Use of a non-hepatic cell line highlights limitations associated with cell-based assessment of metabolically induced toxicity:
- Weyers, Carli, Dingle, Laura M K, Wilhelmi, Brendan S, Edkins, Adrienne L, Veale, Clinton G L
- Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
- Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
- Full Text:
- Date Issued: 2020
- Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
- Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
- Full Text:
- Date Issued: 2020
Theiler’s murine encephalomyelitis virus infection induces a redistribution of heat shock proteins 70 and 90 in BHK-21 cells, and is inhibited by novobiocin and geldanamycin:
- Mutsvunguma, Lorraine Z, Moetlhoa, Boitumelo, Edkins, Adrienne L, Luke, Garry A, Blatch, Gregory L, Knox, Caroline M
- Authors: Mutsvunguma, Lorraine Z , Moetlhoa, Boitumelo , Edkins, Adrienne L , Luke, Garry A , Blatch, Gregory L , Knox, Caroline M
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165085 , vital:41207 , DOI: 10.1007/s12192-011-0262-x
- Description: Theiler’s murine encephalomyelitis virus (TMEV) is a positive-sense RNA virus belonging to the Cardiovirus genus in the family Picornaviridae. In addition to other host cellular factors and pathways, picornaviruses utilise heat shock proteins (Hsps) to facilitate their propagation in cells. This study investigated the localisation of Hsps 70 and 90 in TMEV-infected BHK-21 cells by indirect immunofluorescence and confocal microscopy. The effect of Hsp90 inhibitors novobiocin (Nov) and geldanamycin (GA) on the development of cytopathic effect (CPE) induced by infection was also examined. Hsp90 staining was uniformly distributed in the cytoplasm of uninfected cells but was found concentrated in the perinuclear region during late infection where it overlapped with the signal for non-structural protein 2C within the viral replication complex.
- Full Text:
- Date Issued: 2011
- Authors: Mutsvunguma, Lorraine Z , Moetlhoa, Boitumelo , Edkins, Adrienne L , Luke, Garry A , Blatch, Gregory L , Knox, Caroline M
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165085 , vital:41207 , DOI: 10.1007/s12192-011-0262-x
- Description: Theiler’s murine encephalomyelitis virus (TMEV) is a positive-sense RNA virus belonging to the Cardiovirus genus in the family Picornaviridae. In addition to other host cellular factors and pathways, picornaviruses utilise heat shock proteins (Hsps) to facilitate their propagation in cells. This study investigated the localisation of Hsps 70 and 90 in TMEV-infected BHK-21 cells by indirect immunofluorescence and confocal microscopy. The effect of Hsp90 inhibitors novobiocin (Nov) and geldanamycin (GA) on the development of cytopathic effect (CPE) induced by infection was also examined. Hsp90 staining was uniformly distributed in the cytoplasm of uninfected cells but was found concentrated in the perinuclear region during late infection where it overlapped with the signal for non-structural protein 2C within the viral replication complex.
- Full Text:
- Date Issued: 2011
The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells:
- Aliwaini, Saeb, Peres, Jade, Kröger, Wendy L, Blanckenberg, Angelique, de la Mare, Jo-Anne, Edkins, Adrienne L, Mapolie, Selwyn, Prince, Sharon
- Authors: Aliwaini, Saeb , Peres, Jade , Kröger, Wendy L , Blanckenberg, Angelique , de la Mare, Jo-Anne , Edkins, Adrienne L , Mapolie, Selwyn , Prince, Sharon
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164874 , vital:41180 , DOI: 10.1016/j.canlet.2014.11.027
- Description: Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.
- Full Text:
- Date Issued: 2015
- Authors: Aliwaini, Saeb , Peres, Jade , Kröger, Wendy L , Blanckenberg, Angelique , de la Mare, Jo-Anne , Edkins, Adrienne L , Mapolie, Selwyn , Prince, Sharon
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164874 , vital:41180 , DOI: 10.1016/j.canlet.2014.11.027
- Description: Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.
- Full Text:
- Date Issued: 2015
The networking of chaperones by co-chaperones: control of cellular protein homeostasis
- Edkins, Adrienne L, Blatch, Gregory L
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165107 , vital:41209 , ISBN 978-3-319-11731-7
- Description: Co-chaperones are important mediators of the outcome of chaperone assisted protein homeostasis, which is a dynamic balance between the integrated processes of protein folding, degradation and translocation. The Networking of Chaperones by Co-chaperones describes how the function of the major molecular chaperones is regulated by a cohort of diverse non-client proteins, known as co-chaperones. The second edition includes the current status of the field and descriptions of a number of novel co-chaperones that have been recently identified. This new edition has a strong focus on the role of co-chaperones in human disease and as putative drug targets. The book will be a resource for both newcomers and established researchers in the field of cell stress and chaperones, as well as those interested in cross-cutting disciplines such as cellular networks and systems biology.
- Full Text:
- Date Issued: 2014
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165107 , vital:41209 , ISBN 978-3-319-11731-7
- Description: Co-chaperones are important mediators of the outcome of chaperone assisted protein homeostasis, which is a dynamic balance between the integrated processes of protein folding, degradation and translocation. The Networking of Chaperones by Co-chaperones describes how the function of the major molecular chaperones is regulated by a cohort of diverse non-client proteins, known as co-chaperones. The second edition includes the current status of the field and descriptions of a number of novel co-chaperones that have been recently identified. This new edition has a strong focus on the role of co-chaperones in human disease and as putative drug targets. The book will be a resource for both newcomers and established researchers in the field of cell stress and chaperones, as well as those interested in cross-cutting disciplines such as cellular networks and systems biology.
- Full Text:
- Date Issued: 2014
The in vitro antiplasmodial and antiproliferative activity of new ferrocene-based α-aminocresols targeting hemozoin inhibition and DNA interaction:
- Mbaba, Mziyanda, Dingle, Laura M K, Swart, Tarryn, Cash, Devon, Laming, Dustin, de la Mare, Jo-Anne, Taylor, Dale, Hoppe, Heinrich C, Biot, Christophe, Edkins, Adrienne L, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
- Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
- Full Text:
- Date Issued: 2020
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
- Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
- Full Text:
- Date Issued: 2020
The African coelacanth genome provides insights into tetrapod evolution:
- Amemiya, Chris T, Alföldi, Jessica, Lee, Alison P, Fan, Shaohua, Philippe, Herve´, MacCallum, Iain, Braasch, Ingo, Manousaki, Tereza, Schneider, Igor, Rohner, Nicolas, Organ, Chris, Chalopin, Domitille, Smith, Jeramiah J, Robinson, Mark, Dorrington, Rosemary A, Gerdol, Marco, Aken, Bronwen, Biscotti, Maria Assunta, Barucca, Marco, Baurain, Denis, Berlin, Aaron, Blatch, Gregory L, Buonocore, Francesco, Burmester, Thorsten, Campbell, Michael S, Canapa, Adriana, Cannon, John P, Christoffels, Alan, De Moro, Gianluca, Edkins, Adrienne L, Fan, Lin, Fausto, Anna Maria, Feiner, Nathalie, Forconi, Mariko, Gamieldien, Junaid, Gnerre, Sante, Gnirke, Andreas, Goldstone, Jared V, Haerty, Wilfried, Hahn, Mark E, Hesse, Uljana, Hoffmann, Steve, Johnson, Jeremy, Karchner, Sibel I, Kuraku, Shigehiro, Lara, Marcia, Levin, Joshua Z, Litman, Gary W, Mauceli, Evan, Miyake, Tsutomu, Mueller, M Gail, Nelson, David R, Nitsche, Anne, Olmo, Ettore, Ota, Tatsuya, Pallavicini, Alberto, Panji, Sumir, Picone, Barbara, Ponting, Chris P, Prohaska, Sonja J, Przybylski, Dariusz, Ratan Saha, Nil, Ravi, Vydianathan, Ribeiro, Filipe J, Sauka-Spengler, Tatjana, Scapigliati, Giuseppe, Searle, Stephen M J, Sharpe, Ted, Simakov, Oleg, Stadler, Peter F, Stegeman, John J, Sumiyama, Kenta, Tabbaa, Diana, Tafer, Hakim, Turner-Maier, Jason, van Heusden, Peter, White, Simon, Williams, Louise, Yandell, Mark, Brinkmann, Henner, Volff, Jean-Nicolas, Tabin, Clifford J, Shubin, Neil, Schartl, Manfred, Jaffe, David B, Postlethwait, John H, Venkatesh, Byrappa, Di Palma, Frederica, Lander, Eric S, Meyer, Axel, Lindblad-Toh, Kerstin
- Authors: Amemiya, Chris T , Alföldi, Jessica , Lee, Alison P , Fan, Shaohua , Philippe, Herve´ , MacCallum, Iain , Braasch, Ingo , Manousaki, Tereza , Schneider, Igor , Rohner, Nicolas , Organ, Chris , Chalopin, Domitille , Smith, Jeramiah J , Robinson, Mark , Dorrington, Rosemary A , Gerdol, Marco , Aken, Bronwen , Biscotti, Maria Assunta , Barucca, Marco , Baurain, Denis , Berlin, Aaron , Blatch, Gregory L , Buonocore, Francesco , Burmester, Thorsten , Campbell, Michael S , Canapa, Adriana , Cannon, John P , Christoffels, Alan , De Moro, Gianluca , Edkins, Adrienne L , Fan, Lin , Fausto, Anna Maria , Feiner, Nathalie , Forconi, Mariko , Gamieldien, Junaid , Gnerre, Sante , Gnirke, Andreas , Goldstone, Jared V , Haerty, Wilfried , Hahn, Mark E , Hesse, Uljana , Hoffmann, Steve , Johnson, Jeremy , Karchner, Sibel I , Kuraku, Shigehiro , Lara, Marcia , Levin, Joshua Z , Litman, Gary W , Mauceli, Evan , Miyake, Tsutomu , Mueller, M Gail , Nelson, David R , Nitsche, Anne , Olmo, Ettore , Ota, Tatsuya , Pallavicini, Alberto , Panji, Sumir , Picone, Barbara , Ponting, Chris P , Prohaska, Sonja J , Przybylski, Dariusz , Ratan Saha, Nil , Ravi, Vydianathan , Ribeiro, Filipe J , Sauka-Spengler, Tatjana , Scapigliati, Giuseppe , Searle, Stephen M J , Sharpe, Ted , Simakov, Oleg , Stadler, Peter F , Stegeman, John J , Sumiyama, Kenta , Tabbaa, Diana , Tafer, Hakim , Turner-Maier, Jason , van Heusden, Peter , White, Simon , Williams, Louise , Yandell, Mark , Brinkmann, Henner , Volff, Jean-Nicolas , Tabin, Clifford J , Shubin, Neil , Schartl, Manfred , Jaffe, David B , Postlethwait, John H , Venkatesh, Byrappa , Di Palma, Frederica , Lander, Eric S , Meyer, Axel , Lindblad-Toh, Kerstin
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165030 , vital:41202 , DOI: 10.1038/nature12027
- Description: The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
- Full Text:
- Date Issued: 2013
- Authors: Amemiya, Chris T , Alföldi, Jessica , Lee, Alison P , Fan, Shaohua , Philippe, Herve´ , MacCallum, Iain , Braasch, Ingo , Manousaki, Tereza , Schneider, Igor , Rohner, Nicolas , Organ, Chris , Chalopin, Domitille , Smith, Jeramiah J , Robinson, Mark , Dorrington, Rosemary A , Gerdol, Marco , Aken, Bronwen , Biscotti, Maria Assunta , Barucca, Marco , Baurain, Denis , Berlin, Aaron , Blatch, Gregory L , Buonocore, Francesco , Burmester, Thorsten , Campbell, Michael S , Canapa, Adriana , Cannon, John P , Christoffels, Alan , De Moro, Gianluca , Edkins, Adrienne L , Fan, Lin , Fausto, Anna Maria , Feiner, Nathalie , Forconi, Mariko , Gamieldien, Junaid , Gnerre, Sante , Gnirke, Andreas , Goldstone, Jared V , Haerty, Wilfried , Hahn, Mark E , Hesse, Uljana , Hoffmann, Steve , Johnson, Jeremy , Karchner, Sibel I , Kuraku, Shigehiro , Lara, Marcia , Levin, Joshua Z , Litman, Gary W , Mauceli, Evan , Miyake, Tsutomu , Mueller, M Gail , Nelson, David R , Nitsche, Anne , Olmo, Ettore , Ota, Tatsuya , Pallavicini, Alberto , Panji, Sumir , Picone, Barbara , Ponting, Chris P , Prohaska, Sonja J , Przybylski, Dariusz , Ratan Saha, Nil , Ravi, Vydianathan , Ribeiro, Filipe J , Sauka-Spengler, Tatjana , Scapigliati, Giuseppe , Searle, Stephen M J , Sharpe, Ted , Simakov, Oleg , Stadler, Peter F , Stegeman, John J , Sumiyama, Kenta , Tabbaa, Diana , Tafer, Hakim , Turner-Maier, Jason , van Heusden, Peter , White, Simon , Williams, Louise , Yandell, Mark , Brinkmann, Henner , Volff, Jean-Nicolas , Tabin, Clifford J , Shubin, Neil , Schartl, Manfred , Jaffe, David B , Postlethwait, John H , Venkatesh, Byrappa , Di Palma, Frederica , Lander, Eric S , Meyer, Axel , Lindblad-Toh, Kerstin
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165030 , vital:41202 , DOI: 10.1038/nature12027
- Description: The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
- Full Text:
- Date Issued: 2013
Targeting conserved pathways as a strategy for novel drug development: disabling the cellular stress response:
- Edkins, Adrienne L, Blatch, Gregory L
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165129 , vital:41211 , ISBN 978-3-642-28174-7 , DOI: 10.1007/978-3-642-28175-4_4
- Description: The ability to respond to and cope with stress at a molecular level is essential for cell survival. The stress response is conserved across organisms by the expression of a group of molecular chaperones known as heat shock proteins (HSP). HSP are ubiquitous and highly conserved proteins that regulate cellular protein homeostasis and trafficking under physiological and stressful conditions, including diseases such as cancer and malaria. HSP are good drug targets for the treatment of human diseases, as the significant functional and structural data available suggest that they are essential for cell survival and that, despite conservation across species, there are biophysical and biochemical differences between HSP in normal and disease states that allow HSP to be selectively targeted. In this chapter, we review the international status of this area of research and highlight progress by us and other African researchers towards the characterisation and targeting of HSP from humans and parasites from Plasmodium and Trypanosoma as drug targets.
- Full Text:
- Date Issued: 2012
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165129 , vital:41211 , ISBN 978-3-642-28174-7 , DOI: 10.1007/978-3-642-28175-4_4
- Description: The ability to respond to and cope with stress at a molecular level is essential for cell survival. The stress response is conserved across organisms by the expression of a group of molecular chaperones known as heat shock proteins (HSP). HSP are ubiquitous and highly conserved proteins that regulate cellular protein homeostasis and trafficking under physiological and stressful conditions, including diseases such as cancer and malaria. HSP are good drug targets for the treatment of human diseases, as the significant functional and structural data available suggest that they are essential for cell survival and that, despite conservation across species, there are biophysical and biochemical differences between HSP in normal and disease states that allow HSP to be selectively targeted. In this chapter, we review the international status of this area of research and highlight progress by us and other African researchers towards the characterisation and targeting of HSP from humans and parasites from Plasmodium and Trypanosoma as drug targets.
- Full Text:
- Date Issued: 2012
Synthetic, characterization and cytotoxic studies of ruthenium complexes with Schiff bases encompassing biologically relevant moieties:
- Maikoo, Sanam, Dingle, Laura M K, Chakraborty, Abir, Xulu, Bheki, Edkins, Adrienne L, Booysen, Irvin N
- Authors: Maikoo, Sanam , Dingle, Laura M K , Chakraborty, Abir , Xulu, Bheki , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165429 , vital:41243 , https://doi.org/10.1016/j.poly.2020.114569
- Description: This research study describes the formation and characterization of novel paramagnetic ruthenium complexes, cis-Cl, trans-P-[RuIIICl2(carboim)(PPh3)2] with bidentate chelating carbohydrazide Schiff bases (carboim = bpc for 1, ttc for 2 and tpc for 3). These metal complexes were synthesized by the equimolar coordination reactions of trans-[RuCl2(PPh3)2] with N-[1,3-benzothiazole-2-ylmethylidene]pyridine-2-carbohydrazide (Hbpc), N-((uracil-5-yl)methylene)thiophene-2-carbohydrazide (Httc) and N-[(uracil-5-yl)methylidene]pyridine-2-carbohydrazide (Htpc), respectively. Physicochemical techniques including nuclear magnetic resonance-, electron-spin resonance- and infrared spectroscopy, UV–Vis spectrophotometry, voltammetry as well as molar conductivity measurements provided definitive determinations of the respective ruthenium compounds’ structures.
- Full Text:
- Date Issued: 2020
- Authors: Maikoo, Sanam , Dingle, Laura M K , Chakraborty, Abir , Xulu, Bheki , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165429 , vital:41243 , https://doi.org/10.1016/j.poly.2020.114569
- Description: This research study describes the formation and characterization of novel paramagnetic ruthenium complexes, cis-Cl, trans-P-[RuIIICl2(carboim)(PPh3)2] with bidentate chelating carbohydrazide Schiff bases (carboim = bpc for 1, ttc for 2 and tpc for 3). These metal complexes were synthesized by the equimolar coordination reactions of trans-[RuCl2(PPh3)2] with N-[1,3-benzothiazole-2-ylmethylidene]pyridine-2-carbohydrazide (Hbpc), N-((uracil-5-yl)methylene)thiophene-2-carbohydrazide (Httc) and N-[(uracil-5-yl)methylidene]pyridine-2-carbohydrazide (Htpc), respectively. Physicochemical techniques including nuclear magnetic resonance-, electron-spin resonance- and infrared spectroscopy, UV–Vis spectrophotometry, voltammetry as well as molar conductivity measurements provided definitive determinations of the respective ruthenium compounds’ structures.
- Full Text:
- Date Issued: 2020
Synthesis and evaluation of substituted 4-(N-benzylamino)cinnamate esters as potential anti-cancer agents and HIV-1 integrase inhibitors
- Faridoon, H, Edkins, Adrienne L, Isaacs, Michelle, Mnkandhla, Dumisani, Hoppe, Heinrich C, Kaye, Perry T
- Authors: Faridoon, H , Edkins, Adrienne L , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66289 , vital:28929 , https://doi.org/10.1016/j.bmcl.2016.05.023
- Description: publisher version , Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50 ⩾ 3.0 μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50 ⩾ 9.6 μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
- Full Text: false
- Date Issued: 2016
- Authors: Faridoon, H , Edkins, Adrienne L , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66289 , vital:28929 , https://doi.org/10.1016/j.bmcl.2016.05.023
- Description: publisher version , Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50 ⩾ 3.0 μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50 ⩾ 9.6 μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
- Full Text: false
- Date Issued: 2016
STIP1/HOP regulates the actin cytoskeleton through interactions with actin and changes in actin-binding proteins cofilin and profilin:
- Beckley, Samantha Joy, Hunter, Morgan C, Kituyi, Sarah N, Wingate, Ianthe, Chakraborty, Abantika, Schwarz, Kelly, Makhubu, Matodzi P, Rousseau, Robert P, Ruck, Duncan K, de la Mare, Jo-Anne, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
- Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
- Full Text:
- Date Issued: 2020
- Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
- Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
- Full Text:
- Date Issued: 2020
STAT3 interacts directly with Hsp90:
- Prinsloo, Earl, Kramer, Adam H, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Prinsloo, Earl , Kramer, Adam H , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165142 , vital:41212 , DOI: 10.1002/iub.607
- Description: Heat shock protein 90 (Hsp90) functionally modulates signal transduction. The signal transducer and activator of transcription 3 (STAT3) mediates interleukin‐6 family cytokine signaling. Aberrant activation and mutation of STAT3 is associated with oncogenesis and immune disorders, respectively. Hsp90 and STAT3 have previously been shown to colocalize and coimmunoprecipitate in common complexes.
- Full Text:
- Date Issued: 2012
- Authors: Prinsloo, Earl , Kramer, Adam H , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165142 , vital:41212 , DOI: 10.1002/iub.607
- Description: Heat shock protein 90 (Hsp90) functionally modulates signal transduction. The signal transducer and activator of transcription 3 (STAT3) mediates interleukin‐6 family cytokine signaling. Aberrant activation and mutation of STAT3 is associated with oncogenesis and immune disorders, respectively. Hsp90 and STAT3 have previously been shown to colocalize and coimmunoprecipitate in common complexes.
- Full Text:
- Date Issued: 2012
Sequence and domain conservation of the coelacanth Hsp40 and Hsp90 chaperones suggests conservation of function
- Tastan Bishop, Özlem, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Tastan Bishop, Özlem , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/126932 , vital:35936 , https://doi.10.1002/jez.b.22541
- Description: Molecular chaperones and their associated co‐chaperones play an important role in preserving and regulating the active conformational state of cellular proteins. The chaperone complement of the Indonesian Coelacanth, Latimeria menadoensis, was elucidated using transcriptomic sequences. Heat shock protein 90 (Hsp90) and heat shock protein 40 (Hsp40) chaperones, and associated cochaperones were focused on, and homologous human sequences were used to search the sequence databases. Coelacanth homologs of the cytosolic, mitochondrial and endoplasmic reticulum (ER) homologs of human Hsp90 were identified, as well as all of the major co‐chaperones of the cytosolic isoform. Most of the human Hsp40s were found to have coelacanth homologs, and the data suggested that all of the chaperone machinery for protein folding at the ribosome, protein translocation to cellular compartments such as the ER and protein degradation were conserved. Some interesting similarities and differences were identified when interrogating human, mouse, and zebrafish homologs. For example, DnaJB13 is predicted to be a non‐functional Hsp40 in humans, mouse, and zebrafish due to a corrupted histidine‐proline‐aspartic acid (HPD) motif, while the coelacanth homolog has an intact HPD. These and other comparisons enabled important functional and evolutionary questions to be posed for future experimental studies.
- Full Text:
- Date Issued: 2014
- Authors: Tastan Bishop, Özlem , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/126932 , vital:35936 , https://doi.10.1002/jez.b.22541
- Description: Molecular chaperones and their associated co‐chaperones play an important role in preserving and regulating the active conformational state of cellular proteins. The chaperone complement of the Indonesian Coelacanth, Latimeria menadoensis, was elucidated using transcriptomic sequences. Heat shock protein 90 (Hsp90) and heat shock protein 40 (Hsp40) chaperones, and associated cochaperones were focused on, and homologous human sequences were used to search the sequence databases. Coelacanth homologs of the cytosolic, mitochondrial and endoplasmic reticulum (ER) homologs of human Hsp90 were identified, as well as all of the major co‐chaperones of the cytosolic isoform. Most of the human Hsp40s were found to have coelacanth homologs, and the data suggested that all of the chaperone machinery for protein folding at the ribosome, protein translocation to cellular compartments such as the ER and protein degradation were conserved. Some interesting similarities and differences were identified when interrogating human, mouse, and zebrafish homologs. For example, DnaJB13 is predicted to be a non‐functional Hsp40 in humans, mouse, and zebrafish due to a corrupted histidine‐proline‐aspartic acid (HPD) motif, while the coelacanth homolog has an intact HPD. These and other comparisons enabled important functional and evolutionary questions to be posed for future experimental studies.
- Full Text:
- Date Issued: 2014
Semi-synthesis and evaluation of sargahydroquinoic acid derivatives as potential antimalarial agents:
- Munedzimwe, Tatenda C, van Zyl, Rovyn L, Heslop, Donovan C, Edkins, Adrienne L, Beukes, Denzil R
- Authors: Munedzimwe, Tatenda C , van Zyl, Rovyn L , Heslop, Donovan C , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163456 , vital:41040 , DOI: 10.3390/medicines6020047
- Description: Malaria continues to present a major health problem, especially in developing countries. The development of new antimalarial drugs to counter drug resistance and ensure a steady supply of new treatment options is therefore an important area of research. Meroditerpenes have previously been shown to exhibit antiplasmodial activity against a chloroquinone sensitive strain of Plasmodium falciparum (D10). In this study we explored the antiplasmodial activity of several semi-synthetic analogs of sargahydroquinoic acid.
- Full Text:
- Date Issued: 2019
- Authors: Munedzimwe, Tatenda C , van Zyl, Rovyn L , Heslop, Donovan C , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163456 , vital:41040 , DOI: 10.3390/medicines6020047
- Description: Malaria continues to present a major health problem, especially in developing countries. The development of new antimalarial drugs to counter drug resistance and ensure a steady supply of new treatment options is therefore an important area of research. Meroditerpenes have previously been shown to exhibit antiplasmodial activity against a chloroquinone sensitive strain of Plasmodium falciparum (D10). In this study we explored the antiplasmodial activity of several semi-synthetic analogs of sargahydroquinoic acid.
- Full Text:
- Date Issued: 2019
SDF-1 and PDGF enhance αvβ5-mediated ERK activation and adhesion-independent growth of human pre-B cell lines:
- Acharya, Mridu, Edkins, Adrienne L, Ozanne, B, Cushley, W
- Authors: Acharya, Mridu , Edkins, Adrienne L , Ozanne, B , Cushley, W
- Date: 2009
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165044 , vital:41204 , DOI: 10.1038/leu.2009.126
- Description: CD23 acts through the αvβ5 integrin to promote growth of human pre-B cell lines in an adhesion-independent manner. αvβ5 is expressed on normal B-cell precursors in the bone marrow. Soluble CD23 (sCD23), short CD23-derived peptides containing the arg-lys-cys (RKC) motif recognized by αvβ5 and anti-αvβ5 monoclonal antibodies (MAbs) all sustain growth of pre-B cell lines. The chemokine stromal cell-derived factor-1 (SDF-1) regulates key processes during B-cell development. SDF-1 enhanced the growth-sustaining effect driven by ligation of αvβ5 with anti-αvβ5 MAb 15F-11, sCD23 or CD23-derived RKC-containing peptides. This effect was restricted to B-cell precursors and was specific to SDF-1.
- Full Text:
- Date Issued: 2009
- Authors: Acharya, Mridu , Edkins, Adrienne L , Ozanne, B , Cushley, W
- Date: 2009
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165044 , vital:41204 , DOI: 10.1038/leu.2009.126
- Description: CD23 acts through the αvβ5 integrin to promote growth of human pre-B cell lines in an adhesion-independent manner. αvβ5 is expressed on normal B-cell precursors in the bone marrow. Soluble CD23 (sCD23), short CD23-derived peptides containing the arg-lys-cys (RKC) motif recognized by αvβ5 and anti-αvβ5 monoclonal antibodies (MAbs) all sustain growth of pre-B cell lines. The chemokine stromal cell-derived factor-1 (SDF-1) regulates key processes during B-cell development. SDF-1 enhanced the growth-sustaining effect driven by ligation of αvβ5 with anti-αvβ5 MAb 15F-11, sCD23 or CD23-derived RKC-containing peptides. This effect was restricted to B-cell precursors and was specific to SDF-1.
- Full Text:
- Date Issued: 2009
Sarqaquinoic acid and related synthetic naphthoquinones inhibit the function of Hsp90
- Chiwakata, M, de la Mare, Jo-Anne, Edkins, Adrienne L, Beukes, Denzil R
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
- Date Issued: 2016
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
- Date Issued: 2016
Ruthenium complexes with mono-or bis-heterocyclic chelates: DNA/BSA binding, Antioxidant and Anticancer studies
- Maikoo, Sanam, Chakraborty, Abir, Vukea, Nyeleti, Dingle, Laura M K, Samson, William J, de la Mare, Jo-Anne, Edkins, Adrienne L, Booysen, Irvin N
- Authors: Maikoo, Sanam , Chakraborty, Abir , Vukea, Nyeleti , Dingle, Laura M K , Samson, William J , de la Mare, Jo-Anne , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165463 , vital:41246 , DOI: 10.1080/07391102.2020.1775126
- Description: Deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) binding interactions for a series of ruthenium heterocyclic complexes were monitored using ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence emission spectroscopy and agarose gel electrophoresis. Investigations of the DNA interactions for the metal complexes revealed that they are groove-binders with intrinsic binding constants in the order of 104 – 107 M−1.
- Full Text:
- Date Issued: 2020
- Authors: Maikoo, Sanam , Chakraborty, Abir , Vukea, Nyeleti , Dingle, Laura M K , Samson, William J , de la Mare, Jo-Anne , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165463 , vital:41246 , DOI: 10.1080/07391102.2020.1775126
- Description: Deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) binding interactions for a series of ruthenium heterocyclic complexes were monitored using ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence emission spectroscopy and agarose gel electrophoresis. Investigations of the DNA interactions for the metal complexes revealed that they are groove-binders with intrinsic binding constants in the order of 104 – 107 M−1.
- Full Text:
- Date Issued: 2020
Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1, 3-benzoxazine derivatives
- Mbaba, Mziyanda, Dingle, Laura M K, Cash, Devon, de la Mare, Jo-Anne, Laming, Dustin, Taylor, Dale, Hoppe, Heinrich C, Edkins, Adrienne L, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
- Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
- Full Text:
- Date Issued: 2020
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
- Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
- Full Text:
- Date Issued: 2020
Regulation of the extracellular matrix by heat shock proteins and molecular chaperones:
- Boel, Natasha M-E, Edkins, Adrienne L
- Authors: Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164368 , vital:41112 , ISBN 978-3-319-69040-7 , DOI: 10.1007/978-3-319-69042-1_6
- Description: The extracellular matrix (ECM) serves as a scaffold for cells within tissues and is composed of an intricate network of glycoproteins, growth factors and matricellular proteins which cooperatively function in cell processes such as migration, adhesion and wound healing. ECM morphology is constantly undergoing remodelling (synthesis, assembly and degradation) during normal cell processes and when deregulated may contribute to disease. Heat shock proteins (Hsps) are involved in regulating processes that determine the assembly and degradation of the ECM at multiple levels, in both normal and diseased states. These roles include mediating the activation of ECM-degrading enzymes, maintaining matrix stability and clearing aggregated/misfolded proteins. Hsp may serve as chaperones and receptors or have cytokine-like functions. In this chapter, we review how Hsp90, Hsp70, Hsp40 and a number of ER resident chaperones contribute to ECM regulation. The role of the non-Hsp chaperones, SPARC and clusterin in the ECM is also discussed.
- Full Text:
- Date Issued: 2018
- Authors: Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164368 , vital:41112 , ISBN 978-3-319-69040-7 , DOI: 10.1007/978-3-319-69042-1_6
- Description: The extracellular matrix (ECM) serves as a scaffold for cells within tissues and is composed of an intricate network of glycoproteins, growth factors and matricellular proteins which cooperatively function in cell processes such as migration, adhesion and wound healing. ECM morphology is constantly undergoing remodelling (synthesis, assembly and degradation) during normal cell processes and when deregulated may contribute to disease. Heat shock proteins (Hsps) are involved in regulating processes that determine the assembly and degradation of the ECM at multiple levels, in both normal and diseased states. These roles include mediating the activation of ECM-degrading enzymes, maintaining matrix stability and clearing aggregated/misfolded proteins. Hsp may serve as chaperones and receptors or have cytokine-like functions. In this chapter, we review how Hsp90, Hsp70, Hsp40 and a number of ER resident chaperones contribute to ECM regulation. The role of the non-Hsp chaperones, SPARC and clusterin in the ECM is also discussed.
- Full Text:
- Date Issued: 2018
Regulation of Kaposi’s Sarcoma-Associated Herpesvirus Biology by Host Molecular Chaperones:
- Kirigin, Elisa, Ruck, Duncan Kyle, Jackson, Zoe, Murphy, James, McDonnell, Euan, Okpara, Michael O, Whitehouse, Adrian, Edkins, Adrienne L
- Authors: Kirigin, Elisa , Ruck, Duncan Kyle , Jackson, Zoe , Murphy, James , McDonnell, Euan , Okpara, Michael O , Whitehouse, Adrian , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165385 , vital:41239 , ISBN , https://0-doi.org.wam.seals.ac.za/10.1007/7515_2020_18
- Description: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with development of the human diseases Kaposi’s sarcoma, Primary Effusion Lymphoma and Multicentric Castleman’s Disease. KSHV establishes a chronic latent infection in hosts, with periods of viral lytic replication, where both latent and lytic virus cycles contribute to malignancy, most often in the immunodeficient host.
- Full Text:
- Date Issued: 2020
- Authors: Kirigin, Elisa , Ruck, Duncan Kyle , Jackson, Zoe , Murphy, James , McDonnell, Euan , Okpara, Michael O , Whitehouse, Adrian , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165385 , vital:41239 , ISBN , https://0-doi.org.wam.seals.ac.za/10.1007/7515_2020_18
- Description: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with development of the human diseases Kaposi’s sarcoma, Primary Effusion Lymphoma and Multicentric Castleman’s Disease. KSHV establishes a chronic latent infection in hosts, with periods of viral lytic replication, where both latent and lytic virus cycles contribute to malignancy, most often in the immunodeficient host.
- Full Text:
- Date Issued: 2020
Real-time monitoring of 3T3-L1 preadipocyte differentiation using a commercially available electric cell-substrate impedance sensor system:
- Kramer, Adam H, Joos-Vandewalle, Julia, Edkins, Adrienne L, Frost, Carminita L, Prinsloo, Earl
- Authors: Kramer, Adam H , Joos-Vandewalle, Julia , Edkins, Adrienne L , Frost, Carminita L , Prinsloo, Earl
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164830 , vital:41176 , DOI: 10.1016/j.bbrc.2013.12.123
- Description: Real-time analysis offers multiple benefits over traditional end point assays. Here, we present a method of monitoring the optimisation of the growth and differentiation of murine 3T3-L1 preadipocytes to adipocytes using the commercially available ACEA xCELLigence Real-Time Cell Analyser Single Plate (RTCA SP) system. Our findings indicate that the ACEA xCELLigence RTCA SP can reproducibly monitor the primary morphological changes in pre- and post-confluent 3T3-L1 fibroblasts induced to differentiate using insulin, dexamethasone, 3-isobutyl-1-methylxanthine and rosiglitazone; and may be a viable primary method of screening compounds for adipogenic factors.
- Full Text:
- Date Issued: 2014
- Authors: Kramer, Adam H , Joos-Vandewalle, Julia , Edkins, Adrienne L , Frost, Carminita L , Prinsloo, Earl
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164830 , vital:41176 , DOI: 10.1016/j.bbrc.2013.12.123
- Description: Real-time analysis offers multiple benefits over traditional end point assays. Here, we present a method of monitoring the optimisation of the growth and differentiation of murine 3T3-L1 preadipocytes to adipocytes using the commercially available ACEA xCELLigence Real-Time Cell Analyser Single Plate (RTCA SP) system. Our findings indicate that the ACEA xCELLigence RTCA SP can reproducibly monitor the primary morphological changes in pre- and post-confluent 3T3-L1 fibroblasts induced to differentiate using insulin, dexamethasone, 3-isobutyl-1-methylxanthine and rosiglitazone; and may be a viable primary method of screening compounds for adipogenic factors.
- Full Text:
- Date Issued: 2014