PHYTOMEDICINE
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2025
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IF 8.3
Xin Li,Qilong Li,Ning Jiang,Kexin Zheng,Yiwei Zhang,Xiaoyu Sang,Ying Feng,Ran Chen,Qijun Chen
Background The property of dihydroartemisinin (DHA) in promoting host immunohomeostasis, apart from its potent antimalarial activity, has been well-recognized. However, the mechanism of DHA in activating macrophages to enhance host resistance to malaria remains unexplored. Purpose This study investigated the molecular mechanism by which DHA promotes the polarization of macrophages toward the M1 phenotype during the treatment of malaria. Methods The mouse macrophage cell line RAW 264.7 or the macrophages isolated from mice were stimulated with Plasmodium berghei ANKA infected red blood cells (iRBC) in the presence of DHA. The macrophage phenotypes in both in vivo and in vitro were determined using cytometric bead array and flow cytometry. To dissect the molecular mechanisms underlying macrophage responses to DHA, we initially profiled the expression of 90 genes associated with innate immunity, including the entire NLR family, in macrophages stimulated with DHA. This targeted screen strikingly revealed that only Nlrp12 was significantly upregulated among all tested NLR genes. The function of Nlrp12 was further dissected by Nlrp12 knockdown in macrophages with recombinant lentiviruses encoding Nlrp12 -specific shRNA, within the context of DHA treatment. To comprehensively define the molecular consequences of Nlrp12 deficiency, we performed an integrated analysis by combining single-cell RNA sequencing with label-free quantitative proteomic profiling. This allowed us to systematically characterize the complex transcriptomic and proteomic dynamics in DHA-treated macrophages upon Nlrp12 deletion. Results DHA induced macrophage polarization to M1 phenotype and enhanced phagocytosis by up-regulating the expression of NLRP12. Nlrp12 -knockdown in macrophages reduced the expression of M1 type-associated genes, resulting in a significantly increased expression of the translocator protein (TSPO), which suppressed the secretion of inflammation-associated cytokines and blunting macrophage M1 polarization. The results of single cell RNA sequencing further revealed that DHA promoted the conversion of classical M1 macrophages into lipocalin-2 (Lcn2) high M1 macrophages. Conclusion The activation of NLRP12 induced by DHA is crucial for M1 macrophage polarization, which plays a significant role in the clearance of Plasmodium parasites.
研究领域:
免疫学
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寄生虫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 23
·14903
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IF 6.208
Henan Shi,Zhuqing Wang,Fujie Xu,Jialin Li,Jing Li,Manyuan Wang
In 1972, Nobel laureate Youyou Tu’s research team conducted clinical trials on the dried material ofArtemisia annuaL. from Beijing extracted by ether and then treated with alkali (called “ether neutral dry”), which showed that artemisinin was not the only antimalarial component contained. The biosynthesis of sesquiterpenoids inA. annuahas increased exponentially after unremitting cultivation efforts, and the plant resources are now quite different from those in the 1970s. In consideration of emerging artemisinin resistance, it is of great theoretical and practical value to further study the antimalarial activity ofA. annuaand explore its causes. The purpose of this study is to clarify scientific questions, such as “What ingredients are synergistic with artemisinin inA. annua?”, and “Are there non-artemisinin antimalarial ingredients inA. annua?”. In this paper, Beijing wildA. annuawas used as a control and two representative cultivation species ofA. annuawere selected to evaluate the antimalarial activity of the herbal medicine. The antimalarial activity of different extracts on mice was studied using the Peters’ four-day suppressive test. UPLC-Q-TOF-MS was used to obtain mass spectrum data for all samples, and a UNIFI platform was used for identification. A multivariate statistical method was used to screen the different compounds with positive correlations. The antimalarial activity of different components from the ether extract and alkali treatments was determined and antimalarial components other than artemisinin were obtained. A total of 24 flavonoids, 68 sesquiterpenoids and 21 other compounds were identified. Compounds associated with differential antimalarial activity were identified. The material basis for the antimalarial activity ofA. annuawas clarified. The antimalarial components ofA. annuainclude two categories: first, artemisinin and non-artemisinin antimalarial active components, of which the non-artemisinin antimalarial active components may include 5α-hydroperoxy-eudesma-4(15),11-diene; second, several antimalarial synergistic ingredients inA. annua, including arteanniun B, arteanniun B analogues and polymethoxy flavonoids.Keywords:Artemisia annuaL.;synergistic effect;antimalarial;UPLC-Q-TOF-MS;OPLS-DA
研究领域:
药理学
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代谢组学
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药物化学
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植物科学
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DOI
PubMed
高影响因子
Analytical Methods
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2018
·Vol. 11
·期 1
·88-96
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IF 2.073
Wu Zou,Fuchun Gong,Zhong Cao,Jiaoyun Xia,Tingting Gu,Renxing Deng
Artemisinin (ART) and its derivatives are first-line treatment drugs for falciparum malaria and save millions of lives every year. It is very difficult to design specific fluorescent probes for ART because ART has no groups for binding to except for the peroxide group. We find that alkaline-hydrolyzed ART (a-ART) can specifically recognize and react with vitamin B1 (VB1) and produce fluorimetrically detectable thiochromes. Notably, this chemistry is affected by very low concentrations of a-ART in a Tris–HCl buffer solution (pH 7.5) at room temperature, leading to >260-fold enhancement in the blue emission at 442 nm. By making use of the new signaling mechanism, an effective strategy for detecting ART was developed. The fluorescence intensity of the VB1-based probes linearly increased with increasing ART concentration ranging from 1 to 230 μM mL−1, and a detection limit as low as 11.5 nM mL−1 was achieved, making this method more sensitive than other reported UV-vis absorption and electrochemical methods. Moreover, this assay shows good selectivity over other ions and biomolecules. The proposed method was applied for the determination of ART in tablets and dried leaf samples of Artemisia annua L. with satisfactory results, which confirms its great potential for real sample analysis. The designed assay avoids the preparation of fluorescent probes, and all the detection processes are accomplished within 20 min. Therefore, VB1 can offer a simple, highly sensitive and selective sensing model for fluorescence detection of ART.
研究领域:
药物化学
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分析化学
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生物医学
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DOI
高影响因子
PLoS One
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2025
·Vol. 20
·期 5
·e0322835
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IF 2.6
Fujie Xu,Xiaohang Shan,Jialin Li,Jing Li,Jiqiao Yuan,Daozeng Zou,Manyuan Wang
Artemisinin-based combination therapies (ACTs) constitute the principal strategy for combating malaria in contemporary times, and research into the multifaceted components of Artemisia annua L. ( A. annua ) has garnered widespread interest among scientists. The aim of this study was to prepare A. annua extracts (nACTs) and to explore whether nACTs have higher bioavailability and efficacy than artemisinin (ART) alone due to its multiple bioactive components. Initially, the in vivo antimalarial activity of nACTs was evaluated by two murine malaria models. The results revealed that the antimalarial effect of nACTs was about 10-fold higher than that of ART alone when administered at the same dosage of ART. Then, we analyzed the pharmacokinetic characteristics of nACTs in rat plasma. Remarkably, nACTs exhibited significantly enhanced oral bioavailability, longer half-life as well as extended mean retention time in rats. In addition, the impact of nACTs on P-glycoprotein (P-gp) was evaluated using the Caco-2 cell line. The results showed that both ART and nACTs reduced the efflux rate of the P-gp substrate rhodamine 123 (R123) and induced the expression of P-gp in Caco-2 cells over a range of concentrations. nACTs had certain components-deoxyartemisinin (DEART), artemisinic acid (AA), and dihydroartemisinic acid (DHAA)-that inhibited the efflux and translocation of P-gp and facilitated the reduction of ART efflux. In conclusion, A. annua extracts significantly improved the antimalarial efficacy and bioavailability compared with ART.
研究领域:
药理学
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寄生虫学
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植物化学
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产品关联
DOI
PubMed
高影响因子
Toxins
·
2019
·Vol. 11
·期 7
·379
·
IF 3.895
Yaqun Fang,Xiaoqin He,Pengcheng Zhang,Chuanbin Shen,James Mwangi,Cheng Xu,Guoxiang Mo,Ren Lai,Zhiye Zhang
Antimalarial drug resistance is an enormous global threat. Recently, antimicrobial peptides (AMPs) are emerging as a new source of antimalarials. In this study, an AMP LZ1 derived from snake cathelicidin was identified with antimalarial activity. In the in vitro antiplasmodial assay, LZ1 showed strong suppression of blood stagePlasmodium falciparum(P. falciparum) with an IC50 value of 3.045 μM. In the in vivo antiplasmodial assay, LZ1 exerted a significant antimalarial activity againstPlasmodium berghei(P. berghei) in a dose- and a time- dependent manner. In addition, LZ1 exhibited anti-inflammatory effects and attenuated liver-function impairment duringP. bergheiinfection. Furthermore, by employing inhibitors against glycolysis and oxidative phosphorylation in erythrocytes, LZ1 specifically inhibited adenosine triphosphate (ATP) production in parasite-infected erythrocyte by selectively inhibiting the pyruvate kinase activity. In conclusion, the present study demonstrates that LZ1 is a potential candidate for novel antimalarials development.Keywords:antimicrobial peptide;malaria;cytokine;pyruvate kinase;ATPKey Contribution:This study reports a synthetic peptide derived from the snake cathelicidin, named LZ1. LZ1 shows both in vitro and in vivo antimalarial activity by limiting ATP production in parasite-infected erythrocyte.
研究领域:
药理学
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传染病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
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2022
·Vol. 66
·期 5
·
IF 5.938
Yawei Du,Carlo Giannangelo,Wei He,Gerald J. Shami,Wenya Zhou,Tuo Yang,Darren J. Creek,Con Dogovski,Xinsong Li,Leann Tilley
Current best practice for the treatment of malaria relies on short half-life artemisinins that are failing against emerging Kelch 13 mutant parasite strains. Here, we introduce a liposome-like self-assembly of a dimeric artesunate glycerophosphocholine conjugate (dAPC-S) as an amphiphilic prodrug for the short-lived antimalarial drug, dihydroartemisinin (DHA), with enhanced killing of Kelch 13 mutant artemisinin-resistant parasites. Cryo-electron microscopy (cryoEM) images and the dynamic light scattering (DLS) technique show that dAPC-S typically exhibits a multilamellar liposomal structure with a size distribution similar to that of the liposomes generated using thin-film dispersion (dAPC-L). Liquid chromatography-mass spectrometry (LCMS) was used to monitor the release of DHA. Sustainable release of DHA from dAPC-S and dAPC-L assemblies increased the effective dose and thus efficacy against Kelch 13 mutant artemisinin-resistant parasites in an in vitro assay. To better understand the enhanced killing effect, we investigated processes for deactivation of both the assemblies and DHA, including the roles of serum components and trace levels of iron. Analysis of parasite proteostasis pathways revealed that dAPC assemblies exert their activity via the same mechanism as DHA. We conclude that this easily prepared multilamellar liposome-like dAPC-S with long-acting efficacy shows potential for the treatment of severe and artemisinin-resistant malaria.
研究领域:
药理学
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寄生虫学
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生物化学
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DOI
高影响因子
TALANTA
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2025
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IF 6.1
Tiantian Chen,Qian Xiang,Xuemei Sang,Daxiu Li,Wenjiao zhou,Fengfeng Xu
Malaria remains a significant threat to global health, especially with the emergence of drug-resistant strains. Therefore, precise monitoring of antimalarial drug levels is crucial for assessing and managing drug resistance. Here, we report a multiplex aptasensor that enables simultaneous fluorescence detection of two antimalarial drugs (MQ and PQ) via split dsT7 promoter-mediated transcription of two-color light-up RNA aptamers. The detection mechanism relies on specific binding of target antimalarial drugs (MQ/PQ) to their aptamers, each triggering formation of intact dsT7 promoter to induce amplified transcription of its cognate RNA aptamer. The generated RNA aptamers bind their corresponding organic dyes (TO1-Biotin and MG) with high affinity, yielding 7.7-/25-fold fluorescence enhancement to enable ultrasensitive detection of MQ and PQ with limits of 0.71 ng/mL and 0.069 ng/mL, respectively. The method also exhibits high selectivity and low background signal. Furthermore, this label-free system achieves multiplexed detection of antimalarial drugs in 10-fold diluted human serum (recovery: 98.67–106.84 % for PQ and 99.89–106.19 % for MQ), demonstrating its real utility. This label-free system is adaptable to other biomarkers through aptamer replacement.
研究领域:
生物化学
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分子生物学
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医学诊断
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
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2024
·Vol. 38
·期 23
·e70211
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IF 4.4
Lengshan Mo,Cansheng Hong,Zhihan Jiang,Yiqiang Zhu,Lu Zhou,Simin Tan,Guorong Deng,Yanwei Qi,Tengfei Hu,Qianlian Wu,Yi Zhao,Huaina Qiu,Taizhen Liang,Peibin Lin,Jian Zhang,Xiancai Ma,Quan Yang
Malaria remains a significant global public health problem. T follicular helper (Tfh) cells, a subset of CD4 + T cells, have the capacity to regulate B cells, plasma cells, and antibody production, among other functions. Myeloid-derived suppressor cells (MDSCs) possess strong immunosuppressive abilities and can negatively regulate various immune responses. However, the role of MDSCs in inhibiting Tfh-cell responses during Plasmodium infection remains unclear. In this study, we investigated the regulatory effect of MDSCs on Tfh cell-mediated immune responses upon Plasmodium infection. We found that the numbers of MDSCs increased upon Plasmodium infection. Further mechanism study revealed that MDSC-derived Arg-1 and PD-L1 prevented Tfh cell proliferation and activation. Conversely, the addition of nor-NOHA or anti-PD-L1 monoclonal antibodies enhanced the proliferation and activation of Tfh cells, indicating that the inhibitory effect of MDSCs on Tfh cells was dependent on Arg-1 and PD-1/PD-L1. In vivo depletion of MDSCs enhanced Tfh-cell responses and antibody production, as well as relieved symptoms of infected mice and improved their survival rates. These findings provide insights into the immunosuppressive role of MDSCs in inhibiting Tfh cell immune responses and further impairing humoral immunity. Our study provides new strategies for malaria prevention and control.
研究领域:
免疫学
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寄生虫学
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感染性疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Xuerong Dong,Xiang Zhang,Manyuan Wang,Liwei Gu,Jing Li,Muxin Gong
Heme is a prosthetic group of hemoglobin comprising protoporphyrin IX (PPIX) with Fe 2+ . Studies have shown that modulating heme synthesis pathway in Plasmodium could greatly affect the action mechanism and antimalarial effect of artemisinin and its derivatives. Herein, an intraerythrocytic parasite targeted nanostructured lipid carrier (NLC) was developed for potentiation of artemether (ARM) by combination with PPIX and iron-loaded transferrin (holo-Tf). Firstly, ARM and PPIX were co-loaded into NLCs with high entrapment efficiency. Then, a targeting ligand heparin (HP) was electrostatically adsorbed onto the periphery of NLCs, followed by conjugation with holo-Tf to receive the final formulation Tf-HP-NLC/ARM/PPIX. Tf-HP-NLC/ARM/PPIX exhibited nanoscale particle size (~188 nm) and was relatively stable in simulated gastrointestinal fluids and rat plasma. A sustained drug release characteristic was observed in PBS (pH 7.4). In vitro targeting assay confirmed that Tf-HP-NLC/ARM/PPIX could be specifically and efficiently internalized into intraerythrocytic parasites via HP receptor-meditated endocytosis. Furthermore, due to enhanced intraparasitic accumulation and activated mechanism of ARM, the combinational delivery system Tf-HP-NLC/ARM/PPIX showed increased inhibitory activity against Plasmodium falciparum in culture and enhanced antimalarial effect in Plasmodium berghei -infected murine model, suggesting a promising strategy for development of new therapy based on action mechanism of ARM.
研究领域:
药剂学
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寄生虫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Ji Wang,Wei He,Lei Cheng,Hao Zhang,Yang Wang,Chao Liu,Shuo Dong,Wenhui Zha,Xianghe Kong,Chen Yao,Xinsong Li
Dimeric artesunate phospholipid (ART-GPC), an amphiphilic derivative of artemisinin dimer reported in our previous work, can be applied to treat malaria effectively. The objective of this study is to develop a facile method for the industrial production of ART-GPC liposomes . Conventional methods including thin film hydration (TFH), ethanol injection (EI), and freeze drying (FD) were used to prepare ART-GPC liposomes, and the resultants presented poor physicochemical properties. Fortunately, a modified thin film hydration method (MTFH) by forming thin film of ART-GPC composed of fine lipid bilayer structure in the vials showed promise for the liposomes production. A quality design strategy (solvents, pressure, hydration time, and temperature) was performed to obtain optimal physicochemical characteristics and production conditions. Thereafter, ART-GPC liposomes are produced under GMP conditions with the size of 176.32 nm, PDI of 0.17, zeta potential of −25.79 mV, and osmotic pressure of 297.33 mOsm/kg, confirming the scalability and reproductivity of the MTFH technology. It is the first report that the MTFH method allows liposomes to be preserved in a dry film state and in-situ hydrated in injection vials with excellent performance. Conclusively, the MTFH method is a promising technology for the large-scale production of ART-GPC liposomes.
研究领域:
药剂学
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生物医学工程
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药物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Wei He,Yawei Du,Chuncao Li,Ji Wang,Yang Wang,Con Dogovski,Rui Hu,Zhiyong Tao,Chen Yao,Xinsong Li
Artesunate (ARS) is the only artemisinin-based intravenous drug approved for treatment of malaria in the clinic. ARS is rapidly metabolized in vivo to short lived (∼30–45 min) but fast acting, dihydroartemisinin (DHA). The short half-life of DHA necessitates multiple dose administration to circumvent the risk of recrudescence and development of artemisinin resistance. In this work, we report a stable, safe and potent alternative artemisinin-based injectable nanocomplex consisting of dimeric artesunate-choline conjugate (dACC) micelles coated with hyaluronic acid (HA). Firstly, dACC was synthesized by one-step esterification of two artesunate molecules with 3-(dimethylamino)-1,2-propanediol followed by quaternization. After that, dACC was self-assembled into cationic nanomicelles and further coated with anionic small molecular weight HA. The HA-coated dACC nanocomplex (dACC/HA nanocomplex) has a narrow size distribution of about 30 nm. Hemolytic toxicity and cytotoxicity studies revealed a favorable bio-safety profile. Finally, in vitro and in vivo studies showed the dACC/HA nanocomplex possess superior safety and antimalarial efficacy compared to ARS. Taken together, the dACC/HA nanocomplex is a promising injectable alternative to the traditional clinically used artesunate.
研究领域:
药剂学
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传染病学
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纳米医学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2021
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IF 4.539
Yilin Wu,Rongxin Lin,Faguang Ma,Zhongyi Jiang
Development of membrane-based molecularly imprinted material with rapid rebinding and high-permselectivity performance has become an urgent need in chemical separation and industrial production. Herein, the high-quality membrane-based designs were proposed for the preparation of SiO 2 @polydopamine blended nanocomposite imprinted membranes with hierarchical structure. The high-efficiency antimalarial drug , artemisinin, was used as template molecule during the newly-developed sol-gel artemisinin-imprinted strategy. Importantly in this work, instead of the direct construction of imprinting layers on membranes, the artemisinin-imprinted SiO 2 @polydopamine particles were initially synthesized followed by a phase conversion process to obtain the SPIMs. The SiO 2 -based artemisinin-imprinted polymers on PDA nanospheres would played imprinted-triggered roles for achieving specific artemisinin-imprinted sites. Meanwhile, amount of artemisinin-imprinted cavities and permselectivity were both optimized, high-permselectivity coefficients (more than 11.5), fast adsorption kinetics and enhanced rebinding capacity (45.89 mg g −1 ) could be obtained. That is to say, this new direction of the membrane’s design would become the further design and guide for selective separation membrane materials.
研究领域:
材料科学
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化学工程
·
药学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）