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Neurodevelopment has been studied extensively, especially in respect to abuse, anoxia, nutritional status and prematurity/low birth weight. However, less attention has been paid to innate and environmental factors, as well as to inflammatory conditions that may adversely affect neurodevelopment and learning in children. These include heavy metals, herbicides and polyvinyl chlorides (PVCs), mycotoxins, viral infections and Lyme disease-associated pathogens, as well as number of conditions such as chronic inflammatory response syndrome (CIRS) and Mast cell activation syndrome (MCAS). Early recognition of factors/conditions that could interfere with neurodevelopment is critical. Corrective actions, including the use of some unique natural flavonoids, could have lasting beneficial results.
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In this editorial the authors highlight recent findings which could help design a personalized approach for cancer immunotherapy.
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Chimeric antigen receptor (CAR) T cells are genetically modified T cells that act against cancer. When CAR-T cells are administered they can trigger inflammatory cytokines and increase toxicity. Interleukin (IL)-1 is the classic cytokine that mediates inflammatory reactions including those that occur in CAR-T-cell therapy. IL-1 also induces IL-33 in mast cells (MCs), amplifying the allergic reaction. IL- 37 (ILF7) is an IL-1 family member which binds IL-18 receptor alpha (IL-18Rα) chain and suppresses innate and acquired immunity. IL-37 is an anti-inflammatory cytokine which inhibits pro-inflammatory cytokines including IL-1 and IL-33. Here, we hypothesize that inflammation and toxicity generated in tumor CAR-T therapy could be inhibited by IL-37, contributing to an improvement in the treatment of tumors with CAR-T therapy.
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The purpose of this paper was to investigate the dynamic trend of SIRT5 (Sirtuins 5) protein expression in gastric cancer cells, for which a hypoxic gastric cancer cell line was established. Afterward, the parental gastric cancer cell group and hypo group were designed, and the levels of related proteins and mRNAs were detected by using Western blot along with real-time quantitative fluorescence PCR (RT-PCR). The results showed that the expression of SIRT5 in hypoxic gastric cancer cells increased significantly, which could increase the phosphorylation level of c-MET (hepatocyte growth factor receptor) and promote the migration of gastric cancer cells. When the expression of SIRT5 protein was observed under hypoxic conditions, SIRT5 silencing significantly reduced the migration ability of MGC803/hypo cells. It could be predicted that SIRT5-mediated protein desuccinylation played an important role in promoting the migration of hypoxic gastric cancer cells. Therefore, the migration rate of gastric cancer cells could be affected by controlling the expression of SIRT5 protein, which provides a novel idea for the treatment of gastric cancer in the future.
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In order to study the mechanism of the effect of progesterone receptor on the growth of primary uterine leiomyoma cells, the primary cells were extracted from uterine leiomyoma cells and identified by immunohistochemistry (IHC). Mitochondrial progesterone receptor-positive [PR-M(+)], mitochondrial progesterone receptor-negative [PR-M(-)], progesterone receptor A (PR-A) and progesterone receptor B (PR-B) were screened by Western blotting. Different concentrations of Mifepristone (MIF), a progesterone receptor antagonist, were used to interfere with PR-M(+) and PR-M(-) cell lines, respectively. Proliferation and apoptosis of PR-M(+) and PR-M(-) cell lines were detected by tetramethylazolyl blue method and flow cytometry, respectively. The expression of Caspase-3 and B-cell lymphoma 2 (Bcl-2) protein was detected by Western blotting. The results showed that the growth of PR-M(+) and PR-M(-) uterine leiomyoma cells was inhibited with the increase of MIF concentration. Furthermore, the proliferation inhibition rate and apoptosis rate were gradually increased. However, the expression of Caspase-3 protein on progesterone receptor M increased, while the expression of Bcl-2 decreased. Moreover, progesterone could induce progesterone receptor M to up-regulate apoptotic protein Caspase-3 and down-regulate anti-apoptotic protein Bcl-2, thus it could inhibit the apoptosis of primary cultured uterine leiomyoma cells and promote the proliferation of leiomyoma cells.
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This study aimed to explore the effects of Shenyuan granules on the Klotho/FGFR23/Egr1 signaling pathway and calcium-phosphorus metabolism in diabetic mice models with impairment of renal function. Streptozotocin-induced diabetic nephropathy (DN) mice models were randomly divided into three groups: Shenyuan granules group (n=10), model control group (n=10), and blank control group (n=10). Corresponding drugs were given by gavage for 8 weeks. Blood glucose and serum creatinine (SCr), urea nitrogen (BUN), calcium (Ca), phosphorus (P) and mLAB were detected before and after administration. Moreover, RT-qPCR was performed to detect the expression of CYP24 and CYP27 mRNA in kidney tissue. Blood FGF23 was detected by ELISA. Western-blot and immunohistochemistry were performed to detect the expressions of Klotho, FGFR1, Egr1, CYP24, CYP27, ERK1/2 and p-ERK1/2. Compared with the blank control group, in the model control group serum FGF23,P, SCr and 24-hour proteinuria levels increased (P<0.05), serum Ca significantly decreased (P<0.05), expressionss of Egr1, CYP24, CYP27 and p-ERK1/2 were up-regulated (P<0.05), and the expressions of Klotho and FGFR1 were down-regulated (P<0.05). After treatment, compared with the model control group, in the Shenyuan granule group serum FGF23, P, SCr levels decreased (P<0.05), serum Ca increased (P<0.05), expressions of Egr-1, CYP24, CYP27 and p-ERK1/2 were down-regulated (P<0.05), and the expressions of Klotho and FGFR1 were up-regulated (P<0.05). Shenyuan granules may partly intervene in the expressions of CYP24 and CYP27 through the Klotho/FGF23/Egr1 signaling pathway, thereby improving calcium and phosphorus metabolism and alleviating renal injury in diabetic nephropathy.
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Acute myeloid leukemia (AML) is an invasive hematological malignancy of which the mechanismis still unknown. MicroRNAs (miRNAs) act as critical controllers of target gene expression at posttranscriptionallevel. MiR-1290 is found to abnormally express in multiple cancers, however, its rolein AML is still unknown. In this study, the mRNA and protein expression levels of related genes weredetermined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Westernblot. Luciferase assay was used to verify the target genes of miR-1290. In addition, the cell proliferation,cell cycle and apoptosis of HL-60 and KG-1 cells were detected by Counting Kit-8 (CCK-8) and flowcytometry assay, respectively. Our results showed that the expression of miR-1290 was increased inAML in vivo and in vitro. Gain and loss of function experiments by transfection of miR-1290 mimicsor miR-1290 inhibitors into HL-50 and KG-1 cells indicated that miR-1290 significantly promoted cellproliferation and inhibited cell apoptosis. Furthermore, Forkhead-box gene 1 (FOXG1) and Suppressorof cytokine signaling 3 (SOCS3) were verified to be the target genes of miR-1290. Overexpression ofFOXG1 or SOCS3 inhibited cell proliferation and induced cell apoptosis in HL-50 and KG-1 cells.Moreover, knockdown of miR-1290 inhibited cell proliferation and promoted apoptosis, whereas theseeffects were reversed by silencing of FOXG1 or SOCS3 in HL-50 and KG-1 cells. In conclusion, miR-1290 promoted proliferation and suppressed apoptosis in AML by targeting FOXG1 and SOCS3, whichmight provide a therapeutic target for AML.
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Ascorbic acid (AS), also known as vitamin C or ascorbate, is an essential dietary nutrient which plays a vital role in biological processes through various different mechanisms, in particular for the biosynthesis of collagen. The aim of the study was to establish the possibility of enhancing the osteogenic differentiation potential by manipulating the cellular micro-environment, through AS supplementation in human gingival mesenchymal stem cells (hGMSCs) at different concentrations, such as 60 and 90 μg/mL, for three weeks. Human GMSCs are considered a stem cell population, easily obtainable and displaying a remarkable immunotherapeutic potential and regenerative repair expression. Osteogenic differentiation level induced from AS was assayed by histochemical characterization, using light microscopy through Alizarin red S staining. The transcript levels of Collagen 1A1 (COL1A1), runtrelated transcription factor 2 (RUNX2), bone morphogenetic protein 2/4 (BMP2/4), osteopontin (OPN) and osteonectin (SPARC) were determined by quantitative RT-PCR. Protein expression of COL1A1, RUNX2, BMP2/4, OPN, SPARC were studied through Western blotting and confocal laser scanning microscopy (CLSM). Our results demonstrate that AS supports osteogenic differentiation in stem cells from gingiva niche as shown by osteogenic marker upregulation and by de novo production of calcium phosphate deposits as revealed by Alizarin red S staining. In summary, the results of the current study provide evidence that hGMSCs undergo osteogenic differentiation with AS treatment, for that reason AS could be a promising candidate for the prevention and healing of bone-related diseases
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Magnetic Resonance (MR) is a non-invasive modality of choice for the evaluation of brain morphology, with superior performance as compared to other techniques. However, MR images are typically assessed qualitatively, thus relying on the experience of the involved radiologist. This may lead to errors of interpretation in the presence of subtle alterations and does not exploit the full potential of this technique as a quantitative diagnostic tool. To this end Magnetic Resonance Relaxometry (MRR), which is able to quantitively characterize the tissues under investigation through their relaxation rates, seems extremely promising. Many studies assessed the feasibility of relaxometry as a diagnostic tool in human brain disorders, with the most promising results obtained in the evaluation of neurodegenerative diseases and in the oncologic field. However, despite such extensive literature in human medicine, due to the lack of standardized protocols and the need of high-field MRI scanners, to date few studies have been performed on companion animals. In this work, first we describe relaxometry applications in human neuropathology and their possible extension to companion animals both in the experimental and clinical fields. Then, we present two experiments performed on a typical standard clinical scanner operating at 0.25 T to show that, despite the low field intensity, this technique may be promising even in the clinical setup. We tested the relaxometry protocol in a phantom study and then applied it to a real clinical case study. The results showed that this protocol used on a phantom led to a higher contrast, as compared to the standard approach. Furthermore, when applied to a real case study, this protocol revealed brain lesions undetected by the standard technique which were confirmed by a histopathological examination. These preliminary results are encouraging and support the development of this approach as an advanced diagnostic tool even in a clinical setting where low field MRI scanners are typically employed.
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Pig weaning involves radical changes, which affect health, behavior and performance. Weaning stress dramatically impacts the porcine immune system. This study aimed to evaluate the expression of different cytokines and nuclear factor kappa B (NF-kB) in growing postweaning pigs. Forty piglets weaned at 28 days of age, with an average starting weight of 10.12±0.28 kg were considered for the analysis (time 0) and followed up for 28 days (time 1). Growth performance, skin lesions, cytokines and NF-kB expression were measured. The results showed an increased expression of two cytokines with pro-inflammatory effect, interleukin (IL)-8 and interferon-gamma (IFN-γ), a cytokine with anti-inflammatory effect, IL-4, and a cytokine with both pro- and anti-inflammatory effects, IL-6. An effect of time was observed for body lesions. Compared to females, male piglets had higher levels of all cytokines tested (IL-1β, IL-6, IL-8, IL-10, TNF-α, IL-4) except IFN-γ. Also NF-kB resulted expressed higher in males compared to females. In conclusion, this study demonstrated that weaning in piglets is associated with increased expression of inflammatory cytokines.
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Preliminary studies demonstrated the potential role of CD8+CD25+ T regulatory cells (Tregs) in asthma. However, published data with regard to the relevance of signaling pathways that govern Tregs homeostasis are limited and conflicting. The first aim of this study was to characterize the phosphorylation of STAT-5 in CD8+CD25+ Tregs. The second aim was to investigate the ability of CD8+CD25+ Tregs from patients and controls to respond to interleukin (IL)-2 treatment in vitro. Twenty-five healthy subjects (NC) and 50 patients with either severe (SA) or mild-moderate (MA) asthma were enrolled in the study. STAT-5 phosphorylation was detected in purified CD8+CD25+ Tregs from healthy and asthma subjects, indicating that STAT-5 has a role in their pathobiology. At baseline, asthmas had either significantly lower [(SA=4.5±5% vs NC=26±25%, P<0.001) and (MA=10±7.5% vs NC=26±25%, P<0.001)] or higher [(SA=54±58.5% vs 26±25%, P<0.01) and (MA=71±74.5% vs 26±25%, P<0.01) proportion of Tregs expressing pSTAT-5 than controls. In contrast to healthy subjects, CD8+CD25+ Tregs from asthma subjects had either increased (pSTAT-5high) or decreased (pSTAT-5low) phosphorylated STAT-5 levels within individual cells. These data suggest that the alteration in STAT5 phosphorylation level might be associated with asthma and is a potential molecular basis of skewed CD8+CD25+ Treg differentiation. IL-2 treatment of cells from severe asthma subjects increased the proportion of cells expressing high level of pSTAT-5 while it decreased the proportion of those expressing low level of pSTAT-5. Strikingly, IL-2 increased the proportions of both subsets from mild-moderate asthma subjects. These findings demonstrate that altered IL-2-mediated STAT-5 phosphorylation within individual circulatory CD8+CD25+ Tregs may be associated with asthma and disease severity
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