1,720,977 research outputs found
MOLECULAR SPECIFICITIES OF CD4+ T-CELL-REACTIVE IGM IN HUMAN-IMMUNODEFICIENCY-VIRUS (HIV-1) INFECTION
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Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells
No full textAlthough statins are lipid-lowering drugs that block cholesterol biosynthesis, they exert immunomodulatory, anti-inflammatory, anti-angiogenic and anti-proliferative functions by reducing the isoprenylation of proteins involved in cell signal transduction such as Ras and RhoA. In this study, we provide evidence that several natural (lovastatin, simvastatin and pravastatin) and synthetic (cerivastatin and atorvastatin) statins exert a cytotoxic effect on human T, B and myeloma tumor cells by promoting their apoptosis. Dissimilar susceptibility to apoptosis has been detected in these lines, presumably in relation to the altered expression of proteins involved in the regulation of cellular signals. Cerivastatin promptly activated the cell death even in doxorubicin resistant cell lines such as MCC-2, whereas pravastatin, a hydrophilic compound, failed to induce any effect on either proliferation or apoptosis. The statin-induced apoptotic pathway in these cell lines was presumably regulated by altered prenylation of either Ras or RhoA, as measured by the defective membrane localization of these small GTPases. In addition the cell proliferation was rescued by both farnesylpyrophosphate (FPP) and geranyl-geranylpyrophosphate (GGPP), whereas no effect was obtained with squalene, a direct precursor of cholesterol. Statins primed apoptosis through its intrinsic pathway involving the mitochondria. In fact, we observed the reduction of mitochondrial membrane potential and the cytosolic release of the second mitochondria-derived activator of caspases (Smac/DIABLO). The apoptotic pathway was caspase-dependent since caspases 9, 3 and 8 were efficiently activated. These results support the potential use of statins in association with conventional treatment as apoptosis-triggering agents in these tumors
Perspective in infertility: the ovarian stem cells
Full text linkAbstract
Infertility is a medical and social condition that affects millions of women worldwide and is today considered so far
as a new disease. A considerable progress has been recently pursued in the field of the reproductive medicine and
the infertility treatment may account for novel and modern procedures such as in vitro oocyte fertilization, egg
donation, pregnancy surrogacy and preimplantation diagnosis. However, great interest has lately been reserved to
the ovarian stem cells (OSCs) whose existence in woman ovaries has been proven. OSCs are thus suitable for
developmental studies in infertility and in other clinical applications as endocrine derangements due to premature
ovarian failure, or for infertility treatment after cancer chemotherapies, as well as in restoring the hormonal balance
in postmenopausal age
Ddx4+ Oogonial Stem Cells in Postmenopausal Women's Ovaries: A Controversial, Undefined Role
Full text linkRecent studies support the existence of oogonial stem cells (OSCs) in the ovarian cortex of different mammals, including women.These cells are characterized by small size, membrane expression of DEAD(Asp-Glu-Ala-Asp)-box polypeptide-4 (Ddx4), and stemness properties (such as self-renewal and clonal expansion) as well as the ability to differentiate in vitro into oocyte-like cells. However, the discovery of OSCs contrasts with the popular theory that there is a numerically defined oocyte pool for female fertility which undergoes exhaustion with menopause. Indeed, in the ovarian cortex of postmenopausal women OSCs have been detected that possess both viability and capability to differentiate into oocytes, which is similar to those observed in younger patients. The pathophysiological role of this cell population in aged women is still debated since OSCs, under appropriate stimuli, differentiate into somatic cells, and the occurrence of Ddx4+ cells in ovarian tumor samples also suggests their potential involvement in carcinogenesis. Although further investigation into these observations is needed to clarify OSC function in ovary physiology, clinical investigators and researchers studying female infertility are presently focusing on OSCs as a novel opportunity to restore ovarian reserve in both young women undergoing early ovarian failure and cancer survivors experiencing iatrogenic menopause
Circulating tumor cells from melanoma patients show phenotypic plasticity and metastatic potential in xenograft NOD.CB17 mice
Full text linkBACKGROUND: Innovative therapies have improved the overall survival in melanoma, although a high number of patients still experience disease progression or recurrence. Ex-vivo culture of circulating tumour cells (CTCs) represents a valuable laboratory resource for in-depth characterization of rare cell populations responsible for disease progression. METHODS: CTCs from patients with metastatic melanoma were in-vitro established. Their stemness was demonstrated by both phenotypic and genotypic assays, as well as by functional studies. Xenograft experiments in NOD.CB17 mice injected with CTCs from a single patient were completed. Data were analysed by Student’s test and results expressed as mean ± SEM. RESULTS: CTCs share the mutational profile with primary cells, an intermediate epithelial-mesenchymal transition (EMT) phenotype and high expression of the immunosuppressive factors. A subclonal CTC population exhibited stem cell properties as high aldehyde dehydrogenase 1 activity, melanosphere-forming ability, and expression of major stemness transcription factors. Xenograft experiments confirmed the CTC ability to generate melanoma in-vivo and revealed enhanced metastatic propensity. CONCLUSIONS: CTCs play a relevant role in melanoma and may actively contribute to drive the disease progression and metastasis. Thus, they are a unique potential tool for pharmacogenomic studies to guide treatment strategies in advanced disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09829-1
Negative Regulation of the Osteoblast Function in Multiple Myeloma through the Repressor Gene E4BP4 Activated by Malignant Plasma Cells
No full textPurpose: To explore the pathogenetic mechanisms that suppress the osteoblast function in multiple myeloma because osteogenesis results in defective new bone formation and repair. Experimental Design: Microarray gene analysis revealed the overexpression of E4BP4, a transcriptional repressor gene, in normal osteoblasts; cocultured with myeloma cells that were releasing the parathyroid hormone-related protein (PTHrP). Thus, the effect of E4BP4 was assessed in PTHrP-stimulated osteoblasts by measuring the RNA levels of both Runx2 and Osterix as major osteoblast transcriptional activators. Because E4BP4 is a negative regulator of the cyclooxygenase-2 (COX-2) pathway that drives the expression of both Runx2 and Osterix, these factors were investigated after prostaglandin E(2) treatment to overcome the COX-2 defect as well as in E4BP4-silenced osteoblasts. Finally, E4BP4, PTHrP, Osterix, and osteocalcin levels were measured in vivo in patients with bone disease together with the E4BP4 protein in bone biopsies. Results: E4BP4 was specifically induced by PTHrP and inhibited both Runx2 and Osterix, whereas E4BP4-silenced osteoblasts expressed functional levels of both factors. The prostaglandin E2 treatment of E4BP4-up-regulated osteoblasts promptly restored Runx2 and Osterix activities, suggesting that integrity of COX-2 pathway is essential for their transcription. Down-regulation of Osterix by E4BP4 was confirmed in vivo by its inverse levels in osteoblasts from myeloma patients with increased serum PTHrP, whose bone biopsies expressed the E4BP4 protein. Conclusions: Our data support the role of E4BP4 as osteoblast transcriptional repressor in inhibiting both Runx2 and Osterix in myeloma bone disease and correlate its effect with the increased PTHrP activity
Te avbeta3/avbeta5 blockage by Cilengitide disables the osteoclast-like differentiation of malignant plasma cells in multiple myeloma
No full text[Mesenchymal stem cells and bone regeneration]. FT Cellule staminali mesenchimali e medicina rigenerativa dell'osso.
No full textLFA-1 expressing CD4+CD45RO+ peripheral blood T-lymphocytes in RR MS: effects induced by rIFNb-1a
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