Baicalin ameliorates insulin resistance and regulates hepatic glucose metabolism via activating insulin signaling pathway in obese pre-diabetic mice.

BACKGROUND: Diabetes belongs to the most prevalent metabolic diseases worldwide, which is featured with insulin resistance, closely associated with obesity and urgently needs to be treated. Baicalin, belonging to natural flavonoids, has been reported to inhibit oxidative stress or inflammatoin. PURPOSE: This study investigated the properties of baicalin on modulating abnormal glucolipid metabolism, as well as the underlying in-vitro and in-vivo mechanisms. METHODS: Insulin-resistant (IR)-HepG2 cells were stimulated by dexamethasone (20 µM) and high glucose (50 mM) for 48 h and incubated with or without baicalin or metformin for another 16 h. Male C57BL/6 J mice were fed with a high-fat diet (HFD, 60 % kcal% fat) during the total 14 weeks. Obese mice were then administered with baicalin (50 and 100 mg/kg) or vehicle solution everyday through oral gavage during the last 4-week period. Moreover, baicalin metabolisms in vitro and in vivo were determined using UPLC/MS/MS to study its metabolism situation. RESULTS: Exposure to dexamethasone and high glucose damaged the abilities of glycogen synthesis and glucose uptake with elevated oxidative stress and increased generation levels of advanced glycation end-products (AGEs) in HepG2 cells. These impairments were basically reversed by baicalin treatment. Four-week oral administration with baicalin ameliorated hyperglycemia and dyslipidemia in HFD-induced obese and pre-diabetic mice. Downregulation of IRS/PI3K/Akt signaling pathway accomplished with reduced GLUT4 expression and enhanced GSK-3ß activity was observed in insulin resistant HepG2 cells as well as liver tissues from pre-diabetic mice; and such effect was prevented by baicalin. Moreover, baicalin and its matabolites were detected in IR-HepG2 cells and mouse plasma. CONCLUSION: The study illustrated that baicalin alleviated insulin resistance by activating insulin signaling pathways and inhibiting oxidative stress and AGEs production, revealing the potential of baicalin to be a therapeutic natural flavonoid against hepatic insulin and glucose-lipid metabolic disturbance in pre-diabetes accompanied with obesity.

Mechanisms of Bushen Tiaoxue Granules against controlled ovarian hyperstimulation-induced abnormal morphology of endometrium based on network pharmacology.

Bushen Tiaoxue Granules (BTG) is an empirical Chinese herbal formula that has been used for the treatment of subfertility. The protective effect of BTG on controlled ovarian hyperstimulation (COH)-induced impaired endometrial receptivity has been reported in our previous study. This study aims to explore the mechanisms of BTG on ameliorating abnormal morphology of endometrium based on network pharmacology. Active compounds of BTG were identified via the traditional Chinese medicine systems pharmacology and UPLC-MS technology. The SwissTargetPrediction platform and HERB database were used to screen out the putative targets of BTG. Potential targets of endometrial dysfunction caused by COH were obtained from three GEO databases. Through the STRING database, the protein-protein interaction was carried out according to the cross-common targets of diseases and drugs. GO terms and KEGG pathways enrichment analyses were conducted via the Metascape database. AutoDock Vina was used for docking validation of the affinity between active compounds and potential targets. Finally, in vivo experiments were used to verify the potential mechanisms derived from network pharmacology study. A total of 141 effective ingredients were obtained from TCMSP and nine of which were verified in UPLC-MS. Six genes were selected through the intersection of 534 disease related genes and 165 drug potential targets. Enrichment analyses showed that BTG might reverse endometrial dysfunction by regulating adherens junction and arachidonic acid metabolism. Hematoxylin-eosin staining revealed that BTG ameliorated the loose and edematous status of endometrial epithelium caused by COH. The protein expression of FOXO1A, ß-Catenin and COX-2 was decreased in the COH group, and was up-regulated by BTG. BTG significantly alleviates the edema of endometrial epithelium caused by COH. The mechanisms may be related to adheren junctions and activation of arachidonic acid metabolism. The potential active compounds quercetin, taxifolin, kaempferol, eriodictyol, and isorhamnetin identified from the BTG exhibit marginal cytotoxicity. Both high and low concentrations of kaempferol, eriodictyol, and taxifolin are capable of effectively ameliorating impaired hESC cellular activity.

The effects of reflexology on symptoms in pregnancy: A systematic review of randomized controlled trials.

Objective: This review assessed the effects of reflexology on symptoms in pregnancy. Methods and analysis: PubMed, Embase, Springer, Web of Science, the Cochrane Library, and reference lists of previous systematic reviews were searched for the eligible randomized controlled trials (RCT) from the inception date of each predefined database up to May 31st, 2023. Data were extracted, and methodological quality was evaluated by the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). The efficacy of treatment was assessed using pooled effect sizes (Hedges' g) and 95% confidence intervals (CI). Meta-analysis was performed using the RevMan 5.4 manager, and publication bias was evaluated by Begg's test. Results: The included a total of 13 RCTs in this review, of eleven was high risk of bias and two were low, reported the effects of reflexology on low back and/or pelvic pain (LBPP), labor pain, duration of labor, anxiety, fatigue, sleep quality, constipation symptoms, and ankle and foot edema in pregnancy. The effect sizes (Hedges' g) for reflexology in labor pain, duration of labor, anxiety, fatigue, and sleep quality showed statistical significance, which the meta-analysis also confirmed except for fatigue and sleep quality due to insufficient studies. Conclusion: Reflexology is probably effective and safe for labor pain, duration of labor, and anxiety in pregnancy, while the evidences for reflexology in LBPP, fatigue, sleep quality, constipation symptoms, and ankle and foot edema during pregnancy were insufficient. Based on the low to high quality of included studies, strong supportive evidence is not yet available. Rigorous-design and large-scale clinical trials should be conducted to provide higher-quality, reliable evidence.

Underlying mechanisms of acupuncture therapy on polycystic ovary syndrome: Evidences from animal and clinical studies.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of reproductive age. Current standard treatment includes lifestyle change, oral pharmacological agents, and surgical modalities. However, the efficacy of current therapies is less than satisfactory. Clinical evidence has shown that acupuncture is effective for regulating hormone levels, promoting ovulation, and attenuating insulin resistance in patients with PCOS. Acupuncture may affect the production of ß-endorphin, which may lead to gonadotropin-releasing hormone secretion and then affect ovulation, menstrual cycle, and fertility. The mechanism of acupuncture for patients with PCOS has not been comprehensively reviewed so far. Better understanding of the mechanisms of acupuncture would help popularize the use of acupuncture therapy for patients with PCOS. In this narrative review, we aimed to overview the potential mechanisms and evidence-based data of acupuncture on PCOS, and analyze the most frequently used acupoints based on animal and clinical studies. The results of this study will contribute to a better understanding of the current situation in this field.

The Efficacy of Chinese Herbal Medicine in Animal Models of Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Objective: This study aimed to evaluate the efficacy of Chinese herbal medicine (CHM) on ovarian mass, weight, sex hormone disorders, and insulin resistance in animal models of polycystic ovary syndrome (PCOS). Methods: This systematic review and meta-analysis was conducted through a comprehensive search in three databases to find studies testing CHM in animal models of PCOS. Two researchers independently reviewed the retrieval, extraction, and quality assessment of the dataset. The pooled effects were calculated using random-effect models; heterogeneity was explored through subgroup analysis; and stability was assessed through sensitivity analysis. In addition, publication bias was assessed using the Egger's bias test. Results: Fifteen studies with twelve mice and 463 rats published from 2016 to 2021 met the inclusion criteria. The results of primary outcomes revealed that CHM therapy was significantly different with control animals in ovarian mass and testosterone (SMD, -1.01 (95% CI, -1.58, -1.45); SMD, -1.62 (95% CI, -2.07, -1.16), respectively). The secondary outcomes as well showed an overall positive effect of CHM compared with control animals in weight (SMD, -1.02 (95% CI, -1.39, -0.65)), follicle-stimulating hormone (FSH) (SMD, 0.58 (95% CI, 0.19, 0.97)), luteinizing hormone (LH) (SMD, -0.94 [95% CI, -1.25, -0.64)), homeostasis model assessment-insulin resistance (HOMA-IR) (SMD, -1.24 (95% CI, -1.57, -0.92)). Subgroup analyses indicated that PCOS induction drug, formula composition, random allocation, and assessment of model establishment were relevant factors that influenced the effects of interventions. The stability of the meta-analysis was showed robust through sensitivity analysis. The publication bias was substantial. Conclusions: Administration with CHM revealed a statistically positive effect on ovarian mass, weight, sex hormone disorders, and insulin resistance. Moreover, these data call for further high-quality studies investigating the underlying mechanism in more depth.

Efficacy of Chinese herbal medicine for tPA thrombolysis in experimental stroke: A systematic review and meta-analysis.

BACKGROUND: Tissue-type plasminogen activator (tPA) remains the sole FDA approved thrombolytic drug for ischemic stroke. But delayed thrombolytic therapy with tPA may increase the risk of hemorrhagic transformation. Many Chinese herbal medicines have been used as tPA helpers to enhance the capacity of tPA and minimize the risk of hemorrhagic transformation. The efficacy of Chinese herbal medicines on tPA thrombolysis is not systematically analyzed. METHODS: We searched the following three databases up to January 2022: Web of Science, PubMed, and Scopus. Studies that reported the efficacy and safety of Chinese herbal medicines on tPA thrombolysis in experimental stroke were included. The efficacy outcomes were neurological score and infarct volume, the safety outcomes were cerebral hemorrhage and blood brain barrier (BBB) damage. We used the checklist of CAMARADES to assess the quality of included studies. Standardized mean difference (SMD) with 95% confidence intervals were used to assess all the outcomes. Subgroup analyses were performed to explore the sources of heterogeneity. Trim and fill method and Egger's test were used to assess the potential publication bias. Sensitivity analyses were used to identify the stability of the results. RESULTS: A total of nine studies including 11 Chinese herbal medicines fulfilled the inclusion criteria and were subsequently analyzed. The pooled data demonstrated that Chinese herbal medicines improved neurological score (2.23 SMD, 1.42-3.04), infarct volume (1.08 SMD, 0.62-1.54), attenuated cerebral hemorrhage (1.87 SMD, 1.34-2.4), and BBB dysfunction (1.9 SMD, 1.35-2.45) following tPA thrombolysis in experimental stroke. Subgroup analysis indicated that the route of drug delivery, dosage of tPA, and stroke model used may be factors inducing heterogeneity and influencing the efficacy. CONCLUSION: Treatment with Chinese herbal medicines significantly improved neurological score and infarct volume, reduced cerebral hemorrhage and BBB damage after tPA thrombolysis. This study supports Chinese herbal medicine as an adjuvant therapy in reducing the side effects of tPA thrombolysis after acute ischemic stroke. The results should be interpreted with more caution since this article was based on animal studies.

Melatonin reverses mitochondria dysfunction and oxidative stress-induced apoptosis of Sudan I-exposed mouse oocytes.

Sudan I is one of the industry dyes and widely used in cosmetics, wax agent, solvent and textile. Sudan I has multiple toxicity such as carcinogenicity, mutagenicity, genotoxicity and oxidative damage. However, Sudan I has been illegally used as colorant in food products, triggering worldwide attention about food safety. Nevertheless, the toxicity of Sudan I on reproduction, particularly on oocyte maturation is still unclear. In the present study, using mouse in vivo models, we report the toxicity effects of Sudan I on mouse oocyte. The results reflect that Sudan I exposure disrupts spindle organization and chromosomes alignment as well as cortical actin distribution, thus leading to the failure of polar body extrusion. Based on the transcriptome results, it is found that the exposure of Sudan I leads to the change in expression of 764 genes. Moreover, it's further reflected that the damaging effects of Sudan I are mediated by the destruction of mitochondrial functions, which induces the accumulated ROS to stimulate oxidative stress-induced apoptosis. As an endogenous hormone, melatonin within the ovarian follicle plays function on improving oocyte quality and female reproduction by efficiently suppressing oxidative stress. Moreover, melatonin supplementation also improves oocyte quality and increases fertilization rate during in vitro culture. Consistent with these, we find that in vivo supplementation of melatonin efficaciously suppresses mitochondrial dysfunction and the accompanying apoptosis, thus reverses oocyte meiotic deteriorations. Collectively, our results prove the reproduction toxicity of Sudan I for the exposure of Sudan I reduces the oocyte quality, and demonstrate the protective effects of melatonin against Sudan I-induced meiotic deteriorations.

The Ameliorating Effects of Bushen Huatan Granules and Kunling Wan on Polycystic Ovary Syndrome Induced by Dehydroepiandrosterone in Rats.

AIM: To investigate the effects of Bushen Huatan Granules (BHG) and Kunling Wan (KW), the two Chinese medicines, on the regulation of polycystic ovary syndrome (PCOS) and their underlying mechanisms. MATERIALS AND METHODS: PCOS rat model was established by subcutaneous injection of dehydroepiandrosterone (DHEA) (6 mg/100 g/day) for 20 days, followed by treatment with BHG (0.75, 1.49, and 2.99 g/kg) or KW (0.46, 0.91, and 1.82 g/kg) by gavage for 4 weeks. Estrous cycle was detected by vaginal smears. Follicles development was assessed by histology. Levels of testosterone and insulin in serum were tested by ELISA. Apoptosis of Granulosa cells (GCs) was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining. Pathways associated with apoptosis were detected with western blot. Pregnancy outcome was also assessed. GCs were pre-treated with 10-5 M testosterone in vitro for 24 h, then incubated with serum from rats receiving BHG (1.49 g/kg) or KW (1.82 g/kg). The parameters concerning apoptosis, mitochondrial function and endoplasmic reticulum stress were assessed. RESULTS: Post-treatment with either BHG or KW ameliorated DHEA-induced irregular estrous cycles, follicles development abnormalities, increase of testosterone and insulin in serum, and the apoptosis of GCs. Post-treatment with BHG decreased the expression of cleaved caspase-9/caspase 9, release of cytochrome C from mitochondria, and mitochondria reactive oxygen species production, increased activities of complex I, II, IV of ovarian tissue. Post-treatment with KW decreased the levels of caspase-12, GRP78, C/EBP homologous protein, phosphorylation of IRE-I, x-box-binding protein 1s, as well as phosphorylation of proline-rich receptor-like protein kinase, phosphorylation of eukaryotic translation initiation factor 2α and ATF4 of ovarian tissue and GCs. Both BHG and KW ameliorated pregnancy outcome. CONCLUSION: This study demonstrated BHG or KW as a potential strategy for treatment of PCOS induced by DHEA, and suggested that the beneficial role of the two medicines were mediated by different pathway with the effect of BHG being correlated with the regulation of mitochondria, while the effect of KW being attributable to protection of endoplasmic reticulum stress.

Efficacy of acupuncture for sciatica: study protocol for a randomized controlled pilot trial.

BACKGROUND: Acupuncture is widely used for pain diseases while evidence of its efficacy for sciatica is insufficient. We aim to explore the feasibility and efficacy of acupuncture with different acupoint selecting strategies for sciatica induced by lumbar disc herniation. METHODS: This is a multicenter, three-arm, patient-assessor-blinded randomized controlled pilot trial. Ninety patients will be assigned randomly into 3 groups including disease-affected meridians (DAM) group, non-affected meridians (NAM) group, and sham acupuncture (SA) group in a 1:1:1 ratio. The trial involves a 4-week treatment along with follow-up for 22 weeks. The primary outcome is the change of leg pain intensity measured by the visual analogue scale (VAS) from baseline to week 4 after randomization. Secondary outcomes include functional status, back pain intensity, and quality of life. Adverse events will also be recorded. DISCUSSION: The results will inspire the optimal acupuncture strategy for sciatica and help establish a better design as well as power calculation for a full-scale study. TRIAL REGISTRATION: ChiCTR2000030680 (Chinese Clinical Trial Registry, http://www.chictr.org.cn , registered on 9 March 2020).

[Acupuncture ameliorates negative emotion in PCOS patients: a randomized controlled trial].

OBJECTIVE: To evaluate the effectiveness and possible mechanism of acupuncture treatment for negative emotion in patients with polycystic ovary syndrome (PCOS). METHODS: A total of 40 PCOS patients were randomly divided into an observation group and a control group, 20 cases in each one. Both groups received lifestyle interventions (exercise and diet guidance) on the 5th day of menstruation. On the basis of above treatment, the patients in the observation group received acupuncture at Guanyuan (CV 4), Zhongwan (CV 12), Guilai (ST 29), Futu (ST 32), Liangqiu (ST 34), Sanyinjiao (SP 6), Zusanli (ST 36), Hegu (LI 4), Shenmen (HT 7), Baihui (GV 20) as the main acupoints, and connected the electroacupuncture (continuous wave, 2 Hz, 30 min), once every other day, 3 times a week. The treatment for 1 month was as one course and 4 courses were required totally in both groups. Before and after treatment, the body mass index (BMI), ferriman-gallway (F-G) score, self-rating anxiety scale (SAS) score, self-rating depression scale (SDS) score, PCOS health-related quality of life questionnaire (PCOSQ) score were observed, meanwhile, serum sex hormone, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), progestin (P), prolactin (PRL), testosterone (T), sex hormone-binding globulin (SHBG) and free androgen index (FAI) levels, and serumß-endorphin levels were detected. RESULTS: Compared with before treatment, the BMI, F-G score, SAS score, SDS score and serum FAI level were decreased and the PCOSQ score and the levels of serum SHBG andß-endorphin were increased in the observation group after treatment (all P<0.05). Compared with before treatment, the SDS score was decreased in the control group after treatment (P<0.05). Compared with the control group, the F-G score, SDS score, SAS score, and serum FAI level were lower, and the PCOSQ score and serumß-endorphin level were higher in the observation group after treatment (all P<0.05). CONCLUSION: Applying acupuncture to the treatment of patients with PCOS can effectively relieve anxiety and depression, and the mechanism may be related to the regulation on the levels of serumß-endorphin and androgen.

The ameliorating effects of Bushen Tiaoxue Granules and Kunling Wan on impaired angiogenesis and endometrial receptivity in rats following controlled ovarian hyperstimulation.

OBJECTIVE: To investigate the effects of Bushen Tiaoxue Granules and Kunling Wan, the two Chinese medicines, on vascular dysfunction and the impairment of endometrial receptivity caused by controlled ovarian hyperstimulation and its underlying mechanism. METHODS: Female Sprague Dawley rats with regular estrous cycle were enrolled and given Bushen Tiaoxue Granules or Kunling Wan by gavage for 12 days, and then, controlled ovarian hyperstimulation model was induced. We assessed endometrial microvessels, endometrial blood flow, levels of estradiol and progesterone in serum, vascular endothelial growth factor A upstream molecules estrogen and progesterone receptors in the endometrium, and pregnancy outcome. RESULTS: Pre-treatment of Bushen Tiaoxue Granules or Kunling Wan increases endometrial blood flow of controlled ovarian hyperstimulation rats, up-regulates vascular endothelial growth factor A and microvessels, improves the endometrial morphology of controlled ovarian hyperstimulation rats during implantation, decreases the super physiological concentration of estradiol and progesterone in serum, and increases the expression of vascular endothelial growth factor A upstream molecules estrogen and progesterone receptors in the endometrium. In addition, Bushen Tiaoxue Granules or Kunling Wan elevates the lysophosphatidic acid receptor 3 that participates in vascularization and increases the expression of leukemia inhibitory factor through up-regulating the expression of p53 in the endometrium, ultimately affecting pregnancy outcome. CONCLUSION: This study demonstrated Bushen Tiaoxue Granules or Kunling Wan as a potential strategy for prevention of impairment in angiogenesis and endometrial receptivity induced by controlled ovarian hyperstimulation.

Default Mode Network as a Neural Substrate of Acupuncture: Evidence, Challenges and Strategy.

Acupuncture is widely applied all over the world. Although the neurobiological underpinnings of acupuncture still remain unclear, accumulating evidence indicates significant alteration of brain activities in response to acupuncture. In particular, activities of brain regions in the default mode network (DMN) are modulated by acupuncture. DMN is crucial for maintaining physiological homeostasis and its functional architecture becomes disrupted in various disorders. But how acupuncture modulates brain functions and whether such modulation constitutes core mechanisms of acupuncture treatment are far from clear. This Perspective integrates recent literature on interactions between acupuncture and functional networks including the DMN, and proposes a back-translational research strategy to elucidate brain mechanisms of acupuncture treatment.

Acupuncture or metformin to improve insulin resistance in women with polycystic ovary syndrome: study protocol of a combined multinational cross sectional case-control study and a randomised controlled trial.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is linked to hyperinsulinemia and insulin resistance with dysfunctional glucose metabolism. Pilot studies suggests that acupuncture treatment with combined manual and low-frequency electrical stimulation (electroacupuncture (EA)) of the needles decrease circulating glycated haemoglobulin (HbA1c) and homeostatic model assessment-insulin resistance. Therefore, we here aim to investigate if acupuncture treatment or metformin together with lifestyle or lifestyle management alone improves insulin sensitivity and related symptoms in overweight/obese women with PCOS. METHODS AND ANALYSIS: This is a two-centre multinational (Sweden and China), cross-sectional case-control study combined with an open-labelled randomised controlled trial (RCT). Participants are randomised to one of three groups: (1) EA 2-3 times/week during 4 months+lifestyle management; (2) metformin, 500 mg, three/day during 4 months+lifestyle management; or (3) lifestyle management alone. The primary outcome measure in the RCT is changes in HbA1C. A total of 123 obese overweight women with PCOS will be enrolled and randomised into one of the three groups with a target power of at least 80% and 5% significance level based on two-sided tests. ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethical Review Board of Stockholm and of Peking University Third Hospital, China. Primary outcome data of the RCT will be published in a relevant journal together with supporting secondary outcome measurements. Further, outcome measurements will be published in separate papers as well as case-control data. EXPECTED RESULTS: We anticipate that EA and metformin, both with lifestyle management, are equally effective and superior to lifestyle management alone for improvement of glycaemic control. TRIAL REGISTRATION NUMBERS: NCT02647827 and EudraCT2015-004250-18.

[Effect and regulation mechanism of Chinese Bushen Huoxue prescriptions on endometrial receptivity].

Endometrial receptivity refers to the ability of endometrium to accept and accommodate endometrial implantation in the process of embryo implantation in implantation window period. It is an important factor affecting the rate of blastocyst implantation in assisted reproduction. It is worth mentioning that ovulation-promoting drugs in current assisted reproduction technology could reduce endometrial receptivity and inhibit blastocyst implantation, greatly affecting the success rate of assisted reproduction. By searching Chinese Scientific Citation Database, it was found that 121 studies from 2006 to 2017 showed that Chinese Bushen Huoxue prescriptions could significantly improve the development of pinopodes in the implantation window, promote the expression of endometrial receptors ER, PR, integrinß3, LIF, LPA3 and other molecules, and thus enhancing endometrial receptivity and improving embryo implantation. In the theory of traditional Chinese medicine, kidney deficiency is an important factor causing infertility. Chinese Bushen Huoxue prescriptions could nourish the kidney-essence, and promote blood circulation, playing an important role in treating infertility with combined application of western medicine and traditional Chinese medicine. These studies suggest that Chinese Bushen Huoxue prescriptions could improve endometrial receptivity, and their mechanisms are worth further investigation. This article has summarized the research progress of Chinese Bushen Huoxue prescriptions in the field of assisted reproduction, summarized the deficiency of current researches, and preliminarily discussed the potential application prospect of Chinese Bushen Huoxue prescriptions in the treatment of infertility.

Contralateral Electroacupuncture Relieves Chronic Neuropathic Pain in Rats with Spared Nerve Injury.

BACKGROUND Acupuncture and electroacupuncture (EA) are widely applied in the treatment of various conditions, including pain. Acupuncture stimulation is applied not only in areas close to pain sites, but also in distal regions or on the contralateral side of the body. Identifying which acupuncture paradigms produce best therapeutic effects is of clinical significance. MATERIAL AND METHODS Spared nerve injury (SNI) was applied to establish a rat model of neuropathic pain. We applied 14 sessions of EA (BL 60 and BL 40, 1-2 mA, and 2 Hz, 30 min per session) every other day from days 3 to 29 after surgery on the contralateral or ipsilateral side of pain. von Frey hair was applied to examine mechanical allodynia in the SNI model and analgesic effects of EA. All experimental procedures were approved by the Animal Care and Use Committee of our university, according to the guidelines of the International Association for the Study of Pain. RESULTS SNI produced significant and long-lasting mechanical allodynia (p<0.001) in injured paws. Repeated EA on the contralateral side of the pain significantly attenuated mechanical allodynia from 14 days after surgery (p<0.05). By contrast, ipsilateral EA did not show analgesic effects (p>0.05). CONCLUSIONS These findings indicate that contralateral EA is superior to local EA in some types of pain disorders. Further investigations are needed for a more comprehensive understanding of the central mechanisms of acupuncture.

Randomised controlled trial of contralateral manual acupuncture for the relief of chronic shoulder pain.

OBJECTIVE: To explore the effects of contralateral manual acupuncture (MA) on patients with chronic shoulder pain. METHODS: Eighty patients with chronic shoulder pain were randomly allocated to receive contralateral MA (n=38) for 4 weeks or to remain on a waiting list while receiving conventional orthopaedic therapy (n=42). Visual analogue scale (VAS) scores were taken as the primary outcome measure and used for a priori power calculation. Secondary outcome measures for the assessment of shoulder mobility and quality of life included the Jobe test, the Constant-Murley (CM) score, the Disabilities of the Arm, Shoulder and Hand (DASH) score, and the 36 item Short Form Health Survey (SF-36). RESULTS: Intention-to-treat (ITT) analysis demonstrated significant pain relief with contralateral acupuncture, with mean differences in VAS scores compared to the waiting list group of -19.4 (-28.0 to -10.8) at 2 weeks, -40.4 (-49.0 to -31.8) at 4 weeks, -41.1 (-49.7 to -32.5) at 8 weeks, and -40.9 (-49.5 to -32.3) at 16 weeks. CM and DASH scores were also improved at all time points (p<0.01). Shoulder mobility, physical functioning, social functioning and mental health components of the SF-36 were also improved by contralateral acupuncture at 8 weeks. No significant adverse effects were observed. CONCLUSIONS: These results demonstrate beneficial effects of contralateral acupuncture in the treatment of chronic shoulder pain, both in terms of pain and function. Future research is required to compare directly the effects of local and contralateral acupuncture and to quantify the specific and non-specific effects. TRIAL REGISTRATION NUMBER: NCT01733914.

Comparison of electroacupuncture in restrained and unrestrained rat models.

Acupuncture and electroacupuncture (EA) are widely used to treat a variety of diseases including pain. In preclinical research, EA is usually applied by inserting acupuncture needles into the hindlimbs of rats restrained in small tubes or bags. This restrained model of EA not only causes stress-like behaviors but also is limited in stimulating locations and intensities. In 2004, a novel, unrestrained model of EA was introduced. However, these two EA methods have never been directly compared regarding their analgesic effects and other features such as stress. In the present study, we reported similar analgesic effects between restrained and unrestrained EA in rats of acute inflammatory pain induced by intraplantar injection of CFA. In addition, rats receiving unrestrained EA showed less significant stress-like behaviors and tolerated higher current intensity. These advantages suggest that this unrestrained EA method can replace the traditional restrained procedure with similar analgesic effects and allow for more choices of stimulating intensities and locations.

Anterior cingulate cortex is crucial for contra- but not ipsi-lateral electro-acupuncture in the formalin-induced inflammatory pain model of rats.

Acupuncture and electro-acupuncture (EA) are now widely used to treat disorders like pain. We and others have shown previously that current frequency, intensity and treatment duration all significantly influence the anti-nociceptive effects of EA. There is evidence that stimulating sites also affect the antinociception, with EA applied ipsilaterally to the pain site being more effective under some pain states but contralateral EA under others. It was recently reported that local adenosine A1 receptors were responsible for ipsilateral acupuncture, but what mechanisms specifically mediate the anti-nociceptive effects of contralateral acupuncture or EA remains unclear. In the present study, we applied 100 Hz EA on the ipsi- or contra-lateral side of rats with inflammatory pain induced by intra-plantar injection of formalin, and reported distinct anti-nociceptive effects and mechanisms between them. Both ipsi- and contra-lateral EA reduced the paw lifting time in the second phase of the formalin test and attenuated formalin-induced conditioned place aversion. Contralateral EA had an additional effect of reducing paw licking time, suggesting a supraspinal mechanism. Lesions of rostral anterior cingulate cortex (ACC) completely abolished the anti-nociceptive effects of contra- but not ipsi-lateral EA. These findings were not lateralized effects, since injection of formalin into the left or right hind paws produced similar results. Overall, these results demonstrated distinct anti-nociceptive effects and mechanisms between different stimulating sides and implied the necessity of finding the best stimulating protocols for different pain states.