Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

OBJECTIVE: To evaluate the effectiveness and safety of Zhenqi Buxue Oral Liquid (ZQ), progesterone capsules, and their combination in treating oligomenorrhea and hypomenorrhea with qi-blood and Kidney (Shen) essence deficiency. METHODS: This was a prospective, randomized, multi-center controlled trial between June 2022 to December 2022. Ninety-six oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency were randomly assigned to receive ZQ (ZQ group, 29 cases), progesterone capsules (PG group, 32 cases), or the combined Chinese and Western medicine (COM group, 31 cases) at a ratio of 1:1:1. Patients in the ZQ or PG group took daily 10 mL twice a day of ZQ or 200 mg once a day of progesterone capsules for 10 consecutive days on day 15 of the menstrual cycle respectively, and patients in the COM group received the same ZQ combined with progesterone capsules. The treatment course lasted for 3 months and follow-up was performed at 1 and 3 months after the end of treatment. Primary endpoint was the menstrual Traditional Chinese Medicine Syndrome Scale (TCMSS) scores. Secondary endpoints included pictorial blood loss assessment chart (PBAC) scores, clinical efficacy rate, 36-item Short Form Health Survey (SF-36) scores, sex hormones and thickness of endometrium. Adverse events (AEs) were recorded. RESULTS: TCMSS scores after 1- and 3-month treatment in all groups were significantly lower than those at baseline (P<0.05). Only TCMSS scores after 3-month treatment in the ZQ and COM groups continuously decreased compared with those after 1-month treatment in the same group (P<0.01). TCMSS scores after 3-month treatment in the ZQ and COM groups were significantly lower than those in the PG group (P<0.05, P<0.01). Compared with baseline, PBAC scores in the ZQ and COM groups after 3 months of treatment were also significantly higher (both P<0.01). The total effective rates of TCM syndrome of 3-month treatment were significantly improved in all groups compared with that after 1 month of treatment (P<0.05). The total effective rate of the COM group was the highest in the 3rd month of treatment and significantly higher than that of PG group alone (P<0.05). Compared with baseline, only the SF-36 scores of COM group were significantly improved after 3 months of treatment (P<0.05). No serious adverse reactions were observed after treatment. CONCLUSIONS The combination of ZQ and PG, or ZQ only had better effects on reducing TCMSS scores compared with PG, and COM showed the higher total effective rate compared with monotherapy. Besides, COM could effectively improve menstrual blood loss and quality of life. ZQ combined with PG may be an effective and safe option for oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency.
Female ; Humans ; Progesterone/therapeutic use* ; Qi ; Oligomenorrhea/drug therapy* ; Quality of Life ; Prospective Studies ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/adverse effects* ; Capsules ; Kidney

OBJECTIVE: To systematically evaluate the efficacy of Shengmai San in patients with cardiotoxicity of anthracyclines. METHODS: Randomized controlled trials (RCTs) were identified by searching China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), PubMed, Cochrane Library, and Embase Databases from the inceptions until December 2020. The Cochrane Handbook was used to evaluate the risk of bias in the included studies. Data analysis was conducted using RevMan 5.3 software. RESULTS: Totally 19 RCTs with 2,331 participants were included in this review. Results showed that in improving arrhythmia (13 RCTs, n=1,877, RR=0.37, 95%CI 0.25 to 0.52, P<0.00001), the treatment group was superior to the control group. In terms of reducing left ventricular end-diastolic diameter (LVEDD, 2 RCTs, n=128, MD=-0.79, 95%CI -0.93 to -0.65, P<0.00001) and left ventricular end systolic diameter (LVESD, 2 RCTs, n=128, MD=-0.58, 95%CI -0.82 to -0.35, P<0.00001), the treatment group was also better than the control group. In reducing myocardial enzymes such as creatine kinase (CK) [(3 RCTs, n=256, SMD=-0.80, 95%CI -1.16 to -0.44, P<0.0001), (2 RCTs, n=126, SMD=-0.62, 95%CI -0.98 to -0.26, P=0.0007)], the treatment group was superior to the control group. CONCLUSION Shengmai San has a positive effect on the treatment of cardiotoxicity from anthracyclines. However, in the future, it is still necessary to conduct high-quality RCTs to verify its efficacy.
Anthracyclines/adverse effects* ; Cardiotoxicity/etiology* ; Drug Combinations ; Drugs, Chinese Herbal/adverse effects* ; Humans

Objective To observe the changes of peripheral blood lymphocyte subsets in patients with postoperative colorectal cancer before and after chemotherapy, and to evaluate the changes of immune function status. Methods 74 patients with stage Ⅱ-Ⅲ colorectal cancer after radical resection admitted in Zhejiang Cancer Hospital from January to December 2016 were enrolled. 25 non-malignant patients in the same period in our hospital were selected as the control group. Flow cytometry was used to analyze the proportion of peripheral blood lymphocyte subsets at one day before the first, sixth and eighth cycles of adjuvant chemotherapy. Results There were no differences in CD3+ (P =0.1532), CD3+CD4+ (P=0.1107), CD3+CD8+ (P=0.2576) T cells in the peripheral blood between patients with colorectal cancer after radical operation and control group (P>0.05). While CD3+CD56+NKT cells (P=0.0210) and CD3-CD56+NK cells (P=0.0045) in the patients with colorectal cancer after radical operation were significantly higher than those of the control group (P <0.05). There was no significant change in the proportion of NK and NKT cells before 6 cycles of postoperative adjuvant chemotherapy (P>0.05). There was no significant change in the proportion of NKT cells before 8 cycles (P>0.05), and the proportion of NK cells only decreased slightly (19.10±4.63 vs 20.31±4.66, P=0.046). Conclusion The proportion of NK and NKT cells in patients with colorectal cancer after radical resection was significantly higher than that in healthy people, and the expression rate remains stable after adjuvant chemotherapy.

This study aimed to investigate the antihypertensive effect and possible mechanism of Dendrobium officinale flos on hypertensive rats induced by high glucose and high fat compound alcohol. The hypertensive models were successfully made by high-glucose and high-fat diet, with gradient drinking for 4 weeks, and then divided into model control group, valsartan (5.7 mg·kg⁻¹) positive control group and D. officinale flos groups (3，1 g·kg⁻¹). After 6 weeks of treatment, the blood pressure of rats was measured regularly. After the last administration, endothelin-1 (ET-1), thromboxane B₂ (TXB₂), prostacyclin (PGI₂) and nitric oxide (NO) were tested. Endothelial nitric oxide synthase (eNOS) expression and lesion status in thoracic aorta were detected. The vascular endothelium dependent dilation of the thoracic aorta was detected by the isolated vascular loop tension test. The results showed that D. officinale flos could significantly reduce systolic blood pressure and mean arterial pressure in hypertensive rats, inhibit the thickening of thoracic aorta and the loss of endothelial cells, reduce plasma content of ET-1 and TXB₂, and increase the content of PGI₂ and NO. After long-term administration, vascular endothelium dependent dilation of the thoracic aorta was significantly increased, and could be blocked by the eNOS inhibitor (L-NAME) and increase the expression of eNOS. Therefore, D. officinale flos has an obvious antihypertensive effect on high glucose and high fat compound alcohol-induced hypertensive rats. Its mechanism may be correlated with the improvement of vascular diastolic function by protecting vascular endothelial cells, and finally resist hypertension.
Animals ; Antihypertensive Agents ; pharmacology ; Blood Pressure ; Dendrobium ; chemistry ; Diet, High-Fat ; Drugs, Chinese Herbal ; pharmacology ; Endothelin-1 ; blood ; Endothelium, Vascular ; drug effects ; Epoprostenol ; blood ; Glucose ; Hypertension ; chemically induced ; drug therapy ; Nitric Oxide ; blood ; Nitric Oxide Synthase Type III ; metabolism ; Rats ; T-Box Domain Proteins ; blood ; Vasodilation

Objective To investigate the effects of rapid response system of chest pain on the short-term and long-term prognosis of patients with acute ST segment elevation myocardial infarction (STEMI).Methods Referring to the international association of chest pain centers,the chest pain center was established in this hospital,and the corresponding management system and treatment process were worked out.A total of 374 acute STEMI patients who were recruited as the observation group were admitted to this hospital after the establishment of the chest pain center (December 2014 to June 2016),and 250 STEMI patients admitted before the establishment of the chest pain center (January 2012 to December 2012) were recruited as control group.Patients in observation group were treated in the chest pain center,and those in control groupreceived conventional treatment.The general situation,basic diseases,the finishing time of the first electrocardiogram(ECG),the time of door-to balloon expansion(D2B),the time of hospital stay,the average hospitalization expenses,in-hospital cardiac events and in-6-month cardiac events were compared between the two groups.All patients were followed up for 1 years,left ventricular ejection fraction(LVEF),left ventricular end diastolic diameter (LVEDD),left ventricular aneurysm,B type natriuretic peptide (pro-BNP),serum creatinine (Scr),C-reactive protein (CRP) levels and adverse cardiac events (heart failure,death,readmission rate etc.)were compared between two groups.Results Compared with the control group,the average completion time of the first electrocardiogram in the observation group was shortened (P=0.001),the time of entry balloon dilatation,the time of hospital stay,the average hospitalization expenses were less than that of the control group (P＜0.05),the adverse cardiac events (hospital death and heart failure) were lower in the observation group than in the control group (P＜0.05).After 6 months of follow-up,LVEF was significantly higher in the observation group than in the control group (P＜0.05).the levels of LVEDD,pro-BNP,CRP and adverse cardiac events in the observation group were significantly lower than those in the control group (P＜0.05),there was no significant difference in the formation rate of ventricular aneurysm and Scr between the observation group and the control group (P＞0.05).After 1 year of follow-up,LVEF was still higher in the observation group than in the control group (P＜0.05).The incidence of LVEDD,pro-BNP,CREA,CRP,left ventricular aneurysm formation rate,the incidence of adverse cardiac events were lower in the observation group than in the control group (P＜0.05).Conclusion The establishment of rapid response system of chest pain treatment not only effectively shortenthe treatment time of STEMI patients,improve the treatment efficiency,shorten the hospital stay,reduce the cost of hospitalization,but also improve the quality of life and disease prognosis.

Puerarin is the main active component of flavonoids in Puerariae Lobatae Radix. In this study, agar gel microspheres bonded with β-cyclodextrin (AG-β-CD) were synthesized by using economical agar, and then high-purity puerarin was obtained with AB-8 through high-yield separation. With purity and yield of puerarin, and chromatographic purity of related impurities as indexes, four macroporous resins of different properties, namely ADS-7 (high polarity), ADS-17 (medium polarity), ADS-21 (polarity) and AB-8 (weak polarity), were selected for separation of puerarin and technological optimization. In addition, the AG-β-CD purification process was optimized and verified. The results showed that, AB-8 resins showed the best effect and selected as the pre-treatment resins for crude puerarin, and puerarin with the purity of 87.68% showed a recovery rate of 89.66%. The optimized purification process parameters of AG-β-CD included mobile phase (15% ethanol), loading capacity (the ratio of loading amount to column volume) (1.33 g•L⁻¹), sample concentration (8 g•L⁻¹) and flow rate (1 mL•min⁻¹), puerarin with the purity of 95% showed a recovery rate of more than 97%.

Anxiety is one of the most common diseases endangering human health. Its pathogenesis is complex, the studies on the mechanisms of anxiety disorder are concentrated on neurotransmitter, neuroendocrine, immunologic system. Flavonoids are a kind of compounds which possess a variety of physiological activity, used in plenty of diseases. In recent years, researches of natural flavonoids on anti-anxiety were increasing, but contents were incomplete. It was just involved several neurotransmitters in research area. This paper is based on different anxiolytic effect mechanisms and structure-activity relationships of natural flavonoids, summarizing the researches of domestic and foreign, which can serve as a reference for further studies on anxiolytic effects of natural flavonoids.

Hyperlipidemia is a major risk factor for fatty liver, atherosclerosis, hyperviscosily, coronary artery disease and acute myocardial infarction. In recent years, the incidence of hyperlipidemia was gradually increased and showed younger trend. It has been a research hot point to study the etiology and pathogenesis of hyperlipidemia and develop a new drug reduced blood lipid. It is very important to prepare the animal model of hyperlipidemia for displaying the advantage of traditional Chinese medicine characteristic. However, the success of replicating animal model of hyperlipidemia is one of the key of research in experimental hyperlipidemia. The ideal animal model of hyperlipidemia should be similar to human disease, high repeatability, simple and high generalization. It will affect the reliability of the results and the accuracy of the whole experiment process to copy successfully animal models of hyperlipidemia. This review focused on the recent research progress on copying methods of animal models of experimental hyperlipidemia, which will provide reference and basis for the hypolipidemic developers who choose rationally and effectively replication methods of hyperlipidemia animal models.