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1.
J Neuroinflammation ; 20(1): 247, 2023 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-37880726

RESUMEN

BACKGROUND: The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive. METHODS: Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis. RESULTS: 4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure. CONCLUSIONS: Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses.


Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Factores de Transcripción NFI , Canales Catiónicos TRPV , Animales , Humanos , Ratones , 4-Aminopiridina/efectos adversos , Astrocitos/metabolismo , Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Epilepsia/metabolismo , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/metabolismo , Factores de Transcripción NFI/genética , Factores de Transcripción NFI/metabolismo , Canales Catiónicos TRPV/metabolismo , Regulación hacia Arriba
2.
J Asian Nat Prod Res ; 25(8): 748-755, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36355831

RESUMEN

Two new dihydro-ß-agarofuran sesquiterpenes chiapen T (1) and chiapen U (2), along with chiapen A (3), 1ß-hydroxy-2ß,6α,12-triacetoxy-8ß-(ß-nicotinoyloxy)-9ß-(benzoyloxy)-ß-dihydroagarofuran (4), wilforlide B (5), 3-hydroxy-2-oxo-3-friedelen-29-oic acid (6), epikatonic acid (7), 22-epi-maytenfolic acid (8), maytenoic acid (9), wilforic acid F (10), wilforic acid B (11), were reported for the first time from the Celastrus angulatus. The structures of all the compounds were elucidated by HR-ESI-MS, 1 D and 2 D NMR spectra, as well as single-crystal X-ray diffraction analyses. Compounds 1 and 2 were examined for anti-inflammatory activity, respectively. None of them showed potent activity.

3.
FASEB J ; 35(2): e21330, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33417289

RESUMEN

Epilepsy is a common brain disorder, repeated seizures of epilepsy may lead to a series of brain pathological changes such as neuronal or glial damage. However, whether circular RNAs are involved in neuronal injury during epilepsy is not fully understood. Here, we screened circIgf1r in the status epilepticus model through circRNA sequencing, and found that it was upregulated after the status epilepticus model through QPCR analysis. Astrocytes polarizing toward neurotoxic A1 phenotype and neurons loss were observed after status epilepticus. Through injecting circIgf1r siRNA into the lateral ventricle, it was found that knocking down circIgf1r in vivo would induce the polarization of astrocytes to phenotype A2 and reduce neuronal loss. The results in vitro further confirmed that inhibiting the expression of circIgf1r in astrocytes could protect neurons by converting reactive astrocytes from A1 to the protective A2. In addition, knocking down circIgf1r in astrocytes could functionally promote astrocyte autophagy and relieve the destruction of 4-AP-induced autophagy flux. In terms of mechanism, circIgf1r promoted the polarization of astrocytes to phenotype A1 by inhibiting autophagy. Taken together, our results reveal circIgf1r may serve as a potential target for the prevention and treatment of neuron damage after epilepsy.


Asunto(s)
Astrocitos/metabolismo , Epilepsia/genética , Silenciador del Gen , ARN Circular/metabolismo , Animales , Astrocitos/citología , Células Cultivadas , Epilepsia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neurogénesis , Neuronas/metabolismo , ARN Circular/genética , Receptor IGF Tipo 1/genética
4.
J Neuroinflammation ; 16(1): 214, 2019 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-31722723

RESUMEN

BACKGROUND: Neonatal hypoxic-ischemic brain damage (HIBD), a leading cause of neonatal mortality, has intractable sequela such as epilepsy that seriously affected the life quality of HIBD survivors. We have previously shown that ion channel dysfunction in the central nervous system played an important role in the process of HIBD-induced epilepsy. Therefore, we continued to validate the underlying mechanisms of TRPV1 as a potential target for epilepsy. METHODS: Neonatal hypoxic ischemia and oxygen-glucose deprivation (OGD) were used to simulate HIBD in vivo and in vitro. Primarily cultured astrocytes were used to assess the expression of TRPV1, glial fibrillary acidic protein (GFAP), cytoskeletal rearrangement, and inflammatory cytokines by using Western blot, q-PCR, and immunofluorescence. Furthermore, brain electrical activity in freely moving mice was recorded by electroencephalography (EEG). TRPV1 current and neuronal excitability were detected by whole-cell patch clamp. RESULTS: Astrocytic TRPV1 translocated to the membrane after OGD. Mechanistically, astrocytic TRPV1 activation increased the inflow of Ca2+, which promoted G-actin polymerized to F-actin, thus promoted astrocyte migration after OGD. Moreover, astrocytic TRPV1 deficiency decreased the production and release of pro-inflammatory cytokines (TNF, IL-6, IL-1ß, and iNOS) after OGD. It could also dramatically attenuate neuronal excitability after OGD and brain electrical activity in HIBD mice. Behavioral testing for seizures after HIBD revealed that TRPV1 knockout mice demonstrated prolonged onset latency, shortened duration, and decreased seizure severity when compared with wild-type mice. CONCLUSIONS: Collectively, TRPV1 promoted astrocyte migration thus helped the infiltration of pro-inflammatory cytokines (TNF, IL-1ß, IL-6, and iNOS) from astrocytes into the vicinity of neurons to promote epilepsy. Our study provides a strong rationale for astrocytic TRPV1 to be a therapeutic target for anti-epileptogenesis after HIBD.


Asunto(s)
Astrocitos/metabolismo , Epilepsia/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Inflamación/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Encéfalo/metabolismo , Movimiento Celular/fisiología , Citocinas/metabolismo , Epilepsia/etiología , Hipoxia-Isquemia Encefálica/complicaciones , Ratones , Ratones Noqueados , Neuronas/metabolismo
5.
Am J Physiol Lung Cell Mol Physiol ; 312(4): L477-L487, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28130257

RESUMEN

To investigate the association between store-operated Ca2+ entry (SOCE) and reactive oxygen species (ROS) during hypoxia, this study determined the changes of transient receptor potential canonical 1 (TRPC1) and Orai1, two candidate proteins for store-operated Ca2+ (SOC) channels and their gate regulator, stromal interaction molecule 1 (STIM1), in a hypoxic environment and their relationship with ROS in pulmonary arterial smooth muscle cells (PASMCs). Exposure to hypoxia caused a transient Ca2+ spike and subsequent Ca2+ plateau of SOCE to be intensified in PASMCs when TRPC1, STIM1, and Orai1 were upregulated. SOCE in cells transfected with specific short hairpin RNA (shRNA) constructs was almost completely eliminated by the knockdown of TRPC1, STIM1, or Orai1 alone and was no longer affected by hypoxia exposure. Hypoxia-induced SOCE enhancement was further strengthened by PEG-SOD but was attenuated by PEG-catalase, with correlated changes to intracellular hydrogen peroxide (H2O2) levels and protein levels of TRPC1, STIM1, and Orai1. Exogenous H2O2 could mimic alterations of the interactions of STIM1 with TRPC1 and Orai1 in hypoxic cells. These findings suggest that TRPC1, STIM1, and Orai1 are essential for the initiation of SOCE in PASMCs. Hypoxia-induced ROS promoted the expression and interaction of the SOC channel molecules and their gate regulator via their converted product, H2O2.


Asunto(s)
Canales de Calcio/metabolismo , Calcio/metabolismo , Peróxido de Hidrógeno/farmacología , Hipoxia/metabolismo , Miocitos del Músculo Liso/metabolismo , Arteria Pulmonar/patología , Animales , Catalasa/metabolismo , Células Cultivadas , Técnicas de Silenciamiento del Gen , Hipoxia/genética , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Polietilenglicoles/metabolismo , Unión Proteica/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/metabolismo , Superóxido Dismutasa/metabolismo , Canales Catiónicos TRPC/genética , Canales Catiónicos TRPC/metabolismo , Regulación hacia Arriba/efectos de los fármacos
6.
Mol Neurobiol ; 60(3): 1232-1249, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36434370

RESUMEN

Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel that can be activated by diverse stimuli, such as heat, mechanical force, hypo-osmolarity, and arachidonic acid metabolites. TRPV4 is widely expressed in the central nervous system (CNS) and participates in many significant physiological processes. However, accumulative evidence has suggested that deficiency, abnormal expression or distribution, and overactivation of TRPV4 are involved in pathological processes of multiple neurological diseases. Here, we review the latest studies concerning the known features of this channel, including its expression, structure, and its physiological and pathological roles in the CNS, proposing an emerging therapeutic strategy for CNS diseases.


Asunto(s)
Sistema Nervioso Central , Canales Catiónicos TRPV , Canales Catiónicos TRPV/metabolismo , Sistema Nervioso Central/metabolismo , Ácido Araquidónico/metabolismo , Calor
7.
Pharmacol Ther ; 238: 108180, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35367516

RESUMEN

Cluster of differentiation 20 (CD20) is an integral membrane protein expressed mainly on different developmental stages of B lymphocytes and rarely on T lymphocytes, and it functions as a link to B cell antigen receptor (BCR) and immune microenvironment via regulating calcium ion influx, cell cycle progression and interaction between isotypic BCRs and their co-receptors. Diverse therapeutic monoclonal antibodies (mAbs) targeting CD20 are generated and grouped into two types based on the ability to redistribute CD20 into lipid rafts, which results in huge differences in response. Currently, multiple anti-CD20 mAbs have been approved as drugs for neurological and neuromuscular diseases with promising clinical efficacy. This review aims to summarize the potential mechanisms, development and current evidence for anti-CD20 therapy in neurological and neuromuscular diseases.


Asunto(s)
Antígenos CD20 , Enfermedades Neuromusculares , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/metabolismo , Calcio/metabolismo , Humanos , Enfermedades Neuromusculares/tratamiento farmacológico , Receptores de Antígenos de Linfocitos B
8.
Neurotherapeutics ; 19(2): 660-681, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35182379

RESUMEN

Astrocytes are critical regulators of the immune/inflammatory response in several human central nervous system (CNS) diseases. Emerging evidence suggests that dysfunctional astrocytes are crucial players in seizures. The objective of this study was to investigate the role of transient receptor potential vanilloid 4 (TRPV4) in 4-aminopyridine (4-AP)-induced seizures and the underlying mechanism. We also provide evidence for the role of Yes-associated protein (YAP) in seizures. 4-AP was administered to mice or primary cultured astrocytes. YAP-specific small interfering RNA (siRNA) was administered to primary cultured astrocytes. Mouse brain tissue and surgical specimens from epileptic patient brains were examined, and the results showed that TRPV4 was upregulated, while astrocytes were activated and polarized to the A1 phenotype. The levels of glial fibrillary acidic protein (GFAP), cytokine production, YAP, signal transducer activator of transcription 3 (STAT3), intracellular Ca2+([Ca2+]i) and the third component of complement (C3) were increased in 4-AP-induced mice and astrocytes. Perturbations in the immune microenvironment in the brain were balanced by TRPV4 inhibition or the manipulation of [Ca2+]i in astrocytes. Knocking down YAP with siRNA significantly inhibited 4-AP-induced pathological changes in astrocytes. Our study demonstrated that astrocytic TRPV4 activation promoted neuroinflammation through the TRPV4/Ca2+/YAP/STAT3 signaling pathway in mice with seizures. Astrocyte TRPV4 inhibition attenuated neuroinflammation, reduced neuronal injury, and improved neurobehavioral function. Targeting astrocytic TRPV4 activation may provide a promising therapeutic approach for managing epilepsy.


Asunto(s)
Astrocitos , Convulsiones , Canales Catiónicos TRPV , Animales , Astrocitos/metabolismo , Humanos , Ratones , Neuronas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Convulsiones/inducido químicamente , Convulsiones/genética , Convulsiones/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo
9.
Neurosci Bull ; 37(10): 1427-1440, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34309810

RESUMEN

Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Recent studies have shown that complement component 3 (C3) aggravate the neuronal injury in epilepsy. And our previous studies revealed that TRPV1 (transient receptor potential vanilloid type 1) is involved in epilepsy. Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood. We found that in a mouse model of status epilepticus (SE), complement C3 derived from astrocytes was increased and aggravated neuronal injury, and that TRPV1-knockout rescued neurons from the injury induced by complement C3. Circular RNAs are abundant in the brain, and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV1 and exacerbated neuronal injury. Mechanistically, disorders of neuron-glia interaction mediated by the C3-TRPV1 signaling pathway may be important for the induction of neuronal injury. This study provides support for the hypothesis that the C3-TRPV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.


Asunto(s)
Complemento C3 , Epilepsia , Neuronas/patología , Estado Epiléptico , Canales Catiónicos TRPV , Animales , Astrocitos/metabolismo , Complemento C3/metabolismo , Ratones , Canales Catiónicos TRPV/metabolismo
10.
Front Cell Dev Biol ; 7: 339, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31921851

RESUMEN

Hypoxic-ischemic encephalopathy (HIE) is a serious birth complication with severe long-term sequelae such as cerebral palsy, epilepsy and cognitive disabilities. Na+-K+-2Cl- cotransporters 1 (NKCC1) is dramatically upregulated after hypoxia-ischemia (HI), which aggravates brain edema and brain damage. Clinically, an NKCC1-specific inhibitor, bumetanide, is used to treat diseases related to aberrant NKCC1 expression, but the underlying mechanism of aberrant NKCC1 expression has rarely been studied in HIE. In this study, the cooperative effect of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor of activated T cells 5 (NFAT5) on NKCC1 expression was explored in hippocampal neurons under hypoxic conditions. HI increased HIF-1α nuclear localization and transcriptional activity, and pharmacological inhibition of the HIF-1α transcription activity or mutation of hypoxia responsive element (HRE) motifs recovered the hypoxia-induced aberrant expression and promoter activity of NKCC1. In contrast, oxygen-glucose deprivation (OGD)-induced downregulation of NFAT5 expression was reversed by treating with hypertonic saline, which ameliorated aberrant NKCC1 expression. More importantly, knocking down NFAT5 or mutation of the tonicity enhancer element (TonE) stimulated NKCC1 expression and promoter activity under normal physiological conditions. The positive regulation of NKCC1 by HIF-1α and the negative regulation of NKCC1 by NFAT5 may serve to maintain NKCC1 expression levels, which may shed light on the transcription regulation of NKCC1 in hippocampal neurons after hypoxia.

12.
Ai Zheng ; 24(1): 53-7, 2005 Jan.
Artículo en Zh | MEDLINE | ID: mdl-15642200

RESUMEN

BACKGROUND & OBJECTIVE: The latest researches showed that myc protein could up-regulate the expression of human telomerase reverse transcriptase (hTERT), multidrug resistance gene 1(MDR1), multidrug resistance-related protein (MRP) in some kinds of tumors, and hTERT is correlated with efficiency of anti-tumor chemotherapy. This study was to investigate relations among expressions of hTERT, MDR1, MRP mRNA, and C-myc protein in non-small cell lung cancer (NSCLC). METHODS: Expressions of hTERT, MDR1, MRP mRNA in 113 cases of NSCLC tissues were detected by in situ hybridization, expression of C-myc protein was detected by SP immunohistochemistry, their correlations with clinicopathologic features of NSCLC were statistically analyzed. RESULTS: Positive rates of hTERT, MDR1, MRP mRNA, and C-myc protein in NSCLC tissues were 80.5%, 51.3%, 80.5% and 68.1%, respectively. Expressions of MDR1, MRP mRNA, and C-myc protein were significantly related to that of hTERT mRNA (P<0.05). Expression of C-myc protein did not correlate with expression of MDR1 or MRP mRNA. All 4 factors have no correlation with clinicopathologic features of NSCLC (P>0.05). CONCLUSION: Expression of hTERT mRNA may be related to those of MDR1, MRP mRNA, and C-myc in NSCLC. Overexpression of C-myc protein may be one of the molecular regulatory mechanisms of hTERT mRNA.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas de Unión al ADN/biosíntesis , Neoplasias Pulmonares/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/biosíntesis , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Telomerasa/biosíntesis , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Unión al ADN/genética , Femenino , Genes MDR , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Telomerasa/genética
13.
Ai Zheng ; 23(3): 273-7, 2004 Mar.
Artículo en Zh | MEDLINE | ID: mdl-15025956

RESUMEN

BACKGROUND & OBJECTIVE: Telomerase is a ribonucleoprotein complex, which is silent in normal human somatic cells but may be reactivated by a series of regulators, and cause tumorigenesis. As a critical factor of telomerase activity, much progression has been achieved in the study of regulation of human telomerase reverse transcriptase, but the detail mechanism is still not clear. This study was designed to investigate the relationship of expression of human telomerase reverse transcriptase mRNA (hTERT mRNA) and its regulators including c-myc, mutant p53, protein kinase C alpha (PKCalpha) with clinicopathological significance of expression of the four markers in non-small cell lung carcinoma (NSCLC). METHODS: The expression of hTERT mRNA in 113 NSCLC specimens were detected by in situ hybridization, and the expression of c-myc, mutant p53, and PKCalpha in the same specimens were detected by immunohistochemistry. RESULTS: The positive rates of 113 NSCLC samples for hTERT mRNA, c-myc, mutant p53, and PKCalpha were 80.5%, 68.1%, 61.9%, and 85.0%, respectively. The differences were statistically significant among the expression of hTERT mRNA, c-myc, and PKCalpha (P< 0.05 or P< 0.01), but was not significant between the expression of mutant p53 and hTERT mRNA, c-myc as well as PKCalpha. The expression of mutant p53 was associated with carcinoma cell differentiation (P< 0.05), and its positive rate gradually increased with the extend of differentiation of carcinoma cell. The expression of hTERT mRNA, c-myc, and PKCalpha were not associated with carcinoma cell differentiation. There was no relationship of expression of the four markers with histological types, TNM stages, and lymph node metastasis status. CONCLUSION: C-myc and PKCalphawere associated with the expression of telomerase.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , Telomerasa/genética , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Unión al ADN , Femenino , Regulación Enzimológica de la Expresión Génica , Genes myc , Genes p53 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Proteína Quinasa C/análisis , Proteína Quinasa C-alfa , ARN Mensajero/análisis
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