A 16.5-year-old Indian female presented with secondary amenorrhoea, cubitus valgus, scoliosis and multiple lentigines on the face. Karyotyping revealed mosaic Turner syndrome (TS) with 45, X/46, X iXq. She also had multiple café-au-lait macules and axillary freckles but no neurofibroma and did not fulfil the classic criteria for diagnosis of Neurofibromatosis-1(NF1). Many of her macules were smaller than 15 mm in diameter, which might be due to her hypoestrogenic state. However, exome-sequencing found a pathologic variant consistent with NF1. She was started on daily oral estrogen, and oral progesterone for 10 days every month with close monitoring for neurofibroma and/or glioma expansion. Co-occurrence of NF1 and TS is extremely rare, TS and NF1 can both affect growth and puberty, cause different cutaneous and skeletal deformities, hypertension, vasculopathy and learning disabilities. Our case highlights the need for genetic testing in some cases with NF1 who do not strictly fulfil the NIH diagnostic criteria. We also emphasize the need for close monitoring during therapy with growth hormone, estrogen and progesterone due to the potential risk of tumour expansion in NF1.
Turner syndrome ; Neurofibromatosis 1 ; NF-1

In the development of oxidative stress-relevant diseases, reactive oxygen species (ROS) removal obstacle or excess production results in the damage of the body tissues and organs. Recent studies have demonstrated that nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) axis played a significant role in anti-oxidative stress. The Nrf2/HO-1 axis counteracts oxidative stress injury by its resistance to inflammation, oxidation, mitochondrial damage and calcium influx, apoptosis, pyroptosis, ferroptosis and autophagy, which provides a theoretical basis for its therapeutic effect on various oxidative stress-relevant diseases in multiple organs (respiratory, cardiovascular, nervous, digestive, urinary and blood systems). Therefore, effective regulation of the Nrf2/HO-1 signal axis can be an important strategy for treatment of oxidative stress-relevant diseases.
Heme Oxygenase-1 ; NF-E2-Related Factor 2 ; Oxidative Stress ; Reactive Oxygen Species ; Signal Transduction

Mangostenone F (MF) is a natural xanthone isolated from Garcinia mangostana. However, little is known about the biological activities of MF. This study was designed to investigate the anti-inflammatory effect and underlying molecular mechanisms of MF in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. MF dose-dependently inhibited the production of NO, iNOS, and pro-inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) in LPS-stimulated RAW264.7 macrophages. Moreover, MF decreased the NF-kappaB luciferase activity and NF-kappaB DNA binding capacity in LPS-stimulated RAW264.7 macrophages. Furthermore, MF suppressed the NF-kappaB activation by inhibiting the degradation of IkappaBalpha and nuclear translocation of p65 subunit of NF-kappaB. In addition, MF attenuated the AP-1 luciferase activity and phosphorylation of ERK, JNK, and p38 MAP kinases. Taken together, these results suggest that the anti-inflammatory effect of MF is associated with the suppression of NO production and iNOS expression through the down-regulation of NF-kappaB activation and MAPK signaling pathway in LPS-stimulated RAW264.7 macrophages.
Cytokines ; DNA ; Down-Regulation ; Garcinia mangostana ; Interleukin-6 ; Luciferases ; Macrophages* ; NF-kappa B* ; Phosphorylation ; Phosphotransferases ; Transcription Factor AP-1

OBJECTIVETo investigate the function of tumor necrosis factor receptor-associated factor 1 (TRAF1) and CD30-TRAF1 signaling in Hodgkin's lymphoma.

METHODSEndogenous and CD30 ligand-induced TRAF1 expression at mRNA and protein levels were examined by quantitative RT-PCR and Western blot analyses, respectively. RNA interference was performed to silence the expression of TRAF1 in L428 cells and examine its effect on cell survival. ELISA-based NF-kappaB family transcription factor activity assay was performed to quantify the kappaB DNA-binding activity in nuclear extracts. The expression of JunB was measured by Western blot.

RESULTSTRAF1 expression was detected at both mRNA and protein levels in B cell-derived lymphoma cell lines (L428 and KM-H2). CD30 activation via binding to CD30 ligand induced the TRAF1 expression, the relative mRNA expression was increased to 7.26 +/- 0.23 from 3.50 +/- 0.20, the relative protein expression was increased to 4.53 +/- 0.55 from 2.31 +/- 0.35. The apoptosis rate was increased to (27.7 +/- 5.8)% in TRAF1-silenced L428 cells compared to (5.7 +/- 1.2)% in control cells. The p50 and RelA DNA-binding activity were decreased in TRAF1-silenced L428 cells. The expression of JunB upon CD30 ligand stimulation was not changed in TRAF1-silenced L428 cells.

CONCLUSIONSTRAF1 is overexpressed in B cell-derived Hodgkin's lymphoma cells, which is regulated by CD30 signaling pathway. TRAF1 is a crucial molecule mediating the activation of the classical NF-kappaB activity, which further facilitates the anti-apoptosis.

Apoptosis ; Cell Line, Tumor ; Hodgkin Disease ; Humans ; NF-kappa B ; metabolism ; Signal Transduction ; genetics ; TNF Receptor-Associated Factor 1

The present study aimed to explore the effect of nuclear factor erythroid 2 related factor 2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis(UC). After the UC model was induced by 3% dextran sodium sulfate(DSS), experimental animals were randomly divided into control group, model group, salazosulfapyridine(SASP) group, and low-and high-dose Sishen Pills groups. Drug intervention(ig) was performed for seven consecutive days during modeling. On the 7 th day, the mice were euthanized. The body weight and colon length were recorded, and the histopathological changes of the colon were observed by HE staining. Serum interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and reactive oxygen species(ROS) were detected by ELISA. The protein and mRNA expression of Nrf2, HO-1, and NADPH quinine oxidoreductase-1(NQO-1) was determined by Western blot and reverse transcription-polymerase chain reaction(RT-PCR). Compared with the normal group, the model group exhibited reduced body weight, colon length, and T-AOC, increased IL-6, TNF-α, MDA, and ROS, and diminished protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. Compared with the model group, the SASP group and high-dose Sishen Pills group showed elevated body weight, colon length, and T-AOC, lowered IL-6, TNF-α, MDA, and ROS levels, and increased protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. As assessed by HE staining, Sishen Pills could improve the pathological changes of the colon. The findings suggested that Sishen Pills could protect the colon against UC induced by 3% DSS. The specific mechanism of action may be related to the anti-inflammatory and anti-oxidative stress effects by the activation of the Nrf2/HO-1 signaling pathway.
Animals ; Colitis, Ulcerative/genetics* ; Dextran Sulfate ; Heme Oxygenase-1/metabolism* ; Mice ; NF-E2-Related Factor 2/metabolism* ; Signal Transduction

Objective: To investigate the impact and related mechanisms of glucose fluctuations on aortic fibrosis in rats with type 1 diabetes mellitus. Methods: After injection of streptozotocin (STZ), male Sprague Dawley (SD) (8-12 weeks) rats (n=24) were randomly divided into three groups in accordance with the random number table: controlled STZ-induced diabetes (C-STZ) group (n=8); uncontrolled STZ-induced diabetes (U-STZ) group (n=8); STZ-induced diabetes with glucose fluctuations (STZ-GF) group (n=8). After three weeks, rats were sacrificed and aorta was obtained, aortic fibrosis was detected by Masson trichrome staining. The expression of collagen type 1 (collagen Ⅰ) was tested by immunofluorescence. The expression of runt-related transcription factor 2 (Runx2) was tested by immunohistochemistry. The mRNA levels of collagen Ⅰ and Runx2 were detected by quantitative real-time PCR (qRT-PCR). The protein expressions of collagen Ⅰ, Runx2 and nuclear factor (NF)-κB were determined by Western blot. Primary rat aortic smooth muscle cells (VSMCs) were cultured in three conditions: normal glucose (NG), high glucose (HG) and glucose fluctuations (GF). Cells in GF group were incubated for 72 hours with glucose alternating between 5.5 and 25 mmol/L every 12 hours. TPCA-1, the inhibitor of NF-κB, the expression of collagenⅠin different groups of cells was tested by immunofluorescence. The protein expressions of collagen Ⅰ, Runx2 and NF-κB were also determined by Western blot. Results: (1) The quantitative ratios of the area of fibrosis in the C-STZ group, U-STZ group, STZ-GF group were (8.42±0.10)%, (21.30±0.74)% and (44.39±1.09)% (P<0.05), respectively. The means of integral optical density (IOD) of collagenⅠ in the three groups were 11.92±0.88, 50.04±3.56 and 77.52±2.69, respectively (P<0.05). The mRNA levels of collagenⅠ in the three groups were 1.00±0.10, 2.02±0.28 and 2.83±0.33, respectively (P<0.05). The protein expressions of collagenⅠ in the three groups were 1.05±0.03, 2.06±0.32 and 4.93±0.25, respectively (P<0.05). (2) The average IOD of Runx2 in the three groups were 150.00±7.35, 204.84±2.32 and 391.48±7.13, respectively (P<0.05). The mRNA levels of Runx2 in the three groups were 1.02±0.02, 1.27±0.04 and 2.18±0.12, respectively (P<0.05). The protein expressions of Runx2 in the three groups were 1.03±0.01, 2.34±0.36 and 4.52±0.75, respectively (P<0.05). (3) The protein expressions of NF-κB in the three groups were 1.02±0.01, 1.96±0.13 and 2.64±0.21, respectively (P<0.05). (4) In vitro, application of inhibitor of NF-κB reversed glucose fluctuations-induced upregulation of protein levels of Col Ⅰ and Runx2 (P<0.05). Conclusion: Glucose fluctuations could aggravate aortic fibrosis through activating Runx2 via NF-κB signaling pathways.
Animals ; Aorta ; Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 1 ; Fibrosis ; Glucose ; Male ; NF-kappa B ; Rats ; Rats, Sprague-Dawley

Nrf2 is the key transcription factor mainly for regulating oxidative homeostasis and cytoprotective responses against oxidative stress. Nrf2/Keap1 pathway is one of the most important cellular defense mechanisms against endogenous or exogenous oxidative stress. With its activation, a wide range of stress-related genes is transactivated to restore the cellular homeostasis. Recent studies revealed that the aberrant activation of Nrf2 is related to the malignant progression, chemotherapeutic drug resistance and poor prognosis. Nrf2 plays a crucial role in cancer malignancy and chemotherapeutic resistance by controlling the intracellular redox homeostasis through the activation of cytoprotective antioxidant genes. Nrf2 inhibitor containing many natural products has been deemed as a novel therapeutic strategy for human malignancies. This article reviews the progress of studies of the Nrf2/Keap1 pathway, and its biological impact in solid malignancies and molecular mechanisms for causing Nrf2 hyperactivation in cancer cells. In conclusion, we summarized the deve-lopment of Nrf2 inhibitors in recent years, in the expectation of providing reference for further drug development and clinical studies.
Humans ; Kelch-Like ECH-Associated Protein 1/metabolism* ; NF-E2-Related Factor 2/metabolism* ; Neoplasms/genetics* ; Oxidation-Reduction ; Oxidative Stress

This project aimed to explore the protective effect of ginsenoside Rg_1 on hypoxia/reoxygenation(H/R)-induced H9 c2 cardiomyocyte injury and its underlying signaling pathway. The H/R model of H9 c2 cardiomyocytes was established and then the cells were divided into different treatment groups. CCK-8(cell counting kit-8) was used to detect the activity of cardiomyocytes; Brdu assay was used to detect the proliferation of H9 c2 cells; the caspase-3 activity was tested, and then the protein expression was assessed by Western blot. Flow cytometry was used to evaluate the apoptosis level of cardiomyocytes. Ginsenoside Rg_1 inhibited H/R-induced cardiomyocyte apoptosis and caspase-3 activity, promoted nuclear transcription of nuclear factor erythroid-2 related factor 2(Nrf2), and enhanced the expression of the downstream heme oxygenase-1(HO-1). Ginsenoside Rg_1 could increase Nrf2 nuclear transcription and HO-1 expression with the increase of concentration(10, 20, 40, 60 μmol·L~(-1)). However, the protective effect of ginsenoside Rg_1 on cardiomyocytes was significantly weakened after the transfection of Nrf2-siRNA. Ginsenoside Rg_1 could protect cardiomyocytes by activating the Nrf2/HO-1 pathway.
Apoptosis ; Ginsenosides/pharmacology* ; Heme Oxygenase-1/genetics* ; Humans ; Hypoxia ; Myocytes, Cardiac ; NF-E2-Related Factor 2/genetics*

The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. Male Crj:CD1 (ICR) mice were divided into 6 treatment groups; 1) control, 2) Aβ control, 3) Aβ + NA 20 mg/kg/day (NA20), 4) Aβ + NA40, 5) Aβ + NAM 200 mg/kg/day (NAM200), and 6) Aβ + NAM400. After 1-week acclimation period, the mice orally received NA or NAM once a day for a total of 7 successive days. On day 7, biotinylated Aβ42 was injected into mouse tail vein. At 5 hours after the injection, blood and tissues were collected. Aβ42 injection was confirmed by Western blot analysis of Aβ42 protein in brain tissue. NAM400 pre-treatment significantly reduced the gene expression of amyloid precursor protein and presenilin 1 in brain tissues. And, NAM200 and NAM400 pre-treatments significantly increased sirtuin 1 expression in brain tissues, which is accompanied by the decreased brain expression of nuclear factor kappa B by 2 doses of NAM. Increased expression of AD-related genes was attenuated by the NAM treatment, which suggests that NAM supplementation may be a potential preventive strategy against AD-related deleterious changes.
Acclimatization ; Aging ; Alzheimer Disease ; Amyloid* ; Animals ; Blotting, Western ; Brain* ; Gene Expression ; Humans ; Male ; Mice* ; NF-kappa B ; Niacin ; Niacinamide* ; Presenilin-1* ; Presenilins* ; Sirtuin 1 ; Tail ; Veins*

OBJECTIVETo investigate the influence of carbon monoxide on the expression of adhesion molecules stimulated by inflammatory cytokines on human gingival fibroblasts.

METHODSHuman gingival fibroblasts were stimulated with 50 ng x mL(-1) tumor necrosis factor (TNF)-alpha and 10 ng x mL(-1) interleukin (IL)-1beta concurrently in the presence or absence of 500 micromol x L(-1) carbon monoxide releasing molecule (CORM). Expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 at protein and mRNA level was examined by Western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively. Activity of transcription factor NF-kappaB was evaluated by reporter gene assay.

RESULTSExpression of ICAM-1 and VCAM-1 on human gingival fibroblasts increased dramatically after concurrent stimulation of TNF-alpha and IL-1beta, while CORM inhibited the upregulation of ICAM-1 and VCAM-1. CORM decreased the activity of NF-KB stimulated by TNF-alpha and IL-1beta.

CONCLUSIONCarbon monoxide could be a promising way in treating of periodontitis.

Carbon Monoxide ; Cells, Cultured ; Fibroblasts ; Gingiva ; Humans ; Intercellular Adhesion Molecule-1 ; Interleukin-1beta ; NF-kappa B ; RNA, Messenger ; Tumor Necrosis Factor-alpha ; Vascular Cell Adhesion Molecule-1