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To investigate the effects of cystic fibrosis transmembrane conductance regulator (CFTR) on oxidative stress-induced injury of diabetic retinopathy (DR) rats.DR rat model was constructed treated with Ad-CFTR. Hematoxylin and Eosin (HE) staining was applied for testing the thickness of each layer of retinal tissues. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of serum inflammatory cytokines and contents of oxidative stress related genes in rats. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining was used to detect retinal cell apoptosis, and western blotting to measure the expression of MAPK/NF-κB pathway-related proteins in retinal tissues.Our experiment revealed the remarkable decrease of CFTR protein in retinal tissues of DR rats. DR rats had decreased body weight and increased blood glucose level, with decreased thickness of total retinal thickness (TRT), outer nuclear layer and outer plexiform layer (ONL + OPL), inner nuclear layer (INL), and inner plexiform layer (IPL). Besides, DR rats were apparently up-regulated in the expression of pro-inflammatory cytokines, with increased malondial dehyde (MDA), p-ERK1/2/ERK1/2 and p-JNK1/2/JNK1/2 expressions, decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in retinal tissues, as well as up-regulated p65 protein in nucleus and down-regulated p65 protein in cytoplasm. DR rats treated with Ad-CFTR were effectively improved regarding the above parameters except body weight and blood glucose.CFTR can inhibit MAPK/NF-κB signaling pathway to ameliorate inflammatory response and oxidative stress-induced injury of DR rats, thereby reducing retinal cell apoptosis and playing a protective role in retina.

Objective Transcutaneous auricular vagus nerve stimulation (taVNS) can relieve the symptoms of functional dyspepsia (FD) and improve the quality of life of patients, however, the mechanism underlying this effect remains unclear. Therefore, this study aimed to investigate the effects of taVNS on the expression of intestinal mucosal ligandins. Methods This study was conducted on 24 specific Spathogen-free Sprague–Dawley rats (12 males and 12 females). The rat model of FD was established by tail-clip stimulation. After FD was established successfully, all rats were randomized to either the normal group (n = 6), model group (n = 6), taVNS group (n = 6), or sham-taVNS group (n = 6). After two weeks of the respective intervention, the score of their general conditions, 3 h food intake, gastric emptying rate, and the histology of gastric antrum tissues were observed to evaluate modeling success, and then the effect of taVNS was evaluated. Western blotting was used to assess the expression of the tight junction ligandins —ZO-1 and occludin—and the adhesion ligandin—β-catenin—in the duodenum. The effect of taVNs on the expression of intestinal mucosal barrier ligandins—ZO-1, occludin, and β-catenin—in FD rats was preliminarily investigated. Results When the model-induced period was finished, the manifestations of FD in the model group rats were mental exhaustion, reduced activities, decreased score of the general conditions, and decreased 3 h food intake, compared to the normal group rats. In addition, minimal eosinophil infiltration, without any mucosal erosion or ulcer, was observed in the gastric antrum mucosa. At the end of the study, the mental state of the FD rats improved, and their activities and gastric emptying rate increased in the taVNS group rats. Compared to the normal rats, the duodenal mucosa had less expression of the tight junction ligandins ZO-1 and occludin, but β-catenin expression remained unchangedin the model rats. The expression of the tight junction ligandins ZO-1 and occludin were increased in the duodenal mucosa of model rats after the taVNS intervention. Conclusion TaVNS can improve the gastric motility and mental state of rats with FD. It may play a therapeutic role by improving the expression of the tight junction ligandin ZO-1 and occludin in the duodenal mucosa, while also repairing the duodenal mucosal barrier.

Breast cancer is one of the most common malignancies in women worldwide. Traditional Chinese medicine has been used as adjunctive or complementary therapy for breast cancer. Diterpenoids from Euphorbia fischeriana Steud. have been demonstrated to possess anti-breast-cancer activity. This research was aimed to systematically explore the diterpenoids from E. fischeriana and study the multiple mechanisms on breast cancer. The structures of diterpenoids were identified by the integrated strategy of UHPLC-Q-TOF-MS and molecular networking. A total of 177 diterpenoids belonging to 13 types were collected. In silico ADME analysis was performed on these compounds. It indicated that 130 of 177 diterpenoids completely adjusted to Lipinski’s rule. The targets of compounds were obtained from PharmMapper. The targets of breast cancer were collected from GeneCards. Then, 197 compounds-related targets and 544 breast cancer-related targets were identified. After the intersection process, 58 overlapping targets between compounds-related targets and breast cancer-related targets were acquired. The STRING database was applied to predict the protein-protein interactions. The GO and KEGG pathway enrichment analysis were performed by using the KOBAS database. It indicated that these predicted pathways were closely related to breast cancer. The treatment effect of E. fischeriana on breast cancer might be performed through signaling pathways, such as IL-17 signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. The predicted top genes such as EGFR, ESR, MAPK, SRC, CASP3, CDK2, and KDR were involved in cell proliferation, gene transcription, apoptosis, signal transduction, DNA damage and repair, tumor differentiation, metastasis, and cell cycle, which indicated that E. fischeriana might treat breast cancer comprehensively. A compounds-KEGG pathways-related targets network was built by using cytoHubba to analyze the hub compounds and targets. It concluded that E. fischeriana treated breast cancer not only by the main components but also by the microconstituents, which reflected the overall regulatory role of multicomponents treating breast cancer. To estimate the binding affinities, binding sites, and binding postures, molecular docking simulations between 177 diterpenoids and top 19 targets were carried out. The results are basically in line with expectations. In conclusion, these results can serve as references for researchers studying potential targets of diterpenoids from E. fischeriana on breast cancer in the future.

• Savin juniper is an excellent species for desertification control in arid and semi-arid areas, where it typically establishes under the protection of nurse plants. Ultimately, established plants emerge into full sunlight as they grow, and this transition is accompanied by an increase in the preponderance of scale-like vs. needle-like leaf forms. • To test how age and variable sunlight environments affect shade tolerance in savin juniper, we established a pot study under field conditions with two age cohorts (1- and 4-year-old rooted scions) and three sunlight regimes (10%, 50% and 100% light transmittance). We measured growth, leaf parameters, photosynthesis, chlorophyll fluorescence and foliar pigments on a monthly basis (seven growing months per year, from 2015 to 2017). • Overall, there was little interaction for all variables, and both cohort and light regime had significant effects. Leaf form and spacing varied continuously, tending towards shorter, more closely spaced and more appressed scale leaves with higher dry leaf mass per area in older plants or under higher sunlight. There were no clear age-related patterns in carotenoids but both cohort and light had significant effects on gas exchange and chlorophyll fluorescence variables. • Savin juniper shows an intermediate tolerance to shade that changes with growth in that younger plants were less tolerant of full sun than older plants, consistent with its reliance on nurse plants for ultimate establishment in the open.

Objectives To observe the clinical long-term therapeutic effect on functional dyspepsia (FD) in the comparative study of transcutaneous auricular vagus nerve stimulation (taVNS) with transcutaneous auricular none-vagus nerve stimulation (tnVNS). Methods A total of 90 FD patients were randomized into a taVNS group and a tnVNS group, 45 cases in each one. The patients in both the taNVS group and the tnVNS group were treated 5 times a week, 30 min each time, for 4 weeks totally. Before treatment, after treatment and in follow-up visit, overall symptom points, functional dyspepsia-related quality of life questionnaire (FDQOL), Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD) and self-rating depression scale (SDS) were adopted to evaluate the severity of the symptoms and observe the clinical therapeutic effect of patients. Results Compared with the scores before treatment, the overall symptom points, FDDQL, HAMA, HAMD and SDS at each time point after treatment were all lower in the patients of the taVNS group. The scores of FDDQL after treatment were almost all higher than that before treatment in the self-comparison of each group. All of the above differences were significant statistically (all P Conclusion Transcutaneous auricular vagus nerve stimulation is applicable for the treatment of functional dyspepsia. Compared with the control group, taVNS obtains a better long-term effect.

In savin juniper, age and season can affect photosynthesis, chlorophyll fluorescence and photoprotective pigments. In spring, 2-year-old plants had more lutein than 5-year-olds, but the reverse occurred during summer and autumn. Savin juniper is an endemic evergreen shrub in the Mu Us Desert, where it establishes only with the protection of larger plants. Ultimately, established plants emerge into full sunlight as they grow. To explore how photoprotection responses change during this transition, a pot study was established under field conditions with three sunlight regimes (10%, 50% and 100% light transmittance) and two age cohorts (1- and 4-year-old rooted scions). To avoid potentially confounding effects of differences in leaf form, after one year we measured photosynthesis, chlorophyll fluorescence and foliar pigments of 2- and 5-year-old savin juniper on a monthly basis from April to October. For gas exchange and fluorescence variables, there were no interactions between cohort and sunlight except for intrinsic water-use efficiency in June; however, there were many interactions regarding pigment concentrations and ratios. Generally, 5-year-old plants had higher mean chlorophyll, total carotenoids, and chlorophyll a/b ratios than 2-year-old plants, but lower mean β-carotene/α-carotene ratio, zeaxanthin and lutein. Plants under brighter light had lower mean lutein. There were obvious changes in β-carotene/α-carotene, zeaxanthin and lutein in June, July and August, respectively. Under 100% sunlight, lutein concentration was higher in 2-year-old than 5-year-old plants from April to June, but this pattern reversed from July to October. The effects of age and season, in addition to the prevailing light regime, need to be considered when investigating the role of carotenoids in photoprotection.

To study the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on gastric sensitivity and motility in rats with functional dyspepsia (FD), so as to explore its underlying mechanism in improving FD.A total of 48 young SD rats were randomly divided into control (In comparison with the control group, the EMG change rate at intragastric pressure levels of 40, 60 and 80 mm Hg, expression of NF-κB p65 protein, and contents of IL-6, IL-1β and TNF-α were significantly increased (taVNS can reduce gastric sensitivity and promote gastric emptying in FD model rats, which may be closely related to its functions in up-regulating ACh and α7nAChR contents and inhibiting the activation of NF-κB p65 signaling in the duodenum.

Background impaired glucose tolerance (IGT) is the early stage of diabetes and it would be deteriorated to type 2 diabetes mellitus (T2DM) easily if no intervention provided. In western medicine, drug therapy assisted with the intervention of lifestyle is predominated. However, drug therapy brings serious side effect and high prices, while lifestyle intervention is difficult to be insisted on by patients. Therefore, a green and effective intervention mode is urgently needed. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive and green therapeutic method based on the theory of traditional Chinese medicine (TCM), which can regulate glucose metabolism and reduce blood glucose, but the clinical effect of it has not been clarified yet at present. Hence, this randomized controlled trial (RCT) aims at exploring the effectiveness and safety of taVNS in the treatment of IGT. Methods a total of 158 patients with IGT will be randomized into a taVNS group and a transcutaneous non-auricular vagus nerve stimulation (tnVNS) group, 79 cases in each one. In the taVNS group and the tnVNS group, electric stimulation would be applied to Yidan (胰胆pancreas and gallbladder, CO11) and Pǐ (脾spleen, CO13) on auricular concha and Jiān (肩shoulder SF4,5) on auricular rim respectively. The electric stimulation parameters would be the same in the patients of two groups, for 30 min in each treatment, twice a day, 6 weeks as one course and 2 courses of treatment required totally. In week 0, 6 and 12 of intervention, the effectiveness indicators would be determined, i.e. fasting plasma glucose (FPG), 2 h plasma glucose (2hPG) and glycosylated hemoglobin (HbA1c) successively. On week 0 and 12, body mass index (BMI) would be calculated, respiration, pulse and blood pressure would be recorded separately. Discussion through observing the regulatory effect of taVNS on FPG, 2hPG, HbA1c and BMI as well as the adverse reactions, the effectiveness and safety of taVNS in treatment of IGT would be evaluated. This study will provide a safe, effective, convenient and nontoxic side effect intervention for clinical treatment of IGT and prevention from the occurrence and development of T2DM. Trial registration: This trial has been registered on http://register.clinicaltrials.gov . Clinical Registration Number: ClinicalTrials.gov NCT03343262.

Whether in the West or the East, the connection between the ear and the rest of the body has been explored for a long time. Especially in the past century or more, the relevant theoretical and applied research on the ear has greatly promoted the development of ear therapy, and finally the concept of transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed. The purpose of taVNS is to treat a disease non-invasively by applying electrical current to the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear. In the past two decades, taVNS has been a topic of basic, clinical, and transformation research. It has been applied as an alternative to drug treatment for a variety of diseases. Based on the rapid understanding of the application of taVNS to human health and disease, some limitations in the development of this field have also been gradually exposed. Here, we comprehensively review the origin and research status of the field.

Covalent organic frameworks (COFs) have attracted widespread attention in the electrochemiluminescence (ECL) field owing to their high load capacity of ECL luminophores and porous structures, but their ECL performance is still limited by the intrinsic poor conductivity (generally10

To observe the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the motor function and the expression of glial fibrillary acidic protein (GFAP) and microtubule associated protein 2 (MAP2) in cerebral ischemic penumbra of rats with middle cerebral artery occlusion (MCAO) and explore the mechanism of taVNS in the improvement of motor function in MCAO rats.A total of 48 male SD rats were randomized into a sham-operation group, a model group, a transcutaneous auricular non-vagus nerve stimulation (tnVNS) group and a taVNS group, with 12 rats in each group. The suture-occluded method was adopted to prepare MCAO rat model. The auricular rim was stimulated in the tnVNS group and the concha stimulated in the taVNS group, 2 mA in intensity, 10 Hz in frequency, 30 min each time, once a day, for 14 days consecutively. The nerve functional assessment was recorded in each group. The expressions of nicotinic acetylcholine receptor (α7nAchR) in the cerebral ischemic penumbra and the spleen were detected by using Western blot. With the immunofluorescence, the expressions of GFAP and MAP2 were detected.After modeling, compared with the sham-operation group, the nerve functional score was increased in the model group, the tnVNS group and the taVNS group (TaVNS is effective on neuroprotection in MCAO rats, which may be related to its function of inhibition of GFAP expression and promotion of MAP2 expression in the ischemic penumbra.

We aimed to explore the anti-inflammatory activity of mollugin extracted from Rubia cordifolia L, a traditional Chinese medicine, on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Thirty C57BL/6 mice were divided into a control group (n=6), a model group (n=6), and three experimental groups (40, 20, 10 mg/kg of mollugin, n=6 each). DSS solution (3%) was given to mice in the model group and experimental groups from day 4 to day 10 to induce the mouse UC model. Mice in the experimental groups were intragastrically administrated mollugin from day 1 to day 10. Animals were orally given distilled water in the control group for the whole experiment time and in the model group from day 1 to day 3. The changes in colon pathology were detected by hematoxylin and eosin (HE) staining. Interleukin-1β (IL-1β) in the serum, and tumor necrosis factor-α (TNF-α) and interferon-γ (IFN) in the tissues were measured by enzyme linked immunosorbent assay. Expression levels of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 in the colon tissues were detected by immunohistochemistry. Results showed that mollugin could significantly reduce weight loss and the disease activity index in the DSS-induced UC mouse model. HE examinations demonstrated that mollugin treatment effectively improved the histological damage (P

Objective To explore whether auricular concha eletroacupuncture (ACEA) is effective in regulating lipid-lipoprotein metabolism in rats submitted to cold stress. Methods Thirty-six adult male Sprague–Dawley rats were placed in four groups(9 rats in each group), the rats in three groups of which were submitted to cold stress for fourteen days, the last one of which was a control group. After the cold stress process, in those three groups, the rats of one group were with no treatment (stress only), two were treated with either ACEA or auricular margin eletroacupuncture (AMEA) repeated for fourteen days. On the 14th day, all the rats were sacrificed after all experimental procedure for blood sampling. Blood glucose, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were tested by using the collected serum. Plasma lecithin-cholesterol acyltransferase (LCAT) was measured with ELISA kit. Results ACEA down-regulated the TG level (P Conclusion ACEA played an important role in regulating lipid-lipoprotein metabolism in rats submitted to cold stress.

To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the autonomic nerve function in a rat model of functional dyspepsia (FD), so as to explore the mechanism of taVNS underlying regulation of FD.SD rats were randomly divided into normal control group(n=8) and FD model group(n=26).The FD model was replicated with iodoacetamide gavage. The FD model rats were randomly divided into model, taVNS, sham-taVNS and Zusanli(ST36) groups, with 6 rats in each group. Rats in the taVNS group received electrical stimulation of auricular concha,while the sham-taVNS group received no electrical stimulation and rats in the ST36 group received stimulation at ST36 for 30 min once daily for 14 consecutive days. Cervical trapezius electromyography score and abdominal withdrawal reflex (AWR) score were used to evaluate gastric sensitivity. Histopathological changes of the gastric antrum tissue were observed under microscope after H.E. staining. Autonomic nerve function in rats was recorded and assessed by heart rate variability(HRV). The content of acetylcholine (Ach) and the expression of Ach receptor M3R in gastric antrum was detect by ELISA and Western blot, separately.Compared with the normal control group, the cervical trapezius electromyography and AWR scores of the model group increased (taVNS can increase the activity of the vagus nerve and regulate the balance of the autonomic nerve function, which may be one of the mechanisms of taVNS in reducing the gastric sensitivity of rats with FD. In regulating the vagus nerve function, taVNS and acupuncture at ST36 acupoint have the similar effects.

To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the depressive behavior in depression rats, so as to explore its mechanism underlying improvement of depression.A total of 24 male Sprague Dawley rats were randomly divided into normal, depression model, taVNS, tnVNS (transcutaneous auricular none-vagus nerve stimulaton) groups (Following modeling, the increase amount of body weight was decreased, the forced swimming immobility time and expression TLR4, MyD88 and IL-18 protein in the prefrontal cortex were increased in the model group than those in the normal group (TaVNS is able to improve depression in depression rats, which is probably related to its effect in inhibiting inflammatory response of TLR4/MyD88 signaling pathway in prefrontal cortex.

The hypothalamus-pituitary-adrenal axis is the most important endocrine system to control irritability response. Functional dyspepsia (FD) is closely related to irritability. This study aimed to preliminarily explore the corticotropin-releasing factor (CRF) mechanism of auricular vagus nerve stimulation (aVNS) for FD model rats.Sprague-Dawley adult male rats were randomly divided into normal group, model group, aVNS group, and sham-aVNS group. Except for the normal rats, all other rats were induced into the FD model through tail-clamping stimulation for 3 weeks. Once the rat model was developed successfully, rats in the aVNS group and sham-aVNS group were intervened with aVNS or sham-aVNS for 2 weeks. No intervention was given to rats in the normal and model groups. The effect of aVNS was assessed. The expressions of hippocampal corticotropin-releasing hormone receptor 1 (CRHR1), hypothalamus CRF, adrenocorticotropic hormone (ACTH), and corticosterone in serum were assessed.1. Compared with normal rats, model-developing rats showed FD-like behavior. 2. Compared with model rats, rats in the aVNS group showed an improved general condition score and gastric motility, and increased horizontal and vertical motion scores. 3. The release of corticosterone, ACTH in serum, and CRF in the hypothalamus all increased in model rats but decreased with aVNS instead of sham-aVNS. 4. The expression of hippocampus CRHR1 was lower in model rats but higher in the aVNS group.aVNS ameliorates gastric motility and improves the mental state in the FD-like rat, probably via inhibiting the CRF pathway.

Breast cancer is one of the most common malignancies in women worldwide. Traditional Chinese medicine has been used as adjunctive or complementary therapy for breast cancer. Diterpenoids from Euphorbia fischeriana Steud. have been demonstrated to possess anti-breast-cancer activity. This research was aimed to systematically explore the diterpenoids from E. fischeriana and study the multiple mechanisms on breast cancer. The structures of diterpenoids were identified by the integrated strategy of UHPLC-Q-TOF-MS and molecular networking. A total of 177 diterpenoids belonging to 13 types were collected. In silico ADME analysis was performed on these compounds. It indicated that 130 of 177 diterpenoids completely adjusted to Lipinski's rule. The targets of compounds were obtained from PharmMapper. The targets of breast cancer were collected from GeneCards. Then, 197 compounds-related targets and 544 breast cancer-related targets were identified. After the intersection process, 58 overlapping targets between compounds-related targets and breast cancer-related targets were acquired. The STRING database was applied to predict the protein-protein interactions. The GO and KEGG pathway enrichment analysis were performed by using the KOBAS database. It indicated that these predicted pathways were closely related to breast cancer. The treatment effect of E. fischeriana on breast cancer might be performed through signaling pathways, such as IL-17 signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. The predicted top genes such as EGFR, ESR, MAPK, SRC, CASP3, CDK2, and KDR were involved in cell proliferation, gene transcription, apoptosis, signal transduction, DNA damage and repair, tumor differentiation, metastasis, and cell cycle, which indicated that E. fischeriana might treat breast cancer comprehensively. A compounds-KEGG pathways-related targets network was built by using cytoHubba to analyze the hub compounds and targets. It concluded that E. fischeriana treated breast cancer not only by the main components but also by the microconstituents, which reflected the overall regulatory role of multicomponents treating breast cancer. To estimate the binding affinities, binding sites, and binding postures, molecular docking simulations between 177 diterpenoids and top 19 targets were carried out. The results are basically in line with expectations. In conclusion, these results can serve as references for researchers studying potential targets of diterpenoids from E. fischeriana on breast cancer in the future.

Glaucoma eventually leads to optic nerve damage and vision loss without medical intervention. More than 50% of glaucoma caused blindness are attributed to primary angle closure glaucoma, particularly in Asians. It is reported that immune inflammation is involved in the progress of glaucoma. Increased inflammation cytokines are detected in the aqueous humor of chronic primary angle closure glaucoma (CPACG). IL-36, IL-37 and IL-38, are novel cytokines and are involved in many inflammatory diseases, including inflammatory bowel diseases and acute anterior uveitis, but the possible contributing role in the pathogenesis of CPACG is unclear. In our current study, increased IL-36, IL-37 and IL-38 were detected in the aqueous humor of CPACG compared with age-related cataract (ARC). Furthermore, a significant correlation was detected between mean deviation of visual field (MDVF) of CPACG and IL-36, IL-37 or IL-38, respectively. Our data suggest IL-36, IL-37 and IL-38 might contribute to the immunological mediated pathogenesis of CPACG, despite the eye being an immune-privileged organ under normal conditions. The precise underlying mechanism of these cytokines during the development of CPACG remains to be explored. Our findings may be useful in therapeutic targeting of specific pathology.

Zucker diabetic fatty (ZDF) rats that harbor a mutation in the leptin receptor innately develop type 2 diabetes (T2D) with obesity. Transcutaneous auricular vagal nerve stimulation (taVNS) has an antidiabetic effect in ZDF rats. However, the underlying mechanisms of the weight-gain attenuating effect in ZDF rats by taVNS is still unclear. This study aimed to assess whether the weight-gain attenuating effect of taVNS in ZDF rats is associated with changes in the central nervous system (CNS) expression of P2Y1 receptors (P2Y1R). Adult male ZDF rats were subjected to taVNS and transcutaneous non-vagal nerve stimulation (tnVNS). Their food intake and body weight were recorded daily and weekly, respectively. P2Y1R expression in the hypothalamus, amygdala, and hippocampus was evaluated by western blotting. Hypothalamic P2Y1R expressing cells were detected using immunohistochemistry. Naïve ZDF rats were much heavier ( p 0.05) and suppressed hypothalamic P2Y1R expression in ZDF rats ( p

To investigate the role of miR-93-5p in rats with type 2 diabetic retinopathy (DR) through targeting Sirt1. The targeting correlation between miR-93-5p and Sirt1 was validated by dual-luciferase reporter gene assay. Type 2 diabetes mellitus (T2DM) rat models were received intravitreal injection of antagomir NC (negative control), miR-93-5p antagomir, miR-93-5p agomir and/or recombinant Sirt1, followed by observation of pathological changes in retina via HE staining. Besides, retinal vascular permeability was determined by fluorescein isothiocyanate-bovine serum albumin (FITC-BSA), while the retinal vasculature was observed through retinal trypsin digestion. Expression of miR-93-5p and Sirt1 was measured by qRT-PCR and Western blotting, while the levels of VEGF, proinflammatory cytokines and anti-oxidative indicators were determined using corresponding kits. MiR-93-5p could target Sirt1 as analyzed by the luciferase reporter gene assay. Rats in the T2DM group presented the up-regulation of miR-93-5p and down-regulation of Sirt1 in the retina, and miR-93-5p inhibition could up-regulate Sirt1 expression in the T2DM rats. Recombinant Sirt1 decreased retinal vascular permeability and acellular capillaries with improved pathological changes in retina from T2DM rats, which was abolished by miR-93-5p agomir. Moreover, miR-93-5p inhibition or Sirt1 overexpression decreased the levels of VEGF and proinflammatory cytokines while enhancing the activity of anti-oxidative indicators. However, indicators above had no significant differences between T2DM group and T2DM + agomir + Sirt1 group. MiR-93-5p, via targeting Sirt1, could affect the vascular permeability and acellular capillaries and mitigate the inflammation and oxidative stress in the retinas, which may play a critical role in DR.

In discovering new powerful antitumor agents, two series of novel diosgenin–amino acid–benzoic acid mustard trihybrids (7a–7 g and 12a–12 g) were designed and synthesized. The antiproliferative activities were tested against five human tumor cell lines and one normal cell line using CCK-8 assays. Among the trihybrids, 12e was the most promising compound, which inhibited T24 cells with IC50 value of 6.96 μM, and was stronger than its parent compound diosgenin (IC50 = 32.33 μM). In addition, 12e had weak cytotoxicity on the normal GES-1 cell line (IC50 = 213.74 μM). Moreover, 12e could cause G2/M cell cycle arrest, increase the percentage of apoptosis, induce mitochondrial depolarization, and promote reactive oxygen species generation in T24 cells. Further studies on antitumor mechanism demonstrated that 12e triggered the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways. More importantly, 12e could inhibit T24 cell proliferation in an in vivo zebrafish xenograft model. Therefore, 12e, as a novel trihybrid with potent cytotoxicity, might be applied as a promising skeleton for antitumor agents, which deserved further optimization.

Background To evaluate the coronary plaque characteristics of coronary arteries using computed tomography angiography (CTA) in order to assess the risk of coronary artery disease and the relevance of high sensitivity C reactive protein (hs-CRP) in patients with Diabetes Mellitus (DM). Methods The clinical data of 400 DM patients and 400 non-DM patients from January 2017 to December 2019 were collected, including the results of coronaryCTA. The plasma hs-CRP level of the two groups were divided into three groups: CRP ≤ 1, 1 2. The correlation of the degree of stenosis, the number of plaques, the nature of plaques and hs-CRP value between the two groups was evaluated. Results Compared with non-DM patients, the incidence of coronary artery plaques and lumen stenosis in DM patients was more higher than that in non-DM patients. DM patients were more likely to have more diseased vessels, especially diffuse vascular disease (12.00% vs 1.75%; P p Conclusions Coronary CTA combined with hs-CRP can accurately detect the characteristics of coronary artery stenosis and plaque in DM patients, which has an important clinical value in the risk assessment of coronary heart disease in DM patients.

Objectives After 20 years of development, there is a confusion in the nomenclature of transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN). We performed a systematic review of transcutaneous stimulation of ABVN in nomenclature. Materials and methods A systematic search of the literature was carried out, using the bibliographic search engines PubMed. The search covered articles published up until June 11, 2020. We recorded the full nomenclature and abbreviated nomenclature same or similar to transcutaneous stimulation of ABVN in the selected eligible studies, as well as the time and author information of this nomenclature. Results From 261 studies, 67 full nomenclatures and 27 abbreviated nomenclatures were finally screened out, transcutaneous vagus nerve stimulation and tVNS are the most common nomenclature, accounting for 38.38% and 42.06%, respectively. In a total of 97 combinations of full nomenclatures and abbreviations, the most commonly used nomenclature for the combination of transcutaneous vagus nerve stimulation and tVNS, accounting for 30.28%. Interestingly, the combination of full nomenclatures and abbreviations is not always a one-to-one relationship, there are ten abbreviated nomenclatures corresponding to transcutaneous vagus nerve stimulation, and five full nomenclatures corresponding to tVNS. In addition, based on the analysis of the usage habits of nomenclature in 21 teams, it is found that only three teams have fixed habits, while other different teams or the same team do not always use the same nomenclature in their paper. Conclusions The phenomenon of confusion in the nomenclature of transcutaneous stimulation of ABVN is obvious and shows a trend of diversity. The nomenclature of transcutaneous stimulation of ABVN needs to become more standardized in the future.

Transcutaneous auricular vagus nerve stimulation (taVNS) has gained growing interest as a non-invasive and non-pharmacologic treatment option in various neurological and psychiatric disorders. Animal experiments and clinical trials confirm that taVNS at the auricular concha region has beneficial effects on depression. However, stimulation frequencies are selected empirically, and there is no evidence showing that any frequency is superior to the others. This study explores antidepressant-like effects of three frequencies of taVNS on rats subjected to chronic unpredictable mild stress (CUMS). Sprague-Dawley rats were randomly divided into five groups, i.e., the control, CUMS, 5 Hz-taVNS, 20 Hz-taVNS, and 100 Hz-taVNS groups. The three different frequencies were administered during the 30-min taVNS procedure once a day for 28 consecutive days. Rats exposed to CUMS showed signs of depression-like behaviors, including reduction in sucrose preference and increased immobility time in forced swimming and open field tests as well as significant dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis as detected by plasma corticosterone and adrenocorticotropic hormone concentration. The 28 days' taVNS sessions with three frequencies elicited quite different consequences. Although 20 Hz taVNS significantly reversed the depression-like behaviors and downregulated the hyperactivity of the HPA axis, neither 5 nor 100 Hz showed any antidepressant-like effect on CUMS-induced rat behavior. Based on these results, we propose that, out of the three frequencies for taVNS intervention on depression, 20 Hz may be the optimized frequency to have a better modulation effect on HPA axis function by activating the auricular vagus nerve.

Objective:The current study aimed to evaluate the association of major dietary patterns with anxiety in middle-aged adults in eastern China.Design:Dietary intake was assessed using a semi-quantitative FFQ. Binary logistic regression analysis was used to estimate OR and 95 % CI for anxiety according to quartiles of each dietary pattern score.Setting:Evidence regarding the relationship between dietary patterns and anxiety in the Chinese population is scarce.Participants:The study participants were 1360 Chinese adults aged 45–59 years, who participated in a health survey at the time of periodic check-up in the city of Linyi, Shandong Province, China.Results:Four major dietary patterns were identified by factor analysis: traditional Chinese, western, grains–vegetables and high-salt diets. After adjusting for potential confounders, participants in the highest quartile of the western pattern had greater odds for anxiety, compared with those in the lowest quartile (OR 1·35, 95 % CI 1·000, 3·086, P < 0·05). In contrast, participants in the highest quartile of the grains–vegetables pattern had lower odds for anxiety than did those in the lowest quartile (OR 0·78, 95 % CI 0·574, 1·000, P < 0·05). Moreover, no significant associations were observed between the traditional Chinese and high-salt patterns and the risk of anxiety.Conclusions:Our findings indicate that the western pattern is associated with an increased risk, and the grains–vegetables pattern is associated with a decreased risk of anxiety.

In this study, the relationship between the brain parenchymal density, the cerebral vessel density, the mean corpuscular hemoglobin (MCH) content, the mean corpuscular hemoglobin concentration (MCHC), and the morbidity associated with lacunar infarction of residents living in either the plains or the plateau regions were analyzed and compared for their potential clinical implications. Clinical data from the brain CT scans of individuals living in either the plain or plateau regions (129 each) were collected. Specifically, the CT values for basal ganglia, the middle cerebral artery, and the superior sagittal sinus, along with the number of patients with lacunar infarction, were collected. In addition, the MCH and MCHC values were measured in blood samples collected within 48 h following the CT scans. For statistical analysis, an independent sample t-test, Pearson's correlation test (permutation test), and Chi-squared test were employed. The inhabitants of the plateau had a significantly higher CT value of basal ganglia, the middle cerebral artery, and superior sagittal sinus and also higher levels of MCH and MCHC in the blood (ps p > 0.05). The inhabitants in the plateau have a significantly higher brain parenchymal density, higher CT value for cerebral vessels density, and higher blood MCH and MCHC levels in comparison with individuals occupying the plains. Concurrently, the parenchymal density and the CT values are shown to be positively correlated with the MCH and MCHC content in the blood.

This work aims to investigate how the bile acid metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary bile acids (BAs). The total unconjugated BA profiles were quantitatively determined by enzyme digestion techniques in urine of 21 newborns born by cesarean section, 29 healthy parturient women, 30 healthy males, and 28 healthy nonpregnant females. As expected, because of a lack of developed gut microbiota, newborns exhibited poor metabolism of secondary BAs. Accordingly, the tertiary BAs contributed limitedly to the urinary excretion of BAs in newborns despite their tertiary-to-secondary ratios significantly increasing. As a result, the primary BAs of newborns underwent extensive oxidative metabolism, resulting in elevated urinary levels of some fetal-specific BAs, including 3-dehydroCA, 3β,7α,12α-trihydroxy-5β-cholan-24-oic acid, 3α,12-oxo-hydroxy-5β-cholan-24-oic acid, and nine tetrahydroxy-cholan-24-oic acids (Tetra-BAs). Parturient women had significantly elevated urinary levels of tertiary BAs and fetal-specific BAs compared with female control, indicating that they may be excreted into amniotic fluid for maternal disposition. An in vitro metabolism assay in infant liver microsomes showed that four Tetra-BAs and 3-dehydroCA were hydroxylated metabolites of cholate, glycocholate, and particularly taurocholate. However, the recombinant cytochrome P450 enzyme assay found that the fetal-specific CYP3A7 did not contribute to these oxidation metabolisms as much as expected compared with CYP3A4. In conclusion, newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of secondary BA metabolism. Translational studies following this finding may bring new ideas and strategies for both pediatric pharmacology and diagnosis and treatment of perinatal cholestasis-associated diseases. SIGNIFICANCE STATEMENT: The prenatal BA disposition is different from adults because of a lack of gut microbiota. However, how the BA metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary BAs remains poorly defined. This work demonstrated that the urinary BA profiles of newborns born by cesarean section are characterized by oxidative metabolism of primary BAs, in which the fetal-specific CYP3A7 plays a limited role in the downstream oxidation metabolism of cholate.

In this work, a novel two-dimensional (2D) ultrathin metal-organic layer (MOL) based on the aggregation-induced emission (AIE) ligand H4ETTC (H4ETTC = 4',4''',4''''',4'''''''-(ethene-1,1,2,2-tetrayl)tetrakis(([1,1'-biphenyl]-4-carboxylic acid))) was developed and used to construct a novel electrochemiluminescence (ECL) aptasensor for ultrasensitive detection of carcinoembryonic antigen (CEA). The newly synthesized AIE luminogen (AIEgen)-based MOL (Hf-ETTC-MOL) yielded a higher ECL intensity and efficiency than did H4ETTC monomers, H4ETTC aggregates and 3D bulk Hf-ETTC-MOF. This improvement occurred not only because the ETTC ligands were coordinatively immobilized in a rigid MOL matrix, which restricted the intramolecular free rotation and vibration of these ligands and then reduced the non-radiative transition, but also because the porous ultrathin 2D MOL greatly shortened the transport distances of ions, electrons, coreactant (triethylamine, TEA) and coreactant intermediates (TEA˙ and TEA˙+), which made more ETTC luminophores able to be excited and yielded a high ECL efficiency. On the basis of using the Hf-ETTC-MOL as a novel ECL emitter and rolling circle amplification (RCA) as a signal amplification strategy, the constructed ECL aptasensor exhibited a linear range from 1 fg mL-1 to 1 ng mL-1 with a detection limit of 0.63 fg mL-1. This work has opened up new prospects for developing novel ECL materials and is expected to lead to increased interest in using AIEgen-based MOLs for ECL sensing.

To study the mechanism of rare earth (RE) elements on the mechanical properties of axle steels, trace RE were added to LZ50 axle steel, which was melted in vacuum induction furnace. By calculating the thermodynamic and kinetic of RE inclusions, the formation mechanism of inclusions was discussed. And the effects of RE elements on the microstructures and mechanical properties were investigated. The results show that RE and O elements in the molten steels diffused into the interface and increased the thickness of the liquid film. The inclusions transform into 1–3 μm spherical RE compound inclusions instead of 5 μm Al2O3-SiO2 with sharp edges. The grain sizes of the steels containing 0.0010 %～0.0026 % RE were decreased, impact toughness and fatigue resistance were improved greatly, compared with the steel without RE. The impact toughness and fatigue resistance of the LZ50 steel with the addition of 0.0010 % RE were increased by 1.65 and 2 times, respectively.

Palladium-catalyzed enantioselective C(sp2)–H activation of ferrocenyl ketones is achieved through utilizing catalytic, inexpensive L-tert-leucine as a chiral transient directing group. The transformation allows rapid access to ferrocene scaffolds simultaneously possessing planar- and stereogenic central chirality, widely applied in the ferrocene-based chiral ligand families.

To discuss the value of CT pulmonary angiogram (CTPA) for assessing the treatment outcome of acute pulmonary embolism (APE).CT pulmonary angiogram data and other clinical data were collected for 28 cases diagnosed as APE and analyzed retrospectively. The number and positions of emboli in the pulmonary artery, pulmonary artery obstruction index, right ventricular/left ventricular diameter ratio, main pulmonary artery/ascending aorta diameter ratio and blood oxygen saturation, and pulmonary arterial pressure were compared before and after treatment.Of 28 cases, emboli in the pulmonary artery completely or partially disappeared in 16 and 12 cases, respectively. CPTA indicated that the pulmonary arterial pressure decreased dramatically and the blood oxygen saturation increased after treatment in 26 cases. There were significant differences in the number and positions of pulmonary emboli and in pulmonary artery obstruction index before and after treatment in 28 cases (P .05). However, no significant differences were found in the right ventricular/left ventricular diameter ratio or main pulmonary artery/ascending aorta diameter ratio (P .05).CT pulmonary angiogram proved reliable for assessing the treatment efficacy of APE, providing more clinical information on the patients' status.

Transition metal-free synthesis of planar-chiral 1,2-fused ferrocenes via intramolecular direct C-H bond arylation was achieved. The C-H arylation reactions promoted by a catalytic amount of 1,10-phenanthroline highlighted a unique planar-chiral metallocenic radical intermediate, generated from iodoferrocenes via a single-electron transfer process.