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BACKGROUND: To elucidate the relationship between the triglyceride-glycemic index (TyG) and clinical characteristics of pancreatic ductal adenocarcinoma (PDAC). METHODS: A total of 1,594 individuals diagnosed with pancreatic and periampullary neoplasms were categorized into four groups: PDAC-early (n = 403), locally advanced PDAC (LAPC, n = 315), PDAC-late with distant metastasis (n = 371), and other tumor types (n = 505). TyG-high was defined as a TyG index greater than 8.81 in males and 8.73 in females. RESULTS: The prevalence of TyG-high status was highest in PDAC-early (68.48%), followed by LAPC (53.33%), and lowest in PDAC-late (44.47%). TyG-high status significantly predicted worse PDAC prognosis (P = 0.0166), particularly in PDAC-late (P = 0.0420). Despite similar blood glucose levels across PDAC groups (P = 0.897), PDAC-early patients showed significantly higher rates of glycemic disturbances (56.33% vs. 32.28%) and TyG-high status (68.48% vs. 47.13%) compared to those with other tumors. Progressive increases in glycemic disturbances and TyG-high status were observed from benign to pre-malignant lesions and PDAC-early. PDAC-early patients at the pancreatic head exhibited higher rates of glycemic disturbances (58.12% vs. 33.33%, P < 0.0001), larger pancreatic duct diameters (0.4056 cm vs. 0.3398 cm, P = 0.0043), and poorer prognosis compared to periampullary cancers, although the TyG-high rate and body mass index were similar. CONCLUSION: The TyG index exhibits a complex association with PDAC stages, profoundly shaping glycemic profiles. At the initial stages of PDAC, a notable elevation in TyG-high status and glycemic disturbances is observed. However, in advanced PDAC, while the TyG-high rate diminishes, abnormal glucose levels persist.
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Glucemia , Carcinoma Ductal Pancreático , Progresión de la Enfermedad , Neoplasias Pancreáticas , Triglicéridos , Humanos , Masculino , Femenino , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/diagnóstico , Pronóstico , Persona de Mediana Edad , Triglicéridos/sangre , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico , Glucemia/metabolismo , Índice Glucémico , AncianoRESUMEN
N4-Acetylcytidine (ac4C), a highly conserved post-transcriptional machinery with extensive existence for RNA modification, plays versatile roles in various cellular processes and functions. However, the molecular mechanism by which ac4C modification mediates neuropathic pain remains elusive. Here, it is found that the enhanced ac4C modification promotes the recruitment of polysome in Vegfa mRNA and strengthens the translation efficiency following SNI. Nerve injury increases the expression of NAT10 and the interaction between NAT10 and Vegfa mRNA in the dorsal horn neurons, and the gain and loss of NAT10 function further confirm that NAT10 is involved in the ac4C modification in Vegfa mRNA and pain behavior. Moreover, the ac4C-mediated VEGFA upregulation contributes to the central sensitivity and neuropathic pain induced by SNI or AAV-hSyn-NAT10. Finally, SNI promotes the binding of HNRNPK in Vegfa mRNA and subsequently recruits the NAT10. The enhanced interaction between HNRNPK and NAT10 contributes to the ac4C modification of Vegfa mRNA and neuropathic pain. These findings suggest that the enhanced interaction between HNRNPK and Vegfa mRNA upregulates the ac4C level by recruiting NAT10 and contributes to the central sensitivity and neuropathic pain following SNI. Blocking this cascade may be a novel therapeutic approach in patients with neuropathic pain.
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Sensibilización del Sistema Nervioso Central , Neuralgia , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Asta Dorsal de la Médula Espinal/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
INTRODUCTION: The identification of patients with low risk of clinically relevant postoperative pancreatic fistula (CR-POPF) and postoperative hemorrhage (PPH) can guide drain removal after pancreatoduodenectomy (PD). However, drain fluid amylase (DFA) ≤5,000 U/L on postoperative day (POD) 1 does not robustly predict the absence of CR-POPF. METHODS: Consecutive patients undergoing PD at Sun Yat-sen University Cancer Center between July 2018 and October 2021 were analyzed. Recursive partitioning analysis was used to classify patients into groups with different risks of CR-POPF and PPH. RESULTS: Among 288 consecutive patients included, 99 patients (34.38%) developed CR-POPF (86 grade B and 13 grade C). Patients with CR-POPF had increased levels of preoperative creatinine (CRE) and POD1 CRE. The combination of POD1 CRE (>104 µmol/L or not) and POD1 DFA (>5,000 U/L or not) stratified patients into subgroups with the maximum difference in CR-POPF risk. The CR-POPF rates were 17.82% (36/202) in group A (POD1 CRE ≤104 µmol/L and POD1 DFA ≤5,000 U/L), 53.33% (8/15) in group B (POD1 CRE >104 µmol/L and POD1 DFA ≤5,000 U/L), and 77.46% (55/71) in group C (POD1 DFA >5,000 U/L). The PPH rates were 1.98% (4/202), 20.00% (3/15), and 19.72% (14/71) in groups A, B, and C, respectively. CONCLUSION: Patients with POD1 DFA ≤5,000 U/L and POD1 CRE >104 µmol/L have a high risk of CR-POPF and may not benefit from early drain removal. Patients with POD1 DFA ≤5,000 U/L and POD1 CRE ≤104 µmol/L have low risk of CR-POPF and PPH.
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Fístula Pancreática , Pancreaticoduodenectomía , Humanos , Pancreaticoduodenectomía/efectos adversos , Fístula Pancreática/etiología , Creatinina , Amilasas , Factores de Tiempo , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Hemorragia Posoperatoria/etiología , Drenaje/efectos adversos , Factores de RiesgoRESUMEN
Cell growth is conventionally quantified using CCK-8 or MTT assays, but these methods display considerable sensitivity to initial cell quantities. Inherent sampling errors during cell counting and seeding make it impossible to achieve an absolute equivalence of initial cell numbers, potentially confounding the results of CCK-8 or MTT assays. In the present study, we introduce a novel cell proliferation assay, ComProliM, predicated on cell competition theory. Both numeral simulations and empirical testing demonstrate that ComProliM index (CPMI) reliably represents cell growth rate and is not influenced by variations in initial cell number. Intriguingly, two adherent cells of differing fluorescence states are co-cultured, suggesting that ComProliM can be successfully employed in co-culture system cell proliferation assays, including, for instance, the exploration of subclone interactions. We anticipate ComProliM will provide a viable alternative for quantifying adherent cell growth rates, particularly in cases where conventional methodologies deliver inconsistent or ambiguous results.
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Alternative splicing (AS) is a common and conserved process in eukaryotic gene regulation. It occurs in approximately 95% of multi-exon genes, greatly enriching the complexity and diversity of mRNAs and proteins. Recent studies have found that in addition to coding RNAs, non-coding RNAs (ncRNAs) are also inextricably linked with AS. Multiple different types of ncRNAs are generated by AS of precursor long non-coding (pre-lncRNAs) or precursor messenger RNAs (pre-mRNAs). Furthermore, ncRNAs, as a novel class of regulators, can participate in AS regulation by interacting with the cis-acting elements or trans-acting factors. Several studies have implicated abnormal expression of ncRNAs and ncRNA-related AS events in the initiation, progression, and therapy resistance in various types of cancers. Therefore, owing to their roles in mediating drug resistance, ncRNAs, AS-related factors and AS-related novel antigens may serve as promising therapeutic targets in cancer treatment. In this review, we summarize the interaction between ncRNAs and AS processes, emphasizing their great influences on cancer, especially on chemoresistance, and highlighting their potential values in clinical treatment.
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Neoplasias , ARN Largo no Codificante , Humanos , Empalme Alternativo/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms. The circRNAs are mainly enriched in the central nervous system. However, their function in various physiological and pathological conditions have yet to be determined. Here, we identified circFhit, an exon-intron circRNA expressed in GABAergic neurons, which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain. Moreover, we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R+ neurons by promoting the expression of its parental gene Fhit in cis. Mechanistically, circFhit was directly bound to the intronic region of Fhit, and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron. In summary, we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R+ neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.
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Neuralgia , Células del Asta Posterior , Ratas , Animales , Células del Asta Posterior/metabolismo , Células del Asta Posterior/patología , Asta Dorsal de la Médula Espinal/metabolismo , Transmisión SinápticaRESUMEN
N6-Methyladenosine (m6A) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an m6A binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an m6A-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and m6A modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.
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Glutamina , Leucemia Mieloide Aguda , Humanos , Glutamina/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Estabilidad del ARN , Pronóstico , Antígenos de Histocompatibilidad Menor , Sistema de Transporte de Aminoácidos ASC/genética , Sistema de Transporte de Aminoácidos ASC/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
OBJECTIVES: Trigeminal nerve stimulation (TNS) is a promising strategy in treating diseases of the nervous system. In this study, the effects of TNS on traumatic brain injury (TBI) were investigated in a mouse model. MATERIALS AND METHODS: TBI was induced using a weight-drop device, and TNS treatment was delivered in the first hour after the TBI. Twenty-four hours later, the mice's behavior, brain edema, and expression of inflammatory factors were tested. Functional magnetic resonance imaging also was used to explore the possible effects of TNS on brain activity. RESULTS: TNS alleviates TBI-induced neurological dysfunction in animal behavior tests, besides protecting the blood-brain barrier and reducing the level of brain edema. TNS also effectively reduces the level of tumor necrosis factor-α and interleukin 6 and downregulates the cleaved caspase-3 signaling pathway. A series of brain areas was found to be possibly regulated by TNS, thus affecting the neural functions of animals. CONCLUSION: This study elucidates the role of TNS as an effective treatment for TBI by inhibiting the occurrence of a secondary brain injury.
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Edema Encefálico , Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Animales , Ratones , Lesiones Traumáticas del Encéfalo/terapia , Nervio Trigémino/fisiologíaRESUMEN
BACKGROUND: To determine if trigeminal nerve electrical stimulation (TNS) would be an effective arousal treatment for loss of consciousness (LOC), we applied neuroscientific methods to investigate the role of potential brain circuit and neuropeptide pathway in regulating level of consciousness. METHODS: Consciousness behavioral analysis, Electroencephalogram (EEG) recording, Chemogenetics, Microarray analysis, Milliplex MAP rat peptide assay, Chromatin immune-precipitation (ChIP), Dual-luciferase reporter experiment, Western blot, PCR and Fluorescence in situ hybridization (FISH). RESULTS: TNS can markedly activate the neuronal activities of the lateral hypothalamus (LH) and the spinal trigeminal nucleus (Sp5), as well as improve rat consciousness level and EEG activities. Then we proved that LH activation and upregulated neuropeptide hypocretin are beneficial for promotion of consciousness recovery. We then applied gene microarray experiment and found hypocretin might be mediated by a well-known transcription factor Early growth response gene 1 (EGR1), and the results were confirmed by ChIP and Dual-luciferase reporter experiment. CONCLUSION: This study illustrates that TNS is an effective arousal strategy Treatment for LOC state via the activation of Sp5 and LH neurons and upregulation of hypocretin expression.
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Terapia por Estimulación Eléctrica/métodos , Neuronas/fisiología , Nervio Trigémino/fisiopatología , Inconsciencia/terapia , Animales , Nivel de Alerta/fisiología , Conducta Animal/fisiología , Electroencefalografía , Masculino , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Inconsciencia/fisiopatologíaRESUMEN
BACKGROUND: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. METHODS: Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. RESULTS: We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. CONCLUSION: These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.
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Quimiocinas CXC/biosíntesis , Epigénesis Genética/efectos de los fármacos , Factores de Transcripción NFATC/biosíntesis , Neuralgia/inducido químicamente , Neuralgia/metabolismo , Paclitaxel/toxicidad , Animales , Antineoplásicos Fitogénicos/toxicidad , Secuencia de Bases , Quimiocinas CXC/genética , Epigénesis Genética/fisiología , Masculino , Factores de Transcripción NFATC/genética , Neuralgia/genética , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
KEY POINTS: Spinal cord dorsal horn srGAP3 (slit-robo GTPase activating protein 3) increases in the initiation phase of neuropathic pain and decreases in the maintenance phase. However, Rac1 activity, which can be reduced by srGAP3, decreases in the initiation phase and increases in the maintenance phase. The increased srGAP3 in the initiation phase promotes new immature dendritic spines instigating neuropathic pain. Decreased srGAP3 in the maintenance phase enhances Rac1 activity facilitating maturation of dendritic spines and the persistence of neuropathic pain. SrGAP3 small interfering RNA can ameliorate neuropathic pain only when administrated in the initiation phase. The Rac1 inhibitor can ameliorate neuropathic pain only when administrated in the maintenance phase. Combined targeting of srGAP3 in the initiation phase and Rac1 in the maintenance phase can produce optimal analgesic efficacy. ABSTRACT: Neuropathic pain includes an initiation phase and maintenance phase, each with different pathophysiological processes. Understanding the synaptic plasticity and molecular events in these two phases is relevant to exploring precise treatment strategies for neuropathic pain. In the present study, we show that dendritic spine density increases in the spinal dorsal horn in the initiation phase of neuropathic pain induced by paclitaxel and that the spine maturity ratio increases in the maintenance phase. Increased srGAP3 (slit-robo GTPase activating protein 3) facilitates dendritic spine sprouting in the initiation phase. In the maintenance phase, srGAP3 decreases to upregulate Rac1 activity, which facilitates actin polymerization and dendritic spine maturation and thus the persistence of neuropathic pain. Knockdown of srGAP3 in the initiation phase or inhibition of Rac1 in the maintenance phase attenuates neuropathic pain. Combined intervention of srGAP3 in the initiation phase, and Rac1 in the maintenance phase shows better analgesic efficacy against neuropathic pain. The present study demonstrates the role of srGAP3-Rac1 in dendritic spine plasticity in the two phases of neuropathic pain and, accordingly, provides treatment strategies for different phases of neuropathic pain.
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Espinas Dendríticas , Neuralgia , Animales , Espinas Dendríticas/metabolismo , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Mantenimiento , Neuralgia/tratamiento farmacológico , Paclitaxel/farmacología , Ratas , Ratas Sprague-Dawley , Proteína de Unión al GTP rac1/metabolismoRESUMEN
BACKGROUND: Although the action mechanism of antineoplastic agents is different, oxaliplatin, paclitaxel, or bortezomib as first-line antineoplastic drugs can induce painful neuropathy. In rodents, mechanical allodynia is a common phenotype of painful neuropathy for 3 chemotherapeutics. However, whether there is a common molecular involved in the different chemotherapeutics-induced painful peripheral neuropathy remains unclear. METHODS: Mechanical allodynia was tested by von Frey hairs following i.p. injection of vehicle, oxaliplatin, paclitaxel, or bortezomib in Sprague-Dawley rats. Reduced representation bisulfite sequencing and methylated DNA immunoprecipitation were used to detect the change of DNA methylation. Western blot, quantitative polymerase chain reaction, chromatin immunoprecipitation, and immunohistochemistry were employed to explore the molecular mechanisms. RESULTS: In 3 chemotherapeutic models, oxaliplatin, paclitaxel, or bortezomib accordantly upregulated the expression of transient receptor potential cation channel, subfamily C6 (TRPC6) mRNA and protein without affecting the DNA methylation level of TRPC6 gene in DRG. Inhibition of TRPC6 by using TRPC6 siRNA (i.t., 10 consecutive days) relieved mechanical allodynia significantly following application of chemotherapeutics. Furthermore, the downregulated recruitment of DNA methyltransferase 3 beta (DNMT3b) at paired box protein 6 (PAX6) gene led to the hypomethylation of PAX6 gene and increased PAX6 expression. Finally, the increased PAX6 via binding to the TPRC6 promoter contributes to the TRPC6 increase and mechanical allodynia following chemotherapeutics treatment. CONCLUSIONS: The TRPC6 upregulation through DNMT3b-mediated PAX6 gene hypomethylation participated in mechanical allodynia following application of different chemotherapeutic drugs.
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Antineoplásicos/farmacología , ADN (Citosina-5-)-Metiltransferasas/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Ganglios Espinales/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Hiperalgesia/inducido químicamente , Neuralgia/inducido químicamente , Factor de Transcripción PAX6/efectos de los fármacos , Canales Catiónicos TRPC/efectos de los fármacos , Animales , Bortezomib/farmacología , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Masculino , Neuralgia/complicaciones , Oxaliplatino/farmacología , Paclitaxel/farmacología , Ratas , Ratas Sprague-Dawley , Canales Catiónicos TRPC/antagonistas & inhibidores , Regulación hacia Arriba/efectos de los fármacos , ADN Metiltransferasa 3BRESUMEN
Circular RNAs are non-coding RNAs, and are enriched in the CNS. Dorsal horn neurons of the spinal cord contribute to pain-like hypersensitivity after nerve injury in rodents. Here we show that spinal nerve ligation is associated with an increase in expression of circAnks1a in dorsal horn neurons, in both the cytoplasm and the nucleus. Downregulation of circAnks1a by siRNA attenuates pain-like behaviour induced by nerve injury. In the cytoplasm, we show that circAnks1a promotes the interaction between transcription factor YBX1 and transportin-1, thus facilitating the nucleus translocation of YBX1. In the nucleus, circAnks1a binds directly to the Vegfb promoter, increases YBX1 recruitment to the Vegfb promoter, thereby facilitating transcription. Furthermore, cytoplasmic circAnks1a acts as a miRNA sponge in miR-324-3p-mediated posttranscriptional regulation of VEGFB expression. The upregulation of VEGFB contributes to increased excitability of dorsal horn neurons and pain behaviour induced by nerve injury. We propose that circAnks1a and VEGFB are regulators of neuropathic pain.
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Hipersensibilidad/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , ARN Circular/genética , Médula Espinal/metabolismo , Animales , Secuencia de Bases , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Neuronas/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Transporte de Proteínas , Ratas Sprague-Dawley , Roedores , Asta Dorsal de la Médula Espinal/metabolismo , Regulación hacia Arriba/genética , Factor B de Crecimiento Endotelial Vascular/metabolismoAsunto(s)
Bortezomib/efectos adversos , Quimiocina CCL21/genética , Epigénesis Genética/genética , Factor de Transcripción GATA3/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/metabolismo , Animales , Quimiocina CCL21/metabolismo , Epigénesis Genética/efectos de los fármacos , Factor de Transcripción GATA3/genética , Inmunohistoquímica , Inmunoprecipitación , Masculino , Análisis por Micromatrices , Neuralgia/inducido químicamente , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: Carpal tunnel syndrome (CTS) is one of the most common nerve entrapment syndromes, which has a serious impact on patients' work and life. The most effective conservative treatment is steroid injection but its long-term efficacy is still not satisfactory. The aim of this study was to evaluate the effectiveness of steroid injection combined with miniscalpel-needle (MSN) release for treatment of CTS under ultrasound guidance versus steroid injection alone. We hypothesized that combined therapy could be more beneficial. METHODS: Fifty-one patients with CTS were randomly allocated into two groups, namely, steroid injection combined with MSN release group and steroid injection group. The therapeutic effectiveness was evaluated using Boston Carpal Tunnel Questionnaire (BCTQ), cross-sectional area (CSA) of the median nerve, and four electrophysiological parameters, including distal motor latency (DML), compound muscle action potential (CMAP), sensory nerve action potential (SNAP), and sensory nerve conduction velocity (SNCV) at baseline, 4 and 12 weeks after treatment. RESULTS: Compared with baseline, all the parameters in both groups showed statistically significant improvement at week 4 and week 12 follow-up, respectively (P<0.05). When compared with steroid injection group, the outcomes including BCTQ, DML, CMAP, SNCV, and CSA of the median nerve were significantly better in steroid injection combined with MSN release group at week 12 after treatment (P<0.05). CONCLUSIONS: The effectiveness of steroid injection combined with MSN release for CTS is superior to that of steroid injection alone, which may have important implications for future clinical practice. This Chinese clinical trial is registered with ChiCTR1800014530.
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Síndrome del Túnel Carpiano/tratamiento farmacológico , Terapia Combinada , Esteroides/administración & dosificación , Ultrasonografía Intervencional/métodos , Adulto , Anciano , Síndrome del Túnel Carpiano/diagnóstico por imagen , Síndrome del Túnel Carpiano/fisiopatología , Síndrome del Túnel Carpiano/cirugía , Terapia Combinada/métodos , Femenino , Humanos , Ligamentos/diagnóstico por imagen , Ligamentos/efectos de los fármacos , Masculino , Nervio Mediano/diagnóstico por imagen , Nervio Mediano/efectos de los fármacos , Nervio Mediano/patología , Persona de Mediana Edad , Agujas , Conducción Nerviosa/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Studies showed that upregulation of Nav1.6 increased the neuronal excitability and participated in neuropathic pain in the dorsal root ganglion (DRG). However, the molecular mechanisms underlying Nav1.6 upregulation were not reported yet. METHODS: The paw withdrawal threshold was measured in the rodents following lumbar 5 ventral root transection (L5-VRT). Then qPCR, western blotting, immunoprecipitation, immunohistochemistry, and chromatin immunoprecipitation assays were performed to explore the molecular mechanisms in vivo and in vitro. RESULTS: We found that the levels of Nav1.6 and phosphorylated STAT3 were significantly increased in DRG neurons following L5-VRT, and TNF-α incubation also upregulated the Nav1.6 expression in cultured DRG neurons. Furthermore, immunoprecipitation and chromatin immunoprecipitation assays demonstrated that L5-VRT increased the binding of STAT3 to the Scn8a (encoding Nav1.6) promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of Scn8a by increasing histone H4 acetylation in Scn8a promoter in DRG. Importantly, intraperitoneal injection of the TNF-α inhibitor thalidomide reduced the phosphorylation of STAT3 and decreased the recruitment of STAT3 and histone H4 hyperacetylation in the Scn8a promoter, thus subsequently attenuating Nav1.6 upregulation in DRG neurons and mechanical allodynia induced by L5-VRT. CONCLUSION: These results suggested a new mechanism for Nav1.6 upregulation involving TNF-α/STAT3 pathway activation and subsequent STAT3-mediated histone H4 hyperacetylation in the Scn8a promoter region in DRG, which contributed to L5-VRT-induced neuropathic pain.
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Epigénesis Genética/genética , Ganglios Espinales/metabolismo , Canal de Sodio Activado por Voltaje NAV1.6/biosíntesis , Neuralgia/genética , Factor de Transcripción STAT3/genética , Transducción de Señal/genética , Factor de Necrosis Tumoral alfa/genética , Animales , Células Cultivadas , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/fisiopatología , Inmunohistoquímica , Masculino , Neuralgia/fisiopatología , Ratas , Ratas Sprague-Dawley , Raíces Nerviosas EspinalesRESUMEN
Palmitoylation of δ-catenin is critical to synapse plasticity and memory formation. We found that δ-catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated δ-catenin and the palmitoyl acyltransferase DHHC3 were increased in dorsal root ganglion (DRG) sensory neurons in rat models of neuropathic pain. Inhibiting palmitoyl acyltransferases or decreasing δ-catenin abundance in the DRG by intrathecal injection of 2-bromopalmitate or shRNA, respectively, alleviated oxaliplatin or nerve injury-induced neuropathic pain in the rats. The palmitoylation of δ-catenin, which was induced by the inflammatory cytokine TNF-α, facilitated its interaction with the voltage-gated sodium channel Nav1.6 and the kinesin motor protein KIF3A, which promoted the trafficking of Nav1.6 to the plasma membrane in DRG neurons and contributed to mechanical hypersensitivity and allodynia in rats. These findings suggest that a palmitoylation-mediated KIF3A/δ-catenin/Nav1.6 complex enhances the transmission of mechanical and nociceptive signals; thus, blocking this mechanism may be therapeutic in patients with neuropathic pain.
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Cateninas/metabolismo , Membrana Celular/metabolismo , Cinesinas/metabolismo , Canal de Sodio Activado por Voltaje NAV1.6/metabolismo , Neuralgia/fisiopatología , Células Receptoras Sensoriales/fisiología , Animales , Ganglios Espinales/citología , Células HEK293 , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Hiperalgesia/prevención & control , Lipoilación , Masculino , Neuralgia/inducido químicamente , Neuralgia/metabolismo , Oxaliplatino , Palmitatos/administración & dosificación , Palmitatos/farmacología , Ratas Sprague-Dawley , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Catenina deltaRESUMEN
Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription-3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno-associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats. Furthermore, the expressions of p-STAT3 were colocalized with NLRP3-positive cells in DRG neurons, and inhibition of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3flox/flox mice or inhibitor S3I-201 suppressed the upregulation of NLRP3 and mechanical allodynia induced by bortezomib treatment. Chromatin immunoprecipitation further found that bortezomib increased the recruitment of STAT3, as well as the acetylation of histone H3 and H4, in the NLRP3 promoter region in DRG neurons. Importantly, inhibition of the STAT3 activity by using S3I-201 or DRG local deficiency of STAT3 also significantly prevented the upregulated H3 and H4 acetylation in the NLRP3 promoter region following bortezomib treatment. Altogether, our results suggest that the upregulation of NLRP3 in DRG via STAT3-dependent histone acetylation is critically involved in bortezomib-induced mechanical allodynia.
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Antineoplásicos/toxicidad , Bortezomib/toxicidad , Histonas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Dolor/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Factor de Transcripción STAT3/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Acetilación/efectos de los fármacos , Ácidos Aminosalicílicos/farmacología , Animales , Bencenosulfonatos/farmacología , Modelos Animales de Enfermedad , Ganglios Espinales/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Histonas/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Dolor/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/genética , TransfecciónRESUMEN
Antitubulin chemotherapeutics agents, such as paclitaxel, are effective chemotherapy drugs for cancer treatment. However, painful neuropathy is a major adverse effect limiting the wider application of chemotherapeutics. In this study, we found that A-kinase anchor protein 150 (AKAP150) was significantly upregulated after paclitaxel injection. Inhibition of AKAP150 via siRNA or AKAP150flox/flox in rodents alleviated the pain behavior induced by paclitaxel, and partly restored the decreased calcineurin (CN) phosphatase activity after paclitaxel treatment. Paclitaxel decreased the expression of anti-inflammatory cytokine interleukin-4 (IL-4), and intrathecal injections of IL-4 effectively alleviated paclitaxel-induced hypersensitivity and the frequency of dorsal root ganglion (DRG) neurons action potential. The decreased CN enzyme activity, resulted in reduced protein expression of nuclear factor of activated T cells 2 (NFAT2) in cell nuclei. Chromatin immunoprecipitation showed that, NFAT2 binds to the IL-4 gene promoter regulating the protein expression of IL-4. Overexpression of NFAT2 by intrathecal injection of the AAV5-NFAT2-GFP virus alleviated the pain behavior induced by paclitaxel via increasing the expression of IL-4. Knocked down AKAP150 by siRNA or AAV5-Cre-GFP partly restored the expression of IL-4 in DRG. Our results indicated that regulation of IL-4 via the CN/NFAT2 pathway mediated by AKAP150 could be a pivotal treatment target for paclitaxel-induced neuropathic pain and or other neuropsychiatric disorders.
Asunto(s)
Proteínas de Anclaje a la Quinasa A/metabolismo , Neuralgia/metabolismo , Proteínas de Anclaje a la Quinasa A/fisiología , Animales , Calcineurina/efectos de los fármacos , Calcineurina/metabolismo , Citocinas/metabolismo , Regulación hacia Abajo , Ganglios Espinales/metabolismo , Hiperalgesia/metabolismo , Inyecciones Espinales , Interleucina-4/metabolismo , Masculino , Factores de Transcripción NFATC/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Neuralgia/fisiopatología , Paclitaxel/efectos adversos , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Regulación hacia ArribaRESUMEN
Antimicrotubulin chemotherapeutic agents such as vincristine (VCR), often induce peripheral neuropathic pain. It is usually permanent and seriously harmful to cancer patients' quality of life and can result in the hampering of clinical treatments. Currently, there is no definitive therapy, and many of the drugs approved for the treatment of other neuropathic pain have shown little or no analgesic effect. It is therefore vital to find new and novel therapeutic strategies for patients suffering from chemotherapeutic agent-induced neuropathic pain to improve patients' quality of life. This study shows that intrathecal injections of dexmedetomidine (DEX), or intraperitoneally administered ulinastatin (UTI) significantly reduces Sprague Dawley rats' mechanical allodynia induced by VCR via upregulation of interleukin-10 expression and activating the α2-adrenergic receptor in dorsal root ganglion (DRG). Moreover, when combined there is a synergistic interaction between DEX and UTI, which acts against VCR-induced neuropathic pain. This synergistic interaction between DEX and UTI may be partly attributed to a common analgesic pathway in which the upregulation of interleukin -10 plays an important role via activating α2-adrenergic receptor in rat dorsal root ganglion. The combined use of DEX and UTI does not affect the rat's blood pressure, heart rate, sedation, motor score, spatial learning, or memory function. All of these show that the combined use of DEX and UTI is an effective method in relieving VCR-induced neuropathic pain in rats. PERSPECTIVE: This article documents the synergistic interaction between 2 widely used drugs, DEX and UTI, against VCR-induced neuropathic pain. The results provide a potential target and novel drug administrated method for the clinical treatment of chemotherapy-induced peripheral neuropathic pain.