Ability of GHTD-amide and analogs to enhance insulin activity through zinc chelation and dispersal of insulin oligomers
- Paule, Sarah, Nikolovski, Biljana, Ludeman, Justin, Gray, Robyn, Spiccia, Leone, Zimmet, Paul, Myers, Mark
- Authors: Paule, Sarah , Nikolovski, Biljana , Ludeman, Justin , Gray, Robyn , Spiccia, Leone , Zimmet, Paul , Myers, Mark
- Date: 2009
- Type: Text , Journal article
- Relation: Peptides Vol. 30, no. 6 (2009), p. 1088-1097
- Full Text:
- Reviewed:
- Description: GHTD-amide is a tetrapeptide originally isolated from human urine that has hypoglycemic activity. Insulin occurs in secretory granules of beta cells as zinc-stabilized hexamers and must disperse to monomeric form in order to bind to its receptor. The aim of this study was to identify whether GHTD-amide and an analog called ISF402 (VHTD-amide) reduce blood glucose through enhancement of insulin activity by dispersing oligomers of insulin. Peptides containing the HTD-amide sequence and a free α-amino group were optimal at binding Zn2+ and adopting secondary structure in the presence of Zn2+. Binding was concentration dependent and resulted in a 1:1 Zn:peptide complex. In vitro the tetrapeptides dispersed hexameric insulin to dimers and monomers. GHTD-amide and ISF402 potentiated the activity of hexameric insulin when co-injected into insulin resistant Zucker rats. Injection of peptides with insulin caused reductions in blood glucose and C-peptide significantly larger than achieved with insulin alone, and serum insulin time profiles were also altered consistent with a reduced clearance or enhanced dispersal of the injected insulin. Insulin potentiation by ISF402 was reduced when lispro insulin, which does not form zinc-stabilized hexamers, was used in place of hexameric zinc insulin. In conclusion, GHTD-amide and ISF402 are zinc binding peptides that disperse hexameric insulin in vitro, and potentiate the activity of hexameric insulin more so than monomeric lispro insulin. These results suggest that dispersal of hexameric insulin through chelation of Zn2+ contributes to the hypoglycemic activity of these tetrapeptides. Crown Copyright © 2009.
- Authors: Paule, Sarah , Nikolovski, Biljana , Ludeman, Justin , Gray, Robyn , Spiccia, Leone , Zimmet, Paul , Myers, Mark
- Date: 2009
- Type: Text , Journal article
- Relation: Peptides Vol. 30, no. 6 (2009), p. 1088-1097
- Full Text:
- Reviewed:
- Description: GHTD-amide is a tetrapeptide originally isolated from human urine that has hypoglycemic activity. Insulin occurs in secretory granules of beta cells as zinc-stabilized hexamers and must disperse to monomeric form in order to bind to its receptor. The aim of this study was to identify whether GHTD-amide and an analog called ISF402 (VHTD-amide) reduce blood glucose through enhancement of insulin activity by dispersing oligomers of insulin. Peptides containing the HTD-amide sequence and a free α-amino group were optimal at binding Zn2+ and adopting secondary structure in the presence of Zn2+. Binding was concentration dependent and resulted in a 1:1 Zn:peptide complex. In vitro the tetrapeptides dispersed hexameric insulin to dimers and monomers. GHTD-amide and ISF402 potentiated the activity of hexameric insulin when co-injected into insulin resistant Zucker rats. Injection of peptides with insulin caused reductions in blood glucose and C-peptide significantly larger than achieved with insulin alone, and serum insulin time profiles were also altered consistent with a reduced clearance or enhanced dispersal of the injected insulin. Insulin potentiation by ISF402 was reduced when lispro insulin, which does not form zinc-stabilized hexamers, was used in place of hexameric zinc insulin. In conclusion, GHTD-amide and ISF402 are zinc binding peptides that disperse hexameric insulin in vitro, and potentiate the activity of hexameric insulin more so than monomeric lispro insulin. These results suggest that dispersal of hexameric insulin through chelation of Zn2+ contributes to the hypoglycemic activity of these tetrapeptides. Crown Copyright © 2009.
Changes in the ghrelin hormone pathway maybe part of an unusual gastric system in monotremes
- He, Chuan, Tsend-Ayush, Enkhjargal, Myers, Mark, Forbes, Briony, Grützner, Frank
- Authors: He, Chuan , Tsend-Ayush, Enkhjargal , Myers, Mark , Forbes, Briony , Grützner, Frank
- Date: 2013
- Type: Text , Journal article
- Relation: General and Comparative Endocrinology Vol. 191, no. (2013), p. 74-82
- Full Text:
- Reviewed:
- Description: Ghrelin is a growth hormone (GH)-releasing and appetite-regulating peptide predominately released from the stomach. Ghrelin is evolutionarily highly conserved and known to have a wide range of functions including the regulation of metabolism by maintaining an insulin-glucose balance. The peptide is produced as a single proprotein, which is later proteolytically cleaved. Ghrelin exerts its biological function after O-n-octanoylation at residue serine 3, which is catalyzed by ghrelin O-acyl transferase (GOAT) and allows binding to the growth hormone secretagogue receptor (GHS-R 1a). Genes involved in the ghrelin pathway have been identified in a broad range of vertebrate species, however, little is known about this pathway in the basal mammalian lineage of monotremes (platypus and echidna). Monotremes are particularly interesting in this context, as they have undergone massive changes in stomach anatomy and physiology, accompanied by a striking loss of genes involved in gastric function. In this study, we investigated genes in the ghrelin pathway in monotremes. Using degenerate PCR, database searches and synteny analysis we found that genes encoding ghrelin and GOAT are missing in the platypus genome, whilst, as has been reported in other species, the GHSR is present and expressed in brain, pancreas, kidney, intestine, heart and stomach. This is the first report suggesting the loss of ghrelin in a mammal. The loss of this gene may be related to changes to the platypus digestive system and raises questions about the control of blood glucose levels and insulin response in monotreme mammals. In addition, the conservation of the ghrelin receptor gene in platypus indicates that another ligand(s) maybe acting via this receptor in monotremes. © 2013 Elsevier Inc.
- Description: 2003011207
- Authors: He, Chuan , Tsend-Ayush, Enkhjargal , Myers, Mark , Forbes, Briony , Grützner, Frank
- Date: 2013
- Type: Text , Journal article
- Relation: General and Comparative Endocrinology Vol. 191, no. (2013), p. 74-82
- Full Text:
- Reviewed:
- Description: Ghrelin is a growth hormone (GH)-releasing and appetite-regulating peptide predominately released from the stomach. Ghrelin is evolutionarily highly conserved and known to have a wide range of functions including the regulation of metabolism by maintaining an insulin-glucose balance. The peptide is produced as a single proprotein, which is later proteolytically cleaved. Ghrelin exerts its biological function after O-n-octanoylation at residue serine 3, which is catalyzed by ghrelin O-acyl transferase (GOAT) and allows binding to the growth hormone secretagogue receptor (GHS-R 1a). Genes involved in the ghrelin pathway have been identified in a broad range of vertebrate species, however, little is known about this pathway in the basal mammalian lineage of monotremes (platypus and echidna). Monotremes are particularly interesting in this context, as they have undergone massive changes in stomach anatomy and physiology, accompanied by a striking loss of genes involved in gastric function. In this study, we investigated genes in the ghrelin pathway in monotremes. Using degenerate PCR, database searches and synteny analysis we found that genes encoding ghrelin and GOAT are missing in the platypus genome, whilst, as has been reported in other species, the GHSR is present and expressed in brain, pancreas, kidney, intestine, heart and stomach. This is the first report suggesting the loss of ghrelin in a mammal. The loss of this gene may be related to changes to the platypus digestive system and raises questions about the control of blood glucose levels and insulin response in monotreme mammals. In addition, the conservation of the ghrelin receptor gene in platypus indicates that another ligand(s) maybe acting via this receptor in monotremes. © 2013 Elsevier Inc.
- Description: 2003011207
GHTD-amide : A naturally occurring beta cell-derived peptide with hypoglycemic activity
- Paule, Sarah, Nikolovski, Biljana, Gray, Robyn, Ludeman, Justin, Freemantle, A., Spark, R. A., Kerr, J. B., Ng, F. M., Zimmet, Paul, Myers, Mark
- Authors: Paule, Sarah , Nikolovski, Biljana , Gray, Robyn , Ludeman, Justin , Freemantle, A. , Spark, R. A. , Kerr, J. B. , Ng, F. M. , Zimmet, Paul , Myers, Mark
- Date: 2009
- Type: Text , Journal article
- Relation: Peptides Vol. 30, no. 5 (2009), p. 955-961
- Full Text:
- Reviewed:
- Description: in the early 1970s, a peptide fraction with insulin potentiating activity was purified from human urine but the identity and origins of the active constituent remained unknown. Here we identify the active component and characterize its origins. The active peptide was identified as an alpha amidated tetrapeptide with the sequence GHTD-amide. The peptide was synthesized and tested for stimulation of glycogen synthesis and insulin potentiation by insulin tolerance testing in insulin-deficient rats, which confirmed GHTD-amide as the active peptide. Tissue localization using a peptide-specific anti-serum and epifluorescent and confocal microscopy showed decoration of pancreatic islets but not other tissues. Confocal microscopy revealed co-localization with insulin and immunogold and electron microscopy showed localization to dense core secretory granules. Consistent with these observations GHTD-amide was found in media conditioned by MIN6 islet beta cells. Sequence database searching found no annotated protein in the human proteome encoding a potential precursor for GHTD-amide. We conclude that the insulin potentiating activity originally described in human urine is attributable to the tetrapeptide GHTD-amide. GHTD-amide is a novel peptide produced by pancreatic beta cells and no precursor protein is present in the annotated human proteome. Stimulation of glycogen synthesis and co-localization with insulin in beta cells suggest that GHTD-amide may play a role in glucose homeostasis by enhancing insulin action and glucose storage in tissues. (C) 2008 Elsevier Inc. All rights reserved.
- Authors: Paule, Sarah , Nikolovski, Biljana , Gray, Robyn , Ludeman, Justin , Freemantle, A. , Spark, R. A. , Kerr, J. B. , Ng, F. M. , Zimmet, Paul , Myers, Mark
- Date: 2009
- Type: Text , Journal article
- Relation: Peptides Vol. 30, no. 5 (2009), p. 955-961
- Full Text:
- Reviewed:
- Description: in the early 1970s, a peptide fraction with insulin potentiating activity was purified from human urine but the identity and origins of the active constituent remained unknown. Here we identify the active component and characterize its origins. The active peptide was identified as an alpha amidated tetrapeptide with the sequence GHTD-amide. The peptide was synthesized and tested for stimulation of glycogen synthesis and insulin potentiation by insulin tolerance testing in insulin-deficient rats, which confirmed GHTD-amide as the active peptide. Tissue localization using a peptide-specific anti-serum and epifluorescent and confocal microscopy showed decoration of pancreatic islets but not other tissues. Confocal microscopy revealed co-localization with insulin and immunogold and electron microscopy showed localization to dense core secretory granules. Consistent with these observations GHTD-amide was found in media conditioned by MIN6 islet beta cells. Sequence database searching found no annotated protein in the human proteome encoding a potential precursor for GHTD-amide. We conclude that the insulin potentiating activity originally described in human urine is attributable to the tetrapeptide GHTD-amide. GHTD-amide is a novel peptide produced by pancreatic beta cells and no precursor protein is present in the annotated human proteome. Stimulation of glycogen synthesis and co-localization with insulin in beta cells suggest that GHTD-amide may play a role in glucose homeostasis by enhancing insulin action and glucose storage in tissues. (C) 2008 Elsevier Inc. All rights reserved.
The Zinc Transporter, Slc39a7 (Zip7) Is Implicated in Glycaemic Control in Skeletal Muscle Cells
- Myers, Stephen, Nield, Alex, Chew, Guatsiew, Myers, Mark
- Authors: Myers, Stephen , Nield, Alex , Chew, Guatsiew , Myers, Mark
- Date: 2013
- Type: Text , Journal article
- Relation: Plos One Vol. 8, no. 11 (November 2013 2013), p. 15
- Full Text:
- Reviewed:
- Description: Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.
- Authors: Myers, Stephen , Nield, Alex , Chew, Guatsiew , Myers, Mark
- Date: 2013
- Type: Text , Journal article
- Relation: Plos One Vol. 8, no. 11 (November 2013 2013), p. 15
- Full Text:
- Reviewed:
- Description: Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.
Immunohistochemical analysis of pancreatic islets of platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus ssp.)
- He, Chuan, Myers, Mark, Forbes, Briony, Grützner, Frank
- Authors: He, Chuan , Myers, Mark , Forbes, Briony , Grützner, Frank
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Anatomy Vol. 226, no. 4 (2015), p. 373-380
- Full Text:
- Reviewed:
- Description: Monotremes have undergone remarkable changes to their digestive and metabolic control system; however, the monotreme pancreas remains poorly characterized. Previous work in echidna demonstrated the presence of pancreatic islets, but no information is available for platypus and the fine structure has not been described for either monotreme. Based on our recent finding that monotremes lack the ghrelin gene, which is expressed in mouse and human pancreatic islets, we investigated the structure of monotreme islets in more detail. Generally, as in birds, the islets of monotremes were smaller but greater in number compared with mouse. b-cells were the most abundant endocrine cell population in platypus islets and were located peripherally, while a-cells were observed both in the interior and periphery of the islets. d-cells and pancreatic polypeptide (PP)-cells were mainly found in the islet periphery. Distinct PP-rich (PP-lobe) and PP-poor areas (non-PP-lobe) are present in therian mammals, and we identified these areas in echidna but not platypus pancreas. Interestingly, in some of the echidna islets, a- and b-cells tended to form two poles within the islets, which to our knowledge is the first time this has been observed in any species. Overall, monotreme pancreata share the feature of consisting of distinct PP-poor and PP-rich islets with other mammals. A higher number of islets and a- or b-cell only islets are shared between monotremes and birds. The islets of monotremes were larger than those of birds but smaller compared with therian mammals. This may indicate a trend of having fewer larger islets comprising several endocrine cell types during mammalian evolution. © 2015 Anatomical Society.
- Authors: He, Chuan , Myers, Mark , Forbes, Briony , Grützner, Frank
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Anatomy Vol. 226, no. 4 (2015), p. 373-380
- Full Text:
- Reviewed:
- Description: Monotremes have undergone remarkable changes to their digestive and metabolic control system; however, the monotreme pancreas remains poorly characterized. Previous work in echidna demonstrated the presence of pancreatic islets, but no information is available for platypus and the fine structure has not been described for either monotreme. Based on our recent finding that monotremes lack the ghrelin gene, which is expressed in mouse and human pancreatic islets, we investigated the structure of monotreme islets in more detail. Generally, as in birds, the islets of monotremes were smaller but greater in number compared with mouse. b-cells were the most abundant endocrine cell population in platypus islets and were located peripherally, while a-cells were observed both in the interior and periphery of the islets. d-cells and pancreatic polypeptide (PP)-cells were mainly found in the islet periphery. Distinct PP-rich (PP-lobe) and PP-poor areas (non-PP-lobe) are present in therian mammals, and we identified these areas in echidna but not platypus pancreas. Interestingly, in some of the echidna islets, a- and b-cells tended to form two poles within the islets, which to our knowledge is the first time this has been observed in any species. Overall, monotreme pancreata share the feature of consisting of distinct PP-poor and PP-rich islets with other mammals. A higher number of islets and a- or b-cell only islets are shared between monotremes and birds. The islets of monotremes were larger than those of birds but smaller compared with therian mammals. This may indicate a trend of having fewer larger islets comprising several endocrine cell types during mammalian evolution. © 2015 Anatomical Society.
Zinc transporters, mechanisms of action and therapeutic utility : Implications for type 2 diabetes mellitus
- Myers, Stephen, Nield, Alex, Myers, Mark
- Authors: Myers, Stephen , Nield, Alex , Myers, Mark
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Nutrition and Metabolism Vol. 2012, no. (2012), p. 1-13
- Full Text:
- Reviewed:
- Description: Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a "cellular second messenger" in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy. © 2012 Stephen A. Myers et al.
- Description: 2003010692
- Authors: Myers, Stephen , Nield, Alex , Myers, Mark
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Nutrition and Metabolism Vol. 2012, no. (2012), p. 1-13
- Full Text:
- Reviewed:
- Description: Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a "cellular second messenger" in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy. © 2012 Stephen A. Myers et al.
- Description: 2003010692
Monotreme glucagon-like peptide-1 in venom and gut : One gene - Two very different functions
- Tsend-Ayush, Enkhjargal, He, Chuan, Myers, Mark, Andrikopoulos, Sof, Wong, Nicole, Sexton, Patrick, Wootten, Denise, Forbes, Briony, Grutzner, Frank
- Authors: Tsend-Ayush, Enkhjargal , He, Chuan , Myers, Mark , Andrikopoulos, Sof , Wong, Nicole , Sexton, Patrick , Wootten, Denise , Forbes, Briony , Grutzner, Frank
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-12
- Full Text:
- Reviewed:
- Description: The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication. © The Author(s) 2016.
- Authors: Tsend-Ayush, Enkhjargal , He, Chuan , Myers, Mark , Andrikopoulos, Sof , Wong, Nicole , Sexton, Patrick , Wootten, Denise , Forbes, Briony , Grutzner, Frank
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-12
- Full Text:
- Reviewed:
- Description: The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication. © The Author(s) 2016.
Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma
- Sharma, Revati, Kadife, Elif, Myers, Mark, Kannourakis, George, Prithviraj, Prashanth, Ahmed, Nuzhat
- Authors: Sharma, Revati , Kadife, Elif , Myers, Mark , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2021
- Type: Text , Journal article , Review
- Relation: Journal of Experimental and Clinical Cancer Research Vol. 40, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies. © 2021, The Author(s).
- Authors: Sharma, Revati , Kadife, Elif , Myers, Mark , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2021
- Type: Text , Journal article , Review
- Relation: Journal of Experimental and Clinical Cancer Research Vol. 40, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies. © 2021, The Author(s).
Sympathetic nervous system and atherosclerosis
- Wang, Yutang, Anesi, Jack, Maier, Michelle, Myers, Mark, Oqueli, Ernesto, Sobey, Christopher, Drummond, Grant, Denton, Kate
- Authors: Wang, Yutang , Anesi, Jack , Maier, Michelle , Myers, Mark , Oqueli, Ernesto , Sobey, Christopher , Drummond, Grant , Denton, Kate
- Date: 2023
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 24, no. 17 (2023), p.
- Full Text:
- Reviewed:
- Description: Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (
- Authors: Wang, Yutang , Anesi, Jack , Maier, Michelle , Myers, Mark , Oqueli, Ernesto , Sobey, Christopher , Drummond, Grant , Denton, Kate
- Date: 2023
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 24, no. 17 (2023), p.
- Full Text:
- Reviewed:
- Description: Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (
Dexamethasone leads to Zn2+ accumulation and increased unbound Zn2+ in C2C12 muscle and 3T3-L1 adipose cells
- Maier, Michelle, Nankervis, Scott, Wallace, Morgan, Develyn, Tamekha, Myers, Mark
- Authors: Maier, Michelle , Nankervis, Scott , Wallace, Morgan , Develyn, Tamekha , Myers, Mark
- Date: 2023
- Type: Text , Journal article
- Relation: Journal of Cellular Biochemistry Vol. 124, no. 3 (2023), p. 409-420
- Full Text:
- Reviewed:
- Description: Skeletal muscle atrophy is associated with increases in circulating glucocorticoid levels and insulin resistance. Zinc accumulates in atrophic muscle, but the relationship between atrophy, insulin resistance, and Zn2+ homeostasis remains unclear. In this study, the effect of the glucocorticoid dexamethasone (DEX) on insulin and Zn2+ homeostasis was explored. Treatment of differentiated C2C12 skeletal myotubes and 3T3-L1 adipocytes with DEX significantly increased mRNA expression of the metal-binding proteins Mt1 and 2 and altered energy storage as shown by the increased size of lipid droplets in 3T3-L1 cells. In C2C12 cells the total cellular Zn2+ was higher after DEX treatment, and in both C2C12 and 3T3-L1 adipocytes, free unbound Zn2+ was increased. Insulin treatment led to a gradual increase in free Zn2+ in C2C12 cells, and no significant change in DEX-treated cells such that concentrations were similar 10 min after insulin treatment. These data demonstrate that DEX disturbs Zn2+ homeostasis in muscle and fat cells. Further study of the molecular pathways involved to identify novel therapeutic targets for treatment of skeletal muscle atrophy is warranted. © 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
- Authors: Maier, Michelle , Nankervis, Scott , Wallace, Morgan , Develyn, Tamekha , Myers, Mark
- Date: 2023
- Type: Text , Journal article
- Relation: Journal of Cellular Biochemistry Vol. 124, no. 3 (2023), p. 409-420
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- Description: Skeletal muscle atrophy is associated with increases in circulating glucocorticoid levels and insulin resistance. Zinc accumulates in atrophic muscle, but the relationship between atrophy, insulin resistance, and Zn2+ homeostasis remains unclear. In this study, the effect of the glucocorticoid dexamethasone (DEX) on insulin and Zn2+ homeostasis was explored. Treatment of differentiated C2C12 skeletal myotubes and 3T3-L1 adipocytes with DEX significantly increased mRNA expression of the metal-binding proteins Mt1 and 2 and altered energy storage as shown by the increased size of lipid droplets in 3T3-L1 cells. In C2C12 cells the total cellular Zn2+ was higher after DEX treatment, and in both C2C12 and 3T3-L1 adipocytes, free unbound Zn2+ was increased. Insulin treatment led to a gradual increase in free Zn2+ in C2C12 cells, and no significant change in DEX-treated cells such that concentrations were similar 10 min after insulin treatment. These data demonstrate that DEX disturbs Zn2+ homeostasis in muscle and fat cells. Further study of the molecular pathways involved to identify novel therapeutic targets for treatment of skeletal muscle atrophy is warranted. © 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
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