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Kokron, Cristina M., Paolo R. Errante, Myrthes T. Barros, Gisele V. Baracho, Maristela M. Camargo, Jorge Kalil e Luiz V. Rizzo. "Clinical and laboratory aspects of common variable immunodeficiency". Anais da Academia Brasileira de Ciências 76, n.º 4 (dezembro de 2004): 707–26. http://dx.doi.org/10.1590/s0001-37652004000400007.
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Common variable immunodeficiency (CVID) is an immunological disorder characterized by defective antibody production, recurrent infections, most notably of the respiratory tract, autoimmune phenomena and cancer. Some CVID patients may also present disturbances of the cellular immune response such as a decrease in the number and proportion of different lymphocyte populations, diminished lymphoproliferative response to mitogens and antigens, altered production of cytokines, and deficient expression of cell-surface molecules. Most Brazilian CVID patients included in this study show a decrease in T and B lymphocyte counts in the peripheral blood. Furthermore, their lymphocytes are more susceptible to apoptosis following activation than normal individuals, and they have a decrease in the expression of activation molecules like CD25, CD69, CD40L and CD70. Moreover, they show a decreased synthesis of IL-4 and IL-5 in comparison with normal individuals. The increase in susceptibility to apoptosis following activation, may also be responsible for the decrease in the expression of activation molecules and CD40L, decrease in Th2 cytokines synthesis, and in the number of T and B circulating cells. In this study we discuss some of these immunological disturbances correlating them to the patients' clinical features and comparing our patients' findings to the literature.
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SALIKHOVA, T. R., N. S.-M. OMAROV, A. U. CHERKESOVA, S. M. GADJIMURADOVA e E. R. ASKERKHANOVA. "CLINICO-MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL ASPECTS OF ENDOMETRIAL POLYP PATHOGENESIS IN POSTMENOPAUSE". Periódico Tchê Química 16, n.º 32 (20 de agosto de 2019): 724–31. http://dx.doi.org/10.52571/ptq.v16.n32.2019.742_periodico32_pgs_724_731.pdf.
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To study hypoxia-inducible transcription factor HIF-1α expression in endometrial polyps (EP) considering their clinical-morphological and immunological features during postmenopause. A complex clinical and laboratory examination of 120 postmenopausal patients was carried out. 90 of them developed EP, whereas 30 had morphologically unchanged endometrium. Immune histochemical (ICH) testing was used to evaluate HIF-1α expression in epithelial and stromal cells of polyps in adjacent and control endometrium. A complex of the most significant risk factors in EP genesis such as high rate of inflammatory disorders of genital organs (IDGO), extragenital, metabolic and endocrine disorders and intrauterine contraception (IUC) was found. High expression of HIF-1α in epithelial cells and in the area of inflammatory infiltrate of glandular fibrous EP stroma was established as compared with control endometrium. HIF-1α expression in epithelial cells and in the area of inflammatory infiltrate of EP glandular fibrous stroma against the background of inflammatory, metabolic and endocrine, immunological changes and age-related involutional processes indicated local hypoxia. Epigenetic changes can develop in the processes of proliferation and apoptosis and in the processes that control neoplastic transformation. The obtained data can provide grounds for patient-tailored EP therapy in postmenopausal patients.
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PASSOS, ELIANA M. DOS, VALÉRIA WANDERLEY-TEIXEIRA, EDMILSON J. MARQUES, ÁLVARO A. C. TEIXEIRA e FÁBIO A. BRAYNER. "Cotesia flavipes (CAM) (Hymenoptera: Braconidae) Supresses Immune Responses In Diatraea flavipennella (BOX) (Lepidoptera: Crambidae)". Anais da Academia Brasileira de Ciências 86, n.º 4 (dezembro de 2014): 2013–24. http://dx.doi.org/10.1590/0001-3765201420130393.
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The present research aimed to elucidate which aspects of immune responses in Diatraea flavipennella are suppressed by the parasitoid Cotesia flavipes, thus, ensuring parasitism success. We investigated the presence of apoptosis in fat body cells through the TUNEL technique. According to the results, reduced levels of nitric oxide and phenoloxidase activity were observed in larvae parasitized for three days, and reduced total number of hemocytes, after three and seven days. An increase in plasmatocytes and decrease in spherulocytes numbers were observed in the differential count on the third day of parasitism. The number of melanized microspheres in parasitized larvae was low and indicated less intense melanization. The ultrastructural analysis confirmed the immunosuppressive effect of C. flavipes on the encapsulation response of D. flavipennella because only the formation of hemocytes capsules, adhered to the microspheres' surface, was evidenced in non-parasitized caterpillars. The effect of parasitism was also recorded on the third day with the presence of hemocytes and apoptosis in fat body cells, including aspects of degeneration in the latter. We concluded that C. flavipes suppresses cellular and humoral immunological responses in D. flavipennella and drastically affects the host's fat tissue.
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Signorile, Anna, Anna Ferretta, Maddalena Ruggieri, Damiano Paolicelli, Paolo Lattanzio, Maria Trojano e Domenico De Rasmo. "Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics". Antioxidants 10, n.º 1 (28 de dezembro de 2020): 21. http://dx.doi.org/10.3390/antiox10010021.
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Multiple sclerosis (MS) is a complex inflammatory and neurodegenerative chronic disease that involves the immune and central nervous systems (CNS). The pathogenesis involves the loss of blood–brain barrier integrity, resulting in the invasion of lymphocytes into the CNS with consequent tissue damage. The MS etiology is probably a combination of immunological, genetic, and environmental factors. It has been proposed that T lymphocytes have a main role in the onset and propagation of MS, leading to the inflammation of white matter and myelin sheath destruction. Cyclic AMP (cAMP), mitochondrial dysfunction, and oxidative stress exert a role in the alteration of T lymphocytes homeostasis and are involved in the apoptosis resistance of immune cells with the consequent development of autoimmune diseases. The defective apoptosis of autoreactive lymphocytes in patients with MS, allows these cells to perpetuate, within the CNS, a continuous cycle of inflammation. In this review, we discuss the involvement in MS of cAMP pathway, mitochondria, reactive oxygen species (ROS), apoptosis, and their interaction in the alteration of T lymphocytes homeostasis. In addition, we discuss a series of nutraceutical compounds that could influence these aspects.
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Nicola, Monica-Georgiana, Liliana Mocanu, Aritina Elvira Morosanu, Sorin Berbece e Loredana Elena Stoica. "The Immunohistochemical Expression of Bcl2, Ki 67and CD3 correlated with the Basal Cell Carcinoma Histological Features - a study on 10 cases". Revista de Chimie 71, n.º 1 (7 de fevereiro de 2020): 249–53. http://dx.doi.org/10.37358/rc.20.1.7841.
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The basal cell carcinoma represents a worldwide major health problem due to incidence, functional and aesthetical defects which accompanies the disease and its treatment and high recurrency risk.The various morphoclinical forms of the basal cell carcinoma may be explained due to at least three factors: genetical predisposal, the individual immunological status and the action of the risk factors. In the case in which the histological aspects do present some modifications which cannot be catalogued in the usual patterns, therefore inseriated sections of the hole tumor being imposed, in order to establish correctly the diagnosis and in the case in which microscopical criteria are partially overposable with those specific to another lesion, the immunohistochemical evaluation is imposed.The immunohistochemical studies are also used in research, thus revealing some biological aspects of the basal cell carcinoma. The study of the biological markers of the apoptosis, cellullarproliferation and the immunitary system reaction allows the understanding of the morphofunctional anomalies during the neoplastic transformation process and the early identification of the aggressive forms.
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Yamamoto, Toshiyuki, e Ichiro Katayama. "Vascular Changes in Bleomycin-Induced Scleroderma". International Journal of Rheumatology 2011 (2011): 1–5. http://dx.doi.org/10.1155/2011/270938.
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Systemic sclerosis (SSc) is characterized by vascular injury, immunological abnormalities, and fibrosis of the skin as well as various internal organs. Vascular impairment is the early manifestation and plays a fundamental role in the pathogenesis of SSc. Recent studies suggest that complex interactions among the endothelial cells, pericytes, smooth muscle cells, and fibroblasts are involved in the systemic vasculopathy in SSc, and histological feature of proliferation of vascular wall is seen in the lesional scleroderma skin at the late stage of disease. One of the most representative mouse models for scleroderma is the bleomycin-induced scleroderma; however, aspects of vascular alteration have not been described in detail so far. A number of studies have shown that bleomycin stimulates endothelial cells and fibroblasts to induce proinflammatory and fibrogenic cytokines, apoptosis, reactive oxygen species, and so on. This paper makes a focus on the vascular involvement in the bleomycin-induced murine scleroderma.
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Zivadinovic, Radomir, Aleksandra Petric, Goran Lilic, Vekoslav Lilic e Biljana Djordjevic. "Persistent human papillomavirus infection in the etiology of cervical carcinoma: The role of immunological, genetic, viral and cellular factors". Srpski arhiv za celokupno lekarstvo 142, n.º 5-6 (2014): 378–83. http://dx.doi.org/10.2298/sarh1406378z.
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The aim of this paper was to present the role of human papillomavirus (HPV) in cervical carcinogenesis from several aspects. By explaining the HPV virus lifecycle and structure, its effect on cervical cell cycle and subversion of immune response can be better understood. Early E region of the viral genome encodes proteins that are directly involved in carcinogenesis. The E6 protein binds to p53 protein (product of tumor-suppressor gene) blocking and degrading it, which in turn prevents cell cycle arrest and apoptosis induction. E6 is also capable of telomerase activation, which leads to cell immortalization; it also reacts with host proto-oncogene c-jun, responsible for transcription, shortens G1 phase and speeds up the transition from G1 to S phase of the cells infected by HPV. E7 forms bonds with retinoblastoma protein (product of tumor-suppressor gene) and inactivates it. It can inactivate cyclin inhibitors p21, p27, and abrogate the mitotic spindle checkpoint with the loss of protective effect of pRB and p53. The immune system cannot initiate early immunological reaction since the virus is non-lytic, while the concentration of viral proteins - antigens is low and has a basal intracellular position. Presentation through Langerhans cells (LC) is weak, because the number of these cells is low due to the effect of HPV. E7 HPV reduces the expression of E-cadherin, which is responsible for LC adhesion to HPVtransformed keratinocytes. Based on these considerations, it may be concluded that the process of cervical carcinogenesis includes viral, genetic, cellular, molecular-biological, endocrine, exocrine and immunological factors.
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Brandler, Samantha, Alice Lepelley, Marion Desdouits, Florence Guivel-Benhassine, Pierre-Emmanuel Ceccaldi, Yves Lévy, Olivier Schwartz e Arnaud Moris. "Preclinical Studies of a Modified Vaccinia Virus Ankara-Based HIV Candidate Vaccine: Antigen Presentation and Antiviral Effect". Journal of Virology 84, n.º 10 (10 de março de 2010): 5314–28. http://dx.doi.org/10.1128/jvi.02329-09.
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ABSTRACT Poxvirus-based human immunodeficiency virus (HIV) vaccine candidates are currently under evaluation in preclinical and clinical trials. Modified vaccinia virus Ankara (MVA) vectors have excellent safety and immunogenicity records, but their behavior in human cell cultures remains only partly characterized. We studied here various virological and immunological aspects of the interactions of MVA-HIV, a vaccine candidate developed by the French National Agency for AIDS Research (ANRS), with primary human cells. We report that MVA-HIV infects and drives Gag expression in primary macrophages, dendritic cells (DCs), and epithelial and muscle cells. MVA-HIV-infected DCs matured, efficiently presented Gag, Pol, and Nef antigens, and activated HIV-specific cytotoxic T lymphocytes (CTLs). As expected with this type of vector, infection was cytopathic and led to DC apoptosis. Coculture of MVA-HIV-infected epithelial cells or myotubes with DCs promoted efficient Gag antigen major histocompatibility complex class I (MHC-I) cross-presentation without inducing direct infection and death of DCs. Antigen-presenting cells (APCs) infected with MVA-HIV also activated HIV-specific CD4+ T cells. Moreover, exposure of DCs to MVA-HIV or to MVA-HIV-infected myotubes induced type I interferon (IFN) production and inhibited subsequent HIV replication and transfer to lymphocytes. Altogether, these results show that MVA-HIV promotes efficient MHC-I and MHC-II presentation of HIV antigens by APCs without facilitating HIV replication. Deciphering the immune responses to MVA in culture experiments will help in the design of innovative vaccine strategies.
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Sochacka-Ćwikła, Aleksandra, Andrzej Regiec, Michał Zimecki, Jolanta Artym, Ewa Zaczyńska, Maja Kocięba, Iwona Kochanowska, Iwona Bryndal, Anna Pyra e Marcin Mączyński. "Synthesis and Biological Activity of New 7-Amino-oxazolo[5,4-d]Pyrimidine Derivatives". Molecules 25, n.º 15 (4 de agosto de 2020): 3558. http://dx.doi.org/10.3390/molecules25153558.
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The synthesis of a series of novel 7-aminooxazolo[5,4-d]pyrimidines 5, transformations during their synthesis and their physicochemical characteristics have been described. Complete detailed spectral analysis of the intermediates 2–4, the N′-cyanooxazolylacetamidine by-products 7 and final compounds 5 has been carried out using MS, IR, 1D and 2D NMR spectroscopy. Theoretical research was carried out to explain the privileged formation of 7-aminooxazolo[5,4-d]pyrimidines in relation to the possibility of their isomer formation and the related thermodynamic aspects. Additionally, the single-crystal X-ray diffraction analysis for 5h was reported. Ten 7-aminooxazolo[5,4-d]pyrimidines 5 (SCM1–10) were biologically tested in vitro to preliminarily evaluate their immunological, antiviral and anticancer activity. Compounds SCM5 and SCM9 showed the best immunoregulatory profile. The compounds displayed low-toxicity and strongly inhibited phytohemagglutinin A-induced proliferation of human peripheral blood lymphocytes and lipopolysaccharide-induced proliferation of mouse splenocytes. Compound SCM9 caused also a moderate suppression of tumor necrosis factor α (TNF-α) production in a human whole blood culture. Of note, the compounds also inhibited the growth of selected tumor cell lines and inhibited replication of human herpes virus type-1 (HHV-1) virus in A-549 cell line. Molecular investigations showed that the compounds exerted differential changes in expression of signaling proteins in Jurkat and WEHI-231 cell lines. The activity of SCM5 is likely associated with elicitation of cell signaling pathways leading to cell apoptosis. The compounds may be of interest in terms of therapeutic utility as inhibitors of autoimmune disorders, virus replication and antitumor agents.
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Merani, Shaheed, e A. M. James Shapiro. "Current status of pancreatic islet transplantation". Clinical Science 110, n.º 6 (15 de maio de 2006): 611–25. http://dx.doi.org/10.1042/cs20050342.
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DM (diabetes mellitus) is a metabolic disorder of either absolute or relative insulin deficiency. Optimized insulin injections remain the mainstay life-sustaining therapy for patients with T1DM (Type I DM) in 2006; however, a small subset of patients with T1DM (approx. 10%) are exquisitely sensitive to insulin and lack counter-regulatory measures, putting them at higher risk of neuroglycopenia. One alternative strategy to injected insulin therapy is pancreatic islet transplantation. Islet transplantation came of age when Paul E. Lacy successfully reversed chemical diabetes in rodent models in 1972. In a landmark study published in 2000, Shapiro et al. [A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman and R. V. Rajotte (2000) N. Engl. J. Med. 343, 230–238] reported seven consecutive patients treated with islet transplants under the Edmonton protocol, all of whom maintained insulin independence out to 1 year. Substantial progress has occurred in aspects of pancreas procurement, transportation (using the oxygenated two-layer method) and in islet isolation (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Clinical protocols to optimize islet survival and function post-transplantation improved dramatically with the introduction of the Edmonton protocol, but it is clear that this approach still has potential limitations. Newer pharmacotherapies and interventions designed to promote islet survival, prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials, and it seems likely that clinical outcomes of islet transplantation will continue to improve at the current exponential pace.
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Lawn, Stephen D., Salvatore T. Butera e Thomas M. Folks. "Contribution of Immune Activation to the Pathogenesis and Transmission of Human Immunodeficiency Virus Type 1 Infection". Clinical Microbiology Reviews 14, n.º 4 (1 de outubro de 2001): 753–77. http://dx.doi.org/10.1128/cmr.14.4.753-777.2001.
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SUMMARY The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4+ cell loss by apoptosis, immune activation may further be central to the increased rate of CD4+ cell turnover and eventual development of CD4+ lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo.
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Li, Yanfei, e Ke Ren. "The Mechanism of Contrast-Induced Acute Kidney Injury and Its Association with Diabetes Mellitus". Contrast Media & Molecular Imaging 2020 (23 de junho de 2020): 1–10. http://dx.doi.org/10.1155/2020/3295176.
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Contrast-induced acute kidney injury (CI-AKI) is the third most common hospital-acquired AKI after AKI induced by renal perfusion insufficiency and nephrotoxic drugs, taking great adverse effects on the prognosis and increasing hospital stay and medical cost. Diabetes nephropathy (DN) is a common chronic complication of DM (diabetes mellitus), and DN is an independent risk factor for chronic kidney disease (CKD) and CI-AKI. The incidence of CI-AKI significantly increases in patients with renal injury, especially in DM-related nephropathy. The etiology of CI-AKI is not fully clear, and research studies on how DM becomes a facilitated factor of CI-AKI are limited. This review describes the mechanism from three aspects. ① Pathophysiological changes of CI-AKI in kidney under high-glucose status (HGS). HGS can enhance the oxidative stress and increase ROS which next causes stronger vessel constriction and insufficient oxygen supply in kidney via vasoactive substances. HGS also aggravates some ion pump load and the latter increases oxygen consumption. CI-AKI and HGS are mutually causal, making the kidney function continue to decline. ② Immunological changes of DM promoting CI-AKI. Some innate immune cells and pattern recognition receptors (PRRs) in DM and/or DN may respond to some damage-associated molecular patterns (DAMPs) formed by CI-AKI. These effects overlap with some pathophysiological changes in hyperglycemia. ③ Signaling pathways related to both CI-AKI and DM. These pathways involved in CI-AKI are closely associated with apoptosis, inflammation, and ROS production, and some studies suggest that these pathways may be potential targets for alleviating CI-AKI. In conclusion, the pathogenesis of CI-AKI and the mechanism of DM as a predisposing factor for CI-AKI, especially signaling pathways, need further investigation to provide new clinical approaches to prevent and treat CI-AKI.
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Zhukova, O. B., N. V. Ryazantseva e V. V. Novitsky. "Viral persistence: immunologic and molecular-genetic aspects of pathogenesis". Bulletin of Siberian Medicine 2, n.º 4 (30 de dezembro de 2003): 113–20. http://dx.doi.org/10.20538/1682-0363-2003-4-113-120.
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In the article a view of investigators on the modern understanding of long-term viral persistence forming mechanisms on cellular and molecular levels has been presented. A question on the role of persistent virus in the induction of changes in cellular differentiation character, of chromosome apparatus and of apoptosis of peripheral blood lymphocytes has been discussed.
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Podoprigora, Gennadiy Ignat'evich, Lyudmila Ivanovna Kafarskaya, Nikolay Alekseevich Baynov e Andrey Nikolaevich Shkoporov. "Bacterial Translocation from Intestine: Microbiological, Immunological and Pathophysiological Aspects". Annals of the Russian academy of medical sciences 70, n.º 6 (6 de dezembro de 2015): 640–50. http://dx.doi.org/10.15690/vramn564.
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Bacterial translocation (BT) is both pathology and physiology phenomenon. In healthy newborns it accompanies the process of establishing the autochthonous intestinal microbiota and the host microbiome. In immunodeficiency it can be an aethio-pathogenetic link and a manifestation of infection or septic complications. The host colonization resistance to exogenous microbic colonizers is provided by gastrointestinal microbiota in concert with complex constitutional and adaptive defense mechanisms. BT may be result of barrier dysfunction and self-purification mechanisms involving the host myeloid cell phagocytic system and opsonins. Dynamic cell humoral response to microbial molecular patterns that occurs on the mucous membranes initiates receptor signaling pathways and cascade of reactions. Their vector and results are largely determined by cross-reactivity between microbiome and the host genome. Enterocyte barriers interacting with microbiota play leading role in providing adaptive, homeostatic and stress host reactivity. Microcirculatory ischemic tissue alterations and inflammatory reactions increase the intestinal barrier permeability and BT. These processes a well as mechanisms for apoptotic cells and bacteria clearance are justified to be of prospective research interest. The inflammatory and related diseases caused by alteration and dysfunction of the intestinal barrier are reasonably considered as diseases of single origin. Maternal microbiota affects the formation of the innate immune system and the microbiota of the newborn, including intestinal commensal translocation during lactation. Deeper understanding of intestinal barrier mechanisms needs complex microbiological, immunological, pathophysiological, etc. investigations using adequate biomodels, including gnotobiotic animals.
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Troeger, Anja, Ludmila Glouchkova, Birgit Ackermann, Gabriele Escherich, Roland Meisel, Helmut Hanenberg, Gritta Janka, Ulrich Goebel, Hans-Juergen Laws e Dagmar Dilloo. "High Expression of CD40 on BCP-ALL Blasts Is an Independent Risk Factor Associated with Improved Survival and Enhanced Capacity To Upregulate the Death Receptor CD95." Blood 108, n.º 11 (1 de novembro de 2006): 2282. http://dx.doi.org/10.1182/blood.v108.11.2282.2282.
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Abstract Leukemogenesis is facilitated by deregulated survival signals and escape from immunosurveillance. For immunological control both adequate stimulation of effector cells as well as apoptosis sensitivity of target cells are required. The CD40 receptor, a member of the TNF/NGF receptor family, plays a pivotal role on normal B cells in both aspects as it upregulates the costimulatory molecules enhancing their antigen presenting capacity and the CD95 TNF receptor sensitizing cells to apoptotic stimuli. Due to its physiological immunomodulatory functions, we prospectively studied the prognostic impact of CD40 expression on primary precursor B (BCP)-ALL blasts of pediatric patients (pts) (n=121). Blasts exhibited an immunephenotype of c-ALL (n=81), preB-ALL (n=32) or proB-ALL (n=8). All pts (>1 and <17y) were treated according to the CoALL06-97 study protocol. The criteria for prognostic classification into high risk (HR; n=57) and low risk (LR; n=64) pts at initial diagnosis include immunephenotype, leukocyte count (WBC), age, genetic translocations and the in vitro resistance to chemotherapeutic agents (PVA score). In flow cytometry analysis blasts exhibited a broad range of CD40 expression with a mean of 80%±27% (±SD) positive blasts. In terms of the above mentioned prognostic discrimination criteria, we found significantly lower percentage of CD40 positive blasts in HR pts (median; range: 84%;3–100%) compared to the LR group (98%;3–100%) (p=0.007). With regard to prognostic relevance, pts with very high percentage (above the mean of 80%) CD40 positive blasts exhibited significantly better relapse free survival (RFS; 0.86±0.06 vs 0.65±0.09; p=0.009) in Kaplan Meier analysis and multivariate Cox regression analysis revealed that high CD40 expression was independently associated with superior RFS in our pediatric ALL pt cohort (p=0.006) in contrast to the risk factors age (p=0.72), WBC (p=0.33) and PVA score (p=0.60). In a subset of patients (n=34) we examined whether the level of CD40 expression corresponds to the capacity of blasts to upregulate costimulatory molecules and the CD95 death receptor upon CD40-ligation. CD40-crosslinking in samples with a very high percentage of CD40 positive blasts (>80%) and with intermediate/low expression of CD40 (<80%) did not result in significantly different upregulation of CD80 (37%;3–97% vs 41%;4–68%) and CD86 (83%;5–100% vs 72%;12–96%) in the two sample-sets (p=0.66 and p=0.86). In contrast, expression of CD95 in CD40-stimulated blasts showed a significant correlation with CD40 baseline expression (p=0.009) with a higher percentage of CD95 positive blasts following CD40-activation in samples containing >80% CD40 positive blasts compared to samples with intermediate/low CD40 expression (74%;17–95% vs 38%;9–94%; p=0.065). Thus, high percentage of CD40 positive blasts is an independent prognostic marker that identifies a group of pediatric BCP-ALL pts with favorable outcome. While the capacity to upregulate costimulatory molecules following CD40-activation might contribute to the observed improvement in survival, enhanced upregulation of the CD95 receptor seems to be the leading mechanism mediating sensitization towards apoptotic stimuli.
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Myint, A. M. "Role of Tryptophan-kynurenine Pathway in Depression: Psychopathological Aspect". European Psychiatry 24, S1 (janeiro de 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70521-8.
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It was reported that cytokines such as IFN-γ reduce the synthesis of 5-HT by stimulating the activity of indoleamine 2,3 dioxygenase (IDO) enzyme which degrades tryptophan to kynurenine. Kynurenine is further metabolized to kynurenic acid (KYNA), 3-hydroxykynurenine (3OHK) and quinolinic acid (QA) by kynurenine aminotransferase (KAT), kynurenine 3-monooxygenase (KMO) and kynureninase. Both KMO and kynureninase are also shown to be activated by IFNγ. The 3OHK is neurotoxic apoptotic while QA is the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist. Conversely KYNA is an antagonist of all three ionotropic excitatory amino acid receptors and considered neuroprotective. In the brain, tryptophan catabolism occurs in the astrocytes and. The astrocytes are shown to produce mainly KYNA whereas microglia and macrophages produced mainly 3OHK and QA. The astrocytes have been demonstrated to metabolise the QA produced by the neighbouring microglia.Tryptophan breakdown has been found to be increased but KYNA, the neuroprotective metabolite is decreased in both blood and cerebrospinal fluid of the patients with major depression compared to healthy controls. Moreover, the ratio between KYNA and 3OHK showed significant correlation with response to treatment. These findings lead to the hypothesis an imbalance neuroprotection-neurodegener-ation in terms of kynurenine metabolites and their immunological and biochemical interactions in the brain might further induce the apoptosis of the neuroprotective astrocytes and the vulnerability to stress is thereby enhanced.
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Zhelavskyi, M. M. "Changes in the immunobiological reactivity of the organism of cows in the pathogenesis of mastitis". Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 20, n.º 83 (26 de fevereiro de 2018): 77–82. http://dx.doi.org/10.15421/nvlvet8315.
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Immunobiological aspects of the pathogenesis of mastitis of cows of the Ukrainian black-and-white breed are considered in the article. Based on the relevance of the topic, the aim of our work was to study the functional state of nonspecific immunobiological resistance and the specific immunobiological reactivity of the cows' organism during the development of mastitis. The features of the manifestation of immune reactions in the organism of animals in the development of subclinical and purulent-catarrhal mastitis have been studied. Clinical and experimental studies were conducted in Ukrainian farms (Khmelnytsky and Vinnytsia region). Laboratory studies were carried out in the specialized laboratory of immunology of animal reproduction of the Faculty of Veterinary Medicine of the Podilsky State Agrarian and Technical University (Ukraine). Three groups of animals were formed to conduct clinical and experimental studies. As a result, it was found that subclinical mastitis of cows is accompanied by a change in the immunobiological reactivity. Purulent-catarrhal mastitis in cows was manifested by significant changes in the parameters of nonspecific immunological reactivity. The pathological process was accompanied by a sharp decrease in bactericidal activity of blood serum (P < 0.01), as well as by suppression of phagocytic reactivity of immunocompetent blood cells. In parallel with this, there was an increase in lysozyme activity of blood serum (P < 0.01), which was associated with active degranulation and neutrophil lysis. Obviously, microphages actively migrate to the zone of the pathological process and exhibit active phagocytosis, which was accompanied by partial excretion of cytoplasmic lysozyme. In the peripheral blood of cows with subclinical mastitis, the number of reactive microphages increased sharply (P < 0.001). Simultaneously, the number of activated phagocytes with myeloperoxidase granules also increased in the peripheral blood (P < 0.01). Activation of intra-leukocyte lysozyme phagocytic cells was less intensive. Subclinical udder pathology was accompanied by an increase in the number of degranulated cells (P < 0.001), which is one of the specific properties of cytomorphological changes in programmed death (apoptosis). Subclinical inflammation of the mammary glands mastitis of cows was accompanied by a certain decrease in the number of T-lymphocytes (P < 0.001). Clinical and experimental studies have shown that subclinical and purulent-catarrhal mastitis of cows undergo significant changes in systemic immunity. In the pathophysiological model of subclinical and purulent-catarrhal mastitis, the functional state of the T-link of specific immunity was disturbed, the bactericidal activity of blood serum and phagocytosis were suppressed, which occurred against the background of changes in the cytochemical reactivity of phagocytic cells circulating immune complexes and molecules with an average molecular weigh.
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Zhelavskyi, M. M., e O. Ya Dmytriv. "Immunobiological status of the body of cows during mastitis". Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 20, n.º 88 (25 de agosto de 2018): 3–10. http://dx.doi.org/10.32718/nvlvet8801.
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The work reveals the immunobiological aspects of lactation of cows and changes in immunobiological reactivity in the development of mastitis.The authors present modern scientific data on the local immune protection of the mammary gland of cows. Main stages of ontogenetic development of cellular immunity of the mammary gland of cows were traced during clinical and experimental studies. The number of somatic cells in the secret of the mammary gland of the primates was dependent on the period of the functioning of the mammary gland. In the cytology of colostrum mostly (56.00 ± 1.90%) neutrophil granulocytes were predominant, in the middle period of lactation (3–5th month) the proportion of epithelial cells increased (from 29.51 ± 2.17 to 49.59 ± 1.94%), during the launch period, the population of polymorphonuclear neutrophil granulocytes was changing as well, which virtually recovered to the original level and increased during the dry period. However, at the end of lactation, during the onset and dry, with the development of involutionary processes in the mammary gland, a sharp decrease in cytochemical reactivity of intracellular lysozyme of phagocytic cells was observed. To conduct clinical and experimental studies, three groups of animals were formed. As a result, it was found out that subclinical mastitis of cows is accompanied by a change in the immunobiological reactivity. Purulent-catarrhal mastitis in cows was manifested by significant changes in the parameters of nonspecific immunological reactivity. In the peripheral blood of cows with subclinical mastitis, the number of reactive microphages increased sharply (P < 0.001). In parallel with this, the number of activated phagocytes with myeloperoxidase granules also increased in the peripheral blood (P < 0.01). Activation of intra-leukocyte lysozyme phagocytic cells was less intensive. Subclinical udder pathology was accompanied by an increase in the number of degranulated cells (P < 0.001), which is one of the specific properties of cytomorphological changes in programmed death (apoptosis). Subclinical inflammation of the mammary glands mastitis of cows was accompanied by a certain decrease in the number of T-lymphocytes (P < 0.001). Clinical and experimental studies have shown that subclinical and purulent-catarrhal mastitis of cows undergo significant changes in systemic immunity. In the pathophysiological model of subclinical and purulent-catarrhal mastitis, the functional state of the T-link of specific immunity was disturbed, the bactericidal activity of blood serum and phagocytosis were suppressed, which occurred against the background of changes in the cytochemical reactivity of phagocytic cells circulating immune complexes and molecules with an average molecular weigh.
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Zaitseva, N. V., M. A. Zemlianova e Oleg V. Dolgikh. "GENOMIC, TRANSCRIPTOMIC AND PROTEOMIC TECHNOLOGIES AS A MODERN TOOL FOR HEALTH DISORDERS DIAGNOSTICS, ASSOCIATED WITH THE IMPACT OF ENVIRONMENTAL FACTORS". Hygiene and sanitation 99, n.º 1 (15 de janeiro de 2020): 6–12. http://dx.doi.org/10.33029/0016-9900-2020-99-1-6-12.
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Introduction. Today, it is relevant to use modern critical technologies for identifying and evaluating the negative effects associated with the effects of chemicals at the stages of pre-nosological changes. This improves the efficiency of the early detection of progress in pre-pathological conditions prior to the onset of pronounced functional changes and the aggravation of the disease. The use of molecular diagnostic methods based on genomic, transcriptomic, and proteomic analysis technologies is one of the most promising approaches. Aim of the work is an analysis of both aspects and practical use of the modern critical technologies capabilities (genomic, transcriptomic and proteomic technologies) in the implementation of biomedical and experimental studies for the tasks of the detection biomarkers of negative effects of chemical risk factors on the example of exposure conditions with aluminum compounds. Material and methods. The proteomic analysis was carried out by the method of two-dimensional electrophoresis, polymorphism of alleles and genotypes of candidate genes by a real-time polymerase chain reaction. The transcriptome state was assessed based on the results of gene expression studies. The expression of membrane and serum proteins was studied by biochemical and immunological methods analysis. Statistical processing of the results was carried out in the systems “Gencalculator,” “Gene Expert” and online program “SNPStats”. Results. The results of using proteomic analysis technologies made it possible to identify proteins annexin-13, SH3-domain protein-RF3, cathepsin L1 and, accordingly, genes CTSL, SH3RF3, THO complex subunit 2 as Ohmic markers of aerogenic exposure of inorganic compounds. The results of the analysis of gene polymorphism in the population exposed to environmental pollution allowed establishing the changed frequency of variant alleles and genotypes of genes: immune control - TLR4 (toll-like receptor); vascular factors - eNOS rs1799983 (endothelial NOsintase); detoxification - coproporphyrinogen oxidase CPOX (rs1131857), cytochrome P450 CYP1A1 (rs 1048943); neuro-humoral regulation of ANKK1 rs1800497 (dopamine receptor gene) and HTR2A rs7997012 (serotonin receptor gene). The results of gene expression analysis made it possible to establish negative transcriptomic effects induced by exposure to amphoteric metals due to the isolation of specific CD4+, CD8+, CD16+ cell phenotypes expressing the proteomic profile gene of blood plasma lipoprotein A (LPA gene). Discussion. The obtained results correspond data of a number of scientific studies, noting the importance of identifying polymorphic deviations of genes determining the individual risk of health problems in a variety of stressful environmental factors affecting humans. Minor genotypes of candidate genes under conditions of excessive contamination with amphoteric metal compounds significantly increase the risk of deviations in immune regulation indices, which modifies apoptosis mechanisms, which are crucial for the formation of atopy and onco-proliferation. Conclusion. The use of genome, transcriptomic and proteomic technologies as a modern tool for the diagnostics of health disorders allowed justifying the set of priority exposition and effect Ohmic-markers, associated with aerogenic effect of amphoteric metals, which have a modifying effect on the pathogenetic mechanisms of the formation of disorders of nervous and immune systems, the 1st and 2nd phase of detoxification, the likelihood of vascular disorders and onco-proliferative processes.
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Mair, Johannes, Bertil Lindahl, Ola Hammarsten, Christian Müller, Evangelos Giannitsis, Kurt Huber, Martin Möckel, Mario Plebani, Kristian Thygesen e Allan S. Jaffe. "How is cardiac troponin released from injured myocardium?" European Heart Journal: Acute Cardiovascular Care 7, n.º 6 (27 de dezembro de 2017): 553–60. http://dx.doi.org/10.1177/2048872617748553.
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Cardiac troponin I and cardiac troponin T are nowadays the criterion biomarkers for the laboratory diagnosis of acute myocardial infarction due to their very high sensitivities and specificities for myocardial injury. However, still many aspects of their degradation, tissue release and elimination from the human circulation are incompletely understood. Myocardial injury may be caused by a variety of different mechanisms, for example, myocardial ischaemia, inflammatory and immunological processes, trauma, drugs and toxins, and myocardial necrosis is preceded by a substantial reversible prelethal phase. Recent experimental data in a pig model of myocardial ischaemia demonstrated cardiac troponin release into the circulation from apoptotic cardiomyocytes as an alternative explanation for clinical situations with increased cardiac troponin without any other evidence for myocardial necrosis. However, the comparably lower sensitivities of all currently available imaging modalities, including cardiac magnetic resonance imaging for the detection of particularly non-focal myocardial necrosis in patients, has to be considered for cardiac troponin test result interpretation in clinical settings without any other evidence for myocardial necrosis apart from increased cardiac troponin concentrations as well.
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Johnson, Louise N. "The regulation of protein phosphorylation". Biochemical Society Transactions 37, n.º 4 (22 de julho de 2009): 627–41. http://dx.doi.org/10.1042/bst0370627.
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Phosphorylation plays essential roles in nearly every aspect of cell life. Protein kinases regulate signalling pathways and cellular processes that mediate metabolism, transcription, cell-cycle progression, differentiation, cytoskeleton arrangement and cell movement, apoptosis, intercellular communication, and neuronal and immunological functions. Protein kinases share a conserved catalytic domain, which catalyses the transfer of the γ-phosphate of ATP to a serine, threonine or tyrosine residue in protein substrates. The kinase can exist in an active or inactive state regulated by a variety of mechanisms in different kinases that include control by phosphorylation, regulation by additional domains that may target other molecules, binding and regulation by additional subunits, and control by protein–protein association. This Novartis Medal Lecture was delivered at a meeting on protein evolution celebrating the 200th anniversary of Charles Darwin's birth. I begin with a summary of current observations from protein sequences of kinase phylogeny. I then review the structural consequences of protein phosphorylation using our work on glycogen phosphorylase to illustrate one of the more dramatic consequences of phosphorylation. Regulation of protein phosphorylation is frequently disrupted in the diseased state, and protein kinases have become high-profile targets for drug development. Finally, I consider recent advances on protein kinases as drug targets and describe some of our recent work with CDK9 (cyclin-dependent kinase 9)–cyclin T, a regulator of transcription.
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Agius, Lawrence M. "Neuroinflammation as the Proximate Cause of Signature Pathogenic Pattern Progression in Amyotrophic Lateral Sclerosis, Aids, and Multiple Sclerosis". Pathology Research International 2012 (4 de dezembro de 2012): 1–5. http://dx.doi.org/10.1155/2012/169270.
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The realization of injury to large motor neurons is embedded within contextual reference to the parallel pathways of apoptosis and necrosis of system-patterned evolution. A widespread loss of cell components occurs intracellularly and involves a reactive participation to a neuroinflammation that potentially is immunologically definable. In such terms, sporadic and hereditary forms of amyotrophic sclerosis are paralleled by the components of a reactive nature that involve the aggregation of proteins and conformational misfolding on the one hand and a powerful oxidative degradation that overwhelms the proteasome clearance mechanisms. In such terms, global participation is only one aspect of a disorder realization that induces the development of the defining systems of modulation and of injury that involves the systems of consequence as demonstrated by the overwhelming immaturity of the molecular variants of mutated superoxide dismutase. It is further to such processes of neuroinflammatory consequence that the immune system is integral to the reactive involvement of neurons as patterns of disease recognition and as the system biology of prevalent voluntarily motor character. It is highly significant to recognize various inflammatory states in the nervous system as prototype variability in phenotype expression and as incremental progression in pathogenesis. In fact a determining definition of amyotrophic lateral sclerosis is an incremental phenotype modulation within the pathways of the consequential loss and depletion of motor cell components in the first instance. Neuroinflammation proves a pattern of the contextual spread of such pathogenic progression in the realization of end-stage injury states involving neurons and neuronal networks.
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Vojvodic, Jovana, Goran Mihajlovic, Ana Andonov, Milos Markovic, Jelena Djordjevic e Petar Vojvodic. "Immunological Aspects of Depressive Disorder – The Review". Serbian Journal of Experimental and Clinical Research, 1 de fevereiro de 2019. http://dx.doi.org/10.2478/sjecr-2018-0076.
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AbstractDepression represents a mood disorder and is considered to be one of the most common mental disorders in general. World Health Organization estimates that depression will be the leading cause of disability-adjusted life years, until 2030. Depression is a complex heterogeneous disorder where immune system and its regulation play an important role. Innate and adaptive immunity mecha nisms are included, along with processes of immune activation and suppression. The expression of humoral factors of innate immunity, especially pro-inflammatory cytokines, is increased, whereas the intensity of cellular immune mechanisms, primarily T cells and NK cells, are impaired. The influence of pro-inflammatory cytokines on depression is reflected in their effect on certain enzymes and ensuing reduction of neurotransmitters serotonin and dopamine. They also affect the neuroendocrine function in central nervous system, resulting in increase of cortisol levels and inactivation of glucocorticoid receptors in the periphery, which leads to neurodegeneration and decrease in neurotransmitter production. Certain cytokines affect neuroplasticity through the decreasing of concentration of neurotrophic brain factor and induction of brain cell apoptosis. The results are often contradictory talking about mechanisms of adaptive immunity. On one hand, an increased activity of Tlymphocytes is observed, while on the other, there are evidence of spontaneous apoptosis and impaired function of these cells in depression. In addition, neuroprotective role of autoreactive and regulatory T cells in prevention of depression has also been demonstrated. The aim of this paper is to analyze the current knowledge on the role of immune mechanisms in the pathogenesis of depression.
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Barandalla Sobrados, M., P. Carullo, N. Salvarani, G. Condorelli, M. Miragoli e D. Catalucci. "3072Myocardial delivery of therapeutic miR-133 via inhalable nanoparticles prevents the pathologic development in a model of ventricular pressure overload". European Heart Journal 40, Supplement_1 (1 de outubro de 2019). http://dx.doi.org/10.1093/eurheartj/ehz745.0028.
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Abstract Background MicroRNAs (miRs) are regulators involved in several biological processes and have been recognized as potential novel therapeutic targets for the treatment and prevention of CDs. We previously demonstrated that the cardiac-enriched miR-133, which is inversely related to failing heart conditions, is involved in several aspects of pathological cardiac remodeling via mitigation of cardiac hypertrophy and fibrosis, fine-tuning of the β1-adrenergic receptor signaling, and protection against oxidative stress-mediated apoptosis. However, effective and clinically oriented interventions aiming to delivery exogenous miR-133 for preventing the stress-induced downregulation of miR-133 levels are still missing. Here, we applied an unconventional and effective nanotechnology-based inhalation approach enabling the delivery to diseased heart of exogenous miR-133 loaded into biocompatible and biodegradable calcium phosphate-based nanoparticles (CaPs). Methods Male C57Bl/6J mice (8 weeks) were subjected to a trans-aortic constriction (TAC), to induce a ventricular pressure overload. 4 experimental groups of TAC animals were randomly assigned to different intratracheal administrations of: 1. Saline (TAC Control); 2. CaP-miR133 (TAC CaP-miR133); 3. Pristine miR-133 (TAC miR133); 4. Unloaded CaPs (TAC CaP). Not TAC operated mice served as SHAM group. Intratracheal nebulizations were performed immediately after TAC surgery once-a-day in alternative days for 4 consecutive weeks. Echocardiography (ECO) were conducted before TAC, at 2 and 4 weeks after surgery. ECO as well as molecular and histological analyses were performed at sacrifices. Results ECO analyses showed an effective CaP-miR133-associated reversal of the failure progression, preserving left ventricular internal diameter (LVID) during cardiac cycle, ejection fraction (EF) and fraction shortening (FS), both at 2 and 4 weeks after TAC. This improvement was associated with the restoration of physiological levels of miR-133 in TAC-stressed isolated cardiomyocytes as well as its contractile activity. TAC mice receiving CaP-mir133 showed reduced indexes of fibrosis. In contrast, no beneficial effects were observed when unloaded CaPs or pristine miR-133 were administered. No major alterations of the immunological status of mice were observed after CaP-miR133 administration. Conclusions Intratracheal nebulization of miR-133-loaded nanoparticles is an effective approach for the beneficial restoration of cardiac performance, cell contractility and remodeling in a mouse model of left ventricular pressure overload. Providing the evidence for a potential innovative application of the emerging nanotechnologies, our approach might represent an important step forward for the treatment of cardiovascular diseases. Acknowledgement/Funding Fondazione Umberto Veronesi and CUPIDO project (EU's Horizon 2020, Grant Agreement 720834)
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Chiu, Karen, Shah Tauseef Bashir, Romana A. Nowak, Wenyan Mei e Jodi A. Flaws. "Subacute exposure to di-isononyl phthalate alters the morphology, endocrine function, and immune system in the colon of adult female mice". Scientific Reports 10, n.º 1 (2 de novembro de 2020). http://dx.doi.org/10.1038/s41598-020-75882-0.
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Abstract Di-isononyl phthalate (DiNP), a common plasticizer used in polyvinyl chloride products, exhibits endocrine-disrupting capabilities. It is also toxic to the brain, reproductive system, liver, and kidney. However, little is known about how DiNP impacts the gastrointestinal tract (GIT). It is crucial to understand how DiNP exposure affects the GIT because humans are primarily exposed to DiNP through the GIT. Thus, this study tested the hypothesis that subacute exposure to DiNP dysregulates cellular, endocrine, and immunological aspects in the colon of adult female mice. To test this hypothesis, adult female mice were dosed with vehicle control or DiNP doses ranging from 0.02 to 200 mg/kg for 10–14 days. After the treatment period, mice were euthanized during diestrus, and colon tissue samples were subjected to morphological, biochemical, and hormone assays. DiNP exposure significantly increased histological damage in the colon compared to control. Exposure to DiNP also significantly decreased sICAM-1 levels, increased Tnf expression, decreased a cell cycle regulator (Ccnb1), and increased apoptotic factors (Aifm1 and Bcl2l10) in the colon compared to control. Colon-extracted lipids revealed that DiNP exposure significantly decreased estradiol levels compared to control. Collectively, these data indicate that subacute exposure to DiNP alters colon morphology and physiology in adult female mice.
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Beutgen, Vanessa M., Norbert Pfeiffer e Franz H. Grus. "Serological Levels of Anti-clathrin Antibodies Are Decreased in Patients With Pseudoexfoliation Glaucoma". Frontiers in Immunology 12 (19 de fevereiro de 2021). http://dx.doi.org/10.3389/fimmu.2021.616421.
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Evidence for immunologic contribution to glaucoma pathophysiology is steadily increasing in ophthalmic research. Particularly, an altered abundance of circulating autoantibodies to ocular antigens is frequently observed. Here, we report an analysis of autoantibody abundancies to selected antigens in sera of open-angle glaucoma patients, subdivided into normal-tension glaucoma (N = 31), primary open-angle glaucoma (N = 43) and pseudoexfoliation glaucoma (N = 45), vs. a non-glaucomatous control group (N = 46). Serum samples were analyzed by protein microarray, including 38 antigens. Differences in antibody levels were assessed by ANOVA. Five serological antibodies showed significantly altered levels among the four groups (P < 0.05), which can be used to cluster the subjects in groups consisting mainly of PEXG or POAG/NTG samples. Among the altered autoantibodies, anti-Clathrin antibodies were identified as most important subgroup predictors, enhancing prospective glaucoma subtype prediction. As a second aim, we wanted to gain further insights into the characteristics of previously identified glaucoma-related antigens and their role in glaucoma pathogenesis. To this end, we used the bioinformatics toolset of Metascape to construct protein-protein interaction networks and GO enrichment analysis. Glaucoma-related antigens were significantly enriched in 13 biological processes, including mRNA metabolism, protein folding, blood coagulation and apoptosis, proposing a link of glaucoma-associated pathways to changes in the autoantibody repertoire. In conclusion, our study provides new aspects of the involvement of natural autoimmunity in glaucoma pathomechanisms and promotes advanced opportunities toward new diagnostic approaches.
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Balasiddaiah, Anangi, Haleh Davanian, Soo Aleman, Anna Pasetto, Lars Frelin, Matti Sällberg, Volker Lohmann, Sarene Koh, Antonio Bertoletti e Margaret Chen. "Hepatitis C Virus-Specific T Cell Receptor mRNA-Engineered Human T Cells: Impact of Antigen Specificity on Functional Properties". Journal of Virology 91, n.º 9 (22 de fevereiro de 2017). http://dx.doi.org/10.1128/jvi.00010-17.
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ABSTRACT Therapy with genetically modified autologous T cells has shown great promise in cancer therapy. For an efficient control of hepatitis C virus (HCV) infection, cytotoxic T cells (CTL) are pivotal, but persistence of activated T cells may lead to liver toxicity. Here, anti-HCV T cell receptors (TCRs) recognizing the HCV nonstructural (NS) NS3 or NS5 viral peptide target were examined by mRNA transfection of human peripheral blood lymphocytes (PBLs) derived from healthy donors as well as chronically infected HCV patients. Immunological analysis shows that while the CTLs expressing the NS5-specific TCR reduced HCV RNA replication by a noncytotoxic mechanism, the NS3-specific TCR-redirected CTLs were polyfunctional and inhibited HCV RNA replication through antigen-specific cytotoxicity. Transcriptome signatures from these two types of CTL responses revealed uniquely expressed gene clusters upon encountering hepatoma target cells presenting endogenously expressed HCV proteins. The NS3 TCR induced a rapid expression of apoptotic signaling pathways and formation of embryonic gene clusters, whereas the NS5A TCR activation induced extended proliferative and metabolic pathways as the HCV target cells survived. Our results provide detailed insights into basic HCV T cell immunology and have clinical relevance for redirecting T cells to target virally infected hepatoma cells. IMPORTANCE Due to the protective ability of HCV-specific T cells and the hepatotoxic potential that they possess, there is a great need for the understanding of the functional aspects of HCV-specific T cells. To circumvent the low level of precursor frequency in patients, we engineered primary CD8+ T cells by mRNA TCR vectors to confer HCV specificity to new T cells. HCV TCRs that differ in antigen specificity and polyfunctionality were examined. mRNA TCR engineering of peripheral blood lymphocytes from healthy donors or chronically infected HCV patients resulted in strikingly high levels of HCV TCR expression and HCV-specific responses. While a cytotoxicity response from a polyfunctional T cell activation caused hepatotoxicity and the rapid induction of apoptotic signaling pathways, the noncytotoxic T cell activation showed extended proliferative, metabolic pathways and persistence of HCV target cells. Our results provide detailed insights into basic HCV T cell immunology and have clinical relevance for immune protection of HCV-associated diseases.