This study explored the potential therapeutic targets and mechanisms of Danggui Shaoyao San(DSS) in the prevention and treatment of Alzheimer's disease(AD) through transcriptomics and metabolomics, combined with animal experiments. Fifty male C57BL/6J mice, aged seven weeks, were randomly divided into the following five groups: control, model, positive drug, low-dose DSS, and high-dose DSS groups. After the intervention, the Morris water maze was used to assess learning and memory abilities of mice, and Nissl staining and hematoxylin-eosin(HE) staining were performed to observe pathological changes in the hippocampal tissue. Transcriptomics and metabolomics were employed to sequence brain tissue and identify differential metabolites, analyzing key genes and metabolites related to disease progression. Reverse transcription-quantitative polymerase chain reaction(RT-qPCR) was employed to validate the expression of key genes. The Morris water maze results indicated that DSS significantly improved learning and cognitive function in scopolamine(SCOP)-induced model mice, with the high-dose DSS group showing the best results. Pathological staining showed that DSS effectively reduced hippocampal neuronal damage, increased Nissl body numbers, and reduced nuclear pyknosis and neuronal loss. Transcriptomics identified seven key genes, including neurexin 1(Nrxn1) and sodium voltage-gated channel α subunit 1(Scn1a), and metabolomics revealed 113 differential metabolites, all of which were closely associated with synaptic function, oxidative stress, and metabolic regulation. RT-qPCR experiments confirmed that the expression of these seven key genes was consistent with the transcriptomics results. This study suggests that DSS significantly improves learning and memory in SCOP model mice and alleviates hippocampal neuronal pathological damage. The mechanisms likely involve the modulation of synaptic function, reduction of oxidative stress, and metabolic balance, with these seven key genes serving as important targets for DSS in the treatment of AD.
Animals ; Alzheimer Disease/genetics* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Mice, Inbred C57BL ; Metabolomics ; Transcriptome/drug effects* ; Maze Learning/drug effects* ; Hippocampus/metabolism* ; Humans ; Disease Models, Animal ; Memory/drug effects*

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

OBJECTIVE: To compare the therapeutic efficacy of portal and tail vein transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) against cholestatic liver fibrosis in mice. METHODS: BMSCs were isolated and co-cultured with starvation-activated hepatic stellate cells (HSCs). HSC activation markers were identified using immunofluorescence and qRT-PCR. BMSCs were injected into the liver tissues of bile duct ligation (BDL) mice via the tail and portal veins. Histomorphology, liver function, inflammatory cytokines, and the expression of key proteins were all determined in the liver tissues. RESULTS: BMSCs inhibited HSC activation by reducing α-SMA and collagen I expression. Compared to tail vein injection, DIL-labeled BMSCs injected through the portal vein maintained a high homing rate in the liver. Moreover, BMSCs transplanted through the portal vein resulted in greater improvement in liver color, hardness, and gallbladder size than did those transplanted through the tail vein. Furthermore, BMSCs injected by portal vein, but not tail vein, markedly ameliorated liver function, reduced the secretion of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and decreased α-SMA + hepatic stellate cell (HSC) activation and collagen fiber formation. CONCLUSION The therapeutic effect of BMSCs on cholestatic liver fibrosis in mice via portal vein transplantation was superior to that of tail vein transplantation. This comparative study provides reference information for further BMSC studies focused on clinical cholestatic liver diseases.
Animals ; Mice ; Mesenchymal Stem Cell Transplantation ; Liver Cirrhosis/etiology* ; Male ; Cholestasis/therapy* ; Mice, Inbred C57BL ; Hepatic Stellate Cells ; Mesenchymal Stem Cells

Background and aim:Hepatic ischemia-reperfusion injury(IRI)is a significant challenge in liver trans-plantation,trauma,hypovolemic shock,and hepatectomy,with limited effective interventions available.This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2(LECT2)in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA(shRNA)delivered through adeno-associated virus(AAV)vectors. Materials and methods:This study analyzed human liver and serum samples from five patients under-going the Pringle maneuver.Lect2-knockout and C57BL/6J mice were used.Hepatic IRI was induced by clamping the hepatic pedicle.Treatments included recombinant human LECT2(rLECT2)and AAV-Lect2-shRNA.LECT2 expression levels and serum biomarkers including alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine,and blood urea nitrogen(BUN)were measured.Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed. Results:Serum and liver LECT2 levels were elevated during hepatic IRI.Serum LECT2 protein and mRNA levels increased post reperfusion.Lect2-knockout mice had reduced weight loss;hepatic necrosis;and serum ALT,AST,creatinine,and BUN levels.rLECT2 treatment exacerbated weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN).AAV-Lect2-shRNA treatment significantly reduced weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN),indicating thera-peutic potential. Conclusions:Elevated LECT2 levels during hepatic IRI increased liver damage.Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage,indicating its therapeutic potential.AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI,offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.

The assessment of adverse drug events is an important basis for clinical safety evaluation and post-marketing risk control of drugs,and its causality assessment is gaining increasing attention.The existing methods for assessing the causal relationship between drugs and the occurrence of adverse reactions can be broadly classified into three categories:global introspective methods,standardized methods,and probabilistic methods.At present,there is no systematic introduction of the operational details of the various methods in the domestic literature.This paper compares representative causality assessment methods in terms of definition and concept,methodological steps,industry evaluation and advantages and disadvantages,clarifies the basic process of determining the causality of adverse drug reactions,and discusses how to further improve the adverse drug reaction monitoring and evaluation system,with a view to providing a reference for drug development and pharmacovigilance work in China.

Objective:To investigate the concern about pollen broadcasting in Chinese population from multiple dimensions and to understand the information about allergic rhinitis (AR) in China by analyzing related factors.Methods:From March 1 to September 30, 2022, a large-scale multi-center cross-sectional survey was conducted based on the Questionnaire Star platform in 21 Chinese hospitals. A total of 7 056 subjects from 7 regions in China: Northeast, North, East, Central, South, Southwest, and Northwest China were included. Basic characteristics (including social demographic characteristics and disease characteristics of AR patients), concern about pollen broadcasting, the willingness of pollen-induced AR (PiAR) patients to receive pollen broadcasting, and the treatment satisfaction rate of AR patients were collected. The chi-square test, multivariate linear regression model, and Logistic regression analysis were used to analyze the concern about pollen broadcasting in the Chinese population and related factors from multiple dimensions.Results:Among 7 056 subjects, 23.02% were concerned about pollen broadcasting. Among 3 176 self-reported AR and 1 019 PiAR patients, 25.60% and 39.16% were concerned about pollen broadcasting, respectively, which was higher than that of non-AR or non-PiAR subjects ( χ2 value was 21.74 and 175.11, respectively, both P<0.001). Among AR patients, the proportion of spring and autumn allergen-positive patients concerned about pollen broadcasting was higher than that in perennial allergen-positive patients ( χ2 value was 20.90 and 19.51, respectively, both P<0.001). The proportion of AR patients with asthma, sinusitis, allergic conjunctivitis, and cardiovascular and cerebrovascular diseases was higher than those without complications ( χ2 value was 50.83, 21.97, 56.78, 7.62, respectively, all P<0.05). The proportion of AR patients in North China who could find pollen broadcasting locally was 31.01%, significantly higher than those in other regions (all P<0.05). Multivariate linear regression model analysis showed that among PiAR patients, those with higher per capita household income and higher AR disease cognition levels had been concerned about pollen broadcasting in the past, and those complicated with allergic conjunctivitis had stronger intention to receive pollen broadcasting (B value was 0.24, 0.13, 0.66, 0.47, respectively, all P<0.05). The higher the disease cognition level of PiAR patients, the stronger their willingness to actively participate in treatment ( R2=0.72, P<0.001). Only 18.89% of AR patients felt satisfied with the treatment effect. Logistic regression analysis showed that in AR patients, the treatment satisfaction rate was significantly higher among those concerned about pollen broadcasting compared to those who were not ( OR=1.83, P<0.001). Conclusions:Currently, the dissemination of pollen broadcasting in China is hindered by various factors such as disease cognition level. The treatment satisfaction among AR patients remains unsatisfactory.

Objective:To investigate the correlation between the levels of CC chemokine ligand 2 (CCL2) and periostin (POSTN) in serum and alveolar lavage fluid of patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) complicated with respiratory virus infection and lung function.Methods:From March 2020 to March 2023, 96 patients with acute exacerbation of COPD admitted to our hospital were collected. Among them, 34 patients with concurrent respiratory virus infection were included in the infected group, and 62 patients without respiratory virus infection were included in the uninfected group. Enzyme linked immunosorbent assay (ELISA) was applied to detect the expression levels of CCL2 and POSTN in serum and alveolar lavage fluid. Pearson method was applied to analyze the correlation between CCL2 and POSTN levels in serum and alveolar lavage fluid of infected patients and lung function indicators.Results:The levels of CCL 2 ( t=12.633, 9.253 2, 2) and POSTN ( t=12.370, 7.383) were significantly increased in the infected group compared with the uninfected group ( P<0.05). Compared with the uninfected group, the 6-minute walking test (6 MWT), peak expiratory flow rate (peak expiratory flow, PEF), forced expiratory volume at the first second (forced expiratory volume in one second, FEV 1), and the forced lung capacity (forced vital capacity, FVC), FEV 1/FVC, and maximum middle breath mean flow rate (maximal mid-expiratory flow curve, MMEF) were significantly lower ( t=14.141, 24.165, 22.421, 21.223, 5.278, 29.456, P<0.05). Correlation analysis showed that the levels of CCL2 and POSTN in the serum and alveolar lavage fluid of the infected group were negatively correlated with the levels of 6MWT, PEF, FEV1, FVC, FEV1/FVC, and MMEF ( P<0.05). Conclusions:CCL2 and POSTN levels were highly expressed in serum and alveolar lavage fluid of patients with respiratory virus infection during acute exacerbation of COPD, which were closely related to lung function.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To explore clinical effect of closed reduction percutaneous elastic intramedullary nail assisted by arthrography in the treatment of radial neck fracture in children.Methods A retrospective analysis was performed on 23 chil-dren with radial neck fracture treated with arthrography assisted closed reduction and percutaneous elastic intramedullary nail internal fixation(arthrography with elastic nail group)from January 2019 to December 2022,including 12 males and 11 fe-males,aged from 2 to 12 years old with an average of(7.36±1.89)years old;According to Judet fracture types,14 children were type Ⅲ and 9 children were type Ⅳ.In addition,23 children with radial neck fracture were selected from January 2015 to December 2018 who were treated with closed reduction and percutaneous elastic intramedullary nail fixation(elastic nail group),including 11 males and 12 females,aged from 2 to 14 years old with an average of(7.50±1.91)years old;Judet classi-fication included 15 children were type Ⅲ and 8 children were type Ⅳ.Operative time and intraoperative fluoroscopy times were compared between two groups.Metaizeau evaluation criteria was used to evaluate fracture reduction,and Tibone-Stoltz evaluation criteria was used to evaluate functional recovery of elbow between two groups.Results Both groups were followed up for 12 to 24 months with an average of(16.56±6.34)months.Operative time and intraoperative fluoroscopy times of elastic nail group were(56.64±19.27)min and(21.13±7.87)times,while those of joint angiography with elastic nail group were(40.33±1 1.50)min and(12.10±3.52)times;there were difference between two groups(P＜0.05).According to Metaizeau evaluation,11 patients got excellent result,9 good and 3 fair in joint angiography with elastic nail group,while in elastic nail group,5 ex-cellent,13 good,4 acceptable,and 1 poor;the difference between two groups was statistically significant(P＜0.05).According to Tibone-Stoltz criteria,14 patients got excellent result,8 good,and 1 fair in joint arthrography with elastic nail group;while in elastic nail group,12 patients got excellent result,9 good,1 fair and 1 poor;there was no significant difference between two groups(P＞0.05).Conclusion Compared to percutaneous elastic intramedullary nail fixation,closed reduction assisted by arthrography has advantages of reduced operation time,decreased intraoperative fluoroscopy frequency,and improved fracture reduction.Arthrography enables clear visualization of the anatomical structures of radius,head,neck,bone,and cartilage in children,facilitating comprehensive display of fracture reduction and brachioradial joint alignment.This technique more pre-cisely guides the depth of elastic intramedullary nail implantation in radius neck,thereby enhancing surgical efficiency and success rate.