Authors
Luigi F. Agnati, Manuela Marcoli, Ulrico Agnati, Luca Ferraro, Diego Guidolin,
Guido Maur... more Authors Luigi F. Agnati, Manuela Marcoli, Ulrico Agnati, Luca Ferraro, Diego Guidolin, Guido Maura
A B S T R A C T Some neurobiological aspects and social consequences of religious beliefs are briefly discussed. A basic aspect to be considered is the capability of several living beings to prospect future scenarios. In this context, however, it has to be underlined that only humans know that they have to die. Consequently, all human cultures have proposed dreams, visions and religious beliefs to dispel the fear of death. Awareness of the end of life has played a fundamental role in the emergence of religious beliefs. The social aspects of religions will be considered from Bloch's perspective that modern humans are the only living beings capable of peculiar social interrelationships , namely the transcendental social, which consists of the creation of essentialized roles and groups that exist separately from the individual who holds them. In other words, the transcendental social bonds not only real groups, such as tribes, clans or nations, but also imaginary groups, such as ancestors or gods, thereby allowing the emergence of religion as a uniquely human activity. In the present paper, it is suggested that the concept of exaptation can shed some light on the origin of religions and on their potential positive effects on individual lives and human societies. On the other hand, the concept of mis-exaptation can shed some light on the possible perverse side-effects of religious beliefs. Thus, some aspects of the possible conceptual and neurobiological links between exaptation and mis-exaptation of the religious beliefs will be analyzed.
Intussusceptive microvascular growth (IMG), which occurs by splitting of the existing vasculature... more Intussusceptive microvascular growth (IMG), which occurs by splitting of the existing vasculature by transluminal pillars or transendothelial bridges, has been demonstrated in several tumors such as colon and mammary carcinomas, melanoma and B-cell non-Hodgkin's lymphomas. In this study, we have correlated in human glioma the extent of angiogenesis, evaluated as microvascular density, the immunoreactivity of tumor cells to vascular endothelial growth factor (VEGF), vessel diameter and IMG to the tumor stage. Results demonstrate for the first time a relationship in human glioma progression between angiogenesis, VEGF immunoreactivity of tumor cells, vessel diameter and the number of connections of intraluminal tissue folds with the opposite vascular wall, expression of IMG and suggest that IMG could be a mechanism of compensatory vascular growth occurring in human glioma. The advantages are that (1) blood vessels are generated more rapidly; (2) it is energetically and metabolically more economic; (3) the capillaries thereby formed are less leaky.
In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreac... more In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, Jan 21, 2015
Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is al... more Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is also observed in cell culture. Active locomotion of chondrocytes is controlled by integrins in vitro. Integrins bind to Laminin-A4 (LAMA4), a protein that is highly expressed in vivo in clusters of hypertrophic chondrocytes. We tested if LAMA4 is relevant for cluster formation. Human chondrocytes were cultured in a 2D matrigel model and treated with different concentrations of a monoclonal inhibitory anti-LAMA4-antibody. Migration and cluster formation was analysed using live cell imaging technique. Full genome gene expression analysis was performed to assess the effect of LAMA4 inhibition. The data set were screened for genes relevant to cell motility. F-actin staining was performed to document cytoskeletal changes. Anti-LAMA4 treatment significantly reduced the rate of cluster formation in human chondrocytes. Cells changed their surface morphology and exhibited fewer protrusions. Express...
International Journal of Molecular Medicine, Jun 1, 2005
Several studies have shown that beta-amyloid (beta A) deposits are associated with damage of cere... more Several studies have shown that beta-amyloid (beta A) deposits are associated with damage of cerebral vessels and that in Alzheimer's disease (AD) beta A peptides are cytotoxic for cerebral endothelial cells (ECs). However, little is known about the mechanisms underlying these effects of beta A peptides. Hence, we have investigated the effects of beta A(1-40) and beta A(1-42) on rat neuromicrovascular ECs (NECs) cultured in vitro. NECs were isolated, plated (1.5x10(4) cells/cm2) on collagen/fibronectin-coated Petri dishes and cultured in EC growth medium MV2. After 24 h of culture, NECs were incubated with beta A(1-40) and beta A(1-42) (10(-9) or 10(-7) M) and cultured for another 3, 24 or 48 h. Cell viability was assayed by either trypan blue exclusion or by measuring redox activity (MTS assay). Cell proliferation was assessed by measuring the incorporation of 5'-bromo-2'-deoxyuridine into DNA, cell apoptosis by TUNEL assay and cell necrosis by evaluating the release of lactate dehydrogenase. The morphology of cultured NECs was examined by transmission electron microscopy. Other NECs were plated (2.5x10(4) cells/cm2) on Matrigel coated-wells and incubated for 18 h in the presence or absence of beta A peptides for in vitro angiogenesis assay. Beta A peptides significantly decreased NEC viability and enhanced cell apoptosis and necrosis rates. NEC proliferation was not significantly affected. The effects were seen after an incubation period of 3 h (and also 24 h in the case of the redox activity) but not 48 h and beta A(1-42) was much more effective in its toxic effects than beta A(1-40). NECs incubated for 24 h with beta A peptides displayed ultrastructural signs of cell degeneration. beta A peptides prevented NECs cultured on Matrigel to form a capillary-like network and image analysis showed that the downloading of dimensional and topological parameters of the meshwork was significant only in the case of the incubation with beta A(1-42). Collectively our findings allow us to conclude that i) beta A peptides exert a marked toxic effect on cultured NECs, which conceivably reduces their in vitro angiogenic activity; ii) beta A(1-42) is the more toxic form, which could suggest its main role in the pathogenesis of cerebral vessel lesions in AD and iii) the maximum toxic action occurs after a short incubation period, which could be explained by assuming that beta A peptides are unable to accumulate in NECs due to their rapid degradation, thereby allowing NECs to fully recover within 48 h.
Segmental duplications of the basilar artery, previously reported exclusively as anatomical varia... more Segmental duplications of the basilar artery, previously reported exclusively as anatomical variations, owe their clinical interest to the possible association with aneurysms localized at the junctions of the fenestrated segments. The morphological characteristics of 5 cases of basilar artery segmental duplication without aneurysms, found at autopsy, are reported. In 3 of these the proximal junction of the fenestrated segment was studied with scanning electron microscopy and morphometry. In all cases the tunica media of the medial wall of the 2 branches showed a progressive thinning towards the junctions of the fenestrated segments and a small muscular gap at their apex. The limited medial defect might be embryologically ascribed to the persistence of the morphological individuality of the tunica media of the 2 branches at the point where the fusion of the primitive longitudinal neural arteries stopped. The review of the literature shows that the morphology of the junctions of the fenestrated segments is in conformity with that of the intracranial arterial bifurcations. For this reason the basilar artery fenestration exposes to the blood flow a new distal bifurcation where the same etiologic factors that are still under discussion in the origin of saccular intracranial aneurysms may be active.
The biological responsiveness of neural cells to nerve growth factor (NGF) appears to require exp... more The biological responsiveness of neural cells to nerve growth factor (NGF) appears to require expression and ligand binding to both the low-affinity NGF receptor (LNGFR) and the proto-oncogene product trk, the latter being a receptor tyrosine kinase. Immunolocalization of the LNGFR and the high-affinity component of the NGF receptor, trk (HNGFR) was studied by electron microscopic morphometric analysis on cultured PC12 pheochromocytoma cells, C6 glioma cells and neonatal rat dorsal root ganglia neurons using a double immunogold labeling technique. Two receptor-specific antibodies, anti-LNGFR monoclonal antibody 192-IgG and a polyclonal antibody against the 14 carboxy-terminal amino acids of the Trk protein, were utilized in conjunction with immunoglobulin conjugated to colloidal gold particles of different sizes. All cells treated with NGF (50 ng/ml) displayed significant colocalization of LNGFR/HNGFR-like immunoreactivity. Gold particles associated with LNGFR (LNGFR-like immunoreactivity) were frequently seen near 2 or 3 (or more) particles delineating the HNGFR on all cell surfaces. Positive Trk-like immunoreactivity (HNGFR) thus seems to localize in close proximity to LNGFRs in at least these cell types.
The present study was designed to investigate whether experimental diabetes determines structural... more The present study was designed to investigate whether experimental diabetes determines structural changes in peripheral nerves involved in reflexogenic erection, namely the cavernous and the dorsal nerve of the penis. Myelinated axons were examined in the dorsal nerve of the penis from rats with streptozotocin-induced diabetes (3- and 6-month duration). Morphometric analysis disclosed a significant decrease of myelinated fibre size most likely due to a progressive axonal atrophy. In addition, morphological analysis revealed diffuse accumulation of glycogen within axons, lipid droplets in Schwann cells and pronounced sequestration of axoplasm by adaxonal Schwann cell processes. These signs were particularly prominent in 6-month-diabetic rats. Myelinated and unmyelinated axons of the cavernous nerve were analysed in 6-month-diabetic animals. No substantial ultrastructural abnormalities were found in the cavernous nerves. These results suggest that in experimental diabetes regionally specific structural changes occur in neuronal pathways subserving erectile function.
Adrenomedullin (AM) is a hypotensive peptide, which is produced in several organs and tissues, th... more Adrenomedullin (AM) is a hypotensive peptide, which is produced in several organs and tissues, the functions of which it regulates in a autocrine-paracrine manner. Rat (r) and human (h) AM are 50- and 52-amino acid peptides, which differ for 2-amino acid deletions and six substitutions and contain a disulfide bridge-formed six-membered ring between adjacent cysteine residues in the 14 and 19 and 16 and 21 positions, respectively. The amidated C-terminal sequence is needed for AM to bind its receptors, and the ring structure (but not t he N-terminal sequence) seems to be required for AM to activate its receptors. Hence, we examined the effectiveness of some N-terminus and ring-lackingAM fragments as AM-receptor antagonists in the rat zona glomerulosa (ZG), whose cells are provided with abundant AM binding sites and display an AM-induced inhibition of K+-stimulated aldosterone secretion. Quantitative autoradiographic studies showed that cold rAMI-50, rAM20-50 and rAM24-50 displaced [125I]AM1-50 binding from rat ZG with the same potency and efficacy, which were significantly higher than those of hAM1-52, hAM22-52 and hAM26-52. Accordingly, rAM20-50 and rAM24-50 reversed the inhibitory effect of 10(-8) M rAMI-50 on aldosterone response of dispersed rat ZG cells to 10(-2) M K+ with significantly higher potency and efficacy than hAM22-52 and hAM26-52. Taken together, our findings confirm that CONH2-terminal AM fragments, lacking the six-membered ring structure, act as antagonists of AM receptors in the rat ZG. Moreover, they provide the first evidence that rAMI-50 and its fragments should be used in the investigations carried out in the rat.
Advances in Experimental Medicine and Biology, 2015
The carotid body (CB) increases in volume in response to chronic continuous hypoxia and the mecha... more The carotid body (CB) increases in volume in response to chronic continuous hypoxia and the mechanisms underlying this adaptive response are not fully elucidated. It has been proposed that chronic hypoxia could lead to the generation of a sub-population of type II cells representing precursors, which, in turn, can give rise to mature type I cells. To test whether this process could explain not only the observed changes in cell number, but also the micro-anatomical pattern of tissue rearrangement, a mathematical modeling approach was devised to simulate the hypothetical sequence of cellular events occurring within the CB during chronic hypoxia. The modeling strategy involved two steps. In a first step a "population level" modeling approach was followed, in order to estimate, by comparing the model results with the available experimental data, "macroscopic" features of the cell system, such as cell population expansion rates and differentiation rates. In the second step, these results represented key parameters to build a "cell-centered" model simulating the self-organization of a system of CB cells under a chronic hypoxic stimulus and including cell adhesion, cytoskeletal rearrangement, cell proliferation, differentiation, and apoptosis. The cell patterns generated by the model showed consistency (from both a qualitative and quantitative point of view) with the observations performed on real tissue samples obtained from rats exposed to 16 days hypoxia, indicating that the hypothesized sequence of cellular events was adequate to explain not only changes in cell number, but also the tissue architecture acquired by CB following a chronic hypoxic stimulus.
Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct ... more Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. The hypothesis is given that changes in the function of the dopamine heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson's disease (PD) with l-DOPA and dopamine receptor agonists. In the indirect pathway, the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD are covered and in the direct pathway, the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes. One explanation for the more powerful ability of l-DOPA treatment versus treatment with the partial dopamine receptor agonist/antagonist activity to induce dyskinesias, may be that dopamine formed from l-DOPA acts as a full agonist. The field of D1R and D2R heteroreceptor complexes in the CNS opens up a new understanding of the wearing off ...
Authors
Luigi F. Agnati, Manuela Marcoli, Ulrico Agnati, Luca Ferraro, Diego Guidolin,
Guido Maur... more Authors Luigi F. Agnati, Manuela Marcoli, Ulrico Agnati, Luca Ferraro, Diego Guidolin, Guido Maura
A B S T R A C T Some neurobiological aspects and social consequences of religious beliefs are briefly discussed. A basic aspect to be considered is the capability of several living beings to prospect future scenarios. In this context, however, it has to be underlined that only humans know that they have to die. Consequently, all human cultures have proposed dreams, visions and religious beliefs to dispel the fear of death. Awareness of the end of life has played a fundamental role in the emergence of religious beliefs. The social aspects of religions will be considered from Bloch's perspective that modern humans are the only living beings capable of peculiar social interrelationships , namely the transcendental social, which consists of the creation of essentialized roles and groups that exist separately from the individual who holds them. In other words, the transcendental social bonds not only real groups, such as tribes, clans or nations, but also imaginary groups, such as ancestors or gods, thereby allowing the emergence of religion as a uniquely human activity. In the present paper, it is suggested that the concept of exaptation can shed some light on the origin of religions and on their potential positive effects on individual lives and human societies. On the other hand, the concept of mis-exaptation can shed some light on the possible perverse side-effects of religious beliefs. Thus, some aspects of the possible conceptual and neurobiological links between exaptation and mis-exaptation of the religious beliefs will be analyzed.
Intussusceptive microvascular growth (IMG), which occurs by splitting of the existing vasculature... more Intussusceptive microvascular growth (IMG), which occurs by splitting of the existing vasculature by transluminal pillars or transendothelial bridges, has been demonstrated in several tumors such as colon and mammary carcinomas, melanoma and B-cell non-Hodgkin's lymphomas. In this study, we have correlated in human glioma the extent of angiogenesis, evaluated as microvascular density, the immunoreactivity of tumor cells to vascular endothelial growth factor (VEGF), vessel diameter and IMG to the tumor stage. Results demonstrate for the first time a relationship in human glioma progression between angiogenesis, VEGF immunoreactivity of tumor cells, vessel diameter and the number of connections of intraluminal tissue folds with the opposite vascular wall, expression of IMG and suggest that IMG could be a mechanism of compensatory vascular growth occurring in human glioma. The advantages are that (1) blood vessels are generated more rapidly; (2) it is energetically and metabolically more economic; (3) the capillaries thereby formed are less leaky.
In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreac... more In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, Jan 21, 2015
Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is al... more Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is also observed in cell culture. Active locomotion of chondrocytes is controlled by integrins in vitro. Integrins bind to Laminin-A4 (LAMA4), a protein that is highly expressed in vivo in clusters of hypertrophic chondrocytes. We tested if LAMA4 is relevant for cluster formation. Human chondrocytes were cultured in a 2D matrigel model and treated with different concentrations of a monoclonal inhibitory anti-LAMA4-antibody. Migration and cluster formation was analysed using live cell imaging technique. Full genome gene expression analysis was performed to assess the effect of LAMA4 inhibition. The data set were screened for genes relevant to cell motility. F-actin staining was performed to document cytoskeletal changes. Anti-LAMA4 treatment significantly reduced the rate of cluster formation in human chondrocytes. Cells changed their surface morphology and exhibited fewer protrusions. Express...
International Journal of Molecular Medicine, Jun 1, 2005
Several studies have shown that beta-amyloid (beta A) deposits are associated with damage of cere... more Several studies have shown that beta-amyloid (beta A) deposits are associated with damage of cerebral vessels and that in Alzheimer's disease (AD) beta A peptides are cytotoxic for cerebral endothelial cells (ECs). However, little is known about the mechanisms underlying these effects of beta A peptides. Hence, we have investigated the effects of beta A(1-40) and beta A(1-42) on rat neuromicrovascular ECs (NECs) cultured in vitro. NECs were isolated, plated (1.5x10(4) cells/cm2) on collagen/fibronectin-coated Petri dishes and cultured in EC growth medium MV2. After 24 h of culture, NECs were incubated with beta A(1-40) and beta A(1-42) (10(-9) or 10(-7) M) and cultured for another 3, 24 or 48 h. Cell viability was assayed by either trypan blue exclusion or by measuring redox activity (MTS assay). Cell proliferation was assessed by measuring the incorporation of 5'-bromo-2'-deoxyuridine into DNA, cell apoptosis by TUNEL assay and cell necrosis by evaluating the release of lactate dehydrogenase. The morphology of cultured NECs was examined by transmission electron microscopy. Other NECs were plated (2.5x10(4) cells/cm2) on Matrigel coated-wells and incubated for 18 h in the presence or absence of beta A peptides for in vitro angiogenesis assay. Beta A peptides significantly decreased NEC viability and enhanced cell apoptosis and necrosis rates. NEC proliferation was not significantly affected. The effects were seen after an incubation period of 3 h (and also 24 h in the case of the redox activity) but not 48 h and beta A(1-42) was much more effective in its toxic effects than beta A(1-40). NECs incubated for 24 h with beta A peptides displayed ultrastructural signs of cell degeneration. beta A peptides prevented NECs cultured on Matrigel to form a capillary-like network and image analysis showed that the downloading of dimensional and topological parameters of the meshwork was significant only in the case of the incubation with beta A(1-42). Collectively our findings allow us to conclude that i) beta A peptides exert a marked toxic effect on cultured NECs, which conceivably reduces their in vitro angiogenic activity; ii) beta A(1-42) is the more toxic form, which could suggest its main role in the pathogenesis of cerebral vessel lesions in AD and iii) the maximum toxic action occurs after a short incubation period, which could be explained by assuming that beta A peptides are unable to accumulate in NECs due to their rapid degradation, thereby allowing NECs to fully recover within 48 h.
Segmental duplications of the basilar artery, previously reported exclusively as anatomical varia... more Segmental duplications of the basilar artery, previously reported exclusively as anatomical variations, owe their clinical interest to the possible association with aneurysms localized at the junctions of the fenestrated segments. The morphological characteristics of 5 cases of basilar artery segmental duplication without aneurysms, found at autopsy, are reported. In 3 of these the proximal junction of the fenestrated segment was studied with scanning electron microscopy and morphometry. In all cases the tunica media of the medial wall of the 2 branches showed a progressive thinning towards the junctions of the fenestrated segments and a small muscular gap at their apex. The limited medial defect might be embryologically ascribed to the persistence of the morphological individuality of the tunica media of the 2 branches at the point where the fusion of the primitive longitudinal neural arteries stopped. The review of the literature shows that the morphology of the junctions of the fenestrated segments is in conformity with that of the intracranial arterial bifurcations. For this reason the basilar artery fenestration exposes to the blood flow a new distal bifurcation where the same etiologic factors that are still under discussion in the origin of saccular intracranial aneurysms may be active.
The biological responsiveness of neural cells to nerve growth factor (NGF) appears to require exp... more The biological responsiveness of neural cells to nerve growth factor (NGF) appears to require expression and ligand binding to both the low-affinity NGF receptor (LNGFR) and the proto-oncogene product trk, the latter being a receptor tyrosine kinase. Immunolocalization of the LNGFR and the high-affinity component of the NGF receptor, trk (HNGFR) was studied by electron microscopic morphometric analysis on cultured PC12 pheochromocytoma cells, C6 glioma cells and neonatal rat dorsal root ganglia neurons using a double immunogold labeling technique. Two receptor-specific antibodies, anti-LNGFR monoclonal antibody 192-IgG and a polyclonal antibody against the 14 carboxy-terminal amino acids of the Trk protein, were utilized in conjunction with immunoglobulin conjugated to colloidal gold particles of different sizes. All cells treated with NGF (50 ng/ml) displayed significant colocalization of LNGFR/HNGFR-like immunoreactivity. Gold particles associated with LNGFR (LNGFR-like immunoreactivity) were frequently seen near 2 or 3 (or more) particles delineating the HNGFR on all cell surfaces. Positive Trk-like immunoreactivity (HNGFR) thus seems to localize in close proximity to LNGFRs in at least these cell types.
The present study was designed to investigate whether experimental diabetes determines structural... more The present study was designed to investigate whether experimental diabetes determines structural changes in peripheral nerves involved in reflexogenic erection, namely the cavernous and the dorsal nerve of the penis. Myelinated axons were examined in the dorsal nerve of the penis from rats with streptozotocin-induced diabetes (3- and 6-month duration). Morphometric analysis disclosed a significant decrease of myelinated fibre size most likely due to a progressive axonal atrophy. In addition, morphological analysis revealed diffuse accumulation of glycogen within axons, lipid droplets in Schwann cells and pronounced sequestration of axoplasm by adaxonal Schwann cell processes. These signs were particularly prominent in 6-month-diabetic rats. Myelinated and unmyelinated axons of the cavernous nerve were analysed in 6-month-diabetic animals. No substantial ultrastructural abnormalities were found in the cavernous nerves. These results suggest that in experimental diabetes regionally specific structural changes occur in neuronal pathways subserving erectile function.
Adrenomedullin (AM) is a hypotensive peptide, which is produced in several organs and tissues, th... more Adrenomedullin (AM) is a hypotensive peptide, which is produced in several organs and tissues, the functions of which it regulates in a autocrine-paracrine manner. Rat (r) and human (h) AM are 50- and 52-amino acid peptides, which differ for 2-amino acid deletions and six substitutions and contain a disulfide bridge-formed six-membered ring between adjacent cysteine residues in the 14 and 19 and 16 and 21 positions, respectively. The amidated C-terminal sequence is needed for AM to bind its receptors, and the ring structure (but not t he N-terminal sequence) seems to be required for AM to activate its receptors. Hence, we examined the effectiveness of some N-terminus and ring-lackingAM fragments as AM-receptor antagonists in the rat zona glomerulosa (ZG), whose cells are provided with abundant AM binding sites and display an AM-induced inhibition of K+-stimulated aldosterone secretion. Quantitative autoradiographic studies showed that cold rAMI-50, rAM20-50 and rAM24-50 displaced [125I]AM1-50 binding from rat ZG with the same potency and efficacy, which were significantly higher than those of hAM1-52, hAM22-52 and hAM26-52. Accordingly, rAM20-50 and rAM24-50 reversed the inhibitory effect of 10(-8) M rAMI-50 on aldosterone response of dispersed rat ZG cells to 10(-2) M K+ with significantly higher potency and efficacy than hAM22-52 and hAM26-52. Taken together, our findings confirm that CONH2-terminal AM fragments, lacking the six-membered ring structure, act as antagonists of AM receptors in the rat ZG. Moreover, they provide the first evidence that rAMI-50 and its fragments should be used in the investigations carried out in the rat.
Advances in Experimental Medicine and Biology, 2015
The carotid body (CB) increases in volume in response to chronic continuous hypoxia and the mecha... more The carotid body (CB) increases in volume in response to chronic continuous hypoxia and the mechanisms underlying this adaptive response are not fully elucidated. It has been proposed that chronic hypoxia could lead to the generation of a sub-population of type II cells representing precursors, which, in turn, can give rise to mature type I cells. To test whether this process could explain not only the observed changes in cell number, but also the micro-anatomical pattern of tissue rearrangement, a mathematical modeling approach was devised to simulate the hypothetical sequence of cellular events occurring within the CB during chronic hypoxia. The modeling strategy involved two steps. In a first step a "population level" modeling approach was followed, in order to estimate, by comparing the model results with the available experimental data, "macroscopic" features of the cell system, such as cell population expansion rates and differentiation rates. In the second step, these results represented key parameters to build a "cell-centered" model simulating the self-organization of a system of CB cells under a chronic hypoxic stimulus and including cell adhesion, cytoskeletal rearrangement, cell proliferation, differentiation, and apoptosis. The cell patterns generated by the model showed consistency (from both a qualitative and quantitative point of view) with the observations performed on real tissue samples obtained from rats exposed to 16 days hypoxia, indicating that the hypothesized sequence of cellular events was adequate to explain not only changes in cell number, but also the tissue architecture acquired by CB following a chronic hypoxic stimulus.
Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct ... more Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. The hypothesis is given that changes in the function of the dopamine heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson's disease (PD) with l-DOPA and dopamine receptor agonists. In the indirect pathway, the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD are covered and in the direct pathway, the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes. One explanation for the more powerful ability of l-DOPA treatment versus treatment with the partial dopamine receptor agonist/antagonist activity to induce dyskinesias, may be that dopamine formed from l-DOPA acts as a full agonist. The field of D1R and D2R heteroreceptor complexes in the CNS opens up a new understanding of the wearing off ...
The concept of intramembrane receptor-receptor interactions and evidence for their existences wer... more The concept of intramembrane receptor-receptor interactions and evidence for their existences were introduced in the beginning of the 1980’s, suggesting the existence of receptor heterodimerization. The discovery of GPCR heteromers and the receptor mosaic (higher order oligomers, more than two) has been related to the parallel development and application of a variety of resonance energy transfer techniques such as bioluminescence (BRET), fluorescence (FRET) and sequential energy transfer (SRET). The assembly of interacting GPCRs, heterodimers and receptor mosaic leads to changes in the agonist recognition, signaling, and trafficking of participating receptors via allosteric mechanisms, sometimes involving the appearance of cooperativity. The receptor interface in the GPCR heteromers is beginning to be characterized and the key role of electrostatic epitope-epitope interactions for the formation of the receptor heteromers will be discussed. Furthermore, a "guide-and-clasp" manner of receptor-receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. These interactions probably represent a general molecular mechanism for receptor-receptor interactions. It is proposed that changes in GPCR function (moonlighting) may develop through the intracellular loops and C-terminii of the GPCR heteromers as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptors. The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neurophysiology and neuropathology. Furthermore, novel therapeutic approaches could be possible based on the use of heteromers as targets for drug development based on their unique pharmacology
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Luigi F. Agnati, Manuela Marcoli, Ulrico Agnati, Luca Ferraro, Diego Guidolin,
Guido Maura
A B S T R A C T Some neurobiological aspects and social consequences of religious beliefs are briefly discussed. A basic aspect to be considered is the capability of several living beings to prospect future scenarios. In this context, however, it has to be underlined that only humans know that they have to die. Consequently, all human cultures have proposed dreams, visions and religious beliefs to dispel the fear of death. Awareness of the end of life has played a fundamental role in the emergence of religious beliefs. The social aspects of religions will be considered from Bloch's perspective that modern humans are the only living beings capable of peculiar social interrelationships , namely the transcendental social, which consists of the creation of essentialized roles and groups that exist separately from the individual who holds them. In other words, the transcendental social bonds not only real groups, such as tribes, clans or nations, but also imaginary groups, such as ancestors or gods, thereby allowing the emergence of religion as a uniquely human activity. In the present paper, it is suggested that the concept of exaptation can shed some light on the origin of religions and on their potential positive effects on individual lives and human societies. On the other hand, the concept of mis-exaptation can shed some light on the possible perverse side-effects of religious beliefs. Thus, some aspects of the possible conceptual and neurobiological links between exaptation and mis-exaptation of the religious beliefs will be analyzed.
Luigi F. Agnati, Manuela Marcoli, Ulrico Agnati, Luca Ferraro, Diego Guidolin,
Guido Maura
A B S T R A C T Some neurobiological aspects and social consequences of religious beliefs are briefly discussed. A basic aspect to be considered is the capability of several living beings to prospect future scenarios. In this context, however, it has to be underlined that only humans know that they have to die. Consequently, all human cultures have proposed dreams, visions and religious beliefs to dispel the fear of death. Awareness of the end of life has played a fundamental role in the emergence of religious beliefs. The social aspects of religions will be considered from Bloch's perspective that modern humans are the only living beings capable of peculiar social interrelationships , namely the transcendental social, which consists of the creation of essentialized roles and groups that exist separately from the individual who holds them. In other words, the transcendental social bonds not only real groups, such as tribes, clans or nations, but also imaginary groups, such as ancestors or gods, thereby allowing the emergence of religion as a uniquely human activity. In the present paper, it is suggested that the concept of exaptation can shed some light on the origin of religions and on their potential positive effects on individual lives and human societies. On the other hand, the concept of mis-exaptation can shed some light on the possible perverse side-effects of religious beliefs. Thus, some aspects of the possible conceptual and neurobiological links between exaptation and mis-exaptation of the religious beliefs will be analyzed.
beginning of the 1980’s, suggesting the existence of receptor heterodimerization. The discovery of GPCR heteromers and the receptor mosaic (higher order oligomers, more than two) has been related to the parallel development and application of a variety of resonance energy transfer techniques such as bioluminescence (BRET), fluorescence (FRET) and sequential energy transfer (SRET). The assembly of interacting GPCRs, heterodimers and receptor mosaic leads to changes in the agonist recognition, signaling, and trafficking of participating receptors via allosteric mechanisms, sometimes involving the appearance of cooperativity. The receptor interface in the
GPCR heteromers is beginning to be characterized and the key role of electrostatic epitope-epitope interactions for the formation of the receptor heteromers will be discussed. Furthermore, a "guide-and-clasp" manner of receptor-receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. These interactions probably represent a general molecular mechanism for receptor-receptor interactions. It is proposed that changes in GPCR function (moonlighting) may develop through the intracellular loops and C-terminii of the GPCR heteromers as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptors. The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neurophysiology and neuropathology. Furthermore, novel therapeutic approaches could be possible
based on the use of heteromers as targets for drug development based on their unique pharmacology