Visualized Analysis of Research Hotspots in Acupuncture-Neuro Immunoregulation Based on Bibliometrics

Objective: To review the development of acupuncture and moxibustion-neural network regulation research systematically and comprehensively in China. Method: This study adopted co-word analysis, cluster analysis and other bibliometric methods such as SATI3.2, Citespace and Gephi to visually demonstrate the annual publication volume, cooperation between institutions and co-authorship in the field of acupuncture-neuro immunoregulation research based on the data of more than 70 papers on related topics covering a period of 24 years from 1997 to 2020 in China. Results: The results show that there are three major research institutions in the field of acupuncture-neuro immunoregulation, namely Shanghai, Zhejiang major research institutions in the field of acupuncture-neuro immunoregulation, namely Shanghai, Zhejiang and Heilongjiang Universities of Traditional Chinese Medicine, as well as 7 clusters, including immune function, acupuncture therapy and endogenous opioid peptide. In the future research, a more comprehensive system will be constructed based on the gradually clear relationship between meridians and nerve regulation, humoral regulation, and immune regulation. Application practice will combine traditional acupuncture with modern medicine to create a variety of new therapies, such as electroacupuncture, electric acupuncture, and acupoint injection. Conclusion: The research focus will be expanded on how to improve the clinical efficacy of multiple combined therapies such as acupuncture for the prevention and treatment of diseases through the regulation of immune cells and immune molecules as well as the regulation of the "acupuncture-meridian- neuroendocrine-immune" network.

An Effective and Safe Enkephalin Analog for Antinociception

Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

SEQUENCE ANALYSIS SUGGESTS POSITIVE SELECTION ON THE BOVINE PRODYNORPHIN GENE

Dynorphin A is an endogenous opioid peptide that is part of the KNDy system in the hypothalamus of mammals. This peptide acts as an inhibitor of the GnRH pulse generation, thus regulating the onset of puberty and reproductive cycles. The PDYN gene encodes the propeptide Prodynorphin, the precursor of Dynorphin A. Despite its physiological relevance, PDYN has not emerged as a candidate gene associated with puberty in genomic association studies conducted in cattle. The present work aimed to search for signatures of selection on the PDYN gene among cattle breeds. To this, the whole genome sequences from 57 samples of ten cattle breeds were used. The samples were grouped based on breed selection history and their productive differences, particularly in terms of sexual precocity. The population structure was analyzed using Principal Component Analyses. To evidence recent selection processes, neutrality tests, such as Tajima’s D and Fu & Li’s F* and D* were performed in defined functional regions of PDYN. The putative promoter of PDYN showed a population structure that is in agreement with the criteria considered to make the groups. In that region, neutrality tests were consistently negative and resulted in statistically significant for the dairy breeds. Also, these breeds exhibited less variability in the haplotype analyses than the others. The results presented here suggest that regulatory regions of PDYN could be under positive selection, particularly in dairy breeds. Key words: reproduction; KNDy neurons; Dynorphin; signatures of selection.

β-Endorphin Mediates the Development and Instability of Atherosclerotic Plaques

β-Endorphin, an endogenous opioid peptide, and its μ-opioid receptor are expressed in brain, liver, and peripheral tissues. β-Endorphin induces endothelial dysfunction and is related to insulin resistance. We clarified the effects of β-endorphin on atherosclerosis. We assessed the effects of β-endorphin on the inflammatory response and monocyte adhesion in human umbilical vein endothelial cells (HUVECs), foam cell formation, and the inflammatory phenotype in THP-1 monocyte-derived macrophages, and migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro. We also assessed the effects of β-endorphin on aortic lesions in Apoe−/− mice in vivo. The μ-opioid receptor (OPRM1) was expressed in THP-1 monocytes, macrophages, HASMCs, HUVECs, and human aortic endothelial cells. β-Endorphin significantly increased THP-1 monocyte adhesion to HUVECs and induced upregulation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin via nuclear factor-κB (NF-κB) and p38 phosphorylation in HUVECs. β-Endorphin significantly increased HUVEC proliferation and enhanced oxidized low-density lipoprotein-induced foam cell formation in macrophages. β-Endorphin also significantly shifted the macrophage phenotype to proinflammatory M1 rather than anti-inflammatory M2 via NF-κB phosphorylation during monocyte-macrophage differentiation and increased migration and apoptosis in association with c-jun-N-terminal kinase, p38, and NF-κB phosphorylation in HASMCs. Chronic β-endorphin infusion into Apoe−/− mice significantly aggravated the development of aortic atherosclerotic lesions, with an increase in vascular inflammation and the intraplaque macrophage/smooth muscle cell ratio, an index of plaque instability. Our study provides the first evidence that β-endorphin contributes to the acceleration of the progression and instability of atheromatous plaques. Thus, μ-opioid receptor antagonists may be useful for the prevention and treatment of atherosclerosis.

Phase II double-blind randomised controlled trial of exogenous administration of melatonin in chronic pain (DREAM—CP): a study protocol

IntroductionChronic pain is prevalent, and approximately half of patients with chronic pain experience sleep disturbance. Exogenous melatonin is licensed to treat primary insomnia and there is some evidence for analgesic effects of melatonin.The aim of this study is to investigate the effects of oral melatonin (as Circadin) 2 mg at night in adults with severe non-malignant pain of at least 3 months’ duration.Methods and analysisWe will conduct a randomised double-blind placebo-controlled cross-over study. The primary outcome is sleep disturbance. Secondary outcomes are pain intensity, actigraphy, fatigue, reaction time testing, serum melatonin and endogenous opioid peptide levels along with patient views about study participation.We aim to recruit 60 patients with severe chronic pain (average pain intensity ≥7 on the Brief Pain Inventory (BPI)) from a tertiary referral pain clinic in Northeast Scotland. Participants will be randomised to receive melatonin (as modified release Circadin) 2 mg daily for 6 weeks or placebo, followed by a 4-week washout period, then 6 weeks treatment with the treatment they did not receive. Participants will complete the Verran Snyder-Halpern Sleep Scale, Pittsburgh Sleep Quality Index, Pain and Sleep Questionnaire 3-item index, BPI and psychomotor vigilance reaction time testing at 6 points over 20 weeks. Actigraphy watches will be used to provide objective measures of sleep duration and latency and other sleep measures and will prompt patients to report contemporaneous pain and fatigue scores daily.Cross-over analyses will include tests for effects of treatment, period, treatment–period interaction (carryover effect) and sequence. Within-patient effects and longitudinal data will be analysed using mixed linear models, accounting for potential confounders.Ethics and disseminationApproved by Office for Research Ethics Committees Northern Ireland, reference 19/NI/0007. Results will be published in peer-reviewed journals and will be presented at national and international conferences.Trial registration numberISRCTN12861060

Proenkephalin a 119–159 (penKid) – a novel biomarker for acute kidney injury in sepsis: an observational study

Background Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119–159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED). Method We enrolled 644 patients consecutively during office-hours (6 AM-6 PM) between December 1, 2013 and February 1, 2015. Fifty-six patients were excluded due to incomplete data. We measured penKid in 588 adult patients (patients under 18 years of age were excluded) with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. Logistic regression analysis was used to relate levels of penKid at presentation to AKI, multi-organ failure, 28-day mortality and progression of renal SOFA subscore. Odds ratios are presented as the number of standard deviations from the mean of log-transformed penKid. Results In age and sex adjusted models, penKid predicted AKI within 48 h and 7 days, but these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from rSOFA = 0 and ≤ 1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality. Conclusion PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department.

Proenkephalin A 119-159 (penKid) – a novel biomarker for acute kidney injury in sepsis: An observational study.

Background. Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119-159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED). Method. We enrolled 644 patients consecutively during office-hours (6AM-6PM) between December 1, 2013 and February 1, 2015. 56 patients were excluded due to incomplete data. We measured penKid in 588 adult patients (patients under 18 years of age were excluded) with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. Logistic regression analysis was used to relate levels of penKid at presentation to AKI, multi-organ failure, 28-day mortality and progression of renal SOFA subscore. Odds ratios are presented as the number of standard deviations from the mean of log-transformed penKid. Results. In age and sex adjusted models, penKid predicted AKI within 48 hours and 7 days, but these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from rSOFA=0 and ≤1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality. Conclusion. PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department.

Proenkephalin A 119-159 (penKid) – a novel biomarker for acute kidney injury in sepsis: An observational study.

Background. Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119-159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED). Method. We enrolled 644 patients consecutively during office-hours (6AM-6PM) between December 1, 2013 and February 1, 2015. 56 patients were excluded due to incomplete data. We measured penKid in 588 adult patients (patients under 18 years of age were excluded) with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. Logistic regression analysis was used to relate levels of penKid at presentation to AKI, multi-organ failure, 28-day mortality and progression of renal SOFA subscore. Odds ratios are presented as the number of standard deviations from the mean of log-transformed penKid. Results. In age and sex adjusted models, penKid predicted AKI within 48 hours and 7 days, but these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from rSOFA=0 and ≤1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality. Conclusion. PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department.

Proenkephalin A 119-159 (penKid) – a novel biomarker for acute kidney injury in sepsis: An observational study.

Background Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119-159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED).Method We measured penKid in 588 adult patients with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. and used logistic regression to relate income levels of penKid to outcomes. Logistic regression models were used to derive odds ratios per 1-SD increment of log-transformed penKid to AKI, multi-organ failure, 28-day mortality as well as to progression of renal SOFA subscore (rSOFA) 0 or 1 to higher rSOFA.Results In age and sex adjusted models, penKid predicted AKI development within 48 hours and 7 days, however, these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from income rSOFA=0 and from rSOFA≤1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality.Conclusion PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department.