Ibrahim Benter | Eastern Mediterranean University (original) (raw)

Papers by Ibrahim Benter

Research paper thumbnail of Contribution of cytochrome P450 metabolites of arachidonic acid to hypertension and end-organ damage in spontaneously hypertensive rats treated with l-NAME

Autonomic and Autacoid Pharmacology, Oct 1, 2005

Research paper thumbnail of Inhibition of calcium/calmodulin-dependent protein kinase II normalizes diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bed

Autonomic and Autacoid Pharmacology, Feb 1, 2003

Summary 1 Calcium/calmodulin‐dependent protein kinase II (CaMKII) has an important function in me... more Summary 1 Calcium/calmodulin‐dependent protein kinase II (CaMKII) has an important function in mediating insulin release but its role in the development of diabetes‐induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of KN‐93 (5 mg kg−1alt diem for 4 weeks), an inhibitor of CaMKII, to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)‐induced diabetes. 3 The vasoconstrictor responses induced by noradrenaline (NE), endothelin‐1 (ET‐1), and angiotensin II (Ang II), were significantly increased whereas, vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of the STZ‐diabetic rats as compared with non‐diabetic controls. 4 Inhibition of CaMKII by KN‐93 treatment did not affect blood glucose levels but produced a significant normalization of the altered agonist‐induced vasoconstrictor and vasodilator responses. KN‐93 did not affect agonist‐induced responses in control animals. In addition, KN‐93 significantly reduced weight loss in diabetic rats. 5 The present data suggest that CaMKII is an essential mediator in the development of diabetic vascular dysfunction and may also play an important role in signalling pathways leading to weight loss during diabetes.

Research paper thumbnail of The Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: A Potential Target for Treating Diabetic Cardiovascular Disease

Springer eBooks, Dec 2, 2013

Research paper thumbnail of Cardioprotection from ischemia-reperfusion injury due to Ras-GTPase inhibition is attenuated by glibenclamide in the globally ischemic heart

Cell Biochemistry and Function, 2007

Research paper thumbnail of Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner

Molecular Pharmaceutics, Mar 29, 2016

Research paper thumbnail of Chronic Treatment with Ang-(1-7) Reverses Abnormal Reactivity in the Corpus Cavernosum and Normalizes Diabetes-Induced Changes in the Protein Levels of ACE, ACE2, ROCK1, ROCK2 and Omega-Hydroxylase in a Rat Model of Type 1 Diabetes

Journal of diabetes research, 2014

Research paper thumbnail of The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsiveness of rat carotid artery

Autonomic and Autacoid Pharmacology, Apr 1, 2005

Research paper thumbnail of Emerging innate biological properties of nano-drug delivery systems: A focus on PAMAM dendrimers and their clinical potential

Advanced Drug Delivery Reviews, Nov 1, 2021

Research paper thumbnail of Toxicogenomics of non-viral drug delivery systems for RNAi: Potential impact on siRNA-mediated gene silencing activity and specificity

Advanced Drug Delivery Reviews, Mar 1, 2007

RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene ... more RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene expression. In mammalian cells, RNAi is induced via short (21-23 nt) duplexes of RNA, termed small interfering RNA (siRNA), that can elicit highly sequence-specific gene silencing. However, synthetic siRNA duplexes are polyanionic macromolecules that do not readily enter cells and typically require the use of a delivery vector for effective gene silencing in vitro and in vivo. Choice of delivery system is usually made on its ability to enhance cellular uptake of siRNA. However, recent gene expression profiling (toxicogenomics) studies have shown that separate from their effects on cellular uptake, delivery systems can also elicit wide ranging gene changes in target cells that may impact on the 'off-target' effects of siRNA. Furthermore, if delivery systems also alter the expression of genes targeted for silencing, then siRNA activity may be compromised or enhanced depending on whether the target gene is up-regulated or down-regulated respectively. Citing recent examples from the literature, this article therefore reviews the toxicogenomics of non-viral delivery systems and highlights the importance of understanding the genomic signature of siRNA delivery reagents in terms of their impact on gene silencing activity and specificity. Such information will be essential in the selection of optimally acting siRNA-delivery system combinations for the many applications of RNA interference.

Research paper thumbnail of Inhibition of Ras-GTPase signaling by FPTIII ameliorates development of cardiovascular dysfunction in diabetic–hypertensive rats

Vascular Pharmacology, Oct 1, 2008

Research paper thumbnail of Role of epidermal growth factor receptor (EGFR) in corneal remodelling in diabetes

Acta Ophthalmologica, Dec 1, 2009

.Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on ... more .Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on the organization and remodelling of collagen fibrils (CFs) and proteoglycans (PGs) in the stroma of diabetic rat cornea.Methods: Diabetes was induced in female Wistar rats (n = 5) by streptozotocin (STZ) injection (55 mg/kg). Treatment with a selective inhibitor of EGFR tyrosine kinase, AG1478, was started on the same day as the induction of diabetes and administered every other day for 4 weeks. Corneas were fixed in 4% paraformaldehyde at 4 ° to allow for analysis of CF diameters and in 2.5% glutaraldehyde in sodium acetate buffer containing cuprolinic blue to enable the study of PG distribution. AnalySIS soft imaging software was used to analyse CFs and PGs.Results: Epithelial thickness, and median diameter and area fraction of CF in corneal stroma were decreased in diabetic rat cornea compared with normal cornea (p < 0.001), whereas the median PG area and area fractions were significantly increased (p < 0.001). Treatment with AG1478, although it had no action on normal cornea, prevented these diameter and area fraction changes in CFs and PGs. The cornea of AG1478‐treated diabetic rats showed a slight increase in CF diameter and area fraction and a decreased number density.Conclusions: These data show that the distribution of corneal stroma CFs and PGs was altered after 4 weeks of diabetes and that, furthermore, treatment with an EGFR signalling inhibitor normalized these abnormalities. The data suggest that EGFR plays an important role in the development of diabetes‐induced corneal remodelling.

Research paper thumbnail of Pressor and Reflex Sensitivity Is Altered in Spontaneously Hypertensive Rats Treated With Angiotensin-(1-7)

Hypertension, Dec 1, 1995

We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotens... more We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotensin II (Ang II). This hypothesis was supported by the fact that long-term intravenous infusion of Ang-(1-7) transiently lowers blood pressure in spontaneously hypertensive rats (SHR). We now investigated whether the pressor sensitivity to bolus injections of either phenylephrine (PE) or Ang II was altered on day 12 of an Ang-(1-7) infusion when blood pressure in the SHR had returned to hypertensive levels. SHR (n=10) and WKY rats (n=8) were given Ang-(1-7) intravenously via osmotic minipumps at a dose of 24 μg/kg per hour for 2 weeks. On day 12 of the infusion, mean arterial pressure and heart rate in halothane-anesthetized rats were similar in Ang-(1-7)–treated SHR (142±6 mm Hg; 388±9 beats per minute) and those infused with vehicle (146±5 mm Hg; 392±13 beats per minute). Pressor responsiveness to PE in Ang-(1-7)–treated SHR was 22% less at a dose of 10 μg, while pressor responses to Ang II decreased by 20% and 25% at doses of 0.05 and 0.1 μg, respectively, compared with the vehicle-treated SHR ( P <.05). There were no effects of the Ang-(1-7) infusion on pressor responses to Ang II or PE in WKY rats. In the SHR infused with Ang-(1-7), there was a 35% improvement in sensitivity of the reflex control of heart rate to levels not different from those in the untreated WKY rats (slope of the change in pulse interval versus the change in pressure increased from 0.34±0.03 to 0.46±0.01 ms/mm Hg). These data suggest that Ang-(1-7) may selectively activate antihypertensive mechanisms at the level of the vascular wall or the baroreflex.

Research paper thumbnail of Nonviral delivery of synthetic siRNAs in vivo

Journal of Clinical Investigation, Dec 3, 2007

Research paper thumbnail of On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR–ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells

International Journal of Pharmaceutics, May 1, 2013

Research paper thumbnail of Phosphoinositide 3-kinase mediated signalling contributes to development of diabetes-induced abnormal vascular reactivity of rat carotid artery

Cell Biochemistry and Function, 2005

Research paper thumbnail of Angiotensin-(1–7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity

Research paper thumbnail of Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats

American Journal of Physiology-heart and Circulatory Physiology, Jul 1, 1995

Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiote... more Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiotensin II (ANG II) prompted an investigation of the effects of the heptapeptide on the maintenance of elevated blood pressure in spontaneously hypertensive rats (SHR). ANG-(1-7) (24 micrograms.kg-1.h-1) was infused into the jugular vein of 13-wk-old SHR (n = 64), Wistar-Kyoto (WKY, n = 50), and Sprague-Dawley (SD, n = 18) rats for 2 wk, with the use of osmotic minipumps. Blood pressure, fluid and electrolyte balance, plasma vasopressin, and urinary excretion of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured at days 2, 7, and 12 of the infusion. In SHR, ANG-(1-7) caused a sustained and significant reduction in plasma vasopressin concentration that was associated with an increase in urinary prostaglandin E2 and 6-keto-PGF1 alpha excretion at day 2 after the commencement of the infusion. These changes were accompanied by diuresis and natriuresis during the first 3 days of infusion in SHR but not in WKY or SD rats. Direct measurements of arterial pressure confirmed the lowering effect of ANG-(1-7) on systolic pressure of SHR on day 2 of treatment with a restoration of the pressure by days 7 and 12. These findings, along with our previous demonstration that ANG-(1-7) is an active depressor peptide in the intact animal, suggest that ANG-(1-7) may play a significant role as a vasodepressor system opposing the hemodynamic actions of ANG II in this genetic form of experimental hypertension.

Research paper thumbnail of Cardiovascular actions of angiotensin(1–7)

Peptides, Jul 1, 1993

... Injections of saline (vehicle) or an-Requests for reprints should be addressed to Ibrahim F. ... more ... Injections of saline (vehicle) or an-Requests for reprints should be addressed to Ibrahim F. Benter, Ph.D., Hypertension Center, Bowman Gray School ... New York: McGraw-Hill, Inc.; 1977:183-20 I. 4. Chappell, MC; Brosnihan, KB; Diz, DI; Ferrario, CM Iden-tification of angiotensin ...

Research paper thumbnail of The role of epidermal growth factor receptor in diabetes-induced cardiac dysfunction

DOAJ (DOAJ: Directory of Open Access Journals), 2013

Research paper thumbnail of 09 Calcium/calmodulin-dependent protein kinase II plays a significant role in mediating the beneficial effects of ischemic preconditioning on cardiac function during recovery from global ischemia

Journal of Molecular and Cellular Cardiology, Jul 1, 2002

Research paper thumbnail of Contribution of cytochrome P450 metabolites of arachidonic acid to hypertension and end-organ damage in spontaneously hypertensive rats treated with l-NAME

Autonomic and Autacoid Pharmacology, Oct 1, 2005

Research paper thumbnail of Inhibition of calcium/calmodulin-dependent protein kinase II normalizes diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bed

Autonomic and Autacoid Pharmacology, Feb 1, 2003

Summary 1 Calcium/calmodulin‐dependent protein kinase II (CaMKII) has an important function in me... more Summary 1 Calcium/calmodulin‐dependent protein kinase II (CaMKII) has an important function in mediating insulin release but its role in the development of diabetes‐induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of KN‐93 (5 mg kg−1alt diem for 4 weeks), an inhibitor of CaMKII, to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)‐induced diabetes. 3 The vasoconstrictor responses induced by noradrenaline (NE), endothelin‐1 (ET‐1), and angiotensin II (Ang II), were significantly increased whereas, vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of the STZ‐diabetic rats as compared with non‐diabetic controls. 4 Inhibition of CaMKII by KN‐93 treatment did not affect blood glucose levels but produced a significant normalization of the altered agonist‐induced vasoconstrictor and vasodilator responses. KN‐93 did not affect agonist‐induced responses in control animals. In addition, KN‐93 significantly reduced weight loss in diabetic rats. 5 The present data suggest that CaMKII is an essential mediator in the development of diabetic vascular dysfunction and may also play an important role in signalling pathways leading to weight loss during diabetes.

Research paper thumbnail of The Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: A Potential Target for Treating Diabetic Cardiovascular Disease

Springer eBooks, Dec 2, 2013

Research paper thumbnail of Cardioprotection from ischemia-reperfusion injury due to Ras-GTPase inhibition is attenuated by glibenclamide in the globally ischemic heart

Cell Biochemistry and Function, 2007

Research paper thumbnail of Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner

Molecular Pharmaceutics, Mar 29, 2016

Research paper thumbnail of Chronic Treatment with Ang-(1-7) Reverses Abnormal Reactivity in the Corpus Cavernosum and Normalizes Diabetes-Induced Changes in the Protein Levels of ACE, ACE2, ROCK1, ROCK2 and Omega-Hydroxylase in a Rat Model of Type 1 Diabetes

Journal of diabetes research, 2014

Research paper thumbnail of The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsiveness of rat carotid artery

Autonomic and Autacoid Pharmacology, Apr 1, 2005

Research paper thumbnail of Emerging innate biological properties of nano-drug delivery systems: A focus on PAMAM dendrimers and their clinical potential

Advanced Drug Delivery Reviews, Nov 1, 2021

Research paper thumbnail of Toxicogenomics of non-viral drug delivery systems for RNAi: Potential impact on siRNA-mediated gene silencing activity and specificity

Advanced Drug Delivery Reviews, Mar 1, 2007

RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene ... more RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene expression. In mammalian cells, RNAi is induced via short (21-23 nt) duplexes of RNA, termed small interfering RNA (siRNA), that can elicit highly sequence-specific gene silencing. However, synthetic siRNA duplexes are polyanionic macromolecules that do not readily enter cells and typically require the use of a delivery vector for effective gene silencing in vitro and in vivo. Choice of delivery system is usually made on its ability to enhance cellular uptake of siRNA. However, recent gene expression profiling (toxicogenomics) studies have shown that separate from their effects on cellular uptake, delivery systems can also elicit wide ranging gene changes in target cells that may impact on the 'off-target' effects of siRNA. Furthermore, if delivery systems also alter the expression of genes targeted for silencing, then siRNA activity may be compromised or enhanced depending on whether the target gene is up-regulated or down-regulated respectively. Citing recent examples from the literature, this article therefore reviews the toxicogenomics of non-viral delivery systems and highlights the importance of understanding the genomic signature of siRNA delivery reagents in terms of their impact on gene silencing activity and specificity. Such information will be essential in the selection of optimally acting siRNA-delivery system combinations for the many applications of RNA interference.

Research paper thumbnail of Inhibition of Ras-GTPase signaling by FPTIII ameliorates development of cardiovascular dysfunction in diabetic–hypertensive rats

Vascular Pharmacology, Oct 1, 2008

Research paper thumbnail of Role of epidermal growth factor receptor (EGFR) in corneal remodelling in diabetes

Acta Ophthalmologica, Dec 1, 2009

.Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on ... more .Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on the organization and remodelling of collagen fibrils (CFs) and proteoglycans (PGs) in the stroma of diabetic rat cornea.Methods: Diabetes was induced in female Wistar rats (n = 5) by streptozotocin (STZ) injection (55 mg/kg). Treatment with a selective inhibitor of EGFR tyrosine kinase, AG1478, was started on the same day as the induction of diabetes and administered every other day for 4 weeks. Corneas were fixed in 4% paraformaldehyde at 4 ° to allow for analysis of CF diameters and in 2.5% glutaraldehyde in sodium acetate buffer containing cuprolinic blue to enable the study of PG distribution. AnalySIS soft imaging software was used to analyse CFs and PGs.Results: Epithelial thickness, and median diameter and area fraction of CF in corneal stroma were decreased in diabetic rat cornea compared with normal cornea (p < 0.001), whereas the median PG area and area fractions were significantly increased (p < 0.001). Treatment with AG1478, although it had no action on normal cornea, prevented these diameter and area fraction changes in CFs and PGs. The cornea of AG1478‐treated diabetic rats showed a slight increase in CF diameter and area fraction and a decreased number density.Conclusions: These data show that the distribution of corneal stroma CFs and PGs was altered after 4 weeks of diabetes and that, furthermore, treatment with an EGFR signalling inhibitor normalized these abnormalities. The data suggest that EGFR plays an important role in the development of diabetes‐induced corneal remodelling.

Research paper thumbnail of Pressor and Reflex Sensitivity Is Altered in Spontaneously Hypertensive Rats Treated With Angiotensin-(1-7)

Hypertension, Dec 1, 1995

We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotens... more We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotensin II (Ang II). This hypothesis was supported by the fact that long-term intravenous infusion of Ang-(1-7) transiently lowers blood pressure in spontaneously hypertensive rats (SHR). We now investigated whether the pressor sensitivity to bolus injections of either phenylephrine (PE) or Ang II was altered on day 12 of an Ang-(1-7) infusion when blood pressure in the SHR had returned to hypertensive levels. SHR (n=10) and WKY rats (n=8) were given Ang-(1-7) intravenously via osmotic minipumps at a dose of 24 μg/kg per hour for 2 weeks. On day 12 of the infusion, mean arterial pressure and heart rate in halothane-anesthetized rats were similar in Ang-(1-7)–treated SHR (142±6 mm Hg; 388±9 beats per minute) and those infused with vehicle (146±5 mm Hg; 392±13 beats per minute). Pressor responsiveness to PE in Ang-(1-7)–treated SHR was 22% less at a dose of 10 μg, while pressor responses to Ang II decreased by 20% and 25% at doses of 0.05 and 0.1 μg, respectively, compared with the vehicle-treated SHR ( P <.05). There were no effects of the Ang-(1-7) infusion on pressor responses to Ang II or PE in WKY rats. In the SHR infused with Ang-(1-7), there was a 35% improvement in sensitivity of the reflex control of heart rate to levels not different from those in the untreated WKY rats (slope of the change in pulse interval versus the change in pressure increased from 0.34±0.03 to 0.46±0.01 ms/mm Hg). These data suggest that Ang-(1-7) may selectively activate antihypertensive mechanisms at the level of the vascular wall or the baroreflex.

Research paper thumbnail of Nonviral delivery of synthetic siRNAs in vivo

Journal of Clinical Investigation, Dec 3, 2007

Research paper thumbnail of On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR–ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells

International Journal of Pharmaceutics, May 1, 2013

Research paper thumbnail of Phosphoinositide 3-kinase mediated signalling contributes to development of diabetes-induced abnormal vascular reactivity of rat carotid artery

Cell Biochemistry and Function, 2005

Research paper thumbnail of Angiotensin-(1–7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity

Research paper thumbnail of Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats

American Journal of Physiology-heart and Circulatory Physiology, Jul 1, 1995

Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiote... more Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiotensin II (ANG II) prompted an investigation of the effects of the heptapeptide on the maintenance of elevated blood pressure in spontaneously hypertensive rats (SHR). ANG-(1-7) (24 micrograms.kg-1.h-1) was infused into the jugular vein of 13-wk-old SHR (n = 64), Wistar-Kyoto (WKY, n = 50), and Sprague-Dawley (SD, n = 18) rats for 2 wk, with the use of osmotic minipumps. Blood pressure, fluid and electrolyte balance, plasma vasopressin, and urinary excretion of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured at days 2, 7, and 12 of the infusion. In SHR, ANG-(1-7) caused a sustained and significant reduction in plasma vasopressin concentration that was associated with an increase in urinary prostaglandin E2 and 6-keto-PGF1 alpha excretion at day 2 after the commencement of the infusion. These changes were accompanied by diuresis and natriuresis during the first 3 days of infusion in SHR but not in WKY or SD rats. Direct measurements of arterial pressure confirmed the lowering effect of ANG-(1-7) on systolic pressure of SHR on day 2 of treatment with a restoration of the pressure by days 7 and 12. These findings, along with our previous demonstration that ANG-(1-7) is an active depressor peptide in the intact animal, suggest that ANG-(1-7) may play a significant role as a vasodepressor system opposing the hemodynamic actions of ANG II in this genetic form of experimental hypertension.

Research paper thumbnail of Cardiovascular actions of angiotensin(1–7)

Peptides, Jul 1, 1993

... Injections of saline (vehicle) or an-Requests for reprints should be addressed to Ibrahim F. ... more ... Injections of saline (vehicle) or an-Requests for reprints should be addressed to Ibrahim F. Benter, Ph.D., Hypertension Center, Bowman Gray School ... New York: McGraw-Hill, Inc.; 1977:183-20 I. 4. Chappell, MC; Brosnihan, KB; Diz, DI; Ferrario, CM Iden-tification of angiotensin ...

Research paper thumbnail of The role of epidermal growth factor receptor in diabetes-induced cardiac dysfunction

DOAJ (DOAJ: Directory of Open Access Journals), 2013

Research paper thumbnail of 09 Calcium/calmodulin-dependent protein kinase II plays a significant role in mediating the beneficial effects of ischemic preconditioning on cardiac function during recovery from global ischemia

Journal of Molecular and Cellular Cardiology, Jul 1, 2002