D. Maysinger - Academia.edu (original) (raw)

Papers by D. Maysinger

Alcoholism: Clinical and Experimental Research, 2010

International Journal of Pharmaceutics, 1995

Broxuridine (BrdU) was covalently bound to a,/3-poly[(2-hydroxyetbyl)-oL-aspartamide] (PHEA) and ... more Broxuridine (BrdU) was covalently bound to a,/3-poly[(2-hydroxyetbyl)-oL-aspartamide] (PHEA) and ct,/3poly[(2-aminoethyl)-DL-aspartamide]-a,/3-poly[(2-hydroxyethyl)-DL-aspartamide] (PAHA). BrdU was first chemically modified to 3'-O-acetyl-5'-O-chloroformyl-5-bromo-2'-deoxyuridine (AcCBrdU) and 3'-O-acetyl-5'-O-phosphooxydichloride-5-bromo-2'-deoxyuridine (AcPBrdU). These compounds were bound to PHEA by carbonate and phosphodiester linkages, respectively. 5-Bromo-2'-deoxyuridine 5'-monophosphate (PBrdU) was linked to PAHA by an amide type bond. Neuroepithelial cells were used as a model system to assess the suitability of the conjugated BrdU for cell proliferation. Parallel experiments were performed with unconjugated BrdU and the extent of incorporation into DNA was determined by immunocytochemistry using an BrdU antibody. The results from these studies suggest that conjugated BrdU can be used as an alternative to currently used means of BrdU delivery.

The FASEB Journal, 2004

INGAP peptide comprises the core active sequence of Islet Neogenesis Associated Protein (INGAP), ... more INGAP peptide comprises the core active sequence of Islet Neogenesis Associated Protein (INGAP), a pancreatic cytokine that can induce new islet formation and restore euglycemia in diabetic rodents. The ability of INGAP peptide in vitro to enhance nerve growth from sensory ganglia suggests its potential utility in peripheral nerve disorders. In this study, INGAP peptide was administered alone or in combination with insulin to streptozotocin-induced diabetic mice exhibiting signs of peripheral neuropathy. Following a 2-wk treatment period, thermal hypoalgesia in diabetic mice was significantly improved in groups that received INGAP peptide, without development of hyperalgesia. Explanted dorsal root ganglia (DRG) from these groups showed enhanced nerve outgrowth and evidence of increased mitochondrial activity. Western blotting experiments revealed attenuation of neurofilament hyperphosphorylation, up-regulation of β-tubulin and actin, and increased phosphorylation of the transcription factor STAT3 in DRG. These findings suggest that INGAP peptide can activate some of the signaling pathways implicated in nerve regeneration in sensory ganglia, thereby providing a means of improvement of nociceptive dysfunction in the peripheral nervous system. Key words: dorsal root ganglia • diabetic neuropathy • STAT mong the complications of diabetes, peripheral neuropathy (DN) remains arguably the most debilitating and has presented a major challenge to the development of effective therapeutics (1, 2). The general consensus is that therapy with insulin (3, 4) or with the classical neurotrophins nerve growth factor (NGF) (5) or brain-derived neurotrophic factor (BDNF) (6) is largely ineffective as treatment for this disorder. Recent efforts have focused on other growth factors, including neurotrophin-3 (NT-3) (7, 8), glial-derived neurotrophic factor (GDNF) (9, 10), and insulin-like growth factor 1 (IGF-1) (11-13), whose modes of action in nervous tissue are well defined. More recently, neuroprotective properties of the insulinotropic agents glucagon-like peptide 1 (GLP-1) and its analog exendin-4 have been identified (14-17), and their combined pancreatic and neural effects may make them potentially useful as leads for the development of therapeutics for DN. The ability of the islet neogenic agent INGAP peptide A

Neurochemistry International, 1993

We demonstrated that genetically modifed fibroblasts can be encapsulated into biocompatible, biod... more We demonstrated that genetically modifed fibroblasts can be encapsulated into biocompatible, biodegradable spheres retaining their viability and capacity to continuously secrete nerve growth factor (NGF) for at least two months. Genetically engineered rat fibroblasts producing NGF were encapsulated in an alginate-polylysine gel with the ultimate objective of improving transplantation methodologies. Cultures were suspended in a sodium algmate solution and the suspension was extruded drop-wise into a solution of calcium chloride. Morphological properties of the spheres were assessed by light and electron microscopy. The spheres had a homogenous external membrane, without fibroblasts, protruding from the surface of the capsular membrane. The NGF determinations in culture media showed that encapsulated fibroblasts continued to synthesize NGF for at least 60 days. We also confirmed that secreted NGF was biologically active, by assessing the induction of choline acetyltransferase (CHAT) activity in dissociated embryonic rat septal cultures. These results encourage further studies using in vivo models to determine the value of applying microencapsulated genetically modified cells secreting trophic factors as a therapeutic strategy for central nervous system (CNS) injuries.

Diabetologia, 2006

Aims/hypothesis The phosphatidylinositol 3-kinase (PI3K)/ Akt pathway plays a critical role in pr... more Aims/hypothesis The phosphatidylinositol 3-kinase (PI3K)/ Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. Methods In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. Results We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. Conclusions/interpretation Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway. Keywords Akt. Apoptosis. Diabetes mellitus. Insulin. Islet transplantation. Islets of Langerhans Abbreviations DAPI 4,6-diamidino-2-phenylindole FBS fetal bovine serum FDA fluorescein diacetate IBMX 3-isobutyl-1-methylxanthine IEQ islet equivalent IGFR1 insulin-like growth factor receptor 1 IR insulin receptor JNK c-jun NH 2-terminal kinase MTT 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide PI propidium iodide PI3K phosphatidylinositol 3-kinase TCN triciribine

Cell Biology and Toxicology, 2004

Lower micromolar concentrations of peroxovanadium compound potassium bisperoxo(1,10-phenanthrolin... more Lower micromolar concentrations of peroxovanadium compound potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) [bpV (phen)] stimulate RINm5F cell metabolic activity. 1 and 3 micromol/L bpV (phen) induces strong and sustained activation of extracellular signal-regulated kinase (ERK). However, it seems that bpV (phen) does not effect c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. In addition, bpV (phen) induces mitogen-activated protein kinase phosphatase-1 (MKP-1) expression. We found that ERK activation could be completely abolished if RINm5F cells were incubated with both bpV (phen) and PD 98059, a specific inhibitor of upstream ERK kinase MEK1. On the other hand, this combined treatment up-regulated activation of stress kinases, JNK and p38 MAPK, significantly suppressed MKP-1 expression and induced cell death. Thus, our results suggest that the mechanism underlying bpV (phen) survival-enhancing effect could be associated with induced ERK activation and MKP-1 expression.

FEBS Letters, 1999

Isolation and purification of islet cells exposes them to ischemic, osmotic and mechanical stress... more Isolation and purification of islet cells exposes them to ischemic, osmotic and mechanical stresses. The objective of this study was to determine the roles of the MAP-kinases in islets immediately following isolation. During the first 48 h, activity of JNK1 and JNK2 declined markedly. Activity of p38 increased steadily with time in culture while extracellular signal regulated kinase (ERK) activity declined dramatically within 24 h postisolation. High p38 activation relative to ERK activation immediately following isolation correlated with a decrease in islet survival after 36 h in culture. Absence and/or transiency of ERK signaling in conjunction with sustained activation of p38 pathway could be an important regulator of cell death in islets during and following their isolation by commonly employed procedures.

Pharmazie, 1979

By the condensation of isatin and 5-nitroisatin with substituted aromatic amines, isatin- and 5-n... more By the condensation of isatin and 5-nitroisatin with substituted aromatic amines, isatin- and 5-nitroisatin-3-(phenyl)-imines (azomethines) are formed which are converted into N-Mannich-bases by aminomethylation and may be formulated as azomethines with E configuration. A biotest of Lepidium sativum L. was used to prove mitodepressive properties. Some compounds showed a significant growth-inhibiting activity. It was found that a change in activity is produced by condensation on the carbon atom in position 3 and by aminomethylation on the nitrogen atom in the isatin nucleus.

Progress in Brain Research, 1994

Page 356. L. Svennerholm. AK Asbury_ RA Reisfeld. K. Sandhoff. K. Suzuki, G. Tettamanti and G. To... more Page 356. L. Svennerholm. AK Asbury_ RA Reisfeld. K. Sandhoff. K. Suzuki, G. Tettamanti and G. Toffano (Eds) Progress in Bruin Rereurch, Vul. l () I © 1994 Elsevrer Science BV. All rights reserved. 337 CHAPTER 26 Cooperative ...

Journal of neural transmission. Supplementum, 1996

The neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), are establ... more The neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), are established survival promoting molecules for dopaminergic (DAergic) neurons cultured from the fetal rat midbrain floor. We have cultured and compared the survival of embryonic day (E) 14 mesencephalic cells in fully defined, serum-free medium, with serum-primed cultures (one hour during dissociation). Cultures were characterized using antibodies against neuron-specific enolase (NSE), tyrosine hydroxylase (TH), vimentin, glial fibrillary acidic protein (GFAP), and the antigen A2B5. The absolute absence of serum did not reduce the survival of TH-positive DAergic neurons nor alter the percentages of cells staining for the above markers. Transforming growth factor-beta 3 (TGF-beta 3) and glial cell line-derived neurotrophic factor (GDNF), two members of the TGF-beta superfamily, both promoted the survival of TH-positive cells (TGF-beta 3: 2-fold; GDNF: 1.6-fold) over the 8-day culture period. Surv...

Pharmazie, 1985

Thirty eight propolis samples were collected in several regions of SR Croatia differing in climat... more Thirty eight propolis samples were collected in several regions of SR Croatia differing in climate and vegetation. Amounts of 3,5,7-trihydroxyflavone and of 5,7-dihydroxyflavonone were determined chromatographically in individual propolis samples. Concentrations of each constituent were correlated with the growth inhibitions of Bacillus subtilis (IP-5832).

Pharmazie, 1980

A series of compounds with various basic side chains were derived from 5-nitro-8-hydroxyquinoline... more A series of compounds with various basic side chains were derived from 5-nitro-8-hydroxyquinoline (nitroxoline). Aminomethylation of nitroxoline led exclusively to the formation of o-substituted phenolic Mannich bases. Depending on the kind of the primary or secondary amine participating in the Mannich reaction differently substituted compounds were prepared in order to study the influence of the basic side chain on their biological activity. The compound with N-bis(2-hydroxyethyl)amino group exhibited the highest mitodepressant activity determined in a phyto test on Lepidium sativum L. Preliminary test for antibacterial and antifungal activities using standard test microorganisms indicate rather strong antimicrobial properties of several synthesized compounds.

The composition of 31 samples of propolis extract was investigated by using TLC. Ethanol extract ... more The composition of 31 samples of propolis extract was investigated by using TLC. Ethanol extract of propolis (EEP) prepared from the various propolis samples differ mainly in quantities of identified compounds, and not in kind of components present. According to the inhibitory activity against Bacillus subtilis, the propolis samples were grouped in three categories. It appears that the galangin content in a sample is a main constituent, which determines its antibacterial activity.

Chemischer Informationsdienst, 1986

Reduced estrogens, either through aging or postsurgery breast cancer treatment with the oral nons... more Reduced estrogens, either through aging or postsurgery breast cancer treatment with the oral nonsteroidal aromatase inhibitor letrozole, are linked with declined cognitive abilities. However, a direct link between letrozole and neuronal deficits induced by pathogenic insults associated with aging such as beta amyloid (1-42) has not been established. The objective of this study was to determine if letrozole aggravates synaptic deficits concurrent with 1-42 insult. We examined the effects of letrozole and oligomeric 1-42 treatment in dissociated and organotypic hippocampal slice cultures. Changes in glial cell morphology, neuronal mitochondria, and synaptic structures upon letrozole treatment were monitored by confocal microscopy, as they were shown to be affected by 1-42 oligomers. Oligomeric 1-42 or letrozole alone caused decreases in mitochondrial volume, dendritic spine density, synaptophysin (synaptic marker), and the postsynaptic protein, synaptopodin. Here, we demonstrated that mitochondrial and synaptic structural deficits were exacerbated when letrozole therapy was combined with 1-42 treatment. Our novel findings suggest that letrozole may increase neuronal susceptibility to pathological insults, such as oligomeric 1-42 in Alzheimer's disease (AD). These changes in dendritic spine number, synaptic protein expression, and mitochondrial morphology may, in part, explain the increased prevalence of cognitive decline associated with aromatase inhibitor use.

Cell Death and Disease, 2014

Neurochemistry International, 1992

Mustard derivatives of ethyl-chohne and hemlchollmum-3 have been suggested as possible specific c... more Mustard derivatives of ethyl-chohne and hemlchollmum-3 have been suggested as possible specific chohnerglc neurotoxms In this study a structural analog of hemlchohmum-3, a,a'-bls[dl(2-chloroethyl)ammo]-4,4'-2-blacetophenone (toxin 7), was added to synaptosomes prepared from the cortex, strlatum or hippocampus of rat brain Synaptosomal high affinity chohne uptake (HACU) was slgmficantly decreased m a dose-dependent manner by ad&tion of toxin 7, while synaptosomal uptake of GABA or dopamlne was not changed Incubation of cortical synaptosomes with the monoslaloganghoslde GM1 prevented the decrease m HACU seen following admlmstratlon of toxin 7 This preventative effect of GM1 was greater ff GM 1 was added prior to or concomitant with toxin 7, than ff GMI was added following toxin 7 Two newly synthesized hemacholanlum-3 analogs, 4-[Y-&(2-chloroethyl)ammopropionyl] baphenyl (toxin 5) and 4-[Y-&(2-bromoethyl)ammoproptonyl]blphenyl (toxin 6) caused a large decrease in HACU when added to cortical synaptosomes, this decrease was significantly greater than that seen with the same dose of toxin 7 or ethyl-choline azmdmmm (AF64A) Ultrastructural changes m the synaptosomal membrane following incubation with toxin 7 or toxin 7 with GM1 were examined by electron macroscopy Development of a compound whach ~s both a potent neurotoxm, and as specific for chollnerglc neurons will allow new insights into the normal function of the chohnerglc system in the CNS and provide ammal models of disease states in which chohnergm degeneration is an important element

Journal of Pharmaceutical Sciences, 1979

The antimicrobial and antifungal activities of 29 congeneric isatin N-Mannich bases were investig... more The antimicrobial and antifungal activities of 29 congeneric isatin N-Mannich bases were investigated by testing against standard test microorganisms and 21 pathogenic Gram-negative microorganisms. Considerable growth inhibition of Gram-negative bacteria and yeasts and slight inhibition of Gram-positive bacteria resulted when they were treated with the various N-Mannich bases of isatin and 5-nitroisatin, respectively.