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1.
Neuropharmacology ; 252: 109939, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38570065

RESUMO

To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.


Assuntos
Antígenos Nucleares , Microbioma Gastrointestinal , Proteína Quinase 1 Ativada por Mitógeno , Proteínas do Tecido Nervoso , Neuralgia , Ratos Sprague-Dawley , Triterpenos , Ácido Ursólico , Animais , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Triterpenos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Nervos Espinhais/efeitos dos fármacos , Analgésicos/farmacologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo
2.
Front Cell Neurosci ; 16: 872935, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35602557

RESUMO

Background: Spinal cord injury (SCI) damages the autonomic nervous system and affects the homeostasis of gut microbiota. Ursolic acid (UA) is a candidate drug for treating nervous system injury due to its neuroprotective and antioxidant functions. The purpose of our study was to investigate the role of UA on SCI and its mechanism. Methods: UA was administered to SCI mice and the solvent corn oil was used as control. The weight of the mice was recorded daily. Mice feces were collected 21 days after surgery for 16S rRNA-amplicon sequencing and untargeted metabolomics analysis. The expressions of NF-κB, IL-1ß, and TNF-α in the spinal cord and colon tissues of mice were detected by Western blot and Enzyme-linked immunosorbent assay, respectively. Immunohistochemistry was used to analyze the expression of NeuN, NF-200, and synapsin in the spinal cord tissues. Results: UA treatment increased body weight and soleus muscle weight of SCI mice. UA treatment inhibited inflammatory response and protected neuronal activity in SCI mice. UA improved the relative abundance of Muribaculaceae, Lachnospiraceae_NK4A136_group, and Alloprevotell genus in the gut tract of SCI mice. SCI destroyed the Glutamine_and_D-glutamate_metabolism, Nitrogen_metabolism, Aminoacyl-tRNA_biosynthesis, and Taurine_and_hypotaurine_metabolism in the gut of mice, which might be alleviated by UA. Conclusions: UA treatment could inhibit SCI progression by improving the gut environment and metabolic changes, promoting synaptic regeneration and anti-inflammatory effects.

3.
J Neurotrauma ; 38(3): 353-364, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32977735

RESUMO

Neural stem cells (NSCs) play vital roles in the homeostasis of neurological function. Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) is an important regulator of stem cell phenotypes. In our current study, we aimed to investigate whether the conditional knockout of UTX on neural stem cells alters macrophage assembly in response to spinal cord injury (SCI). Conditional knockout Utx of NSC (Utx-KO) mice was used to generate SCI models by the modified Allen method. We reported that neurological function and scar hyperplasia significantly improved in Utx-KO mice after SCI, accompanied by significantly reduced assembly of macrophages. With a 45-fold pathway array and Western blot, we found that Utx-KO could significantly inhibit NF-κB signaling activation and promote the synthesis and secretion of macrophage migration inhibitory factor (MIF) in NSCs. Administration of the selective NF-κB p65 activator betulinic acid and the selective MIF inhibitor ISO-1 confirmed that the activation of NF-κB p65 phosphorylation or inhibition of MIF could eliminate the benefits of Utx-KO in SCI, such as inhibition of macrophage aggregation and reduction in scar proliferation. This study confirmed that UTX in NSCs could alter macrophage migration and improve neurological function recovery after SCI in mice.


Assuntos
Histona Desmetilases/fisiologia , Macrófagos/fisiologia , NF-kappa B/fisiologia , Células-Tronco Neurais/metabolismo , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/patologia , Animais , Movimento Celular , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/metabolismo
5.
Front Cell Neurosci ; 13: 50, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873006

RESUMO

Neuropathic pain (NP) is among the most intractable comorbidities of spinal cord injury. Dysregulation of non-coding RNAs has also been implicated in the development of neuropathic pain. Here, we identified a novel lncRNA, PKIA-AS1, by using lncRNA array analysis in spinal cord tissue of spinal nerve ligation (SNL) model rats, and investigated the role of PKIA-AS1 in SNL-mediated neuropathic pain. We observed that PKIA-AS1 was significantly upregulated in SNL model rats and that PKIA-AS1 knockdown attenuated neuropathic pain progression. Alternatively, overexpression of PKIA-AS1 was sufficient to induce neuropathic pain-like symptoms in uninjured rats. We also found that PKIA-AS1 mediated SNL-induced neuropathic pain by directly regulating the expression and function of CDK6, which is essential for the initiation and maintenance of neuroinflammation and neuropathic pain. Therefore, our study identifies PKIA-AS1 as a novel therapeutic target for neuroinflammation related neuropathic pain.

6.
J Mater Sci Mater Med ; 27(5): 89, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26975746

RESUMO

To develop adriamycin (ADM)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles in a porous nano-hydroxyapatite/collagen scaffold (ADM-PLGA-NHAC). To provide novel strategies for future treatment of osteosarcoma, the properties of the scaffold, including its in vitro extended-release properties, the inhibition effects of ADM-PLGA-NHAC on the osteosarcoma MG63 cells, and its bone repair capacity, were investigated in vivo and in vitro. The PLGA copolymer was utilized as a drug carrier to deliver ADM-PLGA nanoparticles (ADM-PLGA-NP). Porous nano-hydroxyapatite and collagen were used to materials to produce the porous nano-hydroxyapatite/collagen scaffold (NHAC), into which the ADM-PLGA-NP was loaded. The performance of the drug-carrying scaffold was assessed using multiple techniques, including scanning electron microscopy and in vitro extended release. The antineoplastic activities of scaffold extracts on the human osteosarcoma MG63 cell line were evaluated in vitro using the cell counting kit-8 (CCK8) method and live-dead cell staining. The bone repair ability of the scaffold was assessed based on the establishment of a femoral condyle defect model in rabbits. ADM-PLGA-NHAC and NHAC were implanted into the rat muscle bag for immune response experiments. A tumor-bearing nude mice model was created, and the TUNEL and HE staining results were observed under optical microscopy to evaluate the antineoplastic activity and toxic side effects of the scaffold. The composite scaffold demonstrated extraordinary extended-release properties, and its extracts also exhibited significant inhibition of the growth of osteosarcoma MG63 cells. In the bone repair experiment, no significant difference was observed between ADM-PLGA-NHAC and NHAC by itself. In the immune response experiments, ADM-PLGA-NHAC exhibited remarkable biocompatibility. The in vivo antitumor experiment revealed that the implantation of ADM-PLGA-NHAC in the tumor resulted in a improved antineoplastic effect and fewer adverse side effects than direct intraperitoneal injection of ADM. The ADM-PLGA-NHAC developed in this study exhibited excellent extended-release drug properties, bone repairing and antineoplastic efficacy, which make it a promising osteoconductivity material with the capability to inhibit osteosarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Colágeno/química , Doxorrubicina/química , Durapatita/química , Ácido Láctico/química , Ácido Poliglicólico/química , Alicerces Teciduais/química , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Feminino , Humanos , Ácido Láctico/farmacologia , Masculino , Camundongos , Camundongos Nus , Nanoestruturas , Osteossarcoma , Ácido Poliglicólico/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Coelhos , Ratos , Ratos Sprague-Dawley
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