Publications by authors named "Lorne Hofseth"

82 Publications

Pharmacokinetics of Panaxynol in Mice.

J Cancer Sci Clin Ther 2020 1;4(2):133-143. Epub 2020 Jun 1.

Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA.

The purpose of our study is to explore the pharmacokinetic parameters of panaxynol (PA) and understand its potential and dosage used in pre-clinical animal models. For analysis,5 μM of PA was added to liver microsomes of mouse and human species. Nicotinamide adenine dinucleotide phosphate was added to initiate enzyme reaction except for the negative control. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis was used to measure concentrations. For studies, CD-1 mice were treated with PA by intravenous (IV) injection or oral administration (PO). Concentrations of PA were measured in plasma and tissue using LC-MS/MS. Pharmacokinetic parameters were obtained using non-compartmental analysis. Area under the curve concentration versus time was calculated using a linear trapezoidal model., PA's half-life is 21.4 min and 48.1 min in mouse and human liver microsomes, respectively. , PA has a half-life of 1.5 hr when IV-injected, and 5.9 hr when administered via PO, with a moderate bioavailability of 50.4%. Mice show no signs of toxicity up to 300 mg/kg PO. PA concentrations were highest in colon tissue 2 hr post-treatment at 486 ng/g of colon tissue.PA's pharmacokinetic properties and low toxicity point to the safety and compatibility of PA with mice.
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http://dx.doi.org/10.26502/jcsct.5079059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472592PMC
June 2020

Publisher Correction: Early-onset colorectal cancer: initial clues and current views.

Nat Rev Gastroenterol Hepatol 2020 Aug;17(8):517

Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41575-020-0338-0DOI Listing
August 2020

Molecules from American Ginseng Suppress Colitis through Nuclear Factor Erythroid-2-Related Factor 2.

Nutrients 2020 Jun 21;12(6). Epub 2020 Jun 21.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that affects millions of people worldwide and increases the risk of colorectal cancer (CRC) development. We have previously shown that American ginseng (AG) can treat colitis and prevent colon cancer in mice. We further fractionated AG and identified the most potent fraction, hexane fraction (HAG), and the most potent compound in this fraction, panaxynol (PA). Because (1) oxidative stress plays a significant role in the pathogenesis of colitis and associated CRC and (2) nuclear factor erythroid-2-related factor 2 (Nrf2) is the master regulator of antioxidant responses, we examined the role of Nrf2 as a mechanism by which AG suppresses colitis. Through a series of in vitro and in vivo Nrf2 knockout mouse experiments, we found that AG and its components activate the Nrf2 pathway and decrease the oxidative stress in macrophages (mΦ) and colon epithelial cells in vitro. Consistent with these in vitro results, the Nrf2 pathway is activated by AG and its components in vivo, and Nrf2 mice are resistant to the suppressive effects of AG, HAG and PA on colitis. Results from this study establish Nrf2 as a mediator of AG and its components in the treatment of colitis.
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http://dx.doi.org/10.3390/nu12061850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353434PMC
June 2020

Panaxynol, a bioactive component of American ginseng, targets macrophages and suppresses colitis in mice.

Oncotarget 2020 Jun 2;11(22):2026-2036. Epub 2020 Jun 2.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA.

Ulcerative colitis has a significant impact on the quality of life for the patients, and can substantially increase the risk of colon cancer in patients suffering long-term. Conventional treatments provide only modest relief paired with a high risk of side effects, while complementary and alternative medicines can offer safe and effective options. Over the past decade, we have shown that both American ginseng and its hexane fraction (HAG) have anti-oxidant and anti-inflammatory properties that can suppress mouse colitis and prevent colitis-associated colon cancer. With the goal of isolating a single active compound, we further fractionated HAG, and found the most abundant molecule in this fraction was the polyacetylene, panaxynol (PA). After isolating and characterizing PA, we tested the efficacy of PA in the treatment and prevention of colitis in mice and studied the mechanism of action. We demonstrate here that PA effectively treats colitis in a Dextran Sulfate Sodium mouse model by targeting macrophages for DNA damage and apoptosis. This study provides additional mechanistic evidence that American ginseng can be used for conventional treatment of colitis and other diseases associated with macrophage dysfunction.
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http://dx.doi.org/10.18632/oncotarget.27592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275787PMC
June 2020

Early-onset colorectal cancer: initial clues and current views.

Nat Rev Gastroenterol Hepatol 2020 06 21;17(6):352-364. Epub 2020 Feb 21.

Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.

Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research. In addition, we identify inconsistencies in the evidence implicating a strong effect of increased adiposity and suggest that certain behaviours (such as diet and stress) might place nonobese and otherwise healthy people at risk of this disease. Key risk factors are reviewed, including the global westernization of diets (usually involving a high intake of red and processed meats, high-fructose corn syrup and unhealthy cooking methods), stress, antibiotics, synthetic food dyes, monosodium glutamate, titanium dioxide, and physical inactivity and/or sedentary behaviour. The gut microbiota is probably at the crossroads of these risk factors and EOCRC. The time course of the disease and the fact that relevant exposures probably occur in childhood raise important methodological issues that are also discussed.
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http://dx.doi.org/10.1038/s41575-019-0253-4DOI Listing
June 2020

Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice.

Sci Rep 2019 07 19;9(1):10520. Epub 2019 Jul 19.

Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.

Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, which is studied extensively for its medicinal value. A central gap in the science is the underlying mechanisms surrounding THC's therapeutic effects and the role of gut metabolite profiles. Using a mass-spectrometry based metabolomics, we show here that intraperitoneal injection of THC in C57BL/6 mice modulates metabolic profiles that have previously been identified as integral to health. Specifically, we investigated the effects of acute (single THC injection denoted here as '1X') and short -term (five THC injections on alternate days denoted as '5X') THC administration on fecal and intestinal tissue metabolite profiles. Results are consistent with the hypothesis that THC administration alters host metabolism by targeting two prominent lipid metabolism pathways: glycerophospholipid metabolism and fatty acid biosynthesis.
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http://dx.doi.org/10.1038/s41598-019-46478-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642200PMC
July 2019

Resveratrol-Mediated Attenuation of Enterotoxin B-Induced Acute Liver Injury Is Associated With Regulation of microRNA and Induction of Myeloid-Derived Suppressor Cells.

Front Microbiol 2018 17;9:2910. Epub 2018 Dec 17.

Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States.

Resveratrol (RES) is a polyphenolic compound found abundantly in plant products including red grapes, peanuts, and mulberries. Because of potent anti-inflammatory properties of RES, we investigated whether RES can protect from Staphylococcal enterotoxin B (SEB)-induced acute liver injury in mice. SEB is a potent super antigen that induces robust inflammation and releases inflammatory cytokines that can be fatal. We observed that SEB caused acute liver injury in mice with increases in enzyme aspartate transaminase (AST) levels, and massive infiltration of immune cells into the liver. Treatment with RES (100 mg/kg body weight) attenuated SEB-induced acute liver injury, as indicated by decreased AST levels and cellular infiltration in the liver. Interestingly, RES treatment increased the number of myeloid derived suppressor cells (MDSCs) in the liver. RES treatment led to alterations in the microRNA (miR) profile in liver mononuclear cells (MNCs) of mice exposed to SEB, and pathway analysis indicated these miRs targeted many inflammatory pathways. Of these, we identified miR-185, which was down-regulated by RES, to specifically target Colony Stimulating Factor (CSF1) using transfection studies. Moreover, the levels of CSF1 were significantly increased in RES-treated SEB mice. Because CSF1 is critical in MDSC induction, our studies suggest that RES may induce MDSCs by down-regulating miR-185 leading to increase the expression of CSF1. The data presented demonstrate for the first time that RES can effectively attenuates SEB-induced acute liver injury and that this may result from its action on miRs and induction of MDSCs.
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http://dx.doi.org/10.3389/fmicb.2018.02910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304356PMC
December 2018

Maternal stress and early-onset colorectal cancer.

Med Hypotheses 2018 Dec 21;121:152-159. Epub 2018 Sep 21.

Department of Drug Discovery and Biomedical Science, College of Pharmacy, University of South Carolina, Columbia, SC, USA. Electronic address:

Early-onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) diagnosed before the age of 50. Alarmingly, there has been a significant increase in EOCRC diagnoses' worldwide over the past several decades. Emerging data suggest EOCRCs have distinguishing clinical, pathological, biological and molecular features; and thus, are a fundamentally different subtype of CRCs. Unfortunately, there is no simple explanation for the causes of EOCRC. Scientifically rigorous studies are needed to determine what may be driving the challenging epidemiology of EOCRC. We contend here that a reasonable hypothesis is that prenatal risk factors such as maternal stress and associated sleeping disorders influence offspring epigenetic make-up, and shape immune system and gut health contributing to an increased risk for EOCRC.
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http://dx.doi.org/10.1016/j.mehy.2018.09.035DOI Listing
December 2018

The Dietary Inflammatory Index is associated with elevated white blood cell counts in the National Health and Nutrition Examination Survey.

Brain Behav Immun 2018 03 5;69:296-303. Epub 2017 Dec 5.

Cancer Prevention and Control Program, University of South Carolina, 915 Greene Street, Suite 200, Columbia, SC 29208, United States; Department of Epidemiology and Biostatistics, University of South Carolina, 915 Greene Street, Suite 200, Columbia, SC 29208, United States; Connecting Health Innovations, LLC, 915 Greene Street, Suite 200, Columbia, SC 29208, United States.

White blood cells (WBCs) are considered a reliable biomarker of inflammation. Elevations in both WBCs and pro-inflammatory cytokines are associated with several chronic conditions. Diet is a strong moderator of inflammation and WBCs. The purpose of this study was to examine the association between the Dietary Inflammatory Index (DII®) and WBCs using data from the United States National Health and Nutrition Examination Survey (NHANES). NHANES is a cross-sectional study that occurs in two-year cycles. Respondents from five cycles (n = 26,046) with available data on diet (collected through a single 24-h dietary recall [24HR]) and WBCs (derived using the Coulter method) were included. The DII (theoretical range is about -8 to +8) was derived from the micro and macronutrients calculated from the 24HR. Linear regression models, using survey design procedures, were used to estimate adjusted mean WBC (i.e., total, lymphocytes, monocytes, and neutrophils) counts and percentages by DII quartiles. Among all participants no statistically significant difference in WBCs were observed when comparing DII quartile 4 (most pro-inflammatory) to quartile 1 (most anti-inflammatory). However, a one-unit increase in the DII was associated with a 0.028 (1000 per µL) increase in total WBCs (p = .01). Additionally, a 0.024 increase in neutrophils (p < .01) was observed for a one-unit increase in the DII. In the group of participants with normal body mass index (BMI, 18.5-24.9 kg/m), those in DII quartile 4 had higher levels of total WBCs compared to subjects with normal BMI in DII quartile 1 (7.12 vs. 6.88, p = .01). Similar comparisons were observed for monocytes and neutrophils. However, these relationships were not observed for participants who were overweight or obese, which are pro-inflammatory conditions. Normal-weight individuals consuming more pro-inflammatory diets were more likely to have elevated WBCs. Because of its cross-sectional design, NHANES cannot inform directly on temporal relations, thus limiting causal inference. Future research is needed to examine the impact of anti-inflammatory diet adoption on lowering levels of WBCs, in addition to other inflammatory mediators.
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http://dx.doi.org/10.1016/j.bbi.2017.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857420PMC
March 2018

Getting rigorous with scientific rigor.

Authors:
Lorne J Hofseth

Carcinogenesis 2018 01;39(1):21-25

College of Pharmacy, University of South Carolina, Columbia, SC, USA.

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http://dx.doi.org/10.1093/carcin/bgx085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862244PMC
January 2018

Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation.

PLoS One 2017 22;12(3):e0172914. Epub 2017 Mar 22.

Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.

Many of the symptoms of Gulf War Illness (GWI) that include neurological abnormalities, neuroinflammation, chronic fatigue and gastrointestinal disturbances have been traced to Gulf War chemical exposure. Though the association and subsequent evidences are strong, the mechanisms that connect exposure to intestinal and neurological abnormalities remain unclear. Using an established rodent model of Gulf War Illness, we show that chemical exposure caused significant dysbiosis in the gut that included increased abundance of phylum Firmicutes and Tenericutes, and decreased abundance of Bacteroidetes. Several gram negative bacterial genera were enriched in the GWI-model that included Allobaculum sp. Altered microbiome caused significant decrease in tight junction protein Occludin with a concomitant increase in Claudin-2, a signature of a leaky gut. Resultant leaching of gut caused portal endotoxemia that led to upregulation of toll like receptor 4 (TLR4) activation in the small intestine and the brain. TLR4 knock out mice and mice that had gut decontamination showed significant decrease in tyrosine nitration and inflammatory mediators IL1β and MCP-1 in both the small intestine and frontal cortex. These events signified that gut dysbiosis with simultaneous leaky gut and systemic endotoxemia-induced TLR4 activation contributes to GW chemical-induced neuroinflammation and gastrointestinal disturbances.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172914PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362211PMC
August 2017

Dietary inflammatory index and odds of colorectal cancer in a case-control study from Jordan.

Appl Physiol Nutr Metab 2017 Jul 22;42(7):744-749. Epub 2017 Feb 22.

j Department of Nutrition and Food Technology, The University of Jordan, Faculty of Agriculture, P.O. Box 2920, Amman 11941, Jordan.

Dietary components that promote inflammation of the colon have been suggested to be risk factors in the development of colorectal cancer (CRC). The possible link between inflammatory potential of diet and CRC has been investigated in several developed or Western countries. Despite the fact that dietary choices in the Middle East differ markedly from those in the West, results have not been reported from any study conducted in a Middle-Eastern population. We examined the association between dietary inflammatory index (DII) scores and CRC in a case-control study conducted in Jordan. This study included 153 histopathologically confirmed CRC cases and 202 disease-free control subjects' frequency matched on age, sex, and occupation. Data were collected between January 2010 and December 2012, using interviewer-administered questionnaires. DII scores were computed from dietary data reported using a food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, sex, education, physical activity, body mass index, smoking, and family history of CRC. Subjects with higher DII scores were at increased odds of CRC, with the DII being used both as a continuous variable (OR = 1.45, 95% CI: 1.13-1.85; 1-unit increase corresponding to ≈20% of its range in the current study) and as a categorical variable (OR = 2.13, 95%CI: 1.23-3.72). Our results, based on a Jordanian population, add to the growing literature indicating that a pro-inflammatory diet is associated with increased odds of CRC.
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http://dx.doi.org/10.1139/apnm-2017-0035DOI Listing
July 2017

The Dietary Inflammatory Index Is Associated with Colorectal Cancer Risk in the Multiethnic Cohort.

J Nutr 2017 03 8;147(3):430-438. Epub 2017 Feb 8.

Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC.

Diet is known to influence systemic inflammation, a recognized risk factor for colorectal cancer (CRC). Studies in ethnically diverse populations that examine the association between dietary inflammatory potential and CRC incidence are limited. We used the Dietary Inflammatory Index to clarify the relation between the inflammatory potential of diet and CRC incidence across racial/ethnic groups. We hypothesized that proinflammatory diets would be associated with an increased risk of CRC, and that these associations may differ across racial/ethnic groups. The Multiethnic Cohort (MEC) follows a prospective study design. It includes 190,963 white, African-American, native Hawaiian, Japanese-American, and Latino men and women aged 45-75 y at recruitment and followed over 20 y. Participants completed a food frequency questionnaire from which energy-adjusted Dietary Inflammatory Index (E-DII) scores were computed and categorized into quartiles. CRC incidence was documented through linkage to cancer registry programs. Cox proportional hazards regression was used to estimate HRs and 95% CIs, adjusting for known or expected CRC risk factors. Among all participants, more-proinflammatory diets (highest quartile compared with lowest quartile) were associated with an increased risk of CRC (HR: 1.21; 95% CI: 1.11, 1.32). However, the effect size was larger for men (HR: 1.28; 95% CI: 1.13, 1.45) than for women (HR: 1.16; 95% CI: 1.02, 1.33), although the interaction term for sex was not statistically significant (interaction = 0.17). When stratified by race/ethnicity, the association was significantly different between groups for men (interaction = 0.01), although not for women (interaction = 0.20). Significant associations with HRs ranging from 2.33 to 1.04 were observed in white, Japanese-American, and Latino men, and native Hawaiian women. Overall, more-proinflammatory diets, as identified by the E-DII, were associated with increased CRC risk in MEC participants across racial/ethnic groups. This study adds to the evidence suggesting that diets with high proinflammatory potential may increase CRC risk.
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http://dx.doi.org/10.3945/jn.116.242529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320401PMC
March 2017

Looking for the best anti-colitis medicine: A comparative analysis of current and prospective compounds.

Oncotarget 2017 Jan;8(1):228-237

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, SC, USA.

Ulcerative colitis (UC) is a chronic lifelong inflammatory disorder of the colon, which, while untreated, has a relapsing and remitting course with increasing risk of progression toward colorectal cancer. Current medical treatment strategies of UC mostly focus on inhibition of the signs and symptoms of UC to induce remission and prevent relapse of disease activity, minimizing the impact on quality of life, but not affecting the cause of disease. To date, however, there is no single reliable treatment agent and/or strategy capable of effectively controlling colitis progression throughout the patient's life without side effects, remission, or resistance. Taking into consideration an urgent need for the new colitis treatment strategies, targets and/or modulators of inflammation, we have tested current and prospective compounds for colitis treatment and directly compared their anti-colitis potency using a dextran sulfate sodium (DSS) mouse model of colitis. We have introduced a composite score - a multi-parameters comparison tool - to assess biological potency of different compounds.
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http://dx.doi.org/10.18632/oncotarget.13894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352114PMC
January 2017

Repurposing the anti-malarial drug, quinacrine: new anti-colitis properties.

Oncotarget 2016 Aug;7(33):52928-52939

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with an increased risk of colorectal cancer in 8-10 years after disease onset. Current colitis treatment strategies do not offer a cure for the disease, but only treat the symptoms with limited success and dangerous side-effects. Also, there is no preventive treatment for either UC or colorectal cancer. Quinacrine is an anti-malarial drug with versatile use in the treatment of diseases involving inflammatory response such as rheumatoid arthritis and lupus erythematosus. It also has putative anti-cancer effect. Quinacrine's anti-inflammatory, anti-oxidant properties, and anti-tumorigenic properties make it a potential small molecule preventive agent for both UC and associated colorectal cancer.

Results: There were obvious changes in the CDI, histology, and inflammatory load in quinacrine-treated groups in a dose and time dependent manner in both models of UC, induced by chemical or haptenating agent.

Materials And Methods: We tested quinacrine at two different doses as a colitis treatment agent in two mouse models of UC - the dextran sulfate sodium and oxazolone. The clinical disease index (CDI), histological changes of the colon, levels of inflammatory markers (Cox-2, iNOS, p53) and overall health vitals were evaluated.

Conclusions: We demonstrate that quinacrine successfully suppresses colitis without any indication of toxicity or side-effects in two mouse models of UC.
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http://dx.doi.org/10.18632/oncotarget.10608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288159PMC
August 2016

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Semin Cancer Biol 2015 Dec;35 Suppl:S276-S304

Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.
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http://dx.doi.org/10.1016/j.semcancer.2015.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819002PMC
December 2015

Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer.

Oncotarget 2015 Nov;6(34):36053-62

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.

Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and rectal bleeding. The extent of these symptoms depends on disease severity. The protein arginine deiminase (PAD) family of enzymes converts peptidyl-Arginine to peptidyl-Citrulline through citrullination. PADs are dysregulated, with abnormal citrullination in many diseases, including UC and colorectal cancer (CRC). We have developed the small molecule, pan-PAD inhibitor, Chlor-amidine (Cl-amidine), with multiple goals, including treating UC and preventing CRC. Building off our recent results showing that: 1) Cl-amidine suppresses colitis in vivo in a dextran sulfate sodium (DSS) mouse model; and 2) Cl-amidine induces microRNA (miR)-16 in vitro causing cell cycle arrest, we tested the hypothesis that Cl-amidine can prevent tumorigenesis and that miR-16 induction, by Cl-amidine, may be involved in vivo. Consistent with our hypothesis, we present evidence that Cl-amidine, delivered in the drinking water, prevents colon tumorigenesis in our mouse model of colitis-associated CRC where mice are given carcinogenic azoxymethane (AOM), followed by multiple cycles of 2% DSS to induce colitis. To begin identifying mechanisms, we examined the effects of Cl-amidine on miR-16. Results show miR-16 suppression during the colitis-to-cancer sequence in colon epithelial cells, which was rescued by drinking Cl-amidine. Likewise, Ki67 and cellular proliferation targets of miR-16 (Cyclins D1 and E1) were suppressed by Cl-amidine. The decrease in cell proliferation markers and increase in tumor suppressor miRNA expression potentially define a mechanism of how Cl-amidine is suppressing tumorigenesis in vivo.
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http://dx.doi.org/10.18632/oncotarget.5937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742161PMC
November 2015

A multi-targeted approach to suppress tumor-promoting inflammation.

Semin Cancer Biol 2015 Dec 5;35 Suppl:S151-S184. Epub 2015 May 5.

Department of Surgery, St. Luke's Roosevelt Hospital, New York, NY, United States.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.
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http://dx.doi.org/10.1016/j.semcancer.2015.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635070PMC
December 2015

Identifying panaxynol, a natural activator of nuclear factor erythroid-2 related factor 2 (Nrf2) from American ginseng as a suppressor of inflamed macrophage-induced cardiomyocyte hypertrophy.

J Ethnopharmacol 2015 Jun 14;168:326-36. Epub 2015 Apr 14.

Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA; Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address:

Ethnopharmacological Relevance: American ginseng is capable of ameliorating cardiac dysfunction and activating Nrf2, a master regulator of antioxidant defense, in the heart. This study was designed to isolate compounds from American ginseng and to determine those responsible for the Nrf2-mediated resolution of inflamed macrophage-induced cardiomyocyte hypertrophy.

Materials And Methods: A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. A bioassay-based fractionization of American ginseng was performed to identify the putative substances which could activate Nrf2-mediated suppression of pro-inflammatory cytokine expression in macrophages and macrophage-mediated pro-hypertrophic growth in cardiomyocytes.

Results: A hexane fraction of an anti-inflammatory crude extract of American ginseng was found to be most effective in suppressing the inflammatory responses in macrophages. Preparative, reverse-phase HPLC and a comparative analysis by analytical scale LC-UV/MS revealed the hexane fraction contains predominantly C17 polyacetylenes and linolenic acid. Panaxynol, one of the major polyacetylenes, was found to be a potent Nrf2 activator. Panaxynol posttranscriptionally activated Nrf2 by inhibiting Kelch-like ECH-associated protein (Keap) 1-mediated degradation without affecting the binding of Keap1 and Nrf2. Moreover, panaxynol suppressed a selected set of cytokine expression via the activation of Nrf2 while minimally regulating nuclear factor-kappa B (NF-κB)-mediated cytokine expression in macrophages. It also dramatically inhibited the inflamed macrophage-mediated cardiomyocyte death and hypertrophy by activating Nrf2 in macrophages.

Conclusions: These results demonstrate that American ginseng-derived panaxynol is a specific Nrf2 activator and panaxynol-activated Nrf2 signaling is at least partly responsible for American ginseng-induced health benefit in the heart.
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http://dx.doi.org/10.1016/j.jep.2015.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810680PMC
June 2015

Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation.

Curr Drug Targets 2015 ;16(7):700-10

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy 770 Sumter St., Coker Life Sciences, Rm. 513C University of South Carolina Columbia, SC 29208.

Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, Nacetylation, and citrullination) and these PTMs can alter protein structure and function with consequent effects on the multitude of pathways necessary for maintaining the physiological homeostasis. When dysregulated, however, the enzymes that catalyze these PTMs can impact the genesis of countless diseases. In this review, we will focus on protein citrullination, a PTM catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Specifically, we will describe the roles of the PADs in both normal human physiology and disease. The development of PAD inhibitors and their efficacy in a variety of autoimmune disorders and cancer will also be discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520219PMC
http://dx.doi.org/10.2174/1389450116666150202160954DOI Listing
May 2016

Inhibiting protein arginine deiminases has antioxidant consequences.

J Pharmacol Exp Ther 2015 Apr 29;353(1):64-70. Epub 2015 Jan 29.

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina (E.E.W., X.C., A.B.H., L.J.H.); Shanxi Medical University, Taiyuan, Shanxi, China (X.C.); Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida (V.S.); Department of Chemistry, University of North Florida, Jacksonville, Florida (C.P.C.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (P.R.T.)

Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small-molecule inhibitor of the protein arginine deiminases, suppresses colitis in mice. Because colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has antioxidant properties. Here we show that colitis induced with azoxymethane via intraperitoneal injection + 2% dextran sulfate sodium in the drinking water is suppressed by Cl-amidine (also given in the drinking water). Inducible nitric oxide synthase, an inflammatory marker, was also downregulated in macrophages by Cl-amidine. Because epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and because DNA damage is a procancerous mechanism, our data predict that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis.
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http://dx.doi.org/10.1124/jpet.115.222745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366755PMC
April 2015

A key role of microRNA-29b for the suppression of colon cancer cell migration by American ginseng.

PLoS One 2013 9;8(10):e75034. Epub 2013 Oct 9.

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.

Metastasis of colon cancer cells increases the risk of colon cancer mortality. We have recently shown that American ginseng prevents colon cancer, and a Hexane extract of American Ginseng (HAG) has particularly potent anti-inflammatory and anti-cancer properties. Dysregulated microRNA (miR) expression has been observed in several disease conditions including colon cancer. Using global miR expression profiling, we observed increased miR-29b in colon cancer cells following exposure to HAG. Since miR-29b plays a role in regulating the migration of cancer cells, we hypothesized that HAG induces miR-29b expression to target matrix metalloproteinase-2 (MMP-2) thereby suppressing the migration of colon cancer cells. Results are consistent with this hypothesis. Our study supports the understanding that targeting MMP-2 by miR-29b is a mechanism by which HAG suppresses the migration of colon cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075034PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794036PMC
June 2014

D-amino acid based protein arginine deiminase inhibitors: Synthesis, pharmacokinetics, and in cellulo efficacy.

ACS Med Chem Lett 2012 Oct;3(12):1081-1085

Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, FL 33458.

The protein arginine deiminases (PADs) are known to play a crucial role in the onset and progression of multiple inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and cancer. However, it is not known how each of the five PAD isozymes contributes to disease pathogenesis. As such, potent, selective, and bioavailable PAD inhibitors will be useful chemical probes to elucidate the specific roles of each isozyme. Since D-amino amino acids often possess enhanced in cellulo stability, and perhaps unique selectivities, we synthesized a series of D-amino acid analogs of our pan-PAD inhibitor Cl-amidine, hypothesizing that this change would provide inhibitors with enhanced pharmacokinetic properties. Herein, we demonstrate that d-Cl-amidine and d-o-F-amidine are potent and highly selective inhibitors of PAD1. The pharmacokinetic properties of d-Cl-amidine were moderately improved over those of l-Cl-amidine, and this compound exhibited similar cell killing in a PAD1 expressing, triple-negative MDA-MB-231 breast cancer cell line. These inhibitors represent an important step in our efforts to develop stable, bioavailable, and highly selective inhibitors for all of the PAD isozymes.
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http://dx.doi.org/10.1021/ml300288dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572853PMC
October 2012

The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest.

PLoS One 2013 7;8(1):e53791. Epub 2013 Jan 7.

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.

Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also p53-dependent. Because miRNA-16 is a putative tumor suppressor miRNA, and others have found that miRNA-16 suppresses proliferation, we hypothesized that the p53-dependent G1 arrest associated with PAD inhibition was, in turn, dependent on miRNA-16 expression. Results are consistent with this hypothesis. As well, we found the G1 arrest is at least in part due to the ability of Cl-amidine-mediated expression of miRNA-16 to suppress its' G1-associated targets: cyclins D1, D2, D3, E1, and cdk6. Our study sheds light into the mechanisms by which PAD inhibition can protect against or treat colon cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538596PMC
July 2013

Seeing citrulline: development of a phenylglyoxal-based probe to visualize protein citrullination.

J Am Chem Soc 2012 Oct 3;134(41):17015-8. Epub 2012 Oct 3.

Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, Florida 33458, USA.

Protein arginine deiminases (PADs) catalyze the hydrolysis of peptidyl arginine to form peptidyl citrulline. Abnormally high PAD activity is observed in a host of human diseases, but the exact role of protein citrullination in these diseases and the identities of specific citrullinated disease biomarkers remain unknown, largely because of the lack of readily available chemical probes to detect protein citrullination. For this reason, we developed a citrulline-specific chemical probe, rhodamine-phenylglyoxal (Rh-PG), which we show can be used to investigate protein citrullination. This methodology is superior to existing techniques because it possesses higher throughput and excellent sensitivity. Additionally, we demonstrate that this probe can be used to determine the kinetic parameters for a number of protein substrates, monitor drug efficacy, and identify disease biomarkers in an animal model of ulcerative colitis that displays aberrantly increased PAD activity.
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http://dx.doi.org/10.1021/ja308871vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572846PMC
October 2012

Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease.

PLoS One 2012 6;7(9):e44156. Epub 2012 Sep 6.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

Background: Cellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR). We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD). In vitro experiments tested the ability of macrophages to induce senescence in primary cells. Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation.

Methodology/principal Findings: Quantitative immunohistochemistry identified protein expression by colon cell type. Increased cellular senescence (HP1γ; P = 0.01) or DDR (γH2A.X; P = 0.031, phospho-Chk2, P = 0.014) was associated with high macrophage infiltration in UC. Co-culture with macrophages (ANA-1) induced senescence in >80% of primary cells (fibroblasts MRC5, WI38), illustrating that macrophages induce senescence. Interestingly, macrophage-induced senescence was partly dependent on nitric oxide synthase, and clinically relevant NO• levels alone induced senescence. NO• induced DDR in vitro, as detected by immunofluorescence. In contrast to UC, we noted in Crohn's disease (CD) that senescence (HP1γ; P<0.001) and DDR (γH2A.X; P<0.05, phospho-Chk2; P<0.001) were higher, and macrophages were not associated with senescence. We hypothesize that nitric oxide may modulate senescence in CD; epithelial cells of CD had higher levels of NOS2 expression than in UC (P = 0.001). Microarrays and quantitative-PCR identified miR-21 expression associated with macrophage infiltration and NOS2 expression.

Conclusions: Senescence was observed in IBD with senescence-associated β-galactosidase and HP1γ. Macrophages were associated with senescence and DDR in UC, and in vitro experiments with primary human cells showed that macrophages induce senescence, partly through NO•, and that NO• can induce DDR associated with senescence. Future experiments will investigate the role of NO• and miR-21 in senescence. This is the first study to implicate macrophages and nitrosative stress in a direct effect on senescence and DDR, which is relevant to many diseases of inflammation, cancer, and aging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044156PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435404PMC
May 2013

A limited role of p53 on the ability of a Hexane fraction of American ginseng to suppress mouse colitis.

J Biomed Biotechnol 2012 30;2012:785739. Epub 2012 Jul 30.

Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina and Medical University of South Carolina, Columbia, SC 29208, USA.

Ulcerative colitis (UC) is debilitating and carries a high colon cancer risk. Apoptosis of inflammatory cells is a key mechanism regulating UC. We have recently shown that American ginseng (AG), and to a greater extent, a Hexane fraction of AG (HAG) can cause apoptosis and suppress mouse colitis through a p53-mediated mechanism. Here, we tested the hypothesis that HAG suppresses colitis through a p53 mechanism. We found only a limited impact of p53 in the ability of HAG to induce inflammatory cell apoptosis and suppress mouse colitis in vitro and in vivo. Finally, we asked whether HAG could cause cell cycle arrest of HCT116 colon cancer cells in vitro. Interestingly, HAG caused a G1 arrest of such cells independent of p53 status. Findings are significant because HAG suppresses colitis and associated colon cancer, and mutation in p53 is observed in most colitis-driven colon cancers. Therefore, HAG might be very effective in targeting the inflammatory cells and cancer cells since it induces apoptosis of inflammatory cells and cell cycle arrest in both p53-/- and WT p53 colon cancer cells.
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http://dx.doi.org/10.1155/2012/785739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414200PMC
November 2012

Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.

Proc Natl Acad Sci U S A 2012 Aug 14;109(35):14007-12. Epub 2012 Aug 14.

Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkβ(EE)(IEC) transgenic mice expressing constitutively active IκB kinase β (IKKβ) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkβ(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikkβ(EE)(IEC) mice exhibited more β-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/ΔIEC) mice, and their survival was severely compromised. IEC of Ikkβ(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkβ(EE)(IEC)/Apc(+/ΔIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early β-catenin(+) lesions and tumor load. The results suggest that persistent NF-κB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.
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http://dx.doi.org/10.1073/pnas.1211509109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435160PMC
August 2012
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