Cardiovascular complications in malaria: a review / 中国中药杂志

Malaria, one of the major global public health events, is a leading cause of mortality and morbidity among children and adults in tropical and subtropical regions(mainly in sub-Saharan Africa), threatening human health. It is well known that malaria can cause various complications including anemia, blackwater fever, cerebral malaria, and kidney damage. Conventionally, cardiac involvement has not been listed as a common reason affecting morbidity and mortality of malaria, which may be related to ignored cases or insufficient diagnosis. However, the serious clinical consequences such as acute coronary syndrome, heart failure, and malignant arrhythmia caused by malaria have aroused great concern. At present, antimalarials are commonly used for treating malaria in clinical practice. However, inappropriate medication can increase the risk of cardiovascular diseases and cause severe consequences. This review summarized the research advances in the cardiovascular complications including acute myocardial infarction, arrhythmia, hypertension, heart failure, and myocarditis in malaria. The possible mechanisms of cardiovascular diseases caused by malaria were systematically expounded from the hypotheses of cell adhesion, inflammation and cytokines, myocardial apoptosis induced by plasmodium toxin, cardiac injury secondary to acute renal failure, and thrombosis. Furthermore, the effects of quinolines, nucleoprotein synthesis inhibitors, and artemisinin and its derivatives on cardiac structure and function were summarized. Compared with the cardiac toxicity of quinolines in antimalarial therapy, the adverse effects of artemisinin-derived drugs on heart have not been reported in clinical studies. More importantly, the artemisinin-derived drugs demonstrate favorable application prospects in the prevention and treatment of cardiovascular diseases, and are expected to play a role in the treatment of malaria patients with cardiovascular diseases. This review provides reference for the prevention and treatment of malaria-related cardiovascular complications as well as the safe application of antimalarials.

Artemisinin-based antimalarial combination therapy amongst healthcare professionals in a tertiary facility in south-south Nigeria: preferences, tolerability, and cost considerations

Background: Nigeria adopted the Artemisinin-Based Combination Therapy (ACT) as the mainstay of treating uncomplicated malaria in February 2005. However, the individual preferences for the use of these medicines by health care professionals (HCP) as distinct from their observed prescribing practices is largely unknown. This study determined the preferences, tolerability and cost of the ACTs among HCP in Benin-City. Methods: This descriptive cross-sectional study was conducted in the University of Benin Teaching Hospital, Benin-City, Nigeria. Consenting HCPs were recruited consecutively for the study. Semi structured questionnaires were administered to doctors, nurses and pharmacists in the hospital. Information obtained included demographics, treatment of malaria in the previous year, antimalarial medication preferences and tolerability as well as cost of ACT. Results: A total of 556 HCPs, 295 doctors (54.1%), nurses 200 (36.0%), pharmacists 61(11.0%) completed the questionnaire. In the previous year, 224 (75.9%) doctors, 153 (79.1%) nurses, and 48 (70.5%) pharmacists had treatment for malaria and self-medication was highest among doctors (228,77.3%). Artemether-Lumenfantrine was the most preferred antimalarial used, 294 (52.8%); however, 1.6% used chloroquine sulphate and ACTs were perceived to be ineffective by 25.4%. Adverse effects were experienced by 167 (29.1%) resulting in 50 (9.0%) discontinuing their medication. Between 500 and 1500 Naira (~US$1-4) was expended on ACT by 66.3% of the staff, while 21.4% were concerned about the high cost of medications. Conclusion: This study highlights the use and preferences, self-medication practices, perceived lack of effectiveness and high cost of ACTs from a HCP perspective. There is an urgent need to address these concerns in view of adverse consequences as well as the likely possibility of its the impact on prescribing practices.

Morphological and skeletal abnormalities induced by α/β arteether on developing chick embryo

Introduction: Malaria continues to be one of the India's leading public health problem.α/β artether is one of the most common antimalarial drug used worldwide to treat chloroquine resistant malaria and malaria falciparum. The present study was designed to assess the teratogenic effects of α/β artether on developing chick embryo. Material and Methods: The study was performed on 300 fertilized eggs of white leg horn chicken.The eggs were divided in to five experimental groups A, B, C, D, E having 30 eggs each and five control groups a,b,c,d,e one each for every experimental group respectively having 30 eggs each. On 5th day of incubation eggs from experimental groups A, B, C, D and E were exposed to α/β artether with dose of 0.00039 mg, 0.000585 mg, 0.00078 mg, 0.00097 mg and 0.00117 mg whereas the control groups were treated with same amount of normal saline. Results: The results showed growth retardation and some significant morphological abnormalities like scanty feathers, subcutaneous hemorrhage and skeletal abnormalities like poor ossification of the bones, kyphosis and lordosis. Discussion: The drug is toxic specially when used in higher dose and for a long period. At present there is no alternative drug available for the treatment of chloroquine resistant malaria and malaria falciparum except α/β artether. Therefore α/β artether and other artemisinins should be used only after establishment of proper diagnosis in recommended dose only not in higher dose and not for a long duration.

The effect of artesunate on the expression of HO-1 induced by ESAT-6/CFP-10 of mycobacterium tuberculosis / 中国医师杂志

Objective To investigate the effect of artesunate (ASN) on the expression of Heme oxygenase-1 (HO-1) in THP-1 cells induced by the early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) antigens of Mycobacterium tuberculosis and to investigate its possible mechanism.Methods THP-1 ceils were cultured in vitro.The effects of ESAT-6 and CFP-10 on cell viability were detected by methyl thiazolyl tetrazolium (MTT) assay.THP-1 cells were pre-treated with or without ASN prior to incubation with or without ESAT-6 and CFP-10,the mRNA expression of HO-1 was detected by real time quantitative polymerase chain reaction (RT-qPCR) and Toll-like receptor 2 (TLR2) level was measured by Western blot.Results MTF assay showed that ESAT-6 and CFP-10 were non-toxic to cells in the range of 0-5 μg/ml.Compared with the control group,5 μg/ml ESAT-6 and 5 μg/ml CFP-10 could significantly increased the mRNA expression of HO-1 (P ＜ 0.05).In addition,20 μg/ml ASN could significantly enhance the mRNA expression of HO-1 induced by ESAT-6 and CFP-10,and inhibit the expression of TLR2 induced by ESAT-6.Conclusions ASN in combination with ESAT-6 or CFP-10,may have potential value in treatment of pathogen-associated inflammatory diseases.

Resistance of Plasmodium falciparum to artemisinin derivatives and piperaquine: Epidemic status and mechanism / 第二军医大学学报

Plasmodium falciparum is one of the main parasitic pathogens worldwide. Artemisinin derivatives are the first-line antimalarial drug. Recently, Plasmodium falciparum has been found to be tolerant to the treatment with artemisinin derivatives and its combination with piperaquine in several countries and regions. Scientists have found gene mutations associated with resistance of Plasmodium falciparum to artemisinin derivatives; however the mechanism of piperaquine resistance remains to be further studied. This review sums up the epidemic status and mechanism research of the resistance of Plasmodium falciparum to artemisinin derivatives and piperaquine.

Mechanism of anti-tumor effect of dihydroartemisinin / 国际肿瘤学杂志

Dihydroartemisinin (DHA),the major active metabolite of artemisinin,participates in tumor progression through the following ways:forming free radicals to induce cancer cells death dependent on iron,inducing apoptosis,inhibiting angiogenesis,tumor cells invasion and metastasis,modulating muhidrug resistance,controlling intracellular Ca2+ concentration,regulating cell cycles,cell autophagy and the immune system and so on.Generally,it is considered to be a potential anti-tumor drug.

Effects of artesunate on rosacea-like inflammation in mouse models / 中华皮肤科杂志

Objective To evaluate effects of artesunate on rosacea-like inflammation in mouse models.Methods Twenty-five male BALB/c mice aged 7 weeks were injected subcutaneously with 40 μ1 antibacterial peptide LL-37 into the back once every 12 hours for 4 sessions to establish mouse models with rosacea-like inflammation.These 25 mice were randomly and equally divided into 5 groups:after each injection of LL-37,model group were gavaged with sodium chloride physiological solution,treatment groups gavaged with 25,50 and 100 mg/kg artesunate solution separately,and positive control group gavaged with 30 mg/kg doxycycline hydrochloride solution.Another 5 healthy mice injected subcutaneously with pure water into the back for 4 sessions served as blank control group.Forty-eight hours after the initial injection of LL-37,changes in skin lesions and the intensity of erythema were assessed.Skin tissues at the dorsal injection site were resected and subjected to HE staining,the tissue structure was observed and the number of inflammatory cells was counted.Enzyme-linked immunosorbent assay (ELISA) was performed to estimate the activity of myeloperoxidase (MPO) in skin lesions.Results The model group showed obvious inflammatory reactions,and significantly increased erythema score (3.20 ± 0.84),inflammatory cell count (517.27 ± 99.43) and MPO activity (0.57 ± 0.08) compared with the blank control group (all P ＜ 0.01).The positive control group showed significantly decreased erythema score (1.60 ± 0.89),inflammatory cell count (270.93 ± 124.63) and MPO activity (0.40 ± 0.05) compared with the model group (P ＜ 0.05,0.01,0.01,respectively).Moreover,the erythema score,inflammatory cell counts and MPO activity were all significantly lower in 50-(1.80 ± 0.84,286.00 ± 33.72,0.43 ± 0.05,respectively) and 100-mg/kg artesunate groups (1.40 ± 0.55,258.00 ± 36.44,0.40 ± 0.06,respectively) than in the model group (P ＜ 0.05 or 0.01).However,there were no significant differences in the erythema score,inflammatory cell count and MPO activity between 50-or 100-mg/kg artesunate group and the positive control group (P ＞ 0.05).Conclusion Artesunate can inhibit rosacea-like inflammatory reactions in mouse models,especially the middle-and high-dose artesunate.

Radiosensitization of artemisinin and its derivatives in tumors / 国际肿瘤学杂志

Artemisinin and its derivative is a kind of efficient,quick and low toxicity of anti-malarial drug.In recent years,we find that artemisinin drugs can not only against malaria,but also have pharmacological effects of immunosuppression,antiviral and anticancer.A number of studies have confirmed that artemisinin and its derivatives have the radiosensitization effects in nasopharyngeal carcinoma,cervical cancer,lung cancer and glioma,and their mechanisms are related to decreasing Weel protein expression,increasing Cyclin B1 protein expression,blocking G2-M phase and cell apoptosis.

Effects of artesunate on interstitial pneumonia and submaxillaritis in MRL/lpr mice / 国际中医中药杂志

Objective To investigate the effects of artesunate (ART) on interstitial pneumonia and sialadenitis in MRL/lpr mice.Methods A total of 18 MRL/lpr mice were randomly allocated to a hydroxychloroquine sulfate (HCQ) group,a ART group and a control group.At the age of 18 weeks,the mice in the HCQ group and ART group were given HCQ 150 mg/kg daily and ART 50 mg/kg daily for 12 weeks,respectively.The histopathological changes of pneumonitis and submaxillaritis were assessed by hematoxylin and eosin staining.The levels of monocyte chemoattractant protein-1 (MCP-1) in the serum and urine were measured by the enzyme-linked immunosorbent assay.Results At the age of 30 weeks,the index of peribronchiolar lesion (1.62 ± 0.19,1.52 ± 0.30 vs.1.95 ± 0.34;all P＜0.05),the index of perivascular lesion (1.23 ± 0.18,1.28 ± 0.12 vs.1.57 ± 0.33;all P＜0.05),the alveolar lesions index (1.35 ± 0.16,1.05 ± 0.15 vs.1.72 ± 0.34;all P＜0.05) and the submaxillaritis index (1.48 ± 0.22,1.43 ± 0.15 vs.1.84 ± 0.34;all P＜0.05) in the HCQ group and the ART group were significantly decreased than those in the control group.The MCP-1 levels in the serum (1 103.02 ± 185.56 pg/ml,1 072.37 ± 242.43 pg/ml vs.1 490.67 ± 329.43 pg/ml;all P＜0.05) and urine (189.16 ± 70.85 pg/ml,198.79 ± 113.47 pg/ml vs.446.79 ± 192.31 pg/ml;all P＜0.05) in the HCQ group and the ART group were significantly lower than those in the control group.Conclusion ART can decrease the MCP-1 level,and ameliorate interstitial pneumonitis and sialadenitis in MRL/lpr mice.

Artemether inhibits proliferation and invasion via the mediation of peroxisome proliferator-activated ;receptor-gamma activation pathway in Lewis lung cancer cells / 国际肿瘤学杂志

mRNA in ARE and GW9662 group were 2.276 ±0.534 and 0.362 ±0.026,respectively.Compared with control group,PPARγmRNA level in both of ARE and GW9662 group reached statistical significance (t =4.785,P =0.001 ;t =2.395,P =0.044).PPARγprotein expression in ARE group,GW9662 +ARE group and control group were 27 688.33 ±3 593.06,21 816.00 ±1 644.07,17 716.33 ±2 273.95,respectively,which was higher in ARE group than that in control and GW+ARE group (t =5.159,P =0.001 ;t =3.038,P =0.016). NF-κB p65 mRNA expression in GW9662 +ARE group was 0.346 ±0.149,which in ARE group and GW9662 group were 0.392 ±0.1 87 and 1 .720 ±0.338,respec-tively.The differences of NF-κB p65 mRNA expression level between ARE,and control or GW9662 group were statistically significant (t =3.592,P =0.007;t =7.851 ,P =0.000).While,the differences of Caspase-3 mRNA and protein expression levels among the four groups were not statistically significant (F =1 .1 81 ,P =0.376;F =0.647,P >0.05).Conclusion ARE may restrain NF-κB through up-regulating PPARγto inhibit the proliferation and invasive potential of LLC in vitro, which suggests that PPAR-γmay be a novel therapeutic target for lung cancer.

Medulative effect of dihydroartemisinin on UCHL1 gene expression in human prostate cancer PC-3 cells and its mechanism / 肿瘤

Objective: To investigate the effect of dihydroartemisinin (DHA) on expression of tumor suppressor gene ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in human prostate cancer cell line PC-3, and explore its regulative mechanism. Methods: PC-3 cells were treated with different concentrations (25, 50, and 100 μmol/L) of DHA for 48 h, while PC-3 cells without DHA treatment were used as the control. Then the apoptosis and cell cycle distribution were detected by flow cytometry. The expressions and cellular locations of DNA methyltransferase 1 (DNMT1) and UCHL1 proteins were detected by immunofluorescence staining. The expression levels of UCHL1, DNMT1, phospho-Akt (p-Akt) and Akt proteins were detected by Western blotting. The 1 μmol/L phosphoinositide-3-kinase (PI3K) inhibitor Wortmanin was used as a positive control to analyze the expression of p-Akt protein in DHA-treated group. Results: DHA significantly induced the apoptosis of PC-3 cells and arrested the cell cycle distribution at phase G2/M as compared with those of the control group (both P 0.05) in the DHA-treated group and the positive control group. The downregulation of p-Akt expression was more obvious in high-concentration of DHA-treated group, much closer to that in the positive control group. Conclusion: DHA can inhibit the expression of DNMT1, restore the function of UCHL1 gene, induce the apoptosis of PC-3 cells, and block the cell cycle progression. These mechanisms may be related to the suppressive activity of PI3K/Akt pathway.

Therapeutic effect of 138 imported falciparum malaria patients / 中国血吸虫病防治杂志

Objectives To summarize the clinical characteristics of imported falciparum malaria patients and the treatment so as to provide the evidences for improving the diagnosis and treatment of the disease. Methods A total of 138 imported falci?parum malaria patients who received the treatment in Shandong Institute of Parasitic Diseases from January 2007 to February 2013 were adopted as the observation subjects and their clinical data were collected and analyzed. Results All the 138 pa?tients were back from African countries. The main manifestations were fever headache asthenia and hepatosplenomegaly and most of them were with decreased RBC PLT levels and increased LDH levels and 36.96%of them were misdiagnosed as respiratory diseases nephritis hepatitis and so on. Through antimalarial treatment of artemether or artesunate or dihydroartemis?inin and primaquine or dihydroartemisinin and piperaquine and symptomatic treatment the short?term and long?term cure rates were 98.55%and 94.93%respectively with 1 case unrecovered and 1 died. Conclusions Artemisinins are still the most effective antimalarial drugs for falciparum malaria. However some patients recrudesce as the Plasmodium in their body is resis?tant or insensitive to these drugs. We should pay more attention to the antimalarial and symptomatic treatments in the early stage of severe malaria so as to improve the cure rate.

Effect of artesunate on OAZ gene expressions in MRL/lpr lupus mice / 中华风湿病学杂志

Objective To investigate the in vivo effects of artesunate (ART) treatment on OAZ gene expressions in MRL/lpr lupus mice.Methods Twenty-four 12-week-old female MRL/lpr lupus mice were randomly divided into two groups by the random number table,i.e.,the lupus control group and the ART treatment group,12 in each group.Besides,another 8 BABL/C mice were recruited as the normal control group.Peripheral blood mononuclear cells (PBMC) were collected from lupus mice before treatment as well as 4 week and 8 week after treatment,and RNA was extracted and reverse transcripted to cDNA.mRNA expression levels of OAZ and Id1-3 were measured by using real-time polymerase chain reaction (PCR),and the data between the two groups were analyzed by t test,a plurality of samples were compared with the single factor analysis of variance.Serum levels of IFN-γ,IL-4,BAFF and ANA were tested by enzyme-linked immunosorbent assay (ELISA).Relationships of the gene expression levels with levels of cytokines and ANA were analyzed.Statistical analysis were uising t test,ANOVA and LSD-t test.Results mRNA expression levels of OAZ,Id1 and Id3 gene (△Ct:12.9±0.8,12.0±0.4,10.2±0.8) in lupus mice were significantly different from 8 weeks after the treatment comparing to those in the lupus control group (△Ct:9.8±1.0,9.3± 1.1,8.1±0.8) and the normal control group (△Ct:13.9±1.2,11.4±0.7,4.7±0.8,10.3±1.0)(F=7.46,P=0.008; F=6.37,P=0.032; F=5.63,P=0.042),and alteration of OAZ mRNA expression levels before and after the treatment were positively correlated with changes of Id1,Id3 levels (r=0.867,0.947; P＜0.05),and levels of IL-4 and ANA were significantly lower 8 weeks after the treatment than those in the lupus control group (P＜0.05); while level of IFN-γwas higher than those in the lupus control group (P＜0.05).Alteration of OAZ mRNA expression levels before and after the treatment were negatively correlated with changes of ANA,BAFF levels (r=-0.955,r=-0.937; P＜0.05) and positively correlated with changes of Th1/Th2 levels (r=0.976,P＜0.01).Conclusion The expression of genes involving in the OAZ and downstream gene are effectively reduced along with the alteration of several cytokines and ANA after ART treatment.OAZ signaling pathway can play an important role in ART treatment for SLE.

Influence and significance of DHA on expression of angiogene-sis-related genes in SGC7901 cells / 中国肿瘤临床

Objective: To investigate the influence and significance of DHA on expression of angiogenesis-related genes in SGC7901 cells. Methods:SGC7901 were treated with DHA (5, 10, 20, 40, and 80μmol/l) for different times (24, 48, and 72 h), and the growth inhibition was detected by MTT. The expression of vascular endothelial growth factor (VEGF-C), cyclooxygenase-2 (COX-2) vascular cell adhesion molecule-1 (VCAM-1), and PTEN mRNA were detected by fluorescence-based quantitative poly-merase chain reaction (qRT-PCR). Their corresponding protein levels were tested by Western blot. Results:DHA significantly inhibited the growth of SGC7901 cells in a dose-and time-dependent manner (P<0.05). The expression of the angiogenesis-related genes signifi-cantly changed, as shown by RT-PCR and Western blot analyses. Compared with the control group, the expressions of VEGF-C, COX-2, and VCAM-1 were down-regulated, whereas the expressions of PTEN were up-regulated, after DHA treatment (P<0.05). Con-clusion:DHA inhibits cell growth in gastric cancer SGC7901 cells. The effect may be due to its reduction of VEGF-C, COX-2, and VCAM-1 gene expression, as well as its promotion of PTEN expression in gastric cancer cells.

Effects of dihydroartiminisin on proliferation and phosphorylation of mitogen-activated protein kinase in epithelial ovarian cancer cell lines / 中华妇产科杂志

Objective To determine the effect of dihydroartiminisin on the proliferation and phosphorylation of mitogen-activated protein kinase (MAPK) in SKOV3 and OVCAR3 ovarian cancer cell lines.Methods Methyl thiazolyl tetrazolium assay was performed to evaluate the anti-proliferative effect of dihydroartiminisin in SKOV3 and OVCAR3 cells,and Western blot was used to determine its effect on phosphorylation level of MAPK,including extra-cell regulated kinase (ERK)1/2 and p38 protein kinase,in the two cell lines.Results Dihydroartiminisin inhibited the proliferation of ovarian cancer cells in vitro,with a mean of 50% inhibition concentration (IC50) at 72 h of (9.0 ±1.4) μmol/L for SKOV3 and (5.5 ±1.2)μmol/L for OVCAR3 respectively. Compared to cells without dihydroartiminisin treatment,phosphorylation level of ERK 1/2 in SKOV3 and OVCAR3 cells treated with dihydroartiminisin decreased by 64.2% and 75.3% respectively (P＜0.05),while phosphorylation of p38 protein kinase in SKOV3 and OVCAR3 only decreased by 8.5% and 6.4% respectively (P ＞0.05).Conclusion Dihydroartiminisin can inhibit the proliferation of ovarian cancer cell in vitro, probably through down-regulation of the phosphorylation of ERK 1/2 in ovarian cancer cells.