Yin Yang 1 suppresses tumor invasion and metastasis in nasopharyngeal carcinoma by negatively regulating eIF4E transcriptional activity and expression.

Tumor metastasis is a leading cause of death in nasopharyngeal carcinoma (NPC) patients. Previous research has identified that transcription factor Yin Yang 1 (YY1) acts as a tumor suppressor that inhibits cell proliferation and tumor growth in NPC; however, the role and the molecular mechanisms of YY1 in NPC invasion and metastasis remain unclear. In this study, we discovered that YY1 could inhibit the migration and invasion of NPC cells in vitro as well as NPC xenograft tumor metastasis in vivo. Furthermore, we identified eIF4E as a direct downstream target of YY1, and YY1 could negatively regulate the expression of eIF4E at transcriptional level. Moreover, we found that eIF4E promoted the migration and invasion of NPC cells as well as NPC lung metastasis, suggesting its potential as a pro-metastatic mediator in NPC. Importantly, restoring eIF4E expression could partially reverse the inhibitory effects of YY1 on NPC malignancy. In consistent with these findings, the expression of YY1 was downregulated while eIF4E was upregulated in NPC patients with metastasis, and there was a negative correlation between YY1 and eIF4E expression. Collectively, our results indicate that YY1 suppresses the invasion and metastasis of NPC by negatively regulating eIF4E transcription. Therefore, targeting the YY1/eIF4E transcriptional axis could be a potential therapeutic strategy for the treatment of patients with NPC.

Dissecting the roles and clinical potential of YY1 in the tumor microenvironment.

Yin-Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins and plays a vital dual biological role in cancer as an oncogene or a tumor suppressor during tumorigenesis and tumor progression. The tumor microenvironment (TME) is identified as the "soil" of tumor that has a critical role in both tumor growth and metastasis. Many studies have found that YY1 is closely related to the remodeling and regulation of the TME. Herein, we reviewed the expression pattern of YY1 in tumors and summarized the function and mechanism of YY1 in regulating tumor angiogenesis, immune and metabolism. In addition, we discussed the potential value of YY1 in tumor diagnosis and treatment and provided a novel molecular strategy for the clinical diagnosis and treatment of tumors.

Effects of combining acupuncture with exercise training on relieving dyspnea and improving exercise tolerance in chronic obstructive pulmonary disease patients: a protocol for a single-blind, randomized, sham-controlled trial.

BACKGROUND: Exercise training is beneficial for patients with chronic obstructive pulmonary disease (COPD). However, the effect of exercise training is limited by patients' impaired exercise capacity, exertional dyspnea and other respiratory problems. Acupuncture, as a reliable and safe therapy, is effective in reducing dyspnea, relieving respiratory muscle fatigue, and improving exercise capacity of COPD patients. However, it is not known whether the combination of exercise training and acupuncture reduces dyspnea and improves quality of life of COPD patients or induces more pronounced effects in dyspnea and exercise tolerance. This trial aims to determine whether acupuncture enhances the effect of exercise training in COPD patients compared to sham acupuncture. METHODS: In this single-blind, randomized, sham-controlled trial, 70 COPD patients will be enrolled and randomly assigned (1:1) to the following 2 groups: (I) real acupuncture and exercise training group; and (II) sham acupuncture and exercise training group. For acupoint selection, CV 4, CV 12, CV 17, ST 40, ST 16 and ST 25 will be used for all patients. For sham acupuncture group, Streitberger placebo needles will be used. A single-blind method will be adopted in this trial. Data collectors and statisticians will be blinded in this trial, only the acupuncturists will know the group allocation. The intervention will be conducted 3 times a week for 8 weeks, totaling 24 treatments. Patients will be evaluated at the baseline, after 14 treatments during the 5th week, after 24 treatments during the 8th week, and at a 5-month follow-up period. The primary outcomes will be assessed by a modified British medical research council questionnaire (mMRC), COPD assessment test (CAT), and 6-minute walk test (6MWT). The secondary outcomes will be measured by changes in variables from the lung function test, cardiopulmonary exercise testing, and blood gas analysis. Two-independent sample t-tests will be used to compare differences in the changes in all outcome measures after the intervention between two groups. Safety evaluation will be performed at each treatment visit and assessment by recording adverse events (AE) in the AE Report Form. DISCUSSION: This study will help to determine whether acupuncture increases the benefits obtained from exercise training in COPD patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900028627. Registered on December 29, 2019.

[Effect of electroacupuncture on small airway function in patients with stable chronic obstructive pulmonary disease].

OBJECTIVE: To observe the regulatory effect of electroacupuncture (EA) on small airway function and exercise tolerance in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: A total of 62 patients with stable COPD were randomized into an observation group (31 cases, 1 case dropped off) and a control group (31 cases, 5 cases dropped off). On the base of routine medication and aerobic exercise, the patients of the two groups all received EA at Danzhong (CV 17), Rugen (ST 18), Guanyuan (CV 4), Zhongwan (CV 12), Tianshu (ST 25) and Yingchuang (ST 16). In the observation group, filiform needles were used and inserted perpendicularly, 3 mm in depth. In the control group, the placebo needling method was performed, in which the needle was not inserted through skin at each point. In both groups, electric stimulation with low-frequency electronic pulse instrument was exerted, with continuous wave, 2 Hz in frequency, lasting 30 min each time in the two groups. The treatment was given once every other day, 3 times a week, for 14 treatments totally. Before and after treatment, the following indexes were compared in patients between the two groups, i.e. the lung function indexes (forced expiratory volume in first second [FEV1], forced vital capacity [FVC], the ratio of FEV1 to FVC [FEV1/FVC], maximal voluntary ventilation [MVV], the percentage of maximal expiratory flow [MEF] at 25% of FVC exhaled [MEF25], MEF50 and MEF75 in predicted value), cardiopulmonary exercise test indexs (metabolic equivalent [METS], oxygen uptake per kg body weight [VO2/kg], minute ventilation [VE], the percentage of oxygen pulse [VO2/HR] in predictd value, maximal minute ventilation [VEmax], ventilatory equivalent for oxygen [VE/VO2], ventilatory equivalent for carbon dioxide [VE/VCO2]), 6-minute walk distance (6MWD), the total score of COPD assessment test (CAT), the modified British Medical Research Council (mMRC) score and COPD comprehensive grade. RESULTS: After treatment, FVC%, MVV%, MEF75%, MEF50%, VO2/kg%, METs%, VEmax, VO2/HR%, 6MW and the total CAT score were all improved as compared with those before treatment in the observation group (P<0.05, P<0.01). After treatment, MEF75% and the total CAT score were reduced as compared with those before treatment in the control group (P<0.05). After treatment, MVV%, MEF50%, VO2/kg%, METs%, VEmax and 6MWD in the observation group were all better than those in the control group (P<0.05, P<0.01). CONCLUSION: Electroacupuncture can improve the respiratory function and exercise tolerance in COPD patients through removing small airway obstruction and increasing ventilation.

Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc-mediated microRNA-141 transcription.

Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 (miR-141). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC.

[Electroacupuncture Intervention Improved Pulmonary Function via Promoting Immunoregulation in Chronic Obstructive Pulmonary Disease Rats].

OBJECTIVE: To observe the immunoregulatory effect of electroacupuncture (EA) intervention for muscular dystrophy chronic obstructive pulmonary disease (COPD) rats, so as to investigate its underlying mechanism in improving respiratory function. METHODS: Forty male SD rats were randomly divided into 5 groups: normal, model, EA, exercise, and EA+ exercise (n=8 in each). The muscular dystrophy COPD model was established by placing the rats in a closed box to be exposed to cigarette smoke (3-10 cigarettes/time) for 60 min, twice daily, 6 days a week for 90 days. The EA, exercise and EA+exercise interventions were given beginning from day 80 after exposure to cigarette smoke. EA (2 Hz/40 Hz, 6 mA) was applied to "Danzhong" (CV 17), "Qihai" (CV 6), "Zhongwan" (CV 12), "Liangmen" (ST 21) and bilateral "Quchi" (LI 11) for 10 min, once every other day, for 20 times. The swimming exercise was conducted by forcing the rat to swim in a water box for 10 min, once every other day, for 20 times. The rat's lung function including the resistance of inspiration (RI), functional residual capacity(FRC), pulmonary dynamic compliance (Cdyn), etc., was detected under anesthesia. Pathological changes of the lung tissue were detected by H.E. staining, and the contents of serum TNF-alpha, IL-6 and IL-1 beta assayed by ELISA. RESULTS: After 80 days' exposure to the cigarette smoke, the rats' body weight values in the model, EA, exercise and EA+exercise groups were significantly lower than that of the normal group(P<0.05). Moreover, the RI and FRC levels were significantly increased, and the Cdyn level was remarkably decreased in the model group relevant to the normal group (P<0.01). Following the intervention, both RI and FRC levels were significantly down-regulated in the EA, exercise and EA+exercise groups relevant to the model group (P<0.05), suggesting an improvement of the lung function. But the decreased Cdyn level had no marked improvement in the 3 treatment groups relevant to the model group (P>0.05). The numbers of monocytes and lymphocytes of the lung tissue, and the contents of serum TNF-α, IL-6 and IL-1 ß were significantly higher in the model group than in the normal group (P< 0.01), and significantly lower in the EA, exercise and EA+exercise groups than in the model group (P<0.05), except monocytes in the exercise group (P>0.05). No significant differences were found among the EA, exercise and EA+exercise groups in the levels of RI and FRC, pulmonary monocytes and serum IL-6 and IL-1 ß (P>0.05). The body weight was significantly higher in the exercise and EA+exercise groups than in the EA group, and the pulmonary lymphocytes and serum TNF-α obviously lowered in the EA group than in the exercise group (P<0.05). H.E. staining showed deformation of the bronchial tube cavity, detachment and flattening of the bronchial mucosal epithelial cilia, hyperplasia of Goblet cells, infiltration of abundant inflammatory cells in the submucosal layer and muscular layer, more secretions in the bronchovascular cavity, incomplete alveolar structure, thinning and rupture of the alveolar wall, and expansion of the alveolar cavity to form large pulmonary vesicles after modeling, which was obviously milder in the 3 treatment groups. CONCLUSION: EA intervention can improve the pulmonary function and pathological changes in pulmonary muscular dystrophy COPD rats, which is associated with its effects in reducing pulmonary monocytes and lymphocytes and serum TNF-α, IL-6 and IL-1 ß contents, suggesting an enhancement of immunoregulation.

[Effects of acupuncture on peripheral skeletal muscle exercise ability in patients with chronic obstructive pulmonary disease at stable phase].

OBJECTIVE: To explore the effects of acupuncture on improving the peripheral skeletal muscle exercise ability in patients with chronic obstructive pulmonary disease (COPD) at stable phase. METHODS: Forty-four patients were randomly divided into an observation group (24 cases) and a control group (20 cases). Based on regular western medication treatment and aerobic training, acupuncture was used in the observation group and placebo acupuncture was used in the control group. The acupoints selected were Danzhong (CV 17), Rugen (ST 18), Guanyuan (CV 4), Zhongwan (CV 12), Tianshu (ST 25), etc., 2-3 times per week, and totally 14 treatments were given. The body mass index (BMI), average distance and average maximum heart rate recorded during bicycle exercise, six-min walking distance (6-MWD), maximum power (Wmax) and maximum heart rate (HRmax) recorded during exercise cardiopulmonary function test, and pulmonary function index including forced expiratory volume in one second/estimate value (FEV1%), forced vital capacity/estimate value (FVC%), FEV1/FVC and maximal voluntary ventilation (MVV) were observed in both groups before and after treatment. RESULTS: The BMI before and after treatment in the observation group was not significantly changed (P>0.05), while that in the control group was significantly reduced (P<0.05). Compared before treatment, the average distance of bicycle exercise, 6-MWD, Wmax, FEV1%, FVC% and MVV were significantly improved after treatment in the observation group (P<0.01, P<0.05), which were all superior to those in the control group (P<0.01, P<0.05). The treatment outcomes in the control group were not significantly changed after treatment (all P>0.05). CONCLUSIONS: Acupuncture combined with aerobic training of bicycle and conventional western medication could prevent the reducing of BMI in patients with COPD at stable phase, improve pulmonary ventilation function, and increase the function of peripheral skeletal muscle to improve its performance.

[Regulatory effects of acupuncture on exercise tolerance in patients with chronic obstructive pulmonary disease at stable phase: a randomized controlled trial].

OBJECTIVE: To verify the regulatory effects of acupuncture on exercise tolerance in patients with chronic obstructive pulmonary disease (COPD) at stable phase. METHODS: Thirty cases of COPD were randomly divided into a treatment group (16 cases) and a placebo group (14 cases). Based on specified aerobic exercise, acupuncture was applied in the treatment group and placebo acupuncture was used in the placebo group. The acupoints included Danzhong (CV 17), Rugen (ST 18), Guanyuan (CV 4), Zhongwan (CV 12), Tianshu (ST 25) and so on. The needle did not penetrate into the skin for the placebo group. The treatment was required for 2 to 3 times per week for totally 5 weeks. The indices of exercise tolerance, including 6-min walking distance (6-MWD), exercise time, maximum oxygen uptake (VO2max) forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), maximum ventilatory volume (MVV), St. George respiratory questionnaire (SGRQ) were observed in two groups before and after treatment. RESULTS: (1) Exercise tolerance: the differences of 6-MWD and exercise time were statistically significant between groups, which were more superior in the treatment group (both P<0.01); the VO2max was significantly increased after treatment in the treatment group (P<0.05), but there was no difference between two groups (P>0.05). (2) Pulmonary ventilation function: the differences of FEV1%, FEV1/FVC and MVV% were statistically significant between groups, which were more superior in the treatment group (P<0.05, P<0.01); (3) SGRQ: the SGRQ was significantly improved after treatment in the treatment group (P<0.05), but there was no difference between two groups (P>0.05). CONCLUSION: The acupuncture could improve the exercise tolerance in patients with chronic obstructive pulmonary disease at stable phase, and shorten the onset time of aerobic exercise. Besides, acupuncture combined with aerobic exercise could effectively improve the pulmonary function.

Atorvastatin attenuates inflammatory infiltration and vascular remodeling in lung of hypercholesterolemia rabbits.

Hypercholesterolemia contributes to cardiovascular diseases, but its direct effect on lung is little known. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to exert numerous effects that are dependent and independent of their cholesterol-lowering property. The authors hypothesized that atorvastatin would attenuate hypercholesterolemia-induced lesion in lung. Fifteen rabbits were randomly divided into control group, high-cholesterol forage group, and atrovastatin treatment group. Body weight and blood lipid were measured. All lung tissue and pulmonary arteries were collected for histopathology and immunohistochemistry. Alveolar macrophages (AMs) were cultured and activation of nuclear factor (NF)-κB was detected. Concentrations of interleukin (IL)-6 were measured in serum, bronchoalveolar lavage fluid (BALF), and culture supernatants of AMs. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) of high-cholesterol forage group were higher than control group (P < .05). There were infiltrating of AMs and lymphocytes in lung tissue of high-cholesterol forage group. NF-κB activity in AMs and concentrations of IL-6 in serum, BALF, and culture supernatants of AMs were higher than those of control group (P < .01), and so were all vascular remodeling indexes. TC and LDL-C and other indexes of atrovastatin treatment group were decreased (P < .05). Hypercholesterolemia induced pulmonary inflammatory Infiltration and vascular remodeling. Atorvastatin attenuated inflammatory infiltration and vascular remodeling in lung of hypercholesterolemia rabbits.