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Ellagic acid induces apoptosis through inhibition of nuclear factor κB in pancreatic cancer cells

World Journal of Gastroenterology 2008年第23期14卷 3672-3680页

作者： Mouad Edderkaoui Irina Odinokova Izumi Ohno Ilya Gukovsky Vay Liang W Go Stephen J Pandol Anna S Gukovskaya Department of Medicine Veterans Affairs Greater Los Angeles Healthcare System and University of CaliforniaLos Angeles CA 90073CaliforniaUnited States Institute of Theoretical and Experimental Biophysics Russian Academy of SciencesPushchinoMoscow Region 142290Russia

AIM： To determine the effect of ellagic acid on apoptosis and proliferation in pancreatic cancer cells and to determine the mechanism of the pro-survival effects of ellagic acid.METHODS： The effect of ellagic acid on apoptosis was assessed by measuring Phosphatidylserine externalization, caspase activity, mitochondrial membrane potential and DNA fragmentation; and proliferation by measuring DNA thymidine incorporation. Mitochondrial membrane potential was measured in permeabilized cells, and in isolated mitochondria. Nuclear factor κB （NF-κB） activity was measured by electromobility shift assay （EMSA）. RESULTS： We show that ellagic acid, a polyphenolic compound in fruits and berries, at concentrations 10 to 50 mmol/L stimulates apoptosis in human pancreatic adenocarcinoma cells. Further, ellagic acid decreases proliferation by up to 20-fold at 50 mmol/L. Ellagic acid stimulates the mitochondrial pathway of apoptosis associated with mitochondrial depolarization, cytochrome C release, and the downstream caspase activation. Ellagic acid does not directly affect mitochondria. Ellagic acid dose-dependently decreased NF-κB binding activity. Furthermore, inhibition of NF-κB activity using IkB wild type plasmid prevented the effect of ellagic acid on apoptosis. CONCLUSION： Our data indicate that ellagic acid stimulates apoptosis through inhibition of the prosurvival transcription factor NF-κB.

关键词： Ellagic acid Nuclear factor-κB Apoptosis Pancreatic cancer

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Design and strategy for manufacturing kidney organoids

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Bio-Design and Manufacturing 2020年第1期3卷 7-14页

作者： Masaki Nishikawa Yasuyuki Sakai Norimoto Yanagawa Department of Chemical system Engineering School of EngineeringUniversity of TokyoRm.5A01Engineering Bldg.3Hongo 7‑3‑1BunkyoTokyo 113‑8656Japan Medical and Research Services Greater Los Angeles Veterans Affairs Healthcare System at SepulvedaNorth HillsCAUSA David Geffen School of Medicine University of California at Los AngelesLos AngelesCAUSA

Despite a continuing increase in the number of patients suffering from chronic kidney disease,currently available treatments for these patients,such as dialysis and kidney transplantation,are *** kidney is also a critical target organ vulnerable to the toxicity of various new drugs,and the lack of a reliable in vitro culture model imposes a severe limitation on drug *** the development of induced pluripotent stem cells(iPSCs)revolutionized strategies in biomedical fields,the complexity of the kidney imposed additional challenge to the application of this technology in kidney ***,the recent advancement in our understanding on the developmental origin of kidney progenitor cells and the mechanisms of their reciprocal induction and self-organization has boosted research in kidney *** since then has demonstrated that kidney organoids derived from iPSCs can serve as a useful model for drug discovery and toxicity screening,as well as for disease modeling,especially in combination with gene editing ***,attempts at kidney organoid implantation in animals have suggested their potential as an alternative source of kidney *** this review,we summarize recent progress on the generation of kidney organoids,as well as the obstacles that remain.

关键词： Kidney organoid Kidney development iPSC Progenitor cell Self-organization Regenerative medicine

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Distinguishing normal brain aging from the development of Alzheimer＇s disease：inflammation,insulin signaling and cognition

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Neural Regeneration Research 2018年第10期13卷 1719-1730页

作者： Paul Denver Paula L.McClean greater los angeles veterans Affairs healthcare system West Los Angeles Medical Center and Department of NeurologyUniversity of CaliforniaLos AngelesCAUSA Centre for Molecular Biosciences University of UlsterColeraine Northern Ireland UK Northern Ireland Centre for Stratified Medicine ClinicalTranslational and Research Innovation Centre (C-TRIC)University of UlsterDerry/Londonderry Northern Ireland UK

As populations age, prevalence of Alzheimer＇s disease（AD） is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

关键词： Alzheimer's disease aging inflammation cognitive function spatial learning insulin signaling synapses cytokines

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Cultured circulating tumor cells and their derived xenografts for personalized oncology

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Asian Journal of Urology 2016年第4期3卷 240-253页

作者： Ruoxiang Wang Gina CYChu Stefan Mrdenovic Alagappan A.Annamalai Andrew E.Hendifar Nicholas N.Nissen James S.Tomlinson Michael Lewis Nallasivam Palanisamy Hsian-Rong Tseng Edwin M.Posadas Michael R.Freeman Stephen J.Pandol Haiyen E.Zhau Leland W.K.Chung Uro-Oncology Research Department of MedicineSamuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCAUSA Uro-Oncology Research Department of SurgerySamuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCAUSA Department of Surgery West Los Angeles VA HospitalGreater Los Angeles Veterans Affairs Healthcare SystemLos AngelesCAUSA Department of Pathology West Los Angeles VA HospitalGreater Los Angeles Veterans Affairs Healthcare SystemLos AngelesCAUSA Henry Ford Health system DetroitMIUSA Department of Molecular and Medical Pharmacology University of California Los AngelesLos AngelesCAUSA

Recent cancer research has demonstrated the existence of circulating tumor cells(CTCs)in cancer patient’s *** identified,CTC biomarkers will be invaluable tools for clinical diagnosis,prognosis and *** this review,we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample,to derive enough CTCs for accurate and reproducible characterization of the biophysical,biochemical,gene expressional and behavioral properties of the harvested *** of tumor cell heterogeneity,it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer *** analyzing critical steps and technical issues in ex vivo CTC culture,we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells,relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells.

关键词： Cancer metastasis Peripheral blood Circulating tumor cell ex vivo culture

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Sex hormones in the modulation of irritable bowel syndrome

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World Journal of Gastroenterology 2014年第10期20卷 2433-2448页

作者： Agata Mulak Yvette Taché Muriel Larauche Department of Gastroenterology and Hepatology Wroclaw Medical University 50-556 Wroclaw Poland CURE:Digestive Diseases Research Center and Oppenheimer Family Center for Neurobiology of Stress Digestive Diseases Division Department of MedicineUniversity of California Los Angeles VA Greater Los Angeles Healthcare System Los Angeles CA 90073 United States

Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.

关键词： Brain-gut axis Irritable bowel syndrome Microbiota Pain modulation Sex hormones

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Stress-induced visceral analgesia assessed non-invasively in rats is enhanced by prebiotic diet

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World Journal of Gastroenterology 2012年第3期18卷 225-236页

作者： Muriel Larauche Agata Mulak Pu-Qing Yuan Osamu Kanauchi Yvette Taché CURE： Diges-tive Diseases Research Center and Oppenheimer Family Center for Neurobiology of Stress Department of Medicine Digestive Diseases Division at the University of California Los Angeles VA Greater Los Angeles Healthcare System Los Angeles CA 90073 United States Department of Gastroenterology and Hepatology Wroclaw Medical University Borowska 213 50-556 Wroclaw Poland University of Medical Science Shiga and Central Laboratories for Frontier Technology Kirin Holdings Co. Ltd. 1-13-5 Fukuura Kanazawa-ku Yokohama 236-0004 Japan CURE：Digestive Diseases Research Center and Oppenheimer Family Centerfor Neurobiology of Stress Department of Medicine Digestive Diseases Division at the University of California Los AngelesVA Greater Los Angeles Healthcare System

AIM: To investigate the influence of repeated water avoidance stress (rWAS) on the visceromotor response (VMR) to colorectal distension (CRD) and the modulation of the response by a prebiotic diet in rats using a novel surgery-free method of solid-state ***: Male Wistar rats fed a standard diet with or without 4% enzyme-treated rice fiber (ERF) for 5 wk were subjected to rWAS (1 h daily x 10 d) or no stress. The VMR to graded phasic CRD was assessed by intraluminal colonic pressure recording on days 0 (base-line), 1 and 10 (45 min) and 11 (24 h) after rWAS and expressed as percentage change from baseline. Cecal content of short chain fatty acids and distal colonic histology were assessed on day 11. RESULTS: WAS on day 1 reduced the VMR to CRD at 40 and 60 mmHg similarly by 28.9% ± 6.6% in both diet groups. On day 10, rWAS-induced reduction of VMR occurred only at 40 mmHg in the standard diet group (36.2% ± 17.8%) while in the ERF group VMR was lowered at 20, 40 and 60 mmHg by 64.9% ± 20.9%, 49.3% ± 11.6% and 38.9% ± 7.3% respectively. The visceral analgesia was still observed on day 11 in ERF-but not in standard diet-fed rats. By contrast the non-stressed groups (standard or ERF diet) exhibited no changes in VMR to CRD. In standard diet-fed rats, rWAS induced mild colonic histological changes that were absent in ERF-fed rats exposed to stress compared to non-stressed rats. The reduction of cecal content of isobutyrate and total butyrate, but not butyrate alone, was correlated with lower visceral pain response. Additionally, ERF diet increased rWAS-induced defecation by 26% and 75% during the first 0-15 min and last 15-60 min, respectively, compared to standard diet, and reduced rats' body weight gain by 1.3 fold independently of their stress status. CONCLUSION: These data provide the first evidence of psychological stress-related visceral analgesia in rats that was enhanced by chronic intake of ERF prebiotic.

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Analytical Image Fusion in the Detection of Intrahepatic Hepatocellular Cancer

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Open Journal of Medical Imaging 2017年第2期7卷 56-61页

作者： Hongyun Zhu Michael L. Goris Department of veterans Affairs Greater Los Angeles Healthcare System Los Angeles CA USA 1455 Ormsby Drive Sunnyvale CA USA

Purpose: Since HCC lesions are generally characterized by lower Hounsfield unit value (HU) values and higher tracer uptake (SUV or Standardized Uptake Values), we intended to determine if normalizing the SUV by the HU, for the lesion and normal liver would improve sensitivity and specificity. Material and Methods: Twenty-three consecutive patients with HCC diagnosed clinically or pathologically underwent C11-Acetate (C11-A) and F18-FDG (FDG) PET/CT imaging before surgery during a 424-day interval. After exclusion of treated or calcified lesions, 44 lesions are included in this study. The original metrics are the maximum SUV (SUVmax) and maximum or average HU (HUmax or HUmean) for lesions and normal liver. For the normal liver, an average SUV (SUVmean) was included. The derived values are the ratios of SUV/HU values. The efficacy is the fraction of outcomes of non-overlapping metrics between lesion and normal liver. Results: For FDG the efficacy is 0.489 for the lesions SUVmax versus normal liver SUVmax. For lesion SUVmax/HUmean versus normal liver SUVmax/HUmax, the efficacy is 1.00. For C11-A the corresponding values are 0.045 and 0.920. Conclusion: Normalizing SUV values for changes in HU values increases the contrast between normal liver and lesions. Analytical fusion can be very effective.

关键词： HCC (Hepatocellular Cancer)

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Impact of sustained virologic response on chronic kidney disease progression in hepatitis C

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World Journal of Hepatology 2017年第36期9卷 1352-1360页

作者： Elizabeth S Aby Tien S Dong Jenna Kawamoto Joseph R Pisegna Jihane N Benhammou Division of Gastroenterology Hepatology and Parenteral Nutrition Department of Medicine VA Greater Los Angeles Healthcare System the Vatche and Tamar Manoukian Division of Digestive Diseases UCLA Los Angeles Department of Medicine University of California David Geffen School of Medicine

AIM To determine how sustained virological response at 12 wk(SVR12) with direct acting antivirals(DAAs) for the treatment of hepatitis C virus(HCV) infection affects chronic kidney disease(CKD) progression. METHODS A retrospective analysis was performed in patients aged ≥ 18 years treated for HCV with DAAs at the VA greater los angeles healthcare system from 2014-2016. The treatment group was compared to patients with HCV from 2011-2013 who did not undergo HCV treatment, prior to the introduction of DAAs; the control group was matched to the study group in terms of age, gender, and ethnicity. Analysis of variance and co-variance was performed to compare means between SVR12 subgroups adjusting for *** Five hundred and twenty-three patients were evaluated. When comparing the rate of change in estimated glomerular filtration rate(e GFR) one-year after HCV treatment to one-year before treatment, patients who achieved SVR12 had a decline in GFR of 3.1 m L/min ± 0.75 m L/min per 1.73 m^2 compared to a decline in e GFR of 11.0 m L/min ± 2.81 m L/min per 1.73 m^2 in patients who did not achieve SVR12(P = 0.002). There were no significant clinical differences between patients who achieved SVR12 compared to those who did not in terms of cirrhosis, treatment course, treatment experience, CKD stage prior to treatment, diuretic use or other co-morbidities. The decline in e GFR in those with untreated HCV over 2 years was 2.8 m L/min ± 1.0 m L/min per 1.73 m^2, which was not significantly different from the e GFR decline noted in HCV-treated patients who achieved SVR12(P = 0.43).CONCLUSION Patients who achieve SVR12 have a lesser decline in renal function, but viral eradication in itself may not be associated improvement in renal disease progression.

关键词： Hepatitis C Direct-acting antivirals Chronic kidney disease End stage renal disease Sustained virological response

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Epistaxis in end stage liver disease masquerading as severe upper gastrointestinal hemorrhage

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World Journal of Gastroenterology 2014年第38期20卷 13993-13998页

作者： Marine Camus Dennis M Jensen Jason D Matthews Gordon V Ohning Thomas O Kovacs Rome Jutabha Kevin A Ghassemi Gustavo A Machicado Gareth S Dulai CURE Hemostasis Research Group CURE Digestive Diseases Research CenterDavid Geffen School of Medicine at University of California Division of Digestive Diseases at University of California Los AngelesRonald Reagan Medical Center Department of Gastroenterology Lariboisiere Hospital CURE Hemostasis Research Group CURE Digestive Diseases Research CenterDavid Geffen School of Medicine at University of CaliforniaLos AngelesLos AngelesCA 90095United States Gastroenterology Division at VA greater los angeles healthcare system Hunterdon Gastrointestinal Associates

AIM: To describe the prevalence, diagnosis, treatment, and outcomes of end stage liver disease (ESLD) patients with severe epistaxis thought to be severe upper gastrointestinal hemorrhage (UGIH).

关键词： Epistaxis Upper gastrointestinal bleeding End stage liver disease Cirrhosis Nasogastric tube Liver transplantation Digestive bleeding Nasal packing Coagulopathy

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Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner

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Asian Journal of Urology 2015年第1期2卷 38-45页

作者： Jiabin An Yanchuan Guo Ting Wang Allan J.Pantuck Matthew B.Rettig Department of Medicine Division of Hematology-OncologyVA Greater Los Angeles Healthcare SystemLos AngelesCA90073USA Technical Institute of Physics and Chemistry Chinese Academy of ScienceBeijing100190China Department of Urology David Geffen School of Medicine at UCLALos AngelesCA90095USA Department of Medicine Division of Hematology-OncologyDavid Geffen School of Medicine at UCLALos AngelesCA90095USA

Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor *** effect of VHL inactivation is hypoxia inducible factor alpha(HIFa)-independent constitutive activation of nuclear factor kappa B(NF-κB)and c-jun N-terminal kinase(JNK).Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition(EMT).The purpose of this study was to determine the biochemical effects of pomegranate juice extracts(PE)on RCC cell ***:The pre-clinical effects of PE on NF-κB,JNK,and the EMT phenotype were assayed,including its effect on proliferation,anchorage-independent growth,and invasion of pVHLdeficient ***:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient *** effects of PE are concentration-dependent and affect not only biochemical markers of EMT(i.e.,cadherin expression)but also functional manifestations of EMT,such as *** effects are manifested within days of exposure to PE when diluted *** dilute concentrations of PE(106 dilution),which do not impact these pathways in the short term,were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged ***:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small,localized,incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.

关键词： Pomegranate extract von Hippel-Lindau(VHL)tumor suppressor Clear cell renal cell carcinoma c-Jun N-terminal kinase Epithelial to mesenchymal transition Nuclear factor kappa B

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