DOAJ (DOAJ: Directory of Open Access Journals), Jul 1, 2005
Greg J Dusting1, Chris Triggle21Howard Florey Institute, University of Melbourne, VIC, Australia;... more Greg J Dusting1, Chris Triggle21Howard Florey Institute, University of Melbourne, VIC, Australia; 2School of Medical Sciences, RMIT University, VIC, AustraliaAre we over oxidized? A number of recent clinical trials with antioxidants, notably vitamin C and E, have provided no support for the commonly held view that increasing our intake of antioxidants will offset the ravages of cardiovascular disease as well as other diseases (for extensive critical reviews see: Kritharides and Stocker 2002; Antoniades et al 2003; Touyz 2004). Is this conclusion justified? The role of antioxidant dietary adjuncts and therapy in prevention and treatment remains a highly important clinical question. In this opinion article we address the question: Is there a future for antioxidant therapy in the treatment and prevention of cardiovascular disease? We conclude that there is a need for better-designed studies as well as a re-thinking of the choice of antioxidants.
The COVID-19 vaccines currently in use have undoubtedly played the most significant role in comba... more The COVID-19 vaccines currently in use have undoubtedly played the most significant role in combating the SARS-CoV-2 virus and reducing disease severity and the risk of death among those affected, especially among those with pre-existing conditions, such as diabetes. The management of blood glucose levels has become critical in the context of the COVID-19 pandemic, where data show two- to threefold higher intensive care hospital admissions and more than twice the mortality rate among diabetic COVID-19 patients when compared with their nondiabetic counterparts. Furthermore, new-onset diabetes and severe hyperglycemia-related complications, such as hyperosmolar hyperglycemic syndrome (HHS) and diabetic ketoacidosis (DKA), were reported in COVID-19 patients. However, irrespective of the kind of vaccine and dosage number, possible vaccination-induced hyperglycemia and associated complications were reported among vaccinated individuals. The current article summarizes the available case r...
Despite the efforts devoted to drug discovery and development, the number of new drug approvals h... more Despite the efforts devoted to drug discovery and development, the number of new drug approvals have been decreasing. Specifically, cardiovascular developments have been showing amongst the lowest levels of approvals. In addition, concerns over the adverse effects of drugs to the cardiovascular system have been increasing and resulting in failure at the preclinical level as well as withdrawal of drugs post-marketing. Besides factors such as the increased cost of clinical trials and increases in the requirements and the complexity of the regulatory processes, there is also a gap between the currently existing pre-clinical screening methods and the clinical studies in humans. This gap is mainly caused by the lack of complexity in the currently used 2D cell culture-based screening systems, which do not accurately reflect human physiological conditions. Cell-based drug screening is widely accepted and extensively used and can provide an initial indication of the drugs' therapeutic e...
Canadian Journal of Physiology and Pharmacology, 2020
Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiov... more Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that “one is only as old as one’s endothelium” and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, au...
Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer ... more Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas ...
Metformin, the most widely used anti-diabetic drug, also exhibits anti-cancer properties; however... more Metformin, the most widely used anti-diabetic drug, also exhibits anti-cancer properties; however, the true potential of metformin as an anticancer drug remains largely unknown. In this study using mouse microvascular endothelial cells (MMECs), we investigated the effects of metformin alone or in combination with the glycolytic inhibitor, 2-deoxyglucose (2DG), on angiogenesis-a process known to be an integral part of tumor growth, cancer cell survival and metastasis. MMECs were exposed to 2DG (1–10 mM) for 48 h in the absence or presence of metformin (2 mM). The status of angiogenic and anti-angiogenic marker proteins, proteins of the mTOR pathway and cell-cycle-related proteins were quantified by Western blot analysis. Assays for cell proliferation, migration and tubulogenesis were also performed. We observed robust up-regulation of anti-angiogenic thrombospondin-1 (TSP1) and increased TSP1-CD36 co-localization with a marked decrease in the levels of phosphorylated vascular endothe...
Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. F... more Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have ‘anti-cancer’ activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the ex...
Stress Granules (SGs) are dynamic ribonucleoprotein aggregates, which have been observed in cells... more Stress Granules (SGs) are dynamic ribonucleoprotein aggregates, which have been observed in cells subjected to environmental stresses, such as oxidative stress and heat shock (HS). Although pluripotent stem cells (PSCs) are highly sensitive to oxidative stress, the role of SGs in regulating PSC self-renewal and differentiation has not been fully elucidated. Here we found that sodium arsenite (SA) and HS, but not hydrogen peroxide (H2O2), induce SG formation in human induced (hi) PSCs. Particularly, we found that these granules contain the well-known SG proteins (G3BP, TIAR, eIF4E, eIF4A, eIF3B, eIF4G, and PABP), were found in juxtaposition to processing bodies (PBs), and were disassembled after the removal of the stress. Moreover, we showed that SA and HS, but not H2O2, promote eIF2α phosphorylation in hiPSCs forming SGs. Analysis of pluripotent protein expression showed that HS significantly reduced all tested markers (OCT4, SOX2, NANOG, KLF4, L1TD1, and LIN28A), while SA selective...
1. Relaxation responses were produced by vagal and field stimulation, respectively, of the whole ... more 1. Relaxation responses were produced by vagal and field stimulation, respectively, of the whole oesophagus preparation from the rat and of the isolated tunica muscularis mucosae (t.m.m.) preparation from the rat. These relaxation responses persisted in the presence of antagonists of histamine, serotonin, noradrenaline and acetylcholine. 2. Unlike vagally evoked relaxation, that evoked by low‐frequency field stimulation, i.e. field‐stimulated relaxation (f.s.r.) was generally resistant to tetrodotoxin (TTX). 3. Both types of relaxations exhibited remarkable temperature sensitivity and were abolished by lowering the bath temperature from 37 to 28 degrees C. 4. TTX‐resistant relaxations were also produced by scorpion (Leiurus quinquestriatus) venom, the calcium ionophore, A23187 (calimycin) and by increasing the extracellular potassium by 2 mM. The failure of these agents to inhibit f.s.r. is inconsistent with a releasing and/or depleting action on any endogenous mediator. 5. Relaxati...
In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 a... more In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 and pinacidil, raised the threshold for concentration‐dependent K+ contractions, suppressed contractions evoked by field stimulation of the TMM in the presence of tetrodotoxin (TTX) and tetraethylammonium (TEA), and relaxed tonic contractions resulting from muscarinic cholinoceptor stimulation. BRL 34915 and both (+)− and (−)‐pinacidil increased 86Rb efflux from tracer‐loaded tissues; nifedipine abolished this effect. Relaxations produced by potassium channel openers were inhibited by a temperature drop from 37°C to 26.5°C, an increase in extracellular K+ concentration to 64 mm, and treatment with the calcium channel antagonist, nifedipine. The same treatments also blocked field stimulation‐evoked TTX‐insensitive relaxations. It is concluded that field stimulation of rat oesophageal smooth muscle in the presence of cholinoceptor‐induced tone results in an increase in K+ permeability that ...
The cellular mechanism(s) of action of endothelium‐derived vasodilator substances in the rabbit m... more The cellular mechanism(s) of action of endothelium‐derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium‐derived relaxing factors (EDRFs) in acetylcholine (ACh)‐induced endothelium‐dependent vasorelaxation in this vessel were systematically compared. In the endothelium‐intact RMCA precontracted with histamine (3 μM), ACh induced a concentration‐dependent vasorelaxation, which was sensitive to indomethacin (10 μM) or NG‐nitro‐L‐arginine (L‐NOARG; 100 μM); pD2 values 8.36 vs 7.40 and 6.38, P<0.01 for both, n=6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L‐NOARG and a combination of indomethacin and L‐NOARG. In the presence of indomethacin, relaxation to ACh in the endothelium‐intact RMCA precontracted with histamine was unaffected b...
DOAJ (DOAJ: Directory of Open Access Journals), Jul 1, 2005
Greg J Dusting1, Chris Triggle21Howard Florey Institute, University of Melbourne, VIC, Australia;... more Greg J Dusting1, Chris Triggle21Howard Florey Institute, University of Melbourne, VIC, Australia; 2School of Medical Sciences, RMIT University, VIC, AustraliaAre we over oxidized? A number of recent clinical trials with antioxidants, notably vitamin C and E, have provided no support for the commonly held view that increasing our intake of antioxidants will offset the ravages of cardiovascular disease as well as other diseases (for extensive critical reviews see: Kritharides and Stocker 2002; Antoniades et al 2003; Touyz 2004). Is this conclusion justified? The role of antioxidant dietary adjuncts and therapy in prevention and treatment remains a highly important clinical question. In this opinion article we address the question: Is there a future for antioxidant therapy in the treatment and prevention of cardiovascular disease? We conclude that there is a need for better-designed studies as well as a re-thinking of the choice of antioxidants.
The COVID-19 vaccines currently in use have undoubtedly played the most significant role in comba... more The COVID-19 vaccines currently in use have undoubtedly played the most significant role in combating the SARS-CoV-2 virus and reducing disease severity and the risk of death among those affected, especially among those with pre-existing conditions, such as diabetes. The management of blood glucose levels has become critical in the context of the COVID-19 pandemic, where data show two- to threefold higher intensive care hospital admissions and more than twice the mortality rate among diabetic COVID-19 patients when compared with their nondiabetic counterparts. Furthermore, new-onset diabetes and severe hyperglycemia-related complications, such as hyperosmolar hyperglycemic syndrome (HHS) and diabetic ketoacidosis (DKA), were reported in COVID-19 patients. However, irrespective of the kind of vaccine and dosage number, possible vaccination-induced hyperglycemia and associated complications were reported among vaccinated individuals. The current article summarizes the available case r...
Despite the efforts devoted to drug discovery and development, the number of new drug approvals h... more Despite the efforts devoted to drug discovery and development, the number of new drug approvals have been decreasing. Specifically, cardiovascular developments have been showing amongst the lowest levels of approvals. In addition, concerns over the adverse effects of drugs to the cardiovascular system have been increasing and resulting in failure at the preclinical level as well as withdrawal of drugs post-marketing. Besides factors such as the increased cost of clinical trials and increases in the requirements and the complexity of the regulatory processes, there is also a gap between the currently existing pre-clinical screening methods and the clinical studies in humans. This gap is mainly caused by the lack of complexity in the currently used 2D cell culture-based screening systems, which do not accurately reflect human physiological conditions. Cell-based drug screening is widely accepted and extensively used and can provide an initial indication of the drugs' therapeutic e...
Canadian Journal of Physiology and Pharmacology, 2020
Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiov... more Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that “one is only as old as one’s endothelium” and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, au...
Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer ... more Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas ...
Metformin, the most widely used anti-diabetic drug, also exhibits anti-cancer properties; however... more Metformin, the most widely used anti-diabetic drug, also exhibits anti-cancer properties; however, the true potential of metformin as an anticancer drug remains largely unknown. In this study using mouse microvascular endothelial cells (MMECs), we investigated the effects of metformin alone or in combination with the glycolytic inhibitor, 2-deoxyglucose (2DG), on angiogenesis-a process known to be an integral part of tumor growth, cancer cell survival and metastasis. MMECs were exposed to 2DG (1–10 mM) for 48 h in the absence or presence of metformin (2 mM). The status of angiogenic and anti-angiogenic marker proteins, proteins of the mTOR pathway and cell-cycle-related proteins were quantified by Western blot analysis. Assays for cell proliferation, migration and tubulogenesis were also performed. We observed robust up-regulation of anti-angiogenic thrombospondin-1 (TSP1) and increased TSP1-CD36 co-localization with a marked decrease in the levels of phosphorylated vascular endothe...
Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. F... more Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have ‘anti-cancer’ activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the ex...
Stress Granules (SGs) are dynamic ribonucleoprotein aggregates, which have been observed in cells... more Stress Granules (SGs) are dynamic ribonucleoprotein aggregates, which have been observed in cells subjected to environmental stresses, such as oxidative stress and heat shock (HS). Although pluripotent stem cells (PSCs) are highly sensitive to oxidative stress, the role of SGs in regulating PSC self-renewal and differentiation has not been fully elucidated. Here we found that sodium arsenite (SA) and HS, but not hydrogen peroxide (H2O2), induce SG formation in human induced (hi) PSCs. Particularly, we found that these granules contain the well-known SG proteins (G3BP, TIAR, eIF4E, eIF4A, eIF3B, eIF4G, and PABP), were found in juxtaposition to processing bodies (PBs), and were disassembled after the removal of the stress. Moreover, we showed that SA and HS, but not H2O2, promote eIF2α phosphorylation in hiPSCs forming SGs. Analysis of pluripotent protein expression showed that HS significantly reduced all tested markers (OCT4, SOX2, NANOG, KLF4, L1TD1, and LIN28A), while SA selective...
1. Relaxation responses were produced by vagal and field stimulation, respectively, of the whole ... more 1. Relaxation responses were produced by vagal and field stimulation, respectively, of the whole oesophagus preparation from the rat and of the isolated tunica muscularis mucosae (t.m.m.) preparation from the rat. These relaxation responses persisted in the presence of antagonists of histamine, serotonin, noradrenaline and acetylcholine. 2. Unlike vagally evoked relaxation, that evoked by low‐frequency field stimulation, i.e. field‐stimulated relaxation (f.s.r.) was generally resistant to tetrodotoxin (TTX). 3. Both types of relaxations exhibited remarkable temperature sensitivity and were abolished by lowering the bath temperature from 37 to 28 degrees C. 4. TTX‐resistant relaxations were also produced by scorpion (Leiurus quinquestriatus) venom, the calcium ionophore, A23187 (calimycin) and by increasing the extracellular potassium by 2 mM. The failure of these agents to inhibit f.s.r. is inconsistent with a releasing and/or depleting action on any endogenous mediator. 5. Relaxati...
In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 a... more In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 and pinacidil, raised the threshold for concentration‐dependent K+ contractions, suppressed contractions evoked by field stimulation of the TMM in the presence of tetrodotoxin (TTX) and tetraethylammonium (TEA), and relaxed tonic contractions resulting from muscarinic cholinoceptor stimulation. BRL 34915 and both (+)− and (−)‐pinacidil increased 86Rb efflux from tracer‐loaded tissues; nifedipine abolished this effect. Relaxations produced by potassium channel openers were inhibited by a temperature drop from 37°C to 26.5°C, an increase in extracellular K+ concentration to 64 mm, and treatment with the calcium channel antagonist, nifedipine. The same treatments also blocked field stimulation‐evoked TTX‐insensitive relaxations. It is concluded that field stimulation of rat oesophageal smooth muscle in the presence of cholinoceptor‐induced tone results in an increase in K+ permeability that ...
The cellular mechanism(s) of action of endothelium‐derived vasodilator substances in the rabbit m... more The cellular mechanism(s) of action of endothelium‐derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium‐derived relaxing factors (EDRFs) in acetylcholine (ACh)‐induced endothelium‐dependent vasorelaxation in this vessel were systematically compared. In the endothelium‐intact RMCA precontracted with histamine (3 μM), ACh induced a concentration‐dependent vasorelaxation, which was sensitive to indomethacin (10 μM) or NG‐nitro‐L‐arginine (L‐NOARG; 100 μM); pD2 values 8.36 vs 7.40 and 6.38, P<0.01 for both, n=6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L‐NOARG and a combination of indomethacin and L‐NOARG. In the presence of indomethacin, relaxation to ACh in the endothelium‐intact RMCA precontracted with histamine was unaffected b...
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