Technical note time-variable gravity field from the combination of hlsst and slr

The Earth’s time-variable gravity field is of great significance to study mass change within the Earth’s system. Since 2002, the NASA-DLR Gravity Recovery and Climate Experiment (GRACE) and its successor GRACE follow-on mission provide observations of monthly changes in the Earth gravity field with unprecedented accuracy and resolution by employing low-low satellite-to-satellite tracking (LLSST) measurements. In addition to LLSST, monthly gravity field models can be acquired from satellite laser ranging (SLR) and high-low satellite-to-satellite tracking (HLSST). The monthly gravity field solutions HLSST+SLR were derived by combining HLSST observations of low earth orbiting (LEO) satellites with SLR observations of geodetic satellites. Bandpass filtering was applied to the harmonic coefficients of HLSST+SLR solutions to reduce noise. In this study, we analyzed the performance of the monthly HLSST+SLR solutions in the spectral and spatial domains. The results show that: (1) the accuracies of HLSST+SLR solutions are comparable to those from GRACE for coefficients below degree 10, and significantly improved compared to those of SLR-only and HLSST-only solutions; (2) the effective spatial resolution could reach 1000 km, corresponding to the spherical harmonic coefficient degree 20, which is higher than that of the HLSST-only solutions. Compared with the GRACE solutions, the global mass redistribution features and magnitudes can be well identified from HLSST+SLR solutions at the spatial resolution of 1000 km, although with much noise. In the applications of regional mass recovery, the seasonal variations over the Amazon Basin and the long-term trend over Greenland derived from HLSST+SLR solutions truncated to degree 20 agree well with those from GRACE solutions without truncation, and the RMS of mass variations is 282 Gt over the Amazon Basin and 192 Gt in Greenland. We conclude that HLSST+SLR can be an alternative option to estimate temporal changes in the Earth gravity field, although with far less spatial resolution and lower accuracy than that offered by GRACE. This approach can monitor the large-scale mass transport during the data gaps between the GRACE and the GRACE follow-on missions. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

15-Keto prostaglandin E2 induces heme oxygenase-1 expression through activation of Nrf2 in human colon epithelial CCD 841 CoN cells

Prostaglandin E-2 (PGE(2)) plays a key role in inflammation-associated carcinogenesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of PGE(2) to generate 15-keto PGE(2). 15-PGDH has been known as a tumor suppressor in various malignancies including colon cancer. However, the molecular mechanisms underlying the tumor-suppressive function of 15-PGDH remain largely unresolved. In this study, we found that 15-keto PGE(2) upregulated the expression of heme oxygenase-1 (HO-1), a representative antioxidative and anti-inflammatory enzyme, at both transcriptional and translational levels, in human colon epithelial CCD 841 CoN cells. A redox-sensitive transcription factor, NF-E2-related factor (Nrf2) plays a critical role in the regulation of HO-1 and other cytoprotective proteins. 15-Keto PGE(2) induced translocation of Nrf2 into the nucleus and antioxidant response element-driven luciferase activity. Furthermore, the silencing of the Nrf2 gene abolished 15-keto PGE(2)-induced HO-1 expression in CCD 841 CoN cells. 15-Keto PGE(2) activated AKT signaling, and the pharmacological AKT inhibitor, LY294002 suppressed the 15-keto PGE(2)-induced HO-1 expression. 15-Keto PGE(2) generates the reactive oxygen species which is suppressed by the general antioxidant N-acetyl-L-cysteine. N-acetyl-L-cysteine treatment attenuated the 15-keto PGE(2)-induced phosphorylation of GSK3 beta, transcriptional activity of Nrf2, and subsequently HO-1 expression. However, 13,14-dihydro-15-keto PGE(2) lacking the alpha,beta-unsaturated carbonyl moiety failed to induce intracellular production of reactive oxygen species, HO-1 expression and nuclear translocation of Nrf2. In conclusion, 15-keto PGE(2) induces HO-1 expression through Nrf2 activation in human colon epithelial cells.

Preventive effects of Korean red ginseng on experimentally induced colitis and colon carcinogenesis

© 2020 Center for Food and Biomolecules, National Taiwan UniversityKorean Red Ginseng (KRG) exerts chemopreventive effects on experimentally induced carcinogenesis through multiple mechanisms. In this study, we investigated effects of KRG on dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colon carcinogenesis in mice. Male C57BL/6J mice were fed diet containing 1% KRG or a standard diet throughout the experiment. The mouse colitis was induced by administration of 3% DSS in drinking water for 1 week. DSS caused body weight loss, diarrhea, rectal bleeding and colon length shortening, and all these symptoms were ameliorated by KRG treatment. KRG inhibited DSS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by suppressing activation of nuclear factor-kappa B (NF-κB) and signal transducer and activation of transcription 3 (STAT3). In another experiment, colon carcinogenesis was initiated by single intraperitoneal injection of AOM (10 mg/kg) and promoted by 2% DSS in drinking water. KRG administration relieved the symptoms of colitis and reduced the incidence, the multiplicity and the size of colon tumor. The up-regulation of COX-2, iNOS, c-Myc and Cyclin D1 by AOM plus DSS was attenuated in KRG fed mice which was associated with suppression of NF-κB and STAT3 activation. These results suggest that KRG is a potential candidate for chemoprevention of inflammation-associated cancer in the colon.

Breast cancer cell debris diminishes therapeutic efficacy through heme oxygenase-1-mediated inactivation of M1-like tumor-associated macrophages

Chemotherapy is commonly used as a major therapeutic option for breast cancer treatment, but its efficacy is often diminished by disruption of patient's anti-tumor immunity. Chemotherapy-generated tumor cell debris could hijack accumulated tumor-associated macrophages (TAMs), provoking tumor recurrence. Therefore, reprogramming TAMs to acquire an immunocompetent phenotype is a promising strategy to potentiate therapeutic efficacy. In this study, we analyzed the proportion of immune cells in the breast cancer patients who received chemotherapy. To validate our findings in vivo, we used a syngeneic murine breast cancer (4T1) model. Chemotherapy generates an immunosuppressive tumor microenvironment in breast cancer. Here, we show that phagocytic engulfment of tumor cell debris by TAMs reduces chemotherapeutic efficacy in a 4T1 breast cancer model. Specifically, the engulfment of tumor cell debris by macrophages reduced M1-like polarization through heme oxygenase-1 (HO-1) upregulation. Conversely, genetic or pharmacologic inhibition of HO-1 in TAMs restored the M1-like polarization. Our results demonstrate that tumor cell debris-induced HO-1 expression in macrophages regulates their polarization. Inhibition of HO-1 overexpression in TAMs may provoke a robust anti-tumor immune response, thereby potentiating the efficacy of chemotherapy.

Perilla frutescens Extracts Protects against Dextran Sulfate Sodium-Induced Murine Colitis: NF-κB, STAT3, and Nrf2 as Putative Targets

Perilla frutescens is a culinary and medicinal herb which has a strong anti-inflammatory and antioxidative effects. In the present study, we investigated the effects of Perilla frutescens extract (PE) against dextran sulfate sodium (DSS)-induced mouse colitis, an animal model that mimics human inflammatory bowel disease (IBD). Five-week-old male ICR mice were treated with a daily dose of PE (20 or 100 mg/kg, p.o.) for 1 week, followed by administration of 3% DSS in double distilled drinking water and PE by gavage for another week. DSS-induced colitis was characterized by body weight loss, colon length shortening, diarrhea and bloody stool, and these symptoms were significantly ameliorated by PE treatment. PE administration suppressed DSS-induced expression of proinflammatory enzymes, including cyclooxygenase-2 and inducible nitric oxide synthase as well as cyclin D1, in a dose-dependent fashion. Nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) are major transcriptional regulators of inflammatory signaling. PE administration significantly inhibited the activation of both NF-κB and STAT3 induced by DSS, while it elevated the accumulation of Nrf2 and heme oxygenase-1 in the colon. In another experiment, treatment of CCD841CoN human normal colon epithelial cells with PE (10 mg/ml) resulted in the attenuation of the tumor necrosis factor-α-induced expression/activation of mediators of proinflammatory signaling. The above results indicate that PE has a preventive potential for use in the management of IBD

RvD1 inhibits TNFα-induced c-Myc expression in normal intestinal epithelial cells and destabilizes hyper-expressed c-Myc in colon cancer cells

Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, are persistent disorders that lead to development of colitis-associated cancer (CAC). Facilitated resolution of colitis has been addressed as a novel therapeutic strategy to control development of CAC. Resolvin D1 (RvD1) is an endogenous lipid mediator that is generated from docosahexaenoic acid during the resolution of inflammation. Although the pro-resolving effects of RvDs have been extensively investigated and well defined, the role for RvD1 in CAC remains largely unknown. In this study, we found that RvD1 inhibited the expression of c-Myc in normal colon cells stimulated with tumor necrosis factor-alpha (TNF alpha) and also in colon cancer cells. The suppression of TNF alpha-induced upregulation of c-Myc in normal cells was mediated through attenuation of NF-kappa B signaling. Notably, RvD1 destabilized the constitutively overexpressed cMyc protein in HCT 116 human colon cancer cells by stimulating its ubiquitination and subsequent proteasomal degradation. Further, we revealed that RvD1 stimulated c-Myc degradation through direct interaction with the AIX/FPR2 receptor. This interaction resulted in inhibition of activation of extracellular signal regulated kinase, thereby attenuating phosphorylation-dependent stabilization of c-Myc. (C) 2018 Elsevier Inc. All rights reserved

15-Deoxy-△12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis

Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ(2) on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ(2) on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ(2) hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ(2) accelerated the resolution of experimentally induced colitis. 15d-PGJ(2) treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ(2) treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ(2), endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.

Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation

A key event required for effective resolution of inflammation is efferocytosis, which is defined as phagocytic removal of apoptotic cells mostly by macrophages acquiring an alternatively activated phenotype (M2). c-Myc has been reported to play a role in alternative activation of human macrophages and is proposed as one of the M2 macrophage markers. We found that M2-like peritoneal macrophages from zymosan A-treated mice exhibited a marked accumulation of Myc-nick, a truncated protein generated by a Calpain-mediated proteolytic cleavage of full-length c-Myc. Further, ectopic expression of Myc-nick in murine bone marrow-derived macrophages promoted the M2 polarization and, consequently, enhanced their efferocytic capability. Notably, Myc-nick-induced efferocytosis was found to be tightly associated with -tubulin acetylation by K acetyltransferase 2a (Kat2a/Gcn5) activity. These findings suggest Myc-nick as a novel proresolving mediator that has a fundamental function in maintaining homeostasis under inflammatory conditions.Zhong, X., Lee, H.-N., Kim, S. H., Park, S.-A., Kim, W., Cha, Y.-N., Surh, Y.-J. Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation

Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced Treg differentiation via up-regulating Nr4a2

Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. While SRC1 inhibits the differentiation of regulatory T cells (Tregs) critical for establishing immune tolerance, we show here that SRC2 stimulates Treg differentiation. SRC2 is dispensable for the development of thymic Tregs, whereas naive CD4+ T cells from mice deficient of SRC2 specific in Tregs (SRC2fl/fl/Foxp3YFP-Cre) display defective Treg differentiation. Furthermore, the aged SRC2fl/fl/Foxp3YFP-Cre mice spontaneously develop autoimmune phenotypes including enlarged spleen and lung inflammation infiltrated with IFNγ-producing CD4+ T cells. SRC2fl/fl/Foxp3YFP-Cre mice also develop severer experimental autoimmune encephalomyelitis (EAE) due to reduced Tregs. Mechanically, SRC2 recruited by NFAT1 binds to the promoter and activates the expression of Nr4a2, which then stimulates Foxp3 expression to promote Treg differentiation. Members of SRC family coactivators thus play distinct roles in Treg differentiation and are potential drug targets for controlling immune tolerance

Baicalein Inhibits Dextran Sulfate Sodium-induced Mouse Colitis

Background: Baicalein is a bioactive flavone that is originally extracted from the root of Scutellaria baicalensis Georgi. This plant has long served as Chinese herbal medicine in the management of multiple diseases including inflammatory bowel diseases. Although it has been revealed that baicalein inhibits experimental colitis in mice, the molecular mechanisms still remain largely unrecognized. Methods: The experimental colitis was induced in mice by 3% dextran sulfate sodium (DSS) in drinking water. The mice were given baicalein (10 or 25 mg/kg) by gavage for 7 days before and after DSS administration. Expression of COX-2 and inducible nitric oxide synthase (iNOS) and molecules involved in NF-kappa B signaling, such as inhibitor of kappa B alpha (I kappa B alpha), pI kappa B alpha, p65, and phospho-p65 was examined by Western blot analysis in the tissue of the mouse colon. Activity of I kappa B kinase beta (IKK beta) was assessed by measuring the relative amount of radioactive gamma-phosphate of ATP transferred to the I kappa B alpha substrate protein. The expression and phosphorylation of STAT3 and its target gene cyclin D1 were also measured. Results: Baicalein prominently mitigated the severity of DSS-induced colitis in mice. It inhibited the expression of COX-2 and iNOS. Moreover, baicalein attenuated activity and phosphorylation of IKK beta and subsequent degradation of I kappa B alpha. Baicalein suppressed the phosphorylation and nuclear translocation of p65, resulting in a reduced DNA binding activity of NF-kappa B. Baicalein also suppressed the phosphorylation of STAT3 and expression of cyclin D1. Baicalein exhibited the synergistic effect on inhibition of COX-2 induced by DSS with curcumin, an ingredient of turmeric. Conclusions: Protective effects of baicalein on DSS-induced colitis are associated with suppression of NF-kappa B and STAT3 signaling pathways, which may contribute to its cancer preventive effects on colon carcinogenesis