ObjectiveTo decipher the mechanism by which Zuoguiwan （ZGW） treat hyperthyroidism in rats with kidney-Yin deficiency based on the dopamine receptor D4 （DRD4）/nicotinamide adenine dinucleotide phosphate （NADPH） oxidase 4 （NOX4） signaling pathway. MethodsThe rat model of kidney-Yin deficiency was induced by unilateral intramuscular injection of dexamethasone （0.35 mg·kg^-1）. After successful modeling， the rats were randomized into model， methimazole （positive control， 5 mg·kg^-1）， low-， medium-， and high-dose （1.85， 3.70， 7.40 g·kg^-1， respectively） ZGW， and normal control groups. After 21 days of continuous gavage， the behavioral indexes and body weight changes of rats were evaluated. The pathological changes of the renal tissue were observed by hematoxylin-eosin staining. The serum levels of thyroid hormones ［triiodothyronine （T₃）， thyroxine （T₄）， thyroid-stimulating hormone （TSH）］， renal function indexes ［serum creatine （Scr） and blood urea nitrogen （BUN）］， energy metabolism markers ［cyclic adenosine monophosphate （cAMP） and cyclic guanosine monophosphate （cGMP）］， and oxidative stress-related factors ［superoxide dismutase （SOD）， malondialdehyde （MDA）， and NADPH）］ were measured by enzyme-linked immunosorbent assay （ELISA）. Western blot was employed to analyze the expression of DRD4， NOX4， mitochondrial respiratory chain complex proteins ［NADH：ubiquinone oxidoreductase subunit S4 （NDUFS4） and cytochrome C oxidase subunit 4 （COX4）］， and inflammation-related protein ［tumor necrosis factor-alpha （TNF-α）， interleukin-6 （IL-6）， p38 mitogen-activated protein kinase （MAPK）］ pathway in the renal tissue. ResultsCompared with the normal group， the model group showed mental malaise， body weight decreases （P<0.01）， inflammatory cell infiltration in the renal tissue， a few residual parotid glands in the thyroid， elevations in serum levels of T₃， T₄， Scr， BUN， cAMP， cAMP/cGMP， MDA， and NADPH （P<0.01）， down-regulation in protein levels of TSH， SOD， and DRD4 （P<0.05， P<0.01）， and up-regulation in expression of NOX4， p-p38 MAPK/p38 MAPK， and inflammatory factors （P<0.01）. Compared with the model group， ZGW increased the body weight （P<0.05， P<0.01）， reduced the infiltration of renal interstitial inflammatory cells， restored the thyroid structure and follicle size， lowered the serum levels of T₃， T₄， Scr， BUN， cAMP， cAMP/cGMP， MDA and NADPH （P<0.05， P<0.01）， up-regulated the expression of TSH， SOD and DRD4 （P<0.05， P<0.01）， and down-regulated the expression of NOX4， p-p38 MAPK/p38 MAPK， and inflammatory factors （P<0.05， P<0.01）. Moreover， high-dose ZGW outperformed methimazole （P<0.05）. ConclusionBy activating DRD4， ZGW can inhibit the expression of NOX4 mediated by the p38 MAPK pathway， reduce oxidative stress and inflammatory response， thereby ameliorating the pathological state of hyperthyroidism due to kidney-Yin deficiency. This study provides new molecular mechanism support for the clinical application of ZGW.

ObjectiveTo investigate the mechanisms by which Shangxia Liangji pills improve cognitive function in Alzheimer's disease （AD） mice based on the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） pathway， aiming to provide experimental evidence for its clinical use in AD treatment. MethodsFifty APP/PS1 double-transgenic mice were randomly divided into a model group， Shangxia Liangji pills low-dose group， medium-dose group， high-dose group， and donepezil hydrochloride group， with 10 mice in each group. Additionally， 10 C57BL/6 mice of the same genetic background were assigned to the normal group. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Hippocampal pathological changes were observed using transmission electron microscopy and Nissl staining. Neuroinflammation in hippocampal tissue was detected by enzyme-linked immunosorbent assay （ELISA）. Protein expression levels of PI3K/Akt pathway-related proteins， postsynaptic density protein 95 （PSD95）， and amyloid precursor protein （APP） in hippocampal tissue were measured by Western blot. ResultsCompared with the normal group， the model group exhibited significantly increased total swimming distance and escape latency， significantly reduced number of platform crossings （P<0.01）， and a decreased recognition index （P<0.01）. Marked neuronal apoptosis was observed in the hippocampal region， with a marked reduction in the number of neurons in the CA3 region （P<0.01）. Levels of interleukin-6 （IL-6）， interleukin-1β （IL-1β）， and tumor necrosis factor-α （TNF-α） in hippocampal tissue were significantly elevated （P<0.01）. APP expression in hippocampal tissue was markedly upregulated （P<0.01）， while PSD95， p-PI3K/PI3K， and p-Akt/Akt protein expression were significantly downregulated （P<0.01）. Compared with the model group， the Shangxia Liangji pills high-dose group showed significantly reduced total swimming distance and escape latency， significantly increased number of platform crossings （P<0.01）， and an elevated recognition index （P<0.01）. Hippocampal neuronal apoptosis was alleviated， with a significant increase in the number of neurons in the CA3 region （P<0.01）. Levels of IL-6， IL-1β， and TNF-α were significantly decreased （P<0.01）. APP expression was downregulated （P<0.05）， while PSD95， p-PI3K/PI3K， and p-Akt/Akt protein expression were significantly upregulated （P<0.01）. ConclusionShangxia Liangji pills may improve cognitive function in AD mice by modulating the PI3K/Akt pathway， thereby reducing neuroinflammation and alleviating neuronal and synaptic injury.

OBJECTIVE To evaluate the efficacy and safety of sacituzumab tirumotecan combined with bevacizumab for the treatment of human epidermal growth factor receptor 2-negative （HER2－） breast cancer with brain metastases.METHODS Clinical data of 90 patients with HER2－ breast cancer with brain metastases treated at the First Affiliated Hospital of Nanyang Medical College from December 2024 to November 2025 were retrospectively collected. According to the treatment regimens， the patients were divided into a control group （ n ＝55） and an experimental group （ n ＝35）. Patients in the experimental group received sacituzumab tirumotecan combined with bevacizumab， whereas those in the control group received conventional systemic therapy， including albumin-bound paclitaxel-based regimens， capecitabine-based regimens， or gemcitabine/vinorelbine combined with platinum-based regimens. Short-term efficacy， progression-free survival （PFS）， brain metastasis-related efficacy， adverse events， treatment discontinuation due to adverse events， and treatment-related deaths were compared between the two groups.RESULTS The objective response rate （ORR）， disease control rate， median PFS， intracranial disease control rate， and proportion of patients with improvement in neurological symptoms in the experimental group were significantly higher than in the control group （ P ＜0.05）. Stratified analysis showed that PFS of the experimental group was significantly longer than the control group among patients with Breast-Graded Prognostic Assessment scores ≥2.0 and ＜2.0 （ P ＜0.05）. There were no statistically significant differences in the proportion of patients with glucocorticoid dose reduction/discontinuation， the incidence of adverse events of different grades， or the rate of treatment discontinuation due to adverse events between the two groups （ P ＞0.05）. No treatment-related deaths occurred in either group.CONCLUSIONS Compared with conventional systemic therapy， sacituzumab tirumotecan combined with bevacizumab can improve the ORR and prolong PFS in patients with HER2－ breast cancer with brain metastases， with an overall manageable safety profile.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week ( Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD ( Ptrend = 0.011) and MCEs ( Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD ( Pinteraction = 0.037). CONCLUSIONS Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.
Humans ; Male ; Female ; Prospective Studies ; Middle Aged ; Aged ; Vascular Diseases/etiology* ; Risk Factors ; China/epidemiology* ; Adult ; Proportional Hazards Models ; Cerebrovascular Disorders/epidemiology* ; East Asian People

OBJECTIVE: EPF3 is a fibrinolysin monomer isolated and purified from Pheretima vulgaris Chen, an earthworm used in traditional Chinese medicine as Dilong for treating blood stasis syndrome. Its composition, anticoagulant and fibrinolytic activities, and relevant mechanisms have been confirmed through in vitro experiments. However, whether it has antithrombotic effects in vivo and can be absorbed by the gastrointestinal tract is unknown. This study evaluates the antithrombotic effect in zebrafish and investigates the gastrointestinal stability and intestinal absorption mechanism of this protein in vitro. METHODS: The antithrombotic effect of EPF3 in vivo was verified using the zebrafish thrombus model induced by arachidonic acid and FeCl₃. Then, the protein bands of EPF3 incubated with simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and homogenate of Caco-2 cells (HC2C) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to evaluate its gastrointestinal stability. Finally, the transport behavior and absorption mechanism of EPF3 were studied using Caco-2 cell monolayer. RESULTS: EPF3 could significantly enhance the returned blood volume and blood flow velocity in zebrafish with platelet aggregation thrombus induced by arachidonic acid. It could also prolong the formation time of tail artery thrombus and increase the blood flow velocity in zebrafish with vessel injury thrombus induced by FeCl₃. EPF3 was stable in SIF and HC2C and unstable in SGF. The permeability of EPF3 in Caco-2 monolayer was time-dependent and concentration-dependent. The efflux ratio was less than 1.2 during transport, and the transport behavior was not affected by inhibitors. EPF3 could reversibly reduce the expression of tight junction-related proteins, including zonula occludens-1, occludin, and claudin-1 in Caco-2 cells. CONCLUSION EPF3 could play a thrombolytic and antithrombotic role in zebrafish. It could be transported and absorbed into the intestine through cellular bypass pathway by opening the intestinal epithelium tight junction. This study provides a scientific explanation for the antithrombotic effect of earthworm and provides a basis for the feasibility of subsequent development of EPF3 as an antithrombotic enteric-soluble preparation. Please cite this article as: Zhong WL, Yang JQ, Liu H, Wu YL, Shen HJ, Li PY, Du SY. Antithrombotic effect in zebrafish of a fibrinolytic protein EPF3 from Dilong (Pheretima vulgaris Chen) and its transport mechanism in Caco-2 monolayer through cell bypass pathway. J Integr Med. 2025; 23(4): 415-428.
Animals ; Zebrafish ; Humans ; Caco-2 Cells ; Fibrinolytic Agents/pharmacology* ; Thrombosis/drug therapy* ; Intestinal Absorption

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective To analyze the publication condition and development trends of global post-stroke fatigue(PSF)research from 2004 to 2024.Methods Relevant literature on PSF pub-lished between January 1,2004,and August 1,2024,were systematically searched and screened from WoSCC database.Visual analysis of publication volume,contributing countries,institutions,authors,and keywords in PSF research was conducted using CiteSpace software.Results A total of 373 articles were included in this study.The overall publication volume related to PSF exhibited an upward trend.The country,institution,and author with the highest number of publications were the United Kingdom,the University of Oslo,and LERDAL A,respectively.High-frequency keywords in-cluded quality of life,depression,fatigue severity scale,follow up,epidemiology,symptoms,associ-ations,and rehabilitation,while the emerging keywords were health care professionals,risk factors,and participation.Conclusion PSF-related research has demonstrated an overall upward trend.As-sessment and measurement protocols,rehabilitation treatment approaches,impacts on quality of life,and the intrinsic relationship with depression have emerged as research hotspots.Further exploration of precise and systematic assessment methods,along with the construction of scientific rehabilitation management programs and risk prediction models,will become the focal points of future research.

ObjectiveTo explore the pharmacological mechanism involved in the treatment of allergic cough （AC） by Xiaoer Huatan Zhike granules （XEHT） based on proteomics and network pharmacology. MethodsAfter sensitization by intraperitoneal injection of 1 mL suspension containing 2 mg ovalbumin （OVA） and 100 mg aluminum hydroxide， a guinea pig model of allergic cough was constructed by nebulization with 1% OVA. The modeled guinea pigs were randomized into the model， low-， medium- and high-dose （1， 5， 20 g·kg^-1， respectively） XEHT， and sodium montelukast （1 mg·kg^-1） groups （n=6）， and another 6 guinea pigs were selected as the blank group. The guinea pigs in drug administration groups were administrated with the corresponding drugs by gavage， and those in the blank and model groups received the same volume of normal saline by gavage， 1 time·d^-1. After 10 consecutive days of drug administration， the guinea pigs were stimulated by 1% OVA nebulization， and the coughs were observed. The pathological changes in the lung tissue were observed by hematoxylin-eosin staining. The enzyme-linked immunosorbent assay was performed to measure the levels of C-reactive protein （CRP）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， superoxide dismutase （SOD）， and malondialdehyde （MDA） in the bronchoalveolar lavage fluid （BALF） and immunoglobulin G （IgG） and immunoglobulin A （IgA） in the serum. Immunohistochemistry （IHC） was employed to observe the expression of IL-6 and TNF-α in the lung tissue. Transmission electron microscopy was employed observe the alveolar type Ⅱ epithelial cell ultrastructure. Real-time PCR was employed to determine the mRNA levels of IL-6， interleukin-1β （IL-1β）， and TNF-α in the lung tissue. Label-free proteomics was used to detect the differential proteins among groups. Network pharmacology was used to predict the targets of XEHT in treating AC. The Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis was performed to search for the same pathways from the results of proteomics and network pharmacology. ResultsCompared with the blank group， the model group showed increased coughs （P<0.01）， elevated levels of CRP， TNF-α， IL-6， and MDA and lowered level of SOD in the BALF （P<0.05， P<0.01）， elevated levels of IgA and IgG in the serum （P<0.05， P<0.01）， congestion of the lung tissue and infiltration of inflammatory cells， increased expression of IL-6 and TNF-α （P<0.01）， large areas of low electron density edema in type Ⅱ epithelial cells， obvious swelling and vacuolization of the organelles， karyopyknosis or sparse and dissolved chromatin， and up-regulated mRNA levels of IL-6， IL-1β， and TNF-α （P<0.01）. Compared with the model group， the drug administration groups showed reduced coughs （P<0.01）， lowered levels of CRP， TNF-α， IL-6， and MDA and elevated level of SOD in the BALF （P<0.05， P<0.01）， alleviated lung tissue congestion， inflammatory cell infiltration， and type Ⅱ epithelial cell injury， and decreased expression of IL-6 and TNF-α （P<0.01）. In addition， the medium-dose XEHT group and the montelukast sodium group showcased lowered serum levels of IgA and IgG （P<0.05， P<0.01）. The medium- and high-dose XEHT groups and the montelukast sodium showed down-regulated mRNA levels of IL-6， IL-1β， and TNF-α and the low-dose XEHT group showed down-regulated mRNA levels of IL-6 and TNF-α （P<0.05， P<0.01）. Phospholipase D， mammalian target of rapamycin （mTOR）， and epidermal growth factor receptor family of receptor tyrosine kinase （ErbB） signaling pathways were the common pathways predicted by both proteomics and network pharmacology. ConclusionProteomics combined with network pharmacology reveal that XEHT can ameliorate AC by regulating the phospholipase D， mTOR， and ErbB signaling pathways.

Objective:To evaluate preoperative high-resolution thin-layer cervical enhanced CT used to predict the venous route of the submental flap reflux vein and its relationship with adjacent structures in order to guide the anatomical understanding and protection of submental flap in pharyngeal cancer surgery.Methods:Sixty consecutive patients with pharyngeal cancer who underwent submental flap repair surgery in our department from March 2022 to December 2024, as well as 60 patients who were accepted neck dissection suffering other cancers, were selected. Before surgery, high-resolution cervical enhanced CT scans were performed, and the position of the transverse section of the facial vein in the venous phase horizontal image gradually variation tendency was focused layer by layer. The direction and adjacent relationship of the submental flap reflux veins were determined and recorded. Combined with 60 patients with other head and neck tumors who underwent neck dissection in our department during the same period (a total of 120 cases, 240 sides), the classification and management of the draining veins of Fang′s mental flap were conducted. Type Ⅰ mainly drains into the internal jugular vein; Type Ⅱ mainly drains into the external jugular vein and Type Ⅲ mainly drains into the anterior jugular vein (often accompanied by an external jugular draining branch). The status and proportion of venous drainage were analyzed.Results:Vascular predictive coincidence rate was 98.3% (59/60) among the 60 patients with pharyngeal cancer. Only one patient was predicted to have a simple return to the external jugular vein. However, during the operation, in addition to the main return to the external jugular vein, a small portion also returned to the internal jugular vein. Submental flap reflux vessels were classified into three types based on intraoperative submental flap venous return in 60 cases of laryngopharyngeal cancer, in conjunction with the analysis of venous return patterns from 240 cervical CT scans. Type Ⅰ mainly refluxed to the internal jugular vein, accounting for 42.1%. Type Ⅱ mainly refluxed to the external jugular vein (47.9%). Type Ⅲ mainly refluxed to the anterior jugular vein (10.0%). The total detection rate of CT reading of 240 venous reflux was 98.7% (237/240). Vascular predictive coincidence rate was 97.9%(235/240).Conclusion:The detailed analysis of submental venous return vessels can accurately predict the direction of reflux veins and its surrounding areas by preoperative high-resolution enhanced CT scan. This provides reliable guidance for the anatomy and protection of the submental flap reflux veins during surgery.

Objective:To explore the early- to mid-term therapeutic efficacy of using porous-coated metaphyseal sleeves to reconstruct severe bone defects in revision total knee arthroplasty (rTKA).Methods:A retrospective analysis was conducted of the clinical data of the 39 patients (40 knees) who had undergone rTKA by porous-coated metaphyseal sleeve reconstruction at Department of Orthopaedics, West China Hospital, Sichuan University between May 2017 and September 2023. The cohort included 6 males (6 knees) and 33 females (34 knees), with an age of (67.0±9.7) years. The revision was to cure periprosthetic infection after TKA in 12 knees, to correct prosthesis loosening in 19 knees, to treat periprosthetic fracture in 4 knees, to stabilize postoperative joint instability in 4 knees, and to manage postoperative joint stiffness in 1 knee. All patients underwent standard revision procedures, including removal of the original prosthesis, management of bone defects, implantation of revision prosthesis, and adjustment of ligamentous balance and fixation. The patients' surgical time, intraoperative blood loss, incidence of complications, as well as visual analogue scale (VAS), knee range of motion, and Hospital for Special Surgery (HSS) knee joint scores at the last follow-up were recorded.Results:The surgical time was (2.7±0.8) hours, and intraoperative blood loss (337.5±165.4) mL for this cohort. All the 39 patients were followed up for (4.8±2.1) years after surgery. At the last follow-up, their VAS pain score was 2.0 (1.0, 2.0) points, their knee range of motion reached 116.3°±12.2°, and their total score, pain score, and function score of the HSS system were respectively 87.0 (82.8, 89.3) points, 25.0 (22.8, 29.0) points, and 61.0 (60.0, 62.0) points, all showing statistically significant improvements compared with their preoperative values [(6.8±1.7) points, 70.4°±15.2°, (43.1±9.6) points, (9.3±3.1) points, and (33.8±10.1) points] ( P<0.05). In all patients, incisions healed at one stage after surgery, and no complications such as deep vein thrombosis or neurovascular injury occurred. Complications included popliteal artery thrombosis in 1 patient (1 knee) immediately after surgery, acute infection in 1 patient (1 knee) at 3 years after surgery, and periprosthetic fracture due to a traffic accident in 1 patient (1 knee) at 4 years after surgery, and distal prosthesis-related pain in 3 patients (3 knees). Conclusion:Use of porous-coated metaphyseal sleeves in rTKA to reconstruct severe bone defects exhibits favorable early- to mid-term therapeutic outcomes.