| 1. |
- Lazarczyk, Marzena, et al.
(författare)
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Mouse CCL9 Chemokine Acts as Tumor Suppressor in a Murine Model of Colon Cancer
- 2023
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Ingår i: Current Issues in Molecular Biology. - : MDPI. - 1467-3037 .- 1467-3045. ; 45:4, s. 3446-3461
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer is the third most frequently diagnosed cancer in the world. Despite extensive studies and apparent progress in modern strategies for disease control, the treatment options are still not sufficient and effective, mostly due to frequently encountered resistance to immunotherapy of colon cancer patients in common clinical practice. In our study, we aimed to uncover the CCL9 chemokine action employing the murine model of colon cancer to seek new, potential molecular targets that could be promising in the development of colon cancer therapy. Mouse CT26.CL25 colon cancer cell line was used for introducing lentivirus-mediated CCL9 overexpression. The blank control cell line contained an empty vector, while the cell line marked as CCL9+ carried the CCL9-overexpressing vector. Next, cancer cells with empty vector (control) or CCL9-overexpressing cells were injected subcutaneously, and the growing tumors were measured within 2 weeks. Surprisingly, CCL9 contributed to a decline in tumor growth in vivo but had no effect on CT26.CL25 cell proliferation or migration in vitro. Microarray analysis of the collected tumor tissues revealed upregulation of the immune system-related genes in the CCL9 group. Obtained results suggest that CCL9 reveals its anti-proliferative functions by interplay with host immune cells and mediators that were absent in the isolated, in vitro system. Under specific study conditions, we determined unknown features of the murine CCL9 that have so far bee reported to be predominantly pro-oncogenic.
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| 2. |
- Religa, Piotr, et al.
(författare)
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VEGF significantly restores impaired memory behavior in Alzheimers mice by improvement of vascular survival
- 2013
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Ingår i: Scientific Reports. - : Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group. - 2045-2322. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The functional impact of amyloid peptides (Abs) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimers patients. Here we show substantial accumulation of Abs 40 and 42 in the brain arterioles of Alzheimers patients and of transgenic Alzheimers mice. PurifiedAbs 1-40 and 1-42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimers patients. VEGF significantly prevented Ab-induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimers. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimers disease.
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| 3. |
- Almazan, Nerea Martin, et al.
(författare)
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Influenza-A mediated pre-existing immunity levels to SARS-CoV-2 could predict early COVID-19 outbreak dynamics
- 2023
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Ingår i: iScience. - : CELL PRESS. - 2589-0042. ; 26:12
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is highly variable and could be mediated by a cross-protective pre-immunity. We identified 14 cross-reactive peptides between SARS-CoV-2 and influenza A H1N1, H3N2, and human herpesvirus (HHV)-6A/B with potential relevance. The H1N1 peptide NGVEGF was identical to a peptide in the most critical receptor binding motif in SARS-CoV-2 spike protein that interacts with the angiotensin converting enzyme 2 receptor. About 62%-73% of COVID-19-negative blood donors in Stockholm had antibodies to this peptide in the early pre-vaccination phase of the pandemic. Seasonal flu vaccination enhanced neutralizing capacity to SARS-CoV-2 and T cell immunity to this peptide. Mathematical modeling taking the estimated pre -immunity levels to flu into account could fully predict pre-Omicron SARS-CoV-2 outbreaks in Stockholm and India. This cross-immunity provides mechanistic explanations to the epidemiological observation that influenza vaccination protected people against early SARS-CoV-2 infections and implies that flu-mediated cross-protective immunity significantly dampened the first SARS-CoV-2 outbreaks.
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| 4. |
- Dzabic, Mensur, et al.
(författare)
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Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival
- 2011
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 53:10, s. 969-976
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytomegalovirus (CMV) infection is a risk factor for acute and chronic rejection of transplanted organs and is thought to mediate rejection indirectly. Methods: In this retrospective observational cohort study, early- and end-stage biopsies from renal allografts lost because of chronic allograft dysfunction (n = 29) were examined for CMV antigens and DNA using immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction. Results: CMV immediate-early and late proteins were present in 27 (93%) of 29 of the end-stage chronic allograft dysfunction biopsies and in 64% of the corresponding early biopsies but not in pretransplant biopsies from CMV-seronegative donors (n = 3). Graft survival time was reduced in patients with moderate or high CMV levels in the graft soon after transplantation compared with that in patients with no or low CMV levels in the graft. No significant difference was observed in serum creatinine obtained at the time of early biopsies. Conclusions: We provide evidence that intragraft CMV protein expression is associated with end-stage chronic renal allograft dysfunction, that intragraft CMV levels increase as graft function deteriorates, and that CMV protein expression in the grafts soon after transplant is associated with reduced graft survival. Thus, CMV may have a pathological role in chronic renal allograft dysfunction.
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| 5. |
- Jain, Mayur Vilas, 1987-
(författare)
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PKB/Akt kinase localization and role in stemness maintenance in cancer
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer incidence rates have increased over the last decade. Currently available therapies are only moderately effective in targeting cancer cells. Established cancer treatment protocols fail to eliminate populations of cancer stem cells (CSCs), which develop resistance against the chemotherapeutic drugs and lead to cancer recurrence. Therefore, understanding the mechanisms by which CSCs resist drugs and identifying molecular markers are both necessary to further improve prognosis and to develop new treatment strategies. Increased protein kinase B/Akt1 gene expression and/or activity have been found increased in majority of cancer types. Akt1 is a key player in PI3K-AktmTOR pathway that is vital for cell survival, proliferation, migration, invasion, metastasis, angiogenesis and apoptosis. In this study, we investigated a series of novel markers to improve the characterization of CSCs, with particular focus the roles of Akt in CSC maintenance and the regulatory role of micro-RNA (miR) in cancer cells. While utilizing in breast cancer cells as models, we found that luminescent conjugated oligothiophenes (LCOs), p-HTMI and p-HTAA have the potential to differentially stain various subpopulations of cancer cells, presumably also CSCs among breast cancer cells. However, further studies are needed to confirm these results. Additionally, when we investigated the effect of Akt intracellular compartmentalization on CSC development, the results revealed that nuclear Akt enhances CSC proliferation (ALDH +/High CD44+/High/CD24-/Low) and clonogenicity, which was counter examined and confirmed by using the Aktspecific inibitor triciribine. Furthermore, while investigating the impact of Akt on miR regulation in cancer cells, we found that Akt overexpression decreased.
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| 6. |
- Lazarczyk, Marzena, et al.
(författare)
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The Journey of Cancer Cells to the Brain : Challenges and Opportunities
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:4
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Forskningsöversikt (refereegranskat)abstract
- Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.
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| 7. |
- Religa, Piotr
(författare)
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Development of intimal hyperplasia in transplant arteriosclerosis
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vascular disease is the main cause of disability and mortality in the western world and the major limiting factor for long- term survival of transplanted organs. Occlusive vascular lesions lead to ischemia and structural changes in organs and in transplant arteriosclerosis and restenosis after endovascular procedures, narrowing of the vessel lumen is partly due to intimal hyperplasia caused by smooth muscle cells (SMCs). In this thesis, I have examined the mechanisms involved in intimal hyperplasia in a rat aortic allograft model of transplant arterioscleroris with an emphasis on the biology of SMCs in this process. First, the phenotypic properties of the SMCs involved in the formation of intimal hyperplasia were studied by electron microscopy and immunohistochemistry. A segment of the abdominal aorta was transplanted orthotopically from Fischer to Lewis rats and the transplanted vessels examined after 1-12 weeks. After I week, loss of endothelial cells, adhesion of platelets and leukocytes to the luminal surface, and a phenotypic modification of SMCs in the media were observed. Subsequently, modified SMCs appeared in the intima and lymphocytes and macrophages were found to infiltrate the intima as well as the adventitia. This occurred together with detachment of endothelial cells and activation of SMCs in the media as determined by the induction of cellular retinol-binding protein-1. Later, SMalpha-actin positive SMCs were observed to migrate into the intima and proliferate as judged by staining for cyclin D I and proliferating cell nuclear antigen. TUNEL- and Fas/CD95-positive SMCs, indicating apoptosis, appeared in the media which was followed by a reduction in SMalpha-actins taining in this layer. The continued development of the neointima was associated with a decrease in SMalpha-actin-positive SMCs, an increased staining for the extracellular matrix components fibronectin and osteopontin, and a further accumulation of inflammatory cells. The maximum growth in size of the neointima with an increase both in the number of SMCs and the content of extracellular matrix occurred 4-8 weeks after transplantation. SMCs and monocytes/macrophages in the neointima and in the media were also noted to accumulate lipid, turn into foam cells, and eventually show signs of necrosis and apoptosis. Within the lipid-rich cell remnants, calcification also occurred. Finally, after 12 weeks, the growth in mass of the intimal lesions ceased and reformation of an endothelial lining was detected. In order to examine if SMCs derived from the host animal can participate in intimal hyperplasia, we transplanted aorta of F344 female rats to Lewis male rats with or without cyclosporin A treatment. As a control, one group of animals was transplanted with aortic isografts exposed to prolonged cold ischemia. Infiltration of SMCs and inflammatory cells into the intimal lesions, cell proliferation, and apotosis were analyzed by immunostaining and laser micro-dissection followed by real-time PCR for the SRY gene to determine cell origin. Early after transplantation, proliferating and apoptotic graft SMCs were observed in the neointima and leukocytes and immunoglobulins appeared in the grafts. At this time apoptosis of medial SMCs occurred and proliferating, SRY-positive, host-derived SMCs started to accumulate in the neointima. After 8 weeks, the neointima was mainly composed of host-derived SMCs. Inummosupression with cyclosporin A significantly decreased the number of host SMCs in the neointima and only a small number of host SMCs were observed in isografts exposed to prolonged ischemia. To explore the possible bone marrow origin of allograft cells, female LEW rats were irradiated and substituted with bone marrow from male LEW rats by transplantation of vascularized bone marrow or by infusion of bone marrow cells, followed by transplantation of aorta from female F344 rats. Immunostaining for cell-specific markers and real-time PCR for the SRY gene showed that the number of leukocytes was lower than the number of bone marrow-derived cells in intimal lesions. Primed in situ labeling for the SRY gene combined with immunostaining confirmed the presence of SM-like cells of male origin in the vessel wall in the intima. Similar observations were made after balloon injury of the carotid artery. The findings add further support for the prior assumption that early loss of endothelial cells contribute to the initial response and activation of SMCs, whereas the inflammatory process may be the dominating factor that influence vessel structure later after transplantation. The observations also suggest that progenitors of bone marrow origin give rise to cells with SM-like properties during the formation of intimal hyperplasia after allotransplantation as well as after balloon injury. In addition, the results provide the basis for a novel theory of transplant arteriosclerosis which suggests that the development of intimal hyperplasia in this vasculopathy is a dynamic two-stage process that involves apoptosis of resident graft SMCs triggered by an allogenic immune response which also promotes recruitment of host-derived SMCs.
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