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1.  Sustained AAV-mediated overexpression of CRF in the central amygdala diminishes the depressive-like state associated with nicotine withdrawal 
Translational Psychiatry  2014;4(4):e385-.
Smoking cessation leads to a dysphoric state and this increases the risk for relapse. Animal studies indicate that the dysphoric state associated with nicotine withdrawal is at least partly mediated by an increase in corticotropin-releasing factor (CRF) release in the central nucleus of the amygdala (CeA). In the present study, we investigated whether a sustained overexpression of CRF in the CeA affects the dysphoric-like state associated with nicotine withdrawal. To study brain reward function, rats were prepared with intracranial self-stimulation (ICSS) electrodes in the medial forebrain bundle. An adeno-associated virus (AAV, pseudotype 2/5) was used to overexpress CRF or green fluorescent protein (GFP, control) in the CeA and minipumps were used to induce nicotine dependence. The AAV2/5-CRF vector induced a 40% increase in CRF protein and mRNA levels in the CeA. Administration of the nicotinic receptor antagonist mecamylamine (precipitated withdrawal) or nicotine pump removal (spontaneous withdrawal) led to elevations in ICSS thresholds. Elevations in ICSS thresholds are indicative of a dysphoric-like state. The overexpression of CRF did not affect baseline ICSS thresholds but diminished the elevations in ICSS thresholds associated with precipitated and spontaneous nicotine withdrawal. The real-time reverse transcriptase (RT)–PCR analysis showed that the overexpression of CRF led to a decrease in CRF1 mRNA levels and an increase in CRF2 mRNA levels in the CeA. In conclusion, the overexpression of CRF in the CeA diminishes the dysphoric-like state associated with nicotine withdrawal and this might be driven by neuroadaptive changes in CRF1 and CRF2 receptor gene expression.
doi:10.1038/tp.2014.25
PMCID: PMC4012288  PMID: 24755994
2.  Involvement of Src tyrosine kinase and protein kinase C in the expression of macrophage migration inhibitory factor induced by H2O2 in HL-1 mouse cardiac muscle cells 
Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but not angiotensin II, stimulated MIF expression in HL-1 cells. H2O2-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H2O2-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.
doi:10.1590/1414-431X20132936
PMCID: PMC3854426  PMID: 24036910
Macrophage migration inhibitory factor; HL-1 cells; Hydrogen peroxide; Atrial fibrillation; Protein kinases
3.  A cross-sectional survey of relationship between serum TSH level and blood pressure 
Liu, D | Jiang, F | Shan, Z | Wang, B | Wang, J | Lai, Y | Chen, Y | Li, M | Liu, H | Li, C | Xue, H | Li, N | Yu, J | Shi, L | Bai, X | Hou, X | Zhu, L | Lu, L | Wang, S | Xing, Q | Teng, W
Journal of Human Hypertension  2009;24(2):134-138.
It is still controversial whether subclinical hypothyroidism and euthyroidism affect blood pressure. The study aimed to explore the relationship between different levels of thyroid-stimulating hormone (TSH) and blood pressure in the participants with subclinical hypothyroidism and euthyroidism. A total of 1319 participants were administered a questionnaire survey, and their blood pressure, height and body weight measurements were taken. Blood samples were taken to test serum TSH. FT3 and FT4 were further examined if TSH was abnormal. Participants were divided into euthyroid group and subclinical hypothyroidism group. Euthyroid group was further divided into three groups: group A (TSH 0.3–0.99 mIU l−1), group B (TSH 1.0–1.9 mIU l−1) and group C (TSH 1.91–4.8 mIU l−1). Results showed that different levels of serum TSH had no relation with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The prevalence of hypertension in subclinical hypothyroidism group was significantly higher than euthyroid group in females (41.3 vs 25.6%, P<0.05). The risk of hypertension in subclinical hypothyroidism group was significantly higher than that in the euthyroid group after adjusted for age, gender, smoking status, HOMA-IR (homoeostasis model assessment of insulin resistance) and body mass index (odds ratio (OR)=1.753, 95% confidence interval (CI) 1.067–2.879, P=0.027). This association was stronger in females (OR=3.545, 95% CI 1.576–7.975, P=0.004), but there was no statistical significance in males. Within normal range of TSH, both SBP and DBP were similar among the three groups. The prevalence and risk of hypertension were also similar among the three groups. In conclusion, the prevalence of hypertension in subclinical hypothyroidism group was significantly higher than in euthyroid group in females. Change of TSH in normal range did not affect blood pressure.
doi:10.1038/jhh.2009.44
PMCID: PMC3011094  PMID: 19554027
TSH; subclinical hypothyroidism; blood pressure
4.  Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal 
Annals of the Rheumatic Diseases  2005;64(5):735-742.
Objective: To clarify the effect of interleukin (IL) 18 on cartilage degeneration by studying the profile of IL18 receptor (IL18R) on chondrocytes and the direct effect of IL18 on production of matrix metalloproteinases (MMPs), aggrecanases, and tissue inhibitors of metalloproteinases (TIMPs) in articular chondrocytes.
Methods: Monolayer cultured human articular chondrocytes were isolated from non-arthritic subjects and patients with rheumatoid arthritis or osteoarthritis. Gene expression of IL18, IL18Rα, IL18Rß, MMPs, and aggrecanases was detected by RT-PCR. Protein levels of IL18Rα were analysed by flow cytometry. Protein levels of IL18, MMPs, and TIMPs were measured by ELISA. Aggrecanase-2 mRNA expression was quantitatively analysed by real time RT-PCR. Protein levels of signalling molecules were assayed by western blotting.
Results: IL18 mRNA was constitutively expressed in chondrocytes, and was enhanced by IL1ß stimulation. Flow cytometric analysis showed that IL1ß, tumour necrosis factor α, and IL18 up regulated IL18Rα expression levels. The level of IL18Rß mRNA was much lower than that of IL18Rα, and was slightly up regulated by IL1ß. In chondrocytes responding to IL18, IL18 (1–100 ng/ml) slightly increased the production of MMP-1, MMP-3, and MMP-13, which was blocked by NF-κB inhibitor and p38 mitogen activated protein kinase inhibitor. IL18 up regulated mRNA expression of aggrecanase-2, but not aggrecanase-1. IL18 also slightly stimulated TIMP-1 production?through extracellular signal regulated kinase activation.
Conclusion: IL18 induces production of MMPs from chondrocytes in inflammatory arthritis. Although the direct effect of IL18 on chondrocytes may not be pivotal for the induction of cartilage degeneration, IL18 seems to play some part in the degradation of articular cartilage in arthritis.
doi:10.1136/ard.2004.026088
PMCID: PMC1755478  PMID: 15834055
5.  Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. 
Journal of Clinical Investigation  1993;92(3):1564-1571.
The potential involvement of reactive oxygen species in the expression of genes involved in immune response was examined in mesangial cells. Tumor necrosis factor (TNF-alpha) and aggregated (aggr.) IgG increased mRNA levels for the monocyte chemoattractant protein, JE/MCP-1, and the colony-stimulating factor, CSF-1. Scavengers for free radicals such as di- and tetra-methylthiourea (DMTU and TMTU) attenuated the increase in mRNA levels in response to TNF-alpha and aggr. IgG. Generation of superoxide anion by xanthine oxidase and hypoxanthine increased mRNA levels of these genes, but exogenous H2O2 did not. Addition of NADPH to activate a membrane-bound NADPH-oxidase generated superoxide and caused a dose-dependent increase in mRNA levels and further enhanced the stimulation by TNF-alpha or aggr. IgG. An inhibitor of NADPH-dependent oxidase 4'-hydroxy-3'-methoxy-acetophenone attenuated the rise in mRNA levels in response to TNF-alpha and aggr. IgG. By nuclear run-on experiments TNF-alpha, aggr. IgG and NADPH increased the transcription rates for JE/MCP-1 and CSF-1, effects inhibited by TMTU. We conclude that generation of reactive oxygen species, possibly by NADPH-dependent oxidase, are involved in the induction of the JE/MCP-1 and CSF-1 genes by TNF-alpha and IgG complexes. The concerted expression of leukocyte-directed cytokines represents a general response to tissue injury.
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PMCID: PMC288305  PMID: 8397228

Results 1-5 (5)