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Blocking increased expression of nerve injury-specific long non-coding RNA (NIS-lncRNA) in injured dorsal root ganglia (DRG) through DRG microinjection of NIS-lncRNA small hairpin interfering RNA or generation of NIS-lncRNA knockdown mice mitigates neuropathic pain. However, these strategies are impractical in the clinic. This study employed a Food and Drug Administration (FDA)-approved antisense oligonucleotides strategy to examine the effect of NIS-lncRNA ASOs on neuropathic pain.Effects of intrathecal injection of NIS-lncRNA antisense oligonucleotides on day 7 or 14 after chronic constriction injury (CCI) of the sciatic nerve, fourth lumbar (L4) spinal nerve ligation, or intraperitoneal injection of paclitaxel or streptozotocin on the expression of DRG NIS-lncRNA and C-C chemokine ligand 2 (CCL2, an NIS-lncRNA downstream target) and nociceptive hypersensitivity were examined. We also assessed whether NIS-lncRNA antisense oligonucleotides produced cellular toxicity.Intrathecal NIS-lncRNA antisense oligonucleotides attenuated CCI-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and ongoing nociceptive responses, without changing basal or acute nociceptive responses and locomotor function. Intrathecal NIS-lncRNA antisense oligonucleotides also blocked CCI-induced increases in NIS-lncRNA and CCL2 in the ipsilateral L3 and L4 DRG and hyperactivities of neurones and astrocytes in the ipsilateral L3 and L4 spinal cord dorsal horn. Similar results were found in antisense oligonucleotides-treated mice after spinal nerve ligation or intraperitoneal injection of paclitaxel or streptozotocin. Normal morphologic structure and no cell loss were observed in the DRG and spinal cord of antisense oligonucleotides-treated mice.These findings further validate the role of NIS-lncRNA in trauma-, chemotherapy-, or diabetes-induced neuropathic pain and demonstrate potential clinical application of NIS-lncRNA antisense oligonucleotides for neuropathic pain management.

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.

Metastatic bone pain and chemotherapy-induced peripheral neuropathic pain are the most common clinical symptoms in cancer patients. The current clinical management of these two disorders is ineffective and/or produces severe side effects. The present study employed a dual-target compound named as ZL006-05 and examined the effect of systemic administration of ZL006-05 on RM-1–induced bone cancer pain and paclitaxel-induced neuropathic pain. Intravenous injection of ZL006-05 dose-dependently alleviated RM-1–induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneously ongoing nociceptive responses during both induction and maintenance periods, without analgesic tolerance, affecting basal/acute pain and locomotor function. Similar behavioral results were observed in paclitaxel-induced neuropathic pain. This injection also decreased neuronal and astrocyte hyperactivities in the lumbar dorsal horn after RM-1 tibial inoculation or paclitaxel intraperitoneal injection. Mechanistically, intravenous injection of ZL006-05 potentiated the GABA(A) receptor agonist–evoked currents in the neurons of the dorsal horn and anterior cingulate cortex and also blocked the paclitaxel-induced increase in postsynaptic density-95–neuronal nitric oxide synthase interaction in dorsal horn. Our findings strongly suggest that ZL006-05 may be a new candidate for the management of cancer pain and chemotherapy-induced peripheral neuropathic pain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01158-8.

Background and Purpose: Hemorrhage-caused gene changes in the thalamus likely contribute to thalamic pain genesis. RNA N 6 -methyladenosine modification is an additional layer of gene regulation. Whether FTO (fat-mass and obesity-associated protein), an N 6 -methyladenosine demethylase, participates in hemorrhage-induced thalamic pain is unknown. Methods: Expression of Fto mRNA and protein was assessed in mouse thalamus after hemorrhage caused by microinjection of Coll IV (type IV collagenase) into unilateral thalamus. Effect of intraperitoneal administration of meclofenamic acid (a FTO inhibitor) or microinjection of adeno-associated virus 5 (AAV5) expressing Cre into the thalamus of Fto fl/fl mice on the Coll IV microinjection–induced TLR4 (Toll-like receptor 4) upregulation and nociceptive hypersensitivity was examined. Effect of thalamic microinjection of AAV5 expressing Fto (AAV5- Fto ) on basal thalamic TLR4 expression and nociceptive thresholds was also analyzed. Additionally, level of N 6 -methyladenosine in Tlr4 mRNA and its binding to FTO or YTHDF2 (YTH N 6 -methyladenosine RNA binding protein 2) were observed. Results: FTO was detected in neuronal nuclei of thalamus. Level of FTO protein, but not mRNA, was time-dependently increased in the ipsilateral thalamus on days 1 to 14 after Coll IV microinjection. Intraperitoneal injection of meclofenamic acid or adeno-associated virus-5 expressing Cre microinjection into Fto fl/fl mouse thalamus attenuated the Coll IV microinjection–induced TLR4 upregulation and tissue damage in the ipsilateral thalamus and development and maintenance of nociceptive hypersensitivities on the contralateral side. Thalamic microinjection of AAV5- Fto increased TLR4 expression and elicited hypersensitivities to mechanical, heat and cold stimuli. Mechanistically, Coll IV microinjection produced an increase in FTO binding to Tlr4 mRNA, an FTO-dependent loss of N 6 -methyladenosine sites in Tlr4 mRNA and a reduction in the binding of YTHDF2 to Tlr4 mRNA in the ipsilateral thalamus. Conclusions: Our findings suggest that FTO participates in hemorrhage-induced thalamic pain by stabilizing TLR4 upregulation in thalamic neurons. FTO may be a potential target for the treatment of this disorder.

The management of persistent postsurgical pain and neuropathic pain remains a challenge in the clinic. Local anesthetics have been widely used as simple and effective treatment for these two disorders, but the duration of their analgesic effect is short. We here reported a new poly lactic-co-glycolic acid (PLGA)-coated ropivacaine that was continuously released in vitro for at least 6 days. Peri-sciatic nerve injection of the PLGA-coated ropivacaine attenuated paw incision-induced mechanical allodynia and heat hyperalgesia during the incisional pain period, and spared nerve injury-induced mechanical and cold allodynia for at least 7 days post-injection. This effect was dose-dependent. Peri-sciatic nerve injection of the PLGA-coated ropivacaine did not produce detectable inflammation, tissue irritation, or damage in the sciatic nerve and surrounding muscles at the injected site, dorsal root ganglion, spinal cord or brain cortex, although the scores for grasping reflex were mildly and transiently reduced in the higher dosage-treated groups. PERSPECTIVE: Given that PLGA is an FDA-approved medical material, and that ropivacaine is used currently in clinical practice, the injectable PLGA-coated ropivacaine represents a new and highly promising avenue in the management of postsurgical pain and neuropathic pain.

Toll like receptor 7 (TLR7) is expressed in neurons of the dorsal root ganglion (DRG), but whether it contributes to neuropathic pain is elusive. We found that peripheral nerve injury caused by ligation of the fourth lumbar (L(4)) spinal nerve (SNL) or chronic constriction injury of sciatic nerve led to a significant increase in the expression of TLR7 at mRNA and/or protein levels in mouse injured DRG. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5 expressing TLR7 shRNA into the ipsilateral L(4) DRG alleviated the SNL-induced mechanical, thermal and cold pain hypersensitivities in both male and female mice. This microinjection also attenuated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase ½ (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in L(4) dorsal horn on the ipsilateral side during both development and maintenance periods. Conversely, mimicking this increase through microinjection of AAV5 expressing full-length TLR7 into unilateral L(3/4) DRGs led to elevations in the amounts of p-ERK1/2 and GFAP in the dorsal horn, augmented responses to mechanical, thermal and cold stimuli, and induced the spontaneous pain on the ipsilateral side in the absence of SNL. Mechanistically, the increased TLR7 activated the NF-κB signaling pathway through promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from the injured DRG neurons. Our findings suggest that DRG TLR7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons. TLR7 may be a potential target for therapeutic treatment of this disorder.

Background Chronic pain usually accompanied by tissue damage and inflammation. However, the pathogenesis of chronic pain remains unclear. Methods We investigated the role of nerve growth factor (NGF) in chronic inflammatory pain induced by complete Freund’s adjuvant (CFA), explored the methylation status of CpG islands in the promoter region of the NGF gene, and clarified the function and mechanism of C/EBPα-NGF signaling pathway from epigenetic perspective in the chronic inflammatory pain model. Results CFA induced significant hyperalgesia and continuous upregulation of NGF mRNA and protein levels in the L4–6 dorsal root ganglions (DRGs) in rats. Hypomethylation of CpG islands occurred in the NGF gene promoter region after CFA treatment. At the same time, the miR-29b expression level was significantly increased, while the DNA methyltransferase 3b (DNMT3b) level reduced significantly. Moreover, CFA treatment promoted binding of C/EBPα to the NGF gene promoter region and C/EBPα siRNA treatment obviously decreased expression of NGF levels and also alleviate inflammatory hyperalgesia significantly in rats. Conclusion Collectively, the results indicated that CFA leads to the upregulation of miR-29b level, which represses the expression of DNMT3b, enhances the demethylation of the NGF gene promoter region, and promotes the binding of C/EBPα with the NGF gene promoter, thus results in the upregulation of NGF gene expression and maintenance of chronic inflammatory pain.

Nerve trauma-induced alternations of gene expression in the neurons of dorsal root ganglion (DRG) participate in nerve trauma-caused nociceptive hypersensitivity. Transcription factors regulate gene expression. Whether the transcription factor E74-like factor 1 (ELF1) in the DRG contributes to neuropathic pain is unknown. We report here that peripheral nerve trauma caused by chronic constriction injury (CCI) of unilateral sciatic nerve or unilateral fourth lumbar spinal nerve ligation led to the time-dependent increases in the levels of Elf1 mRNA and ELF1 protein in injured DRG, but not in the spinal cord. Preventing this increase through DRG microinjection of adeno-associated virus 5 expressing Elf1 shRNA attenuated the CCI-induced upregulation of matrix metallopeptidase 9 (MMP9) in injured DRG and induction and maintenance of nociceptive hypersensitivities, without changing locomotor functions and basal responses to acute mechanical, heat, and cold stimuli. Mimicking this increase through DRG microinjection of AAV5 expressing full-length Elf1 upregulated DRG MMP9 and produced enhanced responses to mechanical, heat, and cold stimuli in naive mice. Mechanistically, more ELF1 directly bond to and activated Mmp9 promoter in injured DRG neurons after CCI. Our data indicate that ELF1 participates in nerve trauma-caused nociceptive hypersensitivity likely through upregulating MMP9 in injured DRG. E74-like factor 1 may be a new target for management of neuropathic pain.

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.

Nerve injury‐induced maladaptive changes of gene expression in dorsal root ganglion (DRG) neurons contribute to neuropathic pain. Long non‐coding RNAs (lncRNAs) are emerging as key regulators of gene expression. Here, a conserved lncRNA is reported, named DRG‐specifically enriched lncRNA (DS‐lncRNA) for its high expression in DRG neurons. Peripheral nerve injury downregulates DS‐lncRNA in injured DRG due, in part, to silencing of POU domain, class 4, transcription factor 3, a transcription factor that interacts with the DS‐lncRNA gene promoter. Rescuing DS‐lncRNA downregulation blocks nerve injury‐induced increases in the transcriptional cofactor RALY‐triggered DRG Ehmt2 mRNA and its encoding G9a protein, reverses the G9a‐controlled downregulation of opioid receptors and Kcna2 in injured DRG, and attenuates nerve injury‐induced pain hypersensitivities in male mice. Conversely, DS‐lncRNA downregulation increases RALY‐triggered Ehmt2 /G9a expression and correspondingly decreases opioid receptor and Kcna2 expression in DRG, leading to neuropathic pain symptoms in male mice in the absence of nerve injury. Mechanistically, downregulated DS‐lncRNA promotes more binding of increased RALY to RNA polymerase II and the Ehmt2 gene promoter and enhances Ehmt2 transcription in injured DRG. Thus, downregulation of DS‐lncRNA likely contributes to neuropathic pain by negatively regulating the expression of RALY‐triggered Ehmt2/G9a, a key neuropathic pain player, in DRG neurons., This work reports that nerve trauma‐induced the downregulation of a dorsal root ganglion‐specifically enriched long noncoding RNA (DS‐lncRNA) promotes the binding of the transcription co‐factor RALY to RNA polymerase II (RNP II) and the Ehmt2 gene promoter, increases the expression of Ehmt2 mRNA and G9a protein, downregulates many pain‐associated genes including Oprm1 mRNA and mu opioid receptor (MOR), and causes neuropathic pain.

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K2p 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 2p 1.1 mRNA and its coding K2p 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K2p 1.1 and mimicking this increase reduces DRG K2p 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K2p 1.1 may contribute to chemotherapy-induced neuropathic pain.

BACKGROUND: Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to neuropathic pain genesis. Eukaryotic initiation factor 4 gamma 2 (eIF4G2) is a general repressor of cap-dependent mRNA translation. Whether DRG eIF4G2 participates in nerve injury-induced alternations in gene expression and nociceptive hypersensitivity is unknown. METHODS: The expression and distribution of eIF4G2 mRNA and protein in mouse DRG after spinal nerve ligation (SNL) were assessed. Effects of eIF4G2 siRNA microinjected through a glass micropipette into the injured DRG on the SNL-induced DRG mu opioid receptor (MOR) and Kv1.2 downregulation and nociceptive hypersensitivity were examined. In addition, effects of DRG microinjection of adeno-associated virus 5-expressing eIF4G2 (AAV5-eIF4G2) on basal DRG MOR and Kv1.2 expression and nociceptive thresholds were analysed. RESULTS: eIF4G2 protein co-expressed with Kv1.2 and MOR in DRG neurones. Levels of eIF4G2 mRNA (1.7 [0.24] to 2.3 [0.14]-fold of sham, P

Background The authors’ previous studies have found that spinal protein kinase C γ expressing neurons are involved in the feed-forward inhibitory circuit gating mechanical allodynia in the superficial dorsal horn. The authors hypothesize that nerve injury enhances the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enables Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons. Methods Prkcg-P2A-tdTomato mice were constructed using the clustered regularly interspaced short palindromic repeats and clustered regularly interspaced short palindromic repeats-associated nuclease 9 technology, and were used to analyze the electrophysiologic properties of spinal protein kinase C γ expressing neurons in both normal conditions and pathologic conditions induced by chronic constriction injury of the sciatic nerve. Patch-clamp whole cell recordings were used to identify the nature of the dynamic synaptic drive to protein kinase C γ expressing neurons. Results Aβ fiber stimulation evoked a biphasic synaptic response in 42% (31 of 73) of protein kinase C γ expressing neurons. The inhibitory components of the biphasic synaptic response were blocked by both strychnine and bicuculline in 57% (16 of 28) of neurons. Toll-like receptor 5 immunoreactive fibers made close contact with protein kinase C γ expressing neurons. After nerve injury, the percentage of neurons double-labeled for c-fos and Prkcg-P2A-tdTomato in animals walking on a rotarod was significantly higher than that in the nerve injury animals (4.1% vs. 9.9%, 22 of 539 vs. 54 of 548,P < 0.001). Aβ fiber stimulation evoked burst action potentials in 25.8% (8 of 31) of protein kinase C γ expressing neurons in control animals, while the proportion increased to 51.1% (23 of 45) in nerve injury animals (P = 0.027). Conclusions The Prkcg-P2A-tdTomato mice the authors constructed provide a useful tool for further analysis on how the spinal allodynia gate works. The current study indicated that nerve injury enhanced the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enabled Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Both microwave (MW) ablation and radiofrequency (RF) ablation are widely used for hepatocellular carcinoma (HCC) treatments in clinic. However, it is still unclear if ablative methods could influence the recurrence-free survival (RFS) and overall survival (OS) of HCC patients. Therefore, we carried out this multi-center retrospective cohort study to investigate the differences of recurrence-free survival (RFS) and overall survival (OS) between MW ablation and RF ablation by survival analysis. From January 2014 to December 2016, patients who received thermal ablation surgery for HCC treatment were screened. Finally, 452 patients met the eligibility criteria and finished the follow-up. Univariable and multivariable regression analyses were used to identify independent predictive factors of the RFS and OS. Also, propensity score matching (PSM) was used to balance the bias between two groups. Finally, we found that before the PSM, the univariable and multivariable regression analyses revealed that there were no significant differences on the RFS between two groups. Same results were obtained for the OS. After PSM, 115 pairs of patients were created, and both the univariable and multivariable regression analyses suggested that there were still no significant differences on the RFS between two groups. Same results were obtained for the OS. In conclusion, our present study showed that there were no significant differences between MW ablation and RF ablation for HCC patients on the RFS or OS.

Tumor cells with heterogeneity and diversity can express different markers. At present, positive separation of circulating tumor cells (CTC) taking EpCAM as the marker was used in most cases which could be one-sided, while this study successfully prepared four antibody-modified magnetic immunoliposomes (MIL) by using the self-assembled liposome with antibody derivatives. This study aims to explore the separation efficiency and clinical detection feasibility of single or combined use of MIL with multi-tumor markers on different tumors. Captured CTC were stained with CK-FITC, CD45-PE and DAPI, and fluorescence microscope was used for the observation, analysis and calculation. The result indicated that the CTC number positive rate in blood samples of four different magnetic balls on the same patient could be up to 87.5% in 32 patients with 14 different kinds tumors. While the effect of directly mixed separation by four kinds of magnetic balls was not satisfying. It suggested that the MIL of multi-tumor markers could be a powerful tool for CTC separation in application of tumor screening and prognosis.

Background: MicroRNA can regulate gene expression, and participate in multiple vital activities, such as inflammation, oxidative stress epigenetic modification, cell proliferation, and apoptosis. It plays an important role in the genesis and development of cardiovascular disease.Objective: To assess the role of microRNA-208a in ketamine-induced cardiotoxicity.Methods: All rats were randomly selected into two groups: sham and model groups. After fixed, all rats in the model group was intraperitoneally (IP) injected with 100 mg/kg of ketamine. Heart samples were stained with HE assay. Total RNAs from serum were used to hybridize with the SurePrint G3 Rat Whole Genome GE 8×60 K Microarray G4858A platform.Results: In the rat model with ketamine-induced cardiotoxicity, microRNA-208a expression was increased. Then, over-expression of microRNA-208a increased inflammation and oxidative stress in vitro model. However, down-regulation of microRNA-208a decreased inflammation and oxidative stress in vitro model. Over-expression of microRNA-208a suppressed CHD9 and Notch1, and induced p65 protein expression in vitro model. Overexpression of CHD9 reduced the effects of microRNA-208a on inflammation and oxidative stress in heart cell through Notch/p65 signal pathways. Notch1 activation reduced the effects of microRNA-208a on inflammation and oxidative stress in heart cell through p65 signal pathways.Conclusion: MicroRNA-208a may be a potential biomarker for ketamine-induced cardiotoxicity through inflammation and oxidative stress by Notch/NF-κB signal pathways by CHD9.

Inflammation had showed its important role in the pathogenesis of cerebral ischemia and secondary damage. Safflower yellow B (SYB) had neuroprotective effects against oxidative stress-induced brain injuries, but the mechanisms were still largely unknown to us. In this study, we tried to investigate the anti-inflammation effects of SYB and the possible roles of AMPK/NF-κB signaling pathway on these protective effects. In vivo, brain ischemia/reperfusion (I/R) was induced by transient middle cerebral artery occlusion for 2 h and reperfusion for 20 h. Neurofunctional evaluation, infarction area, and brain water contents were measured. Brain injury markers and inflammatory cytokines levels were measured by ELISA kits. In vitro, cell viability, apoptosis, and LDH leakage were measured after I/R in PC12 cells. The expression and phosphorylation levels of AMPK, NF-κB p65, and P-IκB-α in cytoplasm and nuclear were measured by Western blotting. SiRNA experiment was performed to certify the role of AMPK. The results showed SYB reduced infarct size, improved neurological outcomes, and inhibited brain injury after I/R. In vitro test, SYB treatment alleviated PC12 cells injury and apoptosis and inhibited the inflammatory cytokines (IL-1, IL-6, TNF-α, and COX-2) in a dose-dependent manner. SYB treatment induced AMPK phosphorylation and inhibited NF-κB p65 nuclear translocation both in brain and in PC12 cells. Further studies also showed that the inhibition of NF-κB activity of SYB was through AMPK. In conclusion, SYB protected brain I/R injury through reducing expression of inflammatory cytokines and this effect might be partly due to the inhibition of NF-κB mediated by AMPK.

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K(2p)1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K(2p)1.1 mRNA and its coding K(2p)1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K(2p)1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K(2p)1.1 and mimicking this increase reduces DRG K(2p)1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K(2p)1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K(2p)1.1 may contribute to chemotherapy-induced neuropathic pain.

Background Trigeminal neuralgia is an intense neuralgia involving facial areas supplied by trigeminal nerve. The pain is characterized by sudden onset, short persistence, sharp or lancinating. Trigeminal neuralgia commonly affects frontal areas, infraorbital or paranasal areas, mandibular areas and teeth. While Trigeminal neuralgia affecting merely the upper eyelid is rare. Here we report a case of atypical Trigeminal neuralgia confined to the upper eyelid. The patient was pain free during the follow-up period of 6 months after unusual ophthalmic branch radiofrequency thermocoagulation. Case presentation A 55-year-old female patient was diagnosed as primary trigeminal neuralgia involving the right upper eyelid. As the pain could not be controlled by drug therapy, peripheral nerve branch radiofrequency thermocoagulation was recommended. A combination of infratrochlear, supratrochlear and lacrimal radiofrequency thermocoagulation was implemented in this case. The point where the bridge of the nose abuts the supraorbital ridge and the point slightly above the lateral canthus along outer border of the orbit were selected respectively as the puncture sites. After positive diagnostic test, radiofrequency thermocoagulation of the above-mentioned nerve branches was performed respectively. The patient was pain free immediately after the treatment and during the follow-up period of 6 months. Discussion Trigeminal neuralgia is a common severe and chronic facial neuralgia which requires accurate diagnosis and effective therapy. With typical clinical symptoms, normal neurological signs, normal CT and MRI findings, the patient was diagnosed as classic trigeminal neuralgia. As the patient was drug resistant, some invasive treatments were considered. Peripheral branch neurolysis was chosen for its minimal invasiveness, convenience, low risk and not affecting further invasive treatments. According to the anatomic data and the diagnostic test results, infratrochlear, supratrochlear and lacrimal nerve were responsible, therefore, an unusual combination of infratrochlear, supratrochlear, and lacrimal radiofrequency thermocoagulation was implemented for this patient. Conclusions Radiofrequency thermocoagulation is an effective treatment option for trigeminal neuralgia. Peripheral branch radiofrequency thermocoagulation for trigeminal neuralgia should be considered preferentially due to its minimal invasiveness and convenience. Furthermore, as the sensory innervation of the upper eyelid is complex, the knowledge of peripheral distribution of trigeminal nerve is essential.

Ovarian cancer is the highest mortality rate of all cancers in the female reproductive system. Over the past decades, small interfering RNA (si RNA) has been explored as a promising therapeutic candidate for gene therapy. However, its clinical application is limited by the lack of safe and efficient methods for gene delivery. Graphene oxide (GO) was modified with polyethylene glycol (PEG), polyethylenimine (PEI) and folic acid (FA), for targeted delivery of small interfering RNA (siRNA) that inhibits ovarian cancer cell growth, and the efficacy of such complex was evaluated by a series of in vitro experiments. The synthesized vehicle PEG-GO-PEI-FA was characterized by atomic force microscopy (AFM), Malvern particle size analyzer, UV-visible spectroscopy and Fourier transform infrared spectroscopy (FTIR), and the results showed that PEG, PEI and FA could be covalently grafted to GO surface, forming PEG-GO-PEI-FA particles with a size of [Formula: see text][Formula: see text]nm and a potential of 14.7[Formula: see text]mV. Agarose-gel electrophoresis demonstrated that siRNA can be adsorbed onto the surface of PEG-GO-PEI-FA by electrostatic interaction. Laser confocal microscopy demonstrated that siRNA-adsorbed PEG-GO-PEI-FA could be target into folate receptor (FR)-overexpressing ovarian cancer cells. Compared to the PEG-GO-PEI/siRNA without folate modification, PEG-GO-PEI-FA/siRNA showed more pronounced inhibitory effect on growth of ovarian cancer cells. In conclusion, we have successfully synthesized a vector that is safe, efficient and specific to target tumor cell for gene delivery.