Realgar (As4S4), a traditional Chinese medicine, induces acute promyelocytic leukemia cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway in vitro.

Acute promyelocytic leukemia (APL) is a specific subtype of acute myelogenous leukemia (AML) characterized by the proliferation of abnormal promyelocytes. Realgar, a Chinese medicine containing arsenic, can be taken orally. Traditional Chinese medicine physicians have employed realgar to treat APL for over a thousand years. Therefore, realgar may be a promising candidate for the treatment of APL. Nevertheless, the underlying mechanism behind realgar therapy is largely unclear. The present study aimed to investigate the effect of realgar on cell death in the APL cell line (NB4) in vitro and to elucidate the underlying mechanism. In this study, after APL cells were treated with different concentrations of realgar, the cell survival rate, apoptotic assay, morphological changes, ATP levels and cell cycle arrest were assessed. The expression of Bcl-2, Bax, Cytochrome C (Cyt-C) and apoptosis-inducing factor (AIF) at the mRNA and protein levels were also measured by immunofluorescence, quantitative PCR (qPCR) and Western blotting. We found that realgar could significantly inhibit APL cell proliferation and cell death in a time- and dose-dependent manner. Realgar effectively decreased the ATP levels in APL cells. Realgar also induced APL cell cycle arrest at the S and G2/M phases. Following realgar treatment, the mRNA and protein levels of Bcl-2 were significantly downregulated, whereas the levels of Bax, Cyt-C, and AIF were significantly upregulated. In summary, realgar can induce APL cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway, suggesting that realgar may be an effective therapeutic for APL.

Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy.

BACKGROUND: The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population. OBJECTIVE: The aim of this study was to evaluate the PK and PD of cefiderocol during in vitro and in vivo CRRT and provide optimal dosing recommendations. METHODS: The PK and dialytic clearance of cefiderocol was evaluated via an established in vitro CRRT model across various modes, filter types, and effluent flow rates. These data were combined with in vivo PK data from nine patients receiving cefiderocol while receiving CRRT from phase III clinical trials. Optimal dosing regimens and their respective probability of target attainment (PTA) were assessed via an established population PK model with Bayesian estimation and 1000-subject Monte Carlo simulations at each effluent flow rate. RESULTS: The overall mean sieving/saturation coefficient during in vitro CRRT was 0.90 across all modes, filter types, effluent flow rates, and points of replacement fluid dilution tested. Adsorption was negligible at 10.9%. Three-way analysis of variance (ANOVA) and multiple linear regression analyses demonstrated that effluent flow rate is the primary driver of clearance during CRRT and can be used to calculate optimal cefiderocol doses required to match the systemic exposure observed in patients with normal renal function. Bayesian estimation of these effluent flow rate-based optimal doses in nine patients receiving CRRT from the phase III clinical trials of cefiderocol revealed comparable mean (± standard deviation) area under the concentration-time curve values as patients with normal renal function (1709 ± 539 mg·h/L vs. 1494 ± 58.4 mg·h/L; p = 0.26). Monte Carlo simulations confirmed these doses achieved >90% PTA against minimum inhibitory concentrations ≤4 mg/L at effluent flow rates from 0.5 to 5 L/h. CONCLUSION: The optimal dosing regimens developed from this work have been incorporated into the prescribing information for cefiderocol, making it the first and only antimicrobial with labeled dosing for CRRT. Future clinical studies are warranted to confirm the efficacy and safety of these regimens.

Biomimetic engineering endothelium-like coating on cardiovascular stent through heparin and nitric oxide-generating compound synergistic modification strategy.

Co-immobilization of two or more molecules with different and complementary functions to prevent thrombosis, suppress smooth muscle cell (SMC) proliferation, and support endothelial cell (EC) growth is generally considered to be promising for the re-endothelialization on cardiovascular stents. However, integration of molecules with distinct therapeutic effects does not necessarily result in synergistic physiological functions due to the lack of interactions among them, limiting their practical efficacy. Herein, we apply heparin and nitric oxide (NO), two key molecules of the physiological functions of endothelium, to develop an endothelium-mimetic coating. Such coating is achieved by sequential conjugation of heparin and the NO-generating compound selenocystamine (SeCA) on an amine-bearing film of plasma polymerized allylamine. The resulting surface combines the anti-coagulant (anti-FXa) function provided by the heparin and the anti-platelet activity of the catalytically produced NO. It also endows the stents with the ability to simultaneously up-regulate α-smooth muscle actin (α-SMA) expression and to increase cyclic guanylate monophosphate (cGMP) synthesis of SMC, thereby significantly promoting their contractile phenotype and suppressing their proliferation. Importantly, this endothelium-biomimetic coating creates a favorable microenvironment for EC over SMC. These features impressively improve the antithrombogenicity, re-endothelialization and anti-restenosis of vascular stents in vivo.

[Multi-centered, randomized controlled clinical study on Chinese medicine formula particles for hyperlipidaemia associated with highly active antiretroviral therapy].

OBJECTIVE: To observe the effect and safety of Xiaozhi particles, integrated taohong Siwu tang and Erchen tang and Xuezhikang capsule in treating hyperlipidaemia (HLP) associated with highly active antiretroviral therapy (HAART). METHOD: In the multi-centered, randomized controlled clinical study, 180 hyperlipidaemia associated with highly active antiretroviral therapy cases were divided into the treatment group treated by Xiaozhi particles, integrated Taohong Siwu tang and Erchen tang, and the control group treated by Xuezhikang capsule. The treatment course was 12 weeks. The total cholesterol (Tch), triglyceride (TG), low density lipoprotein (LDL) and high-density lipoprotein(HDL) were observed. RESULT: After 12 weeks, compared with Xuezhikang capsule, the change difference of Tch, LDL, HDL in the Chinese traditional medicine formula groups of patients is significant (P < 0.05), the change of the TG has no significant difference. The effect of Tch, LDL in Xuezhikang capsule groups is better than in traditional Chinese medicine formula group,but the effect of HDL in traditional Chinese medicine formula group is better than in Xuezhikang capsule groups. CONCLUSION: Integrated Taohong Siwu tang and Erchen tang, Xiaozhi particles and Xuezhikang capsule can be used to control the hyperlipidaemia associated with highly active antiretroviral therapy as one of the main Chinese native medicine preparation.

[Randomized controlled study of integrated treatment of traditional Chinese medicine and western medicine on AIDS with pulmonary inflammation patients].

OBJECTIVE: To compare effects of integrated treatment traditional Chinese medicine and Western medicine (TCM-WM) and simple western medicine on TCM clincal symptoms in the patient of AIDS with pulmonary inflammation. METHOD: A multicenter randomized controlled trials of 164 subjects evaluated the effects of clinical symptoms of AIDS with pulmonary inflammation of TWO regimens: the TCM-WM group (n = 111) and western medicine treatment group (n = 53), while incidence of TCM symptoms in different time points in two groups were analyzed. RESULT: Twenty eight days after treatment, the cured and markedly effective rate of TCM symptoms in the TCM-WM group significantly exceeding that in the western medicine treatment group (cured and markedly effective rate significant efficiency 44.55% vs 20.00%), while the incidence rate for the TCM symptoms of fever and headache in the TCM-WM group was significantly lower than that in western medicine group. CONCLUSION: The integrated treatment of traditional Chinese medicine and Western medicine helps to alleviate the TCM clinical symptoms of AIDS with pulmonary inflammation.

[Study of traditional Chinese medicine syndrome features of AIDS-related chronic diarrhea].

OBJECTIVE: To study the AIDS-related chronic diarrhea in traditional Chinese medicine (TCM) clinical manifestations and syndrome factors, explore the characteristics of syndrome. METHOD: A multicenter, prospective collection of 311 cases of AIDS patients with chronic diarrhea, study the characteristics of TCM syndrome by using the method of descriptive statistics and exploratory factor analysis. RESULT: The common clinical manifestation of TCM: fatigue (229 cases, 73.63%), bowel (229 cases, 68.81%), diarrhea (194 cases, 62.38%), thin fur (201 cases, 64.63%), pink tongue (166 cases, 53.38%), greasy fur, thready pulse (126 cases, 40.51%), sink vein (64 cases, 20.58%), slippery pulse. 17 common factors were extracted, common disease syndrome factor as the spleen, stomach, liver, gallbladder and colon syndrome factors of disease, Qi, Yang deficiency, Qi stagnation, dampness and heat evil. CONCLUSION: AIDS-related chronic diarrhea symptoms involving multiple organs, the disease belongs to deficiency and excess.

[Study on quality of life of asymptomatic HIV infected persons with traditional Chinese medicine].

OBJECTIVE: Study on quality of life of asymptomatic HIV infected persons with traditional Chinese medical, which can provide the clinical basis for improving the quality of life. METHOD: This study applied a randomized, double-blind, and placeb-parallel control designed method to select 1 200 persons in the asymptomatic period of HIV infection as the subjects. The subjects were randomly divided into the treatment group and the control group at the ratio of about 2:1. According to the results of monthly differential diagnosis of TCM, the test group and the control group were given homologue Chinese drugs preparations and model Chinese drugs. The total study period was 18 months. Using PRO scale and the world health organization AIDS determination of quality of life short scale form (WHOQOL-HIV-BREF) to investigate asymptomatic HIV infected persons, according to different times, we calculated the total score and each domain score of quality of life of the treatment group and control group, we did statistical analysis. RESULT: Form the PRO scale,we can see that the treatment group showed a trend of stability, compared with the control group with significant statistical difference (P < 0.05) after 6 months; from the WHOQOL-HIV scale analysis, we can see that compared with before treatment, the quality of life of the treatment group was increased, the difference was significant (P < 0.05), but the quality of life of the control quality of life was decreased, the differences was significant (P < 0.05). CONCLUSION: Dialectical therapy of Chinese medicine can significantly improve the patient's quality of life, which can provide the basis for the prevention and control policy formulation and implementation with asymptomatic HIV infected persons.

[Therapeutic effects of Fuzhenghuayu decoction in a CCl4-induced liver cirrhosis rat model and on hepatic stellate cell activation].

OBJECTIVE: To evaluate the influence of Fuzhenghuayu decoction on fibrotic liver tissue and activated hepatic stellate cells (HSCs) using a carbon tetrachloride (CCl4)-induced liver cirrhosis rat model system. METHODS: Sixty-four Sprague-Dawley rats were randomly divided into the following groups: normal (non-model, non-drug intervention), CCl4 liver fibrosis model, and CCl4 liver fibrosis model Fuzhenghuayu drug intervention at low dose (0.75 g/kg/d) and high dose (1.5 g/kg/d). The drug intervention was administered via oral-gastric irrigation once daily for 6 times per week over a 6-week period. Four rats from each group were sacrificed at the end of week 2, 4, and 6 for serum and liver tissue collection. Liver fibrosis was evaluated by histology, and expression of a-smooth muscle actin (a-SMA) was determined by immunohistochemistry. Liver function was assessed by measuring levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil). Between-group comparisons were made by completely random design and ANOVA with Bonferroni correction. RESULTS: At the end of weeks 2, 4 and 6, all four groups showed significantly different levels of ALT, AST, and TBil; in addition, the model group and drug intervention groups had significantly higher levels of ALT, AST, and TBil than the control group, the drug intervention groups showed significantly lower levels of ALT, AST, and TBil than the model group (P less than 0.01 or less than 0.05), and the differences between the low dose and high dose groups reached statistical significance (P less than 0.01 or less than 0.05). At the end of weeks 2, 4 and 6, the model group and drug intervention groups had significantly higher area ratio of liver fibrosis than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but the two drug intervention groups had significantly less area ratio of liver fibrosis than the model group (P less than 0.05) and the high dose group showed the most robust decrease. In addition, the model group and drug intervention groups showed higher expression of a-SMA than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but two drug intervention groups had significantly less a-SMA than the model group (F = model: 46.32, low dose: 40.30, high dose: 58.42, P less than 0.05) and the high dose group showed the most robust decrease. CONCLUSION: The Fuzhenghuayu decoction reduces the numbers of activated HSCs, thereby leading to down-regulated a-SMA expression and reduced degree of liver fibrosis; these effects may represent the mechanism by which this drug suppresses hepatic fibrosis.

[Efficacy controlled observation on acupuncture and western medicine for gastrointestinal dysmotility in liver cirrhosis].

OBJECTIVE: To observe the therapeutic effect of acupuncture on gastrointestinal dysmotility in liver cirrhosis. METHODS: Forty cases of gastrointestinal dysmotility in liver cirrhosis were randomized into an acupuncture group and a motilium group, 20 cases in each one. In the acupuncture group, on the basis of the conventional treatment, electroacupuncture was applied at Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) for 30 min, once a day. In the motilium group, on the basis of the conventional treatment, motilium was taken orally 30 min before meals, 10 mg each time, three times a day. The treatment was required for 2 weeks in both groups. The changes in the digestive tract symptom score and liver function Child-Pugh score were observed and the efficacy was assessed. RESULTS: The total effective rate of digestive tract symptoms was 85.0% (17/20) in the acupuncture group and 70.0% (14/20) in the motilium group. The score improvements in abdominal distention, belching and vomiting in the acupuncture group were superior to those in the motilium group (all P < 0.05). In the acupuncture group, the liver function Child-Pugh total score was 8.40 +/- 0.22 before treatment and reduced to 5.36 +/- 0.17 after treatment, in which the scores for ascites, serum bilirubin and albumin were all reduced (all P < 0.05) and the reducing range was increased in tendency with the improvements in digestive tract symptoms. In the motilium group, Child-Pugh score was not changed obviously as compared with that before treatment. CONCLUSION Acupuncture effectively alleviates digestive tract symptoms and improves liver function for the patients of liver cirrhosis, its efficacy on gastrointestinal dysmotility in liver cirrhosis is superior to motilium.

[Preliminary study on features of syndrome distribution and cluster analysis for AIDS patients with pulmonary infection].

OBJECTIVE: To investigate Chinese medical features of acquired immunodeficiency syndrome (AIDS) patients with pulmonary infection. METHODS: Using cluster analysis method, Chinese medical syndromes of 196 AIDS patients with pulmonary infection were analyzed. The distribution features of each syndrome type were analyzed according to the severity and CD4+ numerical analysis. RESULTS: Basic Chinese medical syndrome types could be summed up as three kinds: exterior invasion of wind heat and phlegm heat obstructing Fei syndrome (61 cases, 31.1%), Fei-Pi deficiency and Fei stagnation of phlegm syndrome (64 cases, 32.7%), Fei-Shen deficiency and yin deficiency induced inner heat syndrome (71 cases, 36.2%). There was statistical difference in the severity degree and the distribution of CD4 among the three syndrome types (P < 0.05). CONCLUSIONS: AIDS patients with pulmonary infection involve Fei, Shen, and Pi. The pathogenic factors were related to "wind", "heat", "phlegm", and "xu". The Chinese medical syndrome distribution was closely correlated with patients' immunity.

Chemical constituents of Trachelospermum jasminoides.

Ten compounds, comprising a new C(8) normonoterpenoid glycoside, trachelinoside (1), structurally as 4-(2-O-beta-D-glucopyranosyl)-hydroxyethyl-5,5-dimethyldihydrofuran-2(3H)-one, together with nine known compounds, were isolated from the 85% ethanol extract of the vines and leaves of Trachelospermum jasminoides (Lindl.) Lem.

[Study on the flavonoids constituents of Trachelospermum jasminoides].

OBJECTIVE: To study the flavonoids constituents of Trachelospemum jasminoides. METHODS: The compounds were separated and purified by column chromatography with silica gel, and identified by IR, MS, NMR and 2D-NMR. RESULTS: Six flavonoids were identified as apigenin (I), apigenin 7-O-beta-glucoside (II), apigenin 7-O-beta-neospheroside (III), luteoloside (IV), narngin (V) 6,8-di-C-glucopyanosylapigenin (VI), respectively. CONCLUSION: Compounds V and VI are isolated from this plant for the first time.

[Inhibitory effect of anluohuaxianwan on experimental hepatic fibrosis in rats].

OBJECTIVE: To investigate the effects of anluohuaqianwan on experimental hepatic fibrosis induced by dimethyl nitrosamine (DMN) in rats. METHODS: 36 male SD rats were randomly dividied into three groups: model group, normal group, anluohuaqianwan group. The rats in the three groups were treated with DMN daily for 4 weeks. The liver function was detected using auto biochemistry analyzer, the serum HA, LN, IV-C, PIIIP were detected by immunoradiometry, the histopathology was observed in the left liver lobe after HE staining, the expression of matrix metalloproteinase-2 (MMP-2) in liver tissue were detected by immunohistochemistry. RESULTS: The serum levels of ALT, AST, ALP, TP, ALB and the contents of HA, LN, IV-C in model group were significantly increased compared to these in the normal group (P less than 0.01). The serum levels of ALT, AST and the contents of HA in anluohuaqianwan group were significantly lower than those in the model group (P less than 0.01). The liver MMP-2 in the model group was significantly increased compared to that in the normal group (P less than 0.05). The expression of MMP-2 in liver tissue of model group was lower than that in the anluohuaqianwan group (P less than 0.05). CONCLUSION: Anluohuaqianwan can inhibit liver fibrosis in rats induced by DMN.

Lignans from Trachelospermum jasminoides.

Seven lignans having a diarylhydroxybutyrolactone skeleton were isolated from the leaves and stems of Trachelospermum jasminoides (Lindl.) Lem. Their structures were elucidated to be nortrachelogenin 8' -O-beta-D-glucopyranoside (1), nortrachelogenin 5'- C- beta-D-glucopyranoside (2), trachelogenin amide (3), nortracheloside, trachelogenin, tracheloside, and trachelogenin 4'- O- beta-gentiobioside, respectively, on the basis of spectroscopic analyses. Lignans 1 - 3 were structurally identified to be new compounds, and 2 was a rare C-glucosyl-lignan.

[Studies on liver-toxicity in rhigoma of Dioscorea bulbifera].

OBJECTIVE: To explore the liver-toxic fraction in Rhigoma of Dioscorea bulbifera. METHOD: The rats were randomized into four groups: control group (20% PVP-water), T001(10% total methanol extraction), F002(5% chloroform fraction) and F003(5% methanol fraction). Direct bilirubin (DBil) and Glutamic-pyruvic transaminase (GPT) were examined, and liver index was measured. The histological and morphological observations were performed with optical and electrical microscope. RESULT: T001 and F002 showed significant liver toxicity. CONCLUSION: The chloroform fraction was the liver-toxic fraction of D. bulbifera.

[Studies on chemical constituents of Ervatamia hainanensis].

OBJECTIVE: To study the chemical constituents of Ervatamia hainanensis. METHOD: The compounds were separated and purified by column chromatography with silica gel, and identified by IR, MS, NMR and 2D-NMR. RESULT: Five compounds were identified as I (isolariciresinol 9-O-beta-D-glucopyranoside), II (cycloartenol), III (beta-amyrin acetate), IV (beta-sitosterol), V (daucosterol), respectively. CONCLUSION: All the compounds were isolated from this plant for the first time.