OBJECTIVE: To investigate the synergistic effect and its mechanism of ginsenoside-Rg5 in combination with imatinib in inhibiting proliferation of chronic myeloid leukemia K562 cells. METHODS: K562 cells were treated with ginsenoside-Rg5 and imatinib. Cell survival was detected by CCK-8 assay, and IC₅₀ were calculated separately for each drug. Based on the value of IC₅₀ of ginsenoside-Rg5 and imatinib, an appropriate concentration gradient was selected for the combination. The synergistic effect of the two drug was analyzed using the online software synergy finder. The effects of single or combination therapy on apoptosis rate and the cell cycle distribution of K562 cells were analyzed by flow cytometry. Western blot was used to detect the expression of PI3K/AKT/mTOR signaling pathway related proteins and apoptosis related proteins in K562 cells after single or combination therapy. RESULTS: Ginsenoside-Rg5 and imatinib were able to inhibit the proliferative activity of K562 cells in a dosedependent manner(r =-0.991， r =-0.942). The synergy score ZIP >10 was measured by Synergy Finder online software, indicating that ginsenoside-Rg5 and imatinib act synergistically on K562 cells. The apoptotic rates of K562 cells after single treatments with ginsenoside-Rg5 and imatinib were 11.96% and 8.13%, respectively, while the rate increased to 21.35% with the combination of two drugs, the apoptosis rate in the combination group was higher than that in the single-drug group ( P <0.05). The proportion of K562 cells in the G₀/G₁ phase was significantly increased with the combined treatment of two drugs( P <0.05). The protein expression levels of p-PI3K, p-AKT, p-mTOR in K562 cells treated with the combination were significantly decreased, with noticeable downregulation of BCL-2 and upregulation of BAX, leading to a decreased Bcl-2/BAX ratio, while no significant changes were observed in the non-phosphorylated forms of PI3K, AKT, and mTOR proteins. CONCLUSION The combination of ginsenoside-Rg5 and imatinib can inhibit the proliferation of CML cells and induce apoptosis, and the mechanism may act through PI3K/AKT/mTOR signaling pathways.
Humans ; Ginsenosides/pharmacology* ; Imatinib Mesylate ; K562 Cells ; TOR Serine-Threonine Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Signal Transduction/drug effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism* ; Drug Synergism ; Apoptosis/drug effects* ; Phosphatidylinositol 3-Kinases/metabolism* ; Cell Proliferation/drug effects*

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Pre-admission is a critical initiative to optimize medical service processes and alleviate the challenge of "difficult access to healthcare. "However, there is currently a lack of standardized protocols for pre-admission procedures. This study aims to systematically analyze key nodes and risk factors in pre-admission process design and propose optimization strategies, providing a foundation for policy formulation and hospital practices. By constructing a "forward-reverse" dual-process model of pre-admission and identifying risk points based on stakeholder theory (patients, hospitals, healthcare administration, and insurance), the study reveals that while pre-admission can reduce the average length of stay, improve bed turnover rates, and enhance patient satisfaction, it also presents risks such as cross-period financial settlement, challenges in insurance policy adaptability, demands for information system integration, and the need for defining medical safety boundaries. To optimize the pre-admission process and mitigate these risks, this study explores framework improvements in areas including eligibility criteria, mode selection, cost settlement, transition between pre-admission and inpatient status, and cancellation of pre-admission, offering practical guidance for public hospitals. The authors argue that pre-admission requires tripartite collaboration among hospitals, insurers, and healthcare administrations: hospitals should establish top-level design, continuously refine processes, and implement dynamic risk assessment mechanisms; insurance providers should support cross-period settlement policies; and healthcare administrations should issue guiding policies or standardized protocols. Through multi-department coordination and collaborative efforts, the optimization and innovation of pre-admission processes can be advanced, ultimately delivering more efficient and convenient healthcare experiences for patients.

Objective:To investigate associations between cardiac biomarkers with stroke severity and short-term outcome in patients with acute ischemic stroke (AIS).Methods:Patients with AIS admitted to the Affiliated Hospital of Qingdao University from June 2018 to February 2024 whose etiological classification was large artery atherosclerosis (LAA), small vessel occlusion (SVO) or cardioembolism (CE) were included retrospectively. According to the National Institutes of Health Stroke Scale score at admission, patients were divided into mild stroke group (≤8) and moderate to severe stroke group (>8). According to the modified Rankin Scale score at discharge, patients were divided into good outcome group (≤2) and poor outcome group (>2). Multivariate logistic regression analysis was used to determine the independent correlation between cardiac biomarkers and short-term outcome. The predictive value of cardiac biomarkers for poor outcome in patients with AIS and different stroke etiology subtypes were evaluated using receiver operating characteristic (ROC) curves. Results:A total of 2 151 patients with AIS were enrolled, including 1 256 males (58.4%), aged 67.40±11.34 years. 1 079 patents were LAA type (50.2%), 679 were SVO type (31.6%), and 393 were CE type (18.3%); 1 223 were mild stroke (56.86%) and 928 (43.14%) were moderate to severe stroke; 1 357 patients (63.09%) had good short-term outcome, and 794 (36.91%) had poor short-term outcome. Multivariate logistic regression analysis showed that N-terminal pro-B type natriuretic peptide (NT-proBNP), NT-proBNP/creatine kinase (CK) isoenzyme MB (CK-MB) ratio, and CK-MB/CK ratio were independent risk factors for poor short-term outcome. ROC curve analysis shows that the CK-MB/CK ratio had a higher predictive value for short-term poor outcome in patients with AIS (the area under the curve, 0.859, 95% confidence interval 0.839-0.879). Various cardiac biomarkers had a higher predictive value for short-term outcome of CE type and LAA type, but the predictive value for short-term outcome of SVO type was lower. Conclusions:Cardiac biomarkers are associated with the severity and poor outcome of AIS. NT-proBNP/CK-MB and CK-MB/CK ratios have higher predictive value for short-term poor outcome of AIS, especially in patients with CE type.

Objective:To investigate the clinical characteristics and treatment of patients with CD4+CD8-T-cell large granular lymphocytic leukemia(T-LGLL).Methods:The clinical manifestations,diagnosis and treatment of 1 case of CD4+CD8-T-LGLL patient were reported,and relevant literatures were reviewed.Results:The patient was a 70-year-old woman with slow clinical progress,mainly manifested by thrombocytopenia and myelodysplasia.The blood smear was mainly composed of large granular lymphocytes.Immunotyping and T-cell receptor gene rearrangement analysis showed that it was in line with T-LGLL.Partial remission(PR)was achieved through the treatment of cyclophosphamide(50 mg/d)combined with prednisone(gradually reduced and stopped later).Conclusion:CD4+CD8-T-LGLL is very rare in clinical practice,and its clinical manifestations are different from those of CD4-CD8+T-LGLL.

Objective:To investigate the characteristics of the CD8+T cells infiltration from the 4 sub-types in medulloblastoma(MB),to analyze the relationship between CD8+T cells infiltration and prog-nosis,to study the function of C-X-C motif chemokine ligand 11(CXCL11)and its receptor in CD8+T cells infiltration into tumors and to explore the potential mechanism,and to provide the necessary clinico-pathological basis for exploring the immunotherapy of MB.Methods:In the study,48 clinical MB sam-ples(12 cases in each of 4 subtypes)were selected from the multiple medical center from 2012 to 2019.The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString Pan-Cancer 10360?Panel(NanoString Technologies).Immunohistochemistry(IHC)staining of formalin-fixed,paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8+T cells in the MB four subtypes.Through bioinformatics analysis,the relation-ship between CD8+T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated.The expression of CXCR3 receptor on the surface of CD8+T cells in MB was verified by double immunofluorescence staining,and the under-lying molecular mechanism of CD8+T cells infiltration into the tumor was explored.Results:The charac-teristic index of CD8+T cells in the WNT subtype of MB was relatively high,suggesting that the number of CD8+T cells in the WNT subtype was significantly higher than that in the other three subtypes,which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus(GEO)database analysis by using R2 online data analysis platform.And the increase of CD8+T cells infiltration was posi-tively correlated with the patient survival.The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes.Immunofluorescence staining showed the presence of CXCL11 receptor,CXCR3,on the surface of CD8+T cells,suggesting that the CD8+T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3.Conclusion:The CD8+T cells infiltrate more in the WNT subtype MB than other subtypes.The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system,and the patients with more infiltration of CD8+T cells in tumor have better prognosis.This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8+T cells infiltration in MB,and give a new potential therapeutic target for the future immunotherapy of MB.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) infection posed a huge threat and burden to public healthcare in late 2022. Non-drug measures of traditional Chinese medicine (TCM), such as acupuncture, cupping and moxibustion, are commonly used as adjuncts in China to help in severe cases, but their effects remain unclear. OBJECTIVES: To observe the clinical effect of TCM non-drug measures in improving respiratory function and symptoms among patients with severe COVID-19. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This study was designed as a multicenter, assessor-blind, randomized controlled trial. Hospitalized patients with COVID-19 were randomly assigned to the treatment or control group. The treatment group received individualized TCM non-drug measures in combination with prone position ventilation, while the control group received prone position ventilation only for 5 consecutive days. MAIN OUTCOME MEASURES: The primary outcome measures were the percentage of patients with improved oxygen saturation (SpO₂) at the end of the 5-day intervention, as well as changes of patients' respiratory rates. The secondary outcome measures included changes in SpO₂ and total score on the self-made respiratory symptom scale. The improvement rate, defined as a 3-day consecutive increase in SpO₂, the duration of prone positioning, and adverse events were recorded as well. RESULTS: Among the 198 patients included in the intention-to-treat analysis, 159 (80.3%) completed all assessments on day 5, and 39 (19.7%) patients withdrew from the study. At the end of the intervention, 71 (91%) patients in the treatment group had SpO₂ above 93%, while 61 (75.3%) in the control group reached this level. The proportion of participant with improved SpO₂ was significantly greater in the intervention group (mean difference [MD] = 15.7; 95% confidence interval [CI]: 4.4, 27.1; P = 0.008). Compared to the baseline, with daily treatment there were significant daily decreases in respiratory rates in both groups, but no statistical differences between groups were found (all P ≥ 0.05). Compared to the control group, the respiratory-related symptoms score was lower among patients in the treatment group (MD = -1.7; 95% CI: -2.8, -0.5; P = 0.008) after day 3 of treatment. A gradual decrease in the total scores of both groups was also observed. Thirty-one adverse events occurred during the intervention, and 2 patients were transferred to the intensive care unit due to deterioration of their illness. CONCLUSION: TCM non-drug measures combined with prone positioning can effectively treat patients with severe COVID-19. The combined therapy significantly increased SpO₂ and improved symptom scores compared to prone positioning alone, thus improving the patients' respiratory function to help them recover. However, the improvement rate did not differ between the two groups. TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR2300068319). Please cite this article as: Yin X, Jin Z, Li F, Huang L, Hu YM, Zhu BC, Wang ZQ, Li XY, Li JP, Lao LX, Mi YQ, Xu SF. Effectiveness and safety of adjunctive non-drug measures in improving respiratory symptoms among patients with severe COVID-19: A multicenter randomized controlled trial. J Integr Med. 2024; 22(6): 637-644.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Acupuncture Therapy/methods* ; China ; COVID-19/complications* ; Medicine, Chinese Traditional/methods* ; Moxibustion/methods* ; Oxygen Saturation ; Prone Position ; Respiration, Artificial ; Treatment Outcome

The potential anti-stroke active components in Taohong Siwu Decoction(THSWD) were identified by target cell trapping coupled with ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry(UPLC-Q-TOF-MS). The underlying mechanism of active components in THSWD in the treatment of ischemic stroke(IS) was explored by network pharmacology, molecular docking, and experimental validation. The UPLC-Q-TOF-MS technology combined with the UNIFI data analysis platform was used to analyze the composition of the cellular fragmentation fluid after co-incubation of THSWD with target cells. The targets of potential active components and IS were collected by network pharmacology, and the common targets underwent protein-protein interaction(PPI), Gene Ontology(GO), and Kyoto Encyclopedia of Genes and Genomes(KEGG) signaling pathway enrichment analyses. The target cell trapping component-core target-signaling pathway network was constructed, and the active components were molecularly docked to the top targets in the PPI network, followed by pharmacodynamic validation in vitro. Fifteen active components were identified in the target cellular fragmentation fluid, including bicyclic monoterpenes, cyanoglycosides, flavonols, quinoid chalcones, phenylpropanoids, and tannins. As revealed by the analysis of network pharmacology, THSWD presumably regulated PI3K-AKT, FoxO, MAPK, Jak-STAT, VEGF, HIF-1, and other signaling pathways to affect inflammatory cascade reaction, angiogenesis, oxidative stress, pyroptosis, apoptosis, and other pathological processes via paeoniflorin, butylphthalide, dehydrated safflower yellow B, 3,4-dicaffeoylquinic acid, amygdalin, paeoniflorin, and ligusticolactone. Molecular docking and in vitro pharmacodynamic validation revealed that the target cell trapping active components could promote neovascularization in rat brain microvascular endothelial cells(rBMECs) in the oxygen-glucose deprivation/reoxygenation(OGD/R) model. The application of target cell trapping coupled with UPLC-Q-TOF-MS technology can rapidly screen out the potential active components in THSWD. The active components of THSWD can be predicted to intervene in the pathogenesis of IS through network pharmacology, and molecular docking combined with experimental validation can further clarify the efficacy, thus providing a theoretical basis for research ideas on the pharmacodynamic substance basis of traditional Chinese medicine compounds.
Animals ; Rats ; Ischemic Stroke/drug therapy* ; Molecular Docking Simulation ; Network Pharmacology ; Endothelial Cells ; Phosphatidylinositol 3-Kinases ; Drugs, Chinese Herbal/pharmacology*

OBJECTIVE: To establish an efficient protocol for directed differentiation of human induced pluripotent stem cells (hiPSCs) into functional midbrain dopaminergic progenitor cells (DAPs) in vitro. METHODS: hiPSCs were induced to differentiate into DAPs in two developmental stages. In the first stage (the first 13 days), hiPSCs were induced into intermediate cells morphologically similar to primitive neuroepithelial cells (NECs) in neural induction medium containing a combination of small molecule compounds. In the second stage, the intermediate cells were further induced in neural differentiation medium until day 28 to obtain DAPs. After CM-DiI staining, the induced DAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of rat models of Parkinson's disease (PD). Eight weeks after transplantation, the motor behaviors of PD rats was evaluated. Immunofluorescence assay of brain sections of the rats was performed at 2 weeks after transplantation to observe the survival, migration and differentiation of the transplanted cells in the host brain microenvironment. RESULTS: hiPSCs passaged stably on Matrigel showed a normal diploid karyotype, expressed the pluripotency markers OCT4, SOX2, and Nanog, and were positive for alkaline phosphatase. The primitive neuroepithelial cells obtained on day 13 formed dense cell colonies in the form of neural rosettes and expressed the neuroepithelial markers (SOX2, Nestin, and PAX6, 91.3%-92.8%). The DAPs on day 28 highly expressed the specific markers (TH, FOXA2, LMX1A and NURR1, 93.3-96.7%). In rat models of PD, the hiPSCs-DAPs survived and differentiated into TH⁺, FOXA2⁺ and Tuj1⁺ neurons at 2 weeks after transplantation. Eight weeks after transplantation, the motor function of PD rats was significantly improved as shown by water maze test (P < 0.0001) and apomorphine-induced rotation test (P < 0.0001) compared with rats receiving vehicle injection. CONCLUSION HiPSCs can be effectively induced to differentiate into DAPs capable of differentiating into functional neurons both in vivo and in vitro. In rat models of PD, the transplanted hiPSCs-DAPs can survive for more than 8 weeks in the MFB and differentiate into multiple functional neurocytes to ameliorate neurological deficits of the rats, suggesting the potential value of hiPSCs-DAPs transplantation for treatment of neurological diseases.
Humans ; Rats ; Animals ; Induced Pluripotent Stem Cells ; Cell Differentiation/physiology* ; Neurons ; Parkinson Disease ; Mesencephalon ; Cells, Cultured