Histology and histopathology Vol.17, nº 4 (2002)

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Open Access
Effects of phthalate esters on actin cytoskeleton of Py1a rat osteoblasts
(Murcia : F. Hernández, 2002) Marchetti, L.; Sabbieti, M.G.; Menghi, M.; Materazzi, S.; Hurley, M.M.; Menghi, Giovanna
We evaluated, by confocal laser scanning microscopy, the actin cytoskeleton of immortalized rat Py1a osteoblasts treated with phthalate esters (butyl benzyl phthalate, BBP and dibutyl phthalate, DBP), endocrine disruptors with estrogenic activity. We observed some peculiar modifications of actin cytoskeleton and cells changing from a spindle shape to a rounded form. In particular, F-actin formed thick bundles around the cell membrane but only a weak labeling was observed in rounded cells. Also influence on apoptosis and short-term effects on FGF-2 were studied. It was found that BBP and DBP exert their action in a similar way, act in a transient manner and do not induce apoptosis.
Open Access
Mortalin: a potential candidate for biotechnology and biomedicine
(Murcia : F. Hernández, 2002) Wadhwa, R.; Taira, K.; Kaul, S.C.
Mortalin is a novel member of the hsp70 family of proteins that exhibits a different staining pattern in normal and immortal cells. It was also cloned as glucose regulated protein, GRP75 and peptidebinding protein, PBP74. It has been assigned multiple functions ranging from stress response, intracellular trafficking, antigen processing, control of cell proliferation, differentiation and tumorigenesis. The present article compiles and reviews information on multiple sites and functions of mortalin. In view of its upregulation in many tumors and transcriptional inactivation function of p53, its potential use in biotechnology and biomedicine is discussed
Open Access
Regulation of smooth muscle cell accumulation in diabetes-accelerated atherosclerosis
(Murcia : F. Hernández, 2002) Askari, B.; Renard, C.B.; Bornfeldt, K.E.
Diabetes leads to accelerated formation/ progression of lesions of atherosclerosis. Cardiovascular disease thus develops earlier in people with type 1 or type 2 diabetes compared to people without diabetes, and cardiovascular (macrovascular) disease is the major cause of death in adults with diabetes. The molecular and cellular mechanisms leading to diabetes-accelerated atherosclerosis are not well understood. The arterial smooth muscle cell (SMC), one of the three or four principal cell types in atherosclerosis, has been extensively studied over the years. Proliferation and accumulation of SMCs are believed to play important roles in the progression of macrophage-rich lesions to fibroatheromas. Further progression of these atheromas into complicated vulnerable lesions that are likely to cause the acute clinical symptoms of atherosclerosis (myocardial infarction and stroke) may involve cell death and loss of SMCs from the fibrous cap of the lesion. Recent animal studies have shown that diabetes causes a marked increase in SMC accumulation and proliferation in atheromas. Hyperglycemia, advanced glycation end-products, insulin and lipid abnormalities associated with the diabetic environment have been suggested to increase SMC accumulation. Indeed, it is becoming increasingly clear that macrovascular disease associated with diabetes is a multifactorial disease. We review the factors and mechanisms that may regulate SMC proliferation and accumulation in different stages of lesion progression in diabetes. We propose that lipid abnormalities associated with diabetes can act in combination with growth factors present in the diabetic environment to increase SMC accumulation and accelerate lesion progression.
Open Access
Animal in vivo models of EBV-associated lymphoproliferative diseases: Special references to rabbit models
(Murcia : F. Hernández, 2002) Hayashi, K.; Teramoto, N.; Akagi, T.
Animal models of human EBV-associated diseases are essential to elucidate the pathogenesis of EBV-associated diseases. Here we review those previous models using EBV or EBV-like herpesviruses and describe the details on our two newly-developed rabbit models of lymphoproliferative diseases (LPD) induced by simian EBV-like viruses. The first is Cynomolgus- EBV-induced T-cell lymphomas in rabbits inoculated intravenously (77- 90%) and orally (82- 89%) during 2 - 5 months. EBV-DNA was detected in peripheral blood by PCR from 2 days after oral inoculation, while anti- EBV-VCA IgG was raised 3 weeks later. Rabbit lymphomas and their cell lines contained EBV-DNA and expressed EBV-encoded RNA-1 (EBER-1). Rabbit lymphoma cell lines, most of which have specific chromosomal abnormality, showed tumorigenicity in nude mice. The second is the first animal model for EBV-infected T-cell LPD with virus-associated hemophagocytic syndrome (VAHS), using rabbits infected with an EBV-like herpesvirus, Herpesvirus papio (HVP). Rabbits inoculated intravenously with HVP-producing cells showed increased anti-EBV-VCAIgG titers, and most (85%) subsequently died of fatal LPD and VAHS, with bleeding and hepatosplenomegaly, during 22-105 days. Peroral spray of cell-free HVP induced viral infection with seroconversion in 3 out of 5 rabbits, with 2 of the 3 infected rabbits dying of LPD with VAHS. Atypical T lymphocytes containing HVPDNA and expressing EBER-1 were observed in many organs. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. These rabbit models are also useful and inexpensive alternative experimental model systems for studying the biology and pathogenesis of EBV, and prophylactic and therapeutic regimens.
Open Access
Desmosomes and disease: an update
(Murcia : F. Hernández, 2002) Chidgey, M.A.J.
Desmosomes play a critical role in the maintenance of normal tissue architecture. Skin blistering can occur when desmosomal adhesion is compromised by antibodies in autoimmune diseases such as pemphigus. Inherited mutations in genes encoding desmosomal constituents can adversely affect the skin, and result in heart abnormalities. Desmosomes may have a tumour suppressor function: expression of desmosomal components is reduced in some human cancers, and desmosomal cadherins have the capacity to suppress the invasiveness of cells in culture. Transgenic animal research has provided important insights into the role of these junctions in normal epithelial morphogenesis and disease.
Open Access
CD26: An expanding role in immune regulation and cancer
(Murcia : F. Hernández, 2002) Dang, N.H.; Morimoto, C.
In this review, we highlight major aspects of the biology of CD26, a dipeptidyl peptidase IV (DPPIV)-containing surface glycoprotein with multiple functions. In particular, we discuss findings demonstrating that CD26/DPPIV has an essential role in immune regulation as a T cell activation molecule and a regulator of chemokine function. We also review recent studies that identify key cellular molecules that physically associate with CD26 and the potential consequences of their interaction, including those with clinically-related implications. Furthermore, we present work suggesting a role for CD26 in the pathogenesis and behavior of selected human cancers, both solid tumors and hematological malignancies. We present recent studies that investigate the potential role of CD26 as a molecular target for novel treatment modalities for T cell lymphoid malignancies and possibly other hematological malignancies, with work involving the use of anti-CD26 monoclonal antibody, CD26-transfected cells as well as soluble CD26 molecules.
Open Access
Morphological changes in the rat exocrine pancreas after pancreatic duct ligation
(Murcia : F. Hernández, 2002) Hamamoto, N.; Ashizawa, N.; Niigaki, M.; Kaji, T.; Katsube, T.; Endoh, H.; Watanabe, M.; Sumi, S.; Kinoshita, Y.
In the present study, morphological changes of the exocrine pancreas in rats after pancreatic duct ligation were examined with light microscopy (hematoxylin-eosin, TUNEL, and PCNA staining) and scanning electron microscopy in order to elucidate the effects of increased pancreatic duct pressure. On the fifth day after pancreatic duct ligation, ductular proliferation, periductal fibrosis, and disappearance of acini were obserbed. TUNEL and PCNA staining demonstrated many apoptotic acinar cells and proliferating ductal cells immediately after ligation, which reached a maximal number on the 2nd or 3rd day. Tortuous or helical interlobular pancreatic ducts with inner surfaces containing many crater-like depressions and long cilia were found after ligation. These changes were almost identical to those observed in the pancreatic tissue of model chronic pancreatitis rats, WBN/Kob rats, and stroke-prone spontaneously hypertensive (SHRSP) rats. In summary, the morphological changes observed after pancreatic duct ligation were similar to those of chronic pancreatitis, therefore, the characteristic changes of pancreatic ducts observed in chronic pancreatitis may be caused by increased pancreatic duct pressure.
Open Access
The controversial nuclear matrix: a balanced point of view
(Murcia : F. Hernández, 2002) Martelli, A.M.; Falcieri, E.; Zweyer, M.; Bortul, R.; Tabellini, G.; Cappellini, A.; Cocco, L.
The nuclear matrix is defined as the residual framework after the removal of the nuclear envelope, chromatin, and soluble components by sequential extractions. According to several investigators the nuclear matrix provides the structural basis for intranuclear order. However, the existence itself and the nature of this structure is still uncertain. Although the techniques used for the visualization of the nuclear matrix have improved over the years, it is still unclear to what extent the isolated nuclear matrix corresponds to an in vivo existing structure. Therefore, considerable scepticism continues to surround the nuclear matrix fraction as an accurate representation of the situation in living cells. Here, we summarize the experimental evidence in favor of, or against, the presence of a diffuse nucleoskeleton as a facilitating organizational nonchromatin structure of the nucleus.
Open Access
Modulation of pulmonary neuroendocrine cells in idiopathic interstitial pneumonia
(Murcia : F. Hernández, 2002) Ito, T.; Ogura, T.; Ogawa, N.; Udaka, N.; Hayashi, H.; Inayama, Y.; Yazawa, T.; Kitamura, H.
In order to reveal modulation of the number of pulmonary neuroendocrine cells (PNEC) in interstitial lung diseases and to clarify significance of cell proliferation activity in occurrence of PNEC, we counted airway PNEC of the patients of idiopathic interstitial pneumonia, secondary interstitial pneumonia and control lungs, and compared the number of PNEC with airway Ki-67 labeling. The lung tissue samples were obtained by video-assisted thoracoscopic surgery from 22 patients with usual interstitial pneumonia (UIP), 7 with nonspecific interstitial pneumonia (NSIP), 8 with chronic hypersensitivity pneumonia (CHP), 13 with collagen vascular disease (CVD), and were compared with agematched control lungs. The tissues were immunostained for chromogranin A and for Ki-67. Average incidence of bronchiolar PNEC in normal, UIP, NSIP, CHP, CVD lungs was 0.169%, 0.348%, 0.326%, 0.175% and 0.201%, respectively, and average Ki-67 labeling index in them was 0.241%, 1.186%, 1.605%, 1.058%, and 2.353%, respectively. And, in UIP lungs, PNEC incidence or Ki-67 labeling index was different according to pathological lesions. Thus, PNEC increase in the bronchiole of UIP, and the incidence of PNEC varies according to degree of activity of epithelial cell proliferation probably related to epithelial cell injury. Moreover, enhanced expression of human homolog of achaete-scute complex (hASH1) mRNA in UIP lungs suggests that hASH1 could play roles in the regulation of PNEC.
Open Access
Microscopic changes induced by the intratracheal inoculation of amniotic fluid and meconium in the lung of neonatal rats
(Murcia : F. Hernández, 2002) Martínez Burnes, J.; Lopez, A.; Wright, Glenda M.; Ireland, William P.; Wadowska, D.W.; Dobbin, G.V.
Meconium aspiration syndrome is a major contributor to neonatal respiratory distress in infants and it has been sporadically recognized in neonatal animals. This investigation was designed to study the short and long term effects of meconium and amniotic fluid in the lungs of neonatal rats. Seven-day-old rats (n=123) divided in three groups were intratracheally inoculated with saline solution, amniotic fluid or meconium. Rats were euthanatized on 1, 3, 7, 14, 28, 56 and 112 postinoculation days (PID) and the lungs were examined by light microscopy. Saline solution did not induce any change while amniotic fluid elicited only a mild foreign body response which disappeared by PID 14. In contrast, meconium induced an exudative alveolitis characterized by recruitment of neutrophilsn in the bronchoalveolar spaces. Meconium also induced atelectasis, hyperinflation and thickening of alveolar septa all of which had disappeared by PID 14. Starting at PID 7, neutrophils were progressively replaced by macrophages, giant cells, and some fibroblasts. There were sporadic foci of mineralization starting at PID 14 and lasting up to PID 112. Some mineralized foci became lined with cuboidal epithelial cells at PID 28. Meconium was slowly degraded but still evident by PID 112. It was concluded that inoculation of meconium in neonatal rats induces acute microscopic changes typical of meconium aspiration syndrome. The long term lesions induced by meconium consisted of persistent multifocal histiocytic alveolitis and bronchiolitis reaction with occasional foci of calcification.
Open Access
On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis
(Murcia : F. Hernández, 2002) Zhu, B.T.
Studies have shown that hyperhomocysteinemia is an important and independent risk factor for a variety of human cardiovascular diseases. In this paper, a unifying hypothesis is proposed which suggests that hyperhomocysteinemia may exert its pathogenic effects largely through metabolic accumulation of Sadenosyl- L-homocysteine, a strong noncompetitive inhibitor of the catechol-O-methyltransferase (COMT)- mediated methylation metabolism of various catechol substrates (such as catecholamines and catechol estrogens). In the case of endogenous catecholamines in peripheral tissues, inhibition of their methylation by Sadenosyl- L-homocysteine will result in elevation of blood or tissue levels of catecholamines, and consequently, over-stimulation of the cardiovascular system’s functions. Moreover, because the vasculature is constantly exposed to high levels of endogenous catecholamines (due to high levels of circulating neurohormone epinephrine plus rich innervation with sympathetic nerve terminals), vascular endothelial cells would incur chronic cumulative damage caused by the large amounts of the oxidative products (catechol quinones/semiquinones and oxyradicals) generated from endogenous catecholamines. This mechanistic explanation for the vascular toxicity of hyperhomocysteinemia is supported by many experimental findings, and it also fully agrees with the known protective effects of folate, vitamins B6 and B12 in hyperhomocysteinemic patients. In addition, based on the predictable effects of hyperhomocysteinemia on the methylation of catecholamines in the central nervous system as well as on the methylation of catechol estrogens in estrogen target organs, it is also suggested that hyperhomocysteinemia is an important risk factor for the development of neurodegerative disorders (Parkinson’s and Alzheimer’s diseases) and estrogeninduced hormonal cancers. More studies are warranted to test these intriguing ideas.
Open Access
Androgen receptor mRNA under-expression in poorly differentiated human hepatocellular carcinoma
(Murcia : F. Hernández, 2002) Tavian, D.; De Petro, G.; Pitozzi, A.; Portolani, N.; Giulini, S.M.; Barlati, S.
Many studies suggest that hepatocellular carcinoma (HCC) is an androgen-dependent tumor with an incidence five times higher in males, but few data are available on the androgen receptor (AR) mRNA levels in different physiological classes of human liver specimens. In this study 108 human hepatic samples have been analyzed for AR mRNA expression by a comparative RT-PCR assay. These consisted of 35 non-tumoral hepatic samples (3 normal parenchymas, 4 steatosis, 10 hepatitis, 18 cirrhosis), 38 tumoral specimens derived from uninodular and multinodular HCCs and 35 peritumoral hepatic tissues. Normalized AR mRNA levels in tumoral and peritumoral liver tissues spanned from 0 to 146% and from 7 to 125% respectively. Only in a relatively small percentage of HCCs, the levels of expression of AR mRNA were higher than in the corresponding peritumoral tissues (16% of total HCCs). Although extremely variable, the AR mRNA levels were related to histological tumoral differentiation and proved to be lower in the highly dedifferentiated HCCs as compared to the well differentiated ones. Therefore, the evaluation of AR expression in HCC patients might be relevant for the planning of clinical studies on anti-androgen therapies, which might be useful only in the cases in which a high level of AR mRNA is detected, considering the high heterogeneity of AR mRNA levels which characterizes HCC samples. It is likely that the HCCs, expressing low or undetectable levels of AR mRNA, would not benefit by the antiandrogen therapy.
Open Access
The possible role of the gut neuroendocrine system in diabetes gastroenteropathy
(Murcia : F. Hernández, 2002) El-Salhy, M.
Gastrointestinal symptoms such as nausea and vomiting, heartburn, abdominal pain, diarrhoea, constipation and faecal incontinence are common in patients with diabetes. Diabetes gastroenteropathy is a clinically relevant problem. In addition to the increased morbidity it causes, it results in severely impaired metabolic control, which in turn increases the risk of hyper-/hypoglycaemia. Moreover, the poorly controlled blood glucose level increases the risk of secondary diabetes complications, namely, retinopathy, nephropathy, neuropathy and cardiovascular affection. Gastrointestinal symptoms may also cause malnutrition in patients with diabetes, which, together with the disturbed immune defence in diabetes, may cause intercurrent infections. Gastrointestinal symptoms in patients with diabetes are attributed to disturbed gastrointestinal motility. Gastrointestinal dysmotility in diabetes is believed to be caused by autonomic neuropathy and/or hyperglycaemia. The neuroendocrine system of the gut secretes peptides/amines that play an important role in regulating gastrointestinal motility. It is conceivable, therefore, to assume that a disturbance in this regulatory system may contribute to the pathogenesis of gastrointestinal complications in diabetes. The present review gives an updated overview of the abnormalities in the gastrointestinal neuroendocrine system in diabetes, speculates upon the possible role of these abnormalities in the pathogenesis of diabetes gastroenteropathy and, finally, predicts the possible clinical implications of these findings.
Open Access
Focal adhesion kinase: Protein interactions and cellular functions
(Murcia : F. Hernández, 2002) Abbi, S.; Guan, J.L.
Integrin-mediated cell adhesion to extracellular matrix (ECM) plays important roles in a variety of biological processes. Recent studies suggested that integrins mediate signal transduction across the plasma membrane via activating several intracellular signaling pathways. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that has been shown to be a major mediator of integrin signal transduction pathways. Upon activation by integrins, FAK undergoes autophosphorylation as well as associations with several other intracellular signaling molecules. These interactions in the signaling pathways have been shown to regulation a variety of cellular functions such as cell spreading, migration, cell proliferation, apoptosis and cell survival. Recent progress in the understanding of FAK interactions with other proteins in the regulation of these cellular functions will be discussed in this review
Open Access
An electron microscopic study of neuronal degeneration and glial cell reaction in the retina of glaucomatous rats
(Murcia : F. Hernández, 2002) Wang, X.; Tay, S.S.W.; Ng, Y.K.
The present investigation was focused on the ultrastructural changes in the neurons and glial cells in the retina of rats with experimentally-induced glaucoma. An experimental glaucoma model was created by limbal-derived vein cauterization. Animals were sacrificed at 1, 3 weeks and 3 months post-operation. Retinae were dissected and processed for electron microscopy. Neuronal degeneration was observed in all the different layers of the retina at both 1 and 3 weeks post-operation. Some degenerating neurons were found in the ganglion cell layer (GCL), inner nuclear layer (INL) and outer nuclear layer (ONL). And the dying neurons presented apoptotic-like more than necrotic neurons. Many degenerating axons and axon terminals were observed between neurons in the GCL, inner plexiform layer (IPL), INL, and outer plexiform layer (OPL). Activated astrocytes and microglial cells were present in close association with degenerating neurons and axons. The Müller cells in the INL also presented longer and darker processes with more microfilaments than in normal cells. Degenerating neuronal debris, degenerating axonal profiles and electron-dense bodies were often found in the cytoplasm of macrophages. The results suggest that both microglial cells and astrocytes are activated in the process of neuronal degeneration in the retina of experimentally-induced glaucomatous rats. It is hypothesized that they may play a protective role in removing degenerating neuronal elements in the retina after the onset of glaucoma.
Open Access
Lectin-histochemical and -cytochemical study of periodic acid Schiff-Positive lysosome granules as a histological feature of the female mouse kidney
(Murcia : F. Hernández, 2002) Yabuki, A.; Suzuki, S.; Matsumoto, M.; Nishinakagawa, H.
Renal proximal straight tubules (PST) of the female mouse contain periodic acid Schiff–positive lysosome granules. An excellent example of this is found in the kidneys of female DBA/2Cr mice. In the present study, lectin-histochemistry showed that lectinpositive granules occur in the PST of DBA/2Cr mice. Out of twenty-one lectins studied, the granules bound WGA, s-WGA, LEL, STL, DSL, GSL-II, VVL, RCA-I, ECL, PSA, LCA and PHA-E. Such granules were also observed in the proximal convoluted tubules (PCT). In addition, heterogeneous binding to the SBA or DBA was observed in the PST. Lectin-cytochemistry for s-WGA, STL, VVL, RCA-I, ECL and PSA, showed that: 1) lysosomes bind a higher level of s-WGA or STL than VVL, RCA-I, ECL or PSA; 2) PSA binding is similar in PST and PCT; 3) there are many PCT lysosomes that are negative for s-WGA, STL, VVL, RCA-I, and ECL lectin binding; and 4) s-WGA binding is highly specific to the lysosomes of the PST. Based on the binding specificities of each lectin, it was suggested that the mannose content of PST and PCT lysosomes is similar, and that PST lysosomes have a high level of N-acetylglucosamine, Nacetylgalactosamine, galactose or galactosyl (ß1,4) Nacetylglucosamine.
Open Access
Aspergillus fumigatus causes in vitro electrophysiological and morphological modifications in human nasal epithelial cells
(Murcia : F. Hernández, 2002) Botterel, F.; Cordonnier, C.; Barbier, V.; Wingerstmann, L.; Liance, M.; Coste, A.; Escudier, E.; Bretagne, S.
The role of the airway epithelium in the development of invasive aspergillosis in immunocompromised hosts has rarely been studied although patients at risk for this infection frequently have epithelial damage. We developed an in vitro model of primary culture of human nasal epithelial cells (HNEC) in air-liquid interface, which allows epithelial cell differentiation and mimics in vivo airway epithelium. We subsequently tested 7-day and 24-hour Aspergillus fumigatus filtrates on the apical side of HNEC to know whether A. fumigatus, the main species responsible for invasive aspergillosis, produces specific damage to the epithelial cells. The results were compared with those obtained with non-pathogenic filamentous fungi. Seven-day culture filtrates of A. fumigatus and Penicillium chrysogenum induced electrophysiological modifications whatever the fungus tested. In contrast, only 24-hour A. fumigatus filtrates induced a specific decrease in transepithelial resistance, hyperpolarization of the epithelium, and cytoplasmic vacuolization of HNEC compared with both A. niger and Penicillium chrysogenum. The inhibition of the A. fumigatus effects with amiloride suggests that the 24- hour fungal filtrate acts through sodium channels of HNEC. These early modifications of the epithelial cells could facilitate colonization of the airways by A. fumigatus. To know whether the molecules involved are specific to A. fumigatus or simply produced more rapidly than by other filamentous fungi warrants further investigation. In this perspective, the primary culture of HNEC represents a suitable model to study the interactions between airway epithelial cells and A. fumigatus.
Open Access
Enhanced accumulation of the isoprostane, 8-epi-PGF2a, in human aortic and pulmonary valves of patients with coronary heart disease
(Murcia : F. Hernández, 2002) Mehrabi, M.R.; Serbecic, N.; Ekmekcioglu, C.; Tamaddon, F.; Wild, T.; Plesch, K.; Sinzinger, H.; Glogar, H.D.
The aim of the present study was to investigate whether the isoprostane 8-epi-PGF2a differently accumulates in semilunar valves of patients suffering from coronary heart disease (CHD, n=19) as compared to valves from healthy heart donors (controls, n=6). Sections from isolated aortic and pulmonary valves were analyzed by semiquantitative immunohistochemistry. The 8-epi-PGF2a-content was determined by using a specific radioimmunoassay. The accumulation of 8-epi-PGF2a in both valves was higher in CHD-patients in comparison to controls (Aortic valves: 36.49±11.26 % vs. 15.78±3.04 %; pulmonary valves: 46.79±9.80 % vs. 14.99±3.57 %). The results from the radioimmunoassay revealed comparable findings in both groups (CHD vs. controls: 395.95±86.09 vs. 139.50±47.46 pg/mg protein in the aortic valves and 430.47±76.30 vs. 147.33±53.84 pg/mg protein in pulmonary valves). Pulmonary valves seem to be more susceptible to oxidative stress than aortic valves as evidenced by a higher accumulation of 8-epi-PGF2a in CHD patients. Considering the data presented in this study, we suggest that 8-epi-PGF2a is a valuable indicator of oxidative injury in human semilunar valve
Open Access
Protein kinase C isoforms and lipid second messengers: a critical nuclear partnership?
(Murcia : F. Hernández, 2002) Neri, L.M.; Borgatti, P.; Capitani, S.; Martelli, A.M.
A growing body of evidence, accumulated over the past 15 years,has highlighted that the protein kinase C family of isozymes is capable of translocating to the nucleus or is resident within the nucleus. The comprehension of protein kinase C isoform regulation within this organelle is under development. At present, it is emerging that lipid second messengers may play at least two roles in the control of nuclear protein kinase C: on one side they serve as chemical attractants, on the other they directly modulate the activity of specific isoforms. One of the best characterized lipid second messenger that could be involved in the regulation of nuclear PKC activity is DAG. The existence of two separate pools of nuclear DAG suggests that this lipid second messenger might be involved in distinct pathways that lead to different cell responses. Nuclear phosphatidylglycerol, D-3 phosphorylated inositol lipids and nuclear fatty acids are involved in a striking variety of critical biological functions which may act by specific PKC activation. The fine tuning of PKC regulation in cells subjected to proliferating or differentiating stimuli, might prove to be of great interest also for cancer therapy, given the fact that PKC-dependent signaling pathways are increasingly being seen as possible pharmacological target in some forms of neoplastic diseases. In this article, we review the current knowledge about lipid second messengers that are involved in regulating the translocation and/or the activity of different protein kinase C isoforms identified at the nuclear level.
Open Access
Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis
(Murcia : F. Hernández, 2002) Mobasheri, A.; Vannucci, S.J.; Bondy, C.A.; Carter, S.D.; Innes, J.F.; Arteaga, M.F.; Trujillo, E.; Ferraz, I.; Shakibaei, M.; Martín Vasallo, P.
Despite the recognition that degenerative cartilage disorders like osteoarthritis (OA) and osteochondritis dissecans (OCD) may have nutritional abnormalities at the root of their pathogenesis, balanced dietary supplementation programs have played a secondary role in their management. This review emphasizes the importance and role of nutritional factors such as glucose and glucose-derived sugars (i.e. glucosamine sulfate and vitamin C) in the development, maintenance, repair, and remodeling of cartilage. Chondrocytes, the cells of cartilage, consume glucose as a primary substrate for ATP production in glycolysis and utilize glucosamine sulfate and other sulfated sugars as structural components for extracellular matrix synthesis and are dependant on hexose uptake and delivery to metabolic and biosynthetic pools. Data from several laboratories suggests that chondrocytes express multiple isoforms of the GLUT/SLC2A family of glucose/polyol transporters. These facilitative glucose transporter proteins are expressed in a tissue and cell-specific manner, exhibit distinct kinetic properties, and are developmentally regulated. They may also be regulated by endocrine factors like insulin and insulin-like growth factor I (IGF-I) and cytokines such as interleukin 1 beta (IL-1ß) and tumour necrosis factor alpha (TNF-a). Recent studies suggest that degeneration of cartilage may be triggered by metabolic disorders of glucose balance and that OA occurs coincident with metabolic disease, endocrine dysfunction and diabetes mellitus. Based on these metabolic, endocrine and developmental considerations we present a novel hypothesis regarding the role of glucose transport and metabolism in cartilage physiology and pathophysiology and speculate that supplementation with sugar-derived vitamins and nutraceuticals may benefit patients with degenerative joint disorders.