1,721,015 research outputs found
A comprehensive review on the role of mesenchymal stromal/stem cells in the management of rheumatoid arthritis
No full textIntroduction: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with systemic manifestations. Although the success of immune modulatory drug therapy is considerable, about 40% of patients do not respond to treatment. Mesenchymal stromal/stem cells (MSCs) have been demonstrated to have therapeutic potential for inflammatory diseases. Areas covered: This review provides an update on RA disease and on pre-clinical and clinical studies using MSCs from bone marrow, umbilical cord, adipose tissue, and dental pulp, to regulate the immune response. Moreover, the clinical use, safety, limitations, and future perspective of MSCs in RA are discussed. Using the PubMed database and ClincalTrials.gov, peer-reviewed full-text papers, abstracts and clinical trials were identified from 1985 through to April 2023. Expert opinion: MSCs demonstrated a satisfactory safety profile and potential for clinical efficacy. However, it is mandatory to deepen the investigations on how MSCs affect the proinflammatory deregulated RA patients' cells. MSCs are potentially good candidates for severe RA patients not responding to conventional therapies but a long-term follow-up after stem cells treatment and standardized protocols are needed. Future research should focus on well-designed multicenter randomized clinical trials with adequate sample sizes and properly selected patients satisfying RA criteria for a valid efficacy evaluation
Effects of polymorphisms in gonadotropin and gonadotropin receptor genes on reproductive function.
No full textGonadotropins, the action of which is mediated at the level of their gonadal receptors, play a key role in sexual development, reproductive functions and in metabolism. The involvement of the gonadotropins and their receptor genotypes on reproductive function are widely studied. A large number of gonadotropins and their receptors gene polymorphisms are known, but the only one considerable as a clear, absolute genetic marker of reproductive features or disfunctions is the FSHR Asn680Ser polymorphism, since it modulates ovarian response to FSH. The aim of these studies would to be the prediction of the genetic causes of sex-related diseases to enable a customized clinical setting based on individual response of patients undergoing gonadotropin stimulation. In this review we discuss the latest information about the effects of polymorphisms of the gonadotropins and their receptor genes on reproductive functions of both male and female, and discuss their patho-physiological implications
Two hormone for one receptors: dissecting out LH and hCG activity with an in vitro approach
No full textIntroduction: LH and hCG act on the same receptor (LHCGR), have different half-lives and in vivo biopotency. It is not known whether they elicit the same cellular and molecular response. The aim of this study was to compare the kinetics of cAMP response to recombinant LH and hCG.
Design: In COS-7 cells permanently expressing the human LHCGR (COS-7/LHCGR) we evaluated LH and hCG dose-response curves, by measuring total cAMP after 3 h of incubation. We then evaluated the time-course of intracellular cAMP production in the presence of ED50 doses of LH and hCG over 3 h. Finally we evaluated the long-term response to LH and hCG by exposing human primary granulosa lutein cells (hGLC) to ED50 doses over 12 h. All incubations were performed in the presence of IBMX.
Results: In COS-7/LHCGR cells, we observed significantly different ED50 for LH (475.75±137.33 pM, mean±S.D.) and hCG (101.75±44.63 pM) (Mann–Whitney’s U-test, P=0.029; n=4). Maximal LH stimulation of intracellular cAMP, about 50 fold over control, reached a plateau in 10 min, while maximal hCG stimulation at similar levels was attained only after 1 h (Anova; P<0.05; n=3). In hGLC continuous exposure to LH and hCG resulted in a repetitive, pulsatile increase of intracellular cAMP with peaks every 3–4 h and significantly higher levels of stimulation in the presence of hCG vs LH (Anova; P<0.05; n=3).
Conclusions: Equimolar concentrations of human recombinant LH and hCG result in significantly higher in vitro biopotency of hCG (about 5-fold). Equipotent concentration (ED50) of LH and hCG stimulate a faster response to LH within the first 3 h, but a quantitatively higher response to hCG over 12 h. hGLC respond to constant LH/hCG stimulation in a pulsatile fashion, suggesting a novel control of gonadotropins action at the receptor level
Inactivating mutations of CYP19A1 (aromatase) gene reduce the protein stability in vitro
No full textRole of inactivating mutation of the aromatase gene on the protein structure, function and degradatio
Human dental pulp stem cells modulate pro-inflammatory macrophages both through cell-to-cell contact and paracrine signaling
Full text linkIntroductionMacrophages play a key role in most of the inflammatory diseases such as Rheumatoid Arthritis (RA), but the mechanism underlying their pathogenesis is still under study. Among stem cells, human dental pulp stem cells (hDPSCs) have attracted attention due to their easy accessibility and immunomodulatory properties, making them a promising adjuvant therapy. In this study, we aimed to evaluate the capacity of hDPSCs to modulate the phenotypes of primary human macrophages. Additionally, we sought to observe the differences induced on macrophages when cultured directly with hDPSCs or through a cell culture insert, mimicking the paracrine communication pathway.MethodsMonocytes, isolated from buffy coats, were differentiated into pro-inflammatory M1 and anti-inflammatory M2 macrophages. Subsequently, they were cultured with hDPSCs either directly or via a cell-culture insert for 48 hours. Finally, they were analyzed for protein, gene expression, cytokines levels and immunofluorescence.ResultsIn our study, we have demonstrated that, hDPSCs, even without priming, can reduce TNFα levels and enhancing IL-10 release in pro-inflammatory macrophages, both through direct contact and paracrine signaling. Furthermore, we found that their effects are more pronounced when in cell-to-cell contact through the decrease of NF-kB and COX-2 expression and of CD80/PD-L1 colocalization. HDPSCs, when in contact with macrophages, showed enhanced expression of NF-kB, COX-2, ICAM-1, PD-L1, FAS-L, TNFα and IFNγ.ConclusionWe showed that hDPSCs exert immunomodulatory effects on pro-inflammatory macrophages, with cell-to-cell contact yielding a more pronounced outcome compared to paracrine signaling. Our work highlights the immunomodulatory properties of hDPSCs on activated pro-inflammatory macrophages and the potential therapeutic role in inflamed tissue
Central hypogonadotropic hypogonadism: genetic complexity of a complex disease
Full text linkCentral hypogonadotropic hypogonadism (CHH) is an emerging pathological condition frequently associated with overweight, metabolic syndrome, diabetes, and midline defects. The genetic mechanisms involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying CHH, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. Indeed, all detected gene variants may explain a small proportion of the affected patients (43%), indicating that other genes or epigenetic mechanisms are involved in the onset of CHH. The aim of this review is to summarize the current knowledge on genetic background of CHH, organizing the large amount of data present in the literature in a clear and concise manner, to produce a useful guide available for researchers and clinicians
The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression
No full textBackground/Aims: MTP1/Ferroportin1/IREG1, the product of the SLC40A1 gene, is a main iron export protein in mammals. However, the way this gene is regulated by iron is still unclear. The aim of this study was to investigate the functional role of genomic SLC40A1 elements in response to iron. Methods: Vectors containing either similar to 2.6 kb 5' flanking region or deletion constructs, including one devoid of an iron responsive element (SLC40A1-DeltaIRE-Luc), were analyzed by luciferase reporter gene in transfected HepG2, CaCO2 and U937 cells. Expression of iron genes and activity of the iron regulatory protein were also studied. Results: Iron increased and desferrioxamine decreased luciferase activity in all the cell types using both the full-length construct and the promoter deletion constructs, in the absence of changes in SLC40A1 or luciferase mRNA levels. To test the role of the SLC40A1 5' untranslated region, we first demonstrated that wild type and not SLC40A1-DeltaIRE-Luc could bind iron regulatory protein. Then, in cells transfected with SLC40A1-DIRE-Luc, we found that, in spite of iron regulatory protein activation, the response to iron manipulation was lost. Conclusions: We demonstrate that the iron responsive element in the SLC40A1 gene is functional and that it controls gene expression through the cytoplasmic iron regulatory protein system. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
A novel compound heterozygous mutation of the aromatase gene in an adult man: new insights into the role of estrogen on gonadal development.
No full textDescription of a new case of human aromatase deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE2) substitution, focusing on bone growth and mineralizatio
The osteoporotic male: overlooked and undermanaged?
Full text linkAge-related bone loss in men is a poorly understood phenomenon, although increasing data on the pathophysiology of bone in men is becoming available. Most of what we know on bone pathophysiology derives from studies on women. The well-known association between menopause and osteoporosis is far from been disproven. However, male osteoporosis is a relatively new phenomenon. Its novelty is in part compensated for by the number of studies on female osteoporosis and bone pathophysiology. On the other hand, the deeper understanding of female osteoporosis could lead to an underestimation of this condition in the male counterpart. The longer life-span exposes a number of men to the risk of mild-to-severe hypogonadism which in turn we know to be one of the pathogenetic steps toward the loss of bone mineral content in men and in women. Hypogonadism might therefore be one among many corrigible risk factors such as cigarette smoking and alcohol abuse against which clinicians should act in order to prevent osteoporosis and its complications. Treatments with calcium plus vitamin D and bisphophonates are widely used in men, when osteoporosis is documented and hypogonadism has been excluded. The poor knowledge on male osteoporosis accounts for the lack of well shared protocols for the clinical management of the disease. This review focuses on the clinical approach and treatment strategy for osteoporosis in men with particular attention to its relationship with male hypogonadism
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