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Phenotypic Characterization and also RT-qPCR Examination of Floral Increase in Forumla1 Transgenics involving Chrysanthemum × grandiflorum.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nerves that presents with either chronic progression or relapsing disease. Recent studies in samples from patients with CIDP and mouse models have delineated how defects in central (thymic) and peripheral (extrathymic) immune tolerance mechanisms can cause PNS autoimmunity. Notably, nerve parenchymal cells actively contribute to local autoimmunity and also control disease outcome. Here, we outline how emerging technologies increasingly enable an integrated view of how immune cells and PNS parenchymal cells communicate in CIDP. We also relate the known heterogeneity of clinical presentation with specific underlying mechanisms. For example, a severe subtype of CIDP with tremor is associated with pathogenic IgG4 autoantibodies against nodal and paranodal proteins. An improved understanding of pathogenic mechanisms in CIDP will form the basis for more effective mechanism-based therapies.Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B - indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra-/-) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.The Notch signaling pathway mediates cell-cell communication regulating cell differentiation and proliferation and cell fate decisions in various tissues. In the urinary bladder, Notch acts as a tumor suppressor in mice, while mutations in Notch pathway components have been identified in human bladder cancer as well. Here we report that the genetic inactivation of Notch in mice leads to downregulation of cell-cell and cell-ECM interaction components, including proteins previously implicated in interstitial cystitis/bladder pain syndrome (IC/BPS), structural defects and mucosal sloughing, inflammation, and leaky urine-blood barrier. Molecular profiling of ailing mouse bladders showed similarities with IC/BPS patient tissue, which also presented low Notch pathway activity as indicated by reduced expression of canonical Notch targets. Urothelial integrity was reconstituted upon exogenous reactivation of the Notch pathway, implying a direct involvement of Notch. Despite damage and inflammation, urothelial cells failed to proliferate, uncovering a possible role for α4 integrin in urothelial homeostasis. Our data uncover a broad role for Notch in bladder homeostasis involving urothelial cell crosstalk with the microenvironment.Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 (SLC2A5). read more Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLC2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.Vascular inflammation is present in many cardiovascular diseases, and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data have shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here, we performed ChIP for the glucocorticoid receptor, followed by next-generation sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in upregulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Furthermore, we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway, Frzb, via a glucocorticoid response element gleaned from our genomic data. These results suggest a role for endothelial Wnt signaling modulation in states of vascular inflammation.We previously established that DNA methyltransferase 3b (Dnmt3b) is the sole Dnmt responsive to fracture repair and that Dnmt3b expression is induced in progenitor cells during fracture repair. In the current study, we confirmed that Dnmt3b ablation in mesenchymal progenitor cells (MPCs) resulted in impaired endochondral ossification, delayed fracture repair, and reduced mechanical strength of the newly formed bone in Prx1-Cre;Dnmt3bf/f (Dnmt3bPrx1) mice. Mechanistically, deletion of Dnmt3b in MPCs led to reduced chondrogenic and osteogenic differentiation in vitro. We further identified Rbpjκ as a downstream target of Dnmt3b in MPCs. In fact, we located 2 Dnmt3b binding sites in the murine proximal Rbpjκ promoter and gene body and confirmed Dnmt3b interaction with the 2 binding sites by ChIP assays. Luciferase assays showed functional utilization of the Dnmt3b binding sites in murine C3H10T1/2 cells. Importantly, we showed that the MPC differentiation defect observed in Dnmt3b deficiency cells was due to the upregulation of Rbpjκ, evident by restored MPC differentiation upon Rbpjκ inhibition. Consistent with in vitro findings, Rbpjκ blockage via dual antiplatelet therapy reversed the differentiation defect and accelerated fracture repair in Dnmt3bPrx1 mice. Collectively, our data suggest that Dnmt3b suppresses Notch signaling during MPC differentiation and is necessary for normal fracture repair.Interleukin-1β (IL-1β) is a key proinflammatory cytokine involved in the progression of many autoinflammatory and autoimmune diseases, including autoimmune inner ear disease (AIED). IL-1β inhibition has been shown to result in clinical hearing improvement in a small cohort of corticosteroid-resistant patients with AIED. Canonical processing of pro-IL-1β by caspase-1 generates an active 17-kDa fragment, capable of instigating a proinflammatory microenvironment. However, in response to LPS, PBMCs from patients with AIED uniquely express a 28-kDa IL-1β fragment, as compared with PBMCs from control subjects. We synthesized and compared the biologic activity of the 28-kDa fragment to the 17-kDa IL-1β product and the pro-IL-1 31-kDa protein. The 28-kDa IL-1β fragment induces IL-6, TNF-α, and CCL3 in PBMCs. Uniquely, only caspase-7 treatment showed a dose- and time-dependent increase in 28-kDa band generation. Mass spectrometry confirmed the putative caspase-7 cleavage site of pro-IL-1β, which was used to generate the 28-kDa fragment used for PBMC stimulation studies. Collectively, these results provide insight into the function of a poorly understood, processed 28-kDa form of IL-1β in patients with AIED that is uniquely generated by caspase-7 and is capable of activating further downstream proinflammatory cytokines. Further investigation may provide novel pharmacologic targets for the treatment of this rare disease.PURPOSE Skin hydration (SH) and transepidermal water loss (TEWL) are important skin biophysical parameters for assessment of childhood eczema. This study investigated whether age, sex, and disease status influence these parameters. METHODS Skin hydration and TEWL were measured by Delfin MoistureMeterSC and Delfin Vapometer SWL5, respectively, among children aged ≤18 years with and without eczema. Disease status was evaluated using Scoring Atopic Dermatitis (SCORAD) and Nottingham Eczema Severity Score (NESS) clinical tools. RESULTS Clinical scores and objective measurements were reviewed for 132 patients with eczema and 120 patients without eczema. In both sexes, SH was significantly higher among children aged ≤2 years with and without eczema than among children aged >2 years with and without eczema. Among children aged >2 years, SH was higher among girls with and without eczema than among boys with and without eczema. Regardless of age or sex, SH was lower among children with eczema than among children without eczema. Age-, sex-, and disease-related differences were not observed for TEWL. Skin hydration was negatively correlated with objective SCORAD (r=-0.418, P less then 0.001), overall SCORAD (r=-0.385, P less then 0.001), oedema/papulation (r=-0.243, P=0.041), lichenification (r=-0.363, P=0.002), dryness (r=-0.415, P less then 0.001), and intensity (r=-0.266, P=0.025). Transepidermal water loss was positively correlated with objective SCORAD (r=0.209, P=0.018), overall SCORAD (r=0.215, P=0.015), and lichenification (r=0.240, P=0.043). Skin hydration was negatively correlated with TEWL among children without eczema (r=-0.401, P less then 0.001), but not among children with eczema. CONCLUSION Skin hydration can be used to distinguish clinical differences in eczema based on age, sex, and disease status.
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