Todd Penberthy - Academia.edu (original) (raw)

Papers by Todd Penberthy

Journal of Lasers in Medical Sciences

Introduction: Photobiomodulation or low-level laser therapy (LLLT;<0.5 W) has been used as a n... more Introduction: Photobiomodulation or low-level laser therapy (LLLT;<0.5 W) has been used as a non-invasive treatment for various medical indications. Short (visible; 635-650 nm) and longer (invisible; 810-850 nm and 915-980 nm) near-infrared wavelengths have been commonly used, but power setting deficiencies or incorrect wavelength settings can cause negative outcomes. The 1064 nm wavelength as the longest wavelength is a relative newcomer in high-powered (>0.5 W) laser photobiomodulation therapy (HPL-PBMT) with unique biophysical characteristics. Methods: A comprehensive search of 2016-2021 PubMed, Google Scholar, and Cochrane databases for "photobiomodulation" restricted to clinical trials for patients with a medical diagnosis was done. "1064 nm" content was identified and restricted to high-powered lasers (>0.5 watt). Cohen’s d was calculated for the effect size and the difference was determined as a measure of relative 1064 nm HPL-PBMT efficacy. Resul...

Present Knowledge in Nutrition, 2020

A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes... more A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development

Acute attacks of multiple sclerosis (MS) are most commonly treated with glucocorticoids, which ca... more Acute attacks of multiple sclerosis (MS) are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA) is now known to involve induction of indoleamine 2,3-dioxygenase (IDO) and interleukin-10 (IL-10), where IL-10 requires subsequent heme oxygenase-1 (HMOX-1) induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2) can prevent demyelination in experimental autoimmune encephalomyelitis (EAE) animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs) demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the pro...

Nature Immunology, 2003

The zebrafish is firmly established as a genetic model for the study of vertebrate blood developm... more The zebrafish is firmly established as a genetic model for the study of vertebrate blood development. Here we have characterized the blood-forming system of adult zebrafish. Each major blood lineage can be isolated by flow cytometry, and with these lineal profiles, defects in zebrafish blood mutants can be quantified. We developed hematopoietic cell transplantation to study cell autonomy of mutant gene function and to establish a hematopoietic stem cell assay. Hematopoietic cell transplantation can rescue multilineage hematopoiesis in embryonic lethal gata1-/mutants for over 6 months. Direct visualization of fluorescent donor cells in embryonic recipients allows engraftment and homing events to be imaged in real time. These results provide a cellular context in which to study the genetics of hematopoiesis.

Gene, 2003

The selective expression of the Xenopus TFIIIA gene in immature oocytes is principally regulated ... more The selective expression of the Xenopus TFIIIA gene in immature oocytes is principally regulated by a single 5 0-flanking DNA sequence element, termed element 3 (i.e. E3). We describe the isolation and characterization of a cDNA for a protein present in immature Xenopus ooctyes, termed B3.65, which appears to bind to and activate E3-mediated expression. The approximate molecular weight of the E3 binding protein(s) was determined by ultraviolet light cross-linking analysis. B3.65, a protein of the appropriate molecular weight, was purified biochemically from immature Xenopus ooctye extracts by affinity chromatography. Antiserum to purified B3.65 super-shifted the E3 activator complex. In addition, B3.65 mRNA was found to be highly enriched in immature oocytes. All of these data are consistent with B3.65 either being the E3 activator, or antigenically related to the specific activator required for XenopusTFIIIA gene transcription. B3.65 is a member of the K-homologous (KH) domain family of proteins, with almost absolute identity to Xenopus Vg1 RBP/VERA (97%) and significant similarity to human koc (82%). The koc mRNA is over-expressed in human pancreatic cancer tissues, and B3.65 mRNA was detected in Xenopus pancreas and kidney. Interestingly, KH proteins, like Vg1RBP/VERA, are most commonly associated with RNA metabolism, in their capacity to regulate RNA localization, stability, and translation. Our results suggest that B3.65 is a key regulator of both RNA-and DNA metabolism.

Frontiers in Bioscience, 2002

Introduction 2.1. Basic developmental advantages of the zebrafish 2.2. Forward genetic screen the... more Introduction 2.1. Basic developmental advantages of the zebrafish 2.2. Forward genetic screen the original impetus for zebrafish 2.3. Limitations and morpholinos 3.

Current Pharmaceutical Design, 2009

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory dem... more The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep autoreactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld S mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld S genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NADcomplementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

Current Drug Metabolism, 2007

Cellular and Molecular Life Sciences, 2011

Primate theta-defensins are physically distinguished as the only known fully-cyclic peptides of a... more Primate theta-defensins are physically distinguished as the only known fully-cyclic peptides of animal origin. Humans do not produce theta-defensin peptides due to a premature stop codon present in the signal sequence of all six theta-defensin pseudogenes. Instead, since the putative coding regions of human theta-defensin pseudogenes have remained remarkably intact, their corresponding peptides, called ''retrocyclins'', have been recreated using solid-phase synthetic approaches. Retrocyclins exhibit an exceptional therapeutic index both as inhibitors of HIV-1 entry and as bactericidal agents, which makes retrocyclins promising candidates for further development as topical microbicides to prevent sexually transmitted diseases. This review presents the evolution, antiretroviral mechanism of action, and potential clinical applications of retrocyclins to prevent sexual transmission of HIV-1. Keywords Retrocyclin Á Defensin Á HIV-1 Á Host defense peptide Á Antimicrobial peptide Á Antiviral Á Microbicide Abbreviations HDP Host-defense peptide RC Retrocyclin RTD Rhesus theta-defensin CXCR4 CXC chemokine receptor 4 CCR5 CC chemokine 5 HNP Human neutrophil peptide RTI Reverse transcriptase inhibitor

Present Knowledge in Nutrition, 2020

Erdman/Present Knowledge in Nutrition, 2012

A reduced niacin-mediated !ush is increasingly accepted today as a positive diagnostic indicator ... more A reduced niacin-mediated !ush is increasingly accepted today as a positive diagnostic indicator for schizophrenia. Schizophrenics that were successfully treated with high dose niacin (nicotinic acid) therapy by Dr. Abram Ho"er in the 1950s recovered from their otherwise pre - viously reduced !ush response simultaneous with recovery from schizophrenia. Signi#cantly, some schizophrenics also recovered after high dose nicotinamide treatment, a di"erent nicoti - namide adenine dinucleotide (NAD) precursor that does not cause a !ush response. Whether the niacin-!ush response is #rst due to replenishment of NAD de#ciency or due to a restora - tion of polyunsaturated fatty acid levels thus restoring niacin-!ush competence is not mutually exclusive. It is possible that nicotinic acid is #rst dedicated to intracellular NAD synthesis at the expense of the !ush response until the schizophrenic's immediate needs for NAD are #nally met. $en the nicotinic acid, rather than entering...

Journal of inherited metabolic disease, Jan 21, 2015

Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that ... more Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaire...

Current pharmaceutical design, 2009

The EPMA Journal, 2010

Type 1 diabetes (T1D) is an autoimmune disease in which a T-cell-mediated reaction demolishes ins... more Type 1 diabetes (T1D) is an autoimmune disease in which a T-cell-mediated reaction demolishes insulinproducing cells of pancreatic islets. Inadequacy of insulin therapy has motivated research focused on mechanisms by which autoimmune reactions can be suppressed. In recent years, the role of indoleamine 2,3 dioxygenase (IDO) in regulation of immune system has been extensively investigated. Initially, IDO was recognized as a host defense mechanism. However, recent studies have suggested an immunomodulatory role for IDO which may contribute to the induction of immune tolerance. In this review, we concentrate on the role of IDO in several pathologic conditions with a focus on T1D to rationalize our hypothesis regarding the potential for inclusion of IDO in certain therapeutic strategies aimed at early detection, treatment or ideally cure of chronic and autoimmune diseases such as T1D.

Journal of Neurochemistry, 2008

Previous studies have demonstrated that bovine chromaffin cells cultured in medium with 10 nM ins... more Previous studies have demonstrated that bovine chromaffin cells cultured in medium with 10 nM insulin-like growth factor-I (IGF-I) secrete about twofold more catecholamine when exposed to secretory stimuli than do cells cultured without IGF-I. The purpose of this study was to determine whether protein kinase C (PKC) is involved in the effect of IGF-I on secretion from these cells. PKC was down-regulated in the cells by 16-18 h of treatment with beta-phorbol didecanoate (beta-PDD; 100 nM). Such treatment had no effect on high-K(+)-stimulated secretion from cells cultured without IGF-I; however, secretion from cells cultured with IGF-I was reduced to a level comparable to that in cells cultured without the peptide. The inactive isomer, alpha-PDD (100 nM), had no effect on secretion from untreated or IGF-I-treated chromaffin cells. The effect of beta-PDD was time and concentration dependent, with 100 nM beta-PDD producing a maximal effect in 8-10 h. In situ PKC activity measured in permeabilized cells treated with PMA (300 nM) was decreased by approximately 40% by 10 h and was reduced to almost basal levels by 18 h. Immunoblotting experiments demonstrated that both alpha- and epsilon-PKC were lost from the cells with time courses similar to that seen in the in situ PKC assay. Overnight treatment with the PKC inhibitor H7 (100 microM) prevented the enhanced secretion normally seen in IGF-I-treated cells, whereas HA1004 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Gene, 2003

In the Xenopus laevis oocyte there is a million fold more transcription factor IIIA (TFIIIA) and ... more In the Xenopus laevis oocyte there is a million fold more transcription factor IIIA (TFIIIA) and its corresponding mRNA than in a somatic cell. These high levels of TFIIIA gene expression are achieved primarily by transcriptional regulation. The TATA box along with three positive cis-elements in the control region of the TFIIIA gene located at positions 2 269 to 2 264 (E1), 2235 to 2 220 (E2), and 2669 to 2 636 (E3) are required for this high level of expression in oocytes. The proteins that bind E1 and E3 of the TFIIIA gene have been identified as Xenopus USF (Xl-USF) and B3 (homolog of Vg1 RBP/VERA). In this study the B2 protein was found to bind E2 in a zinc-dependent fashion and anti-human Sp1 (but not Sp2, Sp3, nor Sp4) supershifted the B2:element 2 complex. The E2 binding protein was purified by DNA affinity chromatography. Based on supershift analysis, molecular weight estimation experiments, and purified human Sp1 DNA binding affinity tests the data strongly support the idea that the B2 protein is the Xenopus ortholog of Sp1, but not Sp2, Sp3, nor Sp4. Xl-USF binds to element 1 of the TFIIIA gene which is immediately adjacent to element 2. Coimmunoprecipitation experiments using crude whole oocyte extracts revealed that Xenopus Sp1 and USF or closely related factors are present together in a high-affinity complex. This structure contributes positively to the initiation of TFIIIA gene transcription in Xenopus oocytes.

Journal of Lasers in Medical Sciences

Introduction: Photobiomodulation or low-level laser therapy (LLLT;<0.5 W) has been used as a n... more Introduction: Photobiomodulation or low-level laser therapy (LLLT;<0.5 W) has been used as a non-invasive treatment for various medical indications. Short (visible; 635-650 nm) and longer (invisible; 810-850 nm and 915-980 nm) near-infrared wavelengths have been commonly used, but power setting deficiencies or incorrect wavelength settings can cause negative outcomes. The 1064 nm wavelength as the longest wavelength is a relative newcomer in high-powered (>0.5 W) laser photobiomodulation therapy (HPL-PBMT) with unique biophysical characteristics. Methods: A comprehensive search of 2016-2021 PubMed, Google Scholar, and Cochrane databases for "photobiomodulation" restricted to clinical trials for patients with a medical diagnosis was done. "1064 nm" content was identified and restricted to high-powered lasers (>0.5 watt). Cohen’s d was calculated for the effect size and the difference was determined as a measure of relative 1064 nm HPL-PBMT efficacy. Resul...

Present Knowledge in Nutrition, 2020

A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes... more A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development

Acute attacks of multiple sclerosis (MS) are most commonly treated with glucocorticoids, which ca... more Acute attacks of multiple sclerosis (MS) are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA) is now known to involve induction of indoleamine 2,3-dioxygenase (IDO) and interleukin-10 (IL-10), where IL-10 requires subsequent heme oxygenase-1 (HMOX-1) induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2) can prevent demyelination in experimental autoimmune encephalomyelitis (EAE) animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs) demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the pro...

Nature Immunology, 2003

The zebrafish is firmly established as a genetic model for the study of vertebrate blood developm... more The zebrafish is firmly established as a genetic model for the study of vertebrate blood development. Here we have characterized the blood-forming system of adult zebrafish. Each major blood lineage can be isolated by flow cytometry, and with these lineal profiles, defects in zebrafish blood mutants can be quantified. We developed hematopoietic cell transplantation to study cell autonomy of mutant gene function and to establish a hematopoietic stem cell assay. Hematopoietic cell transplantation can rescue multilineage hematopoiesis in embryonic lethal gata1-/mutants for over 6 months. Direct visualization of fluorescent donor cells in embryonic recipients allows engraftment and homing events to be imaged in real time. These results provide a cellular context in which to study the genetics of hematopoiesis.

Gene, 2003

The selective expression of the Xenopus TFIIIA gene in immature oocytes is principally regulated ... more The selective expression of the Xenopus TFIIIA gene in immature oocytes is principally regulated by a single 5 0-flanking DNA sequence element, termed element 3 (i.e. E3). We describe the isolation and characterization of a cDNA for a protein present in immature Xenopus ooctyes, termed B3.65, which appears to bind to and activate E3-mediated expression. The approximate molecular weight of the E3 binding protein(s) was determined by ultraviolet light cross-linking analysis. B3.65, a protein of the appropriate molecular weight, was purified biochemically from immature Xenopus ooctye extracts by affinity chromatography. Antiserum to purified B3.65 super-shifted the E3 activator complex. In addition, B3.65 mRNA was found to be highly enriched in immature oocytes. All of these data are consistent with B3.65 either being the E3 activator, or antigenically related to the specific activator required for XenopusTFIIIA gene transcription. B3.65 is a member of the K-homologous (KH) domain family of proteins, with almost absolute identity to Xenopus Vg1 RBP/VERA (97%) and significant similarity to human koc (82%). The koc mRNA is over-expressed in human pancreatic cancer tissues, and B3.65 mRNA was detected in Xenopus pancreas and kidney. Interestingly, KH proteins, like Vg1RBP/VERA, are most commonly associated with RNA metabolism, in their capacity to regulate RNA localization, stability, and translation. Our results suggest that B3.65 is a key regulator of both RNA-and DNA metabolism.

Frontiers in Bioscience, 2002

Introduction 2.1. Basic developmental advantages of the zebrafish 2.2. Forward genetic screen the... more Introduction 2.1. Basic developmental advantages of the zebrafish 2.2. Forward genetic screen the original impetus for zebrafish 2.3. Limitations and morpholinos 3.

Current Pharmaceutical Design, 2009

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory dem... more The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep autoreactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld S mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld S genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NADcomplementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

Current Drug Metabolism, 2007

Cellular and Molecular Life Sciences, 2011

Primate theta-defensins are physically distinguished as the only known fully-cyclic peptides of a... more Primate theta-defensins are physically distinguished as the only known fully-cyclic peptides of animal origin. Humans do not produce theta-defensin peptides due to a premature stop codon present in the signal sequence of all six theta-defensin pseudogenes. Instead, since the putative coding regions of human theta-defensin pseudogenes have remained remarkably intact, their corresponding peptides, called ''retrocyclins'', have been recreated using solid-phase synthetic approaches. Retrocyclins exhibit an exceptional therapeutic index both as inhibitors of HIV-1 entry and as bactericidal agents, which makes retrocyclins promising candidates for further development as topical microbicides to prevent sexually transmitted diseases. This review presents the evolution, antiretroviral mechanism of action, and potential clinical applications of retrocyclins to prevent sexual transmission of HIV-1. Keywords Retrocyclin Á Defensin Á HIV-1 Á Host defense peptide Á Antimicrobial peptide Á Antiviral Á Microbicide Abbreviations HDP Host-defense peptide RC Retrocyclin RTD Rhesus theta-defensin CXCR4 CXC chemokine receptor 4 CCR5 CC chemokine 5 HNP Human neutrophil peptide RTI Reverse transcriptase inhibitor

Present Knowledge in Nutrition, 2020

Erdman/Present Knowledge in Nutrition, 2012

A reduced niacin-mediated !ush is increasingly accepted today as a positive diagnostic indicator ... more A reduced niacin-mediated !ush is increasingly accepted today as a positive diagnostic indicator for schizophrenia. Schizophrenics that were successfully treated with high dose niacin (nicotinic acid) therapy by Dr. Abram Ho"er in the 1950s recovered from their otherwise pre - viously reduced !ush response simultaneous with recovery from schizophrenia. Signi#cantly, some schizophrenics also recovered after high dose nicotinamide treatment, a di"erent nicoti - namide adenine dinucleotide (NAD) precursor that does not cause a !ush response. Whether the niacin-!ush response is #rst due to replenishment of NAD de#ciency or due to a restora - tion of polyunsaturated fatty acid levels thus restoring niacin-!ush competence is not mutually exclusive. It is possible that nicotinic acid is #rst dedicated to intracellular NAD synthesis at the expense of the !ush response until the schizophrenic's immediate needs for NAD are #nally met. $en the nicotinic acid, rather than entering...

Journal of inherited metabolic disease, Jan 21, 2015

Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that ... more Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaire...

Current pharmaceutical design, 2009

The EPMA Journal, 2010

Type 1 diabetes (T1D) is an autoimmune disease in which a T-cell-mediated reaction demolishes ins... more Type 1 diabetes (T1D) is an autoimmune disease in which a T-cell-mediated reaction demolishes insulinproducing cells of pancreatic islets. Inadequacy of insulin therapy has motivated research focused on mechanisms by which autoimmune reactions can be suppressed. In recent years, the role of indoleamine 2,3 dioxygenase (IDO) in regulation of immune system has been extensively investigated. Initially, IDO was recognized as a host defense mechanism. However, recent studies have suggested an immunomodulatory role for IDO which may contribute to the induction of immune tolerance. In this review, we concentrate on the role of IDO in several pathologic conditions with a focus on T1D to rationalize our hypothesis regarding the potential for inclusion of IDO in certain therapeutic strategies aimed at early detection, treatment or ideally cure of chronic and autoimmune diseases such as T1D.

Journal of Neurochemistry, 2008

Previous studies have demonstrated that bovine chromaffin cells cultured in medium with 10 nM ins... more Previous studies have demonstrated that bovine chromaffin cells cultured in medium with 10 nM insulin-like growth factor-I (IGF-I) secrete about twofold more catecholamine when exposed to secretory stimuli than do cells cultured without IGF-I. The purpose of this study was to determine whether protein kinase C (PKC) is involved in the effect of IGF-I on secretion from these cells. PKC was down-regulated in the cells by 16-18 h of treatment with beta-phorbol didecanoate (beta-PDD; 100 nM). Such treatment had no effect on high-K(+)-stimulated secretion from cells cultured without IGF-I; however, secretion from cells cultured with IGF-I was reduced to a level comparable to that in cells cultured without the peptide. The inactive isomer, alpha-PDD (100 nM), had no effect on secretion from untreated or IGF-I-treated chromaffin cells. The effect of beta-PDD was time and concentration dependent, with 100 nM beta-PDD producing a maximal effect in 8-10 h. In situ PKC activity measured in permeabilized cells treated with PMA (300 nM) was decreased by approximately 40% by 10 h and was reduced to almost basal levels by 18 h. Immunoblotting experiments demonstrated that both alpha- and epsilon-PKC were lost from the cells with time courses similar to that seen in the in situ PKC assay. Overnight treatment with the PKC inhibitor H7 (100 microM) prevented the enhanced secretion normally seen in IGF-I-treated cells, whereas HA1004 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Gene, 2003

In the Xenopus laevis oocyte there is a million fold more transcription factor IIIA (TFIIIA) and ... more In the Xenopus laevis oocyte there is a million fold more transcription factor IIIA (TFIIIA) and its corresponding mRNA than in a somatic cell. These high levels of TFIIIA gene expression are achieved primarily by transcriptional regulation. The TATA box along with three positive cis-elements in the control region of the TFIIIA gene located at positions 2 269 to 2 264 (E1), 2235 to 2 220 (E2), and 2669 to 2 636 (E3) are required for this high level of expression in oocytes. The proteins that bind E1 and E3 of the TFIIIA gene have been identified as Xenopus USF (Xl-USF) and B3 (homolog of Vg1 RBP/VERA). In this study the B2 protein was found to bind E2 in a zinc-dependent fashion and anti-human Sp1 (but not Sp2, Sp3, nor Sp4) supershifted the B2:element 2 complex. The E2 binding protein was purified by DNA affinity chromatography. Based on supershift analysis, molecular weight estimation experiments, and purified human Sp1 DNA binding affinity tests the data strongly support the idea that the B2 protein is the Xenopus ortholog of Sp1, but not Sp2, Sp3, nor Sp4. Xl-USF binds to element 1 of the TFIIIA gene which is immediately adjacent to element 2. Coimmunoprecipitation experiments using crude whole oocyte extracts revealed that Xenopus Sp1 and USF or closely related factors are present together in a high-affinity complex. This structure contributes positively to the initiation of TFIIIA gene transcription in Xenopus oocytes.