Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; alpha-Synuclein/metabolism* ; Male ; Prefrontal Cortex/drug effects* ; Rats, Sprague-Dawley ; Depression/metabolism* ; MAP Kinase Signaling System/drug effects* ; Rats ; Parkinson Disease/metabolism* ; Receptor, trkB/metabolism* ; Phosphorylation ; Disease Models, Animal ; Signal Transduction

Objective: To explore the causal link of cumulative ecological risk and future orientation with health risk behaviors among higher vocational college students, so as to provide reference for reducing and preventing health risk behaviors among higher vocational college students. Methods: A longitudinal follow up study was conducted on 612 students using convenience sampling from 2 vocational colleges in Hunan Province. The Cumulative Ecological Risk Scale, Future Orientation Scale, and Health Risk Behavior Scale were used during three follow up visits (T1: September 2022, T2: June 2023, T3: March 2024), and a cross lagged panel model was constructed to examine the longitudinal causal relationship of cumulative ecological risk, future orientation and health risk behaviors. Analysis of longitudinal intermediary effect between variables by Bootstrap. Results: The cumulative ecological risk scores of T1, T2 and T3 among higher vocational college students were (2.94±1.44,2.99±1.63,3.02±1.54), future orientation scores (40.49±4.71,41.51±5.72,41.06±4.35) and health risk behavior scores (3.73±2.01,3.49±2.00,3.23±2.00). The results of repeated measures ANOVA showed that the future orientation score of T2 was higher than that of T1, and the main effect of measurement time was statistically significant ( F=5.09，P＜0.01,η 2=0.02). The health risk behavior score of T1 was higher than that of T2, and the health risk behavior score of T2 was higher than that of T3, and the main effect of measurement time was statistically significant ( F=10.12，P＜0.01,η 2=0.03).The cross lagged model showed good adaptability, with χ 2/df =7.20 ( P <0.01), relative fitting indicators GFI=0.98, CFI=0.99, TLI=0.96, IFI=0.99, NFI =0.99, and absolute fitting indicator RMSEA =0.06. Among them, the T1, T2 cumulative ecological risk showed negatively predictive effects on T2, T3 future orientation ( β =-0.24, -0.47 ), and T1, T2 cumulative ecological risk positively predicted T2, T3 health risk behavior ( β =0.20, 0.24), while T1, T2 future orientation negatively predicted T2, T3 health risk behavior ( β =-0.25, -0.18) ( P ＜0.01). Bootstrap test analysis found that T2 future orientation had a longitudinal mediating effect ( β=0.04, P ＜0.01) on the T1 cumulative ecological risk and T3 health risk behavior. Conclusions The accumulation of ecological risk among higher vocational college students can positively predict health risk behaviors, while future orientation can negatively predict healthrisk behaviors. Moreover, future orientation plays a longitudinal mediating role between accumulated ecological risks and health risk behaviors.

As representatives of the third generation of biomedical materials, hydrogels exhibit revolutionary potential in tissue engineering, precision drug delivery, and smart medical devices due to their ability to construct bionic microenvironments. However, the clinical translation of hydrogels is still limited by multidimensional challenges, including biocompatibility, scalable production, and regulatory complexity. This paper systematically reviews the design innovations, functionalization strategies, and translational bottlenecks of hydrogel materials, integrates the latest technological trends, such as 4D printing and AI-driven design, and proposes a collaborative optimization pathway encompassing materials, technology, clinical applications, and policy. By introducing local Chinese innovation cases and monitoring scientific advancements, this study offers solutions that possess both academic significance and practical guidance for the clinical translation of hydrogels.
Hydrogels ; Tissue Engineering ; Translational Research, Biomedical ; Biocompatible Materials ; Humans ; Drug Delivery Systems

OBJECTIVE: To explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction. METHODS: Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca²⁺ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway. RESULTS: Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca²⁺-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca²⁺ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05). CONCLUSIONS Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals ; Angiotensin II ; Male ; Benzylisoquinolines/therapeutic use* ; Network Pharmacology ; Blood Pressure/drug effects* ; Sequence Analysis, RNA ; Mice ; Hypertension/chemically induced* ; Mice, Inbred C57BL ; Calcium/metabolism*

OBJECTIVE: To explore the effects of electroacupuncture (EA) on pregnancy outcomes after assisted reproduction and mitochondrial function of granulosa cells (GCs) in patients with polycystic ovary syndrome (PCOS) and phlegm-dampness syndrome. METHODS: In this randomized controlled trial, 90 infertile women with PCOS and phlegm-dampness syndrome were recruited between August 2022 and December 2022. Patients were randomly assigned to the EA and control groups using a random sequence of codes in the order of enrolment, with 45 in in each group. Both groups underwent the ovarian stimulation protocol. The patients in the EA group received EA therapy including Zhongwan (CV 12), Qihai (CV 6), bilateral Xuehai (SP 10), Sanyinjiao (SP 6), Yinlingquan (SP 9), Tianshu (ST 25), Zusanli (ST 36), and Fenglong (ST 40), and the patients in the control group was treated with pseudo-acupuncture. The intervention was 25 min twice a week for a total of 6 times until the trigger day after menstruation had ended in the cycle before oocyte retrieval. The primary outcomes were clinical pregnancy rate (CPR) and the number of high-quality embryos. The secondary outcomes were (1) pregnancy-related indicators, including fresh embryo transfer rate (ETR), ovarian hyperstimulation syndrome (OHSS) rate, early pregnancy loss rate (ePLR), ectopic pregnancy rate, live birth rate (LBR), and cumulative CPR; (2) mitochondrial autophagy and mitochondrial membrane potential (MMP) in GCs; and (3) scoring for Chinese medicine syndrome. Adverse events to assess clinical safety were also monitored. RESULTS: The cumulative CPR was significantly higher in the EA group (42/45, 93.3%) than in the control group (38/45, 84.4%, P=0.036). The number of high-quality embryos and fresh ETR in the EA group were higher than those in the control group (3.80±1.65 vs. 2.44±1.34, P<0.001; 46.7% vs 24.4%, P=0.028). Ectopic pregnancies were not observed in either group. There were no significant differences in the fresh CPR, OHSS rate, ePLR or LBR between the two groups (P>0.05). Compared with the control group, the EA group showed lower expression levels of miR-146a-5p mRNA and P62 protein in GCs and higher levels of MMP and the LC3-II/LC3-I protein ratio (all P<0.01). The phlegm-dampness syndrome scores of the EA group were significantly lower than those of the control group (P<0.01). CONCLUSIONS EA significantly improved pregnancy outcomes in patients with PCOS and phlegm dampness syndrome. Mechanistically, this effect may be related to EA in decreasing miR-146a-5p mRNA expression, promoting mitochondrial autophagy in GCs, and improving mitochondrial function, which may contribute to improved oocyte quality. (Trial registration No. ChiCTR2200062915).
Humans ; Female ; Polycystic Ovary Syndrome/therapy* ; Pregnancy ; Electroacupuncture ; Granulosa Cells/metabolism* ; Adult ; Mitochondria/metabolism* ; Pregnancy Outcome ; Pregnancy Rate ; Reproductive Techniques, Assisted ; Infertility, Female/therapy*

Aim To investigate the intervention effect of Rehmannia radix water extract on bleomycin(BLM)-induced pulmonary fibrosis in mice combined with metabolomics and to reveal the potential mechanism,in order to provide new ideas for clinical treatment of pul-monary fibrosis.Methods Male C57BL/6N mice were randomly divided into the control group,model group,pirfenidone group(positive control,PFD,270 mg·kg-1),and low dose(DH-L,4.55 g·kg-1)group,medium dose(DH-M,9.1 g·kg-1)group and high dose(DH-H,18.2 g·kg-1)group of Rehman-nia.Except for the control group,BLM(5 mg·kg-1)was instilled into the trachea to establish the model of pulmonary fibrosis in the other groups.The survival rate,lung index and blood oxygen saturation of mice in each group were evaluated.HE and Masson staining were used to observe the pathological changes of lung tissue.WBP was used to detect lung function.Flow cytometry was used to detect the apoptosis of primary lung cells,ROS and immune cells.ELISA was used to detect the levels of fibrosis markers and inflammatory factors(α-SMA,collagen Ⅰ,collagen Ⅲ,TGF-β1,TNF-α,IL-1 β,and IL-6).Biochemical method was employed to detect the contents of GSH-Px,T-SOD and MDA.Liquid chromatograph mass spectrometer(LC-MS)metabolomics was used to analyze the changes of serum metabolic profile.Results Water extract of Re-hmannia significantly increased the survival rate,oxy-gen saturation and lung function of mice with pulmona-ry fibrosis,reduced the lung coefficient,ameliorated pathological damage and collagen deposition in lung tissue,reduced the levels of apoptosis and oxidative stress,and down-regulated the levels of inflammatory factors in lung tissue.It regulated the levels of metabo-lites such as bile acid metabolism,sphingolipid metabo-lism,and unsaturated fatty acid metabolism.Conclu-sions Water extract of Rehmannia inhibits lung injury and collagen deposition in mice with pulmonary fibrosis by inhibiting inflammatory response,which may be a-chieved by regulating the levels of inflammatory factors through the metabolic pathways of bile acid and sphin-golipid.

Radiotherapy plays a critical role in the management of borderline resectable and unresectable locally advanced pancreatic cancer. Conventional radiotherapy improves local control in pancreatic cancer but has not significantly enhanced overall survival. Stereotactic body radiotherapy (SBRT), which employs single high-dose fractions or a hypofractionated regimen, enhances the biologically effective dose and has demonstrated remarkable efficacy in cancer treatment combined with systemic therapy. Due to the extremely high precision requirements of SBRT for spatial tumor targeting, precise organ motion management and image-guided radiotherapy technologies are essential for its successful implementation. The integration of MR-guided online adaptive radiotherapy with SBRT enables real-time assessment of anatomical changes during each treatment session, allowing online adaptive replanning to optimize dose delivery. This approach significantly improves treatment accuracy. The comprehensive application of these cutting-edge radiotherapy technologies holds promise for establishing groundbreaking therapeutic paradigms in pancreatic cancer.

Objective To investigate the predictive value of pulmonary artery(Pa)to aortic(Ao)diameter ratio(Pa/Ao)for long-term major adverse cardiovascular events(MACEs)in patients with acute decompensated heart failure(ADHF).Methods ADHF patients hospitalized in the Department of Cardiology of Nanjing Drum Tower Hospital from January 2018 to January 2023 were consecutively enrolled.The data of gender,age,past medical history,laboratory examination,echocardiography,chest CT and medication were collected.The diameters of Pa and Ao were measured at the bifurcation of main pulmonary artery on chest CT,and Pa/Ao was calculated.The Kaplan-Meier method was used for survival analysis,and the Log-rank test was used to compare the survival rate between the two groups.Cox proportional hazards regression model was used to analyze the association between Pa/Ao and MACEs,and subgroup analysis was performed according to different age,sex,BMI,B-type natriuretic peptide level,and left ventricular ejection fraction.Results A total of 600 ADHF patients were enrolled,with an average age of 69.6 years and 347(57.8%)males.During a median follow-up of 306(127,624)days,327(54.5%)patients experienced MACEs.The ADHF patients were divided into Pa/Ao<0.93 group and Pa/Ao≥0.93 group according to the analysis of maximum selection rank statistics.Kaplan-Meier curve showed that the incidence of MACEs in Pa/Ao≥0.93 group was significantly higher than that in Pa/Ao<0.93 group(PLog-rank<0.001).Multivariate Cox regression analysis showed that Pa/Ao was an independent predictor of MACEs in ADHF patients(HR=11.62,95%CI:4.91～27.50,P<0.001).Subgroup analysis showed that Pa/Ao had predictive value for different ADHF populations(all P<0.05).Conclusion Elevated Pa/Ao is a predictor of long-term MACEs in ADHF patients.

Objective To investigate the predictive value of pulmonary artery(Pa)to aortic(Ao)diameter ratio(Pa/Ao)for long-term major adverse cardiovascular events(MACEs)in patients with acute decompensated heart failure(ADHF).Methods ADHF patients hospitalized in the Department of Cardiology of Nanjing Drum Tower Hospital from January 2018 to January 2023 were consecutively enrolled.The data of gender,age,past medical history,laboratory examination,echocardiography,chest CT and medication were collected.The diameters of Pa and Ao were measured at the bifurcation of main pulmonary artery on chest CT,and Pa/Ao was calculated.The Kaplan-Meier method was used for survival analysis,and the Log-rank test was used to compare the survival rate between the two groups.Cox proportional hazards regression model was used to analyze the association between Pa/Ao and MACEs,and subgroup analysis was performed according to different age,sex,BMI,B-type natriuretic peptide level,and left ventricular ejection fraction.Results A total of 600 ADHF patients were enrolled,with an average age of 69.6 years and 347(57.8%)males.During a median follow-up of 306(127,624)days,327(54.5%)patients experienced MACEs.The ADHF patients were divided into Pa/Ao<0.93 group and Pa/Ao≥0.93 group according to the analysis of maximum selection rank statistics.Kaplan-Meier curve showed that the incidence of MACEs in Pa/Ao≥0.93 group was significantly higher than that in Pa/Ao<0.93 group(PLog-rank<0.001).Multivariate Cox regression analysis showed that Pa/Ao was an independent predictor of MACEs in ADHF patients(HR=11.62,95%CI:4.91～27.50,P<0.001).Subgroup analysis showed that Pa/Ao had predictive value for different ADHF populations(all P<0.05).Conclusion Elevated Pa/Ao is a predictor of long-term MACEs in ADHF patients.

Objective:This study aimed to investigate the effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs) on the emotional behaviors in wild-type mice and explore the underlying mechanisms.Methods:The study consisted of two parts.(1) Drug effect evaluation: C57BL/6 mice were randomly assigned to saline, semaglutide, or liraglutide groups. After 4 weeks of continuous subcutaneous administration, anxiety-like behaviors were evaluated by the open field tests and elevated plus maze, and depression-like behaviors were assessed by the forced swimming test and tail suspension test. Neurotransmitter levels, including NE, DA, 5-HT, GABA, and glutamate, were measured in target brain regions using LC-MS/MS. Hypothalamic activation subregions were identified by c-fos immunohistochemistry.(2) Time-course analysis: Mice received short-term administration(2 weeks), long-term administration(4 weeks), or drug withdrawal(assessed 4 weeks post-withdrawal). Behavioral performance, hypothalamic neurotransmitter levels, and plasma adrenocorticotropic hormone and corticosterone were measured.Results:Compared with the saline group, both GLP-1RAs significantly prolonged immobility time in the forced swimming and tail suspension tests. Multiple brain regions exhibited neurotransmitter abnormalities, including marked reductions in hypothalamic norepinephrine, dopamine, and γ-aminobutyric acid levels. Both GLP-1RAs significantly increased c-fos positive cell counts in the suprachiasmatic nucleus and arcuate nucleus of the hypothalamus. Time-course analysis revealed that short-term administration did not induce depressive phenotypes, whereas long-term administration led to depression-like behaviors, which recovered after drug withdrawal. Plasma adrenocorticotropic hormone and corticosterone levels were elevated even after short-term treatment and remained high after drug withdrawal, while hypothalamic neurotransmitter abnormalities normalized upon withdrawal.Conclusion:GLP-1RAs induce depression-like behaviors in a time-dependent manner, with neurotransmitter imbalance and persistent hyperactivation of the HPA axis likely contributing to the pathophysiological mechanism.