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*

OBJECTIVE: To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine. METHODS: Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients. RESULTS: Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD. CONCLUSIONS Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).
Humans ; Male ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Hyperuricemia ; Kidney ; Proteinuria ; Renal Insufficiency, Chronic/complications*

OBJECTIVE: To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. METHODS: By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. RESULTS: Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. CONCLUSIONS There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.
Humans ; Syndrome ; Ischemic Stroke ; Medicine, Chinese Traditional ; Liver ; Phenotype

Objective: To analyze the changing trend and characteristics of lymphocyte-platelets ratio (LPR) of early stage in patients with extensive burns, and to explore the prognostic significance of LPR. Methods: A retrospective case series study was conducted. From January 2008 to December 2018, 244 patients with extensive burns were admitted to the First Affiliated Hospital of Naval Medical University, including 181 males and 63 females, aged (44±16) years. The total burned area of patients was 60.0% (42.0%, 85.0%) total body surface area. Platelet and lymphocyte test results of patients were collected on the 1^st, 2^nd and 3^rd day after admission, and LPR of patients was calculated to analyze the changing trend of the three days after admission. Univariate and multivariate logistic regression analysis were conducted to investigate the risk factors or independent risk factors for death of patients, including age, sex, total burn area, area of full-thickness burns and above, inhalation injury, and LPR. According to the 1^st day's LPR after admission of patients, the receiver operating characteristic (ROC) curve predicting death of patients was drawn to find the optimal value of LPR. Patients were divided into high LPR group (n=136) and low LPR group (n=108) based on the optimal value of LPR, and the clinical data of total burn area, area of full-thickness burns and above, inhalation injury, tracheotomy, offline time of patients within 28 days, and mortality in the 2 groups were compared. The surviving curve of patients was drawn by Kaplan-Meier method to predict the difference of the 90-day survival rate between the two groups of patients. Data were statistically analyzed with Student's t test, Mann-Whitney U test, and chi-square test. Results: Within 3 days of admission, the LPR of patients showed a time-dependent upward trend. LPR of patients on the 2^nd and 3^rd day after admission was 8.6 (5.3, 14.4) and 8.6 (4.9, 13.7), respectively, which were significantly higher than the 1^st day's 6.3 (4.2, 9.8), with Z values of -4.25 and -3.43, respectively, P<0.01. Univariate logistic regression analysis showed that age, total burn area, area of full-thickness burns and above, inhalation injury, and LPR were all risk factors for death of patients (with odds ratios of 1.03, 1.73, 1.31, 4.74, and 3.11, respectively, 95% confidence intervals of 1.01-1.06, 1.40-2.13, 1.21-1.42, 1.62-13.86, and 1.41-6.88, respectively, P<0.01). Multivariate logistic regression analysis showed that age, area of full-thickness burns and above, and LPR were independent risk factors for death of patients (with odds ratios of 1.06, 1.36, and 2.85, respectively, 95% confidence intervals of 1.03-1.09, 1.19-1.55, 1.02-7.97, P<0.05 or P<0.01). The area under ROC curve of the 1^st day's LPR, predicting death of patients, was 0.61 (with 95% confidence interval of 0.51-0.71, P<0.05), and the optimal predicted value was 5.8 with corresponding sensitivity of 77% and specificity of 52% respectively. The total burn area, area of full-thickness burns and above, rates of incidence of inhalation injury, tracheotomy, and mortality of patients in high LPR group were significantly higher than those in low LPR group (with Z values of -3.06 and -3.19, χ² values of 5.42, 11.64, and 8.45, respectively, P<0.05 or P<0.01). The offline time of patients within 28 days in high LPR group was significantly shorter than that in low LPR group (Z=-2.98, P<0.01). Kaplan-Meier survival analysis showed that the 90-day survival rate of admission of patients in low LPR group was significantly higher than that of patients in high LPR group (χ²=8.24, P<0.01). Conclusions: The early LPR of patients with extensive burns showed a time-dependent upward trend. The LPR on the first day after admission that is closely correlated with total burn area, area of full-thickness and deeper burns, inhalation injury, tracheotomy, and mortality of patients, is an independent risk factor for the prognosis of patients with extensive burns. The first day's LPR after admission is significantly correlated with the 90-day survival rate of patients, which can be used as an evaluation index for the severity of extensive burns.
Adult ; Blood Platelets ; Burns ; Female ; Humans ; Lymphocytes ; Male ; Middle Aged ; Prognosis ; ROC Curve ; Retrospective Studies

OBJECTIVETo establish rabbit model of scoliosis induced with stable asymmetric lumbar loads.

METHODSScoliosis was induced in 10 two-month-old New Zealand rabbits using 316L stainless steel springs placed between the unilateral transverse processes of L2 and L5. Serial radiographs were documented before and at 1, 4, 8, 9 and 12 weeks after the operation. At weeks, the rabbits were randomly divided into SR group (n=5) with the spring removed and SK group (n=5) without spring removal.

RESULTSAll the rabbits survived the experiment with Cobb angle all greater than 10 degree at the end of the experiment. Significant changes were found in the Cobb angles and kyphotic angles at 1, 4 and 8 weeks after the operation (P<0.05). At 8 weeks, the Cobb angle, the kyphotic angle and the length of the spring were similar between SR and SK groups (P>0.05), and in the 4 weeks following spring removal in SR group, the Cobb angle and the kyphosis decreased significantly compared with those in SK group (P<0.05). Micro-CT showed that the BV/TV of the concave side was greater than that of the convex side. The length of the spring did not show obvious changes during the experiment (P>0.05).

CONCLUSIONSAsymmetric lumbar loading is a convenient, time-saving, and highly reproducible approach for establishing rabbit models of scoliosis.

Animals ; Disease Models, Animal ; Rabbits ; Scoliosis ; physiopathology ; Spine ; pathology

Derris eriocarpa, a traditional Chinese medicine belonging to the family of Leguminosae, is widely distributed mainly over Yunnan, Guangxi and Guizhou of China. Modern pharmacological researches on this herb showed that it had extensive bioactivities, such as promoting urination, removing dampness and cough and reducing inspissated mucus and other biological activities. The extensive studies on the chemical constituents of this plant have resulted in the isolation of triterpenoids, steroids, fatty acid and others, but the flavone compounds haven't reported before. In our further research on the ethyl acetate of this plant, nine flavone compounds were obtained by column chromatography on silica gel, Sephadex LH-20, semi-prep HPLC, polyamide column chromatography and recrystallization for separation and purification. The structures were determined on the basis of extensive spectroscopic analysis, including MS, NMR experiments and comparison with spectroscopic data in the literature, respectively, as diosmetin (1), 3, 3'-di-O-methylquercetin (2), afromosin (3), 6, 3'-dihydroxy-7, 4'-dimethoxyisoflavone (4), odoratin (5), 7, 3'-dihydroxy-8, 4'-dimethoxyisoflavone (6), 6, 4'-dihydroxy-7, 3'-dimethoxyisoflavone (7), 5, 7, 4'-trihydroxy-3, 3', 5'-trimethoxyflavone (8), and alpinumisoflavone (9). All these compounds were isolated from Derris eriocarpa How for the first time. And the in vitro assays showed that compound 2 possessed moderate inhibitory activity against human cancer cells K562 and HEL.
Derris ; chemistry ; Flavonoids ; chemistry ; isolation & purification ; pharmacology ; Humans ; K562 Cells

OBJECTIVETo evaluate efficacy and safety of second-generation tyrosine kinase inhibitors (TKI) dasatinib, nilotinib and imatinib in treatment of newly diagnosed patients with chronic-phase chronic myeloid leukemia (CML).

METHODSThe clinical data and follow-up results of 163 patients with chronic-phase chronic myeloid lenkemia(CP-CML) who were treated in our hospital during the nearly 3 years were analysed retrospectively, among 163 patients 47 received dasatinib, 43 received nilotinib and 73 received imatinib. The efficacy, disease progression and safety were evaluated.

RESULTSAfter treatment for 3 months, the rate of complete hematologic response(CHR) in three treatment groups were 77%, 79% and 67%, respectivily, CHR at 12 months in three treatment groups were 92%, 91% and 90%, respectively. By 3 months, the rates of complete cytogenetic response(CCyR) with dasatinib and nilotinib were higher than that with imatinib (55%, 53% vs 33%)(P<0.05 for both comparisons), CCyR at 12 months in three treatment groups were 86%, 88% vs 69% (P<0.05 for both comparisons). The rates of major molecular response(MMR) for dasatinib (11%) and nilotinib (9%) by 3 months were significantly higher than that for imatinib (1%) (P<0.05 for both comparisons), MMR at 12 months in three treatment groups were 49%, 50% and 28%, respectively (P<0.05 for both comparison). Progression to the accelerated or blast phase of CML occurred in 2 (4%) patients received dasatinib, 2 (5%) received nilotinib and 6 (8%) received imatinib. The safety profiles of these 3 second-generation TKI treatments were similar.

CONCLUSIONBoth dasatinib and nilotinib induced strikingly higher and faster rates of complete cytogenetic response and major molecular response, with a statistically significant difference from imatinib.

Antineoplastic Combined Chemotherapy Protocols ; Blast Crisis ; Dasatinib ; Disease Progression ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Protein Kinase Inhibitors ; Pyrimidines ; Retrospective Studies ; Treatment Outcome

OBJECTIVETo explore the relationship of GSTT1, GSTM1 gene polymorphisms and PAH-DNA adduct with pathogenesis of multiple myeloma.

METHODSThe bone marrow samples from 37 newly-diagnosed MM patients and 52 healthy peoples as controls were collected; the PCR-based restriction fragment length polymorphism (PCR-RFLP) method was used to detecte the polymorphism of GSTT1 and GSTM1, and to analysis their relationship with clinical characters of MM patients; the engyme linked immunosorbent assay (ELISA) was performed to detect the concentration of PAH-DNA adducts.

RESULTSGSTT1 null and GSTM1 null genotypes increased the risk of multiple myeloma with OR 2.57 (P=0.035) and 1.37 (P>0.05) respectively. In MM patients group, GSTT1 null genotype in stage III was significantly higher than that in stages I, II (P=0.038). However, no statistically significant association was found between GSTT1 gene polymorphism and clinical characters, such as age, type, hemoglobin, β2-MG, albumin. Compared with Hb≥85 g/L of the newly-diagnosed MM patients, MM patients with Hb<85 g/L had significantly higher incidence of GSTM1 null genetype (P<0.05). The level of PAH-DNA adducts in MM patients was higher than that in controls (2358±1182 pg/ml vs 1853±996 pg/ml) (P<0.05). GSTT1 null genotype with PAH-DNA level≥2100 pg/ml showed a risk index of MM (OR=4.500, P<0.05).

CONCLUSIONGSTT1 gene may have a critical function in the development of MM, and correlates with staging of MM. GSTM1 gene polymorphism correlates with hemoglobin levels of patients with MM. The content of PAH-DNA adducts may play an important role in the pathogenesis of multiple myeloma.

DNA Adducts ; Genotype ; Glutathione Transferase ; Humans ; Incidence ; Multiple Myeloma ; Polycyclic Aromatic Hydrocarbons ; Polymerase Chain Reaction ; Polymorphism, Genetic

Scutellarin (SCU), a flavonoid from a traditional Chinese medicinal plant. Our previous study has demonstrated that SCU relaxes mouse aortic arteries mainly in an endothelium-depend-ent manner. In the present study, we investigated the vasoprotective effects of SCU against HR-induced endothelial dysfunction (ED) in isolated rat CA and the possible mechanisms involving cyclic guanosine monophosphate (cGMP) dependent protein kinase (PKG). The isolated endothelium-intact and endothelium-denuded rat CA rings were treated with HR injury. Evaluation of endothelium-dependent and -independent vasodilation relaxation of the CA rings were performed using wire myography and the protein expressions were assayed by Western blotting. SCU (10-1 000 μmol·L(-1)) could relax the endothelium-intact CA rings but not endothelium-denuded ones. In the intact CA rings, the PKG inhibitor, Rp-8-Br-cGMPS (PKGI-rp, 4 μmol·L(-1)), significantly blocked SCU (10-1 000 μmol·L(-1))-induced relaxation. The NO synthase (NOS) inhibitor, NO-nitro-L-arginine methylester (L-NAME, 100 μmol·L(-1)), did not significantly change the effects of SCU (10-1 000 μmol·L(-1)). HR treatment significantly impaired ACh-induced relaxation, which was reversed by pre-incubation with SCU (500 μmol·L(-1)), while HR treatment did not altered NTG-induced vasodilation. PKGI-rp (4 μmol·L(-1)) blocked the protective effects of SCU in HR-treated CA rings. Additionally, HR treatment reduced phosphorylated vasodilator-stimulated phosphoprotein (p-VASP, phosphorylated product of PKG), which was reversed by SCU pre-incubation, suggesting that SCU activated PKG phosphorylation against HR injury. SCU induces CA vasodilation in an endothelium-dependent manner to and repairs HR-induced impairment via activation of PKG signaling pathway.
Animals ; Apigenin ; pharmacology ; Cell Adhesion Molecules ; drug effects ; Cell Hypoxia ; Coronary Vessels ; drug effects ; Cyclic GMP ; analogs & derivatives ; metabolism ; pharmacology ; Cyclic GMP-Dependent Protein Kinases ; Glucuronates ; pharmacology ; Microfilament Proteins ; drug effects ; NG-Nitroarginine Methyl Ester ; metabolism ; pharmacology ; Phosphoproteins ; drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; complications ; physiopathology ; Signal Transduction ; drug effects ; Thionucleotides ; metabolism ; pharmacology ; Vasodilation ; drug effects ; physiology