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1.
CNS Neurosci Ther ; 30(9): e70012, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39215404

RESUMEN

AIMS: Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated. METHODS AND RESULTS: We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD+) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD+ level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity. CONCLUSION: The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.


Asunto(s)
Daño del ADN , Mitocondrias , Neuralgia , Paclitaxel , Poli(ADP-Ribosa) Polimerasa-1 , Animales , Masculino , Ratas , Modelos Animales de Enfermedad , Daño del ADN/efectos de los fármacos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , NAD/metabolismo , Neuralgia/inducido químicamente , Neuralgia/metabolismo , Neuralgia/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Paclitaxel/toxicidad , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo
2.
Br J Anaesth ; 131(2): 253-265, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37474241

RESUMEN

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).


Asunto(s)
Anestésicos por Inhalación , Delirio del Despertar , Neoplasias , Propofol , Humanos , Femenino , Anciano , Masculino , Propofol/efectos adversos , Sevoflurano/efectos adversos , Anestésicos por Inhalación/efectos adversos , Estudios de Seguimiento , Anestesia General/efectos adversos , Delirio del Despertar/inducido químicamente , Neoplasias/cirugía
3.
Br J Anaesth ; 131(2): 266-275, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37474242

RESUMEN

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.


Asunto(s)
Neoplasias , Propofol , Sevoflurano , Propofol/efectos adversos , Sevoflurano/efectos adversos , Neoplasias/cirugía , Humanos , Masculino , Femenino , Anciano , Estudios de Seguimiento , Anestésicos Intravenosos , Anestesia por Inhalación , Supervivientes de Cáncer
4.
Biomed Pharmacother ; 149: 112912, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35856853

RESUMEN

Cancer-induced bone pain (CIBP) treatment remains a clinical challenge because the pathophysiological mechanisms are not fully understood. Recently, it was verified that shifting microglial polarization toward the M2 phenotype reveals a potential strategy for CIBP treatment. Naringenin, a natural flavone flavonoid, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. However, the role of naringenin on regulating microglial polarization in CIBP rats and the molecular mechanisms participating in this process have not been fully clarified. Herein, we investigated the potential effect of naringenin on M1/M2 microglial polarization and further explored the potential mechanisms of this action. Our study demonstrated that intraperitoneal administration of naringenin could upregulate the antioxidative molecule glutathione peroxidase 4 (GPx4) level in the spinal cord, as well as bone cancer-induced mechanical allodynia in rats. Moreover, naringenin treatment also suppressed microglia-mediated neuroinflammation by downregulating the phosphorylation of nuclear factor κB (NF-κB) p65 expression and promoting microglial polarization toward the M2 phenotype in CIBP rats. The promoting effects mediated by naringenin on M1/M2 microglial polarization are dependent on the serine/threonine protein kinase adenosine monophosphate-activated protein kinase (AMPK)/proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. Inhibition of AMPK activation with the classical AMPK inhibitor Compound C attenuated this effect of naringenin. These results improved the understanding of the anti-inflammatory property of naringenin on microglial polarization, which might provide new alternative avenues for CIBP treatment.


Asunto(s)
Dolor en Cáncer , Neoplasias , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Dolor en Cáncer/metabolismo , Flavanonas , Microglía , Neoplasias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Ratas , Transducción de Señal
5.
Huan Jing Ke Xue ; 43(4): 2104-2114, 2022 Apr 08.
Artículo en Chino | MEDLINE | ID: mdl-35393834

RESUMEN

In order to explore the spatial distribution and ecological risk of heavy metals in farmland soil around Tongguan Mining area, surface soil samples from Tongguan Mining area were collected in September 2020, and the contents and distribution characteristics of eight heavy metals (Pb, Cu, Cd, Hg, Cr, Ni, Zn, and As) in the samples were analyzed. The Nemerow comprehensive pollution index and potential ecological risk index were used to evaluate soil pollution. The results showed that the contents of the eight types of heavy metal elements in this area exceeded the standard, and the exceeding rates were 97.91%, 84.79%, 100%, 95.41%, 96.87%, 98.54%, 91.45%, and 28.95%, respectively. The variation coefficients of the eight heavy metals were ranked as Hg>Pb>Cu>Cd>Zn>As>Ni>Cr. The variation coefficients of Hg, Pb, Cu, Cd, and Zn were all greater than 1. Correlation analysis showed that these five heavy metals were obviously correlated. In terms of spatial distribution, Pb, Cd, Cu, Hg, Zn, and As were distributed in patches, whereas Cr and Ni were distributed in flakes. The high values of Hg, Cd, Pb, Cu, and Zn were mainly distributed in the southern and central part of the study area. The comprehensive pollution of Nemerow showed that the severe pollution rate reached 87.91%, and the moderate pollution rate and the mild pollution rate were 9.58% and 2.5%, respectively; thus, the overall pollution was severe. The potential ecological risk index showed that Hg, Cd, Pb, and Cu were the main risk elements. The total potential ecological risk index showed that the proportion of samples with strong pollution was 97.08%, and the proportion of extremely strongly, very strongly, and strongly polluted samples were 55.63%, 27.08%, and 14.37%, respectively, indicating that the overall potential ecological risk in the study area was very strong. Combining the two pollution assessment methods, it can be seen that the heavy metal pollution around Tongguan mining area, primarily by Hg, Cd, and Pb, was serious. These results can provide data support for regional pollution control, soil remediation, and ecological protection. It is suggested that the state of soil heavy metal pollution and its transformation in various media should be monitored continuously in the future.


Asunto(s)
Mercurio , Metales Pesados , Contaminantes del Suelo , Cadmio/análisis , China , Monitoreo del Ambiente/métodos , Contaminación Ambiental/análisis , Granjas , Plomo/análisis , Mercurio/análisis , Metales Pesados/análisis , Medición de Riesgo , Suelo , Contaminantes del Suelo/análisis
6.
Int J Med Sci ; 18(1): 73-80, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33390775

RESUMEN

Modern medical imaging facilitates the diagnosis and treatment of human diseases. However, few people are aware of the cons of radiation exposure from medical imaging. Emerging evidence reveals that cumulative doses of radiation exposure will increase the morbidity and mortality of pertaining cancer. As a special young population, patients with adolescent idiopathic scoliosis (AIS) suffer more radiation harms from repeated diagnostic imaging, most of which can be avoided in clinical practice. Accumulating evidence highlights reduced cancer risks of radiation exposure for AIS patients with low/zero radiation imaging modalities proposed, amongst which easy conversion from anterior-posterior (AP) to posterior-anterior (PA) projection for whole-spine radiographs should be stressed. It can greatly reduce radiation doses without compromising the quality of diagnostic imaging. Tight collimation combined with PA projection can further reduce radiation harms, and need to be spread to benefit people globally.


Asunto(s)
Neoplasias/prevención & control , Radiografía/métodos , Escoliosis/diagnóstico , Columna Vertebral/diagnóstico por imagen , Rayos X/efectos adversos , Adolescente , Factores de Edad , Edad de Inicio , Carga Global de Enfermedades , Humanos , Neoplasias/epidemiología , Neoplasias/etiología , Dosis de Radiación , Radiografía/efectos adversos , Escoliosis/epidemiología
7.
Life Sci ; 265: 118778, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33217442

RESUMEN

AIMS: The intervertebral disc is the largest avascular organ of the body. Vascularization of the disc has been typically regarded as a pathological feature of intervertebral disc degeneration (IDD). However, the underlying mechanism of vascularization in IDD is still unclear. The current study aimed to investigate the role of AF cell derived exosome (AF-exo) in the interaction with human umbilical vein endothelial cells (HUVECs) and its potential role in the regulation of vascularization in IDD. MAIN METHODS: Human AF tissues were obtained from patients with IDD and idiopathic scoliosis. The AF-exo were isolated and identified by transmission electron microscopy (TEM), nanoparticle trafficking analysis (NTA) and Western blotting. Then, the AF-exo were used for HUVECs cultures. The migration of HUVECs was observed in 2D and 3D cultures. The inflammatory phenotype of HUVECs was examined by Real-time PCR and enzyme-linked immunosorbent assay (ELISA). Additionally, apoptosis of HUVECs were analyzed by flow cytometry. KEY FINDINGS: Here, we for the first time found that AF cells could secrete AF-exo and that the AF-exo could be phagocytosed by HUVECs. Additionally, we found that degenerated AF-exo exerted pro-vascularization effect on HUVECs by promoting cell migration (in 2D and 3D cultures) and inflammatory factor expression including IL-6, TNF-α, MMP-3, MMP-13 and VEGF, whereas the application of non-degenerated AF-exo demonstrated inverse effects. SIGNIFICANCE: These results showed that AF-exo is an essential regulator mediating intercellular communication between AF cells and HUVECs, suggesting its important role in vascularization in the intervertebral disc.


Asunto(s)
Anillo Fibroso/metabolismo , Movimiento Celular/fisiología , Endotelio/citología , Exosomas/metabolismo , Inflamación/fisiopatología , Degeneración del Disco Intervertebral/patología , Disco Intervertebral/irrigación sanguínea , Adolescente , Adulto , Anciano , Anillo Fibroso/fisiología , Apoptosis , Western Blotting , Endotelio/metabolismo , Endotelio/fisiología , Citometría de Flujo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/fisiopatología , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Escoliosis/metabolismo , Escoliosis/fisiopatología , Adulto Joven
8.
Mol Ther Nucleic Acids ; 22: 1092-1106, 2020 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-33294295

RESUMEN

Angiogenesis is a pathological signature of intervertebral disc degeneration (IDD). Accumulating evidence has shown that notochordal cells (NCs) play an essential role in maintaining intervertebral disc development and homeostasis with inhibitive effect on blood vessel in-growth. However, the anti-angiogenesis mechanism of NCs is still unclear. In the current study, we, for the first time, isolated NC-derived exosomes (NC-exos) and showed their increased concentration following compressive load cultures. We further found that NC-exos from 0.5 MPa compressive load cultures (0.5 MPa/NC-exos) inhibit angiogenesis via transferring high expressed microRNA (miR)-140-5p to endothelial cells and regulating the downstream Wnt/ß-catenin pathway. Clinical evidence showed that exosomal miR-140-5p expression of the nucleus pulposus is negatively correlated with angiogenesis in IDD. Finally, 0.5 MPa/NC-exos were demonstrated to have a therapeutical impact on the degenerated disc with an anti-angiogenesis effect in an IDD model. Consequently, our present findings provide insights into the anti-angiogenesis mechanism of NC-exos, indicating their therapeutic potential for IDD.

9.
Front Microbiol ; 11: 594065, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33240248

RESUMEN

The high incidence of bacterial vaginosis recurrence is common after treatment with an antibiotic agent and suggests the need for new treatments to prevent this. We conducted a randomized trial to evaluate the ability of maltose gel to treat bacterial vaginosis. Eighteen female rhesus macaques were randomly assigned, in a 2:1 ratio, to receive maltose gel or placebo gel by syringe to the fornix of the vagina for five consecutive days. We used 16S rRNA sequencing data from 70 swab samples of vaginal secretions in two groups in total on days 0, 3, and 5 after medication initiation and days 3 and 5 after medication withdrawal for the study of microbiome composition. We found that, in the placebo control group, there was no significant change in the composition and abundance of vaginal microbiota during the follow-up period. In the maltose gel test group, the abundance of Lactobacillus in the vagina microbiota increased gradually with the prolongation of the treatment time on Days 3 and 5 (ANOVA p = 6.99e-5 < 0.01) but began to decrease after the withdrawal of maltose gel, which was different from that of the control group. Correspondingly, the diversity and abundance of BV-related bacteria, Fusobacterium, Parvimonas, Mobiluncus, Campylobacter, Prevotella, and Sneathia, decreased on Day 0 to Day 5 of medication and increased after drug withdrawal in the maltose gel test group. The study confirms that maltose gel can facilitate the proliferation of Lactobacillus and promote the transition of the vaginal microbiota from BV-related bacteria dominant to Lactobacillus dominant in the rhesus macaque.

12.
BMJ Open ; 7(11): e018607, 2017 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-29187413

RESUMEN

INTRODUCTION: Elderly patients who have solid organ cancer often receive surgery. Some of them may develop delirium after surgery and delirium development is associated with worse outcomes. Furthermore, despite all of the advances in medical care, the long-term survival in cancer patients is far from optimal. Evidences suggest that choice of anaesthetics during surgery, that is, either inhalational or intravenous anaesthetics, may influence outcomes. However, the impact of general anaesthesia type on the occurrence of postoperative delirium is inconclusive. Although retrospective studies suggest that propofol-based intravenous anaesthesia was associated with longer survival after cancer surgery when compared with inhalational anaesthesia, prospective studies as such are still lacking. The purposes of this randomised controlled trial are to test the hypotheses that when compared with sevoflurane-based inhalational anaesthesia, propofol-based intravenous anaesthesia may reduce the incidence of early delirium and prolong long-term survival in elderly patients after major cancer surgery. METHODS AND ANALYSIS: This is a multicentre, open-label, randomised controlled trial with two parallel arms. 1200 elderly patients (≥65 years but <90 years) who are scheduled to undergo major cancer surgery (with predicted duration ≥2 hours) are randomised to receive either sevoflurane-based inhalational anaesthesia or propofol-based intravenous anaesthesia. Other anaesthetics and supplemental drugs including sedatives, opioids and muscle relaxants are administered in both arms according to routine practice. The primary early outcome is the incidence of 7-day delirium after surgery and the primary long-term outcome is the duration of 3-year survival after surgery. ETHICS AND DISSEMINATION: The study protocol has been approved by the Clinical Research Ethics Committees of Peking University First Hospital (2015[869]) and all participating centres. The results of early and long-term outcomes will be analysed and reported separately. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-15006209; NCT02662257; NCT02660411.


Asunto(s)
Anestésicos por Inhalación/administración & dosificación , Anestésicos Intravenosos/administración & dosificación , Delirio/epidemiología , Éteres Metílicos/administración & dosificación , Complicaciones Posoperatorias/epidemiología , Propofol/administración & dosificación , Anciano , Anciano de 80 o más Años , Anestesia General , Anestésicos por Inhalación/efectos adversos , Anestésicos Intravenosos/efectos adversos , China , Delirio/etiología , Femenino , Humanos , Masculino , Éteres Metílicos/efectos adversos , Neoplasias/cirugía , Propofol/efectos adversos , Proyectos de Investigación , Sevoflurano , Tasa de Supervivencia
13.
Stem Cells Int ; 2017: 6082684, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28584529

RESUMEN

The use of human telomerase reverse transcriptase-immortalized bone marrow mesenchymal stromal cells (hTERT-BMSCs) as vehicles to deliver antinociceptive galanin (GAL) molecules into pain-processing centers represents a novel cell therapy strategy for pain management. Here, an hTERT-BMSCs/Tet-on/GAL cell line was constructed using a single Tet-on-inducible lentivirus system, and subsequent experiments demonstrated that the secretion of rat GAL from hTERT-BMSCs/Tet-on/GAL was switched on and off under the control of an inducer in a dose-dependent manner. The construction of this cell line is the first promising step in the regulation of GAL secretion from hTERT-immortalized BMSCs, and the potential application of this system may provide a stem cell-based research platform for pain.

14.
Zhongguo Gu Shang ; 30(4): 372-376, 2017 Apr 25.
Artículo en Chino | MEDLINE | ID: mdl-29349992

RESUMEN

OBJECTIVE: To investigate the clinical efficacy of excision of necrotic and infected tissues combined with induced membrane and external fixator technique to treat chronic osteomyelitis in tibia after fracture operation. METHODS: From June 2011 to June 2014, a total of 13 patients with tibia osteomyelitis were treated with excision of necrotic and infected tissues and external fixator technique in the first stage. There were 8 males and 5 females, ranging in age from 16 to 67 years old with an average of (37.3±14.3) years old. Within 6 to 8 weeks the induced membrane was formed and the induced membrane technique was applied to promote new bone forming in the second stage. RESULTS: Thirteen patients had no reinfection and achieved complete bone healing after 24 to 52 months follow-up. All the patients had satisfactory function. CONCLUSIONS: Excision of necrotic and infected tissues combined with induced membrane and external fixator technique to treat chronic osteomyelitis in tibia after fracture operation can provide satisfactory results.


Asunto(s)
Fijadores Externos , Fijación de Fractura/efectos adversos , Complicaciones Posoperatorias/cirugía , Tibia , Fracturas de la Tibia/cirugía , Adolescente , Adulto , Anciano , Artrodesis , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Necrosis/cirugía
15.
Oncotarget ; 7(39): 63166-63176, 2016 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-27542248

RESUMEN

Accumulating evidence indicates noncoding RNAs (ncRNAs) fine-tune gene expression with mysterious machinery. We conducted a combination of mRNA, miRNA, circRNA, LncRNA microarray analyses on 10 adults' lumbar discs. Moreover, we performed additional global exploration on RNA interacting machinery in terms of in silico computational pipeline. Here we show the landscape of RNAs in human lumbar discs. In general, the RNA-abundant landscape comprises 14,635 mRNAs (37.93%), 2,059 miRNAs (5.34%), 18,995 LncRNAs (49.23%) and 2,894 (7.5%) circRNAs. Chromosome 1 contributes for RNA transcription at most (10%). Bi-directional transcription contributes evenly for RNA biogenesis, in terms of 5' to 3' and 3' to 5'. Despite the majority of circRNAs are exonic, antisense (1.49%), intergenic (0.035%), intragenic (1.69%), and intronic (6.29%) circRNAs should not be ignored. A single miRNA could interact with a multitude of circRNAs. Notably, CDR1as or ciRS-7 harbors 66 consecutive binding sites for miR-7-5p (previous miR-7), evidencing our pipeline. The majority of binding sites are perfect-matched (78.95%). Collectively, global landscape of RNAs sheds novel insights on RNA interacting mechanisms in human intervertebral disc degeneration.


Asunto(s)
Degeneración del Disco Intervertebral/genética , Vértebras Lumbares/patología , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Adulto , Sitios de Unión , Biología Computacional , Expresión Génica , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Núcleo Pulposo/patología , Transcripción Genética
17.
J Neuroinflammation ; 13(1): 141, 2016 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-27267059

RESUMEN

Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund's adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.


Asunto(s)
Interleucina-6/fisiología , Dimensión del Dolor/métodos , Dolor/inducido químicamente , Dolor/metabolismo , Animales , Humanos , Interleucina-6/toxicidad , Dolor/patología , Dimensión del Dolor/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
18.
Biomaterials ; 82: 34-47, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26741882

RESUMEN

Various scaffolds have been attempted for intervertebral disc regeneration, but their effectiveness was limited by loss of nutrients within the scaffolds. It has been suggested that the disc is not severely hypoxic and limited availability of oxygen results in disc degeneration. Therefore, a certain oxygen level might be beneficial for disc regeneration, which has not been given enough attention in previous studies. Here, we used perfluorotributylamine (PFTBA) for the first time as an oxygen regulator in alginate scaffold for disc regeneration in vitro and in vivo. We found that the characteristics of alginate were not affected by PFTBA and the oxygen level of the scaffold was regulated. Then, human nucleus pulposus (NP) cells were cultured in the PFTBA-enriched alginates. It was found that PFTBA could promote NP cell survival and proliferation. In addition, 2.5% PFTBA was capable of regulating extracellular matrix (ECM) to a disc-like tissue graft with little effect on the expression of NP cell markers. Finally, 2.5% PFTBA-enriched alginate was found to restore the disc height and the ECM in a mouse disc degeneration model, indicating its beneficial effect on alleviating disc degeneration. These findings highlight the promising application of PFTBA in further intervertebral disc regeneration.


Asunto(s)
Fluorocarburos/química , Degeneración del Disco Intervertebral/fisiopatología , Degeneración del Disco Intervertebral/terapia , Disco Intervertebral/crecimiento & desarrollo , Regeneración , Reeemplazo Total de Disco , Alginatos/química , Animales , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Diseño de Equipo , Análisis de Falla de Equipo , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/patología , Ensayo de Materiales , Ratones , Ratones Endogámicos C57BL , Oxígeno/metabolismo , Andamios del Tejido , Resultado del Tratamiento
19.
Genom Data ; 5: 80-1, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26484230

RESUMEN

Accumulating evidence indicates that noncoding RNAs play important roles in a multitude of biological processes. The striking findings of miRNAs (microRNAs) and lncRNAs (long noncoding RNAs) as members of noncoding RNAs open up an exciting era in the studies of gene regulation. More recently, the reports of circRNAs (circular RNAs) add fuel to the noncoding RNAs research. Human intervertebral disc degeneration (IDD) is a main cause of low back pain as a disabling spinal disease. We have addressed the expression profiles if miRNAs, lncRNAs and mRNAs in IDD (Wang et al., J Pathology, 2011 and Wan et al., Arthritis Res Ther, 2014). Furthermore, we thoroughly analysed noncoding RNAs, including miRNAs, lncRNAs and circRNAs in IDD using the very same samples. Here we delineate in detail the contents of the aforementioned microarray analyses. Microarray and sample annotation data were deposited in GEO under accession number GSE67567 as SuperSeries. The integrated analyses of these noncoding RNAs will shed a novel light on coding-noncoding regulatory machinery.

20.
Int J Biol Sci ; 11(2): 133-43, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25561896

RESUMEN

INTRODUCTION: Abnormal biomechanics plays a role in intervertebral disc degeneration. Adipose-derived stromal cells (ADSCs) have been implicated in disc integrity; however, their role in the setting of mechanical stimuli upon the disc's nucleus pulposus (NP) remains unknown. As such, the present study aimed to evaluate the influence of ADSCs upon NP cells in compressive load culture. METHODS: Human NP cells were cultured in compressive load at 3.0MPa for 48 hours with or without ADSCs co-culture (the ratio was 50:50). We used flow cytometry, live/dead staining and scanning electron microscopy (SEM) to evaluate cell death, and determined the expression of specific apoptotic pathways by characterizing the expression of activated caspases-3, -8 and -9. We further used real-time (RT-) PCR and immunostaining to determine the expression of the extracellular matrix (ECM), mediators of matrix degradation (e.g. MMPs, TIMPs and ADAMTSs), pro-inflammatory factors and NP cell phenotype markers. RESULTS: ADSCs inhibited human NP cell apoptosis via suppression of activated caspase-9 and caspase-3. Furthermore, ADSCs protected NP cells from the degradative effects of compressive load by significantly up-regulating the expression of ECM genes (SOX9, COL2A1 and ACAN), tissue inhibitors of metalloproteinases (TIMPs) genes (TIMP-1 and TIMP-2) and cytokeratin 8 (CK8) protein expression. Alternatively, ADSCs showed protective effect by inhibiting compressive load mediated increase of matrix metalloproteinases (MMPs; MMP-3 and MMP-13), disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs; ADAMTS-1 and 5), and pro-inflammatory factors (IL-1beta, IL-6, TGF-beta1 and TNF-alpha). CONCLUSIONS: Our study is the first in vitro study assessing the impact of ADSCs on NP cells in an un-physiological mechanical stimulation culture environment. Our study noted that ADSCs protect compressive load induced NP cell death and degradation by inhibition of activated caspase-9 and -3 activity; regulating ECM and modulator genes, suppressing pro-inflammatory factors and preserving CK8. Consequently, the protective impact of ADSCs found in this study provides an essential understanding and expands our knowledge as to the utility of ADSCs therapy for intervertebral disc regeneration.


Asunto(s)
Adipocitos/citología , Degeneración del Disco Intervertebral/terapia , Disco Intervertebral/patología , Células del Estroma/citología , Células del Estroma/fisiología , Adolescente , Adulto , Apoptosis , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Células Cultivadas , Desintegrinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Queratina-8/metabolismo , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Microscopía Electrónica de Rastreo , Reacción en Cadena en Tiempo Real de la Polimerasa , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Adulto Joven
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