19 cinnamamide/ester-triazole compounds were designed, synthesized and evaluated for their anti-Alzheimer's disease (AD) activity. Among them, compound 4f displayed excellent anti-β-amyloid protein (Aβ)-mediated cytotoxicity (EC₅₀ = 2.03 ± 2.45 μmol·L^-1) in APPswe cells and acetylcholinesterase inhibiton (IC₅₀ = 4.88 ± 4.70 μmol·L^-1). Further study indicated that, at dosages of (1, 5 and 25 mg·kg^-1), compound 4f was effective in improving spatial learning and memory deficits in Aβ_1-42-impaired mice, which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway, along with the suppression of Aβ-induced Tau phosphorylation. All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology (IMB-20220908D701). In conclusion, compound 4f holds promise as a lead candidate for AD treatment, and the present study lays the foundation for its subsequent development.

Objective:To analyze the independent risk factors for pneumothorax in older adult patients with chronic obstructive pulmonary disease (COPD), construct and validate a prediction model of pneumothorax risk in patients with COPD.Methods:A total of 500 patients with COPD who received treatment at the Department of Emergency, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine from January 2018 to December 2021 were selected using the convenience sampling method and included in this study. Chest CT scan or chest X-ray film findings were used as diagnostic criteria. These patients were divided into a pneumothorax group and a control group according to whether they developed pneumothorax. Taking whether patients develop pneumothorax as a dependent variable and predictive risk factors as independent variables, univariate and multivariate logistic regression analyses of the included risk factors were performed to identify the independent influential factors for developing pneumothorax in patients with COPD. Subsequently, a prediction model for predicting the risk of pneumothorax was constructed and evaluated. A decision curve analysis was conducted to evaluate its clinical practicality.Results:Among 500 patients with COPD, 104 developed pneumothorax, with an incidence of 20.80%. Binary logistic regression analysis showed that long duration of COPD, C-reactive protein, and mechanical ventilation were independent risk factors for the development of pneumothorax in these patients. The percentage of forced expiratory volume in one second (FEV 1%), the FEV 1/forced vital capacity ratio (FEV 1/FVC), and serum albumin are protective factors for the development of pneumothorax in patients with COPD. A prediction model for the risk of developing pneumothorax was constructed. Finally, we obtained the formula: Logit( P) = 12.427 + 2.241 × COPD duration + 0.899 × smoking + 7.715 × CRP + 0.208 × mechanical ventilation history -0.514 × albumin -0.243 × FEV 1%-0.286 FEV 1/FVC. Receiver operating characteristic curve analysis results showed that the area under the curve was 0.815 and the C-Index was 0.781 (95% CI: 0.856-0.891), indicating that the constructed prediction model can better distinguish between patients with and without pneumothorax among those with COPD. Conclusion:C-reactive protein, albumin, FEV 1%, FEV 1/FVC, smoking history, and mechanical ventilation history are all risk factors for the development of pneumothorax. A prediction model has been successfully constructed based on these risk factors, which can effectively predict the risk of pneumothorax. This constructed risk prediction model provides good guidance in taking preventive treatment and nursing measures by medical staff.

Objective To evaluate tolerability,safety and pharmacokinetics of JS026 and JS026-JS016 single dose intravenous infusion in healthy adults.Methods This phase 1,randomized,double-blind,placebo-controlled,dose-escalation study totally included 48 participants:32 healthy subjects were enrolled in JS026 single intravenous infusion groups and 16 healthy subjects were enrolled in JS026-JS016 groups.JS026 was sequentially administered from low dose to high dose(30-1 000 mg),with intravenous infusion of JS026 or placebo in JS026 single-dose groups,and intravenous infusion of JS026-JS016 or placebo in the combination drug groups.Blood was collected according to the time point designed for trial.Serum concentrations of JS026 and JS016 were determined by enzyme linked immunosorbnent assay(ELISA),and pharmacokinetics parameters were calculated by WinNonlin 8.2.The power model method was used to evaluate the linear analysis of dose and drug exposure.Results 47 subjects completed trial and 1 subject lost to follow-up.After a single intravenous injection of JS026 of 30 mg,100 mg,300 mg,600 mg,and 1 000 mg,mean Cmax were(9.47±1.53),(33.20±4.95),(96.10±13.70),(177.00±22.20)and(353.00±56.70)μg·mL-1,respectively;mean AUC0-∞ were(4 225.00±607.00),(1.78 × 104±3 268.00),(5.83 × 104±1 038.00),(1.07 × 105±152.00),(1.66 × 105±327.00)μg·h·mL-1,respectively;mean t1/2 of JS026 were 563-709 h.The Cmax and AUC0-∞ of JS026 were basically similar alone or in combination with JS016.The results of Power model showed that Cmax and AUC0-∞ increased approximately linearly with the increasing dose of JS026.Treatment emergent adverse event was not increasing when dose increased and most of adverse event associated with drugs were abnormal on laboratory tests and haematuria,thus JS026 and JS016 was well tolerated in all groups.Conclusion The single intravenous infusion of JS026 can almost be thought to be a linear relationship between the doses and drug serum exposure.JS016 had no significant effect on serum concentration of JS026 and JS026 was well tolerated and safe in healthy subjects within 30-1 000 mg.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by muscle rigidity, resting tremor, and postural instability, which severely impair the quality of life in middle-aged and elderly individuals. PD’s pathogenesis is complex, involving oxidative stress, immune inflammation, and genetic factors. Despite extensive research, precise therapeutic targets for PD remain elusive, necessitating further investigation into its underlying mechanisms. Recent studies highlight the pivotal role of regional brain iron overload, oxidative stress, and lipid peroxidation in PD’s pathogenesis. Ferroptosis, a form of regulated cell death driven by iron dependency and lipid peroxidation, has emerged as a critical factor in PD pathology. This review examines the relationship between ferroptosis and PD and explores the potential of exercise as a therapeutic intervention to modulate ferroptosis and alleviate PD symptoms. Ferroptosis, distinct from other forms of cell death such as necrosis, autophagy, pyroptosis, and apoptosis, is characterized by mitochondrial shrinkage, reduced cristae, and membrane collapse, without nuclear fragmentation, DNA cleavage, or caspase activation. It is induced by the accumulation of intracellular Fe²⁺, which enhances lipid peroxidation and reactive oxygen species (ROS) generation, ultimately leading to cell death. Studies show disrupted iron metabolism in PD patients, with elevated iron levels in dopaminergic neurons of the substantia nigra correlating with disease severity. Iron chelation therapy has shown promise in alleviating PD symptoms by reducing brain iron levels, highlighting the significance of iron metabolism in PD pathogenesis. Lipid peroxidation, a hallmark of ferroptosis, involves the oxidation of polyunsaturated fatty acids (PUFAs) in cell membranes, compromising membrane integrity and increasing permeability. Elevated lipid peroxidation in the substantia nigra contributes to neuronal damage in PD. Enzymes such as ACSL4 and LPCAT3, crucial in PUFA metabolism, play significant roles in ferroptosis. Exercise has been shown to modulate these enzymes, potentially reducing lipid peroxidation and preventing ferroptosis in PD. Glutathione (GSH) metabolism is another crucial factor in ferroptosis regulation. GSH depletion impairs ROS detoxification, exacerbating oxidative stress and lipid peroxidation. PD patients exhibit reduced GSH levels in the substantia nigra, making dopaminergic neurons more vulnerable to oxidative damage. Exercise enhances GSH synthesis and activity, mitigating oxidative stress and ferroptosis in PD. α-Synuclein aggregation, a hallmark of PD, is closely linked to iron metabolism and oxidative stress. Excessive α‑synuclein binds to iron, promoting its aggregation and inducing ferroptosis. Exercise has been found to reduceα-synuclein accumulation and its pathological phosphorylation, potentially through the upregulation of neuroprotective proteins like DJ-1 and Irisin. These proteins enhance antioxidant defenses and facilitate α‑synuclein degradation, providing a protective effect against PD progression. Additionally, glutamate excitotoxicity, driven by dysregulated glutamate metabolism and receptor activity, contributes to ferroptosis in PD. Exercise modulates glutamate levels and receptor expression, reducing excitotoxicity and iron-induced neuronal damage. In conclusion, emerging research suggests that exercise may inhibit ferroptosis through multiple mechanisms, including regulation of iron metabolism, enhancement of antioxidant defenses, reduction of α-synuclein aggregation, and modulation of glutamate metabolism. These findings highlight the potential of exercise as a non-pharmacological intervention in the prevention and treatment of PD. Further research is needed to elucidate precise mechanisms and optimize exercise protocols for maximum therapeutic benefit.

Objective To construct and apply a management plan for microaspiration of oropharyngeal secretions in ICU intubated patients.Methods Based on evidence summaries and expert consultation,a management plan for microaspiration of oropharyngeal secretions in ICU intubated patients was constructed,consisting of 19 items covering 7 aspects including identification of risk factors,position management,tube and cuff selection,cuff management,mechanical ventilation management,pain and sedation management,removal of oropharyngeal and subglottic secretions,and oral care.Convenience sampling was used to select 141 ICU intubated patients from a tertiary A comprehensive hospital in Suzhou from June,2022 to September,2023.Patients were divided into an experimental group(n=72)and a control group(n=69)according to the wards.The experimental group received the management plan for microaspiration of oropharyngeal secretions in ICU intubated patients.The control group received the nursing bundle for ventilator associated pneumonia(VAP).The incidence and time from intubation to microaspiration and VAP,duration of mechanical ventilation,ICU length of stay,and disease outcome were compared between the 2 groups.Results The incidence of microaspiration of oropharyngeal secretions,the duration of mechanical ventilation,time from intubation to microaspiration showed significant differences between the 2 groups(P<0.05).There were no significant differences in the incidence of ventilator associated pneumonia,ICU length of stay,and disease outcome between the 2 groups(P>0.05).The time from intubation to VAP in the experimental group was 7.5 days,and that in the control group was 3.8 days.Conclusion The application of the management plan for microaspiration of orophaiyngeal secretions in ICU intubated patients is beneficial for reducing the incidence of microaspiration,delaying the time from intubation to microaspiration and VAP,and shortening the duration of mechanical ventilation.

Background/Aims: Functional dyspepsia (FD) overlapping with other gastrointestinal disorders are quite common. The characteristics of FD overlap in Chinese population with latest Rome IV criteria were unclear. This large-scale outpatient-based study assessed the characteristics of FD overlap in South China. Methods: Consecutive FD patients visited the Gastroenterology Clinic at 2 tertiary medical centers in Hangzhou, China who fulfilled the Rome IV criteria were enrolled. Complete questionnaires related to the gastrointestinal symptoms (Rome IV criteria), Reflux Disease Questionnaire, anxiety and depression, quality of sleep and life, and demographic information were collected. Results: Among the total of 3281 FD patients, 50.69% overlapped with gastroesophageal reflux disease, 21.46% overlapped with irritable bowel syndrome, 6.03% overlapped with functional constipation. FD overlap had higher proportion of single/divorced/widowed rate, high education level, being employed, drinking, night shift, unhealthy dietary habit than FD only (P < 0.05). They had higher frequency of consultation and economic burden, as well as lower scores in quality of life (P < 0.001). Multivariate logistic regression showed that increasing age, female, low body mass index, history of gastroenteritis, anxiety, depression, and poor sleep quality were independent risk factors for FD overlap. Conclusions FD overlap was quite common in China with high economic burden and poor quality of life, FD patients with history of gastroenteritis, anxiety, depression, and poor sleep quality were more likely to have overlap disorders. Awareness of the physical and psychosocial stressors in overlapping condition would help optimize the management of FD overlap in clinical practice.

Humans ; Thyrotoxicosis/chemically induced* ; Amiodarone

Objective To investigate the effects of glucose and serum deprivation under hypoxia(GSDH)treatment on oxidative stress and apoptosis in rat bone marrow mesenchymal stem cells (BMSCs), so to provide an experimental support for improving the therapeutic efficacy of BMSCs. Methods The cell injury model was established by hypoxia (1% O

With aging of Chinese population,prevalence of vascular cognitive impairment(VCI)is increasing year by year.At present,drugs for VCI treatment at home and abroad still lack large samples of evidence-based medicine evidence.Compared with western medicine,Chinese medicine has characteristics of multi-component and multi-target.The present article makes a review on research progress of traditional Chinese medicine in treatment of VCI,aiming at providing new thinking for VCI treatment.

Objective: This study aims to investigate the associations between genetic variations of pyroptosis pathway related key genes and adverse events (AEs) of postoperative chemoradiotherapy (CRT) in patients with rectal cancer. Methods: DNA was extracted from the peripheral blood which was collected from 347 patients before CRT. Sequenom MassARRAY was used to detect the genotypes of 43 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight pyroptosis genes, including absent in melanoma 2 (AIM2), caspase-1 (CASP1), caspase-4(CASP4), caspase-5 (CASP5), caspase-11 (CASP11), gasdermin D (GSDMD), gasdermin E (GSDME) and NLR family pyrin domain containing 3 (NLRP3). The associations between 43 htSNPs and AEs were evaluated by the odd ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression models, adjusted for sex, age, clinical stage, tumor grade, Karnofsky performance status (KPS), surgical procedure, and tumor location. Results: Among the 347 patients with rectal cancer underwent concurrent CRT with capecitabine after surgery, a total of 101(29.1%) occurred grade ≥ 2 leukopenia. rs11226565 (OR=0.41, 95% CI: 0.21-0.79, P=0.008), rs579408(OR=1.54, 95% CI: 1.03-2.29, P=0.034) and rs543923 (OR=0.63, 95% CI: 0.41-0.98, P=0.040) were significantly associated with the occurrence of grade ≥ 2 leukopenia. One hundred and fifty-six (45.0%) had grade ≥ 2 diarrhea, two SNPs were significantly associated with the occurrence of grade ≥ diarrhea, including CASP11 rs10880868 (OR=0.55, 95% CI: 0.33-0.91, P=0.020) and GSDME rs2954558 (OR=1.52, 95% CI: 1.01-2.31, P=0.050). In addition, sixty-six cases (19.0%) developed grade ≥2 dermatitis, three SNPs that significantly associated with the risk of grade ≥2 dermatitis included GSDME rs2237314 (OR=0.36, 95% CI: 0.16-0.83, P=0.017), GSDME rs12540919 (OR=0.52, 95% CI: 0.27-0.99, P=0.045) and NLRP3 rs3806268 (OR=1.51, 95% CI: 1.03-2.22, P=0.037). There was no significant difference in the association between other genetic variations and AEs of rectal cancer patients (all P>0.05). Surgical procedure and tumor location had great impacts on the occurrence of grade ≥2 diarrhea and dermatitis (all P<0.01). Conclusion: The genetic variants of CASP4, CASP11, GSDME and NLRP3 are associated with the occurrence of AEs in patients with rectal cancer who received postoperative CRT, suggesting they may be potential genetic markers in predicting the grade of AEs to achieve individualized treatment of rectal cancer.
Humans ; Pyroptosis ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Gasdermins ; Chemoradiotherapy/adverse effects* ; Rectal Neoplasms/surgery* ; Caspases/metabolism* ; Diarrhea/chemically induced* ; Leukopenia/genetics* ; Genetic Variation ; Dermatitis