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Biomedical subjects

M J Rey

Publications and source records attributed to M J Rey.

At least 19 recordsLinked to original sources
PubMed2006

NARP-MILS syndrome caused by 8993 T>G mitochondrial DNA mutation: a clinical, genetic and neuropathological study.

The 8993 T>G mutation in mitochondrial DNA has been associated with variable syndromes of differing severity ranging from maternally inherited Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa (NARP), depending on the mutation loads in affected patients. We report a kindred with several members in the same generation suffering NARP or Leigh's syndrome due to a 8993 T>G mutation. Post-mortem studies of the brain in one affected member clinically presenting with a neurological disorder intermediate between adult Leigh's syndrome and NARP showed symmetrical lesions of the basal ganglia and brainstem closely resembling those usually described in typical Leigh's syndrome. Analysis of mtDNA in different tissues showed a high proportion of mutant genome in brainstem, cerebral cortex, putamen, cerebellum and thalamus. These observations illustrate the continuum of clinical and neuropathological manifestations associated with the 8993 T>G mutation of the mtDNA.

Adenosine Triphosphatases↗
PubMed2006

Glial fibrillary acidic protein is a major target of glycoxidative and lipoxidative damage in Pick's disease.

Pick's disease is a subset of fronto-temporal dementia characterised by severe atrophy of the temporal and frontal lobes due to marked neuronal loss accompanied by astrocytic gliosis enriched in glial acidic protein. The remaining neurones have intracytoplasmic inclusions composed of hyperphosphorylated tau, called Pick bodies, in addition to hyperphosphorylated tau in astrocytes and oligodendrocytes. Gel electrophoresis and western blotting using markers of glycoxidation (advanced glycation end products, N-carboxyethyl-lysine and N-carboxymethyl-lysine: AGE, CEL, CML, respectively) and lipoxidation (4-hydroxy-2-nonenal: HNE, and malondialdehyde-lysine: MDAL) were used in the frontal and occipital cortex in three Pick's disease cases and three age-matched controls. In Pick's disease, increased AGE, CML, CEL, HNE and MDAL bands of about 50 kDa were observed in the frontal cortex (but not in the occipital cortex) in association with increased density of glial acidic protein bands. Bi-dimensional gel electrophoresis and western blotting also disclosed increased amounts and numbers of glial acidic protein isoforms in the frontal cortex in Pick's disease. Moreover, redox proteomics showed glycoxidation, as revealed with anti-CEL antibodies and lipoxidation using anti-HNE antibodies, of at least three glial acidic protein isoforms. The present results demonstrate that glial acidic protein is a target of oxidative damage in the frontal cortex in Pick's disease.

Aldehydes↗
PubMed2006

[MM1 variant of sporadic Creutzfeldt-Jakob disease with long duration akinetic mutism state].

INTRODUCTION: When patients present with a characteristic clinical picture of Creutzfeldt-Jakob disease (CJD) associated with positive 14-3-3 assay, periodic sharp wave complexes, high-signal of the striatum on magnetic resonance imaging, and homozygosis methionine (M) in codon 129, the median survival is 4 to 6 months. CLINICAL CASE: We report a 58-year-old woman with these typical features who survived 21 months, 19 of them in an akinetic mutism state. The autopsy confirmed the diagnosis of the most common CJD phenotype (MM1), usually associated with a shorter survival, and demyleinitation of the white matter (panencephalopathic form). CONCLUSIONS: The MM1 variant of CJD, with a rapidly progressive course leading into an akinetic mutism shortly after disease onset can be followed by a long akinetic mutism state. This profile is suggestive of panencephalopathic form and should be taken into account when counselling about survival.

Akinetic Mutism↗
PubMed2004

Familial Alzheimer disease associated with A713T mutation in APP.

Mutations in APP are associated with familial early-onset Alzheimer disease (FAD). Examination of the genomic sequence in one patient with FAD revealed a change located in the axon 17 of the APP gene at position 275329G>A (GenBank accession number: D87675; GI: 2429080); cDNA sequence 2137G>A (GenBank accession number: X06989; GI: 28720). This corresponds to the mutation A713T in APP. AD stage VI of neurofibrillary degeneration and stage C of Abeta-amyloid burden was found at the post-mortem neuropathological examination. Previous studies have suggested that the mutation A713T in APP is a silent mutation or polymorphism. However, we have not found this change in APP in a control population analyzed by the amplification-refractory mutation system (ARMS). It is concluded that A713T in APP is implicated in the pathogenesis of AD. Since the immunohistochemical study indicates that A713T mutation is not likely to relate with Abeta-amyloid processing, the causative role of this rare mutation remains to be warranted.

Alanine↗
PubMed2004

Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy.

OBJECTIVE: We analyzed the value of topoisomerase IIalpha (Topo II) in predicting the clinical response to anthracycline-based neoadjuvant chemotherapy in breast cancers and the potential changes in Topo II after chemotherapy. In parallel, HER2, which is commonly coexpressed with Topo II, and p53, a modulator of chemotherapy activity, were also analyzed. METHODS: Forty-one patients with primary breast cancer and treated with neoadjuvant anthracycline-based chemotherapy (FAC or FEC) were included for the present study. Topo II, HER2 and p53 expression were measured by immunohistochemistry in pre and post chemotherapy (at the time of surgery), tumor specimens and the results were correlated with the clinical response. RESULTS: Topo II was overexpressed in 16 of 41 (31%) tumors before treatment, and this overexpression was significantly associated with clinical response (p = 0.03). HER2 and p53 were unrelated to response. Notably, Topo II overexpression, but not HER2 or p53, was lost in specimens after chemotherapy (p = 0.01). CONCLUSION: The observed link between Topo II and the clinical response to neoadjuvant anthracycline-based chemotherapy, together with its loss after chemotherapy, implies that Topo II deserves further testing in a prospective setting as a predictive marker.

Adult↗
PubMed2003

Primary progressive aphasia as the initial manifestation of corticobasal degeneration and unusual tauopathies.

The clinical, neuroradiological, neuropathological and biochemical findings in four patients with primary progressive aphasia and tauopathy are described. The aphasic syndrome preceded by several years the appearance of other symptoms in every case. Asymmetrical apraxia with alien hand phenomenon occurred in one case. Frontotemporal symptoms occurred in three cases, but progressed to dramatic cognitive devastation in only one of these. Generalized dementia consistent with probable Alzheimer's disease (AD) developed with time in another. Cerebral computer tomography scans, magnetic resonance imaging and SPECT studies revealed marked asymmetries in one case, and showed nonspecific cerebral atrophy in the remaining ones. The neuropathological examination revealed typical corticobasal degeneration (CBD) in one case; CBD and AD in another; and atypical CBD, argyrophilic grain disease (AGD) and alpha-synucleinopathy consistent with Parkinson's disease in a third. Unique neuropathological findings were found in the remaining case. This was characterized by severe cerebral atrophy, marked neuronal loss in the cerebral cortex and abnormal tau deposition in neurons of the cerebral cortex, diencephalon and brain stem. Ballooned neurons, Pick bodies, generalized cortical neurofibrillary tangles and astrocytic plaques were absent. However, massive globular inclusions, containing phospho-tau, occurred in glial cells, mainly oligodendrocytes, in the white matter. Biochemical studies of frontal homogenates revealed four bands of 73/74, 68, 64 and 60 kDa of phosphorylated tau (using antibodies recognizing phospho-tau Thr181, Ser262 and Ser422) in the patient with AD and CBD, suggesting a predominant AD pattern in this case. Two bands of 68 and 64 kDa of phospho-tau were recovered in the sarkosyl-insoluble fraction in the other three cases. This pattern is similar to that found in CBD, progressive supranuclear palsy and AGD. Taken together, the present series further supports pure and combined CBD as causes of primary progressive aphasia, and they extend the hypothesis that primary progressive aphasia may be the initial symptom of distinct tauopathies.

Aged↗
PubMed2003

Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation.

Tau phosphorylation has been examined by immunohistochemistry in the brain of a patient affected with familial tauopathy with progressive supranuclear palsy-like phenotype linked to the delN296 mutation in the tau gene. Phospho-specific tau antibodies Thr181, Ser202, Ser214, Ser396 and Ser422, and antibodies to glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) and to phosphorylated (P) mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), p38 kinase (p38) and GSK-3betaSer9 have been used to gain understanding of the identification of phosphorylation sites, as well as of the specific kinases that regulate tau phosphorylation at those specific sites, in a familial tauopathy. The neuropathological examination disclosed atrophy of the right precentral gyrus and the brainstem. Neurone loss and gliosis were observed in the substantia nigra, several nuclei of the brainstem and diencephalon. Hyper-phosphorylated tau accumulated in neurones with neurofibrillary tangles and in neurones with pretangles in the substantia nigra, locus ceruleus, peri-aqueductal grey matter, reticular formation, motor nuclei of the brainstem, and thalamus, amygdala and hippocampus. tau-immunoreactive astrocytes and, particularly, oligodendrocytes with coiled bodies were widespread in the brainstem, diencephalons, cerebral white matter and cerebral cortex. Increased expression of MAPK/ERK-P, SAPK/JNK-P, p-38-P and GSK-3beta-P was observed in select subpopulations of neurones with neurofibrillary tangles and in neurones with pretangles. MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3beta-P were also expressed in tau-containing astrocytes and in oligodendrocytes with coiled bodies. These findings show, for the first time, activation of precise kinases that regulate tau phosphorylation at specific sites in familial tauopathy.

Adult↗
PubMed2003

Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease.

Tau phosphorylation was examined in argyrophilic grain disease (AGD) by using the phosphospecific tau antibodies Thr181, Ser202, Ser214, Ser 396 and Ser422, and antibodies to non-phosphorylated and phosphorylated mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), stress-activated kinase (SAPK), c-Jun N-terminal kinase (JNK), p38 kinase (p-38), alpha-calcium/calmodulin-dependent kinase II (alphaCaM kinase II), and glycogen synthase kinase-3 (GSK-3), all of which regulate phosphorylation at specific sites of tau. This is the first study in which the role of protein kinases in tau phosphorylation has been examined in AGD. Hyperphosphorylated tau accumulated in grains and pre-tangles in the hippocampus, dentate gyrus, entorhinal and trans-entorhinal cortices, and amygdala in all cases. Ballooned neurons in the amygdala, entorhinal, insular and cingulate cortex, and claustrum contained alphaB-crystallyn and phosphorylated neurofilament epitopes. Some astrocytes and scattered oligodendrocytes containing coiled bodies were recognized with anti-tau antibodies. A few tangles were observed in the entorhinal cortex and hippocampus corresponding to Alzheimer's disease (AD) stages I-III of Braak and Braak. None of the present cases was associated with progressive supranuclear palsy or with alpha-synuclein pathology. Two bands of phospho-tau of 64 and 68 kDa were observed in Western blots of sarkosyl-insoluble fractions enriched with abnormal filaments in AGD, a pattern that contrasts with the 4-band pattern obtained in AD. No modifications in the expression of non-phosphorylated MEK-1, ERK2 and GSK-3alpha/beta, as revealed by immunohistochemistry, were seen in AGD, but sarkosyl-insoluble fractions were particularly enriched in JNK-1 and alphaCaM kinase II. Increased expression of the phosphorylated (P) forms of MAPK/ERK, SAPK/JNK, p38 and GSK-3beta was found in grains and tau-containing cells in AGD. MAPK/ERK-P immunoreactivity was observed in pre-tangles and, diffusely, in the cytoplasm of ballooned neurons, but not in grains. Strong SAPK/JNK-P and P38-P, and moderate GSK-3b-P immunoreactivities selectively occured in grains, in neurons with pre-tangles and in the peripheral region of the cytoplasm of ballooned neurons. MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3beta-P were expressed in tau-containing astrocytes and in oligodendrocytes with coiled bodies. Western blots revealed kinase expression in sarkosyl-insoluble fractions but none of the phospho-kinase antibodies recognized hyper-phosphorylated tau protein. These findings indicate complex, specific profiles of tau phosphorylation and concomitant activation of precise kinases that have the capacity to phosphorylate tau at specific sites in AGD. These kinases co-localize abnormal tau in selected structures and cells, including neurons with pre-tangles, ballooned neurons, astrocytes and oligodendrocytes. Most of these kinases are involved in cell death and cell survival in certain experimental paradigms. However, double-labeling studies with the method of in situ end-labeling of nuclear DNA fragmentation and cleaved (active) caspase-3 immunohistochemistry show no expression of apoptosis and death markers in cells bearing phosphorylated kinases.

Aged↗
PubMed2002

Intranuclear inclusions, neuronal loss and CAG mosaicism in two patients with Machado-Joseph disease.

UNLABELLED: The presence of neuronal intranuclear inclusions (NIIs) and neuronal mosaicism has been described in some autosomal dominant spinocerebellar ataxias (SCA), but their implication in neurodegenerative mechanisms still remains unclear. OBJECTIVE: To investigate the correlation between neuronal loss and NIIs, and the size of CAG triplet expansion in selected areas of the CNS in two SCA3 patients. MATERIAL AND METHODS: Postmortem neuropathological study was carried out, and the regional distribution of neuronal loss was compared with NIIs. CAG expansion was analysed by PCR amplification in the same regions. RESULTS: Marked neuronal loss was seen in the anterior horn of the spinal cord, pontine nuclei and motor nuclei of the brain stem. Moderate neurone loss was found in the locus ceruleus, colliculus and substantia nigra. Loss of granule and Purkinje cells was found in the cerebellum, mainly in the vermis. NIIs were present in neurones of the involved nuclei of the anterior horn of the spinal cord, medulla oblongata and pons, but not in the locus ceruleus, substantia nigra and cerebellum. A few NIIs were found in the striatum. The number of CAG repeats was 27/70 in the first patient and 21/74 in the second patient. The variation of the expanded allele size among different cerebral areas was +/-1-3 CAG repeats. CONCLUSION: The partial correlation between neuronal loss and NIIs suggests that other factors distinct from NII formation may be involved in the neuronal death. Moreover, the low degree of mosaicism between regions without neuronal loss and regions with marked neuronal loss points to the existence of selective cellular vulnerability to the genetic defect.

Aged↗
PubMed2002

Asymmetric myoclonic parietal syndrome in a patient with Alzheimer's disease mimicking corticobasal degeneration.

We describe a patient who presented a progressive asymmetrical parietal syndrome including ideomotor apraxia, hemiinattention, unilateral limb dystonia and myoclonus. The clinical picture of this patient supported the clinical diagnosis of corticobasal degeneration (CBD). However, the neuropathologic examination revealed abundant cortical betaA4-amyloid deposits, and phosphorylated tau accumulation in neuritic plaques, neurofibrillary tangles and neuropil threads corresponding to Alzheimer's disease (AD) stage V of Braak and Braak. This case supports the clinical heterogeneity in AD and the existence of a clinical overlap between AD and CBD.

Alzheimer Disease↗
PubMed2001

Prion protein expression in senile plaques in Alzheimer's disease.

Prion protein (PrPC) is a glycolipid-anchored cell membrane sialoglycoprotein that localises in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrPC expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labelling immunohistochemistry. Punctate PrPC immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrPC-positive granules reminiscent of dystrophic neurites are observed in neuritic plaques. Finally, PrPC deposition also occurs as dense filamentous and amorphous precipitates in amyloid cores of senile plaques, but not in the walls of blood vessels with amyloid angiopathy. In contrast to PrPC, betaA4-amyloid immunoreactivity is preserved and even enhanced following incubation of the tissue sections with proteinase K prior to immunohistochemistry, thus indicating no PrPC and betaA4-amyloid cross-reactivity in dense amyloid cores of senile plaques. Punctate PrPC deposition in diffuse plaques is similar to that of synaptophysin, a synaptic vesicle-associated protein, as already reported in other studies. Immunoprecipitation, electrophoresis and Western blot studies have shown that synaptophysin, amyloid precursor protein (APP) and betaA4 do not co-precipitate with PrP. These results suggest that synaptophysin, APP and betaA4 are likely not bound to PrP. PrPC accumulation in betaA4-amyloid dense cores may be the consequence of the release of PrP into the extracellular space. Whether PrPC accumulation in the extracellular space is the result of impaired endocytosis and subsequent hydrolysis in the endosomal compartment, in contrast to normal degradation of PrPC, resulting from or occurring in parallel to abnormal APP degradation, deserves further study.

Aged↗
PubMed2001

Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration.

Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in taupathies. The present study examines the involvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), by Western blotting, single and double-labelling immunohistochemistry, and p21Ras activation assay. Since this pathway is also activated in several paradigms of cell death and cell survival, activated ERK expression is also analysed with double-labelling immunohistochemistry and in situ end-labelling of nuclear DNA fragmentation to visualise activated ERK in cells with increased nuclear DNA vulnerability. The MEK1 antibody recognises one band of 45 kD that identifies phosphorylation-independent MEK1, whose expression levels are not modified in diseased brains. The ERK antibody recognises one band of 42 kD corresponding to the molecular weight of phosphorylation-independent ERK2; the expression levels, as well as the immunoreactivity of ERK in individual cells, is not changed in AD, PiD, PSP and CBD. The antibody MAPK-P distinguishes two bands of 44 kD and 42 kD that detect phosphorylated ERK1 and ERK2. MAPK-P expression levels, as seen with Western blotting, are markedly increased in AD, PiD, PSP and CBD. Moreover, immunohistochemistry discloses granular precipitates in the cytoplasm of neurones in AD, mainly in a subpopulation of neurones exhibiting early tau deposition, whereas neurones with developed neurofibrillary tangles are less commonly immunostained. MAPK-P also decorates neurones with Pick bodies in PiD, early tau deposition in neurones in PSP and CBD, and cortical achromatic neurones in CBD. In addition, strong MAPK-P immunoreactivity is found in large numbers of tau-positive glial cells in PSP and CBD, as seen with double-labelling immunohistochemistry. Yet no co-localisation of enhanced phosphorylated ERK immunoreactivity and nuclear DNA fragmentation is found in AD, PiD, PSP and CBD. Finally, activated Ras expression levels are increased in AD cases when compared with controls. These results demonstrate increased phosphorylated (active) ERK expression in association with early tau deposition in neurones and glial cells in taupathies, and suggest activated Ras as the upstream activator of the MEK/ERK pathway of tau phosphorylation in AD.

Aged↗
PubMed2000

Brain-derived neurotrophic factor in Huntington disease.

Trophic factors, administered systemically or delivered via genetically-modified cells grafted into target regions, have been proposed as putative therapeutic agents in human neurodegenerative disorders. In parallel to the study of the beneficial effects in experimental models of particular diseases, a crucial aspect of the study of trophic factors is the gathering of information about the actual trophic factor expression in human diseased states. Brain-derived neurotrophic factor (BDNF) promotes survival and growth of various nerve cell populations during normal development and following various insults in the developing and adult brain. In particular, BDNF prevents cell death of certain striatal populations in excitotoxic models of Huntington disease (HD) following intrastriatal injection of quinolinic acid to the adult rodent brain. The present study examines BDNF expression, by gel electrophoresis and Western blotting, and immunohistochemistry, in the brains of patients who had suffered from HD. Reduced BDNF expression, ranging from 53 to 82%, has been found in the caudate and putamen in HD when compared with age-matched controls. No modifications in BDNF expression levels have been seen in the parietal cortex, temporal cortex and hippocampus. Furthermore, immunohistochemistry has shown reduced BDNF immunoreactivity in caudate neurons, but not in cortical neurons in HD when compared with controls. These data demonstrate selective BDNF decay in regions that are vulnerable to HD, and suggest, in combination with results in experimental models, that a BDNF surplus may have beneficial effects in the treatment of HD.

Aged↗
PubMed2000

Brain-derived neurotrophic factor in patients with frontotemporal dementia.

Brain-derived neurotrophic factor (BDNF) promotes survival and growth of various nerve cell populations during normal development and following different insults in the developing and adult brain. BDNF expression is reduced in Alzheimer disease, but little is known about BDNF expression in other types of dementia. Frontotemporal dementia (FTD) is a common cause of mental impairment in old age, which is characterized by neuron loss in the upper cortical layers mainly of the frontal and temporal cortex. BDNF protein expression has been examined by Western blotting and immunohistochemistry in the cerebral cortex of individuals affected by FTD. Examination of pathological samples (n = 8, mean age: 74.7 years; four men, four women) was conducted in parallel with corresponding samples from age-matched controls (n = 8; mean age: 72.6 years; three men, five women). Post-mortem delay was between 2 and 6 h. Preserved BDNF expression, as revealed by Western blotting, has been observed in the frontal and temporal cortices of patients with FTD. Furthermore, immunohistochemistry has disclosed maintained BDNF immunoreactivity in surviving neurons of the upper cellular layers, as well as in neurons of the inner cellular layers in FTD. These results show that FTD is not associated with a decay of BDNF in cortical neurons, and therefore, that BDNF is differentially regulated in diseases causing dementia.

Aged↗
PubMed1999

Expression of p27/Kip1 is down-regulated in human prostate carcinoma progression.

p27(Kip1) is a cyclin-dependent kinase inhibitor whose down-regulation has been observed in several tumour models, including breast, colorectal, and gastric carcinomas. The purpose of this study was to assess p27(Kip1) protein expression in normal and benign prostatic epithelia as well as the possible existence of abnormalities in prostate carcinoma progression. p27(Kip1) expression was immunohistochemically analysed in 51 normal tissue samples, 11 nodular hyperplasias (NH), 22 high-grade prostatic intraepithelial neoplasias (PIN), 56 localized prostate adenocarcinomas, and 19 metastases. Immunoblotting was performed in ten cases. Normal prostate epithelium and NH showed diffuse and intense p27(Kip1) nuclear expression in most cases. A significant p27(Kip1) down-regulation was observed in many carcinomas when compared with benign epithelium. Forty-seven cases (84 per cent) were low p27(Kip1) expressors (<50 per cent positive cells) and nine cases (16 per cent) were high p27(Kip1) expressors. p27(Kip1) down-regulation was also consistently seen in PIN. Fourteen out of 19 metastases (74 per cent) were low p27(Kip1) expressors. Six metastatic samples had their corresponding primary tumour analysed and three cases showed decreased expression in the metastasis. It is concluded that p27(Kip1) is constitutively expressed in normal and benign prostatic tissue. This expression is clearly down-regulated in neoplastic progression from the preinvasive lesions through invasive carcinoma and metastases and this therefore occurs in early stages of neoplastic transformation.

Adenocarcinoma↗
PubMed1999

Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and cell contraction in cultured human hepatic stellate cells.

Hepatic stellate cells (HSCs) participate in the regulation of hepatic microcirculation and have receptors for many vasoconstrictor factors. It is unknown whether HSCs have receptors for circulating vasodilators such as atrial natriuretic peptide (ANP). This study investigated the presence of ANP receptors in human HSCs and whether ANP antagonizes the effects of endothelin-1 in these cells. ANP receptors were assessed by binding and cross-linking studies, reverse-transcriptase polymerase chain reaction (PCR), and measuring intracellular cyclic guanosine monophosphate concentration. Intracellular calcium concentration ([Ca(2+)](i)) and cell contraction were measured in individual cells loaded with fura-2 using a morphometric method. Binding and cross-linking affinity experiments showed the existence of ANP receptors in human HSCs. PCR products with the expected length were obtained for guanylate cyclase A receptor, the physiological receptor of ANP, both in quiescent and activated human cells. ANP induced a dose-dependent increase in intracellular cyclic guanosine monophosphate concentration and blunted the increase in [Ca(2+)](i) elicited by endothelin-1. Most importantly, ANP markedly reduced cell contraction induced by endothelin-1. HSCs isolated from rats with carbon tetrachloride-induced cirrhosis showed a higher number of ANP receptors compared with HSCs isolated from normal rats, indicating that in vivo activation of HSCs is associated with an up-regulation of ANP receptors. These results indicate that human HSCs have receptors for ANP, the activation of which reduces the effects of endothelin-1 on [Ca(2+)](i) and cell contraction. ANP could participate in regulating the contractility of HSCs by antagonizing the effect of vasoconstrictors.

Animals↗
PubMed1999

BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies.

Brain-derived neurotrophic factor (BDNF), and full-length and truncated tyrosin kinase B receptor (TrkB) protein expression were examined by Western blotting and immunohistochemistry in the frontal cortex and hippocampus of individuals affected by long-lasting severe Alzheimer disease (AD) and age-matched controls. Since preliminary processing studies in the brains of rats have shown loss of immunoreactivity depending on the postmortem delay in tissue processing and on the type, duration, and temperature of the fixative solution, only human samples obtained up to 6 hours (h) after death for biochemical and morphological studies and fixed by immersion in 4% paraformaldehyde for 24 h for morphological studies were included in the present series. Decreased BDNF and full-length TrkB expression accompanied by increased truncated TrkB expression, as revealed by Western blotting, was observed in the frontal cortex of patients with AD. Immunohistochemistry disclosed reduced BDNF and full-length TrkB immunoreactivity in neurons. BDNF decrease was equally observed in tangle-bearing and non-tangle-bearing neurons, as revealed with double-labeling immunohistochemistry to BDNF and phosphorylated tau or phosphorylated neurofilament epitopes. Full-length TrkB immunoreactivity was largely decreased in tangle-bearing neurons, whereas only moderate decreases occurred in neurons with granulovacuolar degeneration. Strong BDNF immunoreactivity was observed in dystrophic neurites surrounding senile plaques, whereas strong TrkB expression occurred in reactive glial cells, including those surrounding senile plaques. Finally, truncated TrkB immunoreactivity was observed in individual neurons and in reactive glial cells in the cerebral cortex and white matter in AD. These results show decay in the expression of BDNF and TrkB in AD neurons, accompanied by altered BDNF, and full-length and truncated TrkB expression in dystrophic neurites and reactive glial cells, respectively, in this disease. The present results demonstrate selective decline of the BDNF/TrkB neurotrophic signaling pathway in the frontal cortex and hippocampus in AD and provide supplemental data that may be relevant in discussing the suitability of the use of BDNF as a therapeutic agent in patients with AD.

Aged↗