Publications by authors named "Tingting Geng"

64 Publications

Early detection of SARS-CoV-2 in circulating immune cells in a mouse model.

bioRxiv 2021 Jun 30. Epub 2021 Jun 30.

SARS-CoV-2 infects the respiratory tract, lung and then other organs. However, its pathogenesis remains largely unknown. We used RareScopeâ"¢ Fluorescence Light Sheet Microscopy (FLSM) and fluorescent in situ hybridization of RNA (RNA-FISH) to detect SARS-CoV-2 RNA and dissemination kinetics in mouse blood circulation. By RNA-FISH, we found that SARS-CoV-2 RNA-positive leukocytes, including CD11c cells, appeared as early as one day after infection and continued through day 10 post infection. Our data suggest that SARS-CoV-2-permissive leukocytes contribute to systemic viral dissemination, and RNA-FISH combined with FLSM can be utilized as a sensitive tool for SARS-CoV-2 detection in blood specimens.
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http://dx.doi.org/10.1101/2021.06.30.450531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259904PMC
June 2021

A critical role for MSR1 in vesicular stomatitis virus infection of the central nervous system.

iScience 2021 Jun 1;24(6):102678. Epub 2021 Jun 1.

Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.

Macrophage scavenger receptor 1 (MSR1) plays an important role in host defense to bacterial infections, M2 macrophage polarization, and lipid homeostasis. However, its physiological function in viral pathogenesis remains poorly defined. Herein, we report that MSR1 facilitates vesicular stomatitis virus (VSV) infection in the central nervous system. Msr1-deficient ( ) mice presented reduced morbidity, mortality, and viral loads in the spinal cord following lethal VSV infection, along with normal viremia and innate immune responses, compared to littermates and wild-type mice. Msr1 expression was most significantly upregulated in the spinal cord, the predominant target of VSV. Mechanistically, through its extracellular domains, MSR1 interacted with VSV surface glycoprotein and facilitated its cellular entry in a low-density lipoprotein receptor-dependent manner. In conclusion, our results demonstrate that MSR1 serves as a cofactor for VSV cellular entry and facilitates its infection preferentially in the spinal cord.
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http://dx.doi.org/10.1016/j.isci.2021.102678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208900PMC
June 2021

UBX Domain Protein 6 Positively Regulates JAK-STAT1/2 Signaling.

J Immunol 2021 Jun 21;206(11):2682-2691. Epub 2021 May 21.

Department of Immunology, School of Medicine, UConn Health, Farmington, CT;

Type I/III IFNs induce expression of hundreds of IFN-stimulated genes through the JAK/STAT pathway to combat viral infections. Although JAK/STAT signaling is seemingly straightforward, it is nevertheless subjected to complex cellular regulation. In this study, we show that an ubiquitination regulatory X (UBX) domain-containing protein, UBXN6, positively regulates JAK-STAT1/2 signaling. Overexpression of UBXN6 enhanced type I/III IFNs-induced expression of IFN-stimulated genes, whereas deletion of UBXN6 inhibited their expression. RNA viral replication was increased in human UBXN6-deficient cells, accompanied by a reduction in both type I/III IFN expression, when compared with UBXN6-sufficient cells. Mechanistically, UBXN6 interacted with tyrosine kinase 2 (TYK2) and inhibited IFN-β-induced degradation of both TYK2 and type I IFNR. These results suggest that UBXN6 maintains normal JAK-STAT1/2 signaling by stabilizing key signaling components during viral infection.
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http://dx.doi.org/10.4049/jimmunol.1901337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164993PMC
June 2021

Probiotics Lactobacillus rhamnosus GG ATCC53103 and Lactobacillus plantarum JL01 induce cytokine alterations by the production of TCDA, DHA, and succinic and palmitic acids, and enhance immunity of weaned piglets.

Res Vet Sci 2021 Jul 14;137:56-67. Epub 2021 Apr 14.

College of Animal Science and Technology, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, China; Ministry of Education Laboratory of Animal PRODUCTION and Quality Security, Jilin Agricultural University, Changchun, China; Jilin Provincial Key Laboratory of Animal Nutrition and Feed Science, Jilin Agricultural University, Changchun, China. Electronic address:

Probiotics, including Lactobacillus rhamnosus GG ATCC53103 and Lactobacillus plantarum JL01, can improve growth performance and immunity of piglets, and relieve weaning stress-related immune disorders such as intestinal infections and inflammation. This study aimed to evaluate the ability of co-administration of the probiotics L. rhamnosus GG ATCC53103 and L. plantarum JL01 to stimulate immune responses and improve gut health during the critical weaning period in piglets. Forty-eight weaned piglets were randomly divided into four groups, and fed daily for 28 days either without, or with the two probiotics independently, or in combination. On day 28, we analyzed the cytokine and bacterial changes in intestinal mucosa and the hepatic portal vein blood metabolites of the weaned piglets. Our results showed that combined L. rhamnosus GG ATCC53103 and L. plantarum JL01 significantly increased (p < 0.05) the growth performance and expression of IL-10 and TGF-β1 mRNAs. In contrast, this treatment significantly decreased (p < 0.05) IL-1β mRNA level in the jejunum, ileum, and cecum. Furthermore, the secretion of IL-6 in the cecum, IL-1β in the jejunum, ileum, and cecum, and TNF-α in the jejunum and ileum was significantly decreased (p < 0.05). The relative abundance of Prevotella_9 and Enterococcus in ileum and cecum was significantly increased (p < 0.05). The relative abundance of Ruminococcus_1 and Ruminococcaceae_UCG-005 in cecum was significantly decreased (p < 0.05). Prevotella_9 and Enterococcus may increase the accumulation of (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA) and tauroursodeoxycholic acid (TCDA) in portal vein blood, while Ruminococcus_1 and Ruminococcaceae_UCG-005 may decrease the accumulation of succinic and palmitic acids. These results indicate that L. rhamnosus GG ATCC53103 and L. plantarum JL01 may regulate cytokine levels by reducing the accumulation of succinic and palmitic acids and increasing the accumulation of TCDA and DHA, thereby enhancing the immunity of weaned piglets.
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http://dx.doi.org/10.1016/j.rvsc.2021.04.011DOI Listing
July 2021

LncRNA LINC00857 strengthens the malignancy behaviors of pancreatic adenocarcinoma cells by serving as a competing endogenous RNA for miR-340-5p to upregulate TGFA expression.

PLoS One 2021 4;16(3):e0247817. Epub 2021 Mar 4.

Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, P. R. China.

Background: Pancreatic adenocarcinoma (PAAD) is a pancreatic disease with a high mortality rate in the world. This present research intends to identify the function of lncRNA LINC00857/miR-340-5p/Transforming growth factor alpha (TGFA) in the progression of PAAD.

Methods: Bioinformatics analysis was used to explore the differentially expressed lncRNA/miRNA/mRNA and analyze the relationship between lncRNA/miRNA/mRNA expression and prognosis of PAAD by enquiring TCGA, GEO and GTEX. KEGG pathway analysis and GO enrichment analysis were implemented to annotate the crucial genes regulated by LINC00857. The biological behaviors of PAAD cells were detected by CCK-8, colony formation and transwell assays. Interactive associations between LINC00857 and miR-340-5p, as well as miR-340-5p and TGFA were analyzed by dual luciferase assay.

Results: By enquiring TCGA database, we got that LINC00857 was highly expressed in patients with PAAD and positively associated with worse prognosis in PAAD patients. Moreover, LINC00857 upregulation promoted the proliferation and clone formation abilities of PAAD cells. Afterwards, the downstream miRNA and mRNA targets of LINC00857 were picked up to construct a ceRNA network. Further study revealed that TGFA expression was positively regulated by LINC00857 and negatively regulated by miR-340-5p. Besides that, the inhibitory effect of miR-340-5p on PAAD cells growth and movement can be blocked by LINC00857 upregulation. While, the malignant behavior of PAAD cells induced by TGFA overexpression can be eliminated by LINC00857 knockdown.

Conclusions: Upregulation of LINC00857 improved growth, invasion and migration abilities of PAAD cells by modulation of miR-340-5p/TGFA, affording potential targets and biomarkers for the clinical diagnosis and treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247817PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932076PMC
March 2021

Birth weight modifies the relation between adulthood levels of insulin-like growth factor-1 and type 2 diabetes: a prospective cohort study.

BMJ Open Diabetes Res Care 2021 01;9(1)

Department of Epidemiology, School of Public Health and Tropical Medicine,Tulane University, New Orleans, Louisiana, USA

Introduction: Insulin-like growth factor-1 (IGF-1) has been implicated in fetal and early-life growth and development of type 2 diabetes (T2D). We aimed to examine the interaction between circulating IGF-1 and birth weight in relation to risk of T2D.

Research Design And Methods: We included 181 090 adults, aged 39-70 years in the UK Biobank Study, who were free of diabetes or major cardiovascular diseases at baseline. Serum IGF-1 levels were determined using chemiluminescent immunoassay method. Birth weight was self-reported; a Genetic Risk Score (GRS) was calculated to define the genetically determined birth weight. The outcome was the incidence of T2D.

Results: We identified 3299 incident T2D cases over an average of 9.9 years of follow-up. Among the participants with birth weight of ≥2.5 kg, IGF-1 levels were inversely associated with T2D risk in a dose-dependent manner (ptrend<0.001). In contrast, the association was not significant among those with birth weight of <2.5 kg (p-interaction=0.001). The GRS of birth weight did not interact with IGF-1 levels on T2D risk.

Conclusions: Our results indicate that birth weight significantly modifies the relation between adulthood levels of circulating IGF-1 and the risk of T2D. Our findings highlight the importance of early-life risk factors in the development of the lifecourse prevention strategies targeting IGF-1 and T2D.
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http://dx.doi.org/10.1136/bmjdrc-2020-001885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925240PMC
January 2021

Differential roles of RIG-I-like receptors in SARS-CoV-2 infection.

bioRxiv 2021 Feb 11. Epub 2021 Feb 11.

The retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) are the major viral RNA sensors that are essential for activation of antiviral immune responses. However, their roles in severe acute respiratory syndrome (SARS)-causing coronavirus (CoV) infection are largely unknown. Herein we investigate their functions in human epithelial cells, the primary and initial target of SARS-CoV-2, and the first line of host defense. A deficiency in MDA5 ( ), RIG-I or mitochondrial antiviral signaling protein (MAVS) greatly enhanced viral replication. Expression of the type I/III interferons (IFN) was upregulated following infection in wild-type cells, while this upregulation was severely abolished in and , but not in cells. Of note, ACE2 expression was ~2.5 fold higher in than WT cells. These data demonstrate a dominant role of MDA5 in activating the type I/III IFN response to SARS-CoV-2, and an IFN-independent anti-SARS-CoV-2 role of RIG-I.
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http://dx.doi.org/10.1101/2021.02.10.430677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885922PMC
February 2021

A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus.

J Infect Dis 2021 Jun;223(12):2186-2196

Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.

The stimulator of interferon gene (STING) pathway controls both DNA and RNA virus infection. STING is essential for induction of innate immune responses during DNA virus infection, while its mechanism against RNA virus remains largely elusive. We show that STING signaling is crucial for restricting chikungunya virus infection and arthritis pathogenesis. Sting-deficient mice (Stinggt/gt) had elevated viremia throughout the viremic stage and viral burden in feet transiently, with a normal type I IFN response. Stinggt/gt mice presented much greater foot swelling, joint damage, and immune cell infiltration than wild-type mice. Intriguingly, expression of interferon-γ and Cxcl10 was continuously upregulated by approximately 7 to 10-fold and further elevated in Stinggt/gt mice synchronously with arthritis progression. However, expression of chemoattractants for and activators of neutrophils, Cxcl5, Cxcl7, and Cxcr2 was suppressed in Stinggt/gt joints. These results demonstrate that STING deficiency leads to an aberrant chemokine response that promotes pathogenesis of CHIKV arthritis.
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http://dx.doi.org/10.1093/infdis/jiaa694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205639PMC
June 2021

CXCL10 Signaling Contributes to the Pathogenesis of Arthritogenic Alphaviruses.

Viruses 2020 11 2;12(11). Epub 2020 Nov 2.

Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.

Emerging and re-emerging arthritogenic alphaviruses, such as Chikungunya virus (CHIKV) and O'nyong nyong virus, cause acute and chronic crippling arthralgia associated with inflammatory immune responses. Approximately 50% of CHIKV-infected patients suffer from rheumatic manifestations that last 6 months to years. However, the physiological functions of individual immune signaling pathways in the pathogenesis of alphaviral arthritis remain poorly understood. Here, we report that a deficiency in CXCL10, which is a chemoattractant for monocytes/macrophages/T cells, led to the same viremia as wild-type animals, but fewer immune infiltrates and lower viral loads in footpads at the peak of arthritic disease (6-8 days post infection). Macrophages constituted the largest immune cell population in footpads following infection, and were significantly reduced in mice. The viral RNA loads in neutrophils and macrophages were reduced in compared to wild-type mice. In summary, our results demonstrate that CXCL10 signaling promotes the pathogenesis of alphaviral disease and suggest that CXCL10 may be a therapeutic target for mitigating alphaviral arthritis.
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http://dx.doi.org/10.3390/v12111252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692144PMC
November 2020

Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice.

Commun Biol 2020 10 8;3(1):556. Epub 2020 Oct 8.

Department of Microbiology & Immunology, School of Medicine, New York Medical College, Valhalla, NY, 10595, USA.

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1 cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.
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http://dx.doi.org/10.1038/s42003-020-01285-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545163PMC
October 2020

Proteomic analysis reveals the molecular mechanism of Hippophae rhamnoides polysaccharide intervention in LPS-induced inflammation of IPEC-J2 cells in piglets.

Int J Biol Macromol 2020 Dec 1;164:3294-3304. Epub 2020 Sep 1.

College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163316, China. Electronic address:

Early weaning can cause intestinal disorders and dysfunction in piglets, and may induce intestinal diseases. Hippophae rhamnoides polysaccharide (HRP) has anti-inflammatory and immune promotion function. However, few studies have explored the change of differentially protein expression by lipopolysaccharide (LPS)-induced porcine intestinal epithelial cell (IPEC-J2) after HRP pre-treatment. In this study, proteomic analysis was used to explore the essential proteins and immune-related pathways that can be regulated by LPS-induced IPEC-J2 cells after HRP pre-treatment. The results indicate that by searching the Sus scrofa database, a total of 18,768 proteins was identified. Among recognized proteins, there are 2052 (1720 up-regulated and 332 down-regulated), 358 (262 up-regulated and 96 down-regulated) and1532 (314 up-regulated and 1218 down-regulated) proteins expressed differently in C vs. L, C vs. H6-L and L vs. H6-L, respectively. The Cluster of Orthologous Groups (COG) analysis divided the identified proteins into 23 categories. Gene Ontology (GO) enrichment analysis revealed that cellular process, cell, cell part, organelle and binding were the most enriched pathways for differentially expressed proteins. KEGG enrichment analysis indicated that the top 20 pathways in the L-vs-H6-L group related to immunity were the Tight junction, MAPK signaling pathway, PI3K-Akt signaling pathway, rap1 signaling pathway, HIF-1 signaling pathway, Ras signaling pathway and Fc gamma R-mediated phagocytosis. Moreover, we also found 42 key proteins related to these immune pathways in this study. Additionally, western blotting analyses confirmed that LPS reduced the levels of claudin2 (CLDN2), insulin-like growth factor 2 (IGF2) and increased phosphorylated mitogen-activated protein kinase 7 (MAPK7), phosphorylated transcription factor p65 (RELA), phosphorylated nuclear factor NF-kappa-B p105 subunit (NF-κB1) and phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NF-κB2). Pre-treatment with HRP increased the levels of CLDN2, IGF2 and reduced the levels of the phosphorylated MAPK7, phosphorylated RELA, phosphorylated NF-κB1 and phosphorylated NF-κB2 in cells. These results also showed that HRP alleviated LPS-induced inflammation in IPEC-J2 cells by inhibiting the MAPK/NF-κB signaling pathway and its related differentially expressed proteins.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.08.235DOI Listing
December 2020

Gene-environment interactions and type 2 diabetes.

Asia Pac J Clin Nutr 2020 ;29(2):220-226

Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China. Email:

Type 2 diabetes (T2D) caused by the complex interplay of both genetic and environmental factors, is a serious public health issue. Compelling evidence from epidemiological studies has highlighted that an unhealthy lifestyle, such as obesity, physical inactivity and poor diet are significant drivers of the epidemic of T2D. Meanwhile, recent genome-wide association studies (GWAS) have identified a large number of T2D and glycemic traits loci. Emerging data emphasize the critical role that gene-environment interactions have played in the development of T2D. Identifying the genetic, environmental factors and their complex interplays may help elucidate the biological pathways of T2D, identify the high-risk groups and characterize heterogeneity in intervention programs. This review summarized the studies investigating gene-environment interactions of T2D.
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http://dx.doi.org/10.6133/apjcn.202007_29(2).0002DOI Listing
May 2021

Hippophae rhamnoides polysaccharides protect IPEC-J2 cells from LPS-induced inflammation, apoptosis and barrier dysfunction in vitro via inhibiting TLR4/NF-κB signaling pathway.

Int J Biol Macromol 2020 Jul 12;155:1202-1215. Epub 2019 Nov 12.

College of Animal Science and Technology, Jilin Agricultural University, Changchun, Jilin 130118, China; Ministry of Education Laboratory of Animal Production and Quality Security, Jilin Agricultural University, Changchun, Jilin 130118, China; Jilin Provincial Key Laboratory of Animal Nutrition and Feed Science, Jilin Agricultural University, Changchun, Jilin 130118, China. Electronic address:

Inflammatory response caused by early weaning stress in piglets is associated with various diseases. The Hippophae rhamnoides polysaccharide (HRP) exhibits anti-inflammatory activity and immunomodulatory properties. The mechanisms for the protective effects of HRP on barrier function, inflammatory damage and apoptosis in intestinal porcine epithelial cells (IPEC-J2) induced by the lipopolysaccharide (LPS) are unknown. In this study, we first demonstrated the cytotoxicity of HRP-induced IPEC-J2 cells by reducing cell viability. IPEC-J2 cells were treated with 0-800 μg/mL doses of HRP, and 0-600 μg/mL doses were used in further experiments. Upon exposure to LPS, the viability of IPEC-J2 cells, ROS production, immunoglobulin levels (immunoglobulin M (IgM), immunoglobulin A (IgA) and immunoglobulin G (IgG)) and tight junction protein level (zonula occludens-1 (ZO-1), occluding, claudin-1) decreased. Inflammatory factors (interleukin-1beta (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α)) and apoptosis (Bcl-2, Bax, caspase-3, caspase-8 and caspase-9) were increased. Cell morphology and internal structure were damaged in the LPS treatment. Pre-treating cells with HRP (0-600 μg/mL) reduced inflammatory factors levels, apoptosis rate, increased immunoglobulins, tight junction protein levels and relieved cell surface morphology damage. Pre-treatment with HRP also reduced the levels of the Toll-like receptor 4 (TLR4) and Myeloid differentiation factor 88 (MyD88) and inhibited the phosphorylated NF-κB factor-kappa B (NF-κB) in cells induced by LPS. These results show that pre-treatment with HRP protected against LPS-induced IPEC-J2 cell damage through its anti-inflammatory activity.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.11.088DOI Listing
July 2020

Correction: H19 lncRNA alters methylation and expression of Hnf4α in the liver of metformin-exposed fetuses.

Cell Death Dis 2019 Aug 7;10(8):592. Epub 2019 Aug 7.

Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06510, USA.

Since publication of this article, Dr Ramanaiah Mamillapalli reported that his last name had published incorrectly as Ramillapalli. The publisher apologizes to the authors and to readers for this error, which has not been fixed in the original article.
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http://dx.doi.org/10.1038/s41419-019-1812-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686012PMC
August 2019

H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPK.

Diabetes 2018 11 10;67(11):2183-2198. Epub 2018 Sep 10.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT

Skeletal muscle plays a pivotal role in regulating systemic glucose homeostasis in part through the conserved cellular energy sensor AMPK. AMPK activation increases glucose uptake, lipid oxidation, and mitochondrial biogenesis, leading to enhanced muscle insulin sensitivity and whole-body energy metabolism. Here we show that the muscle-enriched H19 long noncoding RNA (lncRNA) acts to enhance muscle insulin sensitivity, at least in part, by activating AMPK. We identify the atypical dual-specificity phosphatase DUSP27/DUPD1 as a potentially important downstream effector of H19. We show that DUSP27, which is highly expressed in muscle with previously unknown physiological function, interacts with and activates AMPK in muscle cells. Consistent with decreased H19 expression in the muscle of insulin-resistant human subjects and rodents, mice with genetic H19 ablation exhibit muscle insulin resistance. Furthermore, a high-fat diet downregulates muscle H19 via both posttranscriptional and epigenetic mechanisms. Our results uncover an evolutionarily conserved, highly expressed lncRNA as an important regulator of muscle insulin sensitivity.
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http://dx.doi.org/10.2337/db18-0370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198334PMC
November 2018

To Predict Visual Deterioration According to the Degree of Intracranial Hypertension in Patients with Cerebral Venous Sinus Thrombosis.

Eur Neurol 2018 22;80(1-2):28-33. Epub 2018 Aug 22.

Departments of Neurology and Ophthalmology, Xuanwu Hospital, Capital Medical University, Beijing,

Background: Visual damage is one of the most common complications of cerebral venous sinus thrombosis (CVST)-associated intracranial hypertension (IH). This study is aimed at stratifying the risk of IH-induced visual damage in an attempt to predict its deterioration and prevent high-risk patients from irreversible eyesight impairment promptly.

Methods: A total of 94 patients with confirmed diagnosis of CVST were eligible for enrollment in this study. According to cerebrospinal fluid pressure at admission, the involved patients were classified into mild IH (< 250 mmH2O), moderate IH (250-330 mmH2O), and severe IH (≥330 mmH2O) groups.

Results: The ratio of visual deterioration in the severe IH group was 75%, which was significantly higher than in either the moderate (44.4%) or the mild groups (14.3%). As regards subjects without visual symptoms at admission, visual deterioration occurred in 9.4 ± 4.5 days after admission in the severe group while it occurred in 30.5 ± 16.8 days in the moderate group (p = 0.024). The conditional inference tree and random forest revealed that severe IH might be considered as an index of visual deterioration. Visual field defect, fading eyesight, and papilledema were significantly worse in patients with severe IH as compared to patients with mild or moderate IH, all p < 0.01.

Conclusions: IH ≥330 mmH2O may be a cut-off value to predict the deterioration of visual damage in CVST, revealing that ophthalmologic interventions should be considered in a timely manner in this condition, particularly when recanalization of cerebral venous sinus cannot be achieved within a short time.
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http://dx.doi.org/10.1159/000492184DOI Listing
January 2019

The efficacy and safety of Batroxobin in combination with anticoagulation on cerebral venous sinus thrombosis.

J Thromb Thrombolysis 2018 Oct;46(3):371-378

Departments of Neurology and Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.

Cerebral venous sinus thrombosis (CVST) is an uncommon subtype of stroke with highly variable clinical presentation. Although anticoagulation with heparin and/or warfarin remains the standard treatment for CVST, treatment failure is still common. This study aims to evaluate the safety and efficacy of Batroxobin in combination with anticoagulation on CVST control. In this retrospective study, a total of 61 CVST patients were enrolled and divided into Batroxobin (n = 23) and control (n = 38) groups. In addition to the same standard anticoagulation in control, patients in the treatment group received Batroxobin 5 BU intravenous infusion (10 BU for the first time) every other day, for a total of three infusions. A higher recanalization rate was found in Batroxobin group (adjusted OR [95% CI] of 2.5 [1.1-5.0], p = 0.028) compared to the control group, especially in patients with high levels of fibrinogen (adjusted OR [95% CI] of 4.7 [1.4-16.7], p = 0.015). Statistically significant differences between the two groups were seen regarding the levels of thrombin time, fibrinogen and D-dimer at each cut-off time point (all p < 0.01). Compared with baseline, NIHSS scores at discharge showed significant improvement in the Batroxobin group [0(0, 4.25)-5(2, 11), p = 0.036]. No significant difference in mRS scores was found between the two groups at discharge or at 6-month outpatient follow-up (all p > 0.05). Additionally, Batroxobin did not increase the risk of intracranial hemorrhage. We conclude that Batroxobin is a potentially safe and effective adjunct therapeutic agent promoting CVST recanalization especially in patients with high level of fibrinogen.
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http://dx.doi.org/10.1007/s11239-018-1718-yDOI Listing
October 2018

Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling.

Front Microbiol 2018 25;9:1350. Epub 2018 Jun 25.

Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, United States.

Flaviviruses have evolved complex mechanisms to evade the mammalian host immune systems including the RIG-I (retinoic acid-inducible gene I) like receptor (RLR) signaling. Zika virus (ZIKV) is a re-emerging flavivirus that is associated with severe neonatal microcephaly and adult Guillain-Barre syndrome. However, the molecular mechanisms underlying ZIKV pathogenesis remain poorly defined. Here we report that ZIKV non-structural protein 4A (NS4A) impairs the RLR-mitochondrial antiviral-signaling protein (MAVS) interaction and subsequent induction of antiviral immune responses. In human trophoblasts, both RIG-I and melanoma differentiation-associated protein 5 (MDA5) contribute to type I interferon (IFN) induction and control ZIKV replication. Type I IFN induction by ZIKV is almost completely abolished in cells. NS4A represses RLR-, but not Toll-like receptor-mediated immune responses. NS4A specifically binds the N-terminal caspase activation and recruitment domain (CARD) of MAVS and thus blocks its accessibility by RLRs. Our study provides in-depth understanding of the molecular mechanisms of immune evasion by ZIKV and its pathogenesis.
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http://dx.doi.org/10.3389/fmicb.2018.01350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026624PMC
June 2018

MiR-106b regulates the apoptosis and tumorigenesis of hepatocellular carcinoma via targeting Zinc finger and BTB domain-containing protein 7A (Zbtb7a).

J Biochem Mol Toxicol 2018 Aug 5;32(8):e22169. Epub 2018 Jul 5.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.

MicroRNAs play vital regulatory roles in various type of tumorigenesis. We aimed to explore the functional microRNAs that might play as therapeutic targets in hepatocellular carcinoma (HCC). In this study, our results revealed that microRNA-106b was significantly increased in HCC tumor tissues. However, miR-106b knockdown remarkably suppressed the growth and increased the apoptosis of Hub-7 HCC cells. Biological analysis indicated that miR-106b directly targeted toZinc finger and BTB domain-containing protein 7A (Zbtb7a) to regulate the apoptosis of Hub-7 cells. Extensively, Zbtb7a overexpression reversed Huh-7 cell apoptosis and growth in vitro. Furthermore, in vivo studies confirmed that miR-106b inhibition or Zbtb7a overexpression retarded the growth of Hub-7 xenograft tumor in nude mice. In conclusion, we provide the evidence for the regulatory role of miR-106b in HCC, which is causally linked to targeting of Zbtb7a. This study may provide miR-106b as a potential therapeutic strategy for HCC.
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http://dx.doi.org/10.1002/jbt.22169DOI Listing
August 2018

Deleting MyD88 signaling in myeloid cells promotes development of adenocarcinomas of the colon.

Cancer Lett 2018 10 28;433:65-75. Epub 2018 Jun 28.

Institute of Immunology, Taishan Medical University, Tai'an, Shandong, 271000, China; Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China. Electronic address:

Intestinal myeloid cells are not only essential for keeping local homeostasis, but also play an important role in regulating the occurrence of colitis and colitis-associated cancer (CAC). In these diseases, the manner in which the myeloid cells work and which molecular pathways influence them are still not fully understood. In our study, we discovered that MyD88 signaling in colonic myeloid cells participates in the development of CAC. Myeloid MyD88-deficient mice showed greater susceptibility to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC, as evidenced by the increase in the number and sizes of tumors. Myeloid MyD88 deletion markedly increased production of pro-inflammatory and pro-tumor cytokines; recruitment of more IL-1β producing-neutrophils in colon from bone marrow; increased in epithelial cell apoptosis and decreased in epithelial cell proliferation; enhancement of colon mucosal expression of COX-2, p-STAT3, β-catenin, and cyclinD1; induction of further DNA damage and β-catenin mutation. To sum up, these results suggest that myeloid MyD88 signaling protects the intestine from tumorigenesis during the development of CAC.
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http://dx.doi.org/10.1016/j.canlet.2018.06.036DOI Listing
October 2018

UBXN3B positively regulates STING-mediated antiviral immune responses.

Nat Commun 2018 06 13;9(1):2329. Epub 2018 Jun 13.

Department of Microbiology and Immunology, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA.

The ubiquitin regulatory X domain-containing proteins (UBXNs) are likely involved in diverse biological processes. Their physiological functions, however, remain largely unknown. Here we present physiological evidence that UBXN3B positively regulates stimulator-of-interferon genes (STING) signaling. We employ a tamoxifen-inducible Cre-LoxP approach to generate systemic Ubxn3b knockout in adult mice as the Ubxn3b-null mutation is embryonically lethal. Ubxn3b, like Sting mice, are highly susceptible to lethal herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection, which is correlated with deficient immune responses when compared to Ubxn3b littermates. HSV-1 and STING agonist-induced immune responses are also reduced in several mouse and human Ubxn3b primary cells. Mechanistic studies demonstrate that UBXN3B interacts with both STING and its E3 ligase TRIM56, and facilitates STING ubiquitination, dimerization, trafficking, and consequent recruitment and phosphorylation of TBK1. These results provide physiological evidence that links the UBXN family with antiviral immune responses.
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http://dx.doi.org/10.1038/s41467-018-04759-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998066PMC
June 2018

Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia.

JCI Insight 2018 05 17;3(10). Epub 2018 May 17.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.

Excessive hepatic glucose production (HGP) contributes significantly to the hyperglycemia of type 2 diabetes; however, the molecular mechanism underlying this dysregulation remains poorly understood. Here, we show that fasting temporally increases the expression of H19 long noncoding RNA (lncRNA) in nondiabetic mouse liver, whereas its level is chronically elevated in diet-induced diabetic mice, consistent with the previously reported chronic hepatic H19 increase in diabetic patients. Importantly, liver-specific H19 overexpression promotes HGP, hyperglycemia, and insulin resistance, while H19 depletion enhances insulin-dependent suppression of HGP. Using genome-wide methylation and transcriptome analyses, we demonstrate that H19 knockdown in hepatic cells alters promoter methylation and expression of Hnf4a, a master gluconeogenic transcription factor, and that this regulation is recapitulated in vivo. Our findings offer a mechanistic explanation of lncRNA H19's role in the pathogenesis of diabetic hyperglycemia and suggest that targeting hepatic H19 may hold the potential of new treatment for this disease.
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http://dx.doi.org/10.1172/jci.insight.120304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012507PMC
May 2018

Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis.

Diabetes Care 2018 05 26;41(5):1089-1096. Epub 2018 Feb 26.

Epidemiology Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore

Objective: To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis.

Research Design And Methods: We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia.

Results: We found that a 1-SD increase in childhood BMI (kg/m) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; = 2.5 × 10) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; = 2.1 × 10) at the Bonferroni-adjusted level of significance ( < 0.017) in adults. In addition, a 1-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of ß-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance ( < 0.0026).

Conclusions: A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes.
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http://dx.doi.org/10.2337/dc17-2141DOI Listing
May 2018

H19 lncRNA alters methylation and expression of Hnf4α in the liver of metformin-exposed fetuses.

Cell Death Dis 2017 12 7;8(12):e3175. Epub 2017 Dec 7.

Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.

Metformin is the most widely used anti-diabetic medication worldwide. However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4α (HNF4α). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4α also has an indispensable role in the regulation of expression of gluconeogenic genes. Consistently, H19 overexpression in a human liver cell line leads to decreased methylation and increased expression of Hnf4α, with concomitant activation of the gluconeogenic program. Mechanistically, we show that the methylation change of Hnf4α is induced by H19-mediated regulation of S-adenosylhomocysteine hydrolase. We also provide evidence that altered H19 expression is a direct effect of metformin in the fetal liver. Our results suggest that metformin from the mother can directly act upon the fetal liver to modify Hnf4α expression, a key factor for both liver development and function, and that perturbation of this H19/Hnf4α-mediated pathway may contribute to the fetal origin of adult metabolic abnormalities.
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http://dx.doi.org/10.1038/cddis.2017.392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827203PMC
December 2017

Effects of Dairy Products Consumption on Body Weight and Body Composition Among Adults: An Updated Meta-Analysis of 37 Randomized Control Trials.

Mol Nutr Food Res 2018 01;62(1)

Epidemiology Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

Scope: Effects of dairy consumption on body weight and body composition have been inconsistently observed in randomized control trials (RCTs). Our meta-analysis aims to systematically evaluate the effects of dairy consumption on body weight and body composition among the adults.

Methods And Results: We conducted a comprehensive search of the Cochrane Library, PubMed, and Embase databases of the relevant studies from 1966 to Mar 2017 regarding dairy consumption on body weight and body composition including body fat, lean mass, and waist circumference (WC). The summary results are pooled by using a random-effects meta-analysis. Thirty-seven RCTs with 184 802 participants are included in this meta-analysis. High dairy intervention increased body weight (0.01, 95% CI: -0.25, 0.26, I = 78.3%) and lean mass (0.37, 95% CI: 0.11, 0.62, I = 83.4%); decreased body fat (-0.23, 95% CI: -0.48, 0.02, I = 78.2%) and WC (-1.37, 95% CI: -2.28, -0.46, I = 98.9%) overall. In the subgroup analysis, we found that consumption of dairy products increases body weight (0.36, 95% CI: 0.01, 0.70, I = 83.1%) among participants without energy restriction. Dairy consumption decreases body weight (-0.64, 95% CI: -1.05, -0.24, I = 60.2%), body fat (-0.56, 95%CI: -0.95, -0.17, I = 66.6%), and waist circumference (-2.18, 95%CI: -4.30, -0.06, I = 99.0%) among the adults with energy restriction.

Conclusions: This meta-analysis suggests a beneficial effect of energy-restricted dairy consumption on body weight and body composition. However, high dairy consumption in the absence of caloric restriction may increase body weight.
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http://dx.doi.org/10.1002/mnfr.201700410DOI Listing
January 2018

Fish oil supplementation and insulin sensitivity: a systematic review and meta-analysis.

Lipids Health Dis 2017 Jul 3;16(1):131. Epub 2017 Jul 3.

Department of Nursing, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Lu, Yuzhong District, 400016, Chongqing, People's Republic of China.

Background: Fish oil supplementation has been shown to be associated with a lower risk of metabolic syndrome and benefit a wide range of chronic diseases, such as cardiovascular disease, type 2 diabetes and several types of cancers. However, the evidence of fish oil supplementation on glucose metabolism and insulin sensitivity is still controversial. This meta-analysis summarized the exist evidence of the relationship between fish oil supplementation and insulin sensitivity and aimed to evaluate whether fish oil supplementation could improve insulin sensitivity.

Methods: We searched the Cochrane Library, PubMed, Embase database for the relevant studies update to Dec 2016. Two researchers screened the literature independently by the selection and exclusion criteria. Studies were pooled using random effect models to estimate a pooled SMD and corresponding 95% CI. This meta-analysis was performed by Stata 13.1 software.

Results: A total of 17 studies with 672 participants were included in this meta-analysis study after screening from 498 published articles found after the initial search. In a pooled analysis, fish oil supplementation had no effects on insulin sensitivity compared with the placebo (SMD 0.17, 95%CI -0.15 to 0.48, p = 0.292). In subgroup analysis, fish oil supplementation could benefit insulin sensitivity among people who were experiencing at least one symptom of metabolic disorders (SMD 0.53, 95% CI 0.17 to 0.88, p < 0.001). Similarly, there were no significant differences between subgroups of methods of insulin sensitivity, doses of omega-3 polyunsaturated fatty acids (n-3 PUFA) of fish oil supplementation or duration of the intervention. The sensitivity analysis indicated that the results were robust.

Conclusions: Short-term fish oil supplementation is associated with increasing the insulin sensitivity among those people with metabolic disorders.
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http://dx.doi.org/10.1186/s12944-017-0528-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496233PMC
July 2017

Investigation of the major cytochrome P450 1A2 genetic variant in a healthy Tibetan population in China.

Mol Med Rep 2017 Jul 29;16(1):573-580. Epub 2017 May 29.

School of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, P.R. China.

The cytochrome P450 (CYP) 1A2 gene is involved in the metabolism of several carcinogens and clinically important drugs, generating a high potential for pharmacokinetic interactions. Since no data are available for Tibetan aborigines, the present study aimed to investigate the distribution of variant CYP1A2 alleles in a population living in Tibetan region of China. Genotyping analyses of CYP1A2 were conducted in 96 unrelated, healthy volunteers of Tibetan ancestry using direct sequencing assays. A total of 14 different CYP1A2 polymorphisms, including two novel variants (1690G>A and 2896C>T) in the intron region and a novel non‑synonymous one (795G>C, Gln265His) were detected. CYP1A2*1A (6.77%), CYP1A2*1B (58.33%) and CYP1A2*1F (14.58%) were the most frequent defective alleles identified in the sample. The frequencies of the prevalent genotypes CYP1A2*1A/*1B, *1B/*1B, *1B/*1F were 13.54%, 16.67% and 29.17%, respectively. In addition, the novel non‑synonymous variant 795G>C (Gln265His) was predicted to be benign by PolyPhen‑2 and SIFT tools. The present study provides useful information on the pattern of CYP1A2 polymorphisms in Chinese Tibetan population. The current results may have potential benefits for the development of personalized medicine in the Tibetan population.
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http://dx.doi.org/10.3892/mmr.2017.6645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482113PMC
July 2017

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction.

Oncotarget 2016 Jun;7(25):38398-38407

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-β receptor (TβR3) following H19 knockdown. Decreased TβR3 expression is also seen in FGR placentae. TβR3 repression decreases EVT cell migration and invasion, owing to impaired TGF-β signaling through a non-canonical TGF-β signaling pathway. Further, we identify TβR3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/TβR3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR.
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http://dx.doi.org/10.18632/oncotarget.9534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122399PMC
June 2016

NK cells promote neutrophil recruitment in the brain during sepsis-induced neuroinflammation.

Sci Rep 2016 06 8;6:27711. Epub 2016 Jun 8.

Institute of Immunology, Taishan Medical University, Taian, Shandong, 271000, China.

Sepsis could affect the central nervous system and thus induces neuroinflammation, which subsequently leads to brain damage or dysfunction. However, the mechanisms of generation of neuroinflammation during sepsis remain poorly understood. By administration of lipopolysaccharides (LPS) in mice to mimic sepsis, we found that shortly after opening the blood-brain barrier, conventional CD11b(+)CD27(+) NK subset migrated into the brain followed by subsequent neutrophil infiltration. Interestingly, depletion of NK cells prior to LPS treatment severely impaired neutrophil recruitment in the inflamed brain. By in vivo recruitment assay, we found that brain-infiltrated NK cells displayed chemotactic activity to neutrophils, which depended on the higher expression of chemokines such as CXCL2. Moreover, microglia were also responsible for neutrophil recruitment, and their chemotactic activity was significantly impaired by ablation of NK cells. Furthermore, depletion of NK cells could significantly ameliorate depression-like behavior in LPS-treated mice. These data indicated a NK cell-regulated neutrophil recruitment in the blamed brain, which also could be seen on another sepsis model, cecal ligation and puncture. So, our findings revealed an important scenario in the generation of sepsis-induced neuroinflammation.
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http://dx.doi.org/10.1038/srep27711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897692PMC
June 2016

Cytochrome P450 2C9 (CYP2C9) polymorphisms in Chinese Li population.

Int J Clin Exp Med 2015 15;8(11):21024-33. Epub 2015 Nov 15.

School of Life Sciences, Northwest UniversityXi'an 710069, China; National Engineering Research Center for Miniaturized Detection SystemsXi'an 710069, China.

Background: The frequencies of Cytochrome P450 2C9 (CYP2C9) genotypes were various between populations. The aim of this study was to investigate the frequencies of the major variants of the CYP2C9 in Chinese Li minority populations.

Methods: The promoter, exons and surrounding introns, and 3'-untranslated region of the CYP2C9 gene was detected by DNA sequencing to investigate in 100 unrelated healthy Chinese Li subjects. The protein function prediction was used the online tools: Sorting Intolerant From Tolerant (SIFT) and Phenotyping Version 2 (PolyPhen-2). The comparison of CYP2C9 allele frequencies in different populations were analyzed by Chi-square (χ(2)) test. Linkage disequilibrium (LD) analysis was performed using Haploview software.

Results: We identified 17 different CYP2C9 single nucleotide polymorphisms (SNPs) in the Li population, including two missense mutations (3549 G > A and 42614 A > C) and two silent mutations (3514 T > Cand 50298A > T). The protein function prediction revealed the two missense mutations result in protein damaging. In addition, we detected the allele frequencies of CYP2C9*1, CYP2C9*3 and CYP2C9*42 were 98%, 1%, and 1%, respectively. Finally, we compared three major allelic frequency (CYP2C9*1, CYP2C9*2, and CYP2C9*3) between Li and other populations. We found that our results were similar to East Asians and Africans.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723878PMC
February 2016
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