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Human antiparasitic drugs

Mandy Juarez, Alejandro Schcolnik-Cabrera, Alfonso Dueñas-Gonzalez
Drug repositioning is a highly studied alternative strategy to discover and develop anticancer drugs. This drug development approach identifies new indications for existing compounds. Ivermectin belongs to the group of avermectins (AVM), a series of 16-membered macrocyclic lactone compounds discovered in 1967, and FDA-approved for human use in 1987. It has been used by millions of people around the world exhibiting a wide margin of clinical safety. In this review, we summarize the in vitro and in vivo evidences demonstrating that ivermectin exerts antitumor effects in different types of cancer...
2018: American Journal of Cancer Research
Susanna S Ng, Fernando Souza-Fonseca-Guimaraes, Fabian de Labastida Rivera, Fiona H Amante, Rajiv Kumar, Yulong Gao, Meru Sheel, Lynette Beattie, Marcela Montes de Oca, Camille Guillerey, Chelsea L Edwards, Rebecca J Faleiro, Teija Frame, Patrick T Bunn, Eric Vivier, Dale I Godfrey, Daniel G Pellicci, J Alejandro Lopez, Katherine T Andrews, Nicholas D Huntington, Mark J Smyth, James McCarthy, Christian R Engwerda
Objectives: Innate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T-bet and the ability to produce IFNγ with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection. Methods: We quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of Pc AS-infected mice...
2018: Clinical & Translational Immunology
Carolina Alves Nicolau, Alyson Prorock, Yongde Bao, Ana Gisele da Costa Neves-Ferreira, Richard Hemmi Valente, Jay William Fox
Snake venoms are sources of molecules with proven and potential therapeutic applications. However, most activities assayed in venoms (or their components) are of hemorrhagic, hypotensive, edematogenic, neurotoxic or myotoxic natures. Thus, other relevant activities might remain unknown. Using functional genomics coupled to the connectivity map (C-map) approach, we undertook a wide range indirect search for biological activities within the venom of the South American pit viper Bothrops jararaca . For that effect, venom was incubated with human breast adenocarcinoma cell line (MCF7) followed by RNA extraction and gene expression analysis...
February 6, 2018: Toxins
Gowtham Subramanian, Meenakshi A Belekar, Anurag Shukla, Jie Xin Tong, Ameya Sinha, Trang T T Chu, Akshay S Kulkarni, Peter R Preiser, D Srinivasa Reddy, Kevin S W Tan, Dhanasekaran Shanmugam, Rajesh Chandramohanadas
The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against Plasmodium falciparum and Toxoplasma gondii, we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage T...
January 2018: MSphere
Bruno Demoro, Santiago Rostán, Mauricio Moncada, Zhu-Hong Li, Roberto Docampo, Claudio Olea Azar, Juan Diego Maya, Julia Torres, Dinorah Gambino, Lucía Otero
To face the high costs of developing new drugs, researchers in both industry and academy are looking for ways to repurpose old drugs for new uses. In this sense, bisphosphonates that are clinically used for bone diseases have been studied as agents against Trypanosoma cruzi, causative parasite of Chagas disease. In this work, the development of first row transition metal complexes (M = Co2+, Mn2+, Ni2+) with the bisphosphonate ibandronate (iba, H4iba representing the neutral form) is presented. The in-solution behavior of the systems containing iba and the selected 3d metal ions was studied by potentiometry...
January 18, 2018: Journal of Biological Inorganic Chemistry: JBIC
Biserka Pigac, Silvija Mašić, Valentina Mašić
Enterobius vermicularis is an intestinal nematode of humans and the most common helminth infection. Main transmission path is direct contact between infected and uninfected person meaning ingestion of the eggs. Human infections are usually asymptomatic or manifest as perianal itching. Although ectopic locations are uncommon, Enterobius can occasionally be detected in appendix, kidney, male urinary tract and female genital tract. We present a case from Varaždin General Hospital, Varaždin, Croatia in 2012, involving a 90-yr-old female patient who underwent hysterectomy leading to accidental finding of E...
October 2017: Iranian Journal of Parasitology
Masoud Ghorbani, Ramin Farhoudi
Leishmania is an obligate intracellular pathogen that invades phagocytic host cells. Approximately 30 different species of Phlebotomine sand flies can transmit this parasite either anthroponotically or zoonotically through their bites. Leishmaniasis affects poor people living around the Mediterranean Basin, East Africa, the Americas, and Southeast Asia. Affected regions are often remote and unstable, with limited resources for treating this disease. Leishmaniasis has been reported as one of the most dangerous neglected tropical diseases, second only to malaria in parasitic causes of death...
2018: Drug Design, Development and Therapy
Sho Nambara, Takaaki Masuda, Miki Nishio, Shotaro Kuramitsu, Taro Tobo, Yushi Ogawa, Qingjiang Hu, Tomohiro Iguchi, Yousuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Keishi Sugimachi, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Akira Suzuki, Koshi Mimori
Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model...
December 8, 2017: Oncotarget
Elżbieta Łopieńska-Biernat, Tomasz Molcan, Łukasz Paukszto, Jan Paweł Jastrzębski, Kamil Myszczyński
The trehalose-6-phosphate phosphatase (TPP) enzyme is involved in the synthesis of trehalose, the main sugar in the energy metabolism of nematodes. TPP is a member of the HAD-like hydrolase superfamily and shows a robust and specific phosphatase activity for the substrate trehalose-6-phosphate. The presence of conserved active sites of TPP in closely related nematodes and its absence in humans makes it a promising target for antiparasitic drugs. In the present study, homology modeling, molecular docking and MD simulation techniques were used to explore the structure and dynamics of TPP...
January 2018: Experimental Parasitology
Rajiv Kumar, Shashi Bhushan Chauhan, Susanna S Ng, Shyam Sundar, Christian R Engwerda
Leishmaniasis encompasses a group of diseases caused by protozoan parasites belonging to the genus Leishmania . These diseases range from life threatening visceral forms to self-healing cutaneous lesions, and each disease manifestations can progress to complications involving dissemination of parasites to skin or mucosal tissue. A feature of leishmaniasis is the key role host immune responses play in disease outcome. T cells are critical for controlling parasite growth. However, they can also contribute to disease onset and progression...
2017: Frontiers in Immunology
Giovanni Benelli
Nanomaterials are currently considered for many biological, biomedical and environmental purposes, due to their outstanding physical and chemical properties. The synthesis of gold nanoparticles (Au NPs) is of high interest for research in parasitology and entomology, since these nanomaterials showed promising applications, ranging from detection techniques to drug development, against a rather wide range of parasites of public health relevance, as well as on insect vectors. Here, I reviewed current knowledge about the bioactivity of Au NPs on selected insect species of public health relevance, including major mosquito vectors, such as Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus...
February 2018: Acta Tropica
Lola V Stamm, Lindsay C Strowd
Infestation with Sarcoptes scabiei var. hominis is a common human parasitic affliction endemic in tropical developing countries. Scabies is transmitted by close person-person contact, and outbreaks have been reported in reception centers for asylum seekers. Scabies presents clinically as extremely pruritic excoriated papules and linear burrows in the skin. This infestation predisposes to bacterial skin infections that can result in serious complications affecting the kidneys and possibly the heart. Treatment of individuals with scabies and their close contacts involves the use of antiparasitic agents...
December 2017: American Journal of Tropical Medicine and Hygiene
Chen Zha, Changlu Wang, Johnathan Michael Sheele
The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae), is a blood-feeding ectoparasite which experienced world-wide resurgence during recent decades. The control of bed bugs is often challenging, due to their cryptic nature and resistance to commonly used insecticides. In this study, we evaluated the effect of the antiparasitic drug moxidectin on bed bug survival, reproduction, and development. The LC50 (lethal concentration to kill half the members of a tested population) of moxidectin against bed bug male adults, female adults, and large nymphs were 52...
September 30, 2017: Insects
Emir Salas-Sarduy, Lionel Urán Landaburu, Joel X Karpiak, Kevin P Madauss, Juan José Cazzulo, Fernán Agüero, Vanina Eder Alvarez
American Trypanosomiasis or Chagas disease is a prevalent, neglected and serious debilitating illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi. The current chemotherapy is limited only to nifurtimox and benznidazole, two drugs that have poor efficacy in the chronic phase and are rather toxic. In this scenario, more efficacious and safer drugs, preferentially acting through a different mechanism of action and directed against novel targets, are particularly welcome. Cruzipain, the main papain-like cysteine peptidase of T...
September 21, 2017: Scientific Reports
David Leitsch
The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia annually cause hundreds of millions of human infections which are treated with antiparasitic drugs. Metronidazole is the most often prescribed drug but also other drugs are in use, and novel drugs with improved characteristics are constantly being developed. One of these novel drugs is auranofin, originally an antirheumatic which has been relabelled for the treatment of parasitic infections. Drug effectivity is arguably the most important criterion for its applicability and is commonly assessed in susceptibility assays using in vitro cultures of a given pathogen...
December 2017: International Journal for Parasitology, Drugs and Drug Resistance
Ernest Moles, Silvia Galiano, Ana Gomes, Miguel Quiliano, Cátia Teixeira, Ignacio Aldana, Paula Gomes, Xavier Fernàndez-Busquets
Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum...
August 15, 2017: Biomaterials
Michiko Kodama, Takahiro Kodama, Justin Y Newberg, Hiroyuki Katayama, Makoto Kobayashi, Samir M Hanash, Kosuke Yoshihara, Zhubo Wei, Jean C Tien, Roberto Rangel, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal G Copeland, Nancy A Jenkins
Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
Gökhan Cildir, Harshita Pant, Angel F Lopez, Vinay Tergaonkar
Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions...
September 4, 2017: Journal of Experimental Medicine
Maria R M de Brito, Walter J Peláez, Martín S Faillace, Gardenia C G Militão, Jackson R G S Almeida, Gustavo A Argüello, Zsolt Szakonyi, Ferenc Fülöp, Maria C Salvadori, Fernanda S Teixeira, Rivelilson M Freitas, Pedro L S Pinto, Ana C Mengarda, Marcos P N Silva, Ademar A Da Silva Filho, Josué de Moraes
Oxazine derivatives, a class of heterocyclic compounds, exhibit a variety of biological properties, such as anticonvulsant and antitumor activities. In this study, we evaluated the effect of two cyclohexene-fused 1,3-oxazines (cis‑1-benzyl-N-phenyl-1,4,4a,5,8,8a-hexahydro-3,1-benzoxazin-2-imine (1) and trans‑N-phenyl-1,4,4a,5,8,8a-hexahydro-3,1-benzoxazin-2-imine (2)) in cultures of Bacillus cereus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Serratia marcescens, Shigella flexneri and Staphylococcus aureus by the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC)...
October 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Carolina P Knubel, Constanza Insfran, Fernando F Martinez, Cintia Diaz Lujan, Ricardo E Fretes, Martin G Theumer, Laura Cervi, Claudia C Motran
The antiparasitic activity of 3-hydroxykynurenine (3-HK), one of the major tryptophan catabolites of the kynurenine pathway, against both Trypanosoma cruzi evolutive forms that are important for human infection, trypomastigotes (Tps) and amastigotes (Am), possible targets in the parasite and the drug toxicity to mammalian cells have been investigated. 3-HK showed a potent activity against Am with IC50 values in the micromolar concentration range, while the IC50 values to cause Tps death was ∼6000-times higher, indicating that the replicative form present in the vertebrate hosts is much more susceptible to 3-HK than bloodstream Tps...
July 13, 2017: ACS Medicinal Chemistry Letters
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