Curcumin induces expression of 15-hydroxyprostaglandin dehydrogenase in gastric mucosal cells and mouse stomach in vivo: AP-1 as a potential target

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the conversion of oncogenic prostaglandin E-2 to non-tumerigenic 15-keto prostaglandin E-2. In the present study, we found that curcumin, a yellow coloring agent present in the rhizome of Curcuma Tonga Linn (Zingiberaceae), induced expression of 15-PGDH at the both transcriptional and translational levels in normal rat gastric mucosal cells. By using deletion constructs of 15-PGDH promoter, we were able to demonstrate that activator protein-1 (AP-1) is the principal transcription factor responsible for regulating curcumin-induced 15-PGDH expression. Curcumin enhanced the expression of c-jun and cFos that are functional subunits of AP-1, in the nuclear fraction of cells. Silencing of c-jun suppressed curcumin-induced expression of 15-PGDH. Moreover, the chromatin immunoprecipitation assay revealed curcumin-induced binding of c-Jun to the AP-1 consensus sequence present in the 15-PGDH promoter. Curaimin increased phosphorylation of ERK1/2 and JNK. and pharmacologic inhibition of these kinases abrogated the curcumin-induced phosphorylation of clun and 15-PGDH expression. In contrast, tetrahydrocurcumin which lacks the alpha,beta-unsaturated carbonyl group failed to induce 15-PGDH expression, suggesting that the electrophilic carbonyl group of curcumin is essential for its induction of 15-PGDH expression. Curcumin restored the expression of 15-PGDH which is down-regulated by Helicobater pylori through suppression of DNA methyltransferase 1. In addition, oral administration of curcumin increased the expression of 15-PGDH and its regulators such as p-ERK1/2, p-JNK and c-Jun in the mouse stomach. Taken together, these findings suggest that curcumin-induced upregulation of 15-PGDH may contribute to chemopreventive effects of this phytochemical on inflammation-associated gastric carcinogenesis. (C) 2020 Elsevier Inc. All rights reserved.

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.

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.

Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification

The present study was aimed to investigate the effects of curcumin, a representative chemopreventive phytochemical with pronounced antioxidant and anti-inflammatory properties, on activation of Nrf2 and expression of its target protein heme oxygenase-1 (HO-1) in mouse skin in vivo and in cultured murine epidermal cells. Treatment of mouse epidermal JB6 cells with curcumin resulted in the induction of HO-1 expression, and this was abrogated in cells transiently transfected with Nrf2 siRNA. While curcumin treatment increased protein expression of Nrf2, it did not alter the steady-state level of the Nrf2 mRNA transcript. Treatment of cells with curcumin stabilized Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of this transcription factor. Tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the alpha,beta-unsaturated carbonyl group, failed to induce HO-1 expression as well as nuclear translocation of Nrf2 and its binding to the antioxidant/electrophile response elements. Cells transfected with a mutant Keap1 protein in which cysteine 151 (Cys151) is replaced by serine exhibited marked reduction in curcumin-induced Nrf2 transactivation. Mass spectrometric analysis revealed that curcumin binds to Keap1 Cys151, supporting that this amino acid is a critical target for curcumin modification of Keap1, which facilitates the liberation of Nrf2. Thus, it is likely that the alpha,beta-unsaturated carbonyl moiety of curcumin is essential for its binding to Keap1 and stabilization of Nrf2 by hampering ubiquitination and proteasomal degradation.

A girl with sternal malformation/vascular dysplasia association

Sternal malformation/vascular dysplasia association is a rare congenital dysmorphology, which has not yet been reported in Korea. Its typical clinical features include a sternal cleft covered with atrophic skin, a median abdominal raphe extending from the sternal defect to the umbilicus, and cutaneous craniofacial hemangiomata. We report a case of a full-term newborn who presented with no anomalies at birth, except for a skin defect over the sternum and a supraumbilical raphe. Multiple hemangiomas appeared subsequently on her chin and upper chest wall, and respiratory distress due to subglottic hemangioma developed during the first 2 months of life. Her symptoms were controlled with oral prednisolone administration. No respiratory distress have recurred during the 3-year follow-up period

Extensive Emphysematous Pyelonephritis in a Nondiabetic Female Cat - Treatment with Unilateral Nephroureterectomy

Background: Emphysematous pyelonephritis (EPN) is an acute, severe necrotizing infection of the renal parenchyma and surrounding tissues that results in gas formation in the kidney, collecting system, or surroundings. EPN is a rare condition in veterinary medicine and occurs most frequently in dogs with diabetes mellitus. Although the prognosis of medical management in animals is poor, the standardized treatment protocol according to EPN severity is unclear. This report describes the first case of a nondiabetic female cat with extensive EPN and good prognosis following direct nephroureterectomy (NU). Case: A 10-year-old spayed female cat presented with the chief complaint of an acute loss of weight within 1 week, vomiting, and disorientation including stumbling, discoordination, circling, wobbling, head tilting, and difficulties in standing. At presentation, the patient had a body condition score of 1/9 and weighed 2.6 kg. Blood examination revealed leukocytosis, anemia, and hypoproteinemia. Abdominal radiography revealed severely decreased serosal details. A massive gas silhouette observed in the peritoneal and retroperitoneal cavities, was diagnosed as abdominal free gas. Abdominal ultrasound showed an accumulation of moderately anechoic fluid mixed with gas and cyst-like capsules around the left kidney. Left partial ureteral obstruction and dilation were also observed. Computed tomography (CT) was performed without sedatives or anesthetic drugs. The findings showed severe inflammatory changes in the peritoneum and a loss of the normal inner structure in the left kidney. A pyelogram of the left kidney was not observed after injection of the contrast material. Diffuse fat stranding and free gas observed in the mesentery of the entire abdominal cavity and around the left kidney were considered septic peritonitis. Urinalysis revealed proteinuria and hematuria. Numerous neutrophils with rod-type bacteria were observed in the ascites. Following diagnostic examinations, the patient was diagnosed with extensive left EPN, including inflammatory ascites and abdominal free gas. Therefore, emergency NU of the nonfunctional left kidney and ruptured ureter and thorough abdominal lavage were conducted. Diffuse inflammation and a nephrolith were observed in the section of the harvested kidney. The nephrolith was composed of 100% calcium oxalate monohydrate. The real-time polymerase chain reaction (RT-PCR) test for feline infectious peritonitis (FIP) was negative. Escherichia coli was detected in the ascites, and antibiotic therapy was administered following the antibiotic sensitivity test. The histological findings from the left kidney and ureter included marked chronic inflammation and fibrosis. The patient was discharged 4 days after surgery. During the 8-month follow-up period, the patient’s condition improved. Discussion: This was a unique case of EPN in a nondiabetic cat and the first reported case of EPN with a ruptured ureter, including abdominal free gas, inflammatory ascites, and peritonitis. This patient had a bacterial urinary tract infection with E. coli, which is the most frequently isolated pathogen in humans. This gas-forming bacteria produced a massive amount of gas and inflammation that were considered to have ruptured the urinary tract, so that the gas was released into the abdomen. This case corresponded to class 3B, with two risk factors according to the human EPN classification system. Direct NU and abdominal lavage were performed as emergency surgeries. The patient stabilized gradually and showed a good prognosis. Immediate surgical intervention is recommended in animal patients showing the extensive EPN stage. Keywords: kidney, nephroureterectomy, emphysematous pyelonephritis, peritonitis, cat, E. coli.

Anti-Obesity Effects of Morus alba L. and Aronia melanocarpa in a High-Fat Diet-Induced Obese C57BL/6J Mouse Model

The present study investigated the synergic effect of extracts of Morus alba (MA) and Aronia melanocarpa (Michx.) (AR) against high-fat diet induced obesity. Four-week-old male C57BL/6J mice were randomly divided into five groups that were fed for 14 weeks with a normal diet (ND), high-fat diet (HD), HD with M. alba 400 mg/kg body weight (MA), HD with A. melanocarpa 400 mg/kg body weight (AR), or HD with a mixture (1:1, v/v) of M. alba and A. melanocarpa (400 mg/kg) (MA + AR). Treatment with MA, AR, and MA + AR for 14 weeks reduced high fat diet-induced weight gain and improved serum lipid levels, and histological analysis revealed that MA and AR treatment markedly decreased lipid accumulation in the liver and adipocyte size in epididymal fat. Furthermore, micro-CT images showed MA + AR significantly reduced abdominal fat volume. Expression levels of genes involved in lipid anabolism, such as SREBP-1c, PPAR-gamma, CEBP alpha, FAS, and CD36 were decreased by MA + AR treatment whereas PPAR-alpha, ACOX1, and CPT-1a levels were increased by MA + AR treatment. Protein expression of p-AMPK and p-ACC were increased in the MA + AR group, indicating that MA + AR ameliorated obesity by upregulating AMPK signaling. Together, our findings indicate that MA and AR exert a synergistic effect against diet-induced obesity and are promising agents for managing obesity

17-Oxo-docosahexaenoic acid induces Nrf2-mediated expression of heme oxygenase-1 in mouse skin in vivo and in cultured murine epidermal cells

Recently, growing attention has been given to new classes of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), especially in the context of their role as endogenous signal modulators. One such molecule is 17-oxo-DHA, generated from DHA by the action of COX2 and a dehydrogenase. The redox-sensitive transcription factor, Nrf2 plays a key role in cellular stress responses. In the present study, the effects of 17-oxo-DHA on Nrf2-mediated expression of cytoprotective enzymes were examined in mouse skin in vivo and cultured murine epidermal JB6 cells. Topical application of 17-oxo-DHA markedly elevated the nuclear localization of Nrf2 and expression of heme oxygenase-1 (HO-1) and NAD(P) H:quinone oxidoreductase-1 in hairless mouse skin. In contrast to 17-oxo-DHA, the non-electrophilic metabolic precursor 17-hydroxy-DHA was a much weaker inducer of Nrf2 activation and its target protein expression. Likewise, 17-oxo-DHA significantly enhanced nuclear translocation and transcriptional activity of Nrf2 with concomitant upregulation of HO-1 expression in cultured JB6 cells. 17-Oxo-DHA was a much stronger inducer of Nrf2-mediated antioxidant response than its parent molecule, DHA. HO-1 expression was abolished in Nrf2 knockdown JB6 cells or embryo fibroblasts from Nrf2 knock out mice. 17-Oxo-DHA also markedly reduced the level of Keap1 protein by inducing ubiquitination. Mutation of Cys151 and Cys273 in Keap1 abrogated 17-oxo-DHA-induced ubiquitination and proteasome-mediated degradation of Keap1 as well as HO-1 expression, suggesting that these cysteine residues are putative sites for 17-oxo-DHA binding. Further, Keap1 degradation stimulated by 17-oxo-DHA coincided with accumulation of the autophagy substrate, p62/SQSTM1.

Linguistic, visuospatial, and kinematic writing characteristics in cognitively impaired patients with beta-amyloid deposition

IntroductionBeta-amyloid (Aβ) deposition, a hallmark of Alzheimer’s disease (AD), begins before dementia and is an important factor in mild cognitive impairment (MCI). Aβ deposition is a recognized risk factor for various cognitive impairments and has been reported to affect motor performance as well. This study aimed to identify the linguistic, visuospatial, and kinematic characteristics evident in the writing performance of patients with cognitive impairment (CI) who exhibit Aβ deposition.MethodsA total of 31 patients diagnosed with amnestic mild cognitive impairment (aMCI) with Aβ deposition, 26 patients with Alzheimer’s-type dementia, and 33 healthy control (HC) participants without deposition were administered tasks involving dictation of 60 regular words, irregular words, and non-words consisting of 1–4 syllables. Responses from all participants were collected and analyzed through digitized writing tests and analysis tools.ResultsIn terms of linguistic aspects, as cognitive decline progressed, performance in the dictation of irregular words decreased, with errors observed in substituting the target grapheme with other graphemes. The aMCI group frequently exhibited corrective aspects involving letter rewriting during the task. In terms of visuospatial aspects, the AD group displayed more errors in grapheme combination compared to the HC group. Lastly, in the kinematic aspects, both the aMCI group and the AD group exhibited slower writing speeds compared to the HC group.DiscussionThe findings suggest that individuals in the CI group exhibited lower performance in word dictation tasks than those in the HC group, and these results possibly indicate complex cognitive-language-motor deficits resulting from temporal-parietal lobe damage, particularly affecting spelling processing. These results provide valuable clinical insights into understanding linguistic-visuospatial-kinematic aspects that contribute to the early diagnosis of CI with Aβ deposition