OBJECTIVE: To investigate the effectiveness of Xuanshen Yishen Decoction (XYD) in the treatment of hypertension. METHODS: Hospital electronic medical records from 2019-2023 were utilized to emulate a randomized pragmatic clinical trial. Hypertensive participants were eligible if they were aged ⩾40 years with baseline systolic blood pressure (BP) ⩾140 mm Hg. Patients treated with XYD plus antihypertensive regimen were assigned to the treatment group, whereas those who followed only antihypertensive regimen were assigned to the control group. The primary outcome assessed was the attainment rate of intensive BP control at discharge, with the secondary outcome focusing on the 6-month all-cause readmission rate. RESULTS: The study included 3,302 patients, comprising 2,943 individuals in the control group and 359 in the treatment group. Compared with the control group, a higher proportion in the treatment group achieved the target BP for intensive BP control [8.09% vs. 17.5%; odds ratio (OR)=2.29, 95% confidence interval (CI)=1.68 to 3.13; P<0.001], particularly in individuals with high homocysteine levels (OR=3.13; 95% CI=1.72 to 5.71; P<0.001; P for interaction=0.041). Furthermore, the 6-month all-cause readmission rate in the treatment group was lower than in the control group (hazard ratio=0.58; 95% CI=0.36 to 0.91; P=0.019), and the robustness of the results was confirmed by sensitivity analyse. CONCLUSIONS XYD could be a complementary therapy for intensive BP control. Our study offers real-world evidence and guides the choice of complementary and alternative therapies. (Registration No. ChiCTR2400086589).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antihypertensive Agents/pharmacology* ; Blood Pressure/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Hypertension/physiopathology* ; Patient Readmission ; Treatment Outcome

Objective:To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM)with mSMART 3.0 score.Methods:Clinical data were collected from 16 patients with mSMART3.0 score high-risk relapsed refractory MM treated at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from May 2020 to May 2023,all of whom received daltezumab-based regimen(regimen drugs including dexamethasone,isazomib,bortezomib,lenalidomide).The efficacy and safety of the treatment were retrospectively analyzed.Results:The median age of 16 patients was 63.5(47-70)years old,including 10 cases of IgG type,2 cases of IgA type,and 4 cases of light chain type.The curative efficacy was judged in all 16 patients,with an overall response rate of 93.75％(15/16),including 4 cases of strict complete remission(sCR),1 case of complete remission(CR),2 case of very good partial remission(VGPR),partial remission(PR)in 5 cases,and minor remission(MR)in 3 cases.The median follow-up time was 11(2-30)months,and the median progression-free survival and median overall survival were not achieved in 16 patients at the median follow-up period.The hematologic adverse effects of the treatment regimen using daratumumab-based were mainly neutropenia,and the non-hematologic adverse effects were mainly infusion-related adverse reactions and infections.Conclusion:Daratumumab-based regimen for the treatment of relapsed refractory MM patients with high risk of mSMART3.0 score has better efficacy and safety.

OBJECTIVE: Despite the combination of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) being a recognized Chinese medicinal herbal pair that is commonly used in the treatment of ovarian cancer, there is a poor understanding of their pharmacological mechanisms. This study examines the antitumor properties and potential mechanisms of SB-SD on human ovarian cancer A2780 cells through a multi-omics approach, establishing a pharmacological basis for clinical utilization. METHODS: A range of mass ratios and reagents were used in the hot reflux extraction of SB-SD. The inhibitory effect of the SB-SD extracts on A2780 cell proliferation was assessed using the cell-counting kit 8 assay. A zebrafish tumor implantation model was used to evaluate the effects of SB-SD extracts on tumor growth and metastasis in vivo. Transcriptomics and proteomics were used to investigate alterations in biological pathways in A2780 cells after treatment with different concentrations of SB-SD extract. Cell cycle, cell apoptosis, intracellular free iron concentration, intracellular reactive oxygen species (ROS) concentration, malondialdehyde (MDA), and mitochondrial membrane potential were measured. Real-time quantitative reverse transcription polymerase chain reaction and Western blotting were utilized to investigate the effects of heme catabolism and ferritinophagy on ferroptosis induced by SB-SD extract in A2780 cells. RESULTS: The 70% ethanol extract of SB-SD (a mass ratio of 4:1) inhibited A2780 cell proliferation significantly with a half maximal inhibitory concentration of 660 μg/mL in a concentration- and time-dependent manner. Moreover, it effectively suppressed tumor growth and metastasis in a zebrafish tumor implantation model. SB-SD extract induced the accumulation of free iron, ROS, MDA, and mitochondrial damage in A2780 cells. The mechanisms might involve the upregulated expression of ferritinophagy-related genes microtubule-associated protein 1 light chain 3, autophagy-related gene 5, and nuclear receptor coactivator 4. CONCLUSION SB-SD extract effectively inhibited the development of ovarian cancer both in vitro and in vivo. Its mechanism of action involved inducing ferroptosis by facilitating heme catabolism and ferritinophagy. This herbal pair holds promise as a potential therapeutic option for ovarian cancer treatment and may be utilized in combination with routine treatment to improve the treatment outcomes of ovarian cancer patients. Please cite this article as: Wang Z, Liu M, Li GX, Zhang L, Ding KY, Li SQ, Gao BQ, Chen P, Choe HC, Xia LY, Yang YT, Liu Y, Sui X, Ma JN, Zhang L. A herbal pair of Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang induced ferroptosis in ovarian cancer A2780 cells via inducing heme catabolism and ferritinophagy. J Integr Med. 2024; 22(6): 666-683.
Ferroptosis/drug effects* ; Female ; Humans ; Animals ; Scutellaria/chemistry* ; Ovarian Neoplasms/genetics* ; Zebrafish ; Cell Line, Tumor ; Ferritins/genetics* ; Plant Extracts/pharmacology* ; Heme/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Cell Proliferation/drug effects* ; Reactive Oxygen Species/metabolism* ; Antineoplastic Agents, Phytogenic/pharmacology* ; Autophagy/drug effects* ; Apoptosis/drug effects*

ObjectiveTo explore the underlying mechanism of bile acids and metabolites as well as the key metabolic pathways and important endogenous targets in prehypertension. MethodThe metabolic mechanism of prehypertension was explored with non-targeted metabolomics combined with network analysis. The serum metabolomics of patients with prehypertension was analyzed by ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry. The relevant biological functions and signal targets were predicted and generated by network analysis. Finally，the predicted targets of this important pathway were verified by in vitro experiments，and the relevant information was verified by enzyme-linked immunosorbent assay （ELISA） and Western blot. ResultAs revealed by non-targeted metabolomics，there were 64 potential biomarkers and 13 metabolic pathways in the normal group，the prehypertension group， and the hypertension group. The results of network analysis and biological verification showed that the occurrence of prehypertension was related to vascular inflammation caused by the abnormal metabolism of bile acids and aromatic amino acids. Bile acid metabolism plays an important role in the occurrence and development of prehypertension by regulating the vascular inflammatory response. Amino acid N-acyltransferase，myeloperoxidase， and bile acid downstream receptor TGR5 are critical in the changes of the metabolic network. ConclusionIn prehypertension，bile acids are presumedly involved in regulating vascular inflammation， resulting in damage to blood vessels in prehypertension.

OBJECTIVETo investigate and compare the clinical implications of p16 deletion in childhood and adult B-lineage acute lymphoblastic leukemia (B-ALL).

METHODSA total of 129 cases of de novo childhood (73 cases) and adult (56 cases) B-ALL were examined genetically and immunologically using G-banding techniqhe, interphase fluorescence in situ hybridization (I-FISH) and immunophenotyping by flow cytometry, and their clinical data were retrospectively analyzed.

RESULTSOf 73 childhood cases, the prevalences of homozygous deletion, hemizygous deletion and no deletion of p16 were 24.7% (18 cases), 6.8% (5 cases) and 68.5% (50 cases) respectively, and of 56 adult cases, the incidences as of 14.3% (8 cases), 8.9% (5 cases) and 76.8% (43 cases) respectively. The incidence of p16 deletion between the two groups had no significant difference (P = 0.338). In both groups, patients with or without p16 deletion had no significant difference in terms of white blood cells (WBC) count at diagnosis, BM blast percentage, chromosome karyotype, extra-infiltration and CR1 rate. Of note, there were 2 cases, each in childhood and adult, showed no deletion at the time of diagnosis, their p16 deletions occurred at relapse. The deletion of p16 was associated with poor overall survival and event-free survival (EFS) in both childhood and adults. According to the standard of NCI risk stratification, we divided patients of two groups into standard and high risk category respectively, and performed further analysis. The significance of different risk category in children and adults was disparity. The overall survival (OS) rates of deletion and no deletion of p16 were 45.3% and 79.8% (P = 0.006) in children, and 7.7% and 22.6% (P = 0.002) in adults, respectively. EFS rates of deletion and no deletion of p16 were 33.5% and 58.1% (P = 0.008) in children, and 0 and 10.9% (P < 0.01) in adults, respectively. Of the standard risk category in children, OS rates of deletion and no deletion of p16 were 46.8% and 89.3% (P = 0.015) respectively, and EFS rates of deletion and no deletion of p16 as of 40.9% and 82.1% (P = 0.007) respectively. Of the high risk category in children, OS rates of deletion and no deletion of p16 were 41.7% and 67.4% (P = 0.193) respectively, and EFS rates of deletion and no deletion of p16 were 25.0% and 25.6% (P = 0.305) respectively. Of the standard risk category in adults, OS rates of deletion and no deletion of p16 were 20.0% and 46.9% (P = 0.092) respectively, and EFS rates of deletion and no deletion of p16 were 0 and 25.0% (P = 0.062) respectively. Of the high risk category in adults, OS rates of deletion and no deletion of p16 were 0 and 12.4% (P < 0.001) respectively, and EFS rate of deletion and no deletion of p16 was 0 and 4.8%(P < 0.001), respectively.

CONCLUSIONThis study indicated that deletion of p16 was associated with poor prognosis in both childhood and adult B-ALL, which highlighted an important significance to define the status of p16 in both childhood and adult B-ALL for predicting prognosis and guiding clinical intervention.

Adult ; Child ; Female ; Gene Deletion ; Genes, p16 ; Humans ; Male ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; Prognosis ; Retrospective Studies

BACKGROUNDAtherosclerosis is the primary cause of cardiovascular disease, carotid artery disease, and peripheral vascular disease. However, it is hard to obtain human arterial tissue at different stages of atherosclerosis for a systematic study. The ApoE-deficient (ApoE(-/-)) mice predictably develop spontaneous atherosclerotic plaques with numerous features similar to the human lesions and contain nearly the entire spectrum of lesions observed during atherogenesis in humans. MicroRNA expression profiles at different stages of atherosclerosis in ApoE-deficient mice were screened to find out the differentially expressed microRNAs.

METHODSApoE-deficient mice were euthanized at 4, 8, and 20 weeks of age and divided into three groups according to the three time points, including groups A4 (fed a Western-type diet for 0 week), A8 (fed a Western-type diet for 4 weeks), and A20 (fed a Western-type diet for 16 weeks). Atherosclerotic lesions were analyzed. Fifteen aortas were collected and combined into three pools (five aortas in one pool) in each group. MicroRNA microarray analysis was replicated thrice in each group. The threshold of fold change ≥ 2.0 was used to screen up or down-regulated microRNAs. Differentially expressed microRNAs were subsequently verified with quantitative real-time polymerase chain reaction. Those increasingly up or down-regulated microRNAs during the progression of atherosclerosis were selected.

RESULTSAtherosclerotic lesions first appeared in the aortic arch in group A8. Severe atherosclerotic lesions were observed in group A20. In group A8, seven MicroRNAs were up-regulated while two were down-regulated. In group A20, 15 microRNAs were up-regulated while two were down-regulated. miR-34a-5p and miR-497-5p were increasingly up-regulated, while miR-434-3p was progressively down-regulated when atherosclerosis progressed.

CONCLUSIONSIn this study, we described that microRNAs are differentially expressed at different stages of atherosclerosis in ApoE-deficient mice. Those increasingly up or down-regulated microRNAs during the progression of atherosclerosis may play an important role in the pathogenesis of atherosclerosis and provide us opportunities for investigating atherosclerosis from early to advanced stages.

Animals ; Apolipoproteins E ; deficiency ; genetics ; Atherosclerosis ; genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs ; genetics ; Real-Time Polymerase Chain Reaction

OBJECTIVETo study the effects of insulin like growth factor-1 (IGF-1) on cell viability and tissue factor (TF) in angiotensin II (Ang II) induced vascular endothelial cells and to investigate its mechanisms.

METHODS10(-6) mol/L Ang II was added to human vascular endothelial cells (HUVECs) culture media alone or 30 min after pretreatment with IGF-1 (0.1 microg/ml , 0.5 microg/ml, 2.5 microg/ml). Cell viability and AngII type 1 receptor (AT1-R) mRNA were evaluated after 24 h incubation with AngII. At the optimum concentration of IGF-1 affecting cell viability, the time dependent manner for 12 - 48 h incubation with Ang II was evaluated. TF, NOS and NO were investigated after 24 h incubation with Ang II. In addition, NO synthase inhibitor Nomega-nitro-1-arginine methylester(L-NAME) was added 30 min before addition of IGF-1 and Ang II, and cell viability, TF, AT1-R mRNA, NOS and NO were evaluated after 24 h incubation.

RESULTS(1) Ang II induced a decrease in cell vitality, an upregulation of AT1-R mRNA, an increase in TF, and a decrease in the activity of NOS and content of NO. (2) Pretreatment with IGF-1 significantly inhibited the decreased cell viability and upregulation of AT1-R mRNA. IGF-1 at 0.5 microg/ml showed the most obvious effects. This effect of cell viability recovery was in a time dependent manner during 12 -48 h. (3) IGF-1 also inhibited the increased content of TF, the decreased activity of NOS and the decreased content of NO. (4) The beneficial effects of IGF-1 on cultured endothelial cells were completely abolished by L-NAME.

CONCLUSIONIGF-1 pretreatment could enhance the ang II injured cell viability and anti-thrombosis capacity, and the protective effects may be related to activation of NOS-NO signaling pathway which inhibited AT1-R.

Angiotensin II ; pharmacology ; Cell Survival ; drug effects ; Cells, Cultured ; Endothelial Cells ; drug effects ; metabolism ; physiology ; Humans ; Insulin-Like Growth Factor I ; pharmacology ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; metabolism ; Receptor, Angiotensin, Type 1 ; genetics ; metabolism ; Thromboplastin ; metabolism

OBJECTIVE: To determine the effects of Tongxinluo on cell viability and tissue factor (TF) in AngII induced vascular endothelial cells and to investigate its mechanism. METHODS: AngII(10(-6)mol/L) was added to human vascular endothelial cells (HUVECs) culture media alone or with various concentration of Tongxinluo drug containing plasma (5%,10%, and 20%) added 30 minutes before AngII. Cell viability was evaluated after 24-hour incubation with AngII in a dose manner. TF, AngII type 1 receptor (AT(1)) mRNA, NO synthase (NOS) and NO were observed after 24-hour incubation with AngII. In addition, NOS inhibitor nomega-nitro-larginine (L-NAME) was added 30 minutes before Tongxinluo and AngII. Cell viability, TF, AT(1)mRNA, the level of NOS and NO were evaluated after 24-hour incubation with Tongxinluo and AngII. RESULTS: Tongxinluo significantly improved AngII induced endothelial cell viability and the effect was the most obvious at 10%. Tongxinluo (10%) decreased the TF and AT(1) mRNA while increased the NOS and NO levels. L-NAME obviously inhibited the effects of Tongxinluo on cell viability, TF, AT(1) mRNA, and NOS and NO levels. CONCLUSION Up-regulating NOS-NO signaling may be the mechanism of Tongxinluo on cell viability and TF in AngII induced vacular endothelial cells.
Angiotensin II ; pharmacology ; Cell Line ; Cell Survival ; drug effects ; Cells, Cultured ; Drugs, Chinese Herbal ; pharmacology ; Endothelium, Vascular ; cytology ; drug effects ; metabolism ; Enzyme Inhibitors ; Enzyme-Linked Immunosorbent Assay ; Humans ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide Synthase Type I ; antagonists & inhibitors ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics ; Receptor, Angiotensin, Type 1 ; biosynthesis ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Thromboplastin ; biosynthesis ; genetics

OBJECTIVETo establish a BCR/ABL+ cell line with resistance to imatinib, and investigate the possible mechanisms of the acquired resistance.

METHODSK562 cells were cultured in gradually increased concentrations of imatinib over a period of several months to generate their resistance line. MTT assay, RT-PCR, Western blotting, and FISH were used to study the possible molecular mechanisms of the resistance.

RESULTSA resistant cell line, K562/G01, was established with 15.2 +/- 3.0-fold resistant to imatinib as compared with that of the parental sensitive cell line. The resistant cell line also had the cross-resistance to a broad spectrum of other anticancer agents excepting for DOX. There was no difference between the two cell lines in terms of the cell morphology, proliferation doubling time, and fraction distribution of cell cycle. K562/G01 cells showed increased levels of BCR/ABL, mdr1 mRNA and their coding proteins and the increased tyrosine kinase activity. No point mutation in the BCR/ABL ATP-binding site was detected while the copies of BCR/ABL fusion gene were increased in K562/G01 cells.

CONCLUSIONAn imatinib-resistant human leukemia cell line, K562/G01, was established. The mechanisms of resistance of K562/G01 cells to imatinib involved increased expression of BCR/ABL and mdr1/P-gp, amplification of BCR/ABL fusion gene, and increased activity of BCR/ABL.

ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Antineoplastic Agents ; pharmacology ; Benzamides ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Fusion Proteins, bcr-abl ; genetics ; metabolism ; Humans ; Imatinib Mesylate ; K562 Cells ; drug effects ; metabolism ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology