RESUMO
17-ß Estradiol (E2) has long standing known functions in regulating human physiology as well as immune system. E2 is known to elicit a protective role against experimental autoimmune encephalomyelitis (EAE) and has been used as a drug for treatment against multiple sclerosis. Moreover, E2 regulates the adaptive immune system by directly affecting the T helper cell subsets differentiation and antibody secretion mediated by B cells. Reports have shown that E2 promotes Th1 and Treg cell differentiation; whereas it attenuated the Th17 and Tfh cell differentiation. Albeit multiple and contrasting studies, the mechanisms of behind E2 action on Th2 cells remained understudied. Hence, we sought to dissect the impact of E2 in Th2 cell differentiation. In this study, we elucidated the molecular mechanisms behind E2-mediated regulation of the differentiation of Th2 cells. We observed that E2 significantly attenuated the IL-4-secreting Th2 population in an ERα-dependent manner. We validated these findings using ICI 182, 780, an antagonist to ERα, not ERß and ectopically overexpressing ERα in Th2 cells. We further determined that ERα alters the recruitment of GATA3 and PU.1 to Il4 gene by directly interacting with them. This altered recruitment was observed to be stronger at Il4 than Il13 locus. Interestingly, we detected a distinct recruitment of GATA3 and PU.1 at Il13 gene; however, there was no E2-mediated broad alteration in the recruitment of histone-modifiers at Il13 locus. These findings suggest that E2 regulates Il4 in a distinctly separate mechanism as opposed to Il13 locus in Th2 cells.
Assuntos
Encefalomielite Autoimune Experimental , Células Th2 , Animais , Humanos , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Diferenciação Celular , Células Th1 , Células Th17/metabolismo , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismoRESUMO
BACKGROUND: The mayhem COVID-19 that was ushered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) was declared pandemic by the World Health Organization in March 2020. Since its initial outbreak in late 2019, the virus has affected hundreds of million adults in the world and killing millions in the process. After the approval of newly developed vaccines, severe challenges remain to manufacture and administer them to the adult population globally in quick time. However, we have witnessed several mutations of the virus leading to 'waves' of viral spread and mortality. WHO has categorized these mutations as variants of concern (VOCs) and variants of interest (VOIs). The mortality due to COVID-19 has also been associated with various comorbidities and improper immune response. This has created further complications in understanding the nature of the SARS-CoV2-host interaction that has fuelled doubts in the efficacy of the approved vaccines. Whether there is requirement of booster dose and whether the impending wave could affect the children are some of the hotly debated topics. MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Scopus, Google Scholar was utilized to understand the nature of Delta variant and how it alters our T-cell responses and cytokine production and neutralizes vaccine-generated antibodies. CONCLUSION: In this review, we discuss the variants of SARS-CoV2 with specific focus on the Delta variant. We also specifically review the T-cell response against the virus and bring a narrative of various factors that may hold the key to fight against this marauding virus.
Assuntos
COVID-19 , Vacinas , Adulto , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Criança , Humanos , Pandemias , RNA Viral , SARS-CoV-2 , Linfócitos TRESUMO
Vitamin D can modulate the innate and adaptive immune system. Vitamin D deficiency has been associated with various autoimmune diseases. Th9 cells are implicated in the pathogenesis of numerous autoimmune diseases. Thus, we investigated the role of calcitriol (active metabolite of vitamin D) in the regulation of Th9 cell differentiation. In this study, we have unraveled the molecular mechanisms of calcitriol-mediated regulation of Th9 cell differentiation. Calcitriol significantly diminished IL-9 secretion from murine Th9 cells associated with downregulated expression of the Th9-associated transcription factor, PU.1. Ectopic expression of VDR in Th9 cells attenuated the percentage of IL-9-secreting cells. VDR associated with PU.1 in Th9 cells. Using a series of mutations, we were able to dissect the VDR domain involved in the regulation of the Il9 gene. The VDR-PU.1 interaction prevented the accessibility of PU.1 to the Il9 gene promoter, thereby restricting its expression. However, the expression of Foxp3, regulatory T cell-specific transcription factor, was enhanced in the presence of calcitriol in Th9 cells. When Th9 cells are treated with both calcitriol and trichostatin A (histone deacetylase inhibitor), the level of IL-9 reached to the level of wild-type untreated Th9 cells. Calcitriol attenuated specific histone acetylation at the Il9 gene. In contrast, calcitriol enhanced the recruitment of the histone modifier HDAC1 at the Il9 gene promoter. In summary, we have identified that calcitriol blocked the access of PU.1 to the Il9 gene by reducing its expression and associating with it as well as regulated the chromatin of the Il9 gene to regulate expression.
Assuntos
Calcitriol/farmacologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/imunologia , Interleucina-9/imunologia , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T Reguladores/imunologia , Transativadores/imunologia , Acetilação/efeitos dos fármacos , Animais , Diferenciação Celular/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Histonas/imunologia , Camundongos , Regiões Promotoras Genéticas/imunologia , Receptores de Calcitriol/imunologia , Linfócitos T Reguladores/citologiaRESUMO
Extracellular matrix (ECM) rich whole organ bio-scaffolds, preserving structural integrity and essential growth factors, has potential towards regeneration and reconstruction. Women with cervical anomalies or trauma can benefit from clinical cervicovaginal repair using constructs rich in site specific ECM. In this study, complete human cervix decellularization was achieved using a modified perfusion-based stir bench top decellularization method. This was followed by physico-chemical processes including perfusion of ionic agents, enzymatic treatment and washing using detergent solutions for a duration of 10-12 d. Histopathological analysis, as well as DNA quantification confirmed the efficacy of the decellularization process. Tissue ultrastructure integrity was preserved and the same was validated via scanning electron microscopy and transmission electron microscopy studies. Biochemical analysis and structural characterizations like Fourier transform infrared, Raman spectroscopy of decellularized tissues demonstrated preservation of important proteins, crucial growth factors, collagen, and glycosaminoglycans.In vitrostudies, using THP-1 and human umbilical vein endothelial cell (HUVEC) cells, demonstrated macrophage polarization from M1 to M2 and vascular functional genes enhancement, respectively, when treated with decellularized human cervical matrix (DHCp). Crosslinked DHC scaffolds were recellularized with site specific human cervical epithelial cells and HUVEC, showing non-cytotoxic cell viability and enhanced proliferation. Furthermore, DHC scaffolds showed immunomodulatory effectsin vivoon small rodent model via upregulation of M2 macrophage genes as compared to decellularized rat cervix matrix scaffolds (DRC). DHC scaffolds underwent neo-vascularization followed by ECM remodeling with enhanced tissue integration.
Assuntos
Colo do Útero , Matriz Extracelular Descelularizada , Células Endoteliais da Veia Umbilical Humana , Alicerces Teciduais , Humanos , Feminino , Colo do Útero/citologia , Animais , Matriz Extracelular Descelularizada/química , Matriz Extracelular Descelularizada/farmacologia , Alicerces Teciduais/química , Matriz Extracelular/metabolismo , Matriz Extracelular/química , Ratos , Engenharia Tecidual , Células THP-1 , Macrófagos/metabolismo , Macrófagos/citologia , Ratos Sprague-DawleyRESUMO
The current study involves the removal of Pb(II) ions from an aqueous solution using GO/Mn-Fe hybrids in a fixed bed column study. The capability of the hybrid in the Pb removal was examined using a continuous flow fixed bed column which revealed that the hybrid had the maximum adsorption capacity of 172.768 mg/g at a flow rate of 2 mL/min, bed height of 1 cm, and influent concentration of 200 mg/L. The breakthrough curves obtained from the experiments were examined using three different models, i.e., Bohart-Adams model, Thomas Model, and Yoon-Nelson model, wherein all the models showed high correlation coefficient values. Three consecutive adsorption-desorption cycles in the column yielded regeneration efficiencies of 91.71%, 88.31%, and 85.41%. The column life factor indicated that the fixed bed would have enough capacity to avoid a zero breakthrough time for up to 9 cycles, implying that GO/Mn-Fe could be used as a cheap and efficient adsorbent in the removal of Pb(II) from contaminated water. The adsorption mechanism was postulated based on the characterization of the spent adsorbent by FTIR and SEM. The phenomenon of the adsorption process can be described in accordance with the surface complex formation theory, which suggests that an increase in pH decreases the competition between metal ions and protons, favoring metal ion adsorption. The toxicity of the synthesized hybrid was evaluated on HeLa cells and compared to the toxicity of GO. Increasing the concentration of GO/Mn-Fe hybrid from 50 to 250 g/mL resulted in a decrease in cell viability from 91.90 to 56.52%, whereas increasing the concentration of GO resulted in a decrease in cell viability from 61.59 to 37.19%. The study clearly demonstrates the use of GO/Mn-Fe hybrid as an adsorbent for efficient sequestration of Pb(II) ions with lower environmental toxicity.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Humanos , Águas Residuárias , Chumbo , Células HeLa , Água/química , Íons , Adsorção , Poluentes Químicos da Água/análise , Purificação da Água/métodosRESUMO
Rheumatoid arthritis (RA) is an autoimmune disorder that affects joints associated with inflammation leading to poor quality of life. The phenotype of RA is distinct from osteoarthritis (OA), the degenerative joint disorder. The annual incidence of RA is approximately 4 in 10,000 individuals. Studies suggest dysregulated T cell activation in the initiation and progression of RA. Distinct RA-associated allelic variants encode molecules involved in T-cell activation pathways. Additionally, RA is also associated with aberrant regulation and function of T helper cells. The interplay of distinct T helper cell subsets adds complexity to the regulation of RA. In this review we have aimed to understand the currently known biology of different Th subsets in the context of an autoimmune disease like rheumatoid arthritis and find potential therapeutic approaches to tackle the disease through modulation of responsible T cells.
Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Biomarcadores , Plasticidade Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Imunomodulação , Janus Quinases/metabolismo , Contagem de Linfócitos , Terapia de Alvo Molecular , Fatores de Transcrição STAT/metabolismo , Transdução de SinaisRESUMO
FSHD region gene 1 (FRG1), as the name suggests, is the primary candidate gene for fascioscapulohumeral muscular dystrophy disease. It seemingly affects muscle physiology in normal individuals but in FSHD, where it is found to be highly upregulated, might be involved in disruption of face, scapula and humeral skeletal muscle. Literature on FRG1, reviewed from 1996 to 2016, reveals that it is primarily associated with muscle development and maintenance. Approximately 75% of FSHD patients also show vascular abnormalities indicating that FRG1 might have some part to play in these abnormalities. Research involving vasculature in X. laevis larvae shows that FRG1 positively affects normal vasculature. Few of the well-established angiogenic regulators seem to get affected by abnormal expression level of FRG1. Its primary localization in sub nuclear structures like Cajal bodies and nuclear speckles indicates regulation of the above-mentioned factors by transcriptional and post-transcriptional machineries, but in-depth studies need to be done to conclude a clear statement. In this review, we have attempted to present all the work done on FRG1, all the lacunas which need to be unraveled, and hypothesized a model for our readers to get an insight into its molecular mechanism.