The effectiveness and safety of acupuncture/electroacupuncture for chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis.

OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse effect of anticancer agents with virtually no effective treatment. Safe and effective therapies are needed urgently. Acupuncture shows therapeutic possibilities in this regard but needs to be further evaluated. METHODS: A systematic search was conducted in seven databases from their inception to April 2020. Randomized controlled trials (RCTs) focused on acupuncture/electroacupuncture (EA) for the treatment of CIPN were included. Revman 5.3 software was used for meta-analysis if there was no significant heterogeneity. Otherwise, qualitative analysis was utilized. RESULTS: Nine studies involving 582 patients were included in this review. Most of the studies exhibited unclear risk of bias because some details were not mentioned. As the clinical heterogeneity was significant, qualitative analysis was performed to describe nerve conduction velocity, effective rate for motor neuropathy, pain scores, quality of life and adverse events. Meta-analysis was performed on four studies to analyze the effective rate for sensory neuropathy due to inconspicuous heterogeneity. The results indicated that acupuncture may generate a better effect on sensory neuropathy than vitamin B (risk ratio = 1.60, 95% confidence interval = 1.31-1.95, I2 = 0%, p < 0.00001). The efficacy of EA plus glutathione (GSH) appeared to be better than that of GSH alone in alleviating sensory neurotoxicity and in improving nerve conduction velocity. Acupuncture plus methylcobalamin showed more favorable effects than methylcobalamin alone in relieving neuralgia, restoring nerve conduction velocity and improving quality of life. In terms of pain relief and improved CIPN-specific quality of life, acupuncture plus standard care was better than standard care alone. In terms of pain relief, EA was more effective than usual care. CONCLUSION: Acupuncture may be effective and safe in the treatment of CIPN according to the analyzed studies. However, more studies with higher methodological quality are warranted in order to be able to draw firmer conclusions. Future rigorous RCTs will be necessary to confirm the effectiveness and safety of acupuncture for CIPN.

Effects of Soy-Whey Protein Nutritional Supplementation on Hematopoiesis and Immune Reconstitution in an Allogeneic Transplanted Mice.

Profound malnutrition and immunodeficiency are serious negative effects of radiotherapy and bone marrow transplantation for hematologic malignancy patients. This study aimed to evaluate the effects of nutritional supplementation with a soy-whey protein mixture on hematopoietic and immune reconstitution in an allogeneic transplant mouse model. Male BALB/c (H-2Kd) mice, 6-8 weeks-old, were divided randomly into five groups and then provided with different protein nutrition support. After 28 days, blood samples, bone marrow, spleen, and thymus were harvested to measure the effects. The results showed that soy-whey blended protein supplements promoted hematopoietic stem cell engraftment, body weight recovery, and the recovery of white blood cells, lymphocytes, and neutrophils; triggered the expansion of hematopoietic stem cells and progenitor cell pools by increasing the numbers of the c-kit+ progenitor, Lin-Sca1+c-kit+, short-term hematopoietic stem cells, and multipotent progenitors; enhanced thymus re-establishment and splenic subset recovery in both organ index and absolute number; improved overall nutritional status by increasing total serum protein, albumin, and globulin; protected the liver from radiation-induced injury, and increased antioxidant capacity as indicated by lower concentrations of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, and 4-hydroxynonenal. This study indicated that soy-whey blended protein as important nutrients, from both plant and animal sources, had a greater positive effect on patients with hematological malignancies to accelerate hematopoiesis and immune reconstitution after bone marrow transplantation.

[Effect of acupuncture on hypothalamic functional connectivity in patients with premature ova-rian insufficiency based on resting-state functional magnetic resonance imaging].

OBJECTIVE: To compare the differences in functional connectivity(FC) between the hypothalamus and whole brain regions in patients with premature ovarian insufficiency (POI) and healthy volunteers based on resting-state functional magnetic resonance imaging (rs-fMRI) and investigate the mechanism of acupuncture on treatment of POI. METHODS: Twelve POI patients were recruited to the acupuncture group and 12 healthy volunteers to the control group. Patients in the acupuncture group received acupuncture at two groups of acupoints alternatively, including Baihui (GV20), Zhongwan (CV12), Shenting (GV24), Shenshu (BL23), Ciliao（BL32） and so on, 30 min once time, 3 times per week for 12 weeks. The state of patients was evaluated by modified Kupperman Index (KI) and self-rating anxiety scale (SAS). Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and anti-mullerian hormone (AMH) were tested by microparticle-based chemiluminescence. B ultrasonography was used to detect the antral follicle count (AFC). Meanwhile, POI patients and healthy volunteers underwent the rs-fMRI examination before and after acupuncture treatment and after enrollment, respectively. With hypothalamus as the region of interest, the differences in FC between the hypothalamus and other brain regions in POI patients and healthy volunteers and the changes of FC between the hypothalamus and whole brain regions in POI patients before and after acupuncture were observed. RESULTS: The SAS and KI scores of pre-treatment POI patients were higher than those in the control group （P<0.01）.In compa-rison with those pre-treatment, FSH, LH, and SAS and KI scores of POI patients decreased after treatment, while AFC increased (P<0.05). Compared with the control group, the FC of the left hypothalamus with left central sulcus, right middle occipital gyrus, and left paracentral lobule increased, but decreased with left globus pallidus of the lenticular nucleus in POI patients. Furthermore, the FC of the right hypothalamus with the left hippocampus, the left para-central lobule, and the right central sulcus increased, while the FC between the right hypothalamus and the right superior frontal gyrus decreased (P<0.05). For the acupuncture group, compared with the conditions before treatment, the FC of the right hypothalamus with the left inferior frontal gyrus, the left insula, and right inferior frontal gyrus was strengthened, but weakened with the left gyrus rectus (P<0.05). CONCLUSION: The abnormal FC between the hypothalamus and whole brain regions may be one of the central pathological factors of POI. Acupuncture can improve the ovarian function and clinical symptoms of patients with POI, which may be related to its effect in regulating the FC between the hypothalamus and multiple brain regions.

Regulation of serum microRNA expression by acupuncture in patients with diarrhea-predominant irritable bowel syndrome.

OBJECTIVE: To screen for differentially expressed serum microRNAs (miRNAs) in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) compared with healthy participants and explore the mechanism of acupuncture in the treatment of IBS-D based on miRNAs. METHODS: IBS-D patients that met the Rome III diagnostic criteria and age- and sex-matched healthy participants were enrolled between April 2017 and December 2017. Serum miRNA levels were initially determined using a TaqMan low-density array (TLDA) in pooled samples. Markedly altered miRNAs in IBS-D patients were subsequently validated using quantitative real-time polymerase chain reaction (qRT-PCR) on individual samples. All IBS-D patients accepted the acupuncture therapy for 6 weeks. The disease severity was assessed using the IBS symptom severity scale (IBS-SSS) questionnaire before and after treatment. After acupuncture, the patients' serum was re-analyzed for altered expression of the miRNAs by qRT-PCR. RESULTS: TLDA and qRT-PCR analysis revealed six upregulated miRNAs (miR-1305, miR-575, miR-149-5p, miR-190a-5p, miR-135a-5p, and miR-148a-3p; P < 0.05) and two downregulated miRNAs (miR-194-5p, miR-127-5p; P < 0.05) in IBS-D patients compared with healthy controls. Post acupuncture treatment, total IBS-SSS scores, severity of abdominal pain, duration of abdominal pain, severity of abdominal distention, dissatisfaction with bowel habits and disruption in quality of life decreased significantly (P < 0.001). Furthermore, the upregulated miR-148a-3p levels in IBS-D patients also decreased significantly after acupuncture (P < 0.05). CONCLUSIONS: The over-expression or reduced expression of several miRNAs may contribute to IBS-D pathogenesis. Acupuncture might downregulate miR-148a-3p through multiple pathways to alleviate or relieve IBS-D symptoms. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17010860 (Chinese Clinical Trials Registry).

Analgesic Effect of Electroacupuncture on Postherpetic Neuralgia: A Trial Protocol for a Multicenter Randomized Controlled Trial.

INTRODUCTION: The chronic neuropathic pain associated with postherpetic neuralgia (PHN) can last for several months or even many years, seriously affecting the affected person's work, sleep, mood, and daily life activities. In generaly, current treatments for PHN are at best limited and unsatisfactory, and adverse reactions are common, especially in elderly patients. Electroacupuncture (EA) is widely used clinically to manage painful diseases, but there remains a lack of evidence to support the effectiveness of EA on PHN. This study is designed to assess the efficacy and safety of EA on PHN, and to provide evidence-based medical evidence for EA treatment of PHN. METHODS: This multicenter, prospective, randomized controlled trial will recruit 448 patients with PHN at seven clinical centers. Multicenter stratified variable block randomization will be used, and the eligible patients will be randomly allocated in a ratio of 1:1 to the EA group or sham EA group. The EA group will receive 4 weeks of EA treatment, given as 30-min treatment sessions, once daily, 5 times per week, for a total of 20 treatments; the sham EA group will receive sham EA treatment under the same conditions. PLANNED OUTCOMES: The primary outcome measure is the 11-point Numeric Rating Scale pain score at week 4. The secondary outcome measures, including mechanical pain threshold, pain area of PHN, average number of pain episodes, the short-form McGill Pain Questionnaire 2, Zoster Brief Pain Inventory, the Depression, Anxiety, and Positive Outlook Scale, Patient Global Impression of Change, safety of EA, and use of concomitant medications, among others. The primary analysis of the outcomes will be the mixed-effect model with repeated measurement between groups on an intent-to-treat population. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04560361. Registered 23 September 2020 ( https://clinicaltrials.gov/ct2/show/NCT04560361?term=NCT04560361&draw=2&rank=1 ).

[Mind-regulating and spleen-strengthening needling technique improves abdominal hypersensitivity and emotion by enhancing functional connectivity between hippocampus and brain regions in diarrhea-predominant irritable bowel syndrome patients].

OBJECTIVE: To compare the difference of brain functional connectivity between diarrhea-predominant irritable bowel syndrome (IBS-D) patients and healthy volunteers and changes after acupuncture intervention, so as to investigate the underlying mechanism of acupuncture in regulating functional activities of IBS-D patients by using seed point correlation analysis. METHODS: A total of 25 IBS-D patients and 25 healthy volunteers were recruited in the present study and respectively attributed to acupuncture group and control group. The IBS-D patients received manual acupuncture stimulation of Baihui (GV20), Yintang (EX-HN3), and bilateral Tianshu (ST25), Zusanli (ST36), Shangjuxu (ST37), Sanyinjiao (SP6) and Taichong (LR3) with mind-regulating and spleen-strengthening technique for 30 min, once a day, 3 days a week for 6 weeks. Before and after the intervention, the IBS symptom severity scale (IBS-SSS) was used to assess the patients' state of abdominal pain, distention and defecation, and Hamilton Anxiety Rating Scale (HAMA) employed to evaluate the patients' anxiety severity. The resting state functional magnetic resonance imaging (rs-fMRI) data were acquired and preprocessed by using SPM8 and DPARSE soft-wares. Seeds (bilate-ral hippocampus regions) to whole-brain analysis was performed to obtain the mean time series of the left and right seed regions, followed by making Pearson correlation analysis to obtain the correlation coefficient (time series from each seed region with the rest of the voxels in the brain), and making a multivariate comparative correction to get data of functional connectivity (FC) of bilateral hippocampus regions and to find the related difference in the brain regions. Then, the differences of the FC of brain regions between IBS-D patients and healthy volunteers were compared. RESULTS: Following acupuncture treatment, both the HAMA and IBS-SSS scores were significantly reduced in the acupuncture group compared with its pre-treatment (P<0.01). Compared with the healthy volunteers, there were a reduction in the functional connectivity between the left hippocampus seed region and the right inferior temporal gyrus, left fusiform gyrus and left superior gyrus, and between the right hippocampus region and the right fusiform gyrus, left inferior temporal gyrus, left inferior occipital gyrus, left rectus gyrus, left insula, left precuneus, right angular gyrus, left middle occipital gyrus, right precuneus, and the left superior temporal gyrus, and an increase in the FC between the left hippocampus and left superior temporal gyrus was increased in ISB-D patients. Self-comparison showed that after the treatment, the FC was increased between the left hippocampus seed region and the right inferior temporal gyrus, left fusiform gyrus, bilateral lingual gyrus, left amygdala, right inferior occipital gyrus, right insula, right middle frontal gyrus, left middle frontal gyrus and the left middle occipital gyrus; and between the right hippocampus seed region and the posterior inferior cerebellar lobe, left inferior temporal gyrus, left suboccipital gyrus, right fusiform gyrus, left insula, right inferior frontal gyrus, left superior temporal gyrus, left middle occipital gyrus, right middle frontal gyrus, left supplementary motor area and right supplementary motor area, and decreased between the left hippocampus region and the left anterior cingulate, paracingulate gyrus and the right posterior central gyrus in IBS-D patients. CONCLUSION: Mind-regulating and spleen-strengthening acupuncture intervention may improve the abdominal pain and distension and emotional state in IBS-D patients, which is possibly associated with its effect in enhancing FC between the hippocampus and brain regions.

[Correlation between curative effect and 5-HTTLPR polymorphism in treatment of diarrhea-predominant irritable bowel syndrome with acupuncture for regulating shen and strengthening spleen].

OBJECTIVE: To compare the curative effect on diarrhea-predominant irritable bowel syndrome (IBS-D) between acupuncture for regulating shen and strengthening spleen and pinaverium bromide, and explore the relevant mechanism of curative effect of acupuncture in view of polymorphism of 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR). METHODS: A total of 231 patients with IBS-D were randomized into an acupuncture group (154 cases) and a western medication group (77 cases) at the ratio of 2 to 1. In the acupuncture group, acupuncture was applied to acupoint regimen for regulating shen and strengthening spleen, i.e. Baihui (GV 20), Yintang (GV 29), Tianshu (ST 25), Shangjuxu (ST 37) and Zusanli (ST 36), etc. The treatment was given once every 2 days, 3 times a week. In the western medication group, pinaverium bromide was prescribed for oral administration, 50 mg each time, 3 times daily. The duration of treatment was 6 weeks in each group. Separately, before treatment, after treatment and in 3-month follow-up, the IBS symptom severity scale (IBS-SSS) and IBS quality of life scale (IBS-QOL) scores were adopted in assessment. After treatment, the curative effect and safety were compared between the two groups. Before treatment, 5-HTTLPR genotypes were determined in the patients. RESULTS: After treatment and in follow-up, the total scores of IBS-SSS in the patients of the two groups were all reduced as compared with those before treatment (P<0.01) and the scores in the acupuncture group were lower than those in the western medication group (P<0.01). After treatment and in follow-up, the total scores of IBS-QOL in the two groups were all increased as compared with those before treatment (P<0.01) and the score in the acupuncture group was higher than the western medication group in follow-up (P<0.01). The total effective rate was 79.2% (122/154) in the acupuncture group, higher than 58.4% (45/77) in the western medication group (P<0.01). There was no severe adverse reaction found in the two groups. The difference in the total score of IBS-SSS before and after treatment in the patients with LS and SS genotypes was greater than that in the patients with LL in the acupuncture group (P<0.01). The difference in the total score of ISB-SSS before and after treatment in the patients with SS genotype was greater than that in the patients with LL in the western medication group (P<0.01). The difference in the total score of IBS-SSS before and after treatment in the patients with LS and SS genotypes in the acupuncture group was greater than that in the patients with the same genotypes in the western medication group (P<0.01). CONCLUSION: Acupuncture for regulating shen and strengthening spleen achieves the more curative effect on IBS-D as compared with pinaverium bromide. The acupuncture regimen effectively relieves the clinical symptoms and improves the quality of life in patients as well as presents a satisfactory long-term effect and safety. The clinical curative effect of acupuncture is correlated with 5-HTTLPR polymorphism, in which, the curative effect of acupuncture may be more effective in the patients with LS and SS genotypes.

[Effect of Tiaoshen Jianpi acupuncture therapy on gut microbiota and fecal short-chain fatty acids in patients with diarrhea type irritable bowel syndrome].

OBJECTIVE: To observe the clinical therapeutic effect of Tiaoshen Jianpi acupuncture therapy (acupuncture for regulating the mind and strengthening the spleen) on the gut microbiota and the content of fecal short-chain fatty acids (SCFAs) in patients with diarrhea type irritable bowel syndrome (IBS-D). METHODS: A total of 20 patients with IBS-D and 20 healthy subjects were included. The patients with IBS-D were treated with Tiaoshen Jianpi acupuncture therapy at Baihui (GV 20), Yintang (GV 29), Tianshu (ST 25), Shangjuxu (ST 37), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3). The treatment was given once every two days, 3 times weekly, consecutively for 6 weeks. No intervention was provided for the healthy subjects. Before and after treatment, the IBS symptom severity score (IBS-SSS) was observed in the patients. The fecal samples were collected before and after treatment separately in the patients and in the healthy subjects. Using 16S rRNA sequencing technique, the structure and diversity of gut microbiota were analyzed. Using high-performance liquid chromatography, the content of SCFAs was detected. RESULTS: After treatment, the abdominal pain severity score, the abdominal pain days score, the satisfaction in bowel movement score, the life interference score and the total IBS-SSS score were all lower than those before treatment in the patients with IBS-D (P<0.05). Compared with the healthy subjects, Firmicutes was increased (P<0.05), Bacteroidetes and Proteobacteria were decreased (P<0.05), and Shannon index was reduced (P<0.05) and Simpson index was increased in patients with IBS-D before treatment (P<0.05). Compared before treatment, Firmicutes was decreased (P<0.05), Bacteroidetes and Proteobacteria were increased (P<0.05), and Shannon index was increased (P<0.05) and Simpson index was reduced in the patients with IBS-D after treatment (P<0.05). Besides, the content of SCFAs was reduced after treatment (P<0.05). CONCLUSION: Tiaoshen Jianpi acupuncture therapy relieves abdominal pain and diarrhea, which may be related to regulating the structure and diversity of gut microbiota and reducing the content of fecal SCFAs in the patients with IBS-D.

[Exploration on the relationship between acupuncture for mind-regulation and flow theory].

Based on the story of Chinese idiom, paodingjieniu (a magical and skilled form of craftsmanship) as the breakthrough point, this paper discusses the both paoding (cook) and the experienced acupuncture practitioner have the same high skills and explores the potential relationship between mind-regulation in treatment with acupuncture and flow theory. It is believed that the skills of ancient acupuncture practitioner in mind-regulation with acupuncture is not only a kind of "Tao" mode, but also a state of "flow". By the discussion on mind-regulation and flow theory, modern people may have more clear recognition on the mind regulation in treatment with acupuncture so as to better determine the therapeutic methods of acupuncture for mind-regulation.

Electroacupuncture relieves irritable bowel syndrome by increasing expression of nucleotide-binding oligomerization domain protein-like receptor family pyrin domain containing 6 in water-avoidance stress mice.

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on irritable bowel syndrome (IBS) in mice through regulating nucleotide-binding oligomerization domain protein-like receptor family pyrin domain containing 6 (NLRP6). METHODS: Water-avoidance stress (WAS) mice model was used to investigate the effects and the mechanism of EA. Abdominal withdrawal reflex test, open field test, and intestinal motility test were used to evaluate visceral sensitivity, anxiety, and intestinal motility in mice. The expressions of NLRP6, Mucin-2 (MUC2) and E-cadherin were determined using immunofluorescence and Western blotting assays. RESULTS: EA significantly upregulated the expression of NLRP6 in the intestine of mice. Moreover, EA increased the expressions of MUC2 and E-cadherin in WAS mice. CONCLUSION: Our study found that the relief of IBS symptoms by EA may involve the increase in the expression of NLRP6 in WAS mice.

Effect of Acupuncture in Patients With Irritable Bowel Syndrome: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect and safety of acupuncture for the treatment of irritable bowel syndrome (IBS) through comparisons with those of polyethylene glycol (PEG) 4000 and pinaverium bromide. PATIENTS AND METHODS: This multicenter randomized controlled trial was conducted at 7 hospitals in China and enrolled participants who met the Rome III diagnostic criteria for IBS between May 3, 2015, and June 29, 2018. Participants were first stratified into constipation-predominant or diarrhea-predominant IBS group. Participants in each group were randomly assigned in a 2:1 ratio to receive acupuncture (18 sessions) or PEG 4000 (20 g/d, for IBS-C)/pinaverium bromide (150 mg/d, for IBS-D) over a 6-week period, followed by a 12-week follow-up. The primary outcome was change in total IBS-Symptom Severity Score from baseline to week 6. RESULTS: Of 531 patients with IBS who were randomized, 519 (344 in the acupuncture group and 175 in the PEG 4000/ pinaverium bromide group) were included in the full analysis set. From baseline to 6 weeks, the total IBS-Symptom Severity Score decreased by 123.51 (95% CI, 116.61 to 130.42) in the acupuncture group and 94.73 (95% CI, 85.03 to 104.43) in the PEG 4000/pinaverium bromide group. The between-group difference was 28.78 (95% CI, 16.84 to 40.72; P<.001). No participant experienced severe adverse effects. CONCLUSION: Acupuncture may be more effective than PEG 4000 or pinaverium bromide for the treatment of IBS, with effects lasting up to 12 weeks. TRIAL REGISTRATION: Chinese Clinical Trials Register, ChiCTR-IOR-15006259.

[Professor SHENG Can-ruo's academic thoughts and acupoint selection experience for hot flashes].

Professor SHENG Can-ruo is a well-known national veteran doctor with over 70 years of clinical experience. He has unique academic thoughts and clinical experience for common diseases and some difficult and complicated diseases. This paper mainly introduces professor SHENG 's syndrome-differentiation thought and experience of acupoint selection for hot flashes. It is emphasized that common hot flashes, such as hot flashes and night sweats, are different between yin and yang. While regulating yin and yang, more attention should be paid to ying-wei harmony, which is not only suitable for women's perimenopausal syndrome, but also for a series of clinical diseases caused by refractory drugs such as endocrine therapy after breast cancer surgery. At the same time of acupoint selection based on syndrome differentiation, a more rational prescriptions should be made according to the duration of the disease and the experience acupoints to improve the clinical efficacy.

Electroacupuncture Relieves Visceral Hypersensitivity by Inactivating Protease-Activated Receptor 2 in a Rat Model of Postinfectious Irritable Bowel Syndrome.

BACKGROUND: The role of protease-activated receptor 2 (PAR2) in the analgesic effect of electroacupuncture (EA) on visceral hypersensitivity (VH) in postinfectious irritable bowel syndrome (PI-IBS) has yet to be elucidated. AIM: In this study, we investigated the molecular mechanisms underlying the analgesic effect of EA in a rat model of PI-IBS. METHODS: Visceral hypersensitivity was evaluated by the abdominal withdrawal reflex test before and after administration of the PAR2 agonist, PAR2-AP, and/or EA. The protein expression and mRNA levels of PAR2, CGRP, SP, and TPSP in colon tissues were measured by immunofluorescence, western blot, and RT-PCR. RESULTS: We found that EA could alleviate VH and significantly decrease protein and mRNA levels of PAR2, TPSP, CGRP, and SP in PI-IBS rats. The analgesic effect of EA on VH was slightly reduced in the presence of PAR2-AP. CONCLUSIONS: These results suggest that EA alleviates VH symptoms through downregulation of the levels of the TPSP/PAR2/SP/CGRP signaling axis in colon tissues in PI-IBS rats. Together, our data suggests that PAR2 plays a critical role in the analgesic effect of EA on VH in PI-IBS.

Acupuncture for irritable bowel syndrome: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and change of bowel habit without organic disease. A global perspective given by the World Gastroenterology Organization (WGO) points out that IBS can impact the quality of an individual's daily life, cause socioeconomic problems and potentially impair the patient-physician relationship. It remains a problem to treat IBS due to the complicated pathophysiology. Acupuncture is an alternative therapy recommended for IBS. The aim of this study is to investigate the efficacy and safety of acupuncture therapy for patients with IBS. We also want to explore the correlation between IBS-gene subtypes and acupuncture effect. METHODS/DESIGN: A multicenter randomized controlled trial will be performed in seven hospitals. Six hundred participants will be stratified into two strata (IBS-C or IBS-D). Then, patients within each stratum will be divided into an experimental group and a control group randomly. The experimental group is treated with acupuncture while the control group is treated with Western medicine. All the patients will receive a 6-week treatment and a 3-month follow-up. The primary outcome is the IBS-Symptom Severity Score (IBS-SSS), the secondary outcome is the score of the IBS-Quality of Life (IBS-QoL).The correlation between IBS-gene subtypes and acupuncture effect will be detected based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Outcome measures (including primary and secondary outcome measures) are collected at baseline,1 week, 2 weeks, 4 weeks, and 6 weeks of the intervention, and 12 weeks after the intervention. DISCUSSION: This is a multicenter randomized controlled trial for IBS in China. It may clarify the efficacy of acupuncture as an alternative therapy for IBS. This is the first time ever that the potential mechanism of IBS based on genomics has been investigated. TRIAL REGISTRATION: Chinese Clinical Trials Register, ID: ChiCTR-IOR-15006259 . First registered on 14 April 2015.

[Electroacupuncture of "Tianshu" (ST 25) Suppresses Visceral Pain Possibly by Down-regulating Mast Cell Activation, and Tryptase and SP Expression in Rats with Post-infectious Irritable Bowel Syndrome].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Tianshu" (ST 25) on visceral pain and colonic mast cell (MCs) number and tryptase and SP expression in post-infectious irritable bowel syndrome (PI-IBS) rats, so as to reveal its mechanisms underlying improvement of PI-IBS. METHODS: Forty-five female Wistar rats were randomly divided into control, model and EA groups (15 rats/ group, 3 rats/group used for H. E. staining, and 12 rats/group for immunohistochemistry). The PI-IBS model was established by intra-anal injection of mixed liquor of 50% ethyl alcohol and trinitro-benzene-sulfonic acid (TNBS). EA (2 Hz/15 Hz, 0.5-1.0 mA) was applied to bilateral "Tianshu" (ST 25) for 30 min, once every day for 14 days. The visceral pain was measured by abdominal withdrawal reflex (AWR), for which the rectal implanted air balloon was dilated by infusion of normal saline. The histopathological changes of the colon tissue were observed after H. E. staining, and the colonic MCs were displayed by Toluidine blue staining. The expression of tryptase and SP proteins in the colon specimens were detected by immunohistochemistry. RESULTS: The AWR threshold was significantly lowered in the model group relevant to the control group (P<0.05) and considerably increased after EA intervention in comparison with the model group (P<0.05). The number of MCs and the expression levels of colonic tryptase and SP proteins in the colon tissues were significantly higher in the model group than in the control group (P<0.05), and obviously lower after EA intervention in the EA group than in the model group (P<0.05). CONCLUSION: EA of "Tianshu" (ST 25) can inhibit visceral pain in PI-IBS rats, which may be associated with its effects in activating MCs and down-regulating the expression of tryptase and SP proteins in the colonic tissues.

Effect of acupuncture and its influence on visceral hypersensitivity in IBS-D patients: Study protocol for a randomized controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder associated with visceral hypersensitivity. Increased expression of colonic TRPV1 and decreased expression of microRNA-199 are implicated in the pathogenesis of visceral hypersensitivity in IBS-D patients. Acupuncture is one of the frequently used complementary and alternative therapies for the treatment of IBS. The existing clinical studies mostly use IBS-SSS or other subjective scales, so there is a lack of objective biochemical evidence regarding the effect of acupuncture on IBS. Therefore, we designed this study to investigate whether acupuncture alleviate visceral hypersensitivity by influencing the expression of TRPV1 and microRNA-199. METHOD: This study is a randomized, sham-controlled trial involving 40 patients and 10 healthy volunteers. A total of 40 eligible patients with IBS-D will be randomly assigned to a traditional acupuncture group or sham acupuncture group in a 1:1 ratio. Patients will receive 3 acupuncture treatment sessions per week for 12 consecutive weeks, for a total of 36 sessions during the study. The primary outcome measure is the IBS-Symptom Severity Score (IBS-SSS). Secondary outcomes are Visceral Pain Scale and levels of TRPV1 and microRNA-199 in colonic tissues. Healthy volunteers will not receive any clinical intervention. The safety of interventions will be assessed at every visit. DISCUSSION: The purpose of this trial is to evaluate the efficacy of acupuncture for IBS-D through IBS-SSS and Visceral Pain Scale. Furthermore, we want to explore the intervention mechanism of acupuncture in improving visceral hypersensitivity by analyzing the colonic TRPV1 and microRNA-199. TRIAL REGISTRATION: This trial is registered with Chinese Clinical Trials Register, ChiCTR-IOR- 17010860(http://www.chictr.org.cn/showproj.aspx?proj=18445).

Effects of acupuncture on the levels of serum estradiol and pituitary estrogen receptor beta in a rat model of induced super ovulation.

AIMS: Acupuncture is frequently recommended as a complementary therapy for infertility. However, whether acupuncture can prevent early ovarian hyperstimulation syndrome has not been examined and its potential mechanisms are not well understood. MAIN METHODS: Forty rats were randomized into four groups: Control, Ovarian Stimulation Model, Acupuncture, and Human Chorionic Gonadotropin (HCG). Serum estradiol, progesterone, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels were measured by enzyme-linked immunosorbent assay. Pituitary ER mRNA and ERß expression were detected by real-time PCR and western blotting respectively. The pathology of rat ovaries were observed by light microscopy. KEY FINDINGS: We observed significantly lower estradiol levels in the Acupuncture group than in the Model group and increased LH levels in the HCG group than in Model and Acupuncture groups. Testosterone and FSH levels were significantly lower in the Acupuncture group than in the HCG group. Western blotting showed significantly lower pituitary ERß expression in the Model group than in the Control group and higher expression in the Acupuncture group than in the Model group. Real-time PCR showed lower pituitary ER mRNA expression in the Acupuncture group than in the Model group. Hematoxylin and eosin staining showed a lower proportion of atretic follicles in Acupuncture and HCG groups than in Model and Control groups. Instead, Acupuncture and HCG groups showed growing and mature follicles. SIGNIFICANCE: Our results demonstrate a relationship between acupuncture and the hypothalamic-pituitary-gonadal axis, and the potential mechanism underlying the preventative effects of acupuncture on the incidence of early ovarian hyperstimulation syndrome.

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFß2-bioenergetics-mitochondrial priming.

The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFß2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFß2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone.

Advanced oxidation protein products sensitized the transient receptor potential vanilloid 1 via NADPH oxidase 1 and 4 to cause mechanical hyperalgesia.

Oxidative stress is a possible pathogenesis of hyperalgesia. Advanced oxidation protein products (AOPPs), a new family of oxidized protein compounds, have been considered as a novel marker of oxidative stress. However, the role of AOPPs in the mechanism of hyperalgesia remains unknown. Our study aims to investigate whether AOPPs have an effect on hyperalgesia and the possible underlying mechanisms. To identify the AOPPs involved, we induced hyperalgesia in rats by injecting complete Freund's adjuvant (CFA) in hindpaw. The level of plasma AOPPs in CFA-induced rats was 1.6-fold in comparison with what in normal rats (P<0.05). After intravenous injection of AOPPs-modified rat serum albumin (AOPPs-RSA) in Sprague-Dawley rats, the paw mechanical thresholds, measured by the electronic von Frey system, significantly declined. Immunofluorescence staining indicated that AOPPs increased expressions of NADPH oxidase 1 (Nox1), NADPH oxidase 4 (Nox4), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the dorsal root ganglia (DRG) tissues. In-vitro studies were performed on primary DRG neurons which were obtained from both thoracic and lumbar DRG of rats. Results indicated that AOPPs triggered reactive oxygen species (ROS) production in DRG neurons, which were significantly abolished by ROS scavenger N-acetyl-l-cysteine (NAC) and small-interfering RNA (siRNA) silencing of Nox1 or Nox4. The expressions of Nox1, Nox4, TRPV1 and CGRP were significantly increased in AOPPs-induced DRG neurons. And relevant siRNA or inhibitors notably suppressed the expressions of these proteins and the calcium influxes in AOPPs-induced DRG neurons. In conclusion, AOPPs increased significantly in CFA-induced hyperalgesia rats and they activated Nox1/Nox4-ROS to sensitize TRPV1-dependent Ca2+ influx and CGRP release which led to inducing mechanical hyperalgesia.

[Application of placebo acupuncture in randomized controlled trials in the past 10 years in foreign countries].

The application of placebo acupuncture in randomized controlled trials in the past 10 years (2004-2014) in foreign countries was systematically reviewed to summarize the design of placebo acupuncture; according to category of diseases, advantages and disadvantages were analyzed to explore an ideal placebo acupuncture set. By retrieval in PubMed, EMBASE and OVID databases, the clinical study literature which met the inclusion criteria was searched, and the category of diseases, design of placebo acupuncture and clinical efficacy were analyzed. Totally 29 articles were included. The pain was the leading disease in category of diseases; the most commonly used application of placebo acupuncture design was telescopiform sliding blunt needle, accounting for 45. 16%; the treatment locations were non-acupoints mostly; in the needling depth, approximately 60. 00% selected non-penetrating needling and 26. 67% selected superficial needling; 28 articles indicated that acupuncture and placebo acupuncture had clinical effects, accounting for 96. 55%; 37. 93% of articles indicated acupuncture was superior to placebo acupuncture and 37. 93% of articles indicated acupuncture was not superior to placebo acupuncture. It is concluded that the design of placebo acupuncture should consider multiple factors, including main symptoms, operability, security, blinding and specific effects, and the objective indices should be selected for outcome evaluation.