Skilled research professional with a demonstrated history of working in the higher education industry. Experience in a wide range of laboratory and computer skills, and in managing projects with minimal supervision. Strong interpersonal skills. Excellent written communication and engaging public speaker. Strong experience with social media and networking. Excellent management and organizational skills.
INTRODUCTION: Sensitive assays for measuring heme oxygenase activity have been based on the gas-c... more INTRODUCTION: Sensitive assays for measuring heme oxygenase activity have been based on the gas-chromatographic detection of carbon monoxide using elaborate, expensive equipment. The present study describes a rapid and convenient method for ...
Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk fo... more Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk for the development of atherosclerotic disease which may be attributable to the ability of Lp(a) to attenuate fibrinolysis. A generally accepted mechanism for this effect involves ...
Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been report... more Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been reported to play a critical role in hearing al-though the underlying mechanisms remain elusive. However, its widespread tissue distribution infers a more ubiquitous role in syn-aptic vesicle trafficking. Glutamate, an excitatory neurotransmitter, is converted to its inhibitory counterpart, g-aminobutyric acid (GABA), by L-glutamic acid decarboxylase (GAD), which exists in soluble (GAD67) and membrane-bound (GAD65) forms. For the first time, we have revealed a close association between otoferlin and GAD65 in both HEK293 and neuronal cells, including SH-SY5Y neuroblastoma and primary rat hippocampus cells, showing a direct interaction between GAD65 and otoferlin’s C2 domains. In primary rat hippocampus cells, otoferlin and GAD65 co-localized in a punctate pattern within the cell body, as well as in the axon along the path of vesicular traffic. Significantly, GABA is virtually abolished in otofer...
While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and... more While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and -2 (HO-2) in mammals, our understanding of the functions of these enzymes in health and disease is still incomplete. A significant amount of our knowledge has been garnered through the use of nonselective inhibitors of HOs, and our laboratory has re- cently described more selective inhibitors for HO-1. In addition, our appreciation of HO-1 has benefitted from the availabil- ity of tools for increasing its activity through enzyme induction. By comparison, there is a paucity of information about HO-2 activation, with only a few reports appearing in the literature. This communication describes our observations of the up to 30-fold increase in the in-vitro activation of HO-2 by menadione. This activation was due to an increase in Vmax and was selective, in that menadione did not increase HO-1 activity.
Aims: While great strides have been made in the elucidation of the physiological and pharmacologi... more Aims: While great strides have been made in the elucidation of the physiological and pharmacological roles of heme oxygenases (HO) in experimental animals and humans, there is still an enormous potential for further research discoveries and their application in therapeutics. We have identified the need for improved pharmacological tools for Heme Oxygenase research, and have conducted a program to design and test new compounds for their potential as selective inhibitors and activators of HO-1 and HO-2. Methods & Results: Our first undertaking exploited the "hit" compound, (2S,4S)-2-[2-(4-chlorphenyl)ethyl]-2-[(1H-imidazol- 1-yl)methyl]-4-[((4- aminophenyl)thio)methyl]-1,3-dioxolane, QC-1. New candidates were designed on the basis of QC-1, and synthesized in our laboratories; they were then tested for HO inhibition using spleen and brain microsomal preparations as sources of HO-1 and HO-2, respectively. Many QC-xx compounds were identified as inhibitors of both HO-1 and HO-2...
Abstract: Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared wi... more Abstract: Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared with their crude microsomal counterparts from brain and spleen tissue of adult male rats with respect to their inhibition by azole-based, nonporphyrin HO inhibitors. The drugs ...
The therapeutic potential of angiogenic growth factors has not been realized. This may be because... more The therapeutic potential of angiogenic growth factors has not been realized. This may be because formation of endothelial sprouts is not followed by their muscularization into vasoreactive arteries. Using microarray expression analysis, we discovered that fibroblast growth factor 9 (FGF9) was highly upregulated as human vascular smooth muscle cells (SMCs) assemble into layered cords. FGF9 was not angiogenic when mixed with tissue implants or delivered to the ischemic mouse hind limb, but instead orchestrated wrapping of SMCs around neovessels. SMC wrapping in implants was driven by sonic hedgehog-mediated upregulation of PDGFRβ. Computed tomography microangiography and intravital microscopy revealed that microvessels formed in the presence of FGF9 had enhanced capacity to receive flow and were vasoreactive. Moreover, the vessels persisted beyond 1 year, remodeling into multilayered arteries paired with peripheral nerves. This mature physiological competency was attained by targeting mesenchymal cells rather than endothelial cells, a finding that could inform strategies for therapeutic angiogenesis and tissue engineering.
Journal of Pharmacological and Toxicological Methods, 2011
Sensitive assays for measuring heme oxygenase activity have been based on the gas-chromatographic... more Sensitive assays for measuring heme oxygenase activity have been based on the gas-chromatographic detection of carbon monoxide using elaborate, expensive equipment. The present study describes a rapid and convenient method for screening imidazole-containing candidates for inhibitory activity against heme oxygenase using a plate reader, based on the spectroscopic evaluation of heme degradation. A PowerWave XS plate reader was used to monitor the absorbance (as a function of time) of heme bound to purified truncated human heme oxygenase-1 (hHO-1) in the individual wells of a standard 96-well plate (with or without the addition of a test compound). The degradation of heme by heme oxygenase-1 was initiated using l-ascorbic acid, and the collected relevant absorbance data were analyzed by three different methods to calculate the percent control activity occurring in wells containing test compounds relative to that occurring in control wells with no test compound present. In the cases of wells containing inhibitory compounds, significant shifts in λ(max) from 404 to near 412 nm were observed as well as a decrease in the rate of heme degradation relative to that of the control. Each of the three methods of data processing (overall percent drop in absorbance over 1.5h, initial rate of reaction determined over the first 5 min, and estimated pseudo first-order reaction rate constant determined over 1.5h) gave similar and reproducible results for percent control activity. The fastest and easiest method of data analysis was determined to be that using initial rates, involving data acquisition for only 5 min once reactions have been initiated using l-ascorbic acid. The results of the study demonstrate that this simple assay based on the spectroscopic detection of heme represents a rapid, convenient method to determine the relative inhibitory activity of candidate compounds, and is useful in quickly screening a series or library of compounds for heme oxygenase inhibition.
The crystal structure of human heme oxygenase-1 (HO-1) in complex with (2R,4S)-2-[2-(4-chlorophen... more The crystal structure of human heme oxygenase-1 (HO-1) in complex with (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-trifluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane (4) reveals a novel, inducible binding mode. Inhibitor 4 coordinates the heme iron, with its chlorophenyl group bound in a distal hydrophobic pocket, as seen in previous structures. However, accommodation of the 5-trifluoromethylpyridin-2-yl group requires a significant shift in the proximal helix, inducing the formation of a hydrophobic pocket. This is the first example of an induced binding pocket observed in HO-1.
Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme ... more Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include a series of substituted thiophenol and substituted phenol derivatives of (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[(phenylsulfanyl)methyl]-1,3-dioxolane hydrochloride (3), in addition to smaller functionalized derivatives, continue our structure-activity studies by exploration of the aminothiophenol region ('northeastern region') in our original target structure azalanstat (1). In vitro, most of the compounds in this series were found to be highly potent inhibitors of the stress-induced isozyme HO-1 and the constitutive isozyme HO-2, showing only moderate selectivity for HO-1. Nevertheless, a few of the compounds displayed higher selectivity toward HO-1. None of the compounds having a larger appendage in the northeastern region were inhibitors of CYP2E1, whereas a compound having a relatively small fluorine substituent in this region did inhibit CYP2E1; all of the compounds tested exhibited high inhibitory potency against CYP3A1/3A2.
INTRODUCTION: Sensitive assays for measuring heme oxygenase activity have been based on the gas-c... more INTRODUCTION: Sensitive assays for measuring heme oxygenase activity have been based on the gas-chromatographic detection of carbon monoxide using elaborate, expensive equipment. The present study describes a rapid and convenient method for ...
Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk fo... more Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk for the development of atherosclerotic disease which may be attributable to the ability of Lp(a) to attenuate fibrinolysis. A generally accepted mechanism for this effect involves ...
Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been report... more Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been reported to play a critical role in hearing al-though the underlying mechanisms remain elusive. However, its widespread tissue distribution infers a more ubiquitous role in syn-aptic vesicle trafficking. Glutamate, an excitatory neurotransmitter, is converted to its inhibitory counterpart, g-aminobutyric acid (GABA), by L-glutamic acid decarboxylase (GAD), which exists in soluble (GAD67) and membrane-bound (GAD65) forms. For the first time, we have revealed a close association between otoferlin and GAD65 in both HEK293 and neuronal cells, including SH-SY5Y neuroblastoma and primary rat hippocampus cells, showing a direct interaction between GAD65 and otoferlin’s C2 domains. In primary rat hippocampus cells, otoferlin and GAD65 co-localized in a punctate pattern within the cell body, as well as in the axon along the path of vesicular traffic. Significantly, GABA is virtually abolished in otofer...
While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and... more While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and -2 (HO-2) in mammals, our understanding of the functions of these enzymes in health and disease is still incomplete. A significant amount of our knowledge has been garnered through the use of nonselective inhibitors of HOs, and our laboratory has re- cently described more selective inhibitors for HO-1. In addition, our appreciation of HO-1 has benefitted from the availabil- ity of tools for increasing its activity through enzyme induction. By comparison, there is a paucity of information about HO-2 activation, with only a few reports appearing in the literature. This communication describes our observations of the up to 30-fold increase in the in-vitro activation of HO-2 by menadione. This activation was due to an increase in Vmax and was selective, in that menadione did not increase HO-1 activity.
Aims: While great strides have been made in the elucidation of the physiological and pharmacologi... more Aims: While great strides have been made in the elucidation of the physiological and pharmacological roles of heme oxygenases (HO) in experimental animals and humans, there is still an enormous potential for further research discoveries and their application in therapeutics. We have identified the need for improved pharmacological tools for Heme Oxygenase research, and have conducted a program to design and test new compounds for their potential as selective inhibitors and activators of HO-1 and HO-2. Methods & Results: Our first undertaking exploited the "hit" compound, (2S,4S)-2-[2-(4-chlorphenyl)ethyl]-2-[(1H-imidazol- 1-yl)methyl]-4-[((4- aminophenyl)thio)methyl]-1,3-dioxolane, QC-1. New candidates were designed on the basis of QC-1, and synthesized in our laboratories; they were then tested for HO inhibition using spleen and brain microsomal preparations as sources of HO-1 and HO-2, respectively. Many QC-xx compounds were identified as inhibitors of both HO-1 and HO-2...
Abstract: Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared wi... more Abstract: Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared with their crude microsomal counterparts from brain and spleen tissue of adult male rats with respect to their inhibition by azole-based, nonporphyrin HO inhibitors. The drugs ...
The therapeutic potential of angiogenic growth factors has not been realized. This may be because... more The therapeutic potential of angiogenic growth factors has not been realized. This may be because formation of endothelial sprouts is not followed by their muscularization into vasoreactive arteries. Using microarray expression analysis, we discovered that fibroblast growth factor 9 (FGF9) was highly upregulated as human vascular smooth muscle cells (SMCs) assemble into layered cords. FGF9 was not angiogenic when mixed with tissue implants or delivered to the ischemic mouse hind limb, but instead orchestrated wrapping of SMCs around neovessels. SMC wrapping in implants was driven by sonic hedgehog-mediated upregulation of PDGFRβ. Computed tomography microangiography and intravital microscopy revealed that microvessels formed in the presence of FGF9 had enhanced capacity to receive flow and were vasoreactive. Moreover, the vessels persisted beyond 1 year, remodeling into multilayered arteries paired with peripheral nerves. This mature physiological competency was attained by targeting mesenchymal cells rather than endothelial cells, a finding that could inform strategies for therapeutic angiogenesis and tissue engineering.
Journal of Pharmacological and Toxicological Methods, 2011
Sensitive assays for measuring heme oxygenase activity have been based on the gas-chromatographic... more Sensitive assays for measuring heme oxygenase activity have been based on the gas-chromatographic detection of carbon monoxide using elaborate, expensive equipment. The present study describes a rapid and convenient method for screening imidazole-containing candidates for inhibitory activity against heme oxygenase using a plate reader, based on the spectroscopic evaluation of heme degradation. A PowerWave XS plate reader was used to monitor the absorbance (as a function of time) of heme bound to purified truncated human heme oxygenase-1 (hHO-1) in the individual wells of a standard 96-well plate (with or without the addition of a test compound). The degradation of heme by heme oxygenase-1 was initiated using l-ascorbic acid, and the collected relevant absorbance data were analyzed by three different methods to calculate the percent control activity occurring in wells containing test compounds relative to that occurring in control wells with no test compound present. In the cases of wells containing inhibitory compounds, significant shifts in λ(max) from 404 to near 412 nm were observed as well as a decrease in the rate of heme degradation relative to that of the control. Each of the three methods of data processing (overall percent drop in absorbance over 1.5h, initial rate of reaction determined over the first 5 min, and estimated pseudo first-order reaction rate constant determined over 1.5h) gave similar and reproducible results for percent control activity. The fastest and easiest method of data analysis was determined to be that using initial rates, involving data acquisition for only 5 min once reactions have been initiated using l-ascorbic acid. The results of the study demonstrate that this simple assay based on the spectroscopic detection of heme represents a rapid, convenient method to determine the relative inhibitory activity of candidate compounds, and is useful in quickly screening a series or library of compounds for heme oxygenase inhibition.
The crystal structure of human heme oxygenase-1 (HO-1) in complex with (2R,4S)-2-[2-(4-chlorophen... more The crystal structure of human heme oxygenase-1 (HO-1) in complex with (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-trifluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane (4) reveals a novel, inducible binding mode. Inhibitor 4 coordinates the heme iron, with its chlorophenyl group bound in a distal hydrophobic pocket, as seen in previous structures. However, accommodation of the 5-trifluoromethylpyridin-2-yl group requires a significant shift in the proximal helix, inducing the formation of a hydrophobic pocket. This is the first example of an induced binding pocket observed in HO-1.
Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme ... more Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include a series of substituted thiophenol and substituted phenol derivatives of (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[(phenylsulfanyl)methyl]-1,3-dioxolane hydrochloride (3), in addition to smaller functionalized derivatives, continue our structure-activity studies by exploration of the aminothiophenol region ('northeastern region') in our original target structure azalanstat (1). In vitro, most of the compounds in this series were found to be highly potent inhibitors of the stress-induced isozyme HO-1 and the constitutive isozyme HO-2, showing only moderate selectivity for HO-1. Nevertheless, a few of the compounds displayed higher selectivity toward HO-1. None of the compounds having a larger appendage in the northeastern region were inhibitors of CYP2E1, whereas a compound having a relatively small fluorine substituent in this region did inhibit CYP2E1; all of the compounds tested exhibited high inhibitory potency against CYP3A1/3A2.
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Papers by Mona N Rahman