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Ning Luo,1,* Yi-Chen Zeng,1,* Bai-Tian Fu,1 Je Wie Low,2 Jian-Qiao Fang1 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Institute of International Education of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian-Qiao Fang, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China, Email fangjianqiao7532@163.comIntroduction: Diabetic peripheral neuropathy (DPN) affects patients’ quality of life significantly. To date, selecting the appropriate treatment remains challenging. While electroacupuncture (EA) has shown promise as an effective adjunct therapy for DPN, and infrared thermography (IRT) has been considered as a potential predictor of treatment efficacy, the evidence for both remains inconclusive. As such, the objectives of this trial are twofold: to ascertain the efficacy of EA for DPN, and to explore the feasibility of IRT as an adjunctive objective tool for efficacy assessment.Methods: The study was designed as a randomized, parallel, controlled trial. It spanned over 6 weeks of treatment and an additional 4 weeks of follow-up. 104 eligible participants will be stratified for severity of disease: mild with Toronto clinical scoring system(TCSS) score 6– 8, moderate (TCSS score 9– 11), and severe (TCSS score 12– 19), and each level will be randomised in a 1:1 ratio into a EA group and waiting-list group. The waiting-list group received only the current conventional medication, while the EA group received an additional 12 EA sessions on top of the conventional medication. The primary outcome indicators is nerve conduction velocity (NCV), which will be tested at the baseline and week 6. Total clinical efficiency, TCSS, Clinical symptoms score of Traditional Chinese Medicine (TCM), Patient global impression of change(PGIC), Temperature of regions of interest (ROIs), and Physico chemical examination will be used as secondary outcome indicators. In addition, safety assessment will be determined based on adverse events during the trial.Conclusion: The expected results of this study will determine whether EA improves efficacy in the treatment of DPN with an acceptable safety profile, and investigating variations in the efficacy of EA across different levels of DPN severity. Furthermore, it will explore the viability of IRT as an objective measure for evaluating treatment effectiveness for DPN.Clinical Trial Registration: ClinicalTrials.gov identifier, NCT06054087.Keywords: electroacupuncture, waiting-list, diabetic peripheral neuropathy, clinical trial, infrared thermography

Yuanyuan Wu,1 Xinmiao Yao,2 Yongliang Jiang,1 Xiaofen He,1 Xiaomei Shao,1 Junying Du,1 Zui Shen,1 Qiaoying He,1 Jianqiao Fang1 1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China Abstract: Pain is considered a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component. The negative affective-motivational component of pain is different from the sensory component and amplifies the pain experience. Nowadays, a significant number of preclinical research groups have focused their attention on the affective symptoms of pain. In the present study, we investigated the pain aversion and anxiety-like behavior of the complete Freund’s adjuvant (CFA)-induced chronic pain model. CFA rats experienced spontaneous pain during pain-paired conditioning (pain aversion) and spontaneous pain produces an affective response (anxiety-like behavior). Moreover, pain aversion was gradually attenuated, while the anxiety-like behavior increased in 4 weeks. Therefore, although the negative effect (including pain aversion and anxiety) is always associated with hyperalgesia, the manifestations of negative effect may follow different time courses, which may influence the progress of primary disease. The findings illustrate that targeted therapy should focus on a specific aspect in different stages of pain. Our study emphasizes the necessity of using multiple tests to study pain comorbidities. Keywords: pain, pain aversion, pain affection, anxiety-like behavior, chronic inflammatory pain, rat

Study Objective: To investigate the efficacy and safety profiles of corticosteroid therapy in severe acute respiratory syndrome (SARS) patients.Design: Four hundred one of 1,278 SARS cases treated in Guangzhou China between December 2002 and June 2003 fulfilled the diagnostic criteria issued by the World Health Organization for confirmed identification of SARS. Among them, the diagnosis of critical SARS was defined by criteria of SARS guidelines incorporated with a low oxygenation index (OI) [< 300 mm Hg]. Data of these patients retrieved from a database were retrospectively analyzed by logistic regression and Cox regression for the effect of corticosteroid therapy on death, hospitalization days, and complication presentation.Results: Among the 401 SARS patients studied, 147 of 249 noncritical patients (59.0%) received corticosteroids (mean daily dose, 105.3 +/- 86.1 mg) [+/- SD], and all survived the disease; 121 of 152 critical patients (79.6%) received corticosteroids at a mean daily dose of 133.5 +/- 102.3 mg, and 25 died. Analysis of these 401 confirmed cases did not show any benefits of corticosteroid on the death rate and hospitalization days. However, when focused on 152 critical SARS cases, factors correlated with these end points indicated by univariate analysis included use of corticosteroid, age, rigor at onset, secondary respiratory infections, pulmonary rales, grading of OI, and use of invasive ventilation. After adjustment for possible confounders, treatment with corticosteroid was shown contributing to lower overall mortality, instant mortality, and shorter hospitalization stay (p < 0.05). Incidence of complications was significantly associated with the need for invasive ventilation but not with use of corticosteroids.Conclusion: This Guangzhou retrospective study revealed that proper use of corticosteroid in confirmed critical SARS resulted in lowered mortality and shorter hospitalization stay, and was not associated with significant secondary lower respiratory infection and other complications. [ABSTRACT FROM AUTHOR]

Background: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster infection and affects patients' quality of life. Acupuncture therapy is regarded as a competitive method of treatment for analgesia., Objective: To summarize evidence from systematic reviews (SRs) and evaluate the effectiveness and safety of different acupuncture therapies for treating PHN., Methods: Eight electronic databases were searched from their inception to August 5, 2022, including 4 international electronic databases (PubMed, EMBASE, the Cochrane Library, and Web of Science) and 4 Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, VIP Database and Wanfang Database). Methodological quality was assessed by A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2). The Risk of Bias in Systematic Review (ROBIS) tool was used to assess the risk of bias in SRs. Evidence level was assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Results: Totally, 7 SRs were included, including 128 studies and 9,792 patients. In AMSTAR 2, most of the SRs were of low or critically low levels since they had more than 1 critical deficiency. In ROBIS, 1 SR (14.29%) was rated as high risk, and the other 6 (85.71%) were rated as low risk. In the GRADE system, 9 outcomes (28.13%) were valued as high level, 5 (15.63%) as moderate level, 1 (3.13%) as low, and 17 (53.13%) as very low. In the effectiveness of acupuncture therapy, the group "moxibustion vs. original medical treatment" [mean difference (MD)=-1.44, 95% confidence interval (CI): -1.80 to -1.08, I 2 =99%, P<0.00001] was of the highest heterogeneity and the group "bloodletting vs. original medical treatment" (MD=-2.80, 95% CI: -3.14 to -2.46, I 2 =0, P<0.00001) was of the lowest heterogeneity. Six SRs have reported the safety of their studies and no serious events were shown in the treatment and control groups., Conclusions: Acupuncture therapy seems to be effective in treating PHN. Despite the evidence that suggested the advantages of acupuncture therapy in relieving pain and promoting efficacy and safety, the methodological quality was quite low. Further studies should pay more attention to the quality of original studies and evidence for SRs to confirm these findings. (PROSPERO registration No. CRD42022344790)., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Postpartum hemorrhage (PPH) is a common cause of maternal death worldwide, but data on PPH incidence and influencing factors for nulliparous and multiparous women is scarce. So, the study aimed to assess the differences in PPH incidence and influencing factors between nulliparous and multiparous women., Methods: A multicenter retrospective cohort study was conducted among women who gave birth at ≥ 28 weeks of gestation in Hunan Province, China, from January 2017 to December 2018. Logistic regression assessed PPH-influencing factors, and the receiver operating characteristic curve (ROC curve) assessed the predictive performance of identified factors., Results: A total of 144,845 postpartum women were included in the study. The incidence of PPH (blood loss ≥ 500 ml) was 2.1 % and 1.7 % for nulliparous and multiparous women, respectively. Among the nulliparous and multiparous women, similar influencing factors of PPH included erythrocyte suspension transfusion before childbirth, anemia, soft-birth canal avulsion, Cesarean-section, placenta abruption, and general anesthesia administration before birth. Thrombophlebitis was associated [aOR 18.46(1.67-20.31)] with PPH among only the nulliparous women, while instrument-assisted birth [aOR 1.95(1.16-3.28)] and gestational hypertension [aOR 1.57(1.13-2.19)] were associated with PPH among only the multiparous women. The areas under the ROC-curve for the overall-cohort, nulliparous, and multiparous groups were [0.829(0.821-0.838)], [0.828(0.815-0.840)] and [0.833(0.822-0.844)], respectively., Conclusion: PPH incidence is higher among nulliparous women than among multiparous women, but influencing factors vary relatively by parity. The study findings provide new insights into the use of different approaches to PPH prevention for nulliparous and multiparous women in clinical practice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Diabetic neuropathic pain (DNP) is a common and destructive complication of diabetes mellitus. The discovery of effective therapeutic methods for DNP is vitally imperative because of the lack of effective treatments. Although 2 Hz electroacupuncture (EA) was a successful approach for relieving DNP, the mechanism underlying the effect of EA on DNP is still poorly understood. Here, we established a rat model of DNP that was induced by streptozotocin (STZ) injection. P2X4R was upregulated in the spinal cord after STZ-injection. The upregulation of P2X4R was mainly expressed on activated microglia. Intrathecal injection of a P2X4R antagonist or microglia inhibitor attenuated STZ-induced nociceptive thermal hyperalgesia and reduced the overexpression of brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. We also assessed the effects of EA treatment on the pain hypersensitivities of DNP rats, and further investigated the possible mechanism underlying the analgesic effect of EA. EA relieved the hyperalgesia of DNP. In terms of mechanism, EA reduced the upregulation of P2X4R on activated microglia and decreased BDNF, IL-1β and TNF-α in the spinal cord. Mechanistic research of EA's analgesic impact would be beneficial in ensuring its prospective therapeutic effect on DNP as well as in extending EA's applicability., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: This study aims to explore the efficiency and effectiveness of a body area network-based smart bracelet for trauma care prior to hospitalization., Methods: To test the efficacy of the bracelet, an observational cohort study was conducted on the clinical data of 140 trauma patients pre-admission to the hospital. This study was divided into an experimental group receiving smart bracelets and a control group receiving conventional treatment. Both groups were randomized using a random number table. The primary variables of this study were as follows: time to first administration of life-saving intervention, time to first administration of blood transfusion, time to first administration of hemostatic drugs, and mortality rates within 24 h and 28 days post-admission to the hospital. The secondary outcomes included the amount of time before trauma team activation and the overall length of patient stay in the emergency room., Results: The measurement results for both the emergency smart bracelet as well as traditional equipment showed high levels of consistency and accuracy. In terms of pre-hospital emergency life-saving intervention, there was no significant statistical difference in the mortality rates between both groups within 224 h post-admission to the hospital or after 28-days of treatment in the emergency department. Furthermore, the treatment efficiency for the group of patients wearing smart bracelets was significantly better than that of the control group with regard to both the primary and secondary outcomes of this study. These results indicate that this smart bracelet has the potential to improve the efficiency and effectiveness of trauma care and treatment., Conclusion: A body area network-based smart bracelet combined with remote 5G technology can assist the administration of emergency care to trauma patients prior to hospital admission, shorten the timeframe in which life-saving interventions are initiated, and allow for a quick trauma team response as well as increased efficiency upon administration of emergency care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Han, Yuan, Li, Yang, Fang, Fan and Hou.)

Background: Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery. The effects of transcutaneous electrical acupoint stimulation (TEAS) remain unclear., Aim: To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection., Methods: Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive: (1) TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery, plus two 30-min daily sessions for 3 consecutive days after surgery (perioperative TEAS group); (2) Preoperative and intraoperative TEAS only; (3) Preoperative and postoperative TEAS only; or (4) Sham stimulation. The primary outcome was the time from the end of surgery to the first bowel sound., Results: In total, 441 patients were randomized; 405 patients (58.4 ± 10.2 years of age; 247 males) received the planned surgery. The time to the first bowel sounds did not differ among the four groups ( P = 0.90; log-rank test). On postoperative day 1, the rest pain scores differed significantly among the four groups ( P = 0.04; Kruskal-Wallis test). Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group (1.4 ± 1.2) than in the sham stimulation group (1.7 ± 1.1; P = 0.04). Surgical complications did not differ among the four groups., Conclusion: TEAS provided analgesic effects in adult patients undergoing major abdominal surgery, and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients., Competing Interests: Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: This study aimed to investigate the relationship between chronotypes and aggression in adolescents., Methods: A cross-sectional study was conducted on 755 primary and secondary school students aged 11-16 years in rural areas of Ningxia Province, China. The Chinese version of the Buss-Perry Aggression Questionnaire (AQ-CV) and the Chinese version Morningness-Eveningness Questionnaire (MEQ-CV) were used to assess the aggressive behavior and chronotypes of the study subjects. The Kruskal-Wallis test was then used to compare the differences in aggression among adolescents with different chronotypes, and Spearman correlation analysis to determine the relationship between chronotypes and aggression. Further linear regression analysis was used to investigate the effects of chronotype, personality traits, family environment, and class environment on adolescent aggression., Results: There were significant differences in chronotypes between different age groups and different sexes. Spearman correlation analysis showed that the MEQ-CV total score was negatively correlated with the AQ-CV total score (r = -0.263) and score of each AQ-CV subscale. In Model 1, chronotypes were negatively associated with aggression when controlling for age and sex, and evening-type adolescents might be more likely to exhibit aggressive behavior (b = -0.513, 95% CI: [-0.712, -0.315], P < 0.001); in Model 2, the negative association remained after controlling for family and class environment on the basis of Model 1 (b = -0.404, 95% CI: [-0.601, -0.208], P < 0.001); and in Model 3, the negative association still existed after controlling for personality traits on the basis of Model 2 (b = -0.383, 95% CI: [-0.577, -0.190], P < 0.001)., Conclusion: Compared to morning-type adolescents, evening-type adolescents were more likely to exhibit aggressive behavior. Given social expectations for MT adolescents, adolescents should be actively guided to develop a good circadian rhythm that may be more conducive to their physical and mental development., (© 2023. The Author(s).)

Introduction: Functional magnetic resonance imaging (fMRI) has shown that aging disturbs healthy brain organization and functional connectivity. However, how this age-induced alteration impacts dynamic brain function interaction has not yet been fully investigated. Dynamic function network connectivity (DFNC) analysis can produce a brain representation based on the time-varying network connectivity changes, which can be further used to study the brain aging mechanism for people at different age stages., Method: This presented investigation examined the dynamic functional connectivity representation and its relationship with brain age for people at an elderly stage as well as in early adulthood. Specifically, the resting-state fMRI data from the University of North Carolina cohort of 34 young adults and 28 elderly participants were fed into a DFNC analysis pipeline. This DFNC pipeline forms an integrated dynamic functional connectivity (FC) analysis framework, which consists of brain functional network parcellation, dynamic FC feature extraction, and FC dynamics examination., Results: The statistical analysis demonstrates that extensive dynamic connection changes in the elderly concerning the transient brain state and the method of functional interaction in the brain. In addition, various machine learning algorithms have been developed to verify the ability of dynamic FC features to distinguish the age stage. The fraction time of DFNC states has the highest performance, which can achieve a classification accuracy of over 88% by a decision tree., Discussion: The results proved there are dynamic FC alterations in the elderly, and the alteration was found to be correlated with mnemonic discrimination ability and could have an impact on the balance of functional integration and segregation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Jelfs, Mahmoud, Neville and Fang.)

Diabetic neuropathic pain (DNP) is frequent among patients with diabetes. We previously showed that P2X3 upregulation in dorsal root ganglia (DRG) plays a role in streptozotocin (STZ)-induced DNP but the underlying mechanism is unclear. Here, a rat model of DNP was established by a single injection of STZ (65 mg/kg). Fasting blood glucose was significantly elevated from the 1 st to 3 rd week. Paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) in diabetic rats significantly reduced from the 2 nd to 3 rd week. Western blot analysis revealed that elevated p-CaMKIIα levels in the DRG of DNP rats were accompanied by pain-associated behaviors while CaMKIIα levels were unchanged. Immunofluorescence revealed significant increase in the proportion of p-CaMKIIα immune positive DRG neurons (stained with NeuN) in the 2 nd and 3 rd week and p-CaMKIIα was co-expressed with P2X3 in DNP rats. KN93, a CaMKII antagonist, significantly reduce mechanical hyperalgesia and thermal hyperalgesia and these effects varied dose-dependently, and suppressed p-CaMKIIα and P2X3 upregulation in the DRGs of DNP rats. These results revealed that the p-CaMKIIα upregulation in DRG is involved in DNP, which possibly mediated P2X3 upregulation, indicating CaMKIIα may be an effective pharmacological target for DNP management., (© 2021. The Author(s).)

Diabetic neuropathic pain (DNP) is highly common in diabetes patients. P2X receptors play critical roles in pain sensitization. We previously showed that elevated P2X3 expression in dorsal root ganglion (DRG) contributes to DNP. However, the role of other P2X receptors in DNP is unclear. Here, we established the DNP model using a single high-dose streptozotocin (STZ) injection and investigated the expression of P2X genes in the DRG. Our data revealed elevated P2X2, P2X4, and P2X7 mRNA levels in DRG of DNP rats. The protein levels of P2X4 and P2X7 in DNP rats increased, but the P2X2 did not change significantly. To study the role of P2X4 and P2X7 in diabetes-induced hyperalgesia, we treated the DNP rats with TNP-ATP (2',3'-O-(2,4,6-trinitrophenyl)-adenosine 5'-triphosphate), a nonspecific P2X1-7 antagonist, and found that TNP-ATP alleviated thermal hyperalgesia in DNP rats. 2 Hz electroacupuncture is analgesic against DNP and could downregulate P2X4 and P2X7 expression in DRG. Our findings indicate that P2X4 and P2X7 in L4-L6 DRGs contribute to diabetes-induced hyperalgesia, and that EA reduces thermal hyperalgesia and the expression of P2X4 and P2X7., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Upregulation of P2X3 receptor (P2X3R) has been strongly implicated in nociceptive signaling including bone cancer pain (BCP). The present study, using rat bone cancer model, aimed to explore the role of P2X3R in regulating rat pain behavior under the intervention of electroacupuncture (EA). The BCP model was successfully established by injection with MRMT-1 breast cancer cell into the medullary cavity of left tibia for 3 × 10 4 cells/3 μL PBS in rats as revealed by obvious bone destruction, decreased paw withdrawal thresholds (PWTs), and reduced paw withdrawal latencies (PWLs). Western blot analyses showed that P2X3R expression was significantly upregulated in ipsilateral lumbar 4-6 (L4-6) dorsal root ganglia (DRG), but the difference not seen in spinal cord dorsal horn (SCDH). With the in-depth study of P2X3R activation, we observed that intrathecal injection of P2X3R agonist α,β-meATP aggravated MRMT-1 induced BCP, while injection of P2X3R inhibitor A-317491 alleviated pain. Subsequently, we demonstrated that BCP induced mechanical allodynia and thermal hyperalgesia were attenuated after EA treatment. Under EA treatment, total P2X3R protein expression in ipsilateral DRGs was decreased, and it is worth mentioning that decreased expression of P2X3R membrane protein, which indicated that both the expression and membrane trafficking of P2X3R were inhibited by EA. The immunofluorescence assay showed that EA stimulation exerted functions by reducing the expression of P2X3R-positive cells in ipsilateral DRGs of BCP rats. Ca 2+ imaging analysis revealed that the EA stimulation decreased the percentage of α,β-meATP responsive neurons in DRGs and inhibited calcium influx. Notably, the inhibitory effect of EA on mechanical allodynia and nociceptive flinches was abolished by intrathecal injection of α,β-meATP. These findings demonstrated EA stimulation ameliorated mechanical allodynia and thermal hyperalgesia in rat model of MRMT-1-induced BCP. EA exerts analgesic effect on BCP by reducing the overexpression and functional activity of P2X3R in ipsilateral DRGs of BCP rats. Our work first demonstrates the critical and overall role of P2X3R in EA's analgesia against peripheral sensitization of MRMT-1-induced BCP and further supports EA as a potential therapeutic option for cancer pain in clinic., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: This study was aimed at investigating the carrier rate of, and molecular variation in, α- and β-globin gene mutations in Hunan Province., Methods: We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province. Hematological screening was performed, and molecular parameters were assessed., Results: The overall carrier rate of thalassemia was 7.1%, including 4.83% for α-thalassemia, 2.15% for β-thalassemia, and 0.12% for both α- and β-thalassemia. The highest carrier rate of thalassemia was in Yongzhou (14.57%). The most abundant genotype of α-thalassemia and β-thalassemia was -α 3.7 /αα (50.23%) and β IVS-II-654 /β N (28.23%), respectively. Four α-globin mutations [CD108 (ACC>AAC), CAP +29 (G>C), Hb Agrinio and Hb Cervantes] and six β-globin mutations [CAP +8 (C>T), IVS-II-848 (C>T), -56 (G>C), beta nt-77 (G>C), codon 20/21 (-TGGA) and Hb Knossos] had not previously been identified in China. Furthermore, this study provides the first report of the carrier rates of abnormal hemoglobin variants and α-globin triplication in Hunan Province, which were 0.49% and 1.99%, respectively., Conclusion: Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population. The results should facilitate genetic counselling and the prevention of severe thalassemia in this region., (Copyright © 2023 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Diabetic neuropathic pain (DNP) is a common complication of diabetes. Streptozotocin (STZ)-induced changes of protein in dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) are critical for DNP genesis. However, which proteins change remains elusive. Here, the DNP model was established by a single intraperitoneal injection of STZ, accompanied by increased fasting blood glucose (FBG), decreased body weight (BW), and decreased paw withdrawal latency (PWL). Proteins change in L4-L6 DRGs and SCDH of rats were detected. Western blot and immunofluorescence results showed that expression levels of phosphorylated protein kinase C (p-PKC), transient receptor potential vanilloid-1 (TRPV1), Substance P (SP) and calcitonin gene-related peptide (CGRP) in the DRG and the SCDH of rats were increased after STZ injection. A preliminary study from our previous study showed that 2 Hz electroacupuncture (EA) effectively alleviates DNP. However, the analgesic mechanism of EA needs further elucidation. Here, EA at the bilateral Zusanli (ST36) and KunLun (BL60) acupoints was applied for one week, and to investigate the effect on DNP. EA reversed thermal hyperalgesia in DNP rats and downregulated the expression of p-PKC, TRPV1, SP, and CGRP in DRG and SCDH., Competing Interests: The authors declare no conflicts of interest for this work., (Copyright © 2023 Yi-qi Ma et al.)

Inflammation and oxidative stress are among the leading causes of poor prognosis after peripheral nerve injury (PNI). Urolithin-A (UA), an intermediate product produced by the catabolism of ellagitannins in the gastrointestinal tract, has anti-inflammatory, antioxidant, and immunomodulatory properties for inflammation, oxidative damage, and aging-related diseases. Hence, we prepared UA-loaded hydrogels and embedded them in the lumen of PCL nerve guide conduits (NGCs). The hydrogels continuously released appropriate doses of UA into the microenvironment. Based on in vitro studies, UA facilitates cell proliferation and reduces oxidative damage. Besides, the experimental evaluation revealed good biocompatibility of the materials involved. We implanted NGCs into rat models to bridge the sciatic nerve defects in an in vivo study. The sciatic functional index of the PCL/collagen/UA group was comparable to that of the autograft group. Additionally, the consequences of electrophysiological, gastrocnemius muscle and nerve histology assessment of the PCL/collagen/UA group were better than those in the PCL and PCL/collagen groups and close to those in the autograft group. In this study, UA sustained release via the PCL/collagen/UA NGC was found to be an effective alternative treatment for PNI, validating our hypothesis that UA could promote regeneration of nerve tissue.

An electrical signal is the key basis of normal physiological function of the nerve, and the stimulation of the electric signal also plays a very special role in the repair process of nerve injury. Electric stimulation is shown to be effective in promoting axonal regeneration and myelination, thereby promoting nerve injury repair. At present, it is considered that electric conduction recovery is a key aspect of regeneration and repair of long nerve defects. Conductive neural scaffolds have attracted more and more attention due to their similar electrical properties and good biocompatibility with normal nerves. Herein, PCL and MXene-PCL nerve guidance conduits (NGCs) were prepared; their effect on nerve regeneration was evaluated in vitro and in vivo . The results show that the NGCs have good biocompatibility in vitro . Furthermore, a sciatic nerve defect model (15 mm) of SD rats was made, and then the fabricated NGCs were implanted. MXene-PCL NGCs show similar results with the autograft in the sciatic function index, electrophysiological examination, angiogenesis, and morphological nerve regeneration. It is possible that the conductive MXene-PCL NGC could transmit physiological neural electric signals, induce angiogenesis, and stimulate nerve regeneration. This paper presents a novel design of MXene-PCL NGC that could transmit self-originated electric stimulation. In the future, it can be combined with other features to promote nerve regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nan, Lin, Wang, Jin, Fang, Xu, Liu, Zhang, Wu, Zhou, Chen, Cao, Wang and Liu.)

Background: The neurodevelopmental model of obsessive-compulsive disorder (OCD) suggests that the neurodevelopmental changes in the ventral striatal circuit of the prefrontal lobe are associated with the initial symptoms of OCD. Facial morphology is one of the most consistent anatomical phenotypes of neurodevelopmental disorders, which can reflect brain structure and function. Facial deformity, an easily measured index of brain malformation, can reflect abnormal brain structure and function. Therefore, this study aims to explore the relationship between clinical features and neurodevelopment of adolescents with OCD through facial morphology., Methods: The enrolled study sample comprised 40 adolescents diagnosed with OCD using the Obsessive Compulsive Inventory-Child Version (OCI-CV) and 38 healthy controls (HCs). Facial photos, 21 facial diameters, and 9 facial angles were collected using image software., Results: In males, lower lip red height was significantly lower in OCD patients than in HCs (P < 0.025); no significant differences were observed in other facial indicators (all P > 0.025). In females, the nasolabial angle was smaller in OCD patients than in HCs (P < 0.025); no significant differences were observed in other facial indicators (all P > 0.025). The difference in lower lip red height between the OCD group and HC group was positively correlated with neutralizing symptoms (r = 0.401, P < 0.05)., Conclusions: Male OCD patients had a thinner lower lip and female OCD patients had smaller nasolabial angles. The facial features of adolescents with OCD were positively correlated with lower lip redness and neutralizing symptoms., (© 2021. The Author(s).)

Opiates produce a strong rewarding effect, but abstinence from opiate use emerges with severe negative emotions. Depression is one of the most frequent emotion disorders associated with opiate abstinence, which is thought to be a main cause for relapse. However, neurobiological bases of such an aversive emotion processing are poorly understood. Here, we find that morphine abstinence activates κ-opioid receptors (KORs) by increasing endogenous KOR ligand dynorphin expression in the amygdala, which in turn facilitates glutamate transporter 1 (GLT1) expression by activation of p38 mitogen-activated protein kinase (MAPK). Upregulation of GLT1 expression contributes to opiate-abstinence-elicited depressive-like behaviors through modulating amygdalar glutamatergic inputs to the nucleus accumbens (NAc). Intra-amygdala injection of GLT1 inhibitor DHK or knockdown of GLT1 expression in the amygdala significantly suppresses morphine-abstinence-induced depressive-like behaviors. Pharmacological and pharmacogenetic activation of amygdala-NAc projections prevents morphine-abstinence-induced behaviors. Overall, our study provides key molecular and circuit insights into the mechanisms of depression associated with opiate abstinence., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABA A R agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABA A R antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety., (© 2021. The Author(s).)

TcpC is a multifunctional virulence factor of uropathogenic E. coli (UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we show the influence of TcpC on NETosis and related mechanisms. We show NETosis in the context of a pyelonephritis mouse model induced by TcpC-secreting wild-type E. coli CFT073 (CFT073 wt ) and LPS-induced in vitro NETosis with CFT073 wt or recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses show that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase., Competing Interests: The authors have declared that no competing interests exist.

Background: Since the 1990s, families from the ecologically hostile mountainous southern areas of Ningxia Province, China, have been migrating to the northern areas of the province. This study compared the prevalence of behavioral problems among migrant adolescents to those among host adolescents (adolescents from the northern areas) and adolescents in the region of origin (adolescents from the southern areas), to determine whether ecological migration is related to adolescent behavioral problems, and possible changes in such problems over time., Methods: We used the Children and Adolescents Ecological Migration Survey on Mental Health, administered to 4805 students aged 12-16 years and their parents between 2012 and 2014 (W1), of whom 1753 students and their parents completed the follow-up between 2014 and 2017 (W2). Parents answered questions related to adolescent behavioral problems, main source of family income, parents' desire to reverse migrate, improved standard of living, and parents' educational attainment, while children completed the Eysenck Personality Questionnaire and a classroom environment questionnaire., Results: The prevalence of behavioral problems among the migrant adolescents (28.04%) was significantly higher than among host adolescents (21.59%) or adolescents in the region of origin (24.37%; p < 0.001) at W1. After adjusting for gender and age, parents' work outside the home was the main source of family income (OR = 1.42, 95% CI = 1.13-1.78), and adolescents' learning burden (OR = 1.04, 95% CI = 1.01-1.06) in school negatively influenced behavioral problems. Strong student-teacher relationships (OR = 0.97,95% CI = 0.94-0.99) and parents who had no intention to move back to the original residence (OR = 0.70, 95% CI = 0.52-0.94) exerted a protective effect at W1; at W2, a protective effect was associated with improved living conditions (OR = 0.39-0.55, 95% CI = 0.25-0.84). The extent of behavioral problems among migrant adolescents significantly decreased after two years., Conclusion: Ecological migration will increase children's behavioral problems in the early stage, with various factors influencing the extent of these problems.

Background: This study aimed to observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on bone metastasis pain, anxiety and immune function in cancer patients., Methods: A total of 127 patients with bone metastasis pain from malignant tumors were treated with TEAS or drugs. The TEAS group comprised of 62 patients, while the drug control group comprised of 65 patients. The differences in general indexes, baseline pain and anxiety between these two groups were not statistically significant., Results: Compared with those before treatment, the visual analog scale (VAS) scores of patients in the TEAS group and drug control group decreased after treatment, and the differences were statistically significant. The degrees of pain relief after treatment were similar between the two groups. Anxiety improved in both the TEAS group and drug control group, and the difference between these two groups was not statistically significant. The differences in immune indexes, B cell and CD8 between the TEAS group and drug control group were statistically significant. TEAS treatment could improve the declining trend of CD8 in patients., Conclusions: TEAS treatment and drug treatment can effectively alleviate mild to moderate pain in patients, and the efficacy of these two groups is similar. The treatment for moderate and severe pain needs to be combined with drug treatment to achieve a control effect. TEAS can improve the anxiety and immune function of patients, and prevent the decrease in B cells and CD8 in patients treated with drugs alone.

Objective: The aim of this study was to evaluate the effectiveness of traditional Chinese medicine- (TCM-) guided dietary interventions in improving yang-qi deficiency and yin-blood deficiency TCM syndromes according to the principles of TCM syndrome differentiation theory in male youths undergoing drug detoxification during the rehabilitation period who stayed in a compulsory isolation detoxification center., Methods: Male youths undergoing drug detoxification who met the criteria to be included in the study were randomly divided into the intervention group ( n  = 62) and the control group ( n  = 61) according to a random number table in a 1 : 1 ratio. The intervention group received a TCM-guided diet, and the control group received routine food support. Over an intervention period of 3 months, we observed changes in the TCM syndrome element scores in the two groups before and after intervention., Results: After 3 months, the qi deficiency, yin deficiency, blood deficiency, and yin-blood deficiency syndrome in the intervention group improved significantly ( P values 0.009, 0.000, 0.005, and 0.001, respectively). In the control group, yang deficiency, qi deficiency, and yang-qi deficiency syndromes worsened significantly ( P values 0.003, 0.032, and 0.009, respectively). The differences (post-pre) in yang deficiency, qi deficiency, yang-qi deficiency, yin deficiency, blood deficiency, and yin-blood deficiency syndromes between the two groups were statistically significant ( P values 0.003, 0.003, 0.003, 0.001, 0.005, and 0.002, respectively)., Conclusion: A TCM-guided diet can delay the worsening of yang-qi deficiency syndrome symptoms and improve yin-blood deficiency syndrome and the prognosis of male youth undergoing drug detoxification during the rehabilitation period., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Li-wan Zhang et al.)

Background: Acupuncture stimulation at GV26 during the acute phase of cerebral ischaemia can effectively reduce brain damage induced by ischaemic injury. However, the time course of the effects of acupuncture stimulation has not yet been thoroughly studied., Objective: To investigate the effects of manual acupuncture (MA) on glutamic acid (Glu) and γ-aminobutyric acid (GABA) expression in the cerebrospinal fluid of rats with middle cerebral artery occlusion (MCAO) and determine whether there is a temporal effect of acupuncture on the treatment of cerebral ischaemia., Methods: We performed thread occlusion of the right middle cerebral artery in rats to establish an animal model of MCAO. Simultaneously, during acupuncture treatment, microdialysis was used to continuously and dynamically observe immediate alterations in amino acid metabolism with acupuncture stimulation after cerebral ischaemia in vivo in this rat model of MCAO., Results: We found that, in comparison with an untreated MCAO group, Glu content was significantly decreased during the first acupuncture stimulation and during the course of the acupuncture treatment in the MCAO+MA group (MCAO vs MCAO+MA: day 1, P=0.032; day 2, P=0.021; day 3, P=0.017). These findings were also seen after the end of treatment when acupuncture was no longer applied (MCAO vs MCAO+MA: day 7, P=0.009). Measurements of GABA content following cerebral ischaemic injury showed that GABA peaks 24 hours after damage, falls thereafter and decreases to baseline levels on day 7. In the MCAO+MA group, GABA content on days 1 to day 2 was lower than in the MCAO group (MCAO+MA vs MCAO: day 1, P=0.003; day 2, P=0.001), although it was higher than in the control group (MCAO+MA vs control: day 1, P=0.024; day 2, P=0.009). GABA content on day 3 and day 7 was higher in the MCAO+MA group than in the MCAO group and the control group (MCAO+MA vs MCAO: day 3, P=0.008; day 7, P=0.013; MCAO+MA vs control: day 3, P=0.002; day 7, P=0.009)., Conclusion: Acupuncture stimulation at GV26 can effectively decrease excessive release of Glu induced by ischaemia and maintain the endogenous inhibitory activity of GABA. This phenomenon was seen during the entire course of acupuncture treatment and continued for some time after the end of acupuncture treatment.

Many bacterial pathogens can cause septicemia and spread from the bloodstream into internal organs. During leptospirosis, individuals are infected by contact with Leptospira -containing animal urine-contaminated water. The spirochetes invade internal organs after septicemia to cause disease aggravation, but the mechanism of leptospiral excretion and spreading remains unknown. Here, we demonstrated that Leptospira interrogans entered human/mouse endothelial and epithelial cells and fibroblasts by caveolae/integrin-β1-PI3K/FAK-mediated microfilament-dependent endocytosis to form Leptospira (Lep)-vesicles that did not fuse with lysosomes. Lep-vesicles recruited Rab5/Rab11 and Sec/Exo-SNARE proteins in endocytic recycling and vesicular transport systems for intracellular transport and release by SNARE-complex/FAK-mediated microfilament/microtubule-dependent exocytosis. Both intracellular leptospires and infected cells maintained their viability. Leptospiral propagation was only observed in mouse fibroblasts. Our study revealed that L. interrogans utilizes endocytic recycling and vesicular transport systems for transcytosis across endothelial or epithelial barrier in blood vessels or renal tubules, which contributes to spreading in vivo and transmission of leptospirosis., Competing Interests: YL, KL, WH, DO, JF, SL, XL, JY No competing interests declared, (© 2019, Li et al.)

Background: Patients with functional chronic constipation (CFC) often select nonpharmacological treatments. We aimed to examine the comparative effectiveness of nonpharmacological conservative treatments in treating CFC., Methods: We searched MEDLINE, EMBASE, Cochrane library, CINAHL, AMED, ISI web of knowledge, and conference proceedings from January 2000 to June 2016. Randomized controlled trials comparing nonpharmacological conservative treatments with placebo, sham interventions, or conventional treatments were included. Nonpharmacological conservative treatments were defined as interventions without involvement of medication or surgery. We extracted trial data in duplicate and assessed the risk of bias. We pooled continuous data using standard mean differences (SMDs) and binary data using risk ratios (RRs), and we provided their 95% confidence intervals., Key Results: We included 33 trials (4324 participants and 8 nonpharmacological treatments). Compared with placebo interventions, TENS (SMD 1.60, 95% CI 0.28-2.92), probiotic (SMD 1.40, 95% CI 0.94-1.86), and acupuncture (SMD 1.00, 95% CI 0.39-1.60) had significantly larger effect on stool frequency; acupuncture (RR 1.56, 95% CI 1.14-2.14) had significantly higher responder rate; and moxibustion (SMD 2.50, 95% CI 0.05-4.95) had significant larger effect on Bristol score. Compared with laxative, acupuncture had significantly larger effect on stool frequency (RR 2.01, 95% CI 1.16-3.49) and had lower rate of adverse events (RR 0.38, 95% CI 0.18-0.80)., Conclusions: TENS and acupuncture relatively ranked the best in managing CFC, but the results should be interpreted with caution due to small study effects. Registration number: PROSPERO CRD42014006686., (© 2018 John Wiley & Sons Ltd.)

Painful diabetic neuropathy (PDN) is a common and troublesome diabetes complication. Protein kinase C (PKC)-mediated dorsal root ganglia (DRG) P2X3 receptor upregulation is one important mechanism underlying PDN. Accumulating evidence demonstrated that electroacupuncture (EA) at low frequency could effectively attenuate neuropathic pain. Our previous study showed that 2-Hz EA could relieve pain well in PDN. The study aimed to investigate whether 2-Hz EA relieves pain in PDN through suppressing PKC-mediated DRG P2X3 receptor upregulation. A 7-week feeding of high-fat and high-sugar diet plus a single injection of streptozotocin (STZ) in a dose of 35 mg/kg after a 5-week feeding of the diet successfully induced type 2 PDN in rats as revealed by the elevated body weight, fasting blood glucose, fasting insulin and insulin resistance, and the reduced paw withdrawal threshold (PWT), as well as the destructive ultrastructural change of sciatic nerve. DRG plasma membrane P2X3 receptor level and DRG PKC expression were elevated. Two-hertz EA failed to improve peripheral neuropathy; however, it reduced PWT, DRG plasma membrane P2X3 receptor level, and DRG PKC expression in PDN rats. Intraperitoneal administration of P2X3 receptor agonist αβ-meATP or PKC activator phorbol 12-myristate 13-acetate (PMA) blocked 2-Hz EA analgesia. Furthermore, PMA administration increased DRG plasma membrane P2X3 receptor level in PDN rats subject to 2-Hz EA treatment. These findings together indicated that the analgesic effect of EA in PDN is mediated by suppressing PKC-dependent membrane P2X3 upregulation in DRG. EA at low frequency is a valuable approach for PDN control.

Backgroud: Leptospira interrogans is the major causative agent of leptospirosis, a worldwide zoonotic disease. Hemorrhage is a typical pathological feature of leptospirosis. Binding of von Willebrand factor (vWF) to platelet glycoprotein-Ibα (GPIbα) is a crucial step in initiation of platelet aggregation. The products of L. interrogans vwa-I and vwa-II genes contain vWF-A domains, but their ability to induce hemorrhage has not been determined., Methods: Human (Hu)-platelet- and Hu-GPIbα-binding abilities of the recombinant proteins expressed by L. interrogans strain Lai vwa-I and vwa-II genes (rLep-vWA-I and rLep-vWA-II) were detected by flowcytometry, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Hu-platelet aggregation and its signaling kinases and active components were detected by lumiaggregometry, Western analysis, spectrophotometry and confocal microscopy. Hu-GPIbα-binding sites in rLep-vWA-I and rLep-vWA-II were identified by SPR/ITC measurements., Findings: Both rLep-vWA-I and rLep-vWA-II were able to bind to Hu-platelets and inhibit rHu-vWF/ristocetin-induced Hu-platelet aggregation, but Hu-GPIbα-IgG, rLep-vWA-I-IgG and rLep-vWA-II-IgG blocked this binding or inhibition. SPR and ITC revealed a tight interaction between Hu-GPIbα and rLep-vWA-I/rLep-vWA-II with K D values of 3.87 × 10 -7 -8.65 × 10 -8  M. Hu-GPIbα-binding of rL-vWA-I/rL-vWA-II neither activated the PI3K/AKT-ERK and PLC/PKC kinases nor affected the NO, cGMP, ADP, Ca 2+ and TXA 2 levels in Hu-platelets. G13/R36/G47 in Lep-vWA-I and G76/Q126 in Lep-vWA-II were confirmed as the Hu-GPIbα-binding sites. Injection of rLep-vWA-I or rLep-vWA-II in mice resulted in diffuse pulmonary and focal renal hemorrhage but this hemorrhage was blocked by rLep-vWA-I-IgG or rLep-vWA-II-IgG., Interpretation: The products of L. interrogans vwa-I and vwa-II genes induce hemorrhage by competitive inhibition of vWF-mediated Hu-platelet aggregation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypothesis: Electroacupuncture (EA) has been used as an alternative analgesic therapy for hundreds of years, yet its analgesic potency and therapeutic advantage against bone cancer pain (BCP) in comparison with morphine remains unclear. This study aimed to investigate the effects of EA on mechanical allodynia and cellular immunity of BCP rats, and to further explore the potential mechanism., Methods: The BCP model was established by implanting Walker 256 mammary gland carcinoma cells into the left tibia of adult female Sprague-Dawley rats. EA (dilatational wave, 2/100 Hz, 0.5 mA-1mA-1.5 mA for 10 minutes each intensity) was applied bilaterally to Zusanli (ST 36) and Kunlun (BL 60) for 30 minutes. Both EA stimulation and morphine (10 mg/kg, intraperitoneally) was given once every other day. Naloxone (0.3 mg/kg, intraperitoneally) was injected at 30 minutes prior to EA. Mechanical allodynia were demonstrated by paw withdrawal thresholds (PWTs) which measured by dynamic plantar aesthesiometer. T cell proliferation, percentage of CD3 + , CD4 + and CD8 + T lymphocytes in spleen as well as expression of interleukin-2 (IL-2) in plasma were detected by WST-8, flow cytometry, and enzyme-linked immunosorbent assay technique, respectively., Results: An intratibial inoculation of Walker 256 mammary gland carcinoma cells significantly decreased PWTs to mechanical stimuli. EA stimulation alleviated mechanical allodynia in BCP rats, and the analgesic potency of EA was weaker than that of morphine. In contrast to morphine, EA stimulation of BCP rats increased splenic concanavalin A (Con A)-induced T cell proliferation and plasma IL-2 content, as well as increased the percentages of splenic CD 3 + CD 4 + and CD 3 + CD 8 + T cell subsets. Moreover, both the analgesic effect and the partial immunomodulation of EA were suppressed by an intraperitoneal injection of naloxone., Conclusion: EA could significantly alleviate BCP-induced mechanical allodynia. Although the analgesic effect of EA was weaker than that of morphine, EA had an immunomodulation effect on cellular immunity. Both analgesic and immunomodulatory effect of EA might share the same mechanism via the opioid-mediated pathway, which needs further investigation.

Aims: Observing the parameter-specific anti-hyperalgesic effects of EA with different stimulation times and frequencies on painful hyperalgesia mediated by the level of TRPV1 and P2X3 expression in DRG after CFA injection., Main Methods: The model was induced by the injection of CFA in each rat's right hind paw. EA treatment was applied to the bilateral ST36 and BL60. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested with Von Frey filaments and the radiant heat source of the test instrument, respectively. TRPV1 and P2X3 expressions were measured by immunofluorescence and western blot. αβ-meATP and capsaicine combined with EA were further utilized to investigate the change in PWL., Key Findings: Different stimulation times (20, 30, 45 min) combined with different frequencies (2 Hz, 100 Hz, 2/100 Hz) of EA have analgesic effects on the PWT and PWL; however, the level of the hypoalgesic efficacy of EA was primarily associated with EA frequency. The analgesic effect of EA was better at 100 Hz than at 2 Hz. The level of regulation of 100 Hz EA on TRPV1 and P2X3 in DRG was greater than that of 2 Hz. Furthermore, both TRPV1 agonist and P2X3 agonist may impair the level of EA analgesia., Significance: EA has a parameter-specific effect on chronic inflammatory pain relief, which primarily depend on the stimulation frequency and not on the stimulation time at a certain stimulation time. The parameter-specific analgesic effect of EA is at least partially related to mediation of the protein level of TRPV1 and P2X3 expression in DRG of CFA rats., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mas-related G-protein-coupled receptor C (MrgprC) plays an important role in modulating chronic inflammatory pain. Electroacupuncture (EA) has a satisfactory analgesic effect on chronic pain. This study aimed to investigate the involvement of MrgprC and its transient receptor potential vanilloid 1 (TRPV1) pathway in EA analgesia in chronic inflammatory pain. Chronic inflammatory pain was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the left hind paw. EA (2/100 Hz) stimulation was administered. MrgprC siRNAs were intrathecally administered to inhibit MrgprC expression, and bovine adrenal medulla 8-22 (BAM8-22) was used to activate MrgprC. The mechanical allodynia was decreased by EA significantly since day 3. The piled analgesic effect of EA was partially blocked by 6 intrathecal administrations of MrgprC siRNA. Both EA and BAM8-22 could downregulate the expression of TRPV1 and PKC in both the DRG and the SCDH. Both EA and BAM8-22 could also decrease the TRPV1 translocation and p-TRPV1 level in both the DRG and the SCDH. The effects of EA on PKC ε , TRPV1 translocation, and p-TRPV1 in both the DRG and the SCDH were reversed by MrgprC siRNA. The results indicated that MrgprC played crucial roles in chronic pain modulation and was involved in EA analgesia partially through the regulation of TRPV1 function at the DRG and SCDH levels.

The regioselective demethoxylation and dehalogenation of dihalogenated dibenzocyclooctadiene lignans derivatives were realized in a one-step reaction with excellent yields in the sodium and t-butanol reaction system.

The pain-depression dyad is becoming widespread in the clinic and is attracting increasing attention. A previous study by our group found that 100-Hz electro-acupuncture (EA), but not 2-, 50- and 2/100-Hz EA, was effective against the reserpine-induced pain-depression dyad. This finding is in contrast to the fact that low-frequency EA is commonly used to treat supraspinal-originating diseases. The present study aimed to investigate the mechanism underlying the effects of 100-Hz EA on the pain-depression dyad. Repeated reserpine injection was found to induce allodynia and depressive behaviors in rats. It decreased 5-hydroxytryptamine (5-HT) levels and immunoreactive expressions in the dorsal raphe nucleus (DRN). 100-Hz EA alleviated the pain-depression dyad and upregulated 5-HT in the DRN of reserpine-injected rats. Intracerebroventricular injection of para-chlorophenylalanine, an inhibitor of 5-HT resynthesis, suppressed the upregulation of 5-HT in the DRN by 100-Hz EA and partially counteracted the analgesic and anti-depressive effects of 100-Hz EA. The present study was the first to demonstrate that 5-HT in the DRN is involved in mediating the analgesic and anti-depressive effects of 100-Hz EA on the pain-depression dyad. This finding provided a scientific basis for high-frequency EA as a potential treatment for the pain-depression dyad.

Background: There are no generally accepted standards for evaluation of treatment outcomes in traditional Chinese medicine (TCM). Pattern differentiation and individual treatments are recognized as the most distinguishing features of TCM. Therefore, how practitioners determine curative effects is an issue worthy of research, though little has been done in this area up to this point. This study examines perceptions of the effectiveness of TCM treatments and the means of evaluating clinical outcomes from the practitioners' perspective., Methods: Qualitative analysis of semi-structured interviews., Results: A total of nine TCM practitioners from three university-affiliated hospitals and two scientific institutions participated in the interviews in August 2013. Participants reported evaluation of periodical treatment as an important part of the process of individual treatment based on pattern differentiation. Themes included (1) ways of evaluating treatment outcomes; (2) relationships between treatment outcomes and pathological transformation; and (3) distinguishing manifestations of the healing process from true adverse reactions. These considerations helped determine the optional treatment principles for further follow-up. An additional theme emerged related to the characteristics of diagnosis and treatment in TCM., Conclusions: Health professionals considered all of the following as important ways of evaluating TCM treatment outcomes: patients' input and subjective experience, physicians' intake and examination, laboratory tests and medical device measurements. Pathological conditions were determined based on all the above factors, and no single factor determined the effectiveness from the practitioners' perspectives. If the patients felt no significant beneficial effects, then it was necessary to judge the effectiveness from adverse effect. The follow-up measures were usually based on the previous treatment, and physicians' satisfaction with each phase of TCM treatment was a significant factor in the process of making further decisions.

Background: The effect of electroacupuncture (EA) is affected by both the acupuncture point selection and the frequency of stimulation. However, little is known regarding acupuncture point and simulation frequency selection. Neuronal activation of the nucleus of the solitary tract (NTS) is one of the important targets of EA for modulating gastrointestinal function. This study investigated the effects of various combinations of EA frequencies and acupuncture points on NTS neurons., Methods: Rats were randomly divided into normal, 2 Hz EA, 100 Hz EA and the alternate 2/100 Hz EA groups. Then rats in each group were randomly divided into the following two subgroups according to the acupuncture point: ST 36 group and ST 25 group. All the rats underwent electrode implantation surgery. Rats in all EA groups received one treatment with EA (a constant square wave at, 2 Hz,100 Hz or 2/100 Hz frequencies with intensities ranging from 1 to 2 mA), and NTS neuronal activation was recorded before and after EA treatment. Finally, to confirm the effect of EA on the NTS, minimal acupuncture was administered and its effect on NTS was detected., Results: ST 36 stimulated with 2 Hz EA significantly increased the population of excited NTS neurons and spike frequency. However, ST 36 stimulated with 100 Hz or 2/100 Hz EA produced only a transient effect on the activity of NTS neurons and did not induce any effect on the spike frequency. Furthermore, the excitatory effect of 100 Hz or 2/100 Hz EA on NTS neurons in the ST 36 group was lower than 2 Hz EA at the same point. When applied to ST 25, 2 Hz EA had no significant excitatory effect on NTS neurons or spike frequency. However, 100 Hz EA or 2/100 Hz EA at ST 25 decreased both NTS neuronal excitability and spike frequency. By comparing the effects of different EA combinations, it was shown 2 Hz EA applied to ST 36 had the strongest excitatory effect on NTS neurons, while 100 Hz EA applied to ST 25 had the greatest inhibitory effect. Minimal acupuncture stimulation produced no effect on NTS neurons., Conclusion: EA's effects on NTS were mainly affected by the acupuncture point selection, but the frequency of EA also played a role. Different combinations of acupuncture points and frequency selection may lead to different EA effects on NTS neuronal excitability.

Objective: To investigate the analgesic effects of electroacupuncture (EA) at 2 and 100 Hz on type 2 diabetic neuropathic pain (DNP) and on the expressions of the P2X3 receptor and calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG)., Methods: Rat type 2 DNP was induced by a high calorie and high sugar diet fed for 7 weeks, plus a single intraperitoneal injection of streptozotocin (STZ) after 5 weeks. EA at 2 and 100 Hz was carried out once every day after 7 weeks for 7 consecutive days. Body weight, serum fasting insulin (FINS), fasting blood glucose (FBG), insulin sensitivity index (ISI), and paw withdrawal latency (PWL) were measured. The expressions of L4-L6 DRG P2X3 receptors and CGRP were assessed by immunofluorescence., Results: Type 2 DNP was successfully induced as shown by the increased body weight, FINS, and FBG, as well as the reduced ISI and PWL. Expressions of P2X3 receptors and CGRP in L4-L6 DRGs increased. EA at both 2 and 100 Hz relieved type 2 DNP, but the analgesic effect of EA was stronger at 2 Hz. P2X3 receptor expression decreased in L4-L6 DRGs following EA at 2 Hz and in L5 and L6 DRGs following EA at 100 Hz. EA at both 2 and 100 Hz down-regulated CGRP overexpression in L4-L6 DRGs., Conclusions: These findings indicate that EA at 2 Hz is a good option for the management of type 2 DNP. The EA effect may be related to its down-regulation of the overexpressions of the DRG P2X3 receptors and CGRP in this condition.

Postoperative ileus (POI) after abdominal surgery significantly lowers the life quality of patients and increase hospital costs. However, few treatment strategies have successfully shortened the duration of POI. Electroacupuncture (EA) is a modern way of administering acupuncture and widely used in various gastrointestinal (GI) diseases in the world. Here, we studied the effect of EA on POI and its underlying mechanisms. Intestinal manipulation resulted in significant delays of GI transit, colonic transit and gastric emptying. Surgery also up-regulated c-fos in nucleus of the solitary tract (NTS) and induced inflammation response in the small intestine. Further, operation and inhale anesthesia inhibited NTS neuron excitation duration for the whole observation time. EA administered at ST36 indeed shortened the recovery time of GI and colonic transit, and significantly increased the gastric emptying. EA also significantly activated the NTS neurons after operation. However, there was no anti-inflammation effect of EA during the whole experiment. Finally, atropine blocked the regulatory effect of EA on GI function, when it was injected after surgery, but not before surgery. Thus, the regulatory effect of EA on POI was mainly mediated by exciting NTS neurons to improve the GI tract transit function but not by activating cholinergic anti-inflammatory pathway.

Exogenous and endogenous opioids have been shown to modulate the immune system. Morphine-induced immunosuppression has been investigated extensively. However, the immune-regulating function of endogenous opioid peptides is unclear. The present study aimed to evaluate the difference in effects on cellular immune function between recombinant rat β-endorphin (β-EP; 50 µg/kg) and plant source morphine (10 mg/kg) via intraperitoneal injection treatment in a rat model of bone cancer pain. Walker 256 cells were injected into a tibial cavity injection to establish the bone cancer pain model. The paw withdrawal thresholds and body weights were measured prior to surgery, at 6 days after surgery, and following 1, 3,6 and 8 treatments. The spleen cells were harvested for detection of T cell proliferation, natural killer (NK) cell cytotoxicity, and the relative quantities of T cell subtypes (CD3 + , CD4 + and CD8 + cells). Plasma levels of interleukin-2 (IL-2) were also determined. It was found that single or multiple treatments with β-EP (a homogenous opioid peptide) and morphine (a heterogenous opioid) had good analgesic effects on bone cancer pain, while the analgesia provided by morphine was stronger than that of β-EP. Treatment with β-EP 3, 6 and 8 times increased the body weight gain in the rat model of bone cancer pain, while morphine treatment had on effect on it. With regard to immunomodulatory functions, β-EP treatment increased T cell proliferation and NK cell cytotoxicity, and increased the relative quantities of T cell subtypes, but no effect on T cell secretion. However, morphine treatment decreased T cell proliferation and the levels of T cell subtypes. These data indicate that opioids from different sources have different effects on cellular immune function in vivo . A small dose of homogenous opioid peptide exhibited positive effects (analgesia and immune enhancement) on cancer pain. These results provide experimental evidence supporting the exploitation of human opioids for the treatment of cancer pain.

Objective: To investigate whether analgesic effect of electroacupuncture (EA) is affected by p38 mitogen-activated protein kinase (p38 MAPK) on microglia., Methods: There were two experiments. The experiment 1: 40 male Sprague-Dawley (SD) rats were randomly divided into the normal, surgery, EA and sham EA groups, and the L5 spinal nerve ligation (SNL) on the right side was used to establish neuropathic pain model. EA was applied to bilateral Zusanli (ST36) and Kunlun (BL60) at 24, 48 and 72 h after SNL for 30 min, once per day. The paw withdrawal thresholds (PWTs) were measured before surgery (as base) and at 24, 25, 49 and 73 h after surgery. Phospho-p38 MAPK (p-p38 MAPK), oxycocin-42 (OX-42, marker of microglia), and glial fibrillary acidic protein (GFAP, marker of astrocyte) in bilateral spinal cord dorsal horn (SCDH) were detected by immunofluorescence, respectively. The experiment 2: 40 male SD rats were cannulated for SNL-induced neuropathic pain, and then were randomly divided into the dimethyl sulfoxide (DMSO), EA plus DMSO, 4-(4-fluorophenyl)-2-(4-methylsulfonylpheny)-5-(4-pyridyl)-1H-imidazole (SB203580) and EA plus SB203580 groups. SB203580 (30 nmol/L) was administered 5 min prior to EA treatment. The PWTs and OX-42 in bilateral SCDH were measured as mentioned above., Results: SNL-induced neuropathic pain reduced PWTs and increased the expression of p-p38 MAPK and OX-42 in bilateral lumbar SCDH of rats (P<0.01). Spinal p-p38 MAPK was only co-localized with OX-42 in our study. EA treatment significantly alleviated SNL-mediated mechanical hyperalgesia, and suppressed the expression of p-p38 MAPK and OX-42 in lumbar SCDH (P<0.05 or P<0.01). Intrathecal injection of low dose SB203580 had no influence on PWTs (P>0.05), but significantly inhibited the expression of OX-42 positive cells in bilateral SCDH (P<0.01 or P<0.05). EA plus SB203580 synergistically increased PWTs, and reduced the expression of bilateral spinal OX-42 (P<0.01 or P<0.05)., Conclusions: The central mechanism of EA-induced anti-hyperalgesia may be partially associated with the reduced expression of p-p38 MAPK, and subsequently reducing the activation of OX-42 in neuropathic pain. Therefore, EA may be a new complementary and alternative therapy for neuropathic pain.

Introduction: As a new class of glucose-lowering drugs, sodium-glucose co-transporter 2 (SGLT2) inhibitors are effective for controlling hyperglycaemia, however, the relative effectiveness and safety of 6 recently available SGLT2 inhibitors have rarely been studied. Therefore, we aim to perform pairwise comparisons of the 6 SGLT2 inhibitors., Methods and Analysis: A systematic review and network meta-analysis will be conducted. Clinical studies that examine effectiveness and safety of either canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin or luseogliflozin will be included. These studies will be systematically retrieved in MEDLINE, EMBASE and the Cochrane Library, from inception to November 2015. Two reviewers will independently screen for eligible studies and then extract data from the studies as well as assess risk of bias. Discrepancies in screening and data extraction will be arbitrated by a third reviewer. A traditional meta-analysis will be performed to combine the effect sizes calculated from head-to-head comparisons with a random effect model. The effect sizes computed from indirect comparisons will be further combined in a network meta-analysis. Heterogeneity will be tested with the Cochrane's Q statistic, and publication bias will be assessed using a funnel plot and the Egger's test., Ethics and Dissemination: Relative effectiveness and harms of the 6 SGLT2 inhibitors will be demonstrated through this systematic review and network meta-analysis. The result of the review will be disseminated through a peer-review journal and conference presentations. Patients, clinicians and policymakers will benefit from this review in selecting a SGLT2 inhibitor for glucose control in patients with type 2 diabetes., Trial Registration Number: PROSPERO CRD42015025981., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)