Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To study the regulatory mechanism of p38 MAPK signaling pathway participate in hyperalge-sia reaction in Parkinson's disease(PD)rats model induced by 6-hydroxy dopamine(6-OHDA).Methods:Forty male Sprague Dawley(SD)rats were randomly divided into four groups:Sham group(Sham),model group(6-OHDA),p38 MAPK inhibitor SB203580 treatment group(6-OHDA+SB203580)and p38 MAPK activator anisomycin(ANS)treatment group(6-OHDA+ANS).PD model was established by intra-striatal injection of 6-OHDA stereotactically.6-OHDA+SB203580 and 6-OHDA+ANS groups was injected with 6-OHDA to establish PD model,and treated with inhibitor SB203580 or activator ANS respectively.The von Frey hairs were applied to measure the mechanical paw with-draw threshold(PWT)of rats.Enzyme linked immunosorbent assay(ELISA)was used to detect the content of IL-6,IL-1β,and TNF-α in rat dorsal root ganglion(DRG).The mRNA levels of genes IL-6,IL-1β,TNF-α,and p38 MAPK in rat DRG was detected by real time RT-PCR.Results:In the DRG of 6-OHDA included PD rats,the expres-sion levels of IL-6,IL-1β,TNF-α,and p38 MAPK were significantly increased(P＜0.05),and the PWT of rats were significantly decreased(P＜0.05).The application of activator ANS further increased the expression levels of IL-6,IL-1β,TNF-α,and p38 MAPK,and the PWT of rats were decreased.After application of inhibitor SB203580,the ex-pression levels of IL-6,IL-1β,TNF-α and p38 MAPK were significantly decreased in the DRG of rats(P＜0.05),and the PWT were significantly increased in rats(P＜0.05).Conclusion:6-OHDA induces mechanical hyperalgesia reaction in rats,and the molecular mechanism is related to activation of the p38 MAPK signalling pathway.

Non-alcoholic fatty liver disease(NAFLD)is a series of diseases characterized by hepatic steatosis and is also a metabolism-associated disease and an important factor for liver fibrosis,liver cirrhosis,and hepatocellular carcinoma.Endoplasmic reticulum is a core organelle for the regulation of lipid metabolism,and unfolded protein response is an important process of endoplasmic reticulum stress(ERS).Based on the important stress role of endoplasmic reticulum in metabolism-associated diseases,this article explores the influencing mechanism between ERS and NAFLD and reviews the research advances in lipid metabolism,inflammatory response,hepatocyte death,fibrosis,and ERS-targeted therapies in the pathological development of NAFLD.

Objective: : Post-stroke shoulder pain (PSSP) is a common complication that limits the range of motion (ROM) of the shoulder, the patient’s rehabilitation and in turn, affects the patients’ quality of life (QoL). Several treatment modalities such as sling, positioning, strapping, functional electrical stimulation, and nerve block have been suggested in literatures, however none of the treatments had long-term effects for PSSP. In this study, the authors evaluated clinical efficacy of pulsed radiofrequency (PRF) neuromodulation on the suprascapular nerve for PSSP, and suggested it as a potential treatment with long-term effect. Methods: : This retrospective case series was conducted at a single center, a private practice institution. From 2013 to 2021, 13 patients with PSSP underwent PRF neuromodulation of the suprascapular nerve. The primary outcome measure was the Visual analog scale (VAS) score. The secondary outcome measurements included the shoulder ROM, Disability assessment scale (DAS), modified Ashworth scale, modified Rankin scale (mRS), and EuroQol-5 dimension-3L questionnaire (EQ-5D-3L) scores. These parameters were evaluated before PRF modulation, immediately after PRF modulation, and every 3 months until the final follow-up visit. Results: : Six men and seven women were enrolled, and all patients were followed-up for a minimum of 12 months. The mean VAS score was 7.07 points before PRF neuromodulation and 2.38 points immediately post-procedure. Shoulder ROM for abduction and flexion, DAS for pain, mRS, and EQ-5D-3L demonstrated marked improvement. No complications were reported. Conclusion : PRF neuromodulation of the suprascapular nerve is an effective modality in patients with PSSP, and has long-term effect of pain relief, improvement of QoL.

Objective:To analyze the acoustic characteristics of patients with hypopharyngeal cancer accompanied by vocal cord dysfunction. Methods:A retrospective analysis was conducted on the data of patients with hypopharyngeal cancer who were initially treated at The Second Affiliated Hospital of Xi'an Jiaotong University from January 2018 to April 2024. Patients who had completed electronic laryngoscopy, stroboscopic laryngoscopy, and voice analysis were selected from the data. Among them, patients with hypopharyngeal cancer who had unilateral vocal cord activity disorders were selected as the experimental group, while patients with symmetrical bilateral vocal cord activity were assigned to the control group. Then the clinical characteristics, the vocal parameters, and the stroboscopic laryngoscopy results of patients with hypopharyngeal cancer in the experimental group and the control group were analyzed and compared. Results:Compared with that in the control group, the proportion of lesions located on the inner wall of the piriform fossa in the experimental group increased（83.3% vs 53.8%）, and the difference was statistically significant（P<0.05）. There was no significant difference in vocal parameters such as SPL, Jitter, Shimmer, MPT, DSI, F0, sound intensity, electroglottic value and VHI between the experimental group and the control group（P>0.05）. However, the values of F0, Jitter, Shimmer and VHI in the experimental group were higher than those in the control group. In addition, in terms of the results of stroboscopic laryngoscopy, the proportion of glottic insufficiency（42.9% vs 18.8%） and asymmetric arytenoid cartilage（64.3% vs 0） in the experimental group was significantly higher than that in the control group（P<0.05）. However, the mucosal waves of the vocal cords on the affected side did not weaken in patients in both the experimental group and the control group. In the experimental group of 18 patients with hypopharyngeal cancer who received induction chemotherapy（nituzumab+nedaplatin+5-fluorouracil）, 13 of them had improved vocal cord activity（improvement rate of 72.2%）. Conclusion:Hypopharyngeal cancer in the medial wall of the pyriform fossa is more prone to vocal cord dysfunction, but vocal cord dysfunction has little effect on the vocal parameters of patients with hypopharyngeal cancer.
Humans ; Hypopharyngeal Neoplasms ; Retrospective Studies ; Male ; Female ; Laryngoscopy ; Middle Aged ; Vocal Cord Dysfunction/etiology* ; Vocal Cords/physiopathology* ; Stroboscopy ; Voice Quality ; Aged

Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug delivery. However, it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect. Herein, a localized light-triggered release macrophage cytopharmaceutical (USIP@M) was proposed, which could utilize the tumor targeting and immunotherapy effects of macrophages to reverse the immune suppression of tumor microenvironment (TME). Amphiphilic block copolymers with ultraviolet (UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.

Objective: To investigate the mechanism of VPS26 effect on osteogenesis and adipogenesis differentiation of rat bone marrow mesenchymal stem cells (BMSC) in high fat environment, and to explore the effect of VPS26 on implants osseointegration of high fat rats and ectopic osteogenesis in nude mice. Methods: BMSC were cultured under normal osteogenic induction (osteogenic group) and high-fat osteogenic induction (high-fat group).High-fat group was transfected with VPS26 enhancer and inhibitor, and the expression levels of osteogenesis related genes and adipogenesis related genes were examined. Osteogenesis and adipogenesis of BMSC were detected by alkaline phosphatase (ALP) staining and oil red O staining after 7 and 14 days of induction.In osteogenic group,the binding of VPS26 to β-catenin was detected by immunofluorescence staining and immunoprecipitation, and dual luciferase reporter assay (TOP Flash) was used to analyze the TOP/FOP ratio. Eighteen male 12-week hyperlipidemic Wista rats (160-200 g) were implanted with implants, and six in each group were injected with VPS26 overexpression lentivirus (LV-VPS26 group), negative control lentivirus (LV-nc group) and saline (blank control group).Micro-CT analysis , HE and oil red O staining were used to evaluate the osseointegration of the implants and lipid droplets formation of the femur samples. Twenty female 6-week nude mice (30-40 g) were divided into five groups and subcutaneously implanted with osteogenic BMSC non-transfected and transfected LV-VPS26, LV-nc, shVPS26, and shscr lentivirus on the back. Samples were used to observe ectopic osteogenesis. Results: The mRNA expression levels of ALP in the high-fat group BMSC after overexpression of VPS26 (1.56±0.09) were significantly higher than those of the negative control (1.01±0.03) (t=10.09, P<0.001), while those of peroxisome proliferator-activated receptor-γ (PPAR-γ) (t=6.44, P<0.001) and fatty acid-binding protein4 (FABP4) (t=10.01, P<0.001) were lower than those of the negative control. Western blotting results showed that compared with the negative control, protein expression of ALP and Runt-related transcription gene 2 was enhanced in the high-fat group BMSC after overexpression of VPS26 while PPAR-γ and FABP4 were inhibited. ALP activity of BMSC in the high-fat group was stronger after overexpression of VPS26, and the formation of lipid droplets was weaker than that in negative control. The results of immunofluorescence, immunoprecipitation and dual luciferase reporter assays showed co-localization and interaction of VPS26 with β-catenin and a significant 43.10% increase in the TOP/FOP ratio (t=-3.17, P=0.034). VPS26 overexpression enhanced osseointegration and decreased the number of lipid droplets in high-fat rat and enhanced ectopic osteogenesis of nude mice. Conclusions: VPS26 activated osteogenesis differentiation and inhibited adipogenic differentiation of BMSCs through Wnt/β-catenin pathway, promoting osseointegration of high-fat rat implants and ectopic osteogenesis of nude mice.

Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer;hence,new and efficient strategies are necessary.In this study,a supramolecular nanoreactor(DOC@TA-Fe3+)based on tannic acid(TA),iron ion(Fe3+),and docetaxel(DOC)with microtubule inhibition,reactive oxygen species(ROS)generation,and glutathione peroxidase 4(GPX4)inhibition,is prepared for ferroptosis/apoptosis treatment.After internalization by CT26 cells,the DOC@TA-Fe3+nanoreactor escapes from the lysosomes to release payloads.The subsequent Fe3+/Fe2+conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration.Additionally,Fe3+can consume gluta-thione to repress the activity of GPX4 to induce ferroptosis.Meanwhile,the released DOC controls microtubule dynamics to activate the apoptosis pathway.The superior in vivo antitumor efficacy of DOC@TA-Fe3+nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model.Therefore,the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.

Objective: To investigate the predictive value of glycosylated hemoglobin A1c/apolipoprotein A-1 (HbA1c/ApoA-1) ratio for major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS). Methods: The present study is a retrospective cohort study. ACS patients who were hospitalized and underwent coronary angiography at Beijing Hospital from March 2017 to March 2019 were enrolled. Baseline information such as sex, age, previous history, Gensini score, HbA1c and ApoA-1 were analyzed. Patients were divided into two groups according to presence or absence of MACEs and the difference on HbA1c/ApoA-1 ratio was compared between the two groups. According to the tertiles of HbA1c/ApoA-1 levels, patients were divided into high (5.87-16.12), medium (4.50-5.83) and low (2.11-4.48) HbA1c/ApoA-1 groups. Cox proportional risk model was used to evaluate the differences in MACEs and all-cause mortality among the three groups. Kaplan-Meier survival analysis was used to compare the differences of MACEs between the various HbA1c/ApoA-1 groups. Results: A total of 366 ACS patients were included in this study. The mean age of the patients was (65.9±10.3) years. There were 59 MACEs and 10 all-cause deaths during the mean of (22.3±4.4) months follow-up. After adjusting for age, systolic blood pressure, history of diabetes and Gensini score, the incidence of MACEs was 2.45 times higher in the high HbA1c/ApoA-1 group than in the low HbA1c/ApoA-1 group (95%CI 1.16-5.18, P=0.019). There was no significant difference in all-cause mortality between the high and low HbA1c/ApoA-1 groups (P=1.000). Kaplan-Meier survival analysis showed that patients in the high HbA1c/ApoA-1 group had the highest risk of MACEs, while patients in the low HbA1c/ApoA-1 group had the lowest risk of MACEs (P<0.01). Spearman rank correlation analysis showed that HbA1/ApoA-1 ratio was positively correlated with Gensini score in ACS patients (r=0.274, P<0.01). Conclusion: High HbA1c/ApoA-1 ratio was an independent risk factor for MACEs in ACS patients. Patients with high HbA1c/ApoA-1 ratio had more severe coronary artery disease lesions. HbA1c/ApoA-1 ratio may be used as a potential risk stratification biomarker for ACS patients, it might be useful for the early identification of high-risk population and for predicting the incidence of MACEs among ACS patients.
Aged ; Humans ; Middle Aged ; Acute Coronary Syndrome/diagnosis* ; Apolipoprotein A-I/analysis* ; Biomarkers/analysis* ; Glycated Hemoglobin/analysis* ; Percutaneous Coronary Intervention ; Retrospective Studies ; Risk Factors ; Predictive Value of Tests

Bronchiectasis is a complex and heterogeneous group of diseases with their own characteristics in terms of etiology, symptoms, infections and inflammation, among which infections are both the most common cause of bronchiectasis and the most important factor contributing to the progression of the disease and affecting the prognosis. The current paper will focus on the characterization, diagnosis and treatment of pathogenic bacteria in bronchiectasis.