Long-Term Effects of Individualized Acupuncture for Chronic Neck Pain : A Randomized Controlled Trial.

BACKGROUND: Long-term effects of individualized acupuncture in persons with chronic neck pain (CNP) remain unknown. OBJECTIVE: To evaluate the efficacy and safety of pressure pain, sensory-based individualized acupuncture for relieving CNP. DESIGN: A 24-week multicenter randomized controlled clinical trial. (ChiCTR1800016371). SETTING: Outpatient settings at 4 clinical centers in China from May 2018 to March 2020. PARTICIPANTS: 716 participants with CNP. INTERVENTION: Participants were randomly assigned to a waiting list (WL) group or to 1 of 3 interventions, which consisted of 10 sessions over 4 weeks: higher sensitive acupoints (HSA), lower sensitive acupoints (LSA), and sham acupoints (SA) acupuncture groups. MEASUREMENTS: The primary outcome was the change in the visual analogue scale (VAS) score for neck pain (range, 0 to 100) from baseline to 4 weeks, with a difference of 10 points considered the minimum clinically important threshold. The VAS was also assessed every 4 weeks through 24 weeks. RESULTS: The modified intention-to-treat population included 683 participants. The mean baseline VAS was 50.36, 50.10, 49.24, and 49.16 for HSA, LSA, SA, and WL, respectively. Compared with a mean baseline to week 4 change of -12.16 in the HSA group, the mean changes were -10.19 in the LSA group (net difference [ND], -1.97 [95% CI, -5.03 to 1.09]), -6.11 in the SA group (ND, -6.05 [CI, -9.10 to -3.00]), and -2.24 in the WL group (ND, -9.93 [CI, -12.95 to -6.90]). The intervention effects persisted at 24-week follow-up. LIMITATION: Lack of complete blinding and limited generalizability. CONCLUSION: Individualized acupuncture interventions using high- or low-sensitivity acupuncture points were more effective in reducing CNP than SA and WL control groups sustained through 24 weeks, but the magnitude of relative improvement did not reach a minimal clinically important difference. PRIMARY FUNDING SOURCE: National Natural Science Foundation of China.

[Revealing characteristics and rules of acupoint sensitization phenomena: based on knee osteoarthritis].

OBJECTIVE: To explore the characteristics and rules of acupoint sensitization phenomena based on knee osteoarthritis (KOA), one of the clinical dominant diseases of acupuncture-moxibustion. METHODS: In combination with literature and expert experiences, the acupoints with the highest use frequency in treatment of KOA were screened, e.g. Heding (EX-LE 2), Liangqiu (ST 34), Mingmen (GV 4), Neixiyan (EX-LE 4), Ququan (LR 8) and Dubi (ST 35). In 814 patients with KOA and 217 healthy subjects, the acupoint temperature, mechanic pain threshold and pressure pain threshold were detected separately. Using machine learning method, the sensitization was judged at each acupoint. RESULTS: Compared with healthy subjects, the acupoint temperature was increased and the mechanic pain threshold and pressure pain threshold were reduced in KOA patients (P<0.05). Besides, the cut-off value was presented to distinguish whether the acupoint was sensitized or not. The results of machine learning showed that the highest prediction accuracy of acupoint sensitization was 86.7% (Shenshu [BL 23]) and the lowest one was 73.9% (Heding [EX LE 2]). The prediction accuracy at the third clinical stage trial was higher, the highest was 93.3% (Ququan [LR 8]) in KOA patients. CONCLUSION: It is confirmed that the acupoint sensitization reflects the characteristics of disease and is correlative with the conditions of illness, which may provide the reference for the auxiliary diagnosis and condition assessment of KOA.

Acupuncture methods for allergic rhinitis: a systematic review and bayesian meta-analysis of randomized controlled trials.

BACKGROUND: Allergic rhinitis (AR) is a common symptomatic, inflammatory, and immunological disorder of nasal mucosa. Multiple clinical trials and systematic reviews have implicated acupuncture methods as potentially effective treatment strategies for AR, however, considering the great burden of AR, it is crucial to explore the most recent clinical evidence supporting acupuncture in AR. Besides, the methodologies reported in previous studies as well as those commonly applied during clinical practices greatly vary. Herein, we conducted network meta-analysis to compare the effectiveness of diverse acupuncture methods for AR treatment. METHODS: We conducted a literature search for relevant reports published from inception to 1 July 2020 in several scientific databases, including PubMed, Embase, Cochrane library, Web of Science, CNKI, WF, VIP, CBM, AMED as well as related registration platforms. Primary outcomes as reported in the identified studies were assessed using nasal symptoms. All Meta-analyses were performed with RevMan, ADDIS, and STATA software. To ensure consistency among our reviewers, the intra-class correlation coefficient was used. RESULTS: Exactly 39 studies with 3433 participants were covered in this meta-analysis. The meta-analysis demonstrated that all acupuncture types were superior to sham acupuncture in terms of total nasal symptom score and rhinoconjunctivitis quality of life questionnaire. Moxibustion was recommended as the most effective intervention as it reduced nasal symptoms in 6 treatments. On the other hand, manual acupuncture plus conventional medicine was recommended as the most effective intervention in improving the quality of life in 9 treatments. Notably, moxibustion was recommended as the most effective intervention that changed the content of IgE in 9 treatments. Moreover, adverse events of these interventions were acceptable. CONCLUSION: Our findings revealed that all acupuncture methods are effective and safe for AR. Moreover, either moxibustion or manual acupuncture plus conventional medicine are potentially the most effective treatment strategies for AR. Based on these findings, it is evident that acupuncture therapy is not inferior to pharmacologic therapy. Therefore, for AR patients who are either unresponsive to conventional medicine or are intolerant to adverse events, acupuncture therapy should be administered. However, the quality of these included trials was mainly ranked as moderate quality, we recommend additional well-designed RCTs with larger sample sizes to validate these findings.

Acupuncture for the treatment of marrow suppression after chemotherapy: A protocol for systematic review and meta-analysis.

BACKGROUND: Cancer continues to be a severe global health problem and the leading cause of death worldwide. Chemotherapy as the main treatment has various side effects, of which marrow suppression is the most common one. Acupuncture had shown clinical effects for marrow suppression after chemotherapy in many studies. However, the efficacy and safety of acupuncture therapy for marrow suppression after chemotherapy remains unclear. OBJECTIVE: This protocol aims to evaluate the efficacy and safety of acupuncture for marrow suppression after chemotherapy according to the existing randomized controlled trials. METHODS AND ANALYSIS: The randomized controlled trials on acupuncture therapy for marrow suppression after chemotherapy will be searched in the database of Embase, PubMed and Cochrane Library, Allied and Complementary Medicine Database (AMED), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure (CNKI), WanFang Database (WF), and related registration platforms (WHO ICTRP, Clinical Trials, and Chinese Clinical Trial Register [ChiCTR]), Grey Literature Database from inception to 1 August 2020. The primary outcomes will be assessed using white blood cell (WBC) count, platelet count, hemoglobin count and the number of neutrophils (N). Review Manager V.5.3 software will be applied for statistical analyses. We will measure the risk of bias of the included studies with Cochrane Collaboration Risk of Bias Tool. Finally, Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) will be used to grade the overall quality of evidence. And we will use the intra-group correlation coefficient to assess the consistency of reviewers. RESULT: This systematic review and meta-analysis will put a high-quality synthesis of the efficacy and safety of acupuncture treatment in marrow suppression after chemotherapy. CONCLUSION: The conclusion of this systematic review will provide evidence to assess acupuncture therapy is an efficacy and safe intervention to treat and control marrow suppression after chemotherapy. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020163336.

Acupuncture for chronic neck pain with sensitive points: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Chronic neck pain is a challenging condition to treat in clinical practice and has a considerable impact on quality of life and disability. According to the theory of traditional Chinese medicine, acupoints and tender points may become sensitised when the body is in a diseased state. Stimulation of such sensitive points may lead to disease improvement and improved clinical efficacy. This study aims to evaluate the efficacy and safety of needling at sensitive acupoints in providing pain relief, improvement of cervical vertebral function and quality of life in patients with chronic neck pain. METHODS AND ANALYSIS: This multicentre, randomised controlled, explanatory and parallel clinical trial will include 716 patients with chronic neck pain. Study participants will be randomly assigned in a 1:1:1:1 ratio to four treatment groups: the highly sensitive acupoints group, low/non-sensitive acupoints group, sham acupuncture group and waiting-list control group. The primary outcome will be the change in the visual analogue scale score for neck pain from baseline to 4 weeks. Secondary outcomes will be the Northwick Park Neck Pain Questionnaire and McGill pain questionnaire, 12-item Short-Form health survey, Neck Disability Index, changes in the pressure pain threshold, range of cervical motion, Self-Rating Anxiety Scale, Self-Rating Depression Scale and adverse events before treatment, post-treatment, and at 4, 8, 12, 16 and 20 weeks post-treatment. The intention-to-treat approach will be used in the statistical analysis. Group comparisons will be undertaken using χ2 tests for categorical characteristics, and analysis of variance for continuous variables to analyse whether acupuncture in the highly sensitive acupoints group achieves better treatment outcomes than in each of the other three groups. ETHICS AND DISSEMINATION: Ethical approval of this study has been granted by the local Institutional Review Board (ID: 2017 KL-038). The outcomes of the trial will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR1800016371; Pre-results.

Identification of the optimal points for the acupuncture treatment of neck pain in China: protocol for a multicenter, matched, case-control study.

INTRODUCTION: Neck pain (NP) is a common condition that can be effectively treated by acupuncture. However, several treatment point prescriptions (ie, local acupoints, distal acupoints, and sensitised acupoints) may be used. The present study aims to identify the types of sensitisation and the distribution of sensitised points in patients with NP, to analyse the cut-off values and sensitisation rate for acupoint sensitisation, and to summarise the dominant forms of optimally sensitised points. This information will be helpful when choosing the optimal points to treat NP. METHODS AND ANALYSIS: This multicentre, matched, case-control study will enrol 224 patients with NP, and 224 age-matched and sex-matched healthy participants as controls. Body surface temperature, mechanical pain threshold, pressure pain threshold and skin resistance will be assessed at the 15 acupoints most frequently used to treat NP, and at the five body regions in which pain occurs most frequently. Hypothesis testing will be used to compare the differences in variables between cases and controls. In addition, receiver operating characteristic curve analysis will be used to explore the cut-off values of the sensitive states of heat, pain and electrical resistance, which indicate sensitisation of the acupoint. The optimal points will be comprehensively determined by the acupoint sensitisation rate and OR. ETHICS AND DISSEMINATION: Ethical approval of this study has been granted by the Research Ethical Committee of the Teaching Hospital of Chengdu University of Traditional Chinese Medicine (ID: 2018 KL-016). The outcomes of the study will be disseminated through peer-reviewed publications. TRIAL REGISTRATION: ChiCTR1800016220.

Synthesis and in vitro characterization of ionone-based compounds as dual inhibitors of the androgen receptor and NF-κB.

Current therapeutic strategy for advanced prostate cancer is to suppress the androgen receptor (AR) signaling. However, lethal castration-resistant prostate cancer (CRPC) arises due to AR reactivation via multiple mechanisms, including mutations in the AR and cross-talk with other pathways such as NF-κB. We have previously identified two ionone-based antiandrogens (SC97 and SC245), which are full antagonists of the wild type and the clinically-relevant T877A, W741C and H874Y mutated ARs. Here, we discovered SC97 and SC245 also inhibit NF-κB. By synthesizing a series of derivatives of these two compounds, we have discovered a novel compound 3b that potently inhibits both AR and NF-κB signalling, including the AR F876L mutant. Compound 3b showed low micromolar antiproliferative activites in C4-2B and 22Rv1 cells, which express mutated ARs and are androgen-independent, as well as DU-145 and PC-3 cells, which exhibit constitutively activated NF-κB signalling. Our studies indicate 3b is effective against the CRPC cells.

Antiandrogenic, maspin induction, and antiprostate cancer activities of tanshinone IIA and its novel derivatives with modification in ring A.

Expression of metastatic suppressor maspin is lost in advanced prostate cancer. Clinically relevant mutations in androgen receptor (AR) convert antiandrogens into AR agonists, promoting prostate tumor growth. We discovered tanshinone IIA (TS-IIA) is a potent antagonist of mutated ARs and induces maspin expression through AR. TS-IIA suppressed AR expression and induced apoptosis in LNCaP cells. Syntheses of TS-IIA derivatives (1-9) revealed that the 4,4-dimethyl group at ring A is important for TS-IIA's antiandrogenic and maspin induction activities.

Learning from estrogen receptor antagonism: structure-based identification of novel antiandrogens effective against multiple clinically relevant androgen receptor mutants.

Current treatment strategy for advanced prostate cancer is to suppress androgen receptor (AR) by castration and antiandrogens. However, several clinically relevant AR mutations cause insensitivity to current antiandrogens and convert them into agonists. We aim to identify full AR antagonists even for AR mutants. As crystal structure of AR ligand-binding domain (LBD) at antagonistic form is not available, we decided to learn from estrogen receptor (ER) antagonism: (i) We built a structural model of wild-type AR-LBD complexed with antiandrogen bicalutamide (wild type/bicalutamide) using ERα-LBD/hydroxytamoxifen structure as the template for helix-12. (ii) By comparative structural analysis of 24 ERα-LBD complexes, we found residues D351 and L354 at helix-3 adopt unique conformations, and distance between them is a marker of ERα-LBD/antagonist complexes. The AR residues corresponding to D351 and L354 are E709 and L712, respectively. We found distance between E709 and L712 of the wild type/bicalutamide model is substantially different from that of AR-LBD/agonist complexes, suggesting this distance could be a marker of antagonistic AR-LBD, which was supported by molecular dynamics simulations. Based on the wild type/bicalutamide model, we discovered compound 3 is a novel antiandrogen effective against the wild type and T877A-, W741C-, and H874Y-mutated androgen receptors. We found compound 3 has dual functions, inhibiting androgen receptor and IKK(ß) .

Study of the impact of the T877A mutation on ligand-induced helix-12 positioning of the androgen receptor resulted in design and synthesis of novel antiandrogens.

Antiandrogen flutamide, an antagonist of the wild-type androgen receptor (AR), is used in the clinics for treating metastatic prostate cancer. However, the T877A mutated AR is paradoxically activated by hydroxyflutamide, an active form of flutamide. Despite of crystallographic studies, how the T877A mutation results in antagonist-agonist conversion of hydroxyflutamide remains a puzzle. Here, started from a structural model of the apo form of AR ligand-binding domain (AR-LBD), we have investigated the impact of the T877A mutation on ligand-induced helix-12 positioning by replica-exchange molecular dynamics (REMD) simulations with an unique protocol, which is capable of simulating the H12 dynamics and keeping the main body of AR-LBD unchanged. Specifically, (i) we have computationally demonstrated that on the binding of hydroxyflutamide, the apo form of H12 rearranges into the agonistic form in the T877A mutant, but into the antagonistic forms in the wild-type receptor, shedding light on hydroxyflutamide agonism/antagonism; (ii) By REMD simulations, we have predicted antiandrogen SC184 is a non-agonist of the T877A mutant. This was confirmed by luciferase assays; and (iii) on the basis of the binding modes of hydroxyflutamide and SC184 from the simulations, we designed a novel flutamide derivative called SC333, which was subsequently predicted to be a pure antagonist of the T877A mutant. We then synthesized and experimentally confirmed SC333 is a pan-antiandrogen effective against the wild-type and the T877A and W741C mutated ARs, showing low micromolar cytotoxicity in LNCaP cells. Importantly, we demonstrated that distribution of the H12 conformations from REMD simulations is correlated with ligand agonist/antagonist activity.

Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants.

A crucial event in prostate cancer progression is the transition from a hormone-sensitive to a lethal castration-refractory disease state. The antagonist-to-agonist conversion due to mutation in AR is a critical problem with the current clinically used antiandrogens. We aim to identify novel antiandrogens that remain as a pure antagonist even in the mutated ARs. By synthesizing a series of ionone-based chalcones, we have identified a novel chalcone (17) that is a pan-antagonist of the wild type and the clinically relevant T877A, W741C and H874Y mutated ARs in luciferase reporter assays in PC-3 cells. Further, chalcone 17 demonstrates sub-micromolar to low micromolar antiproliferative activity in LNCaP, MDA-PCa-2b, 22Rv1 and C4-2B prostate cancer cells, all of which express mutated ARs and confer resistance to the current clinically used antiandrogens. The results suggest that chalcone 17 could be a good candidate for further pre-clinical development as a novel antiandrogen for advanced prostate cancer.

Design and synthesis of androgen receptor antagonists with bulky side chains for overcoming antiandrogen resistance.

Incorporation of curcumin and beta-ionone into one chemical entity led to identification of a novel antiandrogen with two bulky side chains, 6, which is a pure antagonist of the wild-type and the T877A, W741C, and H874Y mutated androgen receptors (AR), showing no cross-reactivity with progesterone receptor and low micromolar cytotoxicity in LNCaP, PCa-2b, 22Rv1, and C4-2B prostate cancer cells. Molecular modeling indicates 6 adopts a "Y"-shape conformation and forms multiple hydrogen bonds with AR backbone.

Syntheses and potential anti-prostate cancer activities of ionone-based chalcones.

We report the SAR studies of 43 ionone-based chalcones that demonstrate substantial in vitro anti-proliferative activities in LNCaP, MDA-PCa-2b, 22Rv1, C4-2B and PC-3 prostate cancer cell lines. Compound 25 with an IC(50) value of 0.74 microM in LNCaP cells potently antagonizes DHT-induced transactivation of the wild type and the clinically relevant T877A, W741C and H874Y mutated androgen receptors, representing a novel chalcone as pan-antagonist of androgen receptor.

Diurnal variations in salivary protein carbonyl levels in normal and cognitively impaired human subjects.

Oxidative stress has been documented in tissues and biofluids of subjects with sporadic Alzheimer disease (AD) and mild cognitive impairment (MCI). The aim of this study was to determine whether (a) salivary protein carbonyls are elevated in AD and MCI subjects, (b) salivary protein carbonyl contents in these groups exhibit diurnal variation, and (c) apolipoprotein E epsilon 4 (apoE epsilon 4) carrier status impacts salivary carbonyl concentrations or rhythmicity in the AD and MCI cohorts. Unstimulated saliva was collected at fixed intervals between 8 AM: and 10 PM: from 15 AD subject , 21 MCI subjects, and 30 cognitively-intact controls. Salivary protein carbonyl concentrations were measured by ELISA. ApoE genotyping was performed on the AD and MCI individuals. For all groups, mean protein carbonyl contents were significantly elevated at 2 PM: relative to other time points surveyed. Mean salivary protein carbonyl concentrations did not differ among the diagnostic groups. ApoE epsilon 4 carriers exhibited less temporal variation in salivary protein carbonyls relative to noncarriers. Thus, protein carbonyl content exhibits diurnal variation in adult human saliva. ApoE epsilon 4 carrier status may impact oropharyngeal disease expression by attenuating the inherent diurnal variability in salivary redox homeostasis. Salivary protein carbonyls do not differentiate AD and MCI from normal individuals. In conclusion, oxidative stress has been documented in tissues and biofluids of subjects with sporadic AD and MCI. This article demonstrates that levels of protein carbonyls, a marker of oxidative stress, exhibit robust diurnal variation in the saliva of normal elderly, MCI, and AD subjects. Apolipoprotein E epsilon 4 allele carrier status may attenuate this temporal variability in salivary redox homeostasis and thereby impact the natural history of oropharyngeal diseases.

Effects of heme oxygenase-1 expression on sterol homeostasis in rat astroglia.

Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. Central oxidation of cholesterol to oxysterols has been implicated in neuroembryogenesis, synaptic plasticity, and membrane repair. In the current study, we demonstrated that transient transfection of rat astroglia with human (h)ho-1 cDNA for 3 days significantly decreased intracellular cholesterol concentrations and increased levels of four oxysterol species (measured by GC/MS) compared to untreated control cultures and HO-1-transfected cells exposed to the HO inhibitor, tin mesoporphyrin (SnMP). Relative to control preparations, oxidative stress was augmented in mitochondria (isolated by subcellular fractionation) and culture media derived from HO-1-transfected astrocytes, as evidenced by enhanced oxidation of the synthetic reporter molecules, linoleoyl tyrosine (LT), linoleoyl tyrosine cholesterol ester (LTC), or linoleoyl tyrosine deoxyguanosyl ester (LTG; measured by GC/MS and LC/MS/MS). We also observed enhanced oxidation of exogenous LTC in human neuroblastoma (M17) cells exposed for 18 h to conditioned media collected from HO-1-transfected astrocytes relative to control media. In AD and other pathological states, glial HO-1 induction may transduce ambient noxious stimuli (e.g., beta-amyloid) into altered patterns of glial sterol metabolism which, in turn, may affect neuronal membrane turnover, survival, and adaptability.