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Peripheral nerve injury-induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.
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Regulação para Baixo , Gânglios Espinais , Neuralgia , Células Receptoras Sensoriais , Animais , Masculino , Camundongos , Potenciais de Ação , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Neuralgia/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/genética , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Células Receptoras Sensoriais/metabolismoRESUMO
Introduction: Immune infiltration within the tumor microenvironment (TME) plays a significant role in the onset and progression of hepatocellular carcinoma (HCC). Machine learning applied to pathological images offers a practical means to explore the TME at the cellular level. Our former research employed a transfer learning procedure to adapt a convolutional neural network (CNN) model for cell recognition, which could recognize tumor cells, lymphocytes, and stromal cells autonomously and accurately within the images. This study introduces a novel immune classification system based on the modified CNN model. Method: Patients with HCC from both Beijing Hospital and The Cancer Genome Atlas (TCGA) database were included in this study. Additionally, least absolute shrinkage and selection operator (LASSO) analyses, along with logistic regression, were utilized to develop a prognostic model. We proposed an immune classification based on the percentage of lymphocytes, with a threshold set at the median lymphocyte percentage. Result: Patients were categorized into high or low infiltration subtypes based on whether their lymphocyte percentages were above or below the median, respectively. Patients with different immune infiltration subtypes exhibited varying clinical features and distinct TME characteristics. The low-infiltration subtype showed a higher incidence of hypertension and fatty liver, more advanced tumor stages, downregulated immune-related genes, and higher infiltration of immunosuppressive cells. A reliable prognostic model for predicting early recurrence of HCC based on clinical features and immune classification was established. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was 0.918 and 0.814 for the training and test sets, respectively. Discussion: In conclusion, we proposed a novel immune classification system based on cell information extracted from pathological slices, provides a novel tool for prognostic evaluation in HCC.
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Retinal degeneration (RD) is a leading cause of blindness worldwide and includes conditions such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Stargardt's disease (STGD). These diseases result in the permanent loss of vision due to the progressive and irreversible degeneration of retinal cells, including photoreceptors (PR) and the retinal pigment epithelium (RPE). The adult human retina has limited abilities to regenerate and repair itself, making it challenging to achieve complete self-replenishment and functional repair of retinal cells. Currently, there is no effective clinical treatment for RD. Stem cell therapy, which involves transplanting exogenous stem cells such as retinal progenitor cells (RPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), or activating endogenous stem cells like Müller Glia (MG) cells, holds great promise for regenerating and repairing retinal cells in the treatment of RD. Several preclinical and clinical studies have shown the potential of stem cell-based therapies for RD. However, the clinical translation of these therapies for the reconstruction of substantial vision still faces significant challenges. This review provides a comprehensive overview of stem/progenitor cell-based therapy strategies for RD, summarizes recent advances in preclinical studies and clinical trials, and highlights the major challenges in using stem/progenitor cell-based therapies for RD.
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Degeneração Retiniana , Transplante de Células-Tronco , Humanos , Degeneração Retiniana/terapia , Degeneração Retiniana/patologia , Animais , Células-Tronco/citologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Retina/citologia , Retina/patologiaRESUMO
Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and the therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and NT3 protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking NT3 upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking this increase produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, NT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, NT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. NT3 may be thus a potential target for CINP treatment.
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Quimiocina CCL2 , Gânglios Espinais , Neuralgia , Neurônios , Neurotrofina 3 , Paclitaxel , Receptor trkC , Animais , Feminino , Masculino , Camundongos , Antineoplásicos/efeitos adversos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Gânglios Espinais/metabolismo , Gânglios Espinais/efeitos dos fármacos , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/genética , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurotrofina 3/metabolismo , Neurotrofina 3/genética , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Receptor trkC/metabolismo , Receptor trkC/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismoRESUMO
Since the concept of digital twin technology has been put forward, after decades of rapid development and wide application, it has not only made great achievements in many fields, but also brought broader prospects for the development of the medical field. As an important trend in the medical industry, digital twin hospitals play multiple roles by connecting physical hospitals and virtual hospitals and benefit the "patient-medical staff-hospital administrators", highlighting the immeasurable promising application of digital twin technology in smart hospitals. This review takes digital twin technology as an entry point, briefly introduces the progress of its application in various fields, focuses on the characteristics of digital twin technology, practical application cases in hospitals and their limitations, and also looks forward to its future development prospects, aiming to provide certain useful insights and guidance for the future of digital twin hospitals, and also expecting it to play an important role in changing the future of healthcare to a certain extent.
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Atenção à Saúde , Humanos , Atenção à Saúde/tendências , Hospitais , Tecnologia Digital/tendênciasRESUMO
Atractylodes macrocephala III (ATL III), with anti-inflammatory and antitumor effects, is the main compound of Atractylodes macrocephala. Whether ATL III has an effect on cervical cancer and the specific mechanism are still unclear. Here, we investigated the effects of ATL III on cervical cancer cells at different concentrations and found that ATL III downregulates insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which was found to be highly expressed in cervical cancer tissue by RNA-Seq. In this study, we found that ATL III promotes apoptosis and regulates epithelial-mesenchymal transition (EMT) in cervical cancer cells (HeLa and SiHa cells) and that IGF2BP3 is a common target gene of ATL III in HeLa and SiHa cells. The expression level of IGF2BP3 in cervical cancer cells was proportional to their migration and invasion abilities. This was verified by transfection of cells with a small interfering RNA and an IGF2BP3 overexpression plasmid. After ATL III treatment, the migration and invasion abilities of cervical cancer cells were obviously reduced, but these effects were attenuated after overexpression of IGF2BP3. In addition, the transcription factor IGF2BP3 was predicted by the JASPAR system. After intersection with our sequencing results, we verified the promotional effect of ETV5 (ETS translocation variant 5) on IGF2BP3 and found that ALT III inhibited ETV5. In general, our research showed that ATL III inhibits the migration and invasion of cervical cancer cells by regulating IGF2BP3 through ETV5.
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Atractylodes , Neoplasias do Colo do Útero , Feminino , Humanos , Atractylodes/química , Neoplasias do Colo do Útero/patologia , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Transição Epitelial-Mesenquimal/genética , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a DNA/genéticaRESUMO
Background: We previously found that cimifugin has a potent antiallergic inflammatory effect in atopic dermatitis (AD). However, whether cimifugin has an antipruritic effect in AD was unknown. Methods: Mouse scratching behavior tests were performed to verify the proposed antipruritic effect of cimifugin on DNFB- or FITC-mediated AD. Chloroquine (CQ)- and compound 48/80-evoked acute itch models were employed to clarify the effect of cimifugin on histamine-dependent or -independent itch. Intracellular calcium changes were assessed in a primary culture of mouse dorsal root ganglia (DRG) in response to pruritogen exposure with or without cimifugin treatment, including CQ, histamine, allyl-isothiocyanate (AITC), and capsaicin. Molecular docking and microscale thermophoresis (MST) assays were performed to predict and verify the binding ability and modes between cimifugin and the CQ receptor MrgprA3, respectively. Results: We found that cimifugin attenuates itch behaviors effectively in FITC-induced AD. Notably, cimifugin significantly alleviated acute itching behaviors induced by CQ but not compound 48/80 in vivo. Moreover, cimifugin remarkably inhibited CQ-evoked calcium influx in DRG cells but had no obvious effect on histamine-induced calcium influx. Nevertheless, cimifugin did not interfere with either AITC-stimulated TRPA1 activation- or capsaicin-stimulated TRPV1 activation-mediated calcium influx in DRG cells. Molecular docking predicted that CQ and cimifugin might share similar binding abilities and binding modes with MrgprA3. MST assay confirmed cimifugin directly targeting MrgprA3. Conclusion: The present study demonstrates that cimifugin has a potent antipruritic effect in AD with a histamine-independent mechanism via targeting the CQ receptor MrgprA3. Thus, cimifugin is a promising candidate antipruritic agent for AD.
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BACKGROUND AND PURPOSE: Peripheral nerve trauma-induced dysregulation of pain-associated genes in the primary sensory neurons of dorsal root ganglion (DRG) contributes to neuropathic pain genesis. RNA-binding proteins participate in gene transcription. We hypothesized that RALY, an RNA-binding protein, participated in nerve trauma-induced dysregulation of DRG pain-associated genes and nociceptive hypersensitivity. METHODS AND RESULTS: Immunohistochemistry staining showed that RALY was expressed exclusively in the nuclei of DRG neurons. Peripheral nerve trauma caused by chronic constriction injury (CCI) of unilateral sciatic nerve produced time-dependent increases in the levels of Raly mRNA and RALY protein in injured DRG. Blocking this increase through DRG microinjection of adeno-associated virus 5 (AAV5)-expressing Raly shRNA reduced the CCI-induced elevation in the amount of eukaryotic initiation factor 4 gamma 2 (Eif4g2) mRNA and Eif4g2 protein in injured DRG and mitigated the development and maintenance of CCI-induced nociceptive hypersensitivity, without altering basal (acute) response to noxious stimuli and locomotor activity. Mimicking DRG increased RALY through DRG microinjection of AAV5 expressing Raly mRNA up-regulated the expression of Eif4g2 mRNA and Eif4g2 protein in the DRG and led to hypersensitive responses to noxious stimuli in the absence of nerve trauma. Mechanistically, CCI promoted the binding of RALY to the promoter of Eif4g2 gene and triggered its transcriptional activity. CONCLUSION AND IMPLICATIONS: Our findings indicate that RALY participates in nerve trauma-induced nociceptive hypersensitivity likely through transcriptionally triggering Eif4g2 expression in the DRG. RALY may be a potential target in neuropathic pain management.
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Hiperalgesia , Neuralgia , Gânglios Espinais/metabolismo , Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Hiperalgesia/genética , Hiperalgesia/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Nociceptividade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Receptoras Sensoriais/metabolismoRESUMO
Alternate-day fasting (ADF) has been reported to reduce body weight, neuroinflammation, and oxidative stress damage. However, it is not known whether ADF affects obesity-induced anxiety-like behavior. Here, male C57BL/6 mice were given an alternate fasting and high-fat diet (HFD) or standard chow diet (SD) every other day for 16 or 5 weeks. After the intervention, the degree of anxiety of the mice was evaluated by the open field test (OFT) and the elevated plus maze (EPM) test. Pathological changes in the hippocampus, the expression of Sirt1 and its downstream protein monoamine oxidase A (MAO-A) in the hippocampus, and the expression of 5-hydroxytryptamine (5-HT) were detected. Compared with HFD-fed mice, HFD-fed mice subjected to ADF for 16 weeks had a lower body weight but more brown adipose tissue (BAT), less anxiety behavior, and less pathological damage in the hippocampus, and lower expression of Sirt1 and MAO-A protein and higher 5-HT levels in the hippocampus could be observed. In addition, we noted that long-term ADF intervention could cause anxiety-like behavior in SD mice. Next, we changed the intervention time to 5 weeks. The results showed that short-term ADF intervention could reduce the body weight and increase the BAT mass of SD mice, but it did not affect anxiety. These results indicated that long-term ADF ameliorated obesity-induced anxiety-like behavior and hippocampal damage, but caused anxiety in normal-weight mice. Short-term ADF did not produce adverse emotional reactions in normal-weight mice. Here, we might provide new ideas for the treatment of obesity-induced anxiety.
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Dieta Hiperlipídica , Sirtuína 1 , Masculino , Camundongos , Animais , Camundongos Obesos , Dieta Hiperlipídica/efeitos adversos , Serotonina , Camundongos Endogâmicos C57BL , Peso Corporal , Obesidade/complicações , Obesidade/metabolismo , Jejum , Ansiedade/etiologia , MonoaminoxidaseRESUMO
Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain.Significance Statement Store-operated calcium channel (SOC) Orai1 is expressed and functional in dorsal root ganglion (DRG) neurons. Whether Orai1 contributes to peripheral sensitization is unclear. The present study demonstrates that Orai1-mediated SOC function is enhanced in DRG neurons under inflammatory conditions. Global and conditional deletion of Orai1 attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity. We also demonstrate that prostaglandin E2 (PGE2) potentiates SOC function in DRG neurons through EP1-mediated signaling pathway. Importantly, we have found that Orai1 deficiency diminishes PGE2-induced SOC function increase and reduces PGE2-induced increase in neuronal excitability and pain hypersensitivity. These findings suggest that Orai1 plays an important role in peripheral sensitization associated with inflammatory pain. Our study reveals a novel mechanism underlying PGE2/EP1-induced peripheral sensitization. Orai1 may serve as a potential target for pathological pain.
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Cálcio , Dinoprostona , Animais , Feminino , Masculino , Camundongos , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Dinoprostona/farmacologia , Dinoprostona/metabolismo , Adjuvante de Freund/toxicidade , Adjuvante de Freund/metabolismo , Gânglios Espinais/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , DorRESUMO
Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2 dipeptide in CBD3 as the anchoring Cav2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Cav2.2 from CRMP2, reduced membrane Cav2.2 expression and Ca2+ currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Cav2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.
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Dor Crônica , Peptidomiméticos , Ratos , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Ratos Sprague-Dawley , Peptidomiméticos/farmacologia , Cálcio/metabolismo , Canais de Cálcio Tipo N/genética , Canais de Cálcio Tipo N/metabolismo , Células Receptoras Sensoriais/metabolismo , Gânglios Espinais/metabolismoRESUMO
AIMS: Nerve injury-induced mechanical hypersensitivity is one of major clinical symptoms in neuropathic pain patients. Understanding molecular mechanisms underlying this symptom is crucial for developing effective therapies. The present study was to investigate whether sensory neuron-specific long noncoding RNA (SS-lncRNA) predominantly expressed in small non-peptidergic dorsal root ganglion (DRG) neurons repaired nerve injury-induced mechanical hypersensitivity. MATERIALS AND METHODS: SS-lncRNA downregulation in the mas-related G protein-coupled receptor member D (Mrgprd)-expressed DRG neurons was rescued and mimicked by crossbreeding MrgprdCreERT2/+ lines with Rosa26SS-lncRNA knock-in mice and SS-lncRNAfl/fl mice, respectively, followed by tamoxifen injection. KEY FINDINGS: Rescuing SS-lncRNA downregulation in the Mrgprd-expressed DRG neurons significantly reversed the spinal nerve ligation (SNL)-induced reduction of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in these DRG neurons and alleviated the SNL-induced mechanical hypersensitivity, without affecting the SNL-induced heat and cold nociceptive hypersensitivities, on the ipsilateral side. Conversely, mimicking SS-lncRNA downregulation in the Mrgprd-expressed DRG neurons reduced basal KCNN1 expression in these DRG neurons and produced the enhanced response to mechanical stimulation, but not thermal and cold stimuli, on bilateral sides. Mechanistically, SS-lncRNA downregulation caused a reduction in its binding to lysine-specific demethylase 6B (KDM6B) and consequent recruitment of less KDM6B to Kcnn1 promoter and an increase of H3K27me3 enrichment in this promoter in injured DRG. SIGNIFICANCE: Our findings suggest that SS-lncRNA downregulation in small non-peptidergic sensory neurons is required specifically for nerve injury-induced mechanical hypersensitivity likely through silencing KCNN1 expression caused by KDM6B-gated increase of H3K27me3 enrichment in Kcnn1 promoter in these neurons.
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RNA Longo não Codificante , Ratos , Humanos , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos Sprague-Dawley , Gânglios Espinais/metabolismo , Histonas/metabolismo , Células Receptoras Sensoriais/metabolismo , Hiperalgesia/genética , Hiperalgesia/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismoRESUMO
Primary somatosensory axons stop regenerating as they re-enter the spinal cord, resulting in incurable sensory loss. What arrests them has remained unclear. We previously showed that axons stop by forming synaptic contacts with unknown non-neuronal cells. Here, we identified these cells in adult mice as oligodendrocyte precursor cells (OPCs). We also found that only a few axons stop regenerating by forming dystrophic endings, exclusively at the CNS:peripheral nervous system (PNS) borderline where OPCs are absent. Most axons stop in contact with a dense network of OPC processes. Live imaging, immuno-electron microscopy (immuno-EM), and OPC-dorsal root ganglia (DRG) co-culture additionally suggest that axons are rapidly immobilized by forming synapses with OPCs. Genetic OPC ablation enables many axons to continue regenerating deep into the spinal cord. We propose that sensory axons stop regenerating by encountering OPCs that induce presynaptic differentiation. Our findings identify OPCs as a major regenerative barrier that prevents intraspinal restoration of sensory circuits following spinal root injury.
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Células Precursoras de Oligodendrócitos , Camundongos , Animais , Medula Espinal/fisiologia , Axônios/fisiologia , Raízes Nervosas Espinhais , Gânglios Espinais/fisiologia , Regeneração Nervosa/fisiologiaRESUMO
PURPOSE: Studies have shown that circRNA is involved in the occurrence and development of human cancers. However, it remains unclear that the contribution of circRNA in thyroid carcinoma and its role in the process of tumorigenesis. METHODS: The expression profile of circRNA-miRNA-mRNA in thyroid carcinoma was detected by RNA sequencing and verified by qRT-PCR. The characteristics of circGLIS3 were verified by RNase R and actinomycin assays, subcellular fractionation, and fluorescence in situ hybridization. The functions of circGLIS3 and AIF1L were detected by wound healing, transwell, 3D culture and Western blot. RNA Immunoprecipitation (RIP), RNA pulldown and dual-luciferase reporter assays were used to verify the target genes of circGLIS3 and downstream miRNAs. Functional rescue experiments were performed by transfecting miRNA mimics or siRNA of target genes. Finally, metastatic mouse models were used to investigate circGLIS3 function in vivo. RESULTS: In this study, we discovered a novel circRNA (has_circ_0007368, named as circGLIS3) by RNA sequencing. CircGLIS3 was down-regulated in thyroid carcinoma tissues and cells line, and was negatively associated with malignant clinical features of thyroid carcinoma. Functional studies found that circGLIS3 could inhibit the migration and invasion of thyroid carcinoma cells, and was related to the EMT process. Mechanistically, circGLIS3 can upregulate the expression of the AIF1L gene by acting as a miR-146b-3p sponge to inhibit the progression of thyroid carcinoma. CONCLUSION: Our study identified circGLIS3 as a novel tumor suppressor in thyroid cancer, indicating the potential of circGLIS3 as a promising diagnostic and prognostic marker for thyroid cancer.
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MicroRNAs , Neoplasias da Glândula Tireoide , Animais , Camundongos , Humanos , Hibridização in Situ Fluorescente , RNA Circular/genética , Neoplasias da Glândula Tireoide/genética , MicroRNAs/genética , Transformação Celular Neoplásica , Proliferação de Células , Linhagem Celular TumoralRESUMO
Braid-like coronary artery is very rare. It is featured by the division of the coronary artery into multiple tortuous small channels that later converge into a normal lumen at any segment of the coronary artery. We presented a case of a 27-year-old male patient with occasional chest pain. In coronary CT angiography (CCTA) and coronary angiography, a braid-like appearance was found in the right coronary artery. After multidisciplinary discussion, it was speculated to be a woven coronary artery (WCA). We conducted a literature review about woven coronary arteries.
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Background: Glioma, the most prevalent malignant intracranial tumor, poses a significant threat to patients due to its high morbidity and mortality rates, but its prognostic indicators remain inaccurate. Although TRAF-associated NF-kB activator (TANK) interacts and cross-regulates with cytokines and microenvironmental immune cells, it is unclear whether TANK plays a role in the immunologically heterogeneous gliomas. Methods: TANK mRNA expression patterns in public databases were analyzed, and qPCR and IHC were performed in an in-house cohort to confirm the clinical significance of TANK. Then, we systematically evaluated the relationship between TANK expression and immune characteristics in the glioma microenvironment. Additionally, we evaluated the ability of TANK to predict treatment response in glioma. TANK-associated risk scores were developed by LASSO-Cox regression and machine learning, and their prognostic ability was tested. Results: TANK was specifically overexpressed in glioma and enriched in the malignant phenotype, and its overexpression was related to poor prognosis. The presence of a tumor microenvironment that is immunosuppressive was evident by the negative correlations between TANK expression and immunomodulators, steps in the cancer immunity cycle, and immune checkpoints. Notably, treatment for cancer may be more effective when immunotherapy is combined with anti-TANK therapy. Prognosis could be accurately predicted by the TANK-related risk score. Conclusions: High expression of TANK is associated with the malignant phenotype of glioma, as it shapes an immunosuppressive tumor microenvironment. Additionally, TANK can be used as a predictive biomarker for responses to various treatments and prognosis.
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Neoplasias Encefálicas , Glioma , Humanos , Adjuvantes Imunológicos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Imunossupressores , Prognóstico , Microambiente TumoralRESUMO
BACKGROUND: Ectopic pregnancy (EP) is one of the most common acute abdominal diseases in gynecology. Once the condition of EP is delayed, it may lead to massive hemorrhage, shock, and even death in a short time, seriously threatening the patient's life. Early diagnosis is the key to preventing and improving the prognosis of EP. Transabdominal ultrasound (TAS) and transvaginal ultrasound (TVS) are the main diagnostic methods for abdominal diseases. The purpose of this study is to explore the application value and effect of TAS and TVS in the diagnosis of EP, hoping to provide more valuable references for the diagnosis of EP. AIM: To explore the application value of TAS and TVS in the diagnosis of EP and to improve the level of clinical diagnosis. METHODS: A total of 140 patients with EP admitted to our hospital from July 2018 to July 2020 were selected for this study. All patients were divided into two groups according to the examination methods. 63 patients who underwent abdominal ultrasound examination were set as the TAS group, while 77 patients who underwent TVS examination were set as the TVS group. We compared the diagnostic accuracy and misdiagnosis rates between the two types of ultrasound examinations, as well as the postoperative pathological results of the two diagnostic methods for different types of ectopic pregnancies. We also analyzed the sonograms for the presence of mixed ectopic masses, adnexal masses, ectopic gestational sacs, the presence or absence of visible embryo and fetal heart in the ectopic sac shadow, and the detection of fluid in the rectal fossa of the uterus, such as the adnexal area, yolk sac, and embryo, etc. In addition, the diagnosis time, days of gestational sac appearance, operation time, endometrial thickness, and blood flow resistance index were compared as well. RESULTS: After performing both types of ultrasound examinations in 140 patients with EP, we found that the diagnostic accuracy of TVS was significantly higher than that of TAS, and the misdiagnosis rate was significantly lower than that of TAS. The differences were statistically significant (P < 0.05). In addition, the detection rate of TVS was better than that of TAS for the presence of mixed masses, adnexal masses, ectopic gestational sacs, the presence or absence of visible embryo and fetal heart in the shadow of the ectopic sac, and sonograms such as the adnexal area, yolk sac, and embryo, etc. The coincidence rate of its postoperative pathological examination results was significantly higher than those of TAS. The diagnosis time and the days of gestational sac appearance by TVS were significantly shorter than that by TAS, and the operation time was earlier than that by TAS. What's more, the detection rates of the endometrial thickness £ 1.5 mm and blood flow resistance £ 0.5 were significantly higher in TVS diagnosis of EP than in TAS. All differences were statistically significant (P < 0.05). CONCLUSION: Compared with TAS, TVS has the advantages of high detection accuracy and good sonogram performance.
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Nerve injury to peripheral somatosensory system causes refractory neuropathic pain. Maladaptive changes of gene expression in primary sensory neurons are considered molecular basis of this disorder. Long non-coding RNAs (lncRNAs) are key regulators of gene transcription; however, their significance in neuropathic pain remains largely elusive.Here, we reported a novel lncRNA, named sensory neuron-specific lncRNA (SS-lncRNA), for its expression exclusively in dorsal root ganglion (DRG) and trigeminal ganglion. SS-lncRNA was predominantly expressed in small DRG neurons and significantly downregulated due to a reduction of early B cell transcription factor 1 in injured DRG after nerve injury. Rescuing this downregulation reversed a decrease of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in injured DRG and alleviated nerve injury-induced nociceptive hypersensitivity. Conversely, DRG downregulation of SS-lncRNA reduced the expression of KCNN1, decreased total potassium currents and afterhyperpolarization currents and increased excitability in DRG neurons and produced neuropathic pain symptoms.Mechanistically, downregulated SS-lncRNA resulted in the reductions of its binding to Kcnn1 promoter and heterogeneous nuclear ribonucleoprotein M (hnRNPM), consequent recruitment of less hnRNPM to the Kcnn1 promoter and silence of Kcnn1 gene transcription in injured DRG.These findings indicate that SS-lncRNA may relieve neuropathic pain through hnRNPM-mediated KCNN1 rescue in injured DRG and offer a novel therapeutic strategy specific for this disorder.
Assuntos
Neuralgia , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Células Receptoras Sensoriais/metabolismo , Neuralgia/terapia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genéticaRESUMO
Primary cardiac intimal sarcoma, an extremely rare cardiac tumor subtype, is often mis-diagnosed owing to its rarity and non-specific clinical and radiological features. We report a case of cardiac intimal sarcoma mimicking atrial myxoma in which the clinical presentation and multimodality imaging are described in detail, and diagnostic challenges are highlighted.