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1.
Neuropharmacology ; 259: 110115, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39137872

RESUMO

Immune cells and interleukins play a crucial role in female-specific pain signaling. Interleukin 16 (IL-16) is a cytokine primarily associated with CD4+ T cell function. While previous studies have demonstrated the important role of spinal CD4+ T cells in neuropathic pain, the specific contribution of IL-16 to neuropathic pain remains unclear. In this study, by using a spinal nerve ligation (SNL)-induced neuropathic pain mice model, we found that SNL induced an increase in IL-16 mRNA levels, which persisted for a longer duration in female mice compared to male mice. Immunofluorescence analysis further confirmed enhanced IL-16- and CD4-positive signals in the spinal dorsal horn following SNL surgery in female mice. Knockdown of spinal IL-16 by siRNA or inhibition of CD4 by FGF22-IN-1, a CD4 inhibitor, attenuated established mechanical and thermal pain hypersensitivity induced by SNL. Furthermore, female mice injected with IL-16 intrathecally exhibited significant spontaneous pain, mechanical and thermal hyperalgesia, all of which could be alleviated by FGF22-IN-1 or a CD3 antibody. Additionally, IL-16 induced astrocyte activation but not microglial activation in the spinal dorsal horn of female mice. Meanwhile, astrocyte activation could be suppressed by the CD3 antibody. These results provide compelling evidence that IL-16 promotes astrocyte activation via CD4 on CD3+ T cells, which is critical for maintaining neuropathic pain in female mice.


Assuntos
Astrócitos , Complexo CD3 , Interleucina-16 , Neuralgia , Transdução de Sinais , Animais , Feminino , Camundongos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Hiperalgesia/metabolismo , Interleucina-16/metabolismo , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
2.
Mol Neurobiol ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38963532

RESUMO

The comorbidity of anxiety and depression frequently occurs in patients with neuropathic pain. The ventrolateral orbital cortex (VLO) plays a critical role in mediating neuropathic pain and anxiodepression in rodents. Previous studies suggested that 5-HT6 receptors in the VLO are involved in neuropathic pain. Strong evidence supports a close link between 5-HT6 receptors and affective disorders such as depression and anxiety disorders. However, it remains unclear whether the 5-HT6 receptors in the VLO are involved in neuropathic pain-induced anxiodepression. Using a rat neuropathic pain model of spared nerve injury (SNI), we demonstrated that rats exhibited significant anxiodepression-like behaviors and the expression of VLO 5-HT6 receptors obviously decreased four weeks after SNI surgery. Microinjection of the 5-HT6 receptor agonist EMD-386088 into the VLO or overexpression of VLO 5-HT6 receptors alleviated anxiodepression-like behaviors. These effects were blocked by pre-microinjection of a selective 5-HT6 receptor antagonist (SB-258585) or inhibitors of AC (SQ-22536), PKA (H89), and MEK1/2 (U0126) respectively. Meanwhile, the expression of p-ERK, p-CREB, and BDNF in the VLO decreased four weeks after SNI surgery. Furthermore, administration of EMD-386088 upregulated the expression of BDNF, p-ERK, and p-CREB in the VLO of SNI rats, which were reversed by pre-injection of SB-258585. These findings suggest that activating 5-HT6 receptors in the VLO has anti-anxiodepressive effects in rats with neuropathic pain via activating AC-cAMP-PKA-MERK-CREB-BDNF signaling pathway. Accordingly, 5-HT6 receptor in the VLO could be a potential target for the treatment of the comorbidity of neuropathic pain and anxiodepression.

3.
Neuropharmacology ; 254: 109992, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38723742

RESUMO

Chronic primary pain, characterized by overlapping symptoms of chronic pain, anxiety, and depression, is strongly associated with stress and is particularly prevalent among females. Recent research has convincingly linked epigenetic modifications in the medial prefrontal cortex (mPFC) to chronic pain and chronic stress. However, our understanding of the role of histone demethylation in the mPFC in chronic stress-induced pain remains limited. In this study, we investigated the function of lysine-specific histone demethylase 1A (KDM1A/LSD1) in the context of chronic overlapping pain comorbid with anxiety and depression in female mice. We employed a chronic variable stress model to induce pain hypersensitivity in the face and hindpaws, as well as anxiety-like and depression-like behaviors, in female mice. Our findings revealed that chronic stress led to a downregulation of KDM1A mRNA and protein expression in the mPFC. Notably, overexpressing KDM1A in the mPFC alleviated the pain hypersensitivity, anxiety-like behaviors, and depression-like behaviors in female mice, without affecting basal pain responses or inducing emotional distress. Conversely, conditional knockout of KDM1A in the mPFC exacerbated pain sensitivity and emotional distress specifically in females. In summary, this study highlights the crucial role of KDM1A in the mPFC in modulating chronic stress-induced overlapping pain, anxiety, and depression in females. Our findings suggest that KDM1A may serve as a potential therapeutic target for treating chronic stress-related overlap pain and associated negative emotional disorders.


Assuntos
Dor Crônica , Regulação para Baixo , Histona Desmetilases , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Estresse Psicológico , Animais , Córtex Pré-Frontal/metabolismo , Feminino , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Camundongos , Dor Crônica/metabolismo , Dor Crônica/psicologia , Depressão/metabolismo , Depressão/etiologia , Ansiedade/metabolismo , Camundongos Knockout
4.
iScience ; 27(1): 108722, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38226173

RESUMO

Epigenetic regulation of heart development remains incompletely understood. Here we show that LSD1, a histone demethylase, plays a crucial role in regulating cardiomyocyte proliferation during heart development. Cardiomyocyte-specific deletion of Lsd1 in mice inhibited cardiomyocyte proliferation, causing severe growth defect of embryonic and neonatal heart. In vivo RNA-seq and in vitro functional studies identified Cend1 as a target suppressed by LSD1. Lsd1 loss resulted in elevated Cend1 transcription associated with increased active histone mark H3K4me2 at Cend1 promoter. Cend1 knockdown relieved the cell-cycle arrest and proliferation defect caused by LSD1 inhibition in primary rat cardiomyocytes. Moreover, genetic deletion of Cend1 rescued cardiomyocyte proliferation defect and embryonic lethality in Lsd1 null embryos. Consistently, LSD1 promoted the cell cycle of cardiomyocytes derived from human-induced pluripotent stem cells by repressing CEND1. Together, these findings reveal an epigenetic regulatory mechanism involving the LSD1-CEND1 axis that controls cardiomyocyte proliferation essential for murine heart development.

5.
Neuropharmacology ; 245: 109830, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38160874

RESUMO

The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT5A receptor activation. We found an upregulation of 5-HT5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT5A receptor antagonist SB-699551. Moreover, application of the GABAA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABAA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.


Assuntos
Hiperalgesia , Doenças do Sistema Nervoso Periférico , Ratos , Masculino , Animais , Hiperalgesia/metabolismo , Serotonina/metabolismo , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Medição da Dor , Dor/tratamento farmacológico , Dor/metabolismo , Analgésicos/farmacologia , Doenças do Sistema Nervoso Periférico/metabolismo , Córtex Pré-Frontal
6.
Int Immunopharmacol ; 127: 111411, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38113689

RESUMO

Proinflammatory cytokines are crucial contributors to neuroinflammation in the development of chronic pain. Here, we identified il16, which encodes interleukin-16 (IL-16), as a differentially expressed gene in spinal dorsal horn of a complete Freund's Adjuvant (CFA) inflammatory pain model in mice by RNA sequencing. We further investigated whether and how IL-16 regulates pain transmission in the spinal cord and contributes to the development of inflammatory pain hypersensitivity. RNA sequencing and bioinformatics analysis revealed elevated IL-16 transcript levels in the spinal dorsal horn after CFA injection. This increase was further confirmed by qPCR, immunofluorescence, and western blotting. Knockdown of IL-16 by intrathecal injection of IL-16 siRNA not only attenuated CFA-induced mechanical and thermal pain hypersensitivity, but also inhibited enhanced c-fos expression and glial activation in the spinal dorsal horn in male mice injected with CFA. Moreover, exogenous IL-16 induced nociceptive responses and increased c-fos expression and glial activation in spinal dorsal horn. This effect was largely impaired when CD4, the binding receptor for IL-16, was inhibited. In addition, CD4 expression was upregulated in the spinal dorsal horn after CFA injection and CD4 was present in microglia and in contact with astrocytes and activated spinal neurons. Taken together, these results suggest that enhanced IL-16-CD4 signaling triggers pain and activates microglia and astrocytes in the spinal dorsal horn, thus contributing to inflammatory pain. IL-16 may serve as a promising target for the treatment of inflammatory pain.


Assuntos
Hiperalgesia , Interleucina-16 , Camundongos , Masculino , Animais , Interleucina-16/genética , Interleucina-16/metabolismo , Interleucina-16/farmacologia , Hiperalgesia/metabolismo , Dor/induzido quimicamente , Corno Dorsal da Medula Espinal/metabolismo , Medula Espinal , Neurônios , Adjuvante de Freund , Inflamação/metabolismo
7.
Biol Direct ; 18(1): 85, 2023 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-38071369

RESUMO

INTRODUCTION: Inflammation and nerve injury promote astrocyte activation, which regulates the development and resolution of pain, in the spinal dorsal horn. APOE regulates lipid metabolism and is predominantly expressed in the astrocytes. However, the effect of astrocytic APOE and lipid metabolism on spinal cellular function is unclear. This study aimed to investigate the effect of spinal Apoe on spinal cellular functions using the complete Freund's adjuvant (CFA)-induced inflammatory pain mouse model. METHODS: After intraplantar injection of CFA, we assessed pain behaviors in C57BL6 and Apoe knockout (Apoe-/-) mice using von Frey and Hargreaves' tests and analyzed dorsal horn samples (L4-5) using western blotting, immunofluorescence, quantitative real-time polymerase chain reaction, and RNA sequencing. RESULTS: The Apoe levels were markedly upregulated at 2 h and on days 1 and 3 post-CFA treatment. Apoe was exclusively expressed in the astrocytes. Apoe-/- mice exhibited decreased pain on day 1, but not at 2 h, post-CFA treatment. Apoe-/- mice also showed decreased spinal neuron excitability and paw edema on day 1 post-CFA treatment. Global transcriptomic analysis of the dorsal horn on day 1 post-CFA treatment revealed that the differentially expressed mRNAs in Apoe-/- mice were associated with lipid metabolism and the immune system. Astrocyte activation was impaired in Apoe-/- mice on day 1 post-CFA treatment. The intrathecal injection of Apoe antisense oligonucleotide mitigated CFA-induced pain hypersensitivity. CONCLUSIONS: Apoe deficiency altered lipid metabolism in astrocytes, exerting regulatory effects on immune response, astrocyte activation, and neuronal activity and consequently disrupting the maintenance of inflammatory pain after peripheral inflammation. Targeting APOE is a potential anti-nociception and anti-inflammatory strategy.


Assuntos
Apolipoproteínas E , Hiperalgesia , Metabolismo dos Lipídeos , Dor , Animais , Camundongos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Adjuvante de Freund/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Inflamação , Dor/induzido quimicamente , Dor/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Camundongos Knockout para ApoE
8.
Life Sci ; 332: 122088, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37730112

RESUMO

AIMS: Epigenetic regulation is implicated in the neurogenesis of neuropathic pain. The repressor element 1 (RE1) silencing transcription factor (REST) corepressor (CoREST) proteins function as corepressors in the REST complex and/or LSD1 epigenetic complex. In the current study, we aimed to find the expression profile of CoREST1 in the dorsal root ganglion (DRG) and investigate whether it plays a role in neuropathic pain. MAIN METHODS: The evoked pain behaviors in mice were examined by the von Frey test and thermal test in a spinal nerve ligation (SNL)-induced neuropathic pain mice model. CoREST1 siRNA or virus was administered by DRG microinjection or intrathecal injection. The CoREST1 expression in DRGs was examined by immunofluorescence, quantitative PCR, Western blotting, and co-immunoprecipitation. KEY FINDINGS: CoREST1 was non-selectively expressed in large, medium, and small DRG neurons, and it exclusively colocalized with LSD1. In neuropathic pain models, peripheral nerve injury induced the upregulation of CoREST1 and increased binding of CoREST1 with LSD1 in injured DRGs in male mice. Furthermore, CoREST1 siRNA prevented the development of SNL-induced pain hypersensitivity as well as led to the reduction of established pain hypersensitivity during the maintenance period in SNL mice. Conversely, the overexpression of CoREST1 in DRGs by in vivo transfection of virus-induced pain hypersensitivity in naive mice. SIGNIFICANCE: Our study demonstrated that CoREST1, along with LSD1, was expressed in primary sensory neurons specifically in response to nerve injury, and promoted nociceptive pain hypersensitivity in mice. Thus, CoREST1 might serve as a potential target for treating neuropathic pain.

9.
J Assist Reprod Genet ; 40(1): 3-17, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36508034

RESUMO

The placenta is essential for a successful pregnancy and healthy intrauterine development in mammals. During human pregnancy, the growth and development of the placenta are inseparable from the rapid proliferation, invasion, and migration of trophoblast cells. Previous reports have shown that the occurrence of many pregnancy disorders may be closely related to the dysfunction of trophoblasts. However, the function regulation of human trophoblast cells in the placenta is poorly understood. Therefore, studying the factors that regulate the function of trophoblast cells is necessary. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNA molecules. Increasing evidence suggests that miRNAs play a crucial role in regulating trophoblast functions. This review outlines the role of miRNAs in regulating the function of trophoblast cells and several common signaling pathways related to miRNA regulation in pregnancy disorders.


Assuntos
MicroRNAs , Complicações na Gravidez , Trofoblastos , Feminino , Humanos , Gravidez , Linhagem Celular , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismo
10.
Neuropharmacology ; 224: 109372, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36502869

RESUMO

Apolipoprotein E (ApoE) is an apolipoprotein involved in lipid metabolism and is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). The aim of this study is to explore the role of ApoE in the pathological development of neuropathic pain. First, we examined the location of ApoE in the dorsal root ganglion (DRG) and spinal cord in male mice using immunohistochemistry, and found that ApoE was predominantly expressed in DRG satellite glial cells (SGCs) and macrophages and spinal cord astrocytes. Using a spinal nerve ligation (SNL)-induced neuropathic pain mouse model, we found that nerve injury caused an increase in ApoE expression in the injured DRGs, but not in the spinal cord after SNL surgery. Furthermore, we observed reduced SNL-induced pain hypersensitivity in ApoE knockout mice compared to wild-type mice. Moreover, an antisense oligonucleotide (ASO) targeting the Apoe gene sequence, which was microinjected into the DRG or administered intrathecally, not only reduced ApoE expression in DRG but also attenuated SNL-induced pain hypersensitivity. Finally, we found that a tyrosine kinase receptor AXL, which was previously demonstrated to contribute to neuropathic pain, may mediate ApoE function under neuropathic pain condition. In conclusion, our data suggest that ApoE in DRG promote pain hypersensitivity via the DRG membrane receptor AXL in neurons under neuropathic pain conditions. This study revealed a novel mechanism between lipid homeostasis and neuropathic pain.


Assuntos
Gânglios Espinais , Neuralgia , Animais , Masculino , Camundongos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Ratos Sprague-Dawley , Nervos Espinhais/lesões , Regulação para Cima , Ratos
11.
Brain Res Bull ; 191: 30-39, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36240908

RESUMO

Low back and radicular pain syndromes, usually caused by local inflammation and irritation to the nerve root and dorsal root ganglion (DRG), are common throughout medical practice, but sufficient pain relief is scarce. In this study, we employed a chronic compression of DRG (CCD)-induced radicular pain model in rats to explore whether lysine-specific demethylase 1 (LSD1), a histone demethylase and transcriptional co-repressor, is involved in the pathological process of radicular pain. We found that LSD1 was expressed in various-sized DRG neurons by immunohistochemistry. CCD induced the upregulation of LSD1 in compressed L4-L5 DRGs. Moreover, either LSD1 small interfering RNAs or LSD1 inhibitor attenuated CCD-induced pain hypersensitivities. LSD1 was also upregulated in the injured lumbar 4 (L4) DRG in a spinal nerve ligation (SNL)-induced neuropathic pain mouse model. Nevertheless, LSD1 was not altered in L3-L5 DRGs in complete Freund's adjuvant-induced inflammatory pain mouse model, paclitaxel- or streptozotocin-induced neuropathic pain models. Furthermore, knockdown of LSD1 in the injured L4 DRG reversed SNL-induced pain hypersensitivities in mice. Therefore, we speculate that nerve injury induced the upregulation of LSD1 in the injured DRGs, which contributes to neuropathic pain hypersensitivities; thus, LSD1 may serve as a potential target for the treatment of radicular pain and neuropathic pain.


Assuntos
Hipersensibilidade , Neuralgia , Ratos , Camundongos , Animais , Gânglios Espinais/patologia , Lisina , Ratos Sprague-Dawley , Neuralgia/patologia , Nervos Espinhais/lesões , Modelos Animais de Doenças , Hipersensibilidade/complicações , Hipersensibilidade/patologia , Células Receptoras Sensoriais , Hiperalgesia/patologia
12.
Front Mol Neurosci ; 15: 990260, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36117915

RESUMO

The microtubule-stabilizing drug paclitaxel (PTX) is a chemotherapeutic agent widely prescribed for the treatment of various tumor types. The main adverse effect of PTX-mediated therapy is chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain, which are similar to the adverse effects associated with other chemotherapeutic agents. Dorsal root ganglia (DRG) contain primary sensory neurons; any damage to these neurons or their axons may lead to neuropathic pain. To gain molecular and neurobiological insights into the peripheral sensory system under conditions of PTX-induced neuropathic pain, we used transcriptomic analysis to profile mRNA and non-coding RNA expression in the DRGs of adult male C57BL/6 mice treated using PTX. RNA sequencing and in-depth gene expression analysis were used to analyze the expression levels of 67,228 genes. We identified 372 differentially expressed genes (DEGs) in the DRGs of vehicle- and PTX-treated mice. Among the 372 DEGs, there were 8 mRNAs, 3 long non-coding RNAs (lncRNAs), 16 circular RNAs (circRNAs), and 345 microRNAs (miRNAs). Moreover, the changes in the expression levels of several miRNAs and circRNAs induced by PTX have been confirmed using the quantitative polymerase chain reaction method. In addition, we compared the expression levels of differentially expressed miRNAs and mRNA in the DRGs of mice with PTX-induced neuropathic pain against those evaluated in other models of neuropathic pain induced by other chemotherapeutic agents, nerve injury, or diabetes. There are dozens of shared differentially expressed miRNAs between PTX and diabetes, but only a few shared miRNAs between PTX and nerve injury. Meanwhile, there is no shared differentially expressed mRNA between PTX and nerve injury. In conclusion, herein, we show that treatment with PTX induced numerous changes in miRNA expression in DRGs. Comparison with other neuropathic pain models indicates that DEGs in DRGs vary greatly among different models of neuropathic pain.

13.
DNA Cell Biol ; 41(9): 824-837, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35900288

RESUMO

Atherosclerosis is a complex vascular inflammatory disease in which multiple cell types are involved, including vascular smooth muscle cells (VSMCs). In response to vascular injury and inflammatory stimuli, VSMCs undergo a "phenotypic switching" characterized by extracellular matrix secretion, loss of contractility, and abnormal proliferation and migration, which play a key role in the progression of atherosclerosis. DNA methylation modification is an important epigenetic mechanism that plays an important role in atherosclerosis. Studies investigating abnormal DNA methylation in patients with atherosclerosis have determined a specific DNA methylation profile, and proposed multiple pathways and genes involved in the etiopathogenesis of atherosclerosis. Recent studies have also revealed that DNA methylation modification controls VSMC function by regulating gene expression involved in atherosclerosis. In this review, we summarize the recent advances regarding the epigenetic control of VSMC function by DNA methylation in atherosclerosis and provide insights into the development of VSMC-centered therapeutic strategies.


Assuntos
Aterosclerose , Músculo Liso Vascular , Aterosclerose/metabolismo , Proliferação de Células/genética , Células Cultivadas , Metilação de DNA , Epigênese Genética , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fenótipo
14.
J Clin Invest ; 132(13)2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775484

RESUMO

Maladaptive changes of nerve injury-associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury-specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury-induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury-induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , RNA Longo não Codificante , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/patologia , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
15.
Comput Biol Med ; 147: 105739, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35763932

RESUMO

BACKGROUND: Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the main components of turmeric that commonly used to treat neuropathic pain (NP). However, the mechanism of the therapy is not sufficiently clarified. Herein, network pharmacology, molecular docking and molecular dynamics (MD) approaches were used to investigate the mechanism of curcuminoids for NP treatment. METHODS: Active targets of curcuminoids were obtained from the Swiss Target database, and NP-related targets were retrieved from GeneCards, OMIM, Drugbank and TTD databases. A protein-protein interaction (PPI) network was built to screen the core targets. Furthermore, DAVID was used for GO and KEGG pathway enrichment analyses. Interactions between potential targets and curcuminoids were assessed by molecular docking and the MD simulations were run for 100ns to validate the docking results on the top six complexes. RESULTS: CUR, DMC, and BDMC had 100, 99 and 100 targets respectively. After overlapping with NP there were 33, 33 and 31 targets respectively. PPI network analysis of TOP 10 core targets, TNF, GSK3ß were common targets of curcuminoids. Molecular docking and MD results indicated that curcuminoids bind strongly with the core targets. The GO and KEGG showed that curcuminoids regulated nitrogen metabolism, the serotonergic synapse and ErbB signaling pathway to alleviate NP. Furthermore, specific targets in these three compounds were also analysed at the same time. CONCLUSIONS: This study systematically explored and compared the anti-NP mechanism of curcuminoids, providing a novel perspective for their utilization.


Assuntos
Curcuma , Curcumina , Diarileptanoides , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuralgia , Curcuma/química , Curcumina/química , Curcumina/farmacologia , Bases de Dados Factuais , Diarileptanoides/química , Diarileptanoides/farmacologia , Receptores ErbB/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Nitrogênio/metabolismo , Serotonina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Front Neurosci ; 15: 733779, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602973

RESUMO

Knee osteoarthritis (KOA) is a common and disabling condition characterized by attacks of pain around the joints, and it is a typical disease that develops chronic pain. Previous studies have proved that 5-HT1, 5-HT2, and 5-HT3 receptors in the spinal cord are involved in electroacupuncture (EA) analgesia. The 5-HT7 receptor plays antinociceptive role in the spinal cord. However, it is unclear whether the 5-HT7 receptor is involved in EA analgesia. The 5-HT7 receptor is a stimulatory G-protein (Gs)-coupled receptor that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) formation, which in turn activates protein kinase A (PKA). In the present study, we found that EA significantly increased the tactile threshold and the expression of the 5-HT7 receptor in the dorsal spinal cord. Intrathecal injection of 5-HT7 receptor agonist AS-19 mimicked the analgesic effect of EA, while a selective 5-HT7 receptor antagonist reversed this effect. Moreover, intrathecal injection of AC and PKA antagonists prior to EA intervention prevented its anti-allodynic effect. In addition, GABAA receptor antagonist bicuculline administered (intrathecal, i.t.) prior to EA intervention blocked the EA effect on pain hypersensitivity. Our data suggest that the spinal 5-HT7 receptor activates GABAergic neurons through the Gs-cAMP-PKA pathway and participates in EA-mediated inhibition of chronic pain in a mouse model of KOA.

17.
Org Lett ; 23(18): 7118-7122, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34491766

RESUMO

An efficient tandem nucleophilic aminopalladation and carbene insertion sequence is described for the synthesis of indole fused polycycles. The reaction process provides a variety of substituted indeno[1,2-b]indoles in up to 99% yields.


Assuntos
Indóis/química , Metano/análogos & derivados , Compostos Policíclicos/síntese química , Ciclização , Indóis/síntese química , Metano/química , Estrutura Molecular , Compostos Policíclicos/química
18.
DNA Cell Biol ; 40(7): 1009-1025, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34061680

RESUMO

The vascular endothelium, which plays an essential role in maintaining the normal shape and function of blood vessels, is a natural barrier between the circulating blood and the vascular wall tissue. The endothelial damage can cause vascular lesions, such as atherosclerosis and restenosis. After the vascular intima injury, the body starts the endothelial repair (re-endothelialization) to inhibit the neointimal hyperplasia. Endothelial progenitor cell is the precursor of endothelial cells and plays an important role in the vascular re-endothelialization. However, re-endothelialization is inevitably affected in vivo and in vitro by factors, which can be divided into two types, namely, promotion and inhibition, and act on different links of the vascular re-endothelialization. This article reviews these factors and related mechanisms.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Animais , Artérias/lesões , Movimento Celular , Células Progenitoras Endoteliais/fisiologia , Humanos , Transdução de Sinais/genética , Lesões do Sistema Vascular/fisiopatologia , Veias/lesões
19.
Neuroreport ; 32(7): 548-554, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33850082

RESUMO

Neuron-glial-related cell adhesion molecule (NrCAM) is a neuronal cell adhesion molecule that has been shown to be involved in several cellular processes in the peripheral nervous system, including neurite outgrowth. We recently reported that alternative splicing of Nrcam mRNA at exon 10 in the dorsal root ganglion (DRG) contributes to the peripheral mechanism of neuropathic pain. Specially, Nrcam antisense oligonucleotides (ASO) targeting Nrcam exon 10, attenuated neuropathic pain hypersensitivities in mice. Here, we investigated the effect of Nrcam ASO on neurite outgrowth of DRG neurons in vitro. By immunostaining DRG neurons with different DRG markers, Nrcam ASO significantly reduced neurite lengths in neurofilament 200-, calcitonin gene-related peptide and isolectin B4-positive neurons in primary DRG neuronal culture. Moreover, Nrcam ASO activates epidermal growth factor receptor, which may mediate the effect of Nrcam ASO on neurite outgrowth of cultured DRG neurons. These results provide evidence that Nrcam ASO suppresses neurite outgrowth in DRG neurons by regulating alternative splicing of Nrcam gene at exon 10 and activation of epidermal growth factor receptor signaling, indicating the differential roles of NrCAM variants/isoforms in neurite outgrowth.


Assuntos
Moléculas de Adesão Celular/metabolismo , Gânglios Espinais/metabolismo , Crescimento Neuronal/genética , Oligonucleotídeos Antissenso/farmacologia , Células Receptoras Sensoriais/metabolismo , Processamento Alternativo , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Moléculas de Adesão Celular/genética , Gânglios Espinais/efeitos dos fármacos , Lectinas/metabolismo , Camundongos , Crescimento Neuronal/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos
20.
Org Lett ; 23(9): 3237-3242, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33886335

RESUMO

Palladium-catalyzed C-N bond formation is one of the widely used transformations for the synthesis of structurally diverse N-heterocycles. This work describes an efficient palladium-catalyzed multiple-C-N bond formation reaction for the synthesis of highly π-conjugated N-heterocycles, indolo[3,2-b]indoles with di-tert-butyldiaziridinone. The reaction likely proceeds through the initial formation of an indole-fused palladacycle by nucleophilic aminopalladation and subsequent bisamination to give indolo[3,2-b]indoles.

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