Long non-coding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). The gene mutations of Adenomatous polyposis coli (APC) were found in most colorectal cancer patients. They are functioned as an important inducer of tumorigenesis. Based on our microarray results, we identified a specific upregulated lncRNA in colorectal cancer (SURC). Further analysis showed that high SURC expression correlated with poorer disease-free survival and overall survival in patients with colorectal cancer. Besides, we found that mutated APC genes can promote the transcription of SURC by reducing the degradation of β-catenin protein in colorectal cancer. Functional assays revealed that knockdown of SURC impaired CRC cell proliferation, colony formation, cell cycle and tumor growth. Additionally, SURC can promote CCND2 expression by inhibiting the expression of miR-185-5p in CRC cells. In conclusion, we demonstrate that SURC is a specific upregulated lncRNA in CRC and the SURC/miR-185-5p/CCND2 axis may be targetable for CRC diagnosis and therapy.
Junshu Li, Yanhong Ji, Na Chen, Huiling Wang, Chao Fang, Xiaonan Yin, Zhiyuan Jiang, Zhexu Dong, Dan Zhu, Jiamei Fu, Wencheng Zhou, Ruiyi Jiang, Ling He, Zhang Hantao, Gang Shi, Lin Cheng, Xiaolan Su, Lei Dai, Hongxin Deng
The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response.
Anna L. McNaughton, Robert S. Paton, Matthew Edmans, Jonathan C.W. Youngs, Judith Wellens, Prabhjeet Phalora, Alex Fyfe, Sandra Belij-Rammerstorfer, Jai S. Bolton, Jonathan Ball, George W. Carnell, Wanwisa Dejnirattisai, Christina Dold, David W. Eyre, Philip Hopkins, Alison Howarth, Kreepa Kooblall, Hannah Klim, Susannah Leaver, Lian N. Lee, César López-Camacho, Sheila F. Lumley, Derek C. Macallan, Alexander J. Mentzer, Nicholas M. Provine, Jeremy Ratcliff, Jose L. Slon-Campos, Donal T. Skelly, Lucas B. Stolle, Piyada Supasa, Nigel Temperton, Chris Walker, Beibei Wang, Duncan Wyncoll, Peter Simmonds, Teresa Lambe, John K. Ballie, Malcolm G. Semple, Peter J.M. Openshaw, Uri Obolski, Marc Turner, Miles Carroll, Juthathip Mongkolsapaya, Gavin Screaton, Stephen H. Kennedy, Lisa M. Jarvis, Eleanor Barnes, Susanna Dunachie, José Lourenço, Philippa C. Matthews, Tihana Bicanic, Paul Klenerman, Sunetra Gupta, Craig P. Thompson
We describe a new mechanism responsible for Systemic Lupus Erythematosus (SLE). In humans with SLE and in two SLE murine models, there is marked enrichment of isolevuglandin (isoLG)-adducted proteins in monocytes and dendritic cells (DCs). We found that antibodies form against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduces transcription of all C1q subunits. Treatment of SLE prone mice with the specific isoLG scavenger 2-hydroxybenzlyamine (2HOBA) ameliorates parameters of autoimmunity including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowers blood pressure, attenuates renal injury, and reduces inflammatory gene expression uniquely in C1q expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.
David M. Patrick, Néstor de la Visitación, Jaya Krishnan, Wei Chen, Michelle J. Ormseth, C. Michael Stein, Sean S. Davies, Venkataraman Amarnath, Leslie J. Crofford, Jonathan M. Williams, Shilin Zhao, Charles D. Smart, Sergey Dikalov, Anna Dikalova, Liang Xiao, Justin P. Van Beusecum, Mingfang Ao, Agnes B. Fogo, Annet Kirabo, David G. Harrison
Nephrolithiasis is a common and recurrent disease affecting 9% of the US population. Hyperoxaluria is major risk factor for calcium oxalate kidney stones, which constitutes two-thirds of all kidney stones. Gastrointestinal epithelia play an important role in oxalate handling due to the presence of SLC26A family anion exchangers that facilitate oxalate transport. SLC26A3 (originally named DRA, down-regulated in adenoma) is an anion exchanger of chloride, bicarbonate and oxalate thought to facilitate intestinal oxalate absorption, as evidenced by ~70% reduced urine oxalate excretion in knock-out mice. We previously identified, by high-throughput screening and medicinal chemistry, a small molecule SLC26A3 inhibitor (DRAinh-A270) that selectively inhibited SLC26A3-mediated chloride/bicarbonate exchange (IC50 ~ 35 nM), and, as found here, oxalate/chloride exchange (IC50 ~ 60 nM). In colonic closed loops in mice, luminal DRAinh-A270 inhibited oxalate absorption by 70%. In a model of acute hyperoxaluria produced by oral sodium oxalate loading, DRAinh-A270 largely prevented the ~2.5-fold increase in urine oxalate/creatinine ratio. In a mouse model of oxalate nephropathy produced by a high-oxalate low-calcium diet, vehicle-treated mice by day 14 developed marked hyperoxaluria with elevated serum creatinine, renal calcium oxalate crystal deposition and renal injury, which were largely prevented by DRAinh-A270 (10 mg/kg twice daily). DRAinh-A270 administered over 7 days to healthy mice did not show significant toxicity as assessed by CBC, serum chemistries and tissue histology. Our findings support a major role of SLC26A3 in intestinal oxalate absorption and suggest the therapeutic utility of SLC26A3 inhibition for treatment of hyperoxaluria and prevention of calcium oxalate nephrolithiasis.
Onur Cil, Qi Tifany Chu, Sujin Lee, Peter M. Haggie, Alan S. Verkman
Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single cell RNA sequencing of airway epithelium and mouse modeling, we find that IL-13 expands and programs airway tuft cells towards eicosanoid metabolism, and that tuft cell deficiency leads to a reduction in airway prostaglandin E2 (PGE2)concentration. Allergic airway epithelia bear a signature of prostaglandin E2 activation, and PGE2 activation leads to CFTR-dependent ion and fluid secretion and accelerated mucociliary transport. Together these data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.
Maya E Kotas, Camille M. Moore, Jose G. Gurrola II, Steven D. Pletcher, Andrew N. Goldberg, Raquel Alvarez, Sheyla Yamato, Preston E. Bratcher, Ciaran A. Shaughnessy, Pamela L. Zeitlin, Irene H Zhang, Yingchun Li, Michael T. Montgomery, Keehoon Lee, Emily K. Cope, Richard M. Locksley, Max A. Seibold, Erin D. Gordon
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