Recent Advances in Nanosystems and Strategies for Managing Leishmaniasis

Vaghela, Rudra; Kulkarni, Parthasarathi K.; Osmani, Riyaz Ali M.; Bhosale, Rohit R.; Varma, V. Naga Sravan Kumar

doi:10.2174/1389450117666160401124133

Cited by 15 publications

(6 citation statements)

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“…The fact that PK11195 exhibited therapeutic effect only at higher concentrations may be explained by the hydrophobicity of PK11195, which is known to bind other proteins, such as alpha-1-acidglycoprotein, which it binds with a high affinity ( Lockhart et al 2003 ), and albumin, which it binds with low affinity ( Dougherty et al 2002 , Lockhart et al 2003 ). Our current findings and previous report ( Lockhart et al 2003 ) support the notion that PK11195 must be employed at relatively high concentrations or be associated with a delivery system ( Vaghela et al 2017 ) to exert therapeutic effects ( Tanimoto et al 1999 ).…”

Section: Discussionsupporting

confidence: 88%

In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

Guedes

Dias

Petersen

et al. 2018

Mem. Inst. Oswaldo Cruz

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BACKGROUNDLeishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO) levels are reduced in Leishmania amazonensis-infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for Leishmania chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent.OBJECTIVETo evaluate the leishmanicidal activity of PK11195 against L. amazonensis in infected CBA mouse macrophages in vitro.METHODSThe viability of axenic L. amazonensis, Leishmania major, and Leishmania braziliensis promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 µM). Additionally, intracellular parasite viability was evaluated to determine IC50 values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 µM). Infected macrophages were then treated with PK11195 (25-100 µM) to determine the percentage of L. amazonensis-infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro-inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-γ.FINDINGSMedian IC50 values for PK11195 were 14.2 µM for L. amazonensis, 8.2 µM for L. major, and 3.5 µM for L. braziliensis. The selective index value for L. amazonensis was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron microscopy revealed some morphological alterations suggestive of autophagy. Interestingly, MCP-1 and superoxide levels were reduced in L. amazonensis-infected macrophages treated with PK11195.MAIN CONCLUSIONSPK11195 causes the killing of amastigotes in vitro by mechanisms independent of inflammatory mediators and causes morphological alterations within Leishmania parasites, suggestive of autophagy, at doses that are non-toxic to macrophages. Thus, this molecule has demonstrated potential as an anti-leishmanial agent.

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Section: Discussionsupporting

confidence: 88%

In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

Guedes

Dias

Petersen

et al. 2018

Mem. Inst. Oswaldo Cruz

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“…Highly motile metacyclic promastigotes invade host macrophages and differentiate into the amastigote form, which is highly adapted for intracellular survival. [ 2 ] Current treatments for leishmaniasis (reviewed in [ 3 , 4 ]) are unsatisfactory due to high associated toxicity, cost, complex administration and the emergence of resistant strains. Efforts have greatly increased over the last decade to identify novel compounds with anti-leishmanial properties, or to repurpose existing drugs to widen the therapeutic options for this disease.…”

Section: Introductionmentioning

confidence: 99%

Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays

et al. 2018

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The protozoan parasite Leishmania causes leishmaniasis; a spectrum of diseases of which there are an estimated 1 million new cases each year. Current treatments are toxic, expensive, difficult to administer, and resistance to them is emerging. New therapeutics are urgently needed, however, screening the infective amastigote form of the parasite is challenging. Only certain species can be differentiated into axenic amastigotes, and compound activity against these does not always correlate with efficacy against the parasite in its intracellular niche. Methods used to assess compound efficacy on intracellular amastigotes often rely on microscopy-based assays. These are laborious, require specialist equipment and can only determine parasite burden, not parasite viability. We have addressed this clear need in the anti-leishmanial drug discovery process by producing a transgenic L. mexicana cell line that expresses the luciferase NanoLuc-PEST. We tested the sensitivity and versatility of this transgenic strain, in comparison with strains expressing NanoLuc and the red-shifted firefly luciferase. We then compared the NanoLuc-PEST luciferase to the current methods in both axenic and intramacrophage amastigotes following treatment with a supralethal dose of Amphotericin B. NanoLuc-PEST was a more dynamic indicator of cell viability due to its high turnover rate and high signal:background ratio. This, coupled with its sensitivity in the intramacrophage assay, led us to validate the NanoLuc-PEST expressing cell line using the MMV Pathogen Box in a two-step process: i) identify hits against axenic amastigotes, ii) screen these hits using our bioluminescence-based intramacrophage assay. The data obtained from this highlights the potential of compounds active against M. tuberculosis to be re-purposed for use against Leishmania. Our transgenic L. mexicana cell line is therefore a highly sensitive and dynamic system suitable for Leishmania drug discovery in axenic and intramacrophage amastigote models.

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“…At this meditation, the IONPs-SI-MPA nano systems werecapable to shrink the excretion of human interleukin 2 and lump necrosis factor-α, specifying the stimulus of immune cells. Even though the 10-fold lower MPA stream when equaled to other revisions, this nano systemsstimulated a similar value in cytokine up-regulation [91]. 3.…”

Section: Drugs Bounds To Ionpsmentioning

confidence: 75%

Iron oxide nanoparticles approaching to eradicate her2-positive breast cancer

Kumar

Sagar³

et al. 2022

ijhs

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Background: Breast cancer is the second foremostreason for death in femalesuniversal. The enormously fast level of metastasis and capability to growconfrontationmethods to all the unoriginalmedications make them self-sameproblematic to indulgence which the reasons for in elevation morbidity and mortality are of breast melanoma patients. Expertsall through the world have been directing on the firstdiscovery of breast lump so that conduct can be started at the very primary stage. Furthermore, conventional treatment methods such as chemotherapy, radiotherapy, and local surgical treatmentsmart from innumerablerestrictions including toxicity, genetic mutation of normal cells, and spreading of cancer cells to healthy tissues. Therefore, new treatment schedules with low toxicity to usual cells need to be immediatelyadvanced. Methods: Iron oxide nanoparticles have remainedextensively used for targeting hyperthermia and imaging of breast growth cells. They can be conjugated with drugs, proteins, enzymes, antibodies, or nucleotides to bring them to target organs, tissues, or tumors using an external magnetic field. Results: Iron oxide nanoparticles have remainedpositively used as theranosticscauses for breast malignancy both in vitro and in vivo. Besides, their functions with medications or functional biomolecules increase their drug delivery efficiency and decrease the systemic noxiousness of drugs.

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Recent Advances in Nanosystems and Strategies for Managing Leishmaniasis

Abstract: The reported miscellaneous novel drug delivery systems along with the diverse approaches are seem to be precise, secure and relatively effective; and in an outcome, could lead to the new track for management of leishmaniasis.

Cited by 15 publications

References 0 publications

In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays

Iron oxide nanoparticles approaching to eradicate her2-positive breast cancer

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