Electroacupuncture ameliorates hepatic defects in a rat model of polycystic ovary syndrome induced by letrozole and a high-fat diet.

BACKGROUND: This study was designed to evaluate the effects of low-frequency electroacupuncture (EA) on glucose and lipid disturbances in a rat model of polycystic ovary syndrome (PCOS) characterized by insulin resistance (IR) and hepatic steatosis. METHODS: The PCOS rat model was induced by continuous administration of letrozole (LET) combined with a high-fat diet (HFD). Female Sprague-Dawley rats were divided into the following four groups: control, control + EA, LET + HFD and LET + HFD + EA. EA was administered five or six times a week with a maximum of 20 treatment sessions. Body weight, estrous cyclicity, hormonal status, glucose and insulin tolerance, lipid profiles, liver inflammation factors, liver morphology and changes in the phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway were evaluated. RESULTS: The rat model presented anovulatory cycles, increased body weight, elevated testosterone, abnormal glucose and lipid metabolism, IR, liver inflammation, hepatic steatosis and dysregulation of the insulin-mediated PI3-K/Akt signaling axis. EA reduced fasting blood glucose, fasting insulin, area under the curve for glucose, homeostasis model assessment of IR indices, triglycerides and free fatty acids, and alleviated hepatic steatosis. Furthermore, low-frequency EA downregulated mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6, upregulated mRNA expression of peroxisome proliferator-activated receptor (PPAR)-α, increased protein expression of phosphorylated (p)-Akt (Ser473), p-glycogen synthase kinase (GSK) 3ß (Ser9) and glucose transporter 4 (GLUT4), increased the ratio of p-GSK3ß to GSK3ß and downregulated protein expression of GSK3ß. CONCLUSION: An obese PCOS rat model with IR and hepatic steatosis was successfully established by the combination of LET and HFD. EA improved dysfunctional glucose and lipid metabolism in this PCOS-IR rat model, and the molecular mechanism appeared to involve regulation of the expression of key molecules of the PI3-K/Akt insulin signaling pathway in the liver.

Acupuncture as Treatment for Female Infertility: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The effects of acupuncture on female infertility remain controversial. Also, the variation in the participant, interventions, outcomes studied, and trial design may relate to the efficacy of adjuvant acupuncture. The aim of the study is to systematically evaluate the efficacy and safety of acupuncture for female with infertility and hopefully provide reliable guidance for clinicians and patients. METHODS: We searched digital databases for relevant studies, including EMBASE, PubMed, Cochrane Library, and Web of Science, and the Cochrane Library up to April 2021, for randomized controlled trials (RCTs) evaluating the effects of acupuncture on women undergoing IVF and other treatment. We included studies with intervention groups using acupuncture and control groups consisting of no acupuncture or sham (placebo) acupuncture. Primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR). Meta-regression and subgroup analysis were conducted on the basis of ten prespecified covariates to investigate the variances of the effects of adjuvant acupuncture on pregnancy rates and the sources of heterogeneity. Results: Twenty-seven studies with 7676 participants were included. The results showed that the intervention group contributes more in outcomes including live birth rate (RR = 1.34; 95% CI (1.07, 1.67); P < 0.05), clinical pregnancy rate (RR = 1.43; 95% CI (1.21, 1.69); P < 0.05), biochemical pregnancy rate (RR = 1.42; 95% CI (1.05, 1.91); P < 0.05), ongoing pregnancy rate (RR = 1.25; 95% CI (0.88, 1.79); P < 0.05), adverse events (RR = 1.65; 95% CI (1.15, 2.36); P < 0.05), and implantation rate (MD = 1.19; 95% CI (1.07, 1.33); P < 0.05) when compared with the control group, and the difference is statistically significant. In terms of the number of oocytes retrieved, good-quality embryo rate, miscarriages, and ectopic pregnancy rate, the difference between the acupuncture group and the control group was not statistically significant. Conclusions: Our analysis finds a benefit of acupuncture for outcomes in women with infertility, and the number of acupuncture treatments is a potential influential factor. Given the poor reporting and methodological flaws of existing studies, studies with larger scales and better methodologies are needed to verify these findings. More double-blind RCTs equipped with high quality and large samples are expected for the improvement of the level of evidence.

Effect of acupuncture and metformin on insulin sensitivity in women with polycystic ovary syndrome and insulin resistance: a three-armed randomized controlled trial.

STUDY QUESTION: Does acupuncture improve insulin sensitivity more effectively than metformin or sham acupuncture in women with polycystic ovary syndrome (PCOS) and insulin resistance (IR)? SUMMARY ANSWER: Among women with PCOS and IR, acupuncture was not more effective than metformin or sham acupuncture in improving insulin sensitivity. WHAT IS KNOWN ALREADY: Uncontrolled trials have shown that acupuncture improved insulin sensitivity with fewer side effects compared with metformin in women with PCOS and IR. However, data from randomized trials between acupuncture and metformin or sham acupuncture are lacking. STUDY DESIGN, SIZE, DURATION: This was a three-armed randomized controlled trial enrolling a total of 342 women with PCOS and IR from three hospitals between November 2015 and February 2018, with a 3-month follow-up until October 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged from 18 to 40 years with PCOS and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.14 were randomly assigned (n = 114 per group) to receive true acupuncture plus placebo (true acupuncture), metformin plus sham acupuncture (metformin, 0.5 g three times daily) or sham acupuncture plus placebo (sham acupuncture) for 4 months, with an additional 3-month follow-up. True or sham acupuncture was given three times per week, and 0.5 g metformin or placebo was given three times daily. The primary outcome was change in HOMA-IR from baseline to 4 months after baseline visit. Secondary outcomes included changes in the glucose AUC during an oral glucose tolerance test, BMI and side effects at 4 months after baseline visit. MAIN RESULTS AND THE ROLE OF CHANCE: After 4 months of treatment, the changes of HOMA-IR were -0.5 (decreased 14.7%) in the true acupuncture group, -1.0 (decreased 25.0%) in the metformin group and -0.3 (decreased 8.6%) in the sham acupuncture group, when compared with baseline. True acupuncture is not as effective as metformin in improving HOMA-IR at 4 months after baseline visit (difference, 0.6; 95% CI, 0.1-1.1). No significant difference was found in change in HOMA-IR between true and sham acupuncture groups at 4 months after baseline visit (difference, -0.2; 95% CI, -0.7 to 0.3). During the 4 months of treatment, gastrointestinal side effects were more frequent in the metformin group, including diarrhea, nausea, loss of appetite, fatigue, vomiting and stomach discomfort (31.6%, 13.2%, 11.4%, 8.8%, 14.0% and 8.8%, respectively). Bruising was more common in the true acupuncture group (14.9%). LIMITATIONS, REASONS FOR CAUTION: This study might have underestimated the sample size in the true acupuncture group with 4 months of treatment to enable detection of statistically significant changes in HOMA-IR with fixed acupuncture (i.e. a non-personalized protocol). Participants who withdrew because of pregnancy did not have further blood tests and this can introduce bias. WIDER IMPLICATIONS OF THE FINDINGS: True acupuncture did not improve insulin sensitivity as effectively as metformin in women with PCOS and IR, but it is better than metformin in improving glucose metabolism (which might reduce the risk of type 2 diabetes) and has less side effects. Metformin had a higher incidence of gastrointestinal adverse effects than acupuncture groups, and thus acupuncture might be a non-pharmacological treatment with low risk for women with PCOS. Further studies are needed to evaluate the effect of acupuncture combined with metformin on insulin sensitivity in these women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants 2017A020213004 and 2014A020221060 from the Science and Technology Planning Project of Guangdong Province. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov number: NCT02491333. TRIAL REGISTRATION DATE: 8 July 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 11 November 2015.

Yiqi Jiemin decoction alleviates allergic rhinitis in a guinea pig model by suppressing inflammation, restoring Th1/Th2 balance, and improving cellular metabolism.

We investigated the mechanisms underlying the therapeutic effects of Yiqi Jiemin decoction (YJD), a traditional Chinese medicine (TCM), in the ovalbumin (OVA)-induced allergic rhinitis (AR) model in guinea pigs. YJD significantly decreased infiltration of mast cells and eosinophils into the nasal mucosa of AR model guinea pigs. YJD also increased expression of TGF-ß in the nasal mucosa, restored the balance of Th1/Th2 immune cell responses, and decreased serum levels of various pro-inflammatory mediators, including histamine (HA), neuropeptide Y (NPY), acetylcholine (ACH), norepinephrine and immunoglobulin E (IgE). Metabolic analyses using liquid chromatography coupled with high-resolution mass spectrometry revealed that YJD improved cellular metabolism in AR model guinea pigs and increased serum levels of glycocholic acid while decreasing levels 1-palmitoyl lysophosphatidic acid. RNA-sequencing analysis identified BPIFB2 as a potential diagnostic biomarker and therapeutic target for AR. Functional enrichment analyses showed that YJD significantly inhibited cytokine secretion pathways in AR model guinea pigs. These findings demonstrate that YJD protects against OVA-induced AR in guinea pigs by suppressing inflammation in the nasal mucosa, restoring Th1/Th2 balance, and improving cellular metabolism.

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function.

BACKGROUND: Electroacupuncture is well known for its advantageous neuroanalgesic and therapeutic effects on myocardial ischemia-reperfusion injury. The purpose of the present research was to verify whether electroacupuncture can alleviate bupivacaine-induced myocardial injury. METHODS: Specific pathogen-free Wistar rats were used to establish the bupivacaine-induced myocardial injury model. Western blot, PCR, transmission electron microscope and enzyme-linked immunosorbent (ELISA) methods were used to evaluate bupivacaine-induced structure injury and dysfunction of the mitochondria as well as the alleviating effects of lipid emulsion, acupoint injection, and electroacupuncture pre-treatment of the oxidase stress response. RESULTS: Bupivacaine caused structural damage, degradation, and swelling of mitochondria. Furthermore, it reduced adenosine triphosphate (ATP) synthesis and impaired energy metabolism in the mitochondria. Structural and functional impairment of the mitochondria was alleviated via lipid emulsion injection, acupoint injection, and electroacupuncture pre-treatment. Electroacupuncture pre-treatment of PC6 yielded a greater alleviating effect than others approaches. Following electroacupuncture pre-treatment of PC6 point, the number of mitochondria increased; apoptosis was reduced, enzymatic activity of cytochrome C oxidase (COX) and superoxide dismutase and expression of uncoupling protein 2, voltage-dependent anion channel 1, and Bcl 2 were upregulated and SLC25A6, MDA levels were downregulated. Additionally, our findings indicated that electroacupuncture pre-treatment of PC6 point exerted an effect on the mitochondria via the mitochondrial-transcription-factor-A/nuclear-respiratory-factor-1/proliferator-activated-receptor-gamma-coactivator-1 pathway. CONCLUSION: The present study revealed that electroacupuncture pre-treatment of PC6 could effectively alleviate bupivacaine-induced myocardial mitochondrial damage, thereby providing a theoretical basis for clinical studies and applications of this treatment method.

A multicenter randomized trial of personalized acupuncture, fixed acupuncture, letrozole, and placebo letrozole on live birth in infertile women with polycystic ovary syndrome.

BACKGROUND: Traditional Chinese medicine (TCM) usually involves syndrome differentiation and treatment. Acupuncture, one form of TCM, requires the selection of appropriate acupoints and needling techniques, but many clinical trials on acupuncture have used fixed acupuncture protocols without accounting for individual patient differences. We have designed a multicenter randomized controlled trial (RCT) to evaluate whether personalized or fixed acupuncture increases the likelihood of live births in infertile women with polycystic ovary syndrome (PCOS) compared with letrozole or placebo letrozole. We hypothesize that letrozole is more effective than personalized acupuncture, which in turn is more effective than fixed acupuncture, and that placebo letrozole is the least effective intervention. Moreover, we hypothesize that personalized acupuncture is more likely to reduce the miscarriage rate and the risk of pregnancy complications compared with letrozole. METHODS/DESIGN: The study is designed as an assessor-blinded RCT. A total of 1100 infertile women with PCOS will be recruited from 28 hospitals and randomly allocated to 4 groups: personalized acupuncture, fixed acupuncture, letrozole, or placebo letrozole. They will receive treatment for 16 weeks, and the primary outcome is live birth. Secondary outcomes include ovulation rate, conception rate, pregnancy rate, pregnancy loss rate, changes in hormonal and metabolic parameters, and changes in quality of life scores. Adverse events will be recorded throughout the trial. All statistical analyses will be performed using IBM SPSS Statistics version 21.0 software (IBM Corp., Armonk, NY, USA), and a P value < 0.05 will be considered statistically significant. DISCUSSION: This study will be the first multicenter RCT to compare the effect of personalized or fixed acupuncture with letrozole or placebo letrozole on live birth in infertile women with PCOS. The findings will inform whether personalized acupuncture therapy can be considered an alternative treatment to improve the live birth rate in infertile women with PCOS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03625531. Registered on July 13, 2018. Chinese Clinical Trial Registry, ChiCTR1800017304. Registered on July 23, 2018.

Green Tea Liquid Consumption Alters the Human Intestinal and Oral Microbiome.

SCOPE: GTPs (green tea polyphenols) exert anti-CRC (colorectal cancer) activity. The intestinal microbiota and intestinal colonization by bacteria of oral origin has been implicated in colorectal carcinogenesis. GT modulates the composition of mouse gut microbiota harmonious with anticancer activity. Therefore, the effect of green tea liquid (GTL) consumption on the gut and oral microbiome is investigated in healthy volunteers (n = 12). METHODS AND RESULTS: 16S sequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis of both fecal and saliva samples (collected before intervention, after 2 weeks of GTL (400 mL per day) and after a washout period of one week) in healthy volunteers show changes in microbial diversity and core microbiota and difference in clear classification (partial least squares-discriminant analysis [PLS-DA]). An irreversible, increased FIR:BAC (Firmicutes to Bacteroidetes ratio), elevated SCFA producing genera, and reduction of bacterial LPS synthesis in feces are discovered in response to GTL. GTL alters the salivary microbiota and reduces the functional pathways abundance relevance to carcinogenesis. Similar bacterial networks in fecal and salivary microbiota datasets comprising putative oral bacteria are found and GTL reduces the fecal levels of Fusobacterium. Interestingly, both Lachnospiraceae and B/E (Bifidobacterium to Enterobacteriacea ratio-markers of colonization resistance [CR]) are negatively associated with the presence of oral-like bacterial networks in the feces. CONCLUSION: These results suggest that GTL consumption causes both oral and gut microbiome alterations.

The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels.

The Hedgehog (Hh) signaling pathway plays an essential role in vertebrate embryonic tissue patterning of many developing organs. Signaling occurs predominantly in primary cilia and is initiated by the entry of the G protein-coupled receptor (GPCR)-like protein Smoothened into cilia and culminates in gene transcription via the Gli family of transcription factors upon their nuclear entry. Here we identify an orphan GPCR, Gpr175 (also known as Tpra1 or Tpra40: transmembrane protein, adipocyte associated 1 or of 40 kDa), which also localizes to primary cilia upon Hh stimulation and positively regulates Hh signaling. Interaction experiments place Gpr175 at the level of PKA and upstream of the Gαi component of heterotrimeric G proteins, which itself localizes to cilia and can modulate Hh signaling. Gpr175 or Gαi1 depletion leads to increases in cellular cAMP levels and in Gli3 processing into its repressor form. Thus we propose that Gpr175 coupled to Gαi1 normally functions to inhibit the production of cAMP by adenylyl cyclase upon Hh stimulation, thus maximizing signaling by turning off PKA activity and hence Gli3 repressor formation. Taken together our data suggest that Gpr175 is a novel positive regulator of the Hh signaling pathway.

[Elicitation of mismatch negativity and its influence from stimuli deviant in the healthy youth].

OBJECTIVE: To work out the elicitation plan, obtain the mismatch negativity (MMN) and get out the laboratory normal value as well as to study the influence to MMN from the deviation of auditory stimuli. METHODS: Hearing test of the tone burst stimulation was performed on 21 healthy young volunteers according to oddball stimulation sequence. Each subject was performed two kinds of auditory stimuli including frequency deviant stimuli and intensity deviant stimuli, and of each one included three series of stimulation. MMN was gained by subtracting the ERP of deviant stimuli from the ERP of standard stimuli. The latency and amplitude of each MMN were recorded, and then the effect of the deviant extent for MMN was analyzed. RESULTS: By this setup the MMN of normal young people was recorded and normal value of latency and amplitude of MMN were got. In the group of frequency deviant stimuli, the MMN latency [(155.81 +/- 29.08) ms], if the frequency was up to 2000 Hz, was shorter than that when the frequency deviance was 1000 Hz [(182.89 +/- 45.85) ms, (183.32 +/- 43.33) ms] (P = 0.033, 0.030); when the deviant extent were the same, the latency had no obvious difference if changing the frequency of the standard and deviant stimuli (P = 0.973); the MMN amplitude of three groups [(3.85 +/- 2.22) microV, (2.90 +/- 2.05) microV, (2.66 +/- 2.12) microV] had no obvious difference among them (P > 0.05). In the group of intensity deviant stimuli, the MMN latency [(157.04 +/- 34.87) ms], if the frequency was up to 20 dB, was shorter (P = 0.025, 0.017) than that when the intensity deviance was 10 dB [(184.46 +/- 38.05) ms, (186.24 +/- 42.36) ms]. When the deviant extent were the same, the latency had no obvious difference (P = 0.882) if changing the intensity of the standard and deviant stimuli but only group 4 and group 6 [(3.41 +/- 1.64) microV, (2.37 +/- 1.47) microV] were different in evidence (P = 0.031) while the others had no obvious difference (P = 0.524, 0.122). CONCLUSIONS: MMN was only related to the difference between standard stimuli and deviant stimuli, but there was no relationship between MMN and the notice, which indicate that MMN could objectively reflect the capability of brain to detect the change of stimuli. MMN is the representation of brain high-level sensory function.

Cognitive conflict in audiovisual integration: an event-related potential study.

This study used event-related potentials (ERPs) to investigate the electrophysiological correlates of cognitive conflict in audiovisual integration during an audiovisual task. ERP analyses revealed: (i) the anterior N1 and P1 were elicited in both matched and mismatched conditions and (ii) audiovisual mismatched answers elicited a more negative ERP deflection at 490 ms (N490) than matched answers. Dipole analysis of the difference wave (mismatched minus matched) localized the generator of the N490 to the posterior cingulate cortex, which may be involved in the control and modulation of conflict processing of Chinese characters when visual and auditory information is mismatched.

Human Crossveinless-2 is a novel inhibitor of bone morphogenetic proteins.

Drosophila Crossveinless-2 (dCV-2) is required for local activation of Mad phosphorylation in the fruit fly wing and has been postulated to be a positive regulator of BMP-mediated signaling. In contrast, the presence of 5 Chordin-like cysteine-rich domains in the CV-2 protein suggests that CV-2 belongs to a family of well-established inhibitors of BMP function that includes Chordin and Sog [Development 127 (2000) 3947]. We have identified a human homolog of Drosophila CV-2 (hCV-2). Here we show that purified recombinant hCV-2 protein inhibits BMP-2 and BMP-4 dependent osteogenic differentiation of W-20-17 cells, as well as BMP dependent chondrogenic differentiation of ATDC5 cells. Interestingly, hCV-2 messenger RNA is expressed at high levels in human primary chondrocytes, whereas expression in primary human osteoblasts is low. These results suggest that hCV-2 may regulate BMP responsiveness of osteoblasts and chondrocytes in vivo. Taken together we have shown that contrary to the function predicted from the fruit fly, Crossveinless-2 is a novel inhibitor of BMP function.