The interactions between drugs and the parasite surface

Parasitology ◽  
1988 ◽  
Vol 96 (S1) ◽  
pp. S167-S193 ◽  
Author(s):  
L. H. Chappell
Keyword(s):  
Drug Resistance ◽  
Drug Target ◽  
Drug Acquisition ◽  
Drug Action ◽  
Drug Uptake ◽  
Specific Drug ◽  
Permeability Changes ◽  
And Function ◽  
Uptake Mechanisms

SUMMARYThe interrelationships between drugs and parasite surfaces are considered under the headings of (a) effects on membrane transport, (b) drug uptake mechanisms and (c) effects on surface morphology and function: praziquantel is discussed under a separate heading. The range of chemotherapeutic compounds that cause permeability changes and concomitant morphological disruption is discussed in terms of mode of drug action. Interpretation of the available data renders it difficult to identify the primary mode of action in the drugs considered. Drug uptake mechanisms are known for relatively few compounds; drug resistance as a function of drug acquisition is discussed. The role of the parasite surface as a specific drug target is argued.

scholarly journals Current understanding of thalamic structure and function in migraine

Cephalalgia ◽  
2018 ◽  
Vol 39 (13) ◽  
pp. 1675-1682 ◽  
Author(s):  
Samaira Younis ◽  
Anders Hougaard ◽  
Rodrigo Noseda ◽  
Messoud Ashina
Keyword(s):  
Drug Target ◽  
Critical Role ◽  
Structure And Function ◽  
Pain Modulation ◽  
Clinical Implications ◽  
Important Position ◽  
Cortical Regions ◽  
And Function ◽  
Thalamic Structure

Objective To review and discuss the literature on the role of thalamic structure and function in migraine. Discussion The thalamus holds an important position in our understanding of allodynia, central sensitization and photophobia in migraine. Structural and functional findings suggest abnormal functional connectivity between the thalamus and various cortical regions pointing towards an altered pain processing in migraine. Pharmacological nociceptive modulation suggests that the thalamus is a potential drug target. Conclusion A critical role for the thalamus in migraine-related allodynia and photophobia is well established. Additionally, the thalamus is most likely involved in the dysfunctional pain modulation and processing in migraine, but further research is needed to clarify the exact clinical implications of these findings.

scholarly journals Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

2018 ◽  
Vol 19 (8) ◽  
pp. 2256 ◽  
Author(s):  
Antoni Domagala ◽  
Klaudyna Fidyt ◽  
Malgorzata Bobrowicz ◽  
Joanna Stachura ◽  
Kacper Szczygiel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Treatment Resistance ◽  
Metastatic Potential ◽  
Dependent Cell ◽  
And Function

Lysosomes are conservative organelles with an indispensable role in cellular degradation and the recycling of macromolecules. However, in light of recent findings, it has emerged that the role of lysosomes in cancer cells extends far beyond cellular catabolism and includes a variety of cellular pathways, such as proliferation, metastatic potential, and drug resistance. It has been well described that malignant transformation leads to alterations in lysosomal structure and function, which, paradoxically, renders cancer cells more sensitive to lysosomal destabilization. Furthermore, lysosomes are implicated in the regulation and execution of cell death in response to diverse stimuli and it has been shown that lysosome-dependent cell death can be utilized to overcome apoptosis and drug resistance. Thus, the purpose of this review is to characterize the role of lysosome in cancer therapy and to describe how these organelles impact treatment resistance. We summarized the characteristics of typical inducers of lysosomal cell death, which exert its function primarily via alterations in the lysosomal compartment. The review also presents other anticancer agents with the predominant mechanism of action different from lysosomal destabilization, the activity of which is influenced by lysosomal signaling, including classical chemotherapeutics, kinase inhibitors, monoclonal antibodies, as well as photodynamic therapy.

scholarly journals Reviewing HIV-1 Gag Mutations in Protease Inhibitors Resistance: Insights for Possible Novel Gag Inhibitor Designs

2019 ◽  
Author(s):  
Chinh Tran-To Su ◽  
Darius Wen-Shuo Koh ◽  
Samuel Ken-En Gan
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Drug Target ◽  
Treatment Strategies ◽  
Hiv Treatment ◽  
Gag Polyprotein ◽  
Hiv 1 ◽  
New Strategies

HIV treatment strategies against viral enzymes are continuously hampered by viral drug resistance. Recent findings show that viral substrate Gag contributes to HIV-1 Protease Inhibitor (PI) resistance, leading to demands for new strategies in HIV treatment where Gag is recognized as a drug target. To successfully target Gag, there is a need of in-depth understanding of the Gag polyprotein and the effects of Gag mutations. Here, we propose new strategies in designing novel Gag inhibitors against existing and novel emerging Gag mutations via a structural understanding of the Gag-Protease relationship in PI resistance. In this review, we discuss the role of both novel and previously reported mutations, revealing insights to how they aid in PI resistance, and how new Gag inhibitors can be designed.

scholarly journals Chemogenomic profiling of anti-leishmanial efficacy and resistance in the related kinetoplastid parasite Trypanosoma brucei

2019 ◽  
Author(s):  
Clare F Collett ◽  
Carl Kitson ◽  
Nicola Baker ◽  
Heather B. Steele-Stallard ◽  
Marie-Victoire Santrot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Trypanosoma Brucei ◽  
Mode Of Action ◽  
Drug Action ◽  
Drug Uptake ◽  
Screening Tools ◽  
Cross Resistance ◽  
Starting Point ◽  
Kinetoplastid Parasite

AbstractThe arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by toxicity and emergent resistance. Furthermore, our understanding of drug mode-of-action and potential routes to resistance is limited. Forward genetic approaches have revolutionised our understanding of drug mode-of-action in the related kinetoplastid parasite, Trypanosoma brucei. Therefore, we screened our genome-scale T. brucei RNAi library in the current anti-leishmanial drugs, sodium stibogluconate (antimonial), paromomycin, miltefosine and amphotericin-B. Identification of T. brucei orthologues of the known Leishmania antimonial and miltefosine plasma membrane transporters effectively validated our approach, while a cohort of 42 novel drug efficacy determinants provides new insights and serves as a resource. Follow-up analyses revealed the antimonial selectivity of the aquaglyceroporin, TbAQP3. A lysosomal major facilitator superfamily transporter contributes to paromomycin/aminoglycoside efficacy. The vesicle-associated membrane protein, TbVAMP7B, and a flippase contribute to amphotericin-B and miltefosine action, and are potential cross-resistance determinants. Finally, multiple phospholipid-transporting flippases, including the T. brucei orthologue of the Leishmania miltefosine transporter, a putative β-subunit/CDC50 co-factor, and additional membrane-associated hits, affect amphotericin-B efficacy, providing new insights into mechanisms of drug uptake and action. The findings from this orthology-based chemogenomic profiling approach substantially advance our understanding of anti-leishmanial drug action and potential resistance mechanisms, and should facilitate the development of improved therapies, as well as surveillance for drug-resistant parasites.ImportanceLeishmaniasis is a devastating disease caused by the Leishmania parasites and is endemic to a wide swathe of the tropics and sub-tropics. While there are drugs available for the treatment of leishmaniasis, these suffer from various challenges, including the spread of drug resistance. Our understanding of anti-leishmanial drug action and the modes of drug resistance in Leishmania is limited. The development of genetic screening tools in the related parasite, Trypanosoma brucei, has revolutionised our understanding of these processes in this parasite. Therefore, we applied these tools to the anti-leishmanial drugs, identifying T. brucei orthologues of known Leishmania proteins that drive drug uptake, as well as a panel of novel proteins not previously associated with anti-leishmanial drug action. Our findings substantially advance our understanding of anti-leishmanial mode-of-action and provide a valuable starting point for further research.

scholarly journals Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites

Science ◽  
2013 ◽  
Vol 342 (6164) ◽  
pp. 1385-1389 ◽  
Author(s):  
C. L. L. Valentim ◽  
D. Cioli ◽  
F. D. Chevalier ◽  
X. Cao ◽  
A. B. Taylor ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Basis ◽  
Drug Action ◽  
Specific Drug ◽  
Species Specific

scholarly journals The role of polyphenols in overcoming cancer drug resistance: a comprehensive review

2022 ◽  
Vol 27 (1) ◽  
Author(s):  
Parisa Maleki Dana ◽  
Fatemeh Sadoughi ◽  
Zatollah Asemi ◽  
Bahman Yousefi
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Radical Scavenging ◽  
Epigallocatechin Gallate ◽  
Chemotherapeutic Agents ◽  
Drug Uptake ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Glutathione S Transferases

AbstractChemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in different aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efflux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also affect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs).

Scanning electron microscopic study of collagen fibrillogenesis and extracellular compartmentalization in the chick embryo tendon

1986 ◽  
Vol 44 ◽  
pp. 208-209
Author(s):  
Grace C.H. Yang
Keyword(s):  
Chick Embryo ◽  
Extracellular Space ◽  
Fibroblast Cell ◽  
Collagen Fibrils ◽  
Electron Microscopic ◽  
Voltage Electron ◽  
Scanning Electron Microscopic Study ◽  
Microscopic Studies ◽  
And Function

The size and organization of collagen fibrils in the extracellular matrix is an important determinant of tissue structure and function. The synthesis and deposition of collagen involves multiple steps which begin within the cell and continue in the extracellular space. High-voltage electron microscopic studies of the chick embryo cornea and tendon suggested that the extracellular space is compartmentalized by the fibroblasts for the regulation of collagen fibril, bundle, and tissue specific macroaggregate formation. The purpose of this study is to gather direct evidence regarding the association of the fibroblast cell surface with newly formed collagen fibrils, and to define the role of the fibroblast in the control and the precise positioning of collagen fibrils, bundles, and macroaggregates during chick tendon development.

Role of the Cilia Membrane in Control of Microtubule Sliding

1980 ◽  
Vol 38 ◽  
pp. 612-615
Author(s):  
Edna S. Kaneshiro
Keyword(s):  
Control Mechanism ◽  
Beat Frequency ◽  
Surface Membrane ◽  
Ciliary Membrane ◽  
Ciliary Beating ◽  
Ciliary Reversal ◽  
Voltage Dependent ◽  
Reversal Mechanism ◽  
And Function

It is currently believed that ciliary beating results from microtubule sliding which is restricted in regions to cause bending. Cilia beat can be modified to bring about changes in beat frequency, cessation of beat and reversal in beat direction. In ciliated protozoans these modifications which determine swimming behavior have been shown to be related to intracellular (intraciliary) Ca2+ concentrations. The Ca2+ levels are in turn governed by the surface ciliary membrane which exhibits increased Ca2+ conductance (permeability) in response to depolarization. Mutants with altered behaviors have been isolated. Pawn mutants fail to exhibit reversal of the effective stroke of ciliary beat and therefore cannot swim backward. They lack the increased inward Ca2+ current in response to depolarizing stimuli. Both normal and pawn Paramecium made leaky to Ca2+ by Triton extrac¬tion of the surface membrane exhibit backward swimming only in reactivating solutions containing greater than IO-6 M Ca2+ Thus in pawns the ciliary reversal mechanism itself is left operational and only the control mechanism at the membrane is affected. The topographic location of voltage-dependent Ca2+ channels has been identified as a component of the ciliary mem¬brane since the inward Ca2+ conductance response is eliminated by deciliation and the return of the response occurs during cilia regeneration. Since the ciliary membrane has been impli¬cated in the control of Ca2+ levels in the cilium and therefore is the site of at least one kind of control of microtubule sliding, we have focused our attention on understanding the structure and function of the membrane.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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