Pathogens
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2022
·Vol. 11
·期 5
·550
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IF 4.531
Jia-Li Yu,Qing-Yang Liu,Bo Yang,Yi-Fan Sun,Ya-Ju Wang,Jian Jiang,Bo Wang,Yang Cheng,Qiu-Bo Wang
Plasmodium falciparum, mainly distributed in tropical and subtropical regions of the world, has received widespread attention owing to its severity. As a novel protein,P. falciparumsurface-related antigen (PfSRA) has the structural and functional characteristics to be considered as a malaria vaccine candidate; however, limited information is available on its immunogenicity. Here, we expressed three fragments of recombinant PfSRA in anEscherichia colisystem and further analyzed its immunogenicity. The results showed that rPfSRA-immunized mice produced specific antibodies with high endpoint titers (1:10,000 to 1:5,120,000) and affinity antibodies (i.e., rPfSRA-F1a (97.70%), rPfSRA-F2a (69.62%), and rPfSRA-F3a (91.87%)). In addition, the sera of immunized mice recognized both the native PfSRA and recombinant PfSRA, the rPfSRA antibodies inhibited the invasion ofP. falciparuminto the erythrocytes, and they were dose-dependent in vitro. This study confirmed PfSRA could be immunogenic, especially the F1a at the conserved region N-terminal and provided further support for it as a vaccine candidate againstP.falciparum.Keywords:Plasmodium falciparum;surface-related antigen;immunogenicity;invasion inhibition
研究领域:
疟疾
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免疫学
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疫苗开发
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Muhammad Ismail,Longbing Ling,Yawei Du,Chen Yao,Xinsong Li
Artemisinin and its derivatives are highly effective drugs in the treatment of P. falciparum malaria. However, their clinical applications face challenges because of short half-life, poor bioavailability and growing drug resistance. In this article, novel dimeric artesunate phospholipid (Di-ART-GPC) based liposomes were developed by combination of dimerization and self-assembly to address these shortcomings. Firstly, Di-ART-GPC conjugate was synthesized by a facile esterification of artesunate (ART) and glycerophosphorylcholine (GPC) and confirmed by MS , 1 H NMR and 13 C NMR. The conjugate was then assembled to form liposomes without excipient by thin film hydration method. The assembled Di-ART-GPC liposomes have typical multilamellar vesicle structure with bilayer morphology as determined by transmission electron microscopy (TEM) and cryogenic electron microscopy (cryo-EM). Moreover, the liposomes displayed an average hydrodynamic diameter of 190 nm and negative zeta potential at −20.35 mV as determined by Zetasizer. The loading capacity of ART was calculated approximately 77.6% by weight with this liposomal formulation after a simple calculation. In vitro drug release and degradation results showed that the Di-ART-GPC liposomes were stable in neutral physiological conditions but effectively degraded to release parent ART in simulated weakly acidic microenvironment . In vivo pharmacokinetics study revealed that Di-ART-GPC liposomes and conjugate have longer retention half-life in bloodstream. Importantly, Di-ART-GPC liposomes (IC 50 0.39 nM) and the conjugate (IC 50 1.90 nM) demonstrated excellent in vitro antiplasmodial activities without causing hemolysis of erythrocytes, which were superior to free ART (IC 50 5.17 nM) and conventional ART-loaded liposomes (IC 50 3.13 nM). Furthermore, the assembled liposomes resulted in enhanced parasites killing in P. berghei -infected mice in vivo with delayed recrudescence and improved survivability , compared to free ART administration. Based on these encouraging results, Di-ART-GPC liposomal formulation could be a replacement to parent ART in clinical malarial therapy after thorough investigation.
研究领域:
药学
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寄生虫学
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药物递送系统
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药物化学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2023
·
IF 4.3
Lu Junnan,Tong Ying,Dong Rui,Yang Yijun,Hu Wen,Zhang Minghong,Liu Quan,Zhao Siting,Adams John H.,Qin Li,Chen Xiaoping
CRISPR/Cas9 technology applied to Plasmodium falciparum offers the potential to greatly improve gene editing, but such expectations including large DNA fragment knock-ins and sequential gene editing have remained unfulfilled. Here, we achieved a major advance in addressing this challenge, especially for creating large DNA fragment knock-ins and sequential editing, by modifying our suicide-rescue-based system that has already been demonstrated to be highly efficient for conventional gene editing. This improved approach was confirmed to mediate efficient knock-ins of DNA fragments up to 6.3 kb, to produce “marker-free” genetically engineered parasites and to show potential for sequential gene editing. This represents an important advancement in establishing platforms for large-scale genome editing, which might gain a better understanding of gene function for the most lethal cause of malaria and contribute to adjusting synthetic biology strategies to live parasite malaria vaccine development. Site-directed knock-in of large DNA fragments is highly efficient using suicide-rescue-based CRISPR/Cas9 system, and sequential gene insertion is feasible but further confirmation is still needed.
研究领域:
寄生虫学
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分子生物学
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基因组编辑
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DOI
PubMed
高影响因子
TALANTA
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2020
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IF 5.339
Chun-Xia Zhang,Julian A. Tanner,Hong-Wei Li,Yuqing Wu
Specific detection of Plasmodium vivax lactate dehydrogenase (PvLDH), an important biomarker of malaria, remains a significant challenge. Herein, adenosine monophosphate protected gold-silver bimetallic nanoclusters , Au–AgNCs@AMP were used as a specific and sensitive fluorescence probe to detect PvLDH. After optimizing, a linear response was shown over a wide concentration range (10–100 nM) and an extremely low limit of detection (LOD) at 0.10 nM (3.7 ng mL −1 ) was achieved finally. Albeit the method was able to detect PvLDH sensitively, it could not discriminate different types of LDHs . Consequently, Al 3+ was employed as an “assistant agent”, which induced an assay capacity to discriminate PvLDH from other LDHs. The bimetallic nanoclusters inhibited the activity of PvLDH, suggesting it bound near the active site of PvLDH with high affinity. Zeta potential and UV–vis absorption experiments showed that electrostatic interaction was the main driving force for the interaction between the nanoclusters and PvLDH. Through chemical modification it indicated free thiol groups in PvLDH played an implant role in the interaction. Overall, the fluorescence enhancement and blue-shift were attributed to assembly-induced emission enhancement (AIEE) and hydrophobic transfer. The present study provides a simple, robust, and easy-to-perform approach to detect PvLDH with high sensitivity and selectivity, with significant potential for malaria diagnosis in the developing world.
研究领域:
生物化学
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医学诊断
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纳米技术
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DOI
PubMed
高影响因子
Cell Reports
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2021
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IF 9.423
Mengfei Wang,Yanpeng An,Li Gao,Shengzhang Dong,Xiaofeng Zhou,Yuebiao Feng,Penghua Wang,George Dimopoulos,Huiru Tang,Jingwen Wang
Summary Plant-nectar-derived sugar is the major energy source for mosquitoes, but its influence on vector competence for malaria parasites remains unclear. Here, we show that Plasmodium berghei infection of Anopheles stephensi results in global metabolome changes, with the most significant impact on glucose metabolism. Feeding on glucose or trehalose (the main hemolymph sugars) renders the mosquito more susceptible to Plasmodium infection by alkalizing the mosquito midgut. The glucose/trehalose diets promote proliferation of a commensal bacterium, Asaia bogorensis , that remodels glucose metabolism in a way that increases midgut pH, thereby promoting Plasmodium gametogenesis. We also demonstrate that the sugar composition from different natural plant nectars influences A. bogorensis growth, resulting in a greater permissiveness to Plasmodium . Altogether, our results demonstrate that dietary glucose is an important determinant of mosquito vector competency for Plasmodium, further highlighting a key role for mosquito-microbiota interactions in regulating the development of the malaria parasite.
研究领域:
疟疾生物学
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微生物学
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传染病学
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代谢组学
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昆虫学
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DOI
PubMed
高影响因子
Applied Materials Today
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2024
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IF 7.2
Yuxin Zheng,Ning Jiang,Qilong Li,Ruiming Fan,Kexin Zheng,Ziwei Su,Ran Chen,Ying Feng,Yiwei Zhang,Xiaoyu Sang,Qijun Chen
Artemisinin and its derivatives have been widely applied as the most effective drugs in the treatment of malaria since their introduction in the last century. However, challenges such as short half-life, limited bioavailability, and increasing drug resistance have prompted researchers to explore new strategies in the development of antimalarial drugs. In this study, a nano-targeting drug delivery system (HEP@ART@NEs) is developed consisted of heparin as the outer shell and artemisinin in the inner core, utilizing a high-pressure homogenization approach. The specific targeting effect of HEP@ART@NEs is achieved through surface multivalent interactions between heparin with both Plasmodium falciparum merozoites as well as the surface of infected red blood cells (iRBCs). The physical and chemical properties of HEP@ART@NEs, as well as its anti-malarial activity both in vitro and in vivo , are systematically investigated. HEP@ART@NEs demonstrate enhanced antimalarial effects, delay malaria recrudescence, and improve survivability in a rodent model with P. berghei ANKA infection compared to the treatment with conventional artemisinin treatment. Overall, this study indicates that HEP@ART@NEs hold promise as a platform for a rational design of targeted delivery of antimalarial drugs.
研究领域:
药理学
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纳米技术
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传染病
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药物递送系统
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DOI
高影响因子
International Journal of Pharmaceutics-X
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2025
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IF 6.4
Rongrong Wang,Jiaqi Yang,Jihong Qiang,Qingxia Li,Geng Wang,Canqi Ping,Kesheng Liu,Ruili Wang,Bin Zheng,Guolian Ren,Shuqiu Zhang
Although malaria has been effectively controlled, it still poses a threat to global health. Artemisinins are the first-line antimalarial drugs. However, their therapeutic efficacy is significantly limited by poor solubility and short biological half-life. To overcome these limitations and enhance drug accumulation in Plasmodium , we developed a glucose-functionalized redox-responsive dihydroartemisinin (DHA) prodrug nanosystem (D@GLU-PMs-SS). The nanosystem was prepared by using DHA-dithiodipropionic acid-octadecylamine prodrug and D-α-Tocopherol polyethylene glycol 1000 succinate-arbutin conjugate. The resultant D@GLU-PMs-SS exhibited excellent stability under conditions of storage and physiological environment. D@GLU-PMs-SS could be activated by glutathione (GSH), leading to the dissociation of nanoparticles and subsequent release of free DHA. In vitro experiments revealed that the host erythrocyte uptake of glucose-functionalized nanoparticles was significantly enhanced via GLUT-mediated transport. Cellular experiments illustrated that D@GLU-PMs-SS effectively reduced GSH concentrations in Plasmodium . Furthermore, D@GLU-PMs-SS displayed remarkable efficacy in inhibiting the growth of Plasmodium while maintaining biosafety. Overall, this study developed a strategy to enhance the targeting of nanoparticles to improve their therapeutic efficacy against malaria, warranting further investigation in clinical trials.
研究领域:
药剂学
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纳米医学
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抗菌治疗
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Qingxia Li,Rongrong Wang,Shuqi Han,Nan Shi,Jiaqi Yang,Canqi Ping,Liqing Chai,Ruili Wang,Bin Zheng,Guolian Ren,Shuqiu Zhang
Targeted nanodrug delivery systems are highly anticipated for the treatment of malaria. It is known that Plasmodium can induce new permeability pathways (NPPs) on the membrane of infected red blood cells (iRBCs) for their nutrient uptake. The NPPs also enable the uptake of nanoparticles (NPs) smaller than 80 nm. Additionally, Plasmodium maintains a stable, slightly acidic, and reductive internal environment with higher glutathione (GSH) levels. Based on this knowledge, methyl artelinate (MA, a prodrug-like derivative of dihydroartemisinin) nanoparticles (MA-PCL-NPs) were developed using poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) by a thin-film dispersion method and were further coated with polydopamine (PDA) to obtain MA-PCL@PDA-NPs with a particle size of ∼30 nm. The biomaterial PDA can be degraded in slightly acidic and reductive environments, thereby serving as triggers for drug release. MA could generate reactive oxygen species and decrease GSH levels, consequently causing parasite damage. The in vitro release experiment results indicated that the cumulative release percentage of MA from MA-PCL@PDA-NPs was considerably higher in phosphate buffer with 10 mM GSH at pH 5.5 (88.10%) than in phosphate buffer without GSH at pH 7.4 (16.98%). The green fluorescence within iRBCs of coumarin 6, the probe of NPs (C6-PCL@PDA-NPs), could be reduced significantly after adding the NPP inhibitor furosemide (p < 0.001), which demonstrated that MA-PCL@PDA-NPs could be ingested into iRBCs through NPPs. In vivo antimalarial pharmacodynamics in Plasmodium berghei K173-bearing mice showed that the inhibition ratio of MA-PCL@PDA-NPs (93.96%) was significantly higher than that of commercial artesunate injection (AS-Inj, 63.33%). The above results showed that the developed MA-PCL@PDA-NPs possessed pH-GSH dual-responsive drug release characteristics and targeting efficacy for iRBCs, leading to higher antimalarial efficacy against Plasmodium.
研究领域:
药学
·
纳米技术
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寄生虫学
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药物递送系统
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DOI
PubMed
高影响因子
ACTA TROPICA
·
2025
·
IF 2.5
Haoshen Wen,Yawei Li,Jiayi Luo,Wenhe Zhu,Geoff Hide,Xianmin Feng,Zhao-Rong Lun,De-Hua Lai
Malaria is still one of the most important parasitic diseases with millions of cases reported globally every year. Combination therapies of artemisinin or its derivatives, with a partner drug, are the first-and second-line treatments for malaria. However, recently, artemisinin partial resistance or tolerance has emerged and emphasizes the need for new therapeutic approaches to malaria. For example, the encapsulation of artemisinin and its derivatives within nanoparticles offers a highly promising potential approach to improved therapeutic efficacy. In this study, we investigated the effects of this using artesunate, dihydroartemisinin and artemisinin. These drugs were captured in nanoparticles of zinc-based metal-organic frameworks (MOFs) and tested on Plasmodium berghei clearance in a heavy-parasite-load mouse model. Results showed that the dosage of 16 mg/kg artesunate nanoparticles, with three injections over a 24 hr interval, had a significantly improved effect on parasite clearance and combatting the occurrence of hyperparasitaemia (parasitaemia ≥ 5%). However, the same dosage regime, over a 12 hr interval, only delayed the occurrence of hyperparasitaemia. Using a 4-injection regime over 24 hr, both 10mg/kg dihydroartemisinin nanoparticles and artemisinin nanoparticles showed stronger parasite clearance than the control non-encapsulated artemisinin at the same dose. These findings not only pose opportunities for novel malaria therapeutic approaches against hyperparasitaemia but also indicate a bright future for using nanoparticles for drug development in parasitic protozoa.
研究领域:
寄生虫学
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药理学
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纳米技术
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传染病学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Parasites & Vectors
·
2024
·Vol. 17
·期 1
·1-11
·
IF 3
Li Xin,Jiang Ning,Li Qilong,Zheng Kexin,Zhang Yiwei,Sang Xiaoyu,Feng Ying,Chen Ran,Chen Qijun
Background Artemisinin (ART) is a frontline drug for the treatment of malaria; however, the emergence of ART-resistant Plasmodium strains necessitates increasing ART sensitivity. Given that taurine (TAU) has been shown to have immunomodulatory activity, we investigated the effects of TAU as an adjunct therapy to ART in mice infected with Plasmodium berghei . Methods Mice infected with P. berghei ANKA strain ( P. berghei ANKA) were treated with TAU alone, ART alone or a combination of TAU and ART (TAU + ART), and their survival time and parasitaemia were recorded. The cytotoxic effects of TAU and ART were subsequently assessed. The expression levels of inflammasome-related genes and inflammatory factors in mice infected with P. berghei ANKA were analysed in relation to those in mice treated with TAU alone, ART alone or the TAU + ART combination. The therapeutic effects were further evaluated by histological analysis and measurement of the spleen index. Results Compared with the control mice, P. berghei ANKA-infected mice treated with ART in combination with TAU presented significantly lower parasitaemia and prolonged survival. The combined treatment resulted in significant reductions in the expression levels of inflammasome-related genes in the spleen, including absent in melanoma 2 ( AIM2 ), caspase-1, NOD-, LRR- and pyrin domain-containing protein 3 ( Nlrp3 ), Nlrp1b , Nlrp1b , NLR family CARD domain containing 4 ( Nlrc4 ), Nlrp6 , nucleotide binding oligomerization domain containing 1 ( NOD1 ) and NOD2 , and decreases in the levels of inflammatory cytokines in the serum, including interleukin (IL)-12p70, tumour necrosis factor-alpha, monocyte chemoattractant protein-1, IL-10 and IL-6. Histopathological analysis confirmed that TAU + ART combination treatment reduced spleen pathology caused by P. berghei ANKA infection. Conclusions The findings indicate that TAU potentiates ART efficacy by modulating the immune response in P. berghei -infected mice. Graphical
研究领域:
免疫学
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寄生虫学
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药理学
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疟疾研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Hengtong Zuo,Jihong Qiang,Yidan Wang,Rongrong Wang,Geng Wang,Liqing Chai,Guolian Ren,Yongdan Zhao,Guoshun Zhang,Shuqiu Zhang
Targeting delivery and prolonging action duration of artemisinin drugs are effective strategies for improving antimalarial treatment outcomes. Here, dihydroartemisinin (DHA) loaded poly (lactic- co -glycolic acid) (PLGA) nanoparticles (PDNs) were prepared and further cloaked with red blood cell (RBC) membranes via electrostatic interactions to yield RBC membrane-cloaked PDNs (RPDNs). The prepared RPDNs displayed a notable “core-shell” structure, with a negative surface charge of −29.2 ± 4.19 mV, a relatively uniform size distribution (86.4 ± 2.54 nm , polydispersity index of 0.179 ± 0.011), an average encapsulation efficiency (70.1 ± 0.79%), and a 24-h sustained-release behavior in vitro . Compared with PDNs, RPDNs showed markedly decreased phagocytic activity by RAW 264.7 cells and had prolonged blood circulation duration. The Pearson correlation coefficient of RPDNs distribution in infected red blood cells (iRBCs) was 0.7173, suggesting that RPDNs could effectively target Plasmodium -iRBCs. In Py By265-infected mice, RPDNs showed a higher inhibition ratio (88.39 ± 2.69%) than PDNs (83.13 ± 2.12%) or DHA (58.74 ± 3.78%), at the same dose of 8.8 μmol/kg. The ED 90 of RPDNs (8.13 ± 0.18 μmol/kg) was substantially lower than that of PDNs (14.48 ± 0.23 μmol/kg) and DHA (17.67 ± 3.38 μmol/kg). Furthermore, no apparent abnormalities were detected in routine blood examination, liver function indexes, and pathological analysis of tissue sections of Py By265-infected mice following RPDNs treatment. In conclusion, the prepared RPDNs exhibited enhanced antimalarial efficacy, prolonged circulation, targeted delivery to Plasmodium -iRBCs, and satisfactory biocompatibility .
研究领域:
药学
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纳米技术
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疟疾研究
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）