Native Endophytes of Tripterygium wilfordii-Mediated Biotransformation Reduces Toxicity of Celastrol.

Celastrol (1), obtained from the roots of Tripterygium wilfordii Hook F., is most likely to become an antitumor drug, but with severe cytotoxicity. Due to the lack of modifiable sites in the structure of celastrol, the structural diversity of the modified products obtained by synthesis in the previous studies is insufficient, which hinders the pace of its patent medicine. This study describes a method of microbial transformation to increase the modification site of celastrol and reduce its toxicity. The screening of endophytes from native plants was introduced in this context, which led to two novel stereoselective oxidation products such as S-16-hydroxyl celastrol (2) and A-ring aromatized S-16-hydroxyl celastrol (3), along with a rare 7,9-octadecadienoic acid ester of celastrol (4). Their structures were determined by extensive spectroscopic data analysis, especially 1D and 2D NMR. Compared with 1, compounds 3 and 4 exhibited similar antitumor activity in U251, A549, KG-1, and B16 cell lines. Compound 2 had slightly decreased antitumor activity when compared with compound 1. Furthermore, compound 2-4 showed lower cytotoxicity against BV-2 (about 21-fold lower, 2: 92.82 µM, 3: 34.25 µM, and 4: 74.75 µM vs. celastrol: 4.35 µM), and also identical trends against H9c2 and PC12 cell lines.

Worldwide prevalence of early repolarization pattern in general population and physically active individuals: A meta-analysis.

BACKGROUND: The early repolarization pattern (ERP) has recently been associated with cardiac events such as ventricular arrhythmias and sudden cardiac death. However, estimates of the prevalence of ERP vary widely, especially between the general population and physically active individuals. We performed this systematic review and meta-analysis to quantitatively evaluate the worldwide prevalence of ERP in the general population and physically active individuals. METHODS: We thoroughly searched the PubMed, EMBASE, Web of science, the Cochrane Library, and Scopus databases for relevant studies published until December 20, 2020. Studies in which prevalence was presented or could be estimated from eligible data were included. The pooled prevalence was analyzed using a random-effect model. RESULTS: Finally, we included 29 studies (182,135 subjects) in the general population and 14 studies (8087 subjects) in the physically active individuals. The worldwide pooled prevalence of ERP in the general population was 11.6% (95% confidence interval [CI]: 10.0%-13.3%). The incidence of ERP was 17.0% and 6.2% in men and women, respectively. The prevalence was 20.9% in blacks, 13.4% in Asians, and 10.1% in Caucasians. Additionally, the prevalence of ERP in physically active individuals was 33.9% (95% CI: 25.3%-42.6%). CONCLUSION: A significant difference in the worldwide prevalence of ERP is revealed in this study. The ERP is highly prevalent in men, blacks, and physically active individuals.

Facing coronavirus disease 2019: What do we know so far? (Review).

Although the World Health Organization declared the outbreak of coronavirus disease 2019 (COVID-19), which originated in China, as a public health emergency of international concern as early as January 30, 2020, the current COVID-19 epidemic is spreading rapidly. As of April 19, 2020, total of 2,392,165 confirmed cases had been reported in 211 countries and regions, with 614,421 (25.68%) cured cases and 164,391 (6.87%) deaths. Scientists and clinicians have made great efforts to learn much about COVID-19 so that it can be controlled as soon as possible. Herein, this review will discuss the epidemiology, pathology, clinical features, diagnosis and treatment of COVID-19 based on the current evidence.

Prognostic Utility of the Combination of Platelet Count with Neutrophil-to-Lymphocyte Ratio in Aged Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

METHOD: This was a study recording 637 patients who were diagnosed with acute myocardial infarction. Our patients were grouped according to the combination of platelet count and neutrophil-to-lymphocyte ratio. The prognostic role of the combination of platelet count and neutrophil-to-lymphocyte ratio on mortality was assessed by the univariate and multivariate Cox regression analysis. RESULT: Our study population was divided into three parts according to the median values of platelet count and neutrophil-to-lymphocyte ratio. It was indicated that platelet count and neutrophil-to-lymphocyte ratio were correlative mutually to a certain degree (p=0.010). The Kaplan-Meier analysis showed that the combination of high platelet count and high neutrophil-to-lymphocyte ratio had a greater risk of death in short- and long-term endpoints (log-rank p=0.046, p < 0.001, respectively). Moreover, by multivariate analysis, both high platelet count and high neutrophil-to-lymphocyte ratio groups were an independent predictor (hazard ratio: 2.132, 95% confidence interval: 1.020-4.454, p=0.044) and long-term mortality (hazard ratio: 2.791, 95% confidence interval: 1.406-5.538, p=0.003). CONCLUSION: The combination of platelet count and neutrophil-to-lymphocyte ratio could be a useful predictor for the prediction of in-hospital and long-term mortality in aged patients with acute myocardial infarction.

CD13: A Key Player in Multidrug Resistance in Cancer Chemotherapy.

Cancer is one of the most serious diseases that are harmful to human health. Systemic chemotherapy is an optimal therapeutic strategy for the treatment of cancer, but great difficulty has been encountered in its administration in the form of multidrug resistance (MDR). As an enzyme on the outer cell surface, CD13 is documented to be involved in the MDR development of tumor cells. In this review, we will focus on the role of CD13 in MDR generation based on the current evidence.

Neutrophil to high-density lipoprotein ratio has a superior prognostic value in elderly patients with acute myocardial infarction: a comparison study.

BACKGROUND: The importance of the lipid-related biomarkers has been implicated in the pathological process and prognosis of acute myocardial infarction (AMI). Our work was conducted to discuss and compare the predictive ability of the neutrophil to high-density lipoprotein cholesterol (HDL-C) ratio (NHR) with other existing prognostic indices, for instance, the monocyte to HDL-C ratio (MHR) and the low-density lipoprotein cholesterol (LDL-C) to HDL-C ratio (LDL-C/HDL-C) in elderly patients with AMI. METHODS: Our population was 528 consecutive elderly AMI patients (65-85 years) who were enrolled from Tongji Hospital and grouped according to the cutoff points which were depicted by the receiver operating characteristic (ROC). The Kaplan-Meier curves were plotted with the survival data from the follow-up to investigate the difference between cutoff point-determined groups. Moreover, we assessed the impact of NHR, MHR, LDL-C/HDL-C on the long-term mortality and recurrent myocardial infarction (RMI) with Cox proportional hazard models. RESULTS: Mean duration of follow-up was 673.85 ± 14.32 days (median 679.50 days). According to ROC curve analysis, NHR ≥ 5.74, MHR ≥ 0.67, LDL-C/HDL-C ≥ 3.57 were regarded as high-risk groups. Kaplan-Meier analysis resulted that the high-NHR, high-MHR and high-LDL-C/HDL-C groups presented higher mortality and RMI rate than the corresponding low-risk groups in predicting the long-term clinical outcomes (log-rank test: all P < 0.050). In multivariate analysis, compared with MHR and LDL-C/HDL-C, only NHR was still recognized as a latent predictor for long-term mortality (harzard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.02 to 3.75, P = 0.044) and long-term RMI (HR: 2.23, 95% CI: 1.04 to 4.79, P = 0.040). Furthermore, the positive correlation between NHR and Gensini score (r = 0.15, P < 0.001) indicated that NHR was relevant to the severity of coronary artery to some extent. CONCLUSIONS: NHR, a novel laboratory marker, might be a predictor of the long-term clinical outcomes of elderly patients with AMI, which was superior to MHR and LDL-C/HDL-C.

Could platelet-to-lymphocyte ratio be a predictor for contrast-induced nephropathy in patients with acute coronary syndrome?: A systematic review and meta-analysis.

BACKGROUND: Contrast-induced nephropathy (CIN) is acute renal failure observed after administration of iodinated contrast media during angiographic or other medical procedures. In recent years, many studies have focused on biomarkers that recognize CIN and/or predict its development in advance. One of the many biomarkers studied is the platelet-to-lymphocyte ratio (PLR). We performed a systematic review and meta-analysis to evaluate the correlation between PLR level and CIN. METHODS: Relevant studies were searched in PUBMED, EMBASE, and Web of Science until September 15, 2018. Case-control studies reporting admission PLR levels in CIN and non-CIN group in patients with acute coronary syndrome (ACS) were included. The pooled weighted mean difference (WMD) and 95% confidence intervals (95%CI) were calculated to assess the association between PLR level and CIN using a random-effect model. RESULTS: Six relevant studies involving a total of 10452 ACS patients (9720 non-CIN controls and 732 CIN patients) met our inclusion criteria. A meta-analysis of 6 case-control studies showed that PLR levels were significantly higher in CIN group than those in non-CIN group (WMD = 33.343, 95%CI = 18.863 to 47.823, P < .001, I = 88.0%). CONCLUSION: For patients with ACS after contrast administration, our meta-analysis shows that on-admission PLR levels in CIN group are significantly higher than those of non-CIN group. However, large and matched cohort studies are needed to validate these findings and assess whether there is a real connection or just an association.

Serum Biomarkers for Early Diagnosis of Chinese X-CGD Children: Case Reports and a Literature Review.

Since X-linked chronic granulomatosis disease (X-CGD) exhibits no specific clinical symptoms at an early stage, early diagnosis is difficult and depends predominantly on neonatal screening. Therefore, the aim of this study was to explore routine biomarkers for X-CGD in children and provide clues for early diagnosis. The cases of 10 children with X-CGD diagnosed at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from 2013 to 2016 and 122 Chinese children with X-CGD reported in the literature were summarized. Serum biomarkers and clinical symptoms at acute infection were organized. A total of 132 children with X-CGD were enrolled in this study. For 55.8% of the patients, the diagnosis was delayed more than one year after the onset of the first symptoms because no typical clinical symptoms manifested. Children with X-CGD at an acute infection stage showed three recurrent signs in terms of serum biomarkers: (1) the total number of white blood cells (especially N%) was increased significantly, accompanied by anemia in some cases; (2) C-reactive protein (CRP) levels were increased significantly; and (3) most of the patients exhibited very high serum IgG levels (>12 g/L). Diagnosis of X-CGD at an early age is difficult because of its nonspecific clinical features. Our study suggested children with X-CGD suffering acute infection show increases in three typical serum biomarkers, which can provide clues for early diagnosis.

Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins.

Gastric cancer (GC) is one of the most malignant tumors, accounting for 10% of deaths caused by all cancers. Chemotherapy is often necessary for treatment of GC; the FOLFOX regimen is extensively applied. However, multidrug resistance (MDR) of GC cells prevents wider application of this treatment. Ubenimex, an inhibitor of CD13, is used as an immune adjuvant to treat hematological malignancies. Here, we demonstrate that CD13 expression positively correlates with MDR development in GC cells. Moreover, Ubenimex reverses the MDR of SGC7901/X and MKN45/X cells and enhances their sensitivity to FOLFOX, in part by decreasing CD13 expression, which is accompanied by downregulation of Bcl-xl, Bcl-2, and survivin expression; increased expression of Bax; and activation of the caspase-3-mediated apoptotic cascade. In addition, Ubenimex downregulates expression of membrane transport proteins, such as P-gp and MRP1, by inhibiting phosphorylation in the PI3K/AKT/mTOR pathway to increase intracellular accumulations of 5-fluorouracil and oxaliplatin, a process for which downregulation of CD13 expression is essential. Therefore, the present results reveal a previously uncharacterized function of CD13 in promoting MDR development in GC cells and suggest that Ubenimex is a candidate for reversing the MDR of GC cells.

Association between fetuin-A and prognosis of CAD: A systematic review and meta-analysis.

BACKGROUND: Fetuin-A is an anti-inflammation and anti-calcification factor involved in the course of coronary artery disease (CAD). But the association between serum fetuin-A level and the prognosis of CAD patients was still controversial. To clarify the association between serum fetuin-A level and the prognosis of CAD patients, we conducted the present meta-analysis. METHODS: The included studies should be potentially relevant prospective studies published in English language before January 2019. The target population of the present meta-analysis was restricted to patients with CAD. The results of studies must report hazard ratio (HR) or Kaplan-Meier survival curve for all-cause mortality or incidence of secondary cardiovascular disease (CVD) events. The pooled HRs were analysed by the method of meta-analysis. RESULTS: A total of four prospective studies, including 4256 participants with CAD disease, were chosen to be included. The pooled HR for all-cause mortality was 0.57 (95% CI: 0.37-0.87), showing a statistically significant association between high serum fetuin-A level and low all-cause mortality in CAD patients. For the incidence of secondary CVD events, the pooled HR was 0.86 (95% CI: 0.60-1.23), indicating no statistically significant association between serum fetuin-A level and incidence of secondary CVD events in CAD patients. CONCLUSION: High serum fetuin-A level associated with lower all-cause mortality in patients with CAD. No association between serum fetuin-A level and incidence of secondary CVD events was found in patients with CAD.

Ubenimex suppresses Pim-3 kinase expression by targeting CD13 to reverse MDR in HCC cells.

Hepatocellular carcinoma (HCC) is one of the most serious cancers, with rapid progression and high mortality. However, chemotherapy of HCC is hindered by multi-drug resistance (MDR). It is urgent, therefore, to explore new approaches for overcoming MDR of HCC cells. Ubenimex, an inhibitor of CD13, has been used as an immuno-enhancer for treating hematological neoplasms and other solid tumors. Here, we demonstrate that Ubenimex can also reverse MDR in the HCC cell lines HepG2/5-FU and Bel7402/5-FU. Ubenimex inhibits the expression of the proto-oncogene, Pim-3, which is accompanied by decreased expression of BCL-2 and BCL-XL, decreased phosphorylation of Bad, and increased tumor apoptosis. Moreover, Ubenimex decreases expression of the MDR-associated proteins P-gp, MRP3 and MRP2 to enhance intracellular accumulation of Cisplatin, for which down-regulation of Pim-3 is essential. Our results reveal a previously uncharacterized function of Ubenimex in mediating drug resistance in HCC, which suggests that Ubenimex may provide a new strategy to reverse MDR and improve HCC sensitivity to chemotherapeutic drugs via its effects on Pim-3.

A self-contrast approach to evaluate the inhibitory effect of chrysosplenetin, in the absence and presence of artemisinin, on the in vivo P-glycoprotein-mediated digoxin transport activity.

In this study, we used a self-contrast method, which excluded the individual difference, to evaluate the inhibitory effect of chrysosplentin (CHR) in the presence or absence of artemisinin (ART) on the P-glycoprotein (P-gp) transport activity. A sensitive and rapid UHPLC-MS/MS method was applied for quantification of digoxin, a P-gp-specific substrate, in rat plasma. A pharmacokinetic study was carried out: first after an oral administration of digoxin at a dose of 0.09 mg/kg (first period), followed by a 20-day wash-out, then after another administration of digoxin (second period). During the second period, test compounds were orally given three times per day for seven consecutive days. Results showed that the t1/2 of digoxin in all the groups had no significant difference between the first and second periods. The AUC0-24 , Cmax , tmax , and Clz /F of the negative control and ART alone groups showed no difference. However, the AUC0-24 and Cmax in the CHR alone, CHR-ART (1:2) and verapamil (positive control) groups showed 2.34-, 3.04-, 1.79-, and 1.81-, 1.99-, 2.06-fold increases along with 3.50-, 3.84- and 4.76-fold decreases for CLz /F, respectively. The tmax in the CHR-ART (1:2) group increased 3.73-fold. In conclusion, our self-contrast study suggested that CHR, especially when combined with ART in a ratio of 1:2, inhibited P-gp activity while ART alone has no effect. Copyright © 2016 John Wiley & Sons, Ltd.

[Effect of Qi Benefiting Blood Activating Method on Plasma Fibrinogen and D-dimer in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease].

OBJECTIVE: To explore the therapeutic effect of qi benefiting blood activating method (QB-BAM) on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients with blood stasis syndrome (BSS) by observing its effect on plasma fibrinogen (Fg) and D-dimer (D-D) levels. METHODS: Sixty AECOPD patients with BSS were randomly assigned to the treated group and the control group, 30 in each group. All patients received conventional therapy for AECOPD. Those in the treated group were additionally injected with Shengmai Injection and Tanshinone IIA Injection. Clinical efficacy and indices including levels of Fg, D-D, PaO2, and PaCO2 were measured and compared before and after treatment. RESULTS: The effective rate was 93.3% (28/30 cases) in the treated group, higher than that of the control group [73.3% (22/30 cases) , P < 0.05]. There was no significant difference in all indices between the treated group and the control group before treatment (P >0.05). After treatment all indices were significantly improved in the two groups (P < 0.01). But in the treated group levels of Fg and D-D decreased more and levels of PaO2 increased more (P < 0.01). Plasma levels of Fg and D-D levels were negatively correlated with PaO2 (r = -0.493, r = -0.438, P < 0.01) before treatment, and also negatively correlated with PaO2 (r = -0.452, r = -0.325, P < 0.01, P < 0.05) after treatment, but they were not significantly correlated with PaCO2 before and after treatment (P >0.05). CONCLUSIONS: QBBAM could play a therapeutic role in improving prethrombotic states of AECOPD patients with BSS. Plasma levels of Fg and D-D were related to the severity of AECOPD.

[Determination of chrysosplenetin, metabolic inhibitor of artemisinin, in rat plasma by UPLC-ms/MS and study on its pharmacokinetics].

OBJECTIVE: The study aimed to develop the assay of chrysosplenetin (CHR), a metabolic inhibitor of artemisinin by UPLC-MS/MS in rat plasma and investigate the pharmacokinetics parameters of CHR. METHOD: The plasma samples were precipitated by acetonitrile to remove the proteins. Separation was carried out on a Shim-pack XR-ODS C,18(2. 0 mm x 100 mm, 2. 2 micromp.m) column using a mobile phase containing methanol-0. 1% formic acid (87:13) using by diazepam as internal standard. Mass spectrometer with electrospray ionization (ESI) operated in the positive ion mode was used for analysis. Total analysis time was 2 min. RESULT: The assay was linear in the range 5-5 000 microg L-1 (r =0. 999 3) with recoveries in the range from 69. 0% to 81.2% and satisfied inter-, intra- precision and accuracy. CHR after oral administration is not easy to absorb with double or multimodal peak phenomenon. The t1/2 of CHR after intravenous injection was very short and that of low, medium, and high dosage was (17. 01 +/- 8. 06) , (24. 62 +/- 4. 59), (28. 46+/- 4. 63) min, respectively. CONCLUSION: The developed method was special, rapid, and sensitive for determination of CHR pharmacokinetics. [Key words] UPLC-MS/MS; chrysosplenetin; pharmacokinetics; plasma; rat

[Effect of yifei jianpi recipe on inflammatory cells, levels of interleukin-8 and tumor necrosis factor-alpha in sputum from patients with chronic obstructive pulmonary disease].

OBJECTIVE: To explore the effect and the mechanism of yifei jianpi recipe (YFJPR) on patients with chronic obstructive pulmonary disease (COPD). METHODS: Forty patients with COPD in stable phase were randomly divided into two groups, the treated group and the control group. Indexes including the total and differential count of inflammatory cell in sputum, levels of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), as well as the percentage of forced expiratory volume in one second in its predicted value (FEV1%) and ratio of FEV1/forced vital capacity (FVC) in patients were measured before and after treatment, and compared with those in 20 healthy subjects. RESULTS: All the indexes measured in patients before and after treatment were significantly different from those in healthy subjects (P < 0.01). Differential count of polymorphonuclear neutrophil (PMN) and levels of IL-8 and TNF-alpha in sputum in the treated group significantly decreased after treatment (P < 0.01), while the non-PMN differential count and levels of FEV1% and FEV1/FVC significantly increased (P < 0.01). But in the control group, changes only showed in increasing of FEV1% and FEV1/FVC (P < 0.05 or P < 0.01). And the effects in the treated group were better than those in the control group (P < 0.01). CONCLUSION: YFJPR can play a therapeutic role on patients with COPD by way of reducing the airway inflammatory reaction.