1,721,041 research outputs found
Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment
Full text linkAlthough osteolysis is a common complication in patients with multiple myeloma (MM), the biologic mechanisms involved in the pathogenesis of MM-induced bone disease are poorly understood. Two factors produced by stromal-osteoblastic cells seem critical to the regulation of bone resorption: osteoprotegerin (OPG) and its ligand (OPGL). OPGL stimulates osteoclast differentiation and activity, whereas OPG inhibits these processes. The present study investigated whether myeloma cells affect physiologic OPG/OPGL balance in the bone marrow (BM) environment. Ten human myeloma cell lines and myeloma cells isolated from 26 consecutive patients with MM failed to express OPGL and only rarely produced a low amount of OPG. In a coculture system, human myeloma cells up-regulated OPGL expression but strongly down-regulated OPG production in preosteoblastic (preOB) or stromal cells (BMSCs) of primary human BM at the mRNA and protein levels. This effect, which was dependent on cell-to-cell contact between myeloma cells and BMSCs or preOB, partially involved the integrin VLA-4. In addition, overexpression of OPGL mRNA occurred in ex vivo BM cultures obtained from MM patients as compared with healthy donors, and immunohistochemical staining performed on BM biopsy specimens showed an increase of OPGL and a reduction of OPG expression in MM patients as compared with healthy subjects. In summary, these data indicate that myeloma cells affect the OPG/OPGL ratio in the BM environment and tend to confirm that the OPG/OPGL system is involved in the pathogenesis of MM-induced bone disease
DNA damage and Autophagy
No full textDNA damage and Autophagy
Serena Galati1-2, Maria Carla Gerra1, Mirca Lazzaretti1and Annamaria Buschini1.
1Department of Life Sciences, University of Parma, Parma, Italy; 2Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia, Italy.
Agents such as UV, IR, genotoxic chemicals and ROS could affect DNA integrity. Cells counteract their action through the induction of DNA repair systems and occasionally the activation of cell responses such as cell senescence and death. Autophagy is emerging to be linked to DNA damage response although its role is still not well known.
We have analyzed the involvement of autophagy during the treatment of U937 cell line with chemicals that induce different injuries inside cells (cisplatin, menadione, EMS, bortezomib, bleomycin). To reach this goal we have analysed the toxic and genotoxic effect of each compound and of its combination with rapamycin and chloroquine, inducer or inhibitor of autophagy respectively. Activation of the autophagy was assessed by the use of a plasmid coding for the LC3-GFP protein. The cytotoxic effect of the chemicals on U937 cells was measured by MTS. Genotoxicity was evaluated by the Alkaline Comet Assay.
Modulation of the autophagy brings, in almost all cases, to variation in the cyto- and geno-toxicity induced by the compounds. We have observed a dual role of autophagy in response to injuries: the activation of the pathway induces sometimes the reduction of the toxic potential of the compound and sometimes causes an increase of their toxicity. Dissecting the molecular pathways involved in the autophagy activation in response to DNA damage may open innovative strategies able to reduce toxicity of many compounds, including anticancer drugs
P53, bcl-2 and Ki-67 expression in adenoid cystic carcinoma of the palate. A clinico-pathologic study of 21 cases with long-term follow-up
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Morphological and functional alterations of the myenteric plexus in rats with TNBS-induced colitis
No full textBackground & aims: Ulcerative colitis is associated with deranged motility, with consequent diarrhoea and alterations of the colonic transit. Modifications of smooth muscle functions and of the structure of intramural plexuses have been proposed to explain some clinical features of symptomatic colitis, but histological and functional changes of the intrinsic nerves have not been fully explored. Therefore, we investigated the neuronal alterations in a model of experimental colitis, focusing our attention on the abnormalities in myenteric plexus structure and function.
Methods: Under urethane anaesthesia, rats were given an intrarectal administration of 0.25 ml of trinitrobenzene sulfonic acid (TNBS) (30 mg/rat in 30% ethanol) and sacrificed after a period of 7 or 15 days. Ethanol- or saline-treated rats were used for comparison. Myenteric plexus morphology was studied by immunocytochemical techniques, using specific markers for neurons (PGP 9.5) and synapsis (synaptophysin and SNAP 25). The functional integrity of the cholinergic system was investigated by measuring the 3H-choline uptake in colonic smooth muscle-myenteric plexus (SMMP) preparations and the outflow of tritium in response to electrical field stimulation (EFS, 2 Hz, 1 msec, supramax. amplitude for 3 min). Tritium outflow was used as a marker of the acetylcholine release from cholinergic nerve endings.
Results: TNBS produced a macroscopic damage of the colonic wall, consisting in ulcerative lesions of the mucosa and/or the submucosa and hypertropy of the muscular layers. The lesions were more evident on the distal side of the intestine, close to the site of TNBS injection (8 cm from the anus). The specific neuronal marker PGP 9.5 was significantly increased in areas with partially conserved mucosa or with ulcerative lesions limited to the submucosal layer, at both 7 and 15 days after TNBS treatment. Conversely, in necrotic areas, PGP 9.5 expression was drastically reduced at 7 days and no expression of the marker was measured at 15 days. Similarly, the specific synaptic markers, SNAP-25 and synaptophysin, were increased in areas surrounding the ulcerative lesion, suggesting neuronal plasticity in surviving neurons. In colonic SMMP from rats at 7 or 15 days after pre-treatment, a reduced 3H-choline uptake was observed, compared with preparations from ethanol- or saline-treated animals. The effect was more evident in preparations from the distal portion of the colon, but also evident in the proximal region. Moreover, the tritium outflow evoked by EFS was lower at 7 days, compared to control or ethanol-treated animals, and virtually undetectable at 15 days.
Conclusions: These data suggest that TNBS-induced colitis in rats is characterised by time-dependent alterations in myenteric plexus structure and by a reduced activity of the cholinergic nerve endings. These alterations could be responsible of the altered motility patterns which frequently occur in ulcerative colitis
Claustrum and insula in the human brain ageing. Cytologic and immunohistochemical findings
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