Intrinsic and extrinsic actions of human neural progenitors with SUFU inhibition promote tissue repair and functional recovery from severe spinal cord injury.

Neural progenitor cells (NPCs) derived from human pluripotent stem cells(hPSCs) provide major cell sources for repairing damaged neural circuitry and enabling axonal regeneration after spinal cord injury (SCI). However, the injury niche and inadequate intrinsic factors in the adult spinal cord restrict the therapeutic potential of transplanted NPCs. The Sonic Hedgehog protein (Shh) has crucial roles in neurodevelopment by promoting the formation of motorneurons and oligodendrocytes as well as its recently described neuroprotective features in response to the injury, indicating its essential role in neural homeostasis and tissue repair. In this study, we demonstrate that elevated SHH signaling in hNPCs by inhibiting its negative regulator, SUFU, enhanced cell survival and promoted robust neuronal differentiation with extensive axonal outgrowth, counteracting the harmful effects of the injured niche. Importantly, SUFU inhibition in NPCs exert non-cell autonomous effects on promoting survival and neurogenesis of endogenous cells and modulating the microenvironment by reducing suppressive barriers around lesion sites. The combined beneficial effects of SUFU inhibition in hNPCs resulted in the effective reconstruction of neuronal connectivity with the host and corticospinal regeneration, significantly improving neurobehavioral recovery in recipient animals. These results demonstrate that SUFU inhibition confers hNPCs with potent therapeutic potential to overcome extrinsic and intrinsic barriers in transplantation treatments for SCI.

High-Frequency Spinal Stimulation Suppresses Microglial Kaiso-P2X7 Receptor Axis-Induced Inflammation to Alleviate Neuropathic Pain in Rats.

OBJECTIVE: Neuropathic pain poses a persistent challenge in clinical management. Neuromodulation has emerged as a last-resort therapy. Conventional spinal cord stimulation (Con SCS) often causes abnormal sensations and provides short analgesia, whereas high-frequency spinal cord stimulation (HF SCS) is a newer therapy that effectively alleviates pain without paresthesia. However, the modes of action of 10kHz HF SCS (HF10 SCS) in pain relief remain unclear. To bridge this knowledge gap, we employed preclinical models that mimic certain features of clinical SCS to explore the underlying mechanisms of HF10 SCS. Addressing these issues would provide the scientific basis for improving and evaluating the effectiveness, reliability, and practicality of different frequency SCS in clinical settings. METHODS: We established a preclinical SCS model to examine its effects in a neuropathic pain rat model. We conducted bulk and single-cell RNA sequencing in the spinal dorsal horn (SDH) to examine cellular and molecular changes under different treatments. We employed genetic manipulations through intrathecal injection of a lentiviral system to explore the SCS-mediated signaling axis in pain. Various behavioral tests were performed to evaluate pain conditions under different treatments. RESULTS: We found that HF10 SCS significantly reduces immune responses in the SDH by inactivating the Kaiso-P2X7R pathological axis in microglia, promoting long-lasting pain relief. Targeting Kaiso-P2X7R in microglia dramatically improved efficacy of Con SCS treatment, leading to reduced neuroinflammation and long-lasting pain relief. INTERPRETATION: HF10 SCS could improve the immunopathologic state in the SDH, extending its benefits beyond symptom relief. Targeting the Kaiso-P2X7R axis may enhance Con SCS therapy and offer a new strategy for pain management. ANN NEUROL 2024;95:966-983.

Neuronavigation-guided Percutaneous Rhizotomies to Trigeminal Neuralgia: A Systematic Review.

OBJECTIVE: Neuronavigation improves intraoperative visualization of the cranial structures, which is valuable in percutaneous surgical treatments for patients with trigeminal neuralgia (TN) who are refractory to pharmacotherapy or reluctant to receive open surgery. The objective of this review was to evaluate the available neuronavigation-guided percutaneous surgical treatment modalities with cannulation of foramen ovale to TN, and their relative benefits and limitations. METHODS: This review was conducted based on the PRISMA statement. An initial search was performed on electronic databases, followed by manual and reference searches. Study and patient characteristics, rhizotomy procedure and neuronavigation details, and treatment outcomes (initial pain relief and pain recurrence within 2 y, success rate of forman ovale cannulation, and complications) were evaluated. The risk of bias was assessed with a quality assessment based on the ROBINS-I tools. RESULTS: Ten studies (491 operations, 403 participants) were analyzed. Three percutaneous trigeminal rhizotomy modalities identified were radiofrequency thermocoagulation rhizotomy (RFTR), percutaneous balloon compression, and glycerol rhizotomy. Intraoperative computed tomography and magnetic resonance imaging fusion-based RFTR had the highest initial pain relief rate of 97.0%. The success rate of foramen ovale cannulation ranged from 92.3% to 100% under neuronavigation. Facial hypoesthesia and masticatory muscle weakness were the most reported complications. DISCUSSION: Neuronavigation-guided percutaneous trigeminal rhizotomies showed possible superior pain relief outcomes to that of conventional rhizotomies in TN, with the benefits of radiation reduction and lower complication development rates. The limitations of neuronavigation remain its high cost and limited availability. Higher-quality prospective studies and randomized clinical trials of neuronavigation-guided percutaneous trigeminal rhizotomy were lacking.

A validation study of the Cantonese Chinese version of short form McGill pain questionnaire 2 in Cantonese-speaking patients with chronic pain in Hong Kong.

OBJECTIVE: The study tests the reliability and validity of the Cantonese Chinese version of Short Form McGill Pain Questionnaire 2 (SF-MPQ-2-CC). METHODS: The original Short Form McGill Pain Questionnaire (SF-MPQ-2) was translated into Cantonese Chinese version. Cantonese-speaking chronic pain patients from three pain centers in Hong Kong were recruited and asked to complete SF-MPQ-2-CC, validated Chinese versions of Identification Pain questionnaire (ID Pain), Pain Catastrophizing Scale (PCS), and Short Form Health Survey (SF-36) for evaluation of convergent and divergent validity, 2 weeks apart for evaluation of internal consistency. RESULTS: A total of 333 and 197 participants completed the first and second set of questionnaires, respectively. SF-MPQ-2-CC was shown to have excellent internal consistency, with an overall Cronbach's alpha value of 0.933. The overall correlation coefficient was 0.875 that shows good test-retest reliability. Construct validity was evaluated using confirmatory factor analysis, where a seconder-order factor model demonstrated a good fit with our data (χ2 = 826.51, p < 0.001, CFI = 0.92, TLI = 0.908, RMSEA = 0.097; SRMR = 0.063; error terms adjusted). SF-MPQ-2-CC also showed good convergent validity with Chinese versions of ID Pain (neuropathic pain) and PCS (continuous pain), and divergent validity was shown by a negative correlation with Chinese version of SF-36. CONCLUSIONS: Our study demonstrated that SF-MPQ-2-CC is a valid and reliable pain assessment tool for Cantonese-speaking patients in Hong Kong with a wide range of chronic pain conditions. It also helps to identify the presence of neuropathic pain and negative pain cognition among respondents.

Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel.

BACKGROUND: Chronic orofacial pain (COP) therapy is challenging, as current medical treatments are extremely lacking. Moutan Cortex (MC) is a traditional Chinese medicine herb widely used for chronic inflammatory diseases. However, the mechanism behind MC in COP therapy has not been well-established. The purpose of this study was to identify the active ingredients of MC and their specific underlying mechanisms in COP treatment. METHODS: In this study, the main active ingredients and compound-target network of MC in COP therapy were identified through network pharmacology and bioinformatics analysis. Adult male Sprague-Dawley rats received oral mucosa lipopolysaccharide (LPS) injection to induce COP. Pain behaviors were evaluated by orofacial mechanical nociceptive assessment after intraganglionar injection. In vitro inflammatory cytokines in LPS-pretreated human periodontal ligament stem cells (hPDLSCs) and rat primary cultural trigeminal ganglion (TG) neurons were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Schrödinger software was used to verify the molecular docking of quercetin and critical targets. Whole-cell recording electrophysiology was used to evaluate the effect of quercetin on voltage-gated sodium (Na v ) channel in rat TG neurons. RESULTS: The assembled compound-target network consisted of 4 compounds and 46 targets. As 1 of the active components of MC correlated with most related targets, quercetin alleviated mechanical allodynia in LPS-induced rat model of COP (mechanical allodynia threshold median [interquartile range (IQR) 0.5 hours after drug administration: vehicle 1.3 [0.6-2.0] g vs quercetin 7.0 [6.0-8.5] g, P = .002). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that immune response and membrane functions play essential roles in MC-COP therapy. Five of the related targets were identified as core targets by protein-protein interaction analysis. Quercetin exerted an analgesic effect, possibly through blocking Na v channel in TG sensory neurons (peak current density median [IQR]: LPS -850.2 [-983.6 to -660.7] mV vs LPS + quercetin -589.6 [-711.0 to -147.8] mV, P = .006) while downregulating the expression level of proinflammatory cytokines-FOS (normalized messenger RNA [mRNA] level mean ± standard error of mean [SEM]: LPS [2. 22 ± 0.33] vs LPS + quercetin [1. 33 ± 0.14], P = .034) and TNF-α (normalized mRNA level mean ± SEM: LPS [8. 93 ± 0.78] vs LPS + quercetin [3. 77 ± 0.49], P < .0001). CONCLUSIONS: Identifying Na v as the molecular target of quercetin clarifies the analgesic mechanism of MC, and provides ideas for the development of novel selective and efficient chronic pain relievers.

Synthesis of di/trifluoromethyl cyclopropane-dicarbonitriles via [2+1] annulation of fluoro-based diazoethanes with (alkylidene)malononitriles.

Herein, we describe a [2+1] annulation reaction of di/trifluorodiazoethane with (alkylidene)malononitriles. This protocol offers a streamlined synthesis of a wide range of stereospecific and densely functionalized difluoromethyl and trifluoromethyl cyclopropane-1,1-dicarbonitriles. Further functional group interconversions or skeletal elaborations afford structurally distinct cyclopropyl variants.

Transplanting Human Neural Stem Cells with ≈50% Reduction of SOX9 Gene Dosage Promotes Tissue Repair and Functional Recovery from Severe Spinal Cord Injury.

Neural stem cells (NSCs) derived from human pluripotent stem cells (hPSCs) are considered a major cell source for reconstructing damaged neural circuitry and enabling axonal regeneration. However, the microenvironment at the site of spinal cord injury (SCI) and inadequate intrinsic factors limit the therapeutic potential of transplanted NSCs. Here, it is shown that half dose of SOX9 in hPSCs-derived NSCs (hNSCs) results in robust neuronal differentiation bias toward motor neuron lineage. The enhanced neurogenic potency is partly attributed to the reduction of glycolysis. These neurogenic and metabolic properties retain after transplantation of hNSCs with reduced SOX9 expression in a contusive SCI rat model without the need for growth factor-enriched matrices. Importantly, the grafts exhibit excellent integration properties, predominantly differentiate into motor neurons, reduce glial scar matrix accumulation to facilitate long-distance axon growth and neuronal connectivity with the host as well as dramatically improve locomotor and somatosensory function in recipient animals. These results demonstrate that hNSCs with half SOX9 gene dosage can overcome extrinsic and intrinsic barriers, representing a powerful therapeutic potential for transplantation treatments for SCI.

Regioselective [3 + 2] cycloaddition of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes: a facile access to 3-di/trifluoroalkyl-5-fluoropyrazoles.

Herein we describe the base-mediated [3 + 2] cycloaddition reaction of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes. The reaction protocol provides a direct and facile strategy for the dual incorporation of a fluorine atom and fluoroalkyl group into pyrazole cores, thus allowing rapid access to a wide variety of densely functionalized 3-di/trifluoroalkyl-5-fluoropyrazoles in generally high yields with excellent regioselectivities. Furthermore, several drug-like 3-di/trifluoroalkyl-5-fluoropyrazoles have been synthesized, demonstrating potent inhibitory activities against cyclooxygenase 2 (COX-2).

Sub-anaesthetic dose of propofol attenuates mechanical allodynia in chronic post-ischaemic pain via regulation of PTEN/PI3K/IL-6 signalling.

Background: Propofol is an intravenous anaesthetic drug that has been shown to reduce inflammatory pain. Complex regional pain syndrome (CRPS) type I is a pain condition characterized by autonomic, motor and sensory disturbance. The chronic post-ischaemic pain (CPIP) model is a well-established model to recapture CRPS-I syndromes pre-clinically by non-invasive ischaemic-reperfusion (IR) injury. In this study, we investigated the analgesic effects of propofol and underlying mechanisms in mitigating CRPS pain using the CPIP model. Methods: Sub-anaesthetic dose of propofol (25 mg/kg) was intravenously delivered to the CPIP model and sham control. Nociceptive behavioural changes were assayed by the von Frey test. Molecular assays were used to investigate expression changes of PTEN, PI3K, AKT and IL-6 underlying propofol-mediated analgesic effects. Pharmacological inhibition was applied for PTEN/PI3K/AKT pathway manipulation. Results: Both pre- and post-operative administration of propofol attenuated mechanical allodynia induced by CPIP. Propofol could modulate PTEN/PI3K/AKT signalling pathway by increasing active PTEN and reducing phosphorylated PI3K, phosphorylated AKT and IL-6 expression in the spinal dorsal horn, which promoted pain relief in the CPIP model. Inhibition of PTEN with bpV abolished the analgesic effects produced by propofol in CPIP mice. Conclusion: Sub-anaesthetic dose of propofol administration resulted in the activation of PTEN, inhibition of both PI3K/AKT signalling and IL-6 production in the spinal cord, which dramatically reduced CPIP-induced pain. Our findings lay the foundation in using propofol for the treatment of CRPS with great therapeutic implications.

Use of pain-related gene features to predict depression by support vector machine model in patients with fibromyalgia.

The prevalence rate of depression is higher in patients with fibromyalgia syndrome, but this is often unrecognized in patients with chronic pain. Given that depression is a common major barrier in the management of patients with fibromyalgia syndrome, an objective tool that reliably predicts depression in patients with fibromyalgia syndrome could significantly enhance the diagnostic accuracy. Since pain and depression can cause each other and worsen each other, we wonder if pain-related genes can be used to differentiate between those with major depression from those without. This study developed a support vector machine model combined with principal component analysis to differentiate major depression in fibromyalgia syndrome patients using a microarray dataset, including 25 fibromyalgia syndrome patients with major depression, and 36 patients without major depression. Gene co-expression analysis was used to select gene features to construct support vector machine model. The principal component analysis can help reduce the number of data dimensions without much loss of information, and identify patterns in data easily. The 61 samples available in the database were not enough for learning based methods and cannot represent every possible variation of each patient. To address this issue, we adopted Gaussian noise to generate a large amount of simulated data for training and testing of the model. The ability of support vector machine model to differentiate major depression using microarray data was measured as accuracy. Different structural co-expression patterns were identified for 114 genes involved in pain signaling pathway by two-sample KS test (p < 0.001 for the maximum deviation D = 0.11 > D critical = 0.05), indicating the aberrant co-expression patterns in fibromyalgia syndrome patients. Twenty hub gene features were further selected based on co-expression analysis to construct the model. The principal component analysis reduced the dimension of the training samples from 20 to 16, since 16 components were needed to retain more than 90% of the original variance. The support vector machine model was able to differentiate between those with major depression from those without in fibromyalgia syndrome patients with an average accuracy of 93.22% based on the expression levels of the selected hub gene features. These findings would contribute key information that can be used to develop a clinical decision-making tool for the data-driven, personalized optimization of diagnosing depression in patients with fibromyalgia syndrome.

Analgesic Effect of Buprenorphine for Chronic Noncancer Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Buprenorphine is a partial agonist at the µ-opioid receptor and an antagonist at the delta and kappa opioid receptors. It has high affinity and low intrinsic activity at the µ-opioid receptor. Buprenorphine demonstrates no ceiling effect for clinical analgesia, but demonstrates this for respiratory depression and euphoria. It may provide effective analgesia while producing less adverse effects, making it a promising opioid analgesic. A systematic review and meta-analysis were performed to examine the analgesic efficacy of buprenorphine for patients with chronic noncancer pain. METHODS: PubMed, MEDLNE, Embase, and the Cochrane Library were searched up to January 2022. Randomized controlled trials were included if they compared buprenorphine versus placebo or active analgesic in patients with chronic noncancer pain, where pain score was an outcome. Nonrandomized controlled trials, observational studies, qualitative studies, case reports, and commentaries were excluded. Two investigators independently performed the literature search, study selection, and data collection. A random-effects model was used. The primary outcome was the effect of buprenorphine on pain intensity in patients with chronic noncancer pain based on standardized mean difference (SMD) in pain score. Quality of evidence was assessed using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Two separate literature searches were conducted for patients with and without opioid use disorder (OUD). Only one study met the search criteria for those with OUD. Fourteen randomized controlled trials were included for those without OUD. Buprenorphine was associated with reduced pain score (SMD = -0.368, P < .001, I 2 = 89.37%) compared to placebo or active analgesic. Subgroup meta-analyses showed statistically significant differences in favor of buprenorphine versus placebo (SMD = -0.404, P < .001), for chronic low back pain (SMD = -0.383, P < .001), when administered via the transdermal route (SMD = -0.572, P = .001), via the buccal route (SMD = -0.453, P < .001), with length of follow-up lasting <12 weeks (SMD = -0.848, P < .05), and length of follow-up lasting 12 weeks or more (SMD = -0.415, P < .001). There was no significant difference when compared to active analgesic (SMD = 0.045, P > .05). Quality of evidence was low to moderate. CONCLUSIONS: Buprenorphine was associated with a statistically significant and small reduction in pain intensity compared to placebo. Both the transdermal and buccal routes provided pain relief. There was more evidence supporting its use for chronic low back pain.

Individual-level and neighborhood-level shifts in mortality patterns among drug poisoning deaths in a high-density Asian city: a territory-wide, case-only analysis.

BACKGROUND: The shifts in individual-level and neighborhood-level patterns of drug poisoning deaths in a high-density Asian city over time have been underestimated, although they provide essential information for community-based surveillance and interventions. METHODS: A case-only analysis with a 16-y, territory-wide, population-based registry in Hong Kong was applied to compare drug poisoning deaths from 2001 to 2010 with 2011 to 2016. Drug poisoning deaths, deaths from heroin and deaths from other opioids (codeine or morphine) were extracted (ICD codes: T36-T50, T40.1, T40.2). Binomial regressions were used to estimate the shifts in mortality patterns. RESULTS: Among 3069 drug poisoning deaths, a significant shift in mortality patterns was found despite a decreasing mortality trend in Hong Kong. Overall, drug poisoning deaths shifted towards middle-aged/young-old, widowed/divorced, economically active, white collar and non-local born. Since 2011, more deaths from heroin were in older ages and non-local born, but less were never married and economically inactive. More deaths from other opioids were middle-aged, young-old and divorced. In particular, most decedents shifted towards young-old, especially deaths from other opioids. Compared with deaths during 2001-2010, there were 3.72- and 6.50-fold more deaths from heroin and deaths from other opioids in those aged ≥60 y since 2021 (ORs: 3.72 [2.37, 5.86], 6.50 [3.97, 10.65]), respectively. Additionally, drug poisoning deaths shifted towards areas with less neighborhood deprivation (more high-education individuals and a mix of private/public housing residents), especially deaths from other opioids. CONCLUSION: Misuse of registered drugs (e.g. opioid pain relievers) could be a rising trend among vulnerable subpopulations in Hong Kong other than illegal drug use (heroin). Health officials should provide more advice and support on drug information. Specifically, an improved health system with education regarding the appropriate use of registered drugs for medical treatments should be provided to mid-/high-income and local-born individuals.

Regenerative medicine for the treatment of chronic low back pain: a narrative review.

Low back pain (LBP) is a common and important clinical problem. In addition to pain, patients are also affected by personal, social, and economic burdens. Intervertebral disc (IVD) degeneration is a common cause of LBP, further increasing the patient's morbidity and medical costs. The limitations of current treatment strategies for long-term pain relief mean that increasing attention has been paid to regenerative medicine. We carried out a narrative review to explore the roles of four types of regenerative medicine for treating LBP: marrow-derived stem cells, growth factors, platelet-rich plasma, and prolotherapy. Marrow-derived stem cells are regarded as an ideal cell source for IVD regeneration. Growth factors may stimulate the synthesis of extracellular matrix and attenuate or reverse the degenerative process in IVD, while platelet-rich plasma, which contains multiple growth factors, is thought to be a promising alternative therapy for IVD degeneration. Prolotherapy can initiate the body's inflammatory healing response to repair injured joints and connective tissues. This review summarizes the mechanisms, in vitro and in vivo studies, and clinical applications of these four types of regenerative medicine in patients with LBP.

Histone deacetylase 5-induced deficiency of signal transducer and activator of transcription-3 acetylation contributes to spinal astrocytes degeneration in painful diabetic neuropathy.

Diabetes patients with painful diabetic neuropathy (PDN) show severe spinal atrophy, suggesting pathological changes of the spinal cord contributes to central sensitization. However, the cellular changes and underlying molecular mechanisms within the diabetic spinal cord are less clear. By using a rat model of type 1 diabetes (T1D), we noted an extensive and irreversible spinal astrocyte degeneration at an early stage of T1D, which is highly associated with the chronification of PDN. Molecularly, acetylation of astrocytic signal transducer and activator of transcription-3 (STAT3) that is essential for maintaining the homeostatic astrocytes population was significantly impaired in the T1D model, resulting in a dramatic loss of spinal astrocytes and consequently promoting pain hypersensitivity. Mechanistically, class IIa histone deacetylase, HDAC5 were aberrantly activated in spinal astrocytes of diabetic rats, which promoted STAT3 deacetylation by direct protein-protein interactions, leading to the PDN phenotypes. Restoration of STAT3 signaling or inhibition of HDAC5 rescued astrocyte deficiency and attenuated PDN in the T1D model. Our work identifies the inhibitory axis of HDAC5-STAT3 induced astrocyte deficiency as a key mechanism underlying the pathogenesis of the diabetic spinal cord that paves the way for potential therapy development for PDN.

Efficacy of Peripheral Nerve Field Stimulation for the Management of Chronic Low Back Pain and Persistent Spinal Pain Syndrome: A Narrative Review.

OBJECTIVES: Various approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS. MATERIALS AND METHODS: A comprehensive search for clinical studies on PNFS and PNFS + SCS used for the management of CLBP and/or PSPS was performed using PubMed, EMBASE, MEDLINE via Proquest, and Web of Science. RESULTS: A total of 15 studies were included, of which four were randomized controlled trials (RCTs), nine were observational studies, and two were case series. For patients receiving PNFS, a significant decrease in back pain intensity and analgesic consumption, together with a significant improvement in physical functioning, was observed upon implant of the permanent system. Meanwhile, the addition of PNFS to SCS in refractory cases was associated with a significant reduction in back and leg pain, respectively. CONCLUSIONS: This review suggests that PNFS, when used alone or in combination with SCS, appears to be effective in managing back pain. However, high-quality evidence that supports the long-term analgesic efficacy and safety is still lacking. Hence, RCTs with a larger patient population and of a longer follow-up duration are warranted.

Comparison of the effects of sufentanil-dominant anaesthesia/analgesia and epidural anaesthesia/analgesia on postoperative immunological alterations, stress responses and prognosis in open hepatectomy: a randomized trial.

Background: Both in vitro and in animal studies have shown immunosuppressive effects of opioids which might provoke tumour growth and metastasis, while no definite results were shown in previous clinical studies. To find out the effects between general anaesthesia combined with sufentanil target-controlled infusion (SGA) and general anaesthesia combined with epidural anaesthesia (EGA) on immunological alterations, stress responses and prognosis in patients undergoing open hepatectomy, a prospective, non-inferiority, randomized-controlled study was performed. Methods: Patients with liver neoplasms undergoing open hepatectomy were randomly assigned to either SGA (n=81) or EGA (n=81) group. The primary outcome was the ratio of interferon (IFN)-γ/interleukin (IL)-4 at 24 h after surgery (T3). The secondary outcomes included immune-related cytokines, circulating immune cells, stress-related cytokines, cortisol and blood glucose, visual analogue scale scores. Plasma was sampled at five-time points [baseline/before surgery (T0), 5 min after portal block release (T1), 1 h after surgery (T2), T3, and on a postoperative day (POD)5 (T4)]. Cancer-related outcomes, including recurrence, metastasis and survival, were followed up at 3 months and 1 year after surgery. Results: The IFN-γ/IL-4 ratios were comparable between both groups at T3 {median [interquartile range (IQR)]: 20.78 (12.73-29.18) vs. 19.52 (13.98-29.29), P=0.607}. At T3, the proportions of circulating T cells were decreased, while those of B and natural killer cells were increased. The plasma level of tumour necrosis factor (TNF)-α at T2 was significantly higher in the SGA group [median (IQR): 7.45 (6.20-9.80) vs. 5.95 (4.95-7.45) pg/mL, P<0.001]. Patient-controlled intravenous analgesia was less effective than epidural analgesia on POD0 and POD2. For hepatocellular carcinoma (HCC)-related outcomes, no significant differences were found in either short- or long-term follow-ups. Conclusions: Although the levels of TNF-α were higher in the SGA group, the tumour-related immunological alterations and follow-ups showed no difference between groups. SGA appears not to be inferior to EGA regarding tumour-related immunity and prognosis. Intravenous opioid use appears not to be inferior to epidural anaesthesia, and can be used safely in HCC patients without worsening patients' prognosis. Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR2000035299).

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel.

Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs.

Identification of immune-related endoplasmic reticulum stress genes in sepsis using bioinformatics and machine learning.

Background: Sepsis-induced apoptosis of immune cells leads to widespread depletion of key immune effector cells. Endoplasmic reticulum (ER) stress has been implicated in the apoptotic pathway, although little is known regarding its role in sepsis-related immune cell apoptosis. The aim of this study was to develop an ER stress-related prognostic and diagnostic signature for sepsis through bioinformatics and machine learning algorithms on the basis of the differentially expressed genes (DEGs) between healthy controls and sepsis patients. Methods: The transcriptomic datasets that include gene expression profiles of sepsis patients and healthy controls were downloaded from the GEO database. The immune-related endoplasmic reticulum stress hub genes associated with sepsis patients were identified using the new comprehensive machine learning algorithm and bioinformatics analysis which includes functional enrichment analyses, consensus clustering, weighted gene coexpression network analysis (WGCNA), and protein-protein interaction (PPI) network construction. Next, the diagnostic model was established by logistic regression and the molecular subtypes of sepsis were obtained based on the significant DEGs. Finally, the potential diagnostic markers of sepsis were screened among the significant DEGs, and validated in multiple datasets. Results: Significant differences in the type and abundance of infiltrating immune cell populations were observed between the healthy control and sepsis patients. The immune-related ER stress genes achieved strong stability and high accuracy in predicting sepsis patients. 10 genes were screened as potential diagnostic markers for sepsis among the significant DEGs, and were further validated in multiple datasets. In addition, higher expression levels of SCAMP5 mRNA and protein were observed in PBMCs isolated from sepsis patients than healthy donors (n = 5). Conclusions: We established a stable and accurate signature to evaluate the diagnosis of sepsis based on the machine learning algorithms and bioinformatics. SCAMP5 was preliminarily identified as a diagnostic marker of sepsis that may affect its progression by regulating ER stress.

Advantages of Transmuscular Quadratus Lumborum Block via Subfascial Approach Versus Extrafascial Approach for Postoperative Analgesia After Laparoscopic Cholecystectomy: A Randomized Controlled Study.

OBJECTIVE: We aimed to compare the analgesic effect and incidence of lower limb weakness of transmuscular quadratus lumborum (TQL) block via subfascial approach with that via extrafascial after laparoscopic cholecystectomy (LC). METHODS: Eighty patients undergoing LC were randomized to receive ultrasound-guided bilateral TQL block via subfascial (subfascial group) or extrafascial (extrafascial group) using 30 mL of 0.33% ropivacaine unilaterally. Pain scores of port sites while rest and coughing at 1, 6, 12, 24, 36, and 48 hours postoperatively as primary outcome were compared. Modified Lovett Rating Scale, ambulatory dependency, and rescue analgesia requirement was also compared. RESULTS: The pain score of the subxiphoid and of the right subcostal port site for up to the postoperative 36 hours (2 [1 to 2]) and 24 hours (2 [2 to 3]) in the subfascial group was significantly lower than that in extrafascial group (2 [2 to 2] and 3 [2.25 to 4]). Up to postoperative 24 hours, the rescue analgesia requirement in subfascial group was significantly lower than that in extrafascial group, namely less fentanyl consumption and parecoxib (1.3 [±5.5] µg vs. 5.6 [±10.6] µg; 17.5% vs. 37.5%). The ratio of patients with LRS score of 6 at postoperative 1 hour (65.0%), and with dependent ambulation at postoperative 1 and 6 hours in subfascial group (15.0% and 0.0%) was significantly lower than that in extrafascial group (10.0%, 80.0%, and 17.5%). CONCLUSION: TQL block via subfascial had the advantages of better analgesic effect and less lower limbs weakness after LC over that via extrafascial.

Mode of action of astrocytes in pain: From the spinal cord to the brain.

Chronic pain is a maladaptive condition affecting 7%- 10% of the population worldwide and can be accompanied by depression, anxiety, and insomnia. In particular, chronic pain is becoming more common due to the increasing incidence of diabetes mellitus, cancer, systemic (body-wide) autoimmune, trauma, and infections that attack nerve tissues with an aging global population. Upon stimuli, pain responses are evoked from nociceptive primary sensory neurons in the peripheral nervous system (PNS). Still, pathological changes leading to central sensitization of the pain circuitry in the central nervous system (CNS) is a key mechanism underlying pain maintenance. In humans, chronic pain can last for years, even after the observable signs and symptoms of the primary inflammation or damage have resolved. It is clear that astrocytes, the most abundant cell type in the CNS, are highly involved in regulating pain signaling under health and disease. Multiple astrocyte subsets and diversified activation states driven by intrinsic and extrinsic cues have recently been identified in the spinal cord and brain, playing complex roles in pain development and resolution. Targeting detrimental astrocyte subtypes and activity is considered a promising pain management strategy. Here, we integrate the latest findings to review differential astrocytes activities in distinct regions of the CNS during pain pathophysiology and discuss the underlying molecular mechanisms that control their mode of action in beneficial or/and harmful aspects of pain. Finally, we provide a translational overview of current progress for pain therapies via modulating astrocytic activity.