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https://www.readbyqxmd.com/read/29779481/absorptive-and-secretory-transport-of-selected-artemisinin-derivatives-across-caco-2-cell-monolayers
#1
Jaco Heyns, Clarissa Willers, Richard K Haynes, Ho N Wong, Josias H Hamman, Chrisna Gouws
Malaria continues to be a major health concern and affects more than 200 million people a year. Drugs currently used for treatment of malaria are increasingly rendered ineffectual by the ongoing emergence of parasite resistance. For any new drugs, however, knowledge of their membrane permeability is an essential pre-requisite for eventual use. Treatment failure and emergence of resistance can occur as a result of reduced availability of the drug at the desired site of action. Cell-based permeability assays such as Caco-2 cell monolayers serve as a model for predicting drug absorption and efflux, and provide an estimate of drug bioavailability...
May 18, 2018: Current Drug Delivery
https://www.readbyqxmd.com/read/29765991/immune-response-and-evasion-mechanisms-of-plasmodium-falciparum-parasites
#2
REVIEW
Esmael Besufikad Belachew
Malaria causes approximately 212 million cases and 429 thousand deaths annually. Plasmodium falciparum is responsible for the vast majority of deaths (99%) than others. The virulence of P. falciparum is mostly associated with immune response-evading ability. It has different mechanisms to evade both Anopheles mosquito and human host immune responses. Immune-evading mechanisms in mosquito depend mainly on the Pfs47 gene that inhibits Janus kinase-mediated activation. Host complement factor also protects human complement immune attack of extracellular gametes in Anopheles mosquito midgut...
2018: Journal of Immunology Research
https://www.readbyqxmd.com/read/29739485/inhibition-of-ex-vivo-erythropoiesis-by-secreted-and-haemozoin-associated-plasmodium-falciparum-products
#3
Daniela Boehm, Lydia Healy, Sarah Ring, Angus Bell
It has been estimated that up to a third of global malaria deaths may be attributable to malarial anaemia, with children and pregnant women being those most severely affected. An inefficient erythropoietic response to the destruction of both infected and uninfected erythrocytes in infections with Plasmodium spp. contributes significantly to the development and persistence of such anaemia. The underlying mechanisms, which could involve both direct inhibition of erythropoiesis by parasite-derived factors and indirect inhibition as a result of modulation of the immune response, remain poorly understood...
May 9, 2018: Parasitology
https://www.readbyqxmd.com/read/29718775/multiple-e-pharmacophore-modelling-pooled-with-high-throughput-virtual-screening-docking-and-molecular-dynamics-simulations-to-discover-potential-inhibitors-of-plasmodium-falciparum-lactate-dehydrogenase-pfldh
#4
Shalini Saxena, Laxman Durgam, Lalitha Guruprasad
Development of new antimalarial drugs continues to be of huge importance because of the resistance of malarial parasite towards currently used drugs. Due to the reliance of parasite on glycolysis for energy generation, glycolytic enzymes have played important role as potential targets for the development of new drugs. Plasmodium falciparum lactate dehydrogenase (PfLDH) is a key enzyme for energy generation of malarial parasites and is considered to be a potential antimalarial target. Presently, there are nearly 15 crystal structures bound with inhibitors and substrate that are available in the protein data bank (PDB)...
May 2, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29703587/the-genome-of-artemisia-annua-provides-insight-into-the-evolution-of-asteraceae-family-and-artemisinin-biosynthesis
#5
Qian Shen, Lida Zhang, Zhihua Liao, Shengyue Wang, Tingxiang Yan, Pu Shi, Meng Liu, Xueqing Fu, Qifang Pan, Yuliang Wang, Zongyou Lv, Xu Lu, Fangyuan Zhang, Weimin Jiang, Yanan Ma, Minghui Chen, Xiaolong Hao, Ling Li, Yueli Tang, Gang Lv, Yan Zhou, Xiaofen Sun, Peter E Brodelius, Jocelyn K C Rose, Kexuan Tang
Artemisia annua, commonly known as sweet wormwood or Qinghao, is a shrub native to China and has long been used for medicinal purposes. A. annua is now cultivated globally as the only natural source of a potent anti-malarial compound, artemisinin. Here, we report a high-quality draft assembly of the 1.74-gigabase genome of A. annua, which is highly heterozygous, rich in repetitive sequences, and contains 63 226 protein-coding genes, one of the largest numbers among the sequenced plant species. We found that, as one of a few sequenced genomes in the Asteraceae, the A...
April 20, 2018: Molecular Plant
https://www.readbyqxmd.com/read/29697785/host-parasite-interactions-and-ecology-of-the-malaria-parasite-a-bioinformatics-approach
#6
Dariusz Izak, Joanna Klim, Szymon Kaczanowski
Malaria remains one of the highest mortality infectious diseases. Malaria is caused by parasites from the genus Plasmodium. Most deaths are caused by infections involving Plasmodium falciparum, which has a complex life cycle. Malaria parasites are extremely well adapted for interactions with their host and their host's immune system and are able to suppress the human immune system, erase immunological memory and rapidly alter exposed antigens. Owing to this rapid evolution, parasites develop drug resistance and express novel forms of antigenic proteins that are not recognized by the host immune system...
April 25, 2018: Briefings in Functional Genomics
https://www.readbyqxmd.com/read/29692251/the-anti-malarial-drug-artesunate-blocks-wnt-%C3%AE-catenin-pathway-and-inhibits-growth-migration-and-invasion-of-uveal-melanoma-cells
#7
Lei Zheng, Jingxuan Pan
BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. So far, there have been no effective targeted therapeutic agents in patients with uveal melanoma. Artesunate is a semi-synthetic derivative of artemisinin extracted from traditional Chinese medicine Artemisia annua L for treatment of severe and multidrug-resistant malaria. Besides its anti-malarial activity, artesunate is identified as an anti-cancer drug due to the inhibition of Wnt/b-catenin pathway in multiple types of cancer...
April 25, 2018: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/29674705/children-with-cerebral-malaria-or-severe-malarial-anaemia-lack-immunity-to-distinct-variant-surface-antigen-subsets
#8
Mark A Travassos, Amadou Niangaly, Jason A Bailey, Amed Ouattara, Drissa Coulibaly, Kirsten E Lyke, Matthew B Laurens, Jozelyn Pablo, Algis Jasinskas, Rie Nakajima, Andrea A Berry, Matthew Adams, Christopher G Jacob, Andrew Pike, Shannon Takala-Harrison, Li Liang, Bourema Kouriba, Abdoulaye K Kone, J Alexandra Rowe, JoAnn Moulds, Dapa A Diallo, Ogobara K Doumbo, Mahamadou A Thera, Philip L Felgner, Christopher V Plowe
Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or "lacunae", in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls...
April 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29669282/an-unusual-prohibitin-regulates-malaria-parasite-mitochondrial-membrane-potential
#9
Joachim Michael Matz, Christian Goosmann, Kai Matuschewski, Taco Wilhelmus Antonius Kooij
Proteins of the stomatin/prohibitin/flotillin/HfIK/C (SPFH) family are membrane-anchored and perform diverse cellular functions in different organelles. Here, we investigate the SPFH proteins of the murine malaria model parasite Plasmodium berghei, the conserved prohibitin 1, prohibitin 2, and stomatin-like protein and an unusual prohibitin-like protein (PHBL). The SPFH proteins localize to the parasite mitochondrion. While the conserved family members could not be deleted from the Plasmodium genome, PHBL was successfully ablated, resulting in impaired parasite fitness and attenuated virulence in the mammalian host...
April 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/29664138/characterization-of-the-catalytic-subunits-of-the-rna-exosome-like-complex-in-plasmodium-falciparum
#10
Ning Jiang, Shengchao Yu, Na Yang, Ying Feng, Xiaoyu Sang, Yao Wang, Mats Wahlgren, Qijun Chen
The eukaryotic ribonucleic acid (RNA) exosome is a versatile multi-ribonuclease complex that mediates the processing, surveillance and degradation of virtually all classes of RNA in both the nucleus and cytoplasm. The complex, composed of ten to eleven subunits, has been widely described in many organisms. Bioinformatic analyses revealed that there may be also an exosome-like complex in Plasmodium falciparum, a parasite of great importance in public health, with eight predicted subunits having high sequence similarity to their counterparts in yeast and human...
April 17, 2018: Journal of Eukaryotic Microbiology
https://www.readbyqxmd.com/read/29626096/the-mitochondrial-ribosomal-protein-l13-is-critical-for-the-structural-and-functional-integrity-of-the-mitochondrion-in-plasmodium-falciparum
#11
Hangjun Ke, Swati Dass, Joanne M Morrisey, Michael W Mather, Akhil B Vaidya
The phylum Apicomplexa contains a group of protozoan causing diseases in humans and livestock. Plasmodium spp. , the causative agent of malaria, contains a mitochondrion that is very divergent from that of their hosts. The malarial mitochondrion is a clinically validated target for the antimalarial drug atovaquone, which specifically blocks the electron transfer activity of the bc1 complex of the mitochondrial electron transport chain (mtETC). Most mtETC proteins are nuclear-encoded and imported from the cytosol, but three key protein subunits are encoded in the Plasmodium mitochondrial genome: cyt b, COXI, and COXIII...
April 6, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29578710/chemogenomic-profiling-of-human-and-microbial-fk506-binding-proteins
#12
Sebastian Pomplun, Claudia Sippel, Andreas Hähle, Donald Tay, Kensuke Shima, Alina Klages, Can Murat Ünal, Benedikt Rieß, Hui Ting Toh, Guido Hansen, Ho Sup Yoon, Andreas Bracher, Peter Rainer Preiser, Jan Rupp, Michael Steinert, Felix Hausch
FK506-binding proteins (FKBPs) are evolutionary conserved proteins that display peptidyl-prolyl isomerase activity and act as co-receptors for immunosuppressants. Microbial macrophage infectivity potentiator (Mip) type FKBPs can enhance infectivity. However, developing drug-like ligands for FKBPs or Mips has proven difficult and many FKBPs/Mips still lack a biologically useful ligand. To explore the scope and potential of C5-substituted-[4.3.1]-aza-bicyclic sulfonamides as a broadly applicable class of FKBP inhibitors, we developed a new synthesis for the bicyclic core scaffold and used it to prepare a FKBP/Mip-focused library...
March 26, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29578406/neurovascular-sequestration-in-paediatric-p-falciparum-malaria-is-visible-clinically-in-the-retina
#13
Valentina Barrera, Ian Jc MacCormick, Gabriela Czanner, Paul Stephenson Hiscott, Valerie Ann White, Alister G Craig, Nicholas Alexander Venton Beare, Lucy Hazel Culshaw, Yalin Zheng, Simon Charles Biddolph, Danny A Milner, Steve Kamiza, Malcolm E Molyneux, Terrie E Taylor, Simon Peter Harding
Retinal vessel changes and retinal whitening, distinctive features of malarial retinopathy, can be directly observed during routine eye examination in children with P.falciparum cerebral malaria. We investigated their clinical significance and underlying mechanisms through linked clinical, clinicopathological and image analysis studies. Orange vessels and severe foveal whitening (clinical examination, n=817, OR, 95% CI: 2.90, 1.96-4.30; 3.4, 1.8-6.3, both p<0.001), and arteriolar involvement by intravascular filling defects (angiographic image analysis, n=260, 2...
March 26, 2018: ELife
https://www.readbyqxmd.com/read/29566695/cerebrospinal-fluid-plasmodium-falciparum-histidine-rich-protein-2-in-pediatric-cerebral-malaria
#14
Kiran T Thakur, Jimmy Vareta, Kathryn A Carson, Samuel Kampondeni, Michael J Potchen, Gretchen L Birbeck, Ian MacCormick, Terrie Taylor, David J Sullivan, Karl B Seydel
BACKGROUND: Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM. METHODS: Patients included in the study were admitted (2009-2013) to the Pediatric Research Ward (Queen Elizabeth Central Hospital, Blantyre, Malawi) meeting World Health Organization criteria for CM with findings of malarial retinopathy...
March 23, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29559198/new-phenylaniline-derivatives-as-modulators-of-amyloid-protein-precursor-metabolism
#15
Marion Gay, Pascal Carato, Mathilde Coevoet, Nicolas Renault, Paul-Emmanuel Larchanché, Amélie Barczyk, Saïd Yous, Luc Buée, Nicolas Sergeant, Patricia Melnyk
The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques...
March 12, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29552677/mechanistic-studies-of-1-deoxy-d-xylulose-5-phosphate-synthase-from-deinococcus-radiodurans
#16
Sumit Handa, Daniel R Dempsey, Divya Ramamoorthy, Nanci Cook, Wayne C Guida, Tyler J Spradling, Justin K White, H Lee Woodcock, David J Merkler
The non-mevalonate dependent (NMVA) pathway for the biosynthesis of isopentenyl pyrophosphate and dimethylallyl pyrophosphate is the sole source of these terpenoids for the production of isoprenoids in the apicomplexan parasites, in many eubacteria, and in plants. The absence of this pathway in higher organisms has opened a new platform for the development of novel antibiotics and anti-malarials. The enzyme catalyzing the first step of the NMVA pathway is 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). DXPS catalyzes the thiamine pyrophosphate- and Mg (II)-dependent conjugation of pyruvate and D-glyceraldehyde-3-phosphate to form 1-deoxy-D-xylulose-5-phosphate and CO2 ...
2018: Biochemistry & Molecular Biology Journal
https://www.readbyqxmd.com/read/29530046/the-d113n-mutation-in-the-ring-e3-ubiquitin-protein-ligase-gene-is-not-associated-with-ex-vivo-susceptibility-to-common-anti-malarial-drugs-in-african-plasmodium-falciparum-isolates
#17
Mathieu Gendrot, Francis Tsombeng Foguim, Marie Gladys Robert, Rémy Amalvict, Joel Mosnier, Nicolas Benoit, Marylin Madamet, Bruno Pradines
BACKGROUND: Plasmodium falciparum resistance to artemisinin-based combination therapy has emerged and spread in Southeast Asia. In areas where artemisinin resistance is emerging, the efficacy of combination is now based on partner drugs. In this context, the identification of novel markers of resistance is essential to monitor the emergence and spread of resistance to these partner drugs. The ubiquitylation pathway could be a possible target for anti-malarial compounds and might be involved in resistance...
March 12, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29529207/host-cell-cytosolic-immune-response-during-plasmodium-liver-stage-development
#18
Carolina Agop-Nersesian, Livia Niklaus, Rahel Wacker, Volker Heussler
Recent years have witnessed a great gain in knowledge regarding parasite-host cell interactions during Plasmodium liver stage development. It is now an accepted fact that a large percentage of sporozoite invading a hepatocyte fail to form infectious merozoites. There appears to be a delicate balance between parasite survival and elimination and we now start to understand why this is so. Plasmodium liver stages replicate within the parasitophorous vacuole (PV), formed during invasion by invagination of the host cell plasma membrane...
February 26, 2018: FEMS Microbiology Reviews
https://www.readbyqxmd.com/read/29499522/the-social-role-of-c-reactive-protein-point-of-care-testing-to-guide-antibiotic-prescription-in-northern-thailand
#19
Marco J Haenssgen, Nutcha Charoenboon, Thomas Althaus, Rachel C Greer, Daranee Intralawan, Yoel Lubell
New and affordable point-of-care testing (POCT) solutions are hoped to guide antibiotic prescription and to help limit antimicrobial resistance (AMR)-especially in low- and middle-income countries where resource constraints often prevent extensive diagnostic testing. Anthropological and sociological research has illuminated the role and impact of rapid point-of-care malaria testing. This paper expands our knowledge about the social implications of non-malarial POCT, using the case study of a C-reactive-protein point-of-care testing (CRP POCT) clinical trial with febrile patients at primary-care-level health centres in Chiang Rai province, northern Thailand...
April 2018: Social Science & Medicine
https://www.readbyqxmd.com/read/29458365/temporal-changes-in-genetic-diversity-of-msp-1-msp-2-and-msp-3-in-plasmodium-falciparum-isolates-from-grande-comore-island-after-introduction-of-act
#20
Bo Huang, Fei Tuo, Yuan Liang, Wanting Wu, Guangchao Wu, Shiguang Huang, Qirun Zhong, Xin-Zhuan Su, Hongying Zhang, Mingqiang Li, Affane Bacar, Kamal Said Abdallah, Ahamada M S A Mliva, Qi Wang, Zhaoli Yang, Shaoqin Zheng, Qin Xu, Jianping Song, Changsheng Deng
BACKGROUND: Malaria is still one of the serious public health problems in Grande Comore Island, although the number of annual cases has been greatly reduced in recent years. A better understanding of malaria parasite population diversity and transmission dynamics is critical for assessing the effectiveness of malaria control measures. The objective of this study is to investigate temporal changes in genetic diversity of Plasmodium falciparum populations and multiplicity of infection (MOI) in Grande Comore 10 years after introduction of ACT...
February 20, 2018: Malaria Journal
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