ObjectiveTo reveal the mechanism of Zuogui Jiangtang Jieyu prescription against damage to hippocampal synaptic microenvironment via suppressing glutamate receptor 2 （GluR2）/Parkin signal-mediated mitophagy in rats with diabetes-related depression （DD）. MethodsEighty male SD rats underwent adaptive feeding for 5 days before the study. Ten rats were randomly assigned to the normal group. The model of DD rats was established with the rest by 2-week high-fat diet + streptozotocin （STZ） tail intravenous injection + 28 days of chronic unpredictable mild stress （CUMS） combined with isolation. The rats were randomly divided into a normal group， a model group， a GluR2 blocker group （5 μg·kg^-1）， a GluR2 agonist group （10 μg·kg^-1）， a metformin + fluoxetine group （0.18 g·kg^-1 metformin + 1.8 mg·kg^-1 fluoxetine）， and high- and low-dose Zuogui Jiangtang Jieyu prescription groups （20.52 and 10.26 g·kg^-1， respectively）. The rats in the GluR2 blocker group and the GluR2 agonist group were continuously injected with CNQX and Cl-HIBO in the dentate gyrus of the hippocampus once a week starting from stress modeling， respectively， while the metformin + fluoxetine group and the high- and low-dose Zuogui Jiangtang Jieyu prescription groups were continuously given intragastric administration for 28 d at the same time of stress modeling. Depression-like behavior was evaluated by open field and forced swimming experiments. The levels of serum insulin and adenosine triphosphate （ATP） in hippocampus were detected by biochemical analysis. The levels of 5-hydroxytryptamine （5-HT） and dopamine （DA） in hippocampus were detected by enzyme-linked immunosorbent assay （ELISA）. The autophagosomes of hippocampal neurons were observed by transmission electron microscopy. The morphology and structure of dendrites and spines of hippocampal neurons were evaluated by Golgi staining. Western blot detected the expression levels of GluR2 and Parkin proteins in hippocampus. The expression levels of GluR2， Parkin， regulating synaptic membrane exocytosis protein 3 （RIMS3）， and postsynaptic density protein 95 （PSD95） in the dentate gyrus of the hippocampus were detected by immunofluorescence. ResultsCompared with the normal group， the model group exhibited reduced total activity distance in the open field and increased immobility time in forced swimming （P<0.01）， lowered levels of serum insulin and ATP， 5-HT， and DA in hippocampus （P<0.01）， increased autophagosomes of hippocampal neurons， significantly damaged morphology and structure of dendrites and spines of hippocampal neurons， decreased expression levels of GluR2， RIMS3， and PSD95 in hippocampus， and an increased Parkin expression level （P<0.05， P<0.01）. Compared with the model group， the GluR2 blocker group and the GluR2 agonist group showed aggravation and alleviation of the above abnormal changes， respectively （P<0.05， P<0.01）. The above depression-like behavior was significantly improved in the high- and low-dose Zuogui Jiangtang Jieyu prescription groups to different degrees. Specifically， the two groups saw elevated levels of serum insulin and ATP， 5-HT， and DA in hippocampus （P<0.05， P<0.01）， restrained increase in autophagosomes and damage to morphology and structure of dendrites and spines of hippocampal neurons， up-regulated protein expression levels of GluR2， RIMS3， and PSD95， and down-regulated Parkin expression level （P<0.05， P<0.01）. ConclusionZuogui Jiangtong Jieyu prescription can ameliorate the mitophagy-mediated damage to hippocampal synaptic microenvironment in DD rats， the mechanism of which might be related to the regulation of GluR2/Parkin signaling pathway.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

BACKGROUND: Preclinical studies have indicated that Angong Niuhuang Pills (ANP) reduce cerebral infarct and edema volumes. This study aimed to investigate whether ANP safely reduces cerebral infarct and edema volumes in patients with moderate to severe acute ischemic stroke. METHODS: This randomized, double-blind, placebo-controlled pilot trial included patients with acute ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores ranging from 10 to 20 in 17 centers in China between April 2021 and July 2022. Patients were allocated within 36 h after onset via block randomization to receive ANP or placebo (3 g/day for 5 days). The primary outcomes were changes in cerebral infarct and edema volumes after 14 days of treatment. The primary safety outcome was severe adverse events (SAEs) for 90 days. RESULTS: There were 57 and 60 patients finally included in the ANP and placebo groups, respectively for modified intention-to-treat analysis. The median age was 66.0 years, and the median NIHSS score at baseline was 12.0. The changes in cerebral infarct volume at day 14 were 0.3 mL and 0.4 mL in the ANP and placebo groups, respectively (median difference: -7.1 mL; interquartile range [IQR]: -18.3 to 2.3 mL, P = 0.30). The changes in cerebral edema volume of the ANP and placebo groups on day 14 were 11.4 mL and 4.0 mL, respectively ( median difference: 3.0 mL, IQR: -1.3 to 9.9 mL, P = 0.15). The rates of SAE within 90 days were similar in the ANP (3/57, 5%) and placebo (7/60, 12%) groups ( P = 0.36). Changes in serum mercury and arsenic concentrations were comparable. In patients with large artery atherosclerosis, ANP reduced the cerebral infarct volume at 14 days (median difference: -12.3 mL; IQR: -27.7 to -0.3 mL, P = 0.03). CONCLUSIONS: ANP showed a similar safety profile to placebo and non-significant tendency to reduce cerebral infarct volume in patients with moderate-to-severe stroke. Further studies are warranted to assess the efficacy of ANP in reducing cerebral infarcts and improving clinical prognosis. TRAIL REGISTRATION Clinicaltrials.gov , No. NCT04475328.
Aged ; Female ; Humans ; Male ; Middle Aged ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Ischemic Stroke/drug therapy* ; Pilot Projects ; Stroke/drug therapy* ; Treatment Outcome

Objective To evaluate the predictive ability and clinical application value of artificial intelligence (AI) systems in the benign and malignant differentiation and pathological type of pulmonary nodules, and to summarize clinical application experience. Methods A retrospective analysis was conducted on the clinical data of patients with pulmonary nodules admitted to the Department of Thoracic Surgery, Second Hospital of Lanzhou University, from February 2016 to February 2025. Firstly, pulmonary nodules were divided into benign and non-benign groups, and the discriminative abilities of AI systems and clinicians were compared. Subsequently, lung nodules reported as precursor glandular lesions (PGL), microinvasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) in postoperative pathological results were analyzed, comparing the efficacy of AI systems and clinicians in predicting the pathological type of pulmonary nodules. Results In the analysis of benign/non-benign pulmonary nodules, clinical data from a total of 638 patients with pulmonary nodules were included, of which there were 257 males (10 patients and 1 patient of double and triple primary lesions, respectively) and 381 females (18 patients and 1 patient of double and triple primary lesions, respectively), with a median age of 55.0 (47.0, 61.0) years. Different lesions in the same patient were analyzed as independent samples. Univariate analysis of the two groups of variables showed that, except for nodule location, the differences in the remaining variables were statistically significant (P<0.05). Multivariate logistic regression analysis showed that age, nodule type (subsolid pulmonary nodule), average density, spicule sign, and vascular convergence sign were independent influencing factors for non-benign pulmonary nodules, among which age, nodule type (subsolid pulmonary nodule), spicule sign, and vascular convergence sign were positively correlated with non-benign pulmonary nodules, while average density was negatively correlated with the occurrence of non-benign pulmonary nodules. The area under the receiver operating characteristic curve (AUC) of the malignancy risk value given by the AI system in predicting non-benign pulmonary nodules was 0.811, slightly lower than the 0.898 predicted by clinicians. In the PGL/MIA/IAC analysis, clinical data from a total of 411 patients with pulmonary nodules were included, of which there were 149 males (8 patients of double primary lesions) and 262 females (17 patients of double primary lesions), with a median age of 56.0 (50.0, 61.0) years. Different lesions in the same patient were analyzed as independent samples. Univariate analysis results showed that, except for gender, nodule location, and vascular convergence sign, the differences in the remaining variables among the three groups of PGL, MIA, and IAC patients were statistically significant (P<0.05). Multinomial multivariate logistic regression analysis showed that the differences between the parameters in the PGL group and the MIA group were not statistically significant (P>0.05), and the maximum diameter and average density of the nodules were statistically different between the PGL and IAC groups (P<0.05), and were positively correlated with the occurrence of IAC as independent risk factors. The average AUC value, accuracy, recall rate, and F1 score of the AI system in predicting lung nodule pathological type were 0.807, 74.3%, 73.2%, and 68.5%, respectively, all better than the clinical physicians’ prediction of lung nodule pathological type indicators (0.782, 70.9%, 66.2%, and 63.7% respectively). The AUC value of the AI system in predicting IAC was 0.853, and the sensitivity, specificity, and optimal cutoff value were 0.643, 0.943, and 50.0%, respectively. Conclusion This AI system has demonstrated high clinical value in predicting the benign and malignant nature and pathological type of lung nodules, especially in predicting lung nodule pathological type, its ability has surpassed that of clinical physicians. With the optimization of algorithms and the adequate integration of multimodal data, it can better assist clinical physicians in formulating individualized diagnostic and treatment plans for patients with lung nodules.

Objective: To investigate the effects of Zuogui Jiangtang Jieyu Formula (ZGJTJYF) on histone H3 lysine 18 lactylation (H3K18la) in the hippocampus of rats with diabetes mellitus complicated with depression (DD) and predict the regulatory genes of H3K18la. Methods: Male Sprague-Dawley rats were divided into control, model, and positive drug (metformin [0.18 g/kg] and fluoxetine [1.8 mg/kg]) groups, and the three groups were treated with high, medium, and low ZGJTJYF doses (20.52, 10.26, and 5.13 g/kg, respectively), with 10 rats per group. After treatment, the forced swimming and water maze tests were performed to assess depressive-like behaviors and cognitive function. An enzyme-linked immunosorbent assay was used to measure blood insulin, glycosylated hemoglobin, lactate levels, and lactate content in the hippocampus. Western blotting was used to detect H3K18la expression in the hippocampus. Cleavage Under Targets and lagmentation(CUT&Tag) experiments targeted hippocampal H3K18la epigenetic modification regions to analyze the transcription factors bound by H3K18la. Kyoto Encyclopedia of Genes and Genomes and Protein-Protein Interaction networks were constructed to identify key pathways and target genes regulated by H3K18la. Results: Compared with the normal group, the model group rats showed prolonged immobility time in the forced swim test, increased escape latency in the water maze experiment, decreased target quadrant distance ratio (P<0.01), increased serum lactate content, and decreased lactate content in hippocampal homogenate (P<0.01), as well as decreased H3K18la protein expression in the hippocampus (P<0.01). Compared with the model group, ZGJTJYF reduced the immobility time in the forced swim test and the escape latency in the water maze test (P<0.01), while the distance ratio in the target quadrant increased (P<0.01) in model rats. Lowered fasting blood glucose, insulin, and glycosylated hemoglobin levels (P<0.05, P<0.01) were also observed. ZGJTJYF also increased the lactate content and H3K18la protein expression in hippocampal homogenate (P<0.05, P<0.01). The DNA sequences bound by H3K18la were predominantly enriched at the transcription start sites. ZGJTJYF modulated H3K18la-associated pathways, including cell adhesion junctions, tumor growth factor-beta (TGF-β) signaling, stem cell pluripotency regulation, mitogen-activated protein kinase(MAPK) signaling pathway, and insulin resistance, leading to the identification of 12 target genes. Conclusion ZGJTJYF enhances hippocampal lactate levels and H3K18la modification in DD rats, which may regulate neural cell interactions, neurogenic stem cell function, TGF-β signaling, MAPK signaling, and insulin resistance pathways.

INTRODUCTION: Adolescent depression is prevalent, and teen suicide rates are on the rise locally. A systemic review to understand associated risk and protective factors is important to strengthen measures for the prevention and early detection of adolescent depression and suicide in Singapore. This systematic review aims to identify the factors associated with adolescent depression in Singapore. METHODS: A systematic search on the following databases was performed on 21 May 2020: PubMed, EMBASE and PsycINFO. Full texts were reviewed for eligibility, and the included studies were appraised for quality using the Newcastle Ottawa Scale. Narrative synthesis of the finalised articles was performed through thematic analysis. RESULTS: In total, eight studies were included in this review. The four factors associated with adolescent depression identified were: (1) sociodemographic factors (gender, ethnicity); (2) psychological factors, including childhood maltreatment exposure and psychological constructs (hope, optimism); (3) coexisting chronic medical conditions (asthma); and (4) lifestyle factors (sleep inadequacy, excessive internet use and pathological gaming). CONCLUSION The identified factors were largely similar to those reported in the global literature, except for sleep inadequacy along with conspicuously absent factors such as academic stress and strict parenting, which should prompt further research in these areas. Further research should focus on current and prospective interventions to improve mental health literacy, targeting sleep duration, internet use and gaming, and mitigating the risk of depression in patients with chronic disease in the primary care and community setting.
Humans ; Singapore/epidemiology* ; Adolescent ; Risk Factors ; Depression/etiology* ; Protective Factors ; Male ; Female ; Life Style ; Suicide

Objective:To characterize the epidemiology, antimicrobial susceptibility, and molecular mechanisms of carbapenem-resistant Enterobacterales (CRE) carrying multiple carbapenemase genes in China, and to provide evidence for infection control and antibiotic stewardship.Methods:From 2016 to 2023, 115 CRE isolates harboring at least two carbapenemase genes were collected from 41 hospitals in 18 provinces across China. Species identification, antimicrobial susceptibility testing, and whole-genome sequencing were performed. Multilocus sequence typing (MLST) and capsular typing were conducted using Kleborate, plasmid replicon types were identified with PlasmidFinder, and a core genome phylogenetic tree was constructed.Results:The majority of isolates belonged to Klebsiella spp. (80.0%, 92/115), followed by E. cloacae (8.7%, 10/115) and E. coli (6.1%, 7/115). The isolates were mainly from Hebei, Beijing, Shandong, and Hunan (60.9%, 70/115), and sputum was the predominant specimen (43.5%, 50/115). The most common genotype was bla KPC+bla NDM (73.0%, 84/115), primarily in Klebsiella spp. (79.8%, 67/84), followed by bla NDM+bla IMP (15.7%, 18/115). The prevalent plasmid replicon types were IncFII (77.5%, 86/111), IncFIB (68.5%, 76/111), IncR (51.4%, 57/111), and IncX3 (20.7%, 23/111). Notably, 88.6% (31/35) of ST11-KL64 K. pneumoniae strains co-harbored IncFII, IncFIB, and IncR plasmids simultaneously. Between 2016 and 2022, the dominant subtype among Klebsiella spp. isolates was bla KPC-2+bla NDM-1 (56.2%, 36/64). In 2023, the bla KPC-2+bla NDM-13 subtype (29.5%, 19/64) emerged and exhibited clonal transmission (single nucleotide polymorphism 2?74 bp) in Hebei, Beijing, and Jilin. Susceptibility testing showed widespread resistance to β-lactams (90.2%-100%). Aztreonam-avibactam, tigecycline, and colistin retained high activity, with susceptibility rates of 90.16%-98.36%. Conclusions:In China, the majority of clinical Enterobacteriaceae strains that harbor multiple carbapenemases are Klebsiella spp. co-producing KPC and NDM enzymes. Dissemination is driven by both clonal expansion of ST11-KL64 and horizontal transfer of IncFII, IncFIB, and IncR plasmids. The recent emergence and regional clonal spread of the bla KPC-2+bla NDM-13 genotype underscore the urgent need for strengthened surveillance and containment measures.

Cognitive impairment is one of the most common non-motor symptoms of Parkinson′s disease, which seriously affects the health and quality of life of patients. Therefore, it is particularly important to identify and predict the future cognitive decline of this population. Cognitive reserve can compensate for brain damage caused by aging and brain diseases, and reduce and delay cognitive decline, reflecting the different sensitivity of individuals to cognitive impairment. However, the specific relationship between the two is not fully understood. This paper mainly analyzes the concept, measurement method, genetics and functional imaging of cognitive reserve in Parkinson′s disease to further reveal the relationship between cognitive impairment and cognitive reserve in Parkinson′s disease.

Objective To investigate the distribution and antimicrobial resistance profiles of clinically isolated Haemophilus influenzae and Moraxella catarrhalis in hospitals across China from 2015 to 2021,and provide evidence for rational use of antimicrobial agents.Methods Data of H.influenzae and M.catarrhalis strains isolated from 2015 to 2021 in CHINET program were collected for analysis,and antimicrobial susceptibility testing was performed by disc diffusion method or automated systems according to the uniform protocol of CHINET.The results were interpreted according to the CLSI breakpoints in 2022.Beta-lactamases was detected by using nitrocefin disk.Results From 2015 to 2021,a total of 43 642 strains of Haemophilus species were isolated,accounting for 2.91％of the total clinical isolates and 4.07％of Gram-negative bacteria in CHINET program.Among the 40 437 strains of H.influenzae,66.89％were isolated from children and 33.11％were isolated from adults.More than 90％of the H.influenzae strains were isolated from respiratory tract specimens.The prevalence of β-lactamase was 53.79％in H.influenzae strains.The H.influenzae strains isolated from children showed higher resistance rate than the strains isolated from adults.Overall,779 strains of H.influenzae did not produce β-lactamase but were resistant to ampicillin(BLNAR).Beta-lactamase-producing strains showed significantly higher resistance rates to these antimicrobial agents than the β-lactamase-nonproducing strains.Of the 16 191 M.catarrhalis strains,80.06％were isolated from children and 19.94％isolated from adults.M.catarrhalis strains were mostly susceptible to both amoxicillin-clavulanic acid and cefuroxime,evidenced by resistance rate lower than 2.0％.Conclusions The emergence of antibiotic-resistant H.influenzae due to β-lactamase production poses a challenge for clinical anti-infective treatment.Therefore,it is very important to implement antibiotic resistance surveillance for H.influenzae and guide rational antibiotic use.All local clinical microbiology laboratories should actively improve antibiotic susceptibility testing and strengthen antibiotic resistance surveillance for H.influenzae.