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    Novel Anti-Acanthamoebic Activities of Irosustat and STX140 and Their Nanoformulations
    (Mdpi, 2023) Siddiqui, Ruqaiyyah; Rawas-Qalaji, Mutasem; El-Gamal, Mohammed I.; Sajeev, Sreedevi; Jagal, Jayalakshmi; Zaraei, Seyed-Omar; Sbenati, Rawan M.
    Pathogenic Acanthamoeba produce keratitis and fatal granulomatous amoebic encephalitis. Treatment remains problematic and often ineffective, suggesting the need for the discovery of novel compounds. For the first time, here we evaluated the effects of the anticancer drugs Irosustat and STX140 alone, as well as their nanoformulations, against A. castellanii via amoebicidal, excystment, cytopathogenicity, and cytotoxicity assays. Nanoformulations of the compounds were successfully synthesized with high encapsulation efficiency of 94% and 82% for Irosustat and STX140, respectively. Nanoparticles formed were spherical in shape and had a unimodal narrow particle size distribution, mean of 145 and 244 nm with a polydispersity index of 0.3, and surface charge of -14 and -15 mV, respectively. Irosustat and STX140 exhibited a biphasic release profile with almost 100% drug released after 48 h. Notably, Irosustat significantly inhibited A. castellanii viability and amoebae-mediated cytopathogenicity and inhibited the phenotypic transformation of amoebae cysts into the trophozoite form, however their nanoformulations depicted limited effects against amoebae but exhibited minimal cytotoxicity when tested against human cells using lactate dehydrogenase release assays. Accordingly, both compounds have potential for further studies, with the hope of discovering novel anti-Acanthamoeba compounds, and potentially developing targeted therapy against infections of the central nervous system.
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    Novel anti-Acanthamoebic properties of raloxifene sulfonate/sulfamate derivatives
    (Elsevier, 2023) Siddiqui, Ruqaiyyah; El-Gamal, Mohammed I.; Sajeev, Sreedevi; Zaraei, Seyed-Omar; Khan, Naveed Ahmed
    Acanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of these amoebae to switch phenotypes, from an active trophozoite to a resistant cyst form is not well understood; the cyst stage is often resistant to chemotherapy, which is of concern given the rise of contact lens use and the ineffective disinfectants available, versus the cyst stage. Herein, for the first time, a range of raloxifene sulfonate/sulfamate derivatives which target nucleotide pyrophosphatase/phosphodiesterase enzymes, were assessed using amoebicidal and excystation tests versus the trophozoite and cyst stage of Acanthamoeba. Moreover, the potential for cytopathogenicity inhibition in amoebae was assessed. Each of the derivatives showed considerable anti-amoebic activity as well as the ability to suppress phenotypic switching (except for compound 1a). Selected raloxifene derivatives reduced Acanthamoeba-medi-ated host cell damage using lactate dehydrogenase assay. These findings suggest that pyrophosphatase/phosphodiesterase enzymes may be valuable targets against Acanthamoeba infections.
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    The potential of nanocomposites (patuletin-conjugated with gallic acid-coated zinc oxide) against free-living amoebae pathogens
    (Springer science and business media deutschland GmbH, 2024) Siddiqui, Ruqaiyyah; Khatoon, Bushra; Kawish, Muhammad; Sajeev, Sreedevi; Faizi, Shaheen; Shah, Muhammad Raza; Alharbi, Ahmad M.; Khan, Naveed Ahmed
    Free-living amoebae infections are on the rise while the prognosis remains poor. Current therapies are ineffective, and there is a need for novel effective drugs which can target Naegleria, Balamuthia, and Acanthamoeba species. In this study, we determined the effects of a nano-formulation based on flavonoid patuletin-loaded gallic acid functionalized zinc oxide nanoparticles (PA-GA-ZnO) against Acanthamoeba, Balamuthia, and Naegleria trophozoites. Characterization of the nano-formulation was accomplished utilizing analytical tools, namely Fourier-transform infrared spectroscopy, drug entrapment efficiency, polydispersity index, dimensions, and surface morphologies. Anti-amoebic effects were investigated using amoebicidal assay, cytopathogenicity assay, and cytotoxicity of the nano-formulation on human cells. The findings revealed that nano-formulation (PA-GA-ZnO) displayed significant anti-amoebic properties and augmented effects of patuletin alone against all three brain-eating amoebae. When tested alone, patuletin nano-formulations showed minimal toxicity effects against human cells. In summary, the nano-formulations evaluated herein depicts efficacy versus Acanthamoeba, Balamuthia, and Naegleria. Nonetheless, future studies are needed to comprehend the molecular mechanisms of patuletin nano-formulations versus free-living amoebae pathogens, in addition to animal studies to determine their potential value for clinical applications.