Neohesperidin Alleviates the Neuropathic Pain Behavior of Rats by Downregulating the P2X4 Receptor.

Neuropathic pain (NP) is a type of chronic pain affecting 6-8% of human health as no effective drug exists. The purinergic 2X4 receptor (P2X4R) is involved in NP. Neohesperidin (NH) is a dihydroflavonoside compound, which has anti-inflammatory and antioxidative properties. This study aimed to investigate whether NH has an effect on P2X4R-mediated NP induced by chronic constriction injury (CCI) of the sciatic nerve in rats. In this study, the CCI rat model was established to observe the changes of pain behaviors, P2X4R, and satellite glial cells (SGCs) activation in dorsal root ganglion (DRG) after NH treatment by using RT-PCR, immunofluorescence double labeling and Western blotting. Our results showed CCI rats had mechanical and thermal hyperalgesia with an increased level of P2X4R. Furthermore, SGCs were activated as indicated by increased expression of glial fibrillary acidic protein and increased tumor necrosis factor-alpha receptor 1and interleukin-1ß. In addition, phosphorylated extracellular regulated protein kinases and interferon regulatory factor 5 in CCI rats increased. After NH treatment in CCI rats, the levels of above protein decreased, and the pain reduced. Overall, NH can markedly alleviate NP by reducing P2X4R expression and SGCs activation in DRG.

Effect of Wearing N95 Mask on the Quality of Chest Compressions in Prehospital Emergency Personnel: A Cross-over Study.

OBJECTIVE: To evaluate the effect of wearing an N95 mask on the quality of chest compression and fatigue of prehospital emergency personnel during cardiopulmonary resuscitation (CPR). METHODS: Twenty-four eligible participants were recruited. Participants' age, sex, height, and weight were recorded. After completing the CPR training and examination, participants were tested twice, wearing surgical mask or an N95 mask, while performing chest compressions for 2 minutes. The quality of chest compression (including compression frequency, depth, rebound, and position) was recorded by the simulator. Borg fatigue scores and physiological parameters (including heart rate, mean arterial pressure, pulse oxygen saturation, and respiratory rate) were recorded before and after chest compressions. RESULTS: Compared to wearing surgical masks, participants wearing N95 masks had significantly lower quality of chest compression, including compression frequency (98.3 ± 4.9 bpm vs 104.0 ± 6.0 bpm, P < 0.001), depth (47.1 ± 4.5 mm vs 50.5 ± 5.4 mm, P < 0.001), and rebound (90.2 ± 2.7% vs 94.3 ± 2.1%, P < 0.001). The compression position was not affected. The period data showed that the difference in compression quality started after 1 minute of compressions. Participants wearing N95 masks had higher Borg fatigue scores [6.1(2) vs 5.1(2), P < 0.001], heart rates (121.2 ± 5.7 bpm vs 109.9 ± 6.0 bpm, P < 0.001), mean arterial pressures (106.3 ± 8.0 mmHg vs 99.0 ± 8.5 mmHg, P = 0.012), and respiratory rates (29.5 ± 2.7 bpm vs 24.7 ± 2.5 bpm, P < 0.001). CONCLUSION: This study showed that the use of an N95 mask by prehospital emergency personnel during the performance of chest compressions resulted in a reduction of compression quality and increased clinician fatigue. There is a need for CPR training for medical personnel wearing personal protective equipment.

Effect of perioperative ultrasound guided fascia iliaca compartment block in elderly adults with hip fractures undergoing arthroplasty in spinal anesthesia-a randomized controlled trial.

BACKGROUND: For elderly adults undergoing hip arthroplasty, fascia iliaca compartment block (FICB) is often used before spinal anesthesia to reduce the pain of posture placement. However, the impact of FICB within 48 h needs further study. METHODS: 89 elderly adults scheduled to undergo arthroplasty for hip fracture were enrolled and randomized into the FICB group (n = 45) and the control group (n = 44). The fascia iliaca on the operated side was located using ultrasound, and a puncture needle was placed under the fascia iliaca. The FICB group was injected with 40 ml of 0.5% ropivacaine, and the control group was injected with 40 ml of normal saline. Spinal anesthesia was performed after 20 min. Our primary outcome measures were: duration of analgesia, muscle strength, and Quality of Recovery (QoR). RESULTS: The duration of analgesia in the FICB group was 403.5 ± 39.6 min, which was longer than that (357.5 ± 35.9 min) of the control group (P = 0.012). There were 19 (42.2%) patients with muscle strength of grade 4 in the FICB group and 36 (81.8%) patients with muscle strength of grade 4 in the control group. FICB group was lower (P < 0.001). QoR-15 at 24 h after surgery was 114.1 ± 8.3 in the FICB group and 104.6 ± 8.4 in the control group (P < 0.001). QoR-15 at 48 h after surgery was 122.7 ± 8.4 in the FICB group and 120.5 ± 9.5 in the control group (P = 0.232). CONCLUSIONS: For elderly adults with hip fractures, FICB provided longer analgesia and improved 24-h QoR, but reduced postoperative muscle strength. TRAIL REGISTRATION: Chinese Clinical Registry Center, ChiCTR2200056937, 23/02/2022.

Application of a preoperative pain management mode based on instant messaging software in elderly hip fracture patients: a randomized controlled trial.

BACKGROUND: Preoperative analgesia of hip fracture in elderly patients is important, but it is also lacking. In particular, nerve block was not provided in time. In order to provide more effective analgesia, we designed a multimodal pain management mode based on instant messaging software. METHODS: From May to September 2022, a total of 100 patients with unilateral hip fracture aged over 65 were randomly divided into the test group and the control group. Finally, 44 patients in each group completed the result analysis. A new pain management mode was used in the test group. This mode focuses on the full information exchange between medical personnel in different departments, early fascia iliaca compartment block (FICB), and closed-loop pain management. Outcomes include the time when FICB is completed for the first time; The number of cases of FICB completed by emergency doctors; Patients' pain score, pain duration. RESULTS: The time for patients in the test group to complete FICB for the first time was 3.0 [1.925-3.475] h, which was less than the time for patients in the control group (4.0 [3.300-5.275] h). The difference was statistically significant (P < 0.001). Compared with 16 patients in the control group, 24 patients in the test group completed FICB by emergency doctors, and there was no statistical difference between the two groups (P = 0.087). The test group was superior to the control group in the highest NRS score (4.00 [3.00-4.00] vs 5.00 [4.00-5.75]), the duration of the highest NRS score (20.00 [20.00-25.00] mins vs 40.00 [30.00-48.75] mins), and the NRS > 3 time (35.00 [20.00-45.00] mins vs 72.50 [60.00-45.00] mins). The analgesic satisfaction of patients in the test group (5.00 [4.00-5.00]) was also significantly higher than that of the control group (3.00 [3.00-4.00]). The above four indexes were different between the two groups (P < 0.001). CONCLUSIONS: Using instant messaging software, the new model of pain management can enable patients to receive FICB as soon as possible and improve the timeliness and effectiveness of analgesia. TRIAL REGISTRATION: Chinese Clinical Registry Center, ChiCTR2200059013, 23/04/2022.

Mechanism of SET8 Activates the Nrf2-KEAP1-ARE Signaling Pathway to Promote the Recovery of Motor Function after Spinal Cord Injury.

Background: Spinal cord injury (SCI) is a common injury of the central nervous system (CNS), and astrocytes are relatively abundant glial cells in the CNS that impairs the recovery of motor function after SCI. It was confirmed that the oxidative stress of mitochondria leads to the accumulation of reactive oxygen species (ROS) in cells, which plays a key role in the motor function of astrocytes. However, the mechanism by which oxidative stress affects astrocyte motility after SCI is still unexplained. Therefore, this study investigated the influence of SET8-regulated oxidative stress on astrocyte autophagy levels after SCI in rats and the potential mechanisms of action. Methods: We used real-time quantitative PCR, western blotting, and immunohistochemical staining to analyze SET8, Keap1, and Nrf2 expression at the cellular level and in SCI tissues. ChIP to detect H4K20me1 enrichment in the Keap1 promoter region under OE-SET8 (overexpression of SET8) conditions. Western blotting was used to assess the expression of signature proteins of astrocytes, proteins associated with autophagy, proteins associated with glial scar formation, reactive oxygen species (ROS) levels in cells using DHE staining, and astrocyte number, morphological alterations, and induction of glial scar formation processes using immunofluorescence. In addition, the survival rate of neurons after SCI in rats was examined by using NiSSl staining. Results: OE-SET8 upregulates the enrichment of H4K20me1 in Keap1, inhibits Keap1 expression, activates the Nrf2-ARE signaling pathway to suppress ROS accumulation, inhibits oxidative stress-induced autophagy and glial scar formation in astrocytes, and leads to reduced neuronal loss, which promoted the recovery and improvement of motor function after SCI in rats. Conclusion: Overexpression of SET8 alleviated oxidative stress by regulating Keap1/Nrf2/ARE, inhibited astrocyte autophagy levels, and reduced glial scar formation as well as neuronal loss, thereby promoting improved recovery of motor function after SCI. Thus, the SET8/H4K20me1 regulatory function may be a promising cellular therapeutic intervention point after SCI.

Comparison of LPS and MS-induced depressive mouse model: behavior, inflammation and biochemical changes.

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.

Generating Daily Soil Moisture at 16 m Spatial Resolution Using a Spatiotemporal Fusion Model and Modified Perpendicular Drought Index.

Soil moisture (SM) is an important parameter in land surface processes and the global water cycle. Remote sensing technologies are widely used to produce global-scale SM products (e.g., European Space Agency's Climate Change Initiative (ESA CCI)). However, the current spatial resolutions of such products are low (e.g., >3 km). In recent years, using auxiliary data to downscale the spatial resolutions of SM products has been a hot research topic in the remote sensing research area. A new method, which spatially downscalesan SM product to generate a daily SM dataset at a 16 m spatial resolution based on a spatiotemporal fusion model (STFM) and modified perpendicular drought index (MPDI), was proposed in this paper. (1) First, a daily surface reflectance dataset with a 16 m spatial resolution was produced based on an STFM. (2) Then, a spatial scale conversion factor (SSCF) dataset was obtained by an MPDI dataset, which was calculated based on the dataset fused in the first step. (3) Third, a downscaled daily SM product with a 16 m spatial resolution was generated by combining the SSCF dataset and the original SM product. Five cities in southern Hebei Province were selected as study areas. Two 16 m GF6 images and nine 500 m MOD09GA images were used as auxiliary data to downscale a timeseries 25 km CCI SM dataset for nine dates from May to June 2019. A total of 151 in situ SM observations collected on 1 May, 21 May, 1 June, and 11 June were used for verification. The results indicated that the downscaled SM data with a 16 m spatial resolution had higher correlation coefficients and lower RMSE values compared with the original CCI SM data. The correlation coefficients between the downscaled SM data and in situ data ranged from 0.45 to 0.67 versus 0.33 to 0.54 for the original CCI SM data; the RMSE values ranged from 0.023 to 0.031 cm3/cm3 versus 0.027 to 0.032 cm3/cm3 for the original CCI SM data. The findings described in this paper can ensure effective farmland management and other practical production applications.

Ultrasound-guided supra-inguinal fascia Iliaca compartment block for older adults admitted to the emergency department with hip fracture: a randomized controlled, double-blind clinical trial.

BACKGROUND: Hip fracture is common in older adults, and can cause severe post-fracture pain. Fascia iliaca nerve block has consequently been used for preoperative analgesia. METHODS: We performed a randomized, controlled, double-blind clinical trial and recruited older patients with hip fractures. These patients were randomized into two groups and received ultrasound-guided fascia iliaca compartment block using either the supra-inguinal approach (group F) or the classical approach (group C). Heart rate, blood pressure, and resting and exercising visual analog scales were recorded before the procedure and at 30 min, and 6, 12, and 24 h after completion of the procedure. We recorded the duration of the procedure-as well as complications such as bleeding, hypotension, and intractable vomiting; the sleep duration in a 24 h period was also documented. RESULTS: A total of 38 patients completed the trial, and we observed no differences in the baseline characteristics or pre-procedural measurements between the two groups. Compared with the patients in group C, patients in group F exhibited significantly lower exercising VAS scores at 6 and 12 h after the procedure, faster heart rates at 6 and 24 h after the procedure, a longer procedural duration, and a longer sleep duration. There were no differences in the frequencies of complications between the two groups. The percentages of patients who took oral analgesics and the numbers of medications consumed were also not different between the two groups. CONCLUSIONS: The supra-inguinal FICB provided effective analgesia and improved exercise tolerance compared with the classical approach. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100045644, registration date: 2021 April 20).

Bioactivity of naringin and related mechanisms.

Naringin is a flavonoid compound, which can be used to treat or prevent various diseases, such as obesity, heart disease, diabetes, and metabolic syndrome. The medicinal value of naringin is mainly reflected in its antioxidant and anti-inflammatory functions, and it has a protective effect on pathophysiology. Furthermore, naringin has shown potential to become an alternative as traditional anti-inflammatory drug, because it exerts less side effects than chemically synthesized compounds. In this paper, we are reviewing the specific molecular mechanisms of anti-inflammatory and antioxidant properties of naringin. We analyze and discuss the primary role of naringin in the treatment of diseases such as acute and chronic liver injury, lung injury, bowel disease, and neurodegenerative diseases. Besides, the bactericidal effect of naringin is also reviewed.

Correction to: LncRNA NONRATT021972 involved the pathophysiologic processes mediated by P2X7 receptors in stellate ganglia after myocardial ischemic injury.

In the original article, Figs. 2, 3b, and 4b were published incorrectly.

Quercetin relieved diabetic neuropathic pain by inhibiting upregulated P2X4 receptor in dorsal root ganglia.

The upregulation of nociceptive ion channels expressed in dorsal root ganglia (DRG) contributes to the development and retaining of diabetic pain symptoms. The flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) is a component extracted from various fruits and vegetables and exerts anti-inflammatory, analgesic, anticarcinogenic, antiulcer, and antihypertensive effects. However, the exact mechanism underlying quercetin's analgesic action remains poorly understood. The aim of this study was to investigate the effects of quercetin on diabetic neuropathic pain related to the P2X4 receptor in the DRG of type 2 diabetic rat model. Our data showed that both mechanical withdrawal threshold and thermal withdrawal latency in diabetic rats treated with quercetin were higher compared with those in untreated diabetic rats. The expression levels of P2X4 messenger RNA and protein in the DRG of diabetic rats were increased compared with the control rats, while quercetin treatment significantly inhibited such enhanced P2X4 expression in diabetic rats. The satellite glial cells (SGCs) enwrap the neuronal soma in the DRG. Quercetin treatment also lowered the elevated coexpression of P2X4 and glial fibrillary acidic protein (a marker of SGCs) and decreased the upregulation of phosphorylated p38 mitogen-activated protein kinase (p38MAPK) in the DRG of diabetic rats. Quercetin significantly reduced the P2X4 agonist adenosine triphosphate-activated currents in HEK293 cells transfected with P2X4 receptors. Thus, our data demonstrate that quercetin may decrease the upregulation of the P2X4 receptor in DRG SGCs, and consequently inhibit P2X4 receptor-mediated p38MAPK activation to relieve the mechanical and thermal hyperalgesia in diabetic rats.

Involvement of purinergic 2X4 receptor in glycoprotein 120-induced pyroptosis in dorsal root ganglia.

Pyroptosis is a type of programmed cell death, displaying caspase-1-dependent and pro-inflammatory features. Purinergic 2X4 (P2X4 ) receptor activation in response to high-adenosine triphosphate release can induce inflammation. Envelope glycoprotein 120 (gp120) of human immunodeficiency virus type 1 is considered one of the primary pathogens leading to neuronal injury. In this study, we investigated the possible role of P2X4 receptor activation in gp120-triggered pyroptosis in cultured satellite glial cells (SGCs) of rat dorsal root ganglia (DRG). MTS assay, TdT-mediated dUTP Nick-end labeling assay, real-time RT-PCR, and western blotting et al. methods were used. The results indicated that the expression of P2X4 receptor in SGCs of DRG was up-regulated upon cultured with gp120 for 24 h. The highest decrease in viability of SGCs due to gp120 treatment was accompanied by marked increases of positive pyroptosis cells and cellular lactate dehydrogenase release, elevated levels of interleukin-1ß, interleukin-18, active caspase-1 and NOD-like receptor family, pyrin domain containing 1, and enhanced phosphorylation of p38MAPK. These abnormal changes because of gp120 were significantly inhibited and cell viability was markedly improved when SGCs of DRG were treated with short hairpin RNAs targeting P2X4 receptor. Our data suggest that silencing of P2X4 receptor may act effectively against gp120-induced pyroptosis mediated by the activation of NOD-like receptor family, pyrin domain containing 1 inflammasome and caspase-1 signaling in SGCs of DRG.

Expression and Regulation of Brain Natriuretic Peptide and Natriuretic Peptide Receptor A (NPR-A) in L6-S1 Dorsal Root Ganglia in a Rat Model of Chronic Nonbacterial Prostatitis.

BACKGROUND The study aimed to investigate the expression of brain natriuretic peptide (BNP) and natriuretic peptide receptor A (NPR-A) in L6-S1 dorsal root ganglia (DRG) in a rat model of chronic nonbacterial prostatitis (CNP). MATERIAL AND METHODS One hundred specific pathogen-free (SPF) male Sprague-Dawley rats were randomly divided into a control group (N=50) and a study group (N=50). The control group underwent prostatic injection of 0.1 ml of normal saline on days 3, 7, 10, 14, and 28. The study group, or rat model of CNP, underwent prostatic injection of 0.1 ml of complete Freund's adjuvant on days 3, 7, 10, 14, and 28. At the end of the study, the rats were euthanized, and the prostate tissues and L6-S1 DRG were removed. Histology was performed on the prostate tissue from the rats in the study group and control group. Real-time fluorescence-based quantitative polymerase chain reaction (PCR) and Western blot were used to study the expression of BNP and NPR-A mRNA and protein in the DRG from the rats in the study group and control group. RESULTS In the rat model of CNP, the expression of BNP and NPR-A were significantly increased in L6-S1 DRG compared with the controls. CONCLUSIONS In a rat model of CNP, the increased expression of BNP and NPR-A in L6-S1 DRG may have a role in pain signaling pathways associated with chronic prostatitis.

Role of hesperidin in P2X3 receptor-mediated neuropathic pain in the dorsal root ganglia.

Aim: This study investigated whether the neuronal P2X3 receptor in rat dorsal root ganglia (DRG) mediated the effects of hesperidin on neuropathic pain. Materials and methods: The chronic constriction injury (CCI) model was used as a model of neuropathic pain. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured. The mRNA and protein expression levels were assayed by real-time RT-PCR and Western blotting. Results: The results showed that mechanical and thermal hyperalgesia in the CCI rats were increased as compared to those in the sham group. The expression levels of P2X3 mRNA and protein in CCI rats were higher than those in the sham group. Dual-labelling immunofluorescence showed that the elevated P2X3 receptor was co-expressed with the neuronal marker NeuN in the DRG of CCI rats. Hesperidin treatment decreased both the mechanical and thermal hyperalgesia, and upregulated P2X3 expression in the CCI rats. Hesperidin treatment also reduced the ERK1/2 phosphorylation in the DRG of CCI rats. Moreover, hesperidin inhibited the P2X3 agonist ATP-induced currents in HEK293 cells transfected with the P2X3 plasmid. Therefore, hesperidin treatment could reverse the elevated expression of neuronal P2X3 receptor and reduce the activation of ERK1/2 in the DRG of CCI rats. Conclusions: Our findings suggested that hesperidin inhibited the nociceptive transmission mediated by the P2X3 receptor in neurons of DRG, and thus, relieved the mechanical and thermal hyperalgesia in CCI rats.

Downregulation of P2Y12 in the superior cervical ganglia alleviates abnormal sympathetic activity after myocardial ischemia.

Superior cervical ganglia (SCG) innervate the myocardium and participate in sympathoexcitatory transmission. P2Y12 receptor is expressed in satellite glial cells (SGCs). This study seeks to clarify whether the P2Y12 receptor is involved in the sympathoexcitation reflex after myocardial ischemia (MI). MI model was induced by occlusion of the left coronary artery. P2Y12 were assayed by real time PCR and Western blotting. Our results showed that expression levels of P2Y12 mRNA and protein were significantly higher in the MI group than in the sham group. Administration of P2Y12 short hairpin RNA (shRNA) caused downregulation of the P2Y12 receptor in the SCG. In MI rats plus P2Y12 shRNA treatment group, the abnormal changes in diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate (HR), electrocardiograms (ECGs), and cardiac tissue structures were alleviated. When the treatment of P2Y12 shRNA in MI rats, upregulated co-expression values of P2Y12 and glial fibrillary acidic protein (GFAP), the upregulation of tumor necrosis factor α (TNF-α) and phosphorylated P38 mitogen activated protein kinase (p-P38 MAPK) in the SCG were decreased. Downregulation of the P2Y12 receptor in the SCG after MI may improve cardiac function by alleviating the sympathoexcitatory reflex.

P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats.

Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin-1ß (IL-1ß) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL-1ß, and tumor necrosis factor-receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p-P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats.

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2',3'-dideoxycytidine.

The direct neurotoxicity of HIV and neurotoxicity of combination antiretroviral therapy medications both contribute to the development of neuropathic pain. Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in mechanical and thermal hyperalgesia. The P2Y12 receptor expressed in SGCs of the DRG is involved in pain transmission. In this study, we explored the role of the P2Y12 receptor in neuropathic pain induced by HIV envelope glycoprotein 120 (gp120) combined with ddC (2',3'-dideoxycytidine). A rat model of gp120+ddC-induced neuropathic pain was used. Peripheral nerve exposure to HIV-gp120+ddC increased mechanical and thermal hyperalgesia in gp120+ddC-treated model rats. The gp120+ddC treatment increased expression of P2Y12 receptor mRNA and protein in DRG SGCs. In primary cultured DRG SGCs treated with gp120+ddC, the levels of [Ca2+]i activated by the P2Y12 receptor agonist 2-(Methylthio) adenosine 5'-diphosphate trisodium salt (2-MeSADP) were significantly increased. P2Y12 receptor shRNA treatment inhibited 2-MeSADP-induced [Ca2+]i in primary cultured DRG SGCs treated with gp120+ddC. Intrathecal treatment with a shRNA against P2Y12 receptor in DRG SGCs reduced the release of pro-inflammatory cytokines, decreased phosphorylation of p38 MAPK in the DRG of gp120+ddC-treated rats. Thus, downregulating the P2Y12 receptor relieved mechanical and thermal hyperalgesia in gp120+ddC-treated rats.

Resveratrol-decreased hyperalgesia mediated by the P2X7 receptor in gp120-treated rats.

Background Chronic pain is a common symptom in human immunodeficiency virus (HIV)-1 infection/acquired immunodeficiency syndrome patients. The literature shows that the HIV envelope glycoprotein 120 (gp120) can directly cause hyperalgesia by stimulating primary sensory afferent nerves. The P2X7 receptor in the dorsal root ganglia (DRG) is closely related to neuropathic and inflammatory pain. In this study, we aimed to explore the effect of resveratrol (RES) on gp120-induced neuropathic pain that is mediated by the P2X7 receptor in the rat DRG. Results Mechanical hyperalgesia in rats treated with gp120 was increased compared with that in the sham group. The P2X7 expression levels in rats treated with gp120 were higher than those in the sham group. Co-localization of the P2X7 receptor and glial fibrillary acidic protein (GFAP, a marker of satellite glial cells [SGCs]) in the DRG SGCs of the gp120 group exhibited more intense staining than that of the sham group. RES decreased the mechanical hyperalgesia and P2X7 expression levels in gp120 treatment rats. Co-localization of the P2X7 receptor and GFAP in the gp120+ RES group was significantly decreased compared to the gp120 group. RES decreased the IL-1ß and TNF-α receptor (R) expression levels and ERK1/2 phosphorylation levels as well as increased IL-10 expression in the DRG of gp120-treated rats. Whole cell clamping demonstrated that RES significantly inhibited adenosine triphosphate-activated currents in HEK293 cells that were transfected with the P2X7 plasmid. Conclusions RES relieved mechanical hyperalgesia in gp120-treated rats by inhibiting the P2X7 receptor.

Co-expression changes of lncRNAs and mRNAs in the cervical sympathetic ganglia in diabetic cardiac autonomic neuropathic rats.

Cardiac autonomic neuropathy in Type 2 diabetes (T2D) is often a devastating complication. Long non-coding RNAs (lncRNAs) have important effects on both normal development and disease pathogenesis. In this study, we explored the expression profiles of some lncRNAs involved in inflammation which may be co-expressed with messenger RNA (mRNA) in superior cervical and stellate ganglia after type 2 diabetic injuries. Total RNA isolated from 10 pairs of superior cervical and stellate ganglia in diabetic and normal male rats was hybridized to lncRNA arrays for detections. Pathway analysis indicated that the most significant gene ontology (GO) processes that were upregulated in diabetes were associated with immune response, cell migration, defense response, taxis, and chemotaxis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that most of the target genes of the lncRNAs were located in cytokine-cytokine receptor interactions, the chemokine signaling pathway and cell adhesion molecules, which were involved in T2D. Gene co-expression network construction showed that the co-expression network in the experimental rats consisted of 268 regulation edges among 105 lncRNAs and 11 mRNAs. Our studies demonstrated the co-expression profile of lncRNAs and mRNAs in diabetic cardiac autonomic ganglia, suggesting possible roles for multiple lncRNAs as potential targets for the development of therapeutic strategies or biomarkers for diabetic cardiac autonomic neuropathy. © 2016 Wiley Periodicals, Inc.

Nanoparticle-encapsulated emodin decreases diabetic neuropathic pain probably via a mechanism involving P2X3 receptor in the dorsal root ganglia.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). More than 90% of all cases of DM belong to type 2 diabetes mellitus (T2DM). Emodin is the main active component of Radix et rhizoma rhei and has anti-bacterial, anti-viral, anti-ulcerogenic, anti-inflammatory, and anti-cancer effects. Nanoparticle encapsulation of drugs is beneficial for drug targeting and bioavailability as well as for lowering drug toxicity side effects. The aim of this study was to investigate the effects of nanoparticle-encapsulated emodin (nano emodin) on diabetic neuropathic pain (DNP) mediated by the Purin 2X3 (P2X3) receptor in the dorsal root ganglia (DRG). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values in T2DM rats were lower than those of control rats. MWT and TWL in T2DM rats treated with nano emodin were higher compared with those in T2DM rats. Expression levels of P2X3 protein and messenger RNA (mRNA) in the DRG of T2DM rats were higher than those of controls, while levels in T2DM rats treated with nano emodin were significantly lower than those of the T2DM rats. Phosphorylation and activation of ERK1/2 in the T2DM DRG were decreased by nano emodin treatment. Nano emodin significantly inhibited currents activated by the P2X3 agonist α,ß-meATP in HEK293 cells transfected with the P2X3 receptor. Therefore, nano emodin treatment may relieve DNP by decreasing excitatory transmission mediated by the DRG P2X3 receptor in T2DM rats.