimmunoassay exhibited there were notably increased concentrations of plasma corticosterone in ethanol-withdrawn rats compared with saline-treated rats (P < .05). Additionally, high performance liquid chromatography analysis also showed the levels of norepinephrine and 3-methoxy-4-hydroxy-phenylglycol were markedly increased while the levels of dopamine and 3,4-dihydroxyphenylacetic acid were significantly decreased in the central nucleus of the amygdala of ethanol-withdrawn rats compared with saline-treated rats (P < .01). Acupuncture groups were treated with acupuncture at acupoint HT7 or PC6 (Nei-Guan). Acupuncture at HT7 but not PC6 greatly attenuated the anxiety-like behavior during ethanol withdrawal as evidenced by significant increases in the percentage of time spent in open arms (P < .05). In the meantime, acupuncture at HT7 also markedly inhibited the alterations of neuro-endocrine parameters induced by ethanol withdrawal (P < .05). These results suggest that acupuncture may attenuate anxiety-like behavior during ethanol withdrawal through regulation of neuro-endocrine system.

7.
J Tissue Eng ; 11: 2041731420980136, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-34956585

RESUMEN

Previous animal studies have demonstrated that the flavonoid small-molecule TrkB agonist, 7, 8-dihydroxyflavone (DHF), promotes axon regeneration in transected peripheral nerves. In the present study, we investigated the combined effects of 7, 8-DHF treatment and bone marrow-derived stem/stromal cells (BMSCs) engraftment into acellular nerve allografts (ANAs) and explore relevant mechanisms that may be involved. Our results show that TrkB and downstream ERK1/2 phosphorylation are increased upon 7, 8-DHF treatment compared to the negative control group. Also, 7, 8-DHF promotes proliferation, survival, and Schwann-like cell differentiation of BMSCs in vitro. While selective ERK1/2 inhibitor U0126 suppressed the effect of upregulation of ERK1/2 phosphorylation and decreased cell proliferation, survival, and Schwann-like cell differentiation partially induced by 7, 8-DHF. In vivo, 7, 8-DHF promotes survival of transplanted BMSCs and upregulates axonal growth and myelination in regenerating ANAs. 7, 8-DHF+BMSCs also improved motor endplate density of target musculature. These benefits were associated with increased motor functional recovery. 7, 8-DHF+BMSCs significantly upregulated TrkB and ERK1/2 phosphorylation expression in regenerating ANA, and increased TrkB expression in the lumbar spinal cord. The mechanism of 7, 8-DHF action may be related to its ability to upregulate TrkB signaling, and downstream activation of survival signaling molecules ERK1/2 in the regenerating ANAs and spinal cord and improved survival of transplanted BMSCs. This study provides novel foundational data connecting the benefits of 7, 8-DHF treatment in neural injury and repair to BMSCs biology and function and demonstrates a potential combination approach for the treatment of injured peripheral nerve via nerve graft transplant.

8.
Clin Exp Pharmacol Physiol ; 36(8): 850-6, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19298536

RESUMEN

1. Suppressing apoptosis and downregulating K(+) channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of pulmonary vascular medial hypertrophy and pulmonary arterial hypertension (PAH). Previous studies have shown that selective serotonin re-uptake inhibitors (SSRIs) protected against PAH. The aim of the present study was to investigate the involvement of Kv1.5 channels and apoptosis in the protective effect of the SSRI fluoxetine against PAH. 2. Monocrotaline (MCT) was used to establish PAH in Wistar rats. Fluoxetine (2 and 10 mg/kg per day) was administered by gavage once a day for 3 weeks. Three weeks after the induction of PAH by MCT, pulmonary haemodynamic measurements and pulmonary artery morphological assessments were undertaken, along with detection of apoptosis and Kv1.5. 3. Fluoxetine (2 and 10 mg/kg per day) decreased pulmonary artery pressure, reduced the right ventricular index and inhibited the increase in medial wall thickness of pulmonary arteries in established PAH. Fluoxetine (10 mg/kg per day) reduced the expression of Bcl-2 and Bcl-xL protein, increased the expression of cleaved caspase 3 protein and enhanced the expression of Kv1.5 protein and mRNA in pulmonary arteries. Furthermore, fluoxetine (10 mg/kg per day) significantly suppressed proliferation and enhanced apoptosis of PASMC in MCT-induced PAH. 4. In conclusion, fluoxetine protects against MCT-induced PAH by suppressing PASMC proliferation, inducing PASMC apoptosis and upregulating Kv1.5 channels.


Asunto(s)
Apoptosis/efectos de los fármacos , Fluoxetina/uso terapéutico , Hipertensión Pulmonar/prevención & control , Canal de Potasio Kv1.5/biosíntesis , Arteria Pulmonar/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fluoxetina/administración & dosificación , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Monocrotalina , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Circulación Pulmonar/efectos de los fármacos , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas de Transporte de Serotonina en la Membrana Plasmática/biosíntesis , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Factores de Tiempo , Regulación hacia Arriba
9.
Neurosci Bull ; 34(3): 419-437, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29356943

RESUMEN

A previous study has indicated that Krüppel-like factor 7 (KLF7), a transcription factor that stimulates Schwann cell (SC) proliferation and axonal regeneration after peripheral nerve injury, is a promising therapeutic transcription factor in nerve injury. We aimed to identify whether inhibition of microRNA-146b (miR-146b) affected SC proliferation, migration, and myelinated axon regeneration following sciatic nerve injury by regulating its direct target KLF7. SCs were transfected with miRNA lentivirus, miRNA inhibitor lentivirus, or KLF7 siRNA lentivirus in vitro. The expression of miR146b and KLF7, as well as SC proliferation and migration, were subsequently evaluated. In vivo, an acellular nerve allograft (ANA) followed by injection of GFP control vector or a lentiviral vector encoding an miR-146b inhibitor was used to assess the repair potential in a model of sciatic nerve gap. miR-146b directly targeted KLF7 by binding to the 3'-UTR, suppressing KLF7. Up-regulation of miR-146b and KLF7 knockdown significantly reduced the proliferation and migration of SCs, whereas silencing miR-146b resulted in increased proliferation and migration. KLF7 protein was localized in SCs in which miR-146b was expressed in vivo. Similarly, 4 weeks after the ANA, anti-miR-146b increased KLF7 and its target gene nerve growth factor cascade, promoting axonal outgrowth. Closer analysis revealed improved nerve conduction and sciatic function index score, and enhanced expression of neurofilaments, P0 (anti-peripheral myelin), and myelinated axon regeneration. Our findings provide new insight into the regulation of KLF7 by miR-146b during peripheral nerve regeneration and suggest a potential therapeutic strategy for peripheral nerve injury.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Factores de Transcripción de Tipo Kruppel/metabolismo , MicroARNs/metabolismo , Regeneración Nerviosa/fisiología , Neuropatía Ciática/terapia , Animales , Movimiento Celular/genética , Proliferación Celular/genética , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/citología , Regulación de la Expresión Génica/genética , Células HEK293 , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Masculino , MicroARNs/genética , Placa Motora/genética , Proteína P0 de la Mielina/metabolismo , Regeneración Nerviosa/genética , Proteínas del Tejido Nervioso/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Neuropatía Ciática/metabolismo , Neuropatía Ciática/cirugía
10.
Artículo en Inglés | MEDLINE | ID: mdl-28656054

RESUMEN

The ginsenoside Rg1 exerts a neuroprotective effect during cerebral ischemia/reperfusion injury. Rg1 has been previously reported to improve PPARγ expression and signaling, consequently enhancing its regulatory processes. Due to PPARγ's role in the suppression of oxidative stress and inflammation, Rg1's PPARγ-normalizing capacity may play a role in the observed neuroprotective action of Rg1 during ischemic brain injury. We utilized a middle cerebral artery ischemia/reperfusion injury model in rats in addition to an oxygen glucose deprivation model in cortical neurons to elucidate the mechanisms underlying the neuroprotective effects of Rg1. We found that Rg1 significantly increased PPARγ expression and reduced multiple indicators of oxidative stress and inflammation. Ultimately, Rg1 treatment improved neurological function and diminished brain edema, indicating that Rg1 may exert its neuroprotective action on cerebral ischemia/reperfusion injury through the activation of PPARγ signaling. In addition, the present findings suggested that Rg1 was a potent PPARγ agonist in that it upregulated PPARγ expression and was inhibited by GW9662, a selective PPARγ antagonist. These findings expand our previous understanding of the molecular basis of the therapeutic action of Rg1 in cerebral ischemic injury, laying the ground work for expanded study and clinical optimization of the compound.

11.
Neuroscience ; 340: 319-332, 2017 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-27826105

RESUMEN

Our former study demonstrated that Krüppel-like Factor 7 (KLF7) is a transcription factor that stimulates axonal regeneration after peripheral nerve injury. Currently, we used a gene therapy approach to overexpress KLF7 in Schwann cells (SCs) and assessed whether KLF7-transfected SCs graft could promote sciatic nerve regeneration. SCs were transfected by adeno-associated virus 2 (AAV2)-KLF7 in vitro. Mice were allografted by an acellular nerve (ANA) with either an injection of DMEM (ANA group), SCs (ANA+SCs group) or AAV2-KLF7-transfected SCs (ANA+KLF7-SCs group) to assess repair of a sciatic nerve gap. The results indicate that KLF7 overexpression promoted the proliferation of both transfected SCs and native SCs. The neurite length of the dorsal root ganglia (DRG) explants was enhanced. Several beneficial effects were detected in the ANA+KLF7-SCs group including an increase in the compound action potential amplitude, sciatic function index score, enhanced expression of PKH26-labeling transplant SCs, peripheral myelin protein 0, neurofilaments, S-100, and myelinated regeneration nerve. Additionally, HRP-labeled motoneurons in the spinal cord, CTB-labeled sensory neurons in the DRG, motor endplate density and the weight ratios of target muscles were increased by the treatment while thermal hyperalgesia was diminished. Finally, expression of KLF7, NGF, GAP43, TrkA and TrkB were enhanced in the grafted SCs, which may indicate that several signal pathways may be involved in conferring the beneficial effects from KLF7 overexpression. We concluded that KLF7-overexpressing SCs promoted axonal regeneration of the peripheral nerve and enhanced myelination, which collectively proved KLF-SCs as a novel therapeutic strategy for injured nerves.


Asunto(s)
Factores de Transcripción de Tipo Kruppel/metabolismo , Regeneración Nerviosa/fisiología , Células de Schwann/metabolismo , Células de Schwann/trasplante , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Aloinjertos , Animales , Supervivencia Celular/fisiología , Técnicas de Cocultivo , Dependovirus/genética , Femenino , Vectores Genéticos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Actividad Motora/fisiología , Placa Motora/metabolismo , Placa Motora/patología , Neurogénesis/fisiología , Proyección Neuronal/fisiología , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/cirugía , Distribución Aleatoria , Células de Schwann/patología , Nervio Ciático/patología , Transfección
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