A case report on a nasal and oral cavity involving large solitary fibrous tumor and comprehensive review of case literature.

Solitary fibrous tumor (SFT) represents an uncommon spindle cell sarcoma predominantly situated within soft tissue, with a notably infrequent occurrence in the nasal cavity and paranasal sinuses. In this report, we present a case involving a middle-aged male with a sizable solitary fibrous tumor affecting both the nasal and oral cavities.

Rigidifying AIEgens in covalent organic framework nanosheets for electrochemiluminescence enhancement: TABE-PZ-CON as a novel emitter for microRNA-21 detection.

Enhancing electrochemiluminescence (ECL) properties of luminophores is a hot direction in the current ECL field. Herein, we found that covalent rigidification of the aggregation-induced emission luminogens (AIEgens) TABE (TABE = tetra-(4-aldehyde-(1,1-biphenyl))ethylene) into covalent organic framework nanosheets (TABE-PZ-CON, PZ = piperazine) could result in stronger ECL emission than those of TABE aggregates and TABE monomers. We termed the interesting phenomenon "covalent rigidification-triggered electrochemiluminescence (CRT-ECL) enhancement". The superior ECL performance of TABE-PZ-CON not only because massive TABE luminogens were covalently assembled into the rigid TABE-PZ-CON network, which limited the intramolecular motions of TABE and hampered the radiationless transition, but also because the ultrathin porous TABE-PZ-CON significantly reduced the transportation distance of ions, electrons, and coreactants, which enabled the electrochemical excitation of more TABE luminogens and thus enhanced the ECL efficiency. Bearing in mind the exceptional ECL performance of TABE-PZ-CON, it was utilized as a high-efficient ECL indicator in combination with the DNA walker and duplex-specific nuclease-assisted target recycling amplification strategies to design an "off-on" ECL biosensor for the ultrasensitive assay of microRNA-21, exhibiting a favorable response range (100 aM-1 nM) with an ultralow detection limit of 17.9 aM. Overall, this work offers a valid way to inhibit the intramolecular motions of AIEgens for ECL enhancement, which gives a new vision for building high-performance AIEgen-based ECL materials, thus offering more chances for assembling hypersensitive ECL biosensors.

Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer.

The clinical implications of extrachromosomal DNA (ecDNA) in cancer therapy remain largely elusive. Here, we present a comprehensive analysis of ecDNA amplification spectra and their association with clinical and molecular features in multiple cohorts comprising over 13,000 pan-cancer patients. Using our developed computational framework, GCAP, and validating it with multifaceted approaches, we reveal a consistent pan-cancer pattern of mutual exclusivity between ecDNA amplification and microsatellite instability (MSI). In addition, we establish the role of ecDNA amplification as a risk factor and refine genomic subtypes in a cohort from 1015 colorectal cancer patients. Importantly, our investigation incorporates data from four clinical trials focused on anti-PD-1 immunotherapy, demonstrating the pivotal role of ecDNA amplification as a biomarker for guiding checkpoint blockade immunotherapy in gastrointestinal cancer. This finding represents clinical evidence linking ecDNA amplification to the effectiveness of immunotherapeutic interventions. Overall, our study provides a proof-of-concept of identifying ecDNA amplification from cancer whole-exome sequencing (WES) data, highlighting the potential of ecDNA amplification as a valuable biomarker for facilitating personalized cancer treatment.

Early postsurgical lethal outcome due to splenic littoral cell angioma: A case report.

BACKGROUND: Littoral cell angioma (LCA) is a rare benign vascular tumor of the spleen. Given its rarity, standard diagnostic and therapeutic recommendations have yet to be developed for reported cases. Splenectomy is the only method of obtaining a pathological diagnosis and providing treatment to obtain a favorable prognosis. CASE SUMMARY: A 33-year-old female presented with abdominal pain for one month. Computed tomography and ultrasound revealed splenomegaly with multiple lesions and two accessory spleens. The patient underwent laparoscopic total splenectomy and accessory splenectomy, and splenic LCA was confirmed by pathology. Four months after surgery, the patient presented with acute liver failure, was readmitted, rapidly progressed to multiple organ dysfunction syndrome and died. CONCLUSION: Preoperative diagnosis of LCA is challenging. We systematically reviewed online databases to identify the relevant literature and found a close relationship between malignancy and immunodysregulation. When a patient suffers from both splenic tumors and malignancy or immune-related disease, LCA is possible. Due to potential malignancy, total splenectomy (including accessory spleen) and regular follow-up after surgery are recommended. If LCA is diagnosed after surgery, a comprehensive postoperative examination is needed.

Cystic Fibrosis Transmembrane Conductance Regulator Attenuates Oxidative Stress-Induced Injury in Diabetic Retinopathy Rats.

PURPOSE: To investigate the effects of cystic fibrosis transmembrane conductance regulator (CFTR) on oxidative stress-induced injury of diabetic retinopathy (DR) rats. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prolonged Longitudinal Transcutaneous Auricular Vagus Nerve Stimulation Effect on Striatal Functional Connectivity in Patients with Major Depressive Disorder.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) is effective for treating major depressive disorder (MDD). We aimed to explore the modulating effect of prolonged longitudinal taVNS on the striatal subregions' functional connectivity (FC) in MDD patients. METHODS: Sixteen MDD patients were enrolled and treated with taVNS for 8 weeks. Sixteen healthy control subjects (HCs) were recruited without intervention. The resting-state FC (rsFC) based on striatal subregion seed points and the Hamilton Depression Scale (HAMD) were evaluated in the MDD patients and HCs at baseline and after 8 weeks. A two-way ANCOVA test was performed on each rsFC metric to obtain the (group-by-time) interactions. RESULTS: The rsFC values between the left ventral caudate (vCa) and right ventral prefrontal cortex (vPFC), and between the right nucleus accumbens (NAc) and right dorsal medial prefrontal cortex (dmPFC) and ventrolateral prefrontal cortex (vlPFC) are lower in the MDD patients compared to the HCs at baseline, and increase following taVNS; the rsFC values between the left vCa and right, superior occipital gyrus (SOG), and between the left dorsal caudate (dCa) and right cuneus are higher in MDD patients and decrease following taVNS. CONCLUSIONS: Prolonged longitudinal taVNS can modulate the striatum rsFC with the prefrontal cortex, occipital cortex, temporal cortex, and intra-striatum, and these changes partly underlie any symptomatic improvements. The results indicate that prolonged longitudinal taVNS may produce beneficial treatment effects by modulating the cortical striatum circuitry in patients with MDD.

Electroacupuncture relieves hyperalgesia by regulating neuronal-glial interaction and glutamate transporters of spinal dorsal horns in rats with acute incisional neck pain.

Objective: Glial cells are involved in the analgesic effect of electroacupuncture (EA) in rats with chronic neurological pain. The objective of this study was to observe the role of neuronal-glial interaction and glutamate (Glu) transporters in EA-induced acute neck pain relief in rats. Materials and methods: Male rats were placed into the following five groups: control, model, EA Futu (LI18), EA Hegu (LI4)-Neiguan (PC6), and EA Zusanli (ST36)-Yanglingquan (GB34). The incisional neck pain model was established by making a longitudinal incision along the midline of the neck. The thermal pain threshold (TPT) was measured using a radiation heat detector. The immunoactivities of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), neurokinin-1 receptor (NK-1R), Glu aspartate transporter (GLAST), and Glu transporter-1 (GLT-1) in the dorsal horns (DHs) of the cervico-spinal cord (C2-C5) were detected using immunofluorescence histochemistry. The expression levels of GFAP, Iba-1, GLAST, and GLT-1 mRNAs were determined using quantitative real-time polymerase chain reaction (PCR). Results: The TPT and levels of mRNAs expression and immunoactivity of GLT-1 and GLAST were significantly decreased, and those of Iba-1 and GFAP were significantly increased in the model group than those of the control group (P < 0.05). The activated microgliacytes were gathered around the NK-1R positive neurons, and co-expression of NK-1R and astrocytes was observed in the model group. EA LI18 significantly increased the TPT and expression of GLAST and GLT-1 mRNAs (P < 0.05) and notably decreased the number of Iba-1 positive cells and Iba-l mRNA expression (P < 0.05), whereas GLAST and GLT-1 antagonists inhibited the analgesic effect of EA LI18. However, these effects, except for the downregulation of Iba-1 mRNA, were not observed in the EA ST36-GB34 group. Fewer NK-1R-positive neurons were visible in the spinal DHs in the EA LI18 group, and the co-expression of NK-1R and astrocytes was also lower than that in the three EA groups. Conclusion: Electroacupuncture of LI18 had an analgesic effect in rats with neck incisions, which may be related to its functions in suppressing the neuronal-glial cell interaction through NK-1R and upregulating the expression of GLAST and GLT-1 in the spinal DHs.

The pro-inflammatory factors contribute to the EEG microstate abnormalities in patients with major depressive disorder.

Pro-inflammatory factors may be associated with abnormalities in functional brain networks, which may be a mechanism in the pathogenesis of major depressive disorder (MDD). Electroencephalogram (EEG) microstates reflect the functioning of brain networks. However, the relationship between pro-inflammatory factors and the microstate abnormalities in patients with MDD is poorly understood. 24 MDD patients and 24 age-and sex-matched healthy controls (HC) were recruited. Montgomery-Asberg Depression Rating Scale(MADRS) were assessed. Serum (interleukin- 2(IL- 2), tumor necrosis factor-α (TNF-α) and hs-C-reactive protein (CRP)and EEG data were collected. K-means clustering was performed to characterize different microstates. For each microstate, duration, occurrence and coverage were estimated. Four microstates (e.g. A, B, C, D) were characterized, MDD group showed lower duration, occurrence and coverage of microstate B and microstate D, while higher duration of microstate A and microstate C and levels of IL-2, TNF-α, hs-CRP than HC group. The duration, occurrence and coverage of microstate D were negatively correlated with levels of pro-inflammatory factors (IL-2, TNF- α and hs- CRP) (all P < 0.05). Serum pro-inflammatory induced the abnormalities of microstate D. Together, these findings add to the understanding of the pathophysiology of MDD and point to pro-inflammatory factors contribute to EEG microstate abnormalities in patients with MDD.

[Transcutaneous auricular vagus nerve stimulation promotes gastric motility by up-rgulating α7nAChR and suppressing NF-κB p65 expression in duodenum in rats with functional dyspepsia].

OBJECTIVE: 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. METHODS: A total of 48 young SD rats were randomly divided into control (n=10), model (n=9), taVNS (n=9), subdiaphragmatic vagus nerve stimulation (SDVNS, n=9) and sham SDVNS (n=7) groups. The FD model was established by gavage of 0.1% iodoa-cetamide+2% glucose, once daily for 6 days. Rats in the taVNS group received taVNS (0.5 mA) of optopoint "Heart" and "Stomach" for 30 min, once daily for 14 days, while rats in the SDVNS group received subdiaphragmatic vagus nerve stimulation through the implanted electrode, and those of the sham SDVNS group received only application of the same electrodes without electrical stimulation. Electromyogram (EMG) of the cervical trapezius muscle (reflecting gastric sensitivity) was recorded before and after intragastric expansion via an air ballon and the gastric emptying rate was calculated for assessing the gastric motility. The contents of acetylcholine (ACh), nicotinic acetylcholine receptor α7 subunit (α7nAChR), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the duodenum tissue were detected by enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) p65 in the duodenum tissue was determined by Western blot. RESULTS: 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-1ß and TNF-α were significantly increased (P<0.05,P<0.01, P<0.001), while the gastric emptying rate, ACh and α7nAChR contents considerably decreased (P<0.05, P<0.001) in the model group. After interventions, the EMG change rate, contents of IL-6, IL-1ß and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.05, P<0.01, P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.05, P<0.001) in both taVNS and SDVNS groups relevant to the model group. In comparison with the sham SDVNS group, the EMG change rate, contents of IL-6, IL-1ß and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.01, P<0.05,P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.01, P<0.001) in the both SDVNS and taVNS groups. CONCLUSION: 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.

Transcutaneous Auricular Vagus Nerve Stimulation Modulates the Prefrontal Cortex in Chronic Insomnia Patients: fMRI Study in the First Session.

Objectives: Transcutaneous auricular vagus nerve stimulation (taVNS) has been reported to be effective for chronic insomnia (CI). However, the appropriate population for taVNS to treat insomnia is unclear. Methods: Total twenty-four patients with CI and eighteen health controls (HC) were recruited. Rest-state functional magnetic resonance imaging (Rs-fMRI) was performed before and after 30 min' taVNS at baseline. The activated and deactivated brain regions were revealed by different voxel-based analyses, then the seed-voxel functional connectivity analysis was calculated. In the CI group, 30 min of taVNS were applied twice daily for 4 weeks. Pittsburgh Sleep Quality Index (PSQI) and Flinders Fatigue Scale (FFS) were also assessed before and after 4 weeks of treatment in the CI group. The HC group did not receive any treatment. The correlations were estimated between the clinical scales' score and the brain changes. Results: The scores of PSQI (p < 0.01) and FFS (p < 0.05) decreased after 4 weeks in the CI group. Compared to the HC group, the first taVNS session up-regulated left dorsolateral prefrontal cortex (dlPFC) and decreased the functional connectivity (FCs) between dlPFC and bilateral medial prefrontal cortex in the CI group. The CI groups' baseline voxel wised fMRI value in the dlPFC were negatively correlated to the PSQI and the FFS score after 4 weeks treatment. Conclusions: It manifests that taVNS has a modulatory effect on the prefrontal cortex in patients with CI. The initial state of dlPFC may predict the efficacy for taVNS on CI.

Atorvastatin reduces IOP in ocular hypertension in vivo and suppresses ECM in trabecular meshwork perhaps via FGD4.

To explore the role of atorvastatin in regulating intraocular pressure (IOP) in glaucoma in vivo, and to investigate its related molecular pathway in vitro, an ocular hypertension model was generated by intravitreal injection of an adenoviral vector encoding transforming growth factor (TGF)­ß2 in the right eye of BALB/cJ mice, while the left was treated with an empty control adenovirus. To determine its anti­intraocular hypertension role, these induced hyper­IOP mice were gavaged with atorvastatin (20 mg/kg/day). Furthermore, extracellular matrix (ECM) factors were examined in the primary human trabecular meshwork (HTM) cells followed atorvastatin (0~200 µM) treatment in vitro. Whole genome microarray was employed to identify potential therapeutic target molecules associated with ECM regulation. Unilateral murine ocular hypertension was induced, via intravitreal injection of the adenoviral vector carrying the human TGF­ß2 gene (Ad.hTGF­ß2226/228), raising IOP from 12±1.6 to 32.3±0.7 mmHg (n=6, P<0.05) at day 15, which plateaued from day 15 to 30. Atorvastatin administration from day 15 to 30 decreased IOP from 32.3±0.7 to 15.4±1.1 mmHg (n=6, P<0.05) at day 30. Additionally, atorvastatin administration changed the morphology of cultured HTM cells from an elongated and adherent morphology into rounded, less elongated and less adherent cells, accompanied with suppressed expression of ECM. Gene Ontology and Genome analysis revealed that FGD4 (FYVE, RhoGEF and PH domain containing 4) might be a key factor contributing to these changes. Our data demonstrated that atorvastatin reduced TGF­ß2­induced ocular hypertension in vivo, perhaps via modifying cellular structure and decreasing ECM, using the FGD4 signaling pathway, as demonstrated in HTM cells. Our findings provide some useful information for the management of glaucoma, with statin therapy revealing a potential novel therapeutic pathway for glaucoma treatment.

[Effect of transcutaneous auricular vagus nerve stimulation on the expressions of GFAP and MAP2 in ischemic penumbra of rats with middle cerebral artery ischemia].

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 (P<0.01), suggesting the success of modeling. After treatment, the score was increased in the model group (P<0.01) as compared with the sham-operation group. Compared with the model group, the neurological deficit score was reduced in the taVNS group (P<0.01). Compared with the sham-operation group, GFAP expression was increased and MAP2 expression was reduced remarkably in the cerebral ischemic penumbra in the model group (P<0.05). In comparison with the model group, GFAP expression was reduced, while MAP2 expression was increased remarkably in the cerebral ischemic penumbra in the taVNS group (P<0.05). There were no significant differences in the abovementioned indexes between the model group and tnVNS group (P>0.05). The differences in the expression of α7nAchR in the cerebral ischemic penumbra and the spleen had no statistical significance among groups (P>0.05). CONCLUSION: 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.

Conductive Covalent Organic Frameworks with Conductivity- and Pre-Reduction-Enhanced Electrochemiluminescence for Ultrasensitive Biosensor Construction.

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 (generally <10-8 S m-1). To address this shortcoming, we used 2,3,6,7,10,11-hexaaminotriphenylene (HATP) and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) to synthesize a conductive COF (HHTP-HATP-COF, conductivity = 3.11 × 10-4 S m-1). Compared with HATP, HHTP, and low-conductive HHTP-DABZ-COF, HHTP-HATP-COF exhibited superior ECL performance, not only because HHTP-HATP-COF possessed massive ECL luminophores but also because its conductive porous framework accelerated charge transport in the whole framework and improved the utilization ratio of ECL luminophores. More interestingly, the ECL intensity of the HHTP-HATP-COF/S2O82- system was further improved after pre-reduction electrolysis due to the accumulation of HHTP-HATP-COF cation radicals. The experimental results showed that the ECL intensity of the HHTP-HATP-COF/S2O82- system after pre-reduction was about 1.64-, 3.96-, 6.88-, and 8.09-fold higher than those of HHTP-HATP-COF/S2O82-, HHTP-DABZ-COF/S2O82-, HHTP/S2O82-, and HATP/S2O82- systems, respectively. Considering the superior ECL property of the HHTP-HATP-COF/S2O82- system after pre-reduction, it was used as a high-efficient ECL beacon together with an aptamer/protein proximity binding-induced three-dimensional bipedal DNA walker to construct an ultrasensitive biosensor for thrombin detection, which displayed broad linearity (100 aM to 1 nM) with a detection limit of 62.1 aM. Overall, the work offered effective ways to increase ECL performance by the enhancement of conductivity and by the pre-reduction, proposing new ideas to design high-efficiency COF-based ECL materials and endowing conductive COFs with ECL biosensor application for the first time.

Auricular Vagus Nerve Stimulation Ameliorates Functional Dyspepsia with Depressive-Like Behavior and Inhibits the Hypothalamus-Pituitary-Adrenal Axis in a Rat Model.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: aVNS ameliorates gastric motility and improves the mental state in the FD-like rat, probably via inhibiting the CRF pathway.

[Systematic review and Meta-analysis on the auriculotherapy in treatment of insomnia].

OBJECTIVE: To review the effectiveness and safety of auriculotherapy in treatment of insomnia. METHODS: The articles were collated by computer retrieval from 8 databases from the initiation to April 30, 2021, i.e. PubMed, EMbase, the Cochrane Library, the Web of Science, CNKI, Wanfang database, VIP and Chinese biomedical literature database (SinoMed). Meta-analysis was conducted with RevMan5.3 software. RESULTS: A total of 38 articles were included, with 3 707 cases involved. The results showed: ①The effective rate of auriculotherapy was better than that of single application of western medication with sleeping pills (RR=1.26, 95%CI:1.15 to 1.39, Z=4.77, P<0.000 01), conventional acupuncture (RR=1.10, 95%CI: 1.05 to 1.16, Z=3.83, P=0.000 1) and Chinese herbal medicine (RR=1.41, 95%CI: 1.23 to 1.63, Z=4.80, P<0.000 01), respectively. ② The total score of PSQI was reduced remarkably under the auriculotherapy when compared with the single application of western medication (MD=-1.61, 95%CI: -2.61 to -0.60, Z=3.14, P=0.002) and Chinese herbal medicine (MD=-3.76, 95%CI: -4.84 to -2.68, Z=6.84, P<0.000 01). But the difference was not significant when compared with conventional acupuncture (MD=-1.02, 95%CI: -2.11 to 0.08, Z=1.82, P=0.07). ③Auricular point selection: the auricular points distributed in the areas of vagus nerve were more advantageous in reducing PSQI score (MD=-3.21, 95%CI: -4.45 to -1.96, Z=5.03, P<0.000 01) compared with the points in other areas. ④Stimulant selection: the difference in the effective rate was not significant among different stimulants (magnetic beads, the seeds of Vaccaria segetalis, micro-needles) (MD=1.62, 95%CI: 0.71 to 3.73, Z=1.14, P=0.25). ⑤Stimulation frequency: there was no significant difference between high-frequency stimulation and low-frequency stimulation of auricular point sticking in improving the effective rate and reducing PSQI score (P>0.05). But the result should be considered cautiously in terms of the sensitivity analysis. ⑥Adverse reactions: the case numbers of adverse reactions of auriculotherapy (auricular point sticking) were less than those of western medication (MD=0.15, 95%CI: 0.06 to 0.35, Z=4.38, P<0.000 1). CONCLUSION: Auriculotherapy has certain curative advantages in treatment of insomnia compared with western and Chinese medications as well as conventional acupuncture. This therapy may relieve the symptoms of insomnia and has less adverse effects. But those outcomes need to be further verified with more high-quality randomized controlled trials.

Integrated Strategy of UHPLC-Q-TOF-MS and Molecular Networking for Identification of Diterpenoids from Euphorbia fischeriana Steud. and Prediction of the Anti-Breast-Cancer Mechanism by the Network Pharmacological Method.

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.

[Effects of transcutaneous auricular vagus nerve stimulation on autonomic nervous function in rats with functional dyspepsia].

OBJECTIVE: 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. METHODS: 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. RESULTS: Compared with the normal control group, the cervical trapezius electromyography and AWR scores of the model group increased (P<0.01, P<0.001), and there was no erosion in the gastric antral mucosa and muscle layer. The high-frequency power (HF) in HRV decreased (P<0.05), the ratio of low-frequency power/high-frequency power (LF/HF) increased (P<0.001), and the Ach content and its receptor M3R expression in gastric antrum tissue decreased (P<0.05). Following interventions, the cervical trapezius electromyography and AWR scores decreased (P<0.01,P<0.001, P<0.05), HF in HRV increased and LF/HF decreased(P<0.01，P<0.05,P<0.001), and the content of Ach in gastric antrum tissue and the expression of its receptor M3R increased (P<0.01, P<0.05) in both taVNS and ST36 groups relevant to the model group. CONCLUSION: 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.

[Effect of transcutaneous auricular vagus nerve stimulation on the expression of TLR4、MyD88、IL-18 protein in the prefrontal cortex of depression rats].

OBJECTIVE: 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. METHODS: A total of 24 male Sprague Dawley rats were randomly divided into normal, depression model, taVNS, tnVNS (transcutaneous auricular none-vagus nerve stimulaton) groups (n=6 in each group). The depression model was established by chronic unpredictable mild stimulation combined with solitary raising for 35 consecutive days. After 14 days modeling, transcutaneous electrostimulation (2 mA, 2 Hz/15 Hz) was applied to auricular concha or auricular margin, respectively. Each intervention was conducted for 30 minutes, once daily for 21 days. The depression-like behavior was evaluated by forced swimming immobility time and body weight. The expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and interleukin-18 (IL-18) protein in the prefrontal cortex were detected by Western blot. RESULTS: 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 (P<0.01). Following the treatment and compared with the model group, the increase amount of body weight in the taVNS group was obviously increased (P<0.05), the swimming immobility time and the expression of TLR4, MyD88, IL-18 protein in the taVNS and tnVNS groups were significantly decreased (P<0.01). CONCLUSION: 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.

MicroRNA-93-5p participates in type 2 diabetic retinopathy through targeting Sirt1.

OBJECTIVE: To investigate the role of miR-93-5p in rats with type 2 diabetic retinopathy (DR) through targeting Sirt1. METHODS: 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. RESULTS: 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. CONCLUSION: 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.