The Emerging Spectrum of Early Life Exposure-Related Inflammation and Epigenetic Therapy

Qiwei Yang*, Mohamed Ali, Abdeljabar El Andaloussi, Ayman Al-Hendy

Corresponding Author

Qiwei Yang, PhD

Research Associate Professor, Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL 60612, USA; E-mail: qiwei@uic.edu

Affiliation

Qiwei Yang, PhD1*; Mohamed Ali, BPharm, MSc1,2 ; Abdeljabar El Andaloussi, PhD1 ; Ayman Al-Hendy, MD, PhD1

1Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL, USA
2Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

Corresponding Author

Qiwei Yang, PhD

Research Associate Professor, Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL 60612, USA; E-mail: qiwei@uic.edu

Article History

Received: August 21st, 2018; Accepted: September 17th, 2018; Published: September 17th, 2018

Cite this Article

Yang Q, Ali M, El Andaloussi A, Al-Hendy A. The emerging spectrum of early life exposure-related inflammation and epigenetic therapy. Cancer Stud Mol Med Open J. 2018; 4(1): 13-23. doi: 10.17140/CSMMOJ-4-125

Copyright

©2018 by Yang Q. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited.

Doi

10.17140/CSMMOJ-4-125

Early life exposure to a variety of insults during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. During this process, inflammation triggered by a variety of adverse exposures plays an important role in the initiation and development of many types of diseases including tumorigenesis. This systematic review article summaries the current knowledge about the role and mechanism of inflammation in development of diseases. In addition, epigenome alteration related to inflammation and treatment options using epigenetic modifiers are highlighted and discussed.

INTRODUCTION

Inflammation is part of the biological response of body tissues and defense mechanism to harmful stimuli. The immune system recognizes damaged cells, irritants, and pathogens, and the body is attempted to remove harmful stimuli and begin the healing process.1 During the development, the environmental disruptors create prolonged inflammation status, and increase the risk of genomic instability and the introduction of novel mutations. Several signaling pathways involved in the regulation of inflammatory response have been described under the control of epigenetics. Therefore, inflammation is well recognized as a hallmark feature linked to the development of many diseases including varied types of tumors.2,3,4,5,6,7,8,9,10 Inflammatory cells and cytokines in the local tissue microenvironment promote a pro-inflammatory milieu, which can act in an autocrine and/or paracrine manner on the infiltrating immune cells and modified malignant cells. Thus the composition of the inflammatory microenvironment has a pivotal influence on risk of disease development and progression.2 In the case of tumors, inflammation switches to immunosuppression due to tumor evasion from anti-tumor immune response. A promising approach for reversing the tumor immune evasion phenotype is epigenetic therapy, which exhibit efficacy in patients with refractory advanced non-small cell lung cancer. In this study, the epigenetic therapy was able to increases the numbers of activated immune cells in a mouse model of ovarian cancer.11 The goal of this systematic review is to summarize the available information on the therapeutic effect of epigenetic agents, which are able to reverse pro-inflammatory phenotype of diseases.

DEVELOPMENTAL ENVIRONMENTAL FACTORS INDUCE INFLAMMATION RESPONSE

Inflammation plays an important role in the initiation and development of much type of diseases including cardiovascular disease, diabetes, mental health dysfunction, and certain types of cancer.12,13 Several perinatal environmental factors including nutrition, stress, air pollution, antibiotics can cause and increase the risk of adult diseases via inflammation (Figure 1). An association between early life inflammation and later life diseases has been reported in many literatures.14,15,16,17,18 Epidemiological studies have highlighted the link between perinatal factors (such as breastfeeding, cesarean delivery, and antibiotic use) and an increased risk for inflammatory bowel disease and/or celiac disease.19 Perinatal environment determines susceptibility to intestinal inflammatory disorders. Although the mechanisms underlying joint effects remain unclear, one hypothesis is that toxic social and environmental exposures have synergistic effects on inflammatory processes that underlie the development of chronic disease.20 During maternal obesity along with increased inflammatory markers in the maternal circulation, increased placental production of pro-inflammatory mediators can be found, suggesting that the resulting inflammatory milieu where the fetus develops may have critical consequences for later diseases such as obesity.21 The association between prenatal undernutrition and later-life metabolic disorders has been well established in multiple animal studies.22,23 For instance, placentas from protein-restricted rats exhibit a marked reduction of 11-β-hydroxysteroid dehydrogenase 2 enzyme (11-β-HSD2), which leads to fetal exposure to abnormally high glucocorticoid levels during gestation and later hypertension in the adult offspring.23 During this process, pro-inflammatory cytokines can cause decreased activity of 11-β-HSD2, and thus may play a role in programming by maternal diet.24 Similarly, prenatal cytokine exposure is sufficient to induce obesity later in life.24,25

Figure 1. Early Life Exposure to a Variety of Insults Increases the Risk and Development of Diseases in Later Life via Inflammatory Pathway by Reprogramming the Epigenome. Epigenetic Modifiers Targeting Inflammatory Pathways are Capable of Inhibiting the Pro-inflammatory Phenotype, Therefore Leading to Suppressing/Preventing the Development of Diseases.

CSMMOJ-4-125Fig1

PRO-INFLAMMATORY PHENOTYPE AND EPIGENETIC REGULATION

Epigenetics refers to changes in phenotype mediated by altered gene expression. These changes do not occur as a result of the alteration in DNA sequencing.26 DNA methylation and histone modification are the two major epigenetic mechanisms, which collaborate to package genes in euchromatinor heterochromatin, a packaging that determines whether a gene is activated or silenced. DNA methylation refers to the covalent addition of a methyl group to a cytosine residue in a CpG dinucleotide. Histone modification is a covalent post-translational modification (PTM) to histone proteins, which includes methylation, acetylation, phosphorylation, ubiquitylation, and sumoylation. The histones with varied PTMs can impact gene expression pattern by changing chromatin structure or recruiting histone modifiers. Hypermethylation of promoter CpG islands is linked with repressive transcriptional activity because of loss of affinity for transcriptional factors and accessibility by the transcriptional machinery. The crosstalk between DNA methylation and histone modification has also been discovered. The heterochromatin has increased affinity for methylated DNA-binding proteins (MBPs), which further recruit other transcriptional corepressors including histone deacetyltransferases (HDACs), DNA methylases (DNMTs,), etc. Hypermethylation of promoter regions is associated with repressive histone marks, while unmethylated promoters are associated with active histone marks. Under latter circumstance, the gene expression is activated, since affinity for MBPs is reduced, and enrichment for activate histone marks is increased.

An increased body of evidence shows that a variety of pro-inflammatory mediators is regulated via epigenetic mechanism, which contributes to pathogenesis of diseases.27,28,29,30,31,32,33 A recent study by Li et al demonstrates that epigenetic regulation of ke ratinocytes can contribute to chronic skin inflammation.34 Actin polymerizing molecule N-WASP is capable of modulating interleukin IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, as well as H3K9 dimethylation level of the IL-23 promoter. This mechanism mediates the induction of IL-23 by tumor necrosis factor (TNF-α), a known inducer of IL-23 in psoriasis.34

During a plastic interval of the prenatal and neonatal segments of life, a stable reprogramming of gene expression can occur and may predispose the individuals to adult disease.35,36,37 At a molecular level, epigenetic processes including DNA methylation and histone modifications constitute a major mechanism by which environmental factors may establish a new phenotypic trait during this plastic interval.38 A recent study demonstrates that preterm infant outcomes are associated with modulation of host immune and inflammatory responses, which are impaired by acute intrauterine and microbiota factors. The latter one plays a pivotal role in maturation of the immune system and in the prevention or development of diseases occurring during lifetime.39,40 Concomitantly, prenatal inflammatory exposure results in hypermethylation of promoter regions for TLR-signaling pathways, which play a role in the innate immune response.35

Several clinical studies have shown that epigenetics may be involved in the pathogenesis of chronic inflammatory diseases. In the intestinal mucosa of celiac disease patients, DNA methylation play a role in regulating the NF-kB pathway, associated with dysregulation of the inflammatory response.19 Activation of NFkB has been shown to elevate the expression of genes encoding for cytokines, chemokines, and other pro-inflammatory mediators such as IL-6, IL-8.20,41 In addition, early-life stress has been associated with modification of hypothalamic-pituitary-adrenal (HPA) axis- and neuroplasticity-related methylations. Changes in DNA methylation status of glucocorticoid receptor (GR) gene, a key regulator of inflammatory activity and others, was observed in response to early life stress.42

In addition to DNA methylation, histone modification has been reported to be associated with regulation of pro-inflammatory phenotype and adult disease due to early life insults. For example, an animal study demonstrates that the promoter of gene (GR/NR3C1) that encodes the GR, which play an important role in creating a pro-inflammatory environment, exhibits differential levels of histone acetylation as well as DNA methylation in the hippocampus of offspring of high versus low licking and grooming (LG) and arched-back nursing (ABN) mothers. Importantly, central infusion of the HDAC inhibitor (TSA) is capable of elevating H3K9 acetylation and hypermethylation of GR promoter with increased NGF1-A binding, GR expression as well as HPA response to stress in the offspring of the low-LG-ABN mothers.42

PRO-INFLAMMATORY PHENOTYPE OF UTERINE FIBROIDS

Uterine fibroids (UFs) are hormonally-regulated benign smooth muscle myometrial tumors that severely affect female reproductive health, although their unknown etiology limits effective care.43,44 An increasing body of evidence supports the hypothesis that UFs originate from stem cells in the myometrium, although the specific cell of origin for these tumors has remained elusive.45 Myometrial stem/progenitor cells (MMSCs) and UF stem/progenitor cells (UFSCs) have been identified.46,47,48,49 MMSCs are a subset of cells residing in the uterine myometrium, that remain their capacity to self-renew through asymmetric division rates as well as producing differentiated cells, which play an important role in tissue regeneration. UFSCs represent a subgroup of cells with a tumor cell population, which also retain the ability to reconstitute tumors.50 Notably, the difference between MMSCs and UFSCs at DNA level is that MED12 mutations were found only in UFSCs, but not MMSCs.46 In addition, the defect of DNA repair response was recently observed in UFSCs.51 In UFs, a recent study shows that higher numbers of macrophages are present inside and close to UFs as compared to the more distant myometrium.52 Notably, several key pro-inflammatory mediators including IL11, IL-13 and TGF-β are overexpressed in UFs. The latter one in particular is a potent chemoattractant factor for macrophages. Another group has reported that many pro-inflammatory mediators that trigger or enhance specific aspects of inflammation are upregulated in UF tumors as compared to adjacent myometrium tissues.50 In addition, the levels of tumor necrosis factor TNF-α, a cell-signaling protein involved in systemic inflammation, is elevated in Caucasian women with clinically symptomatic UFs.53 A recent study also shows that UF progenitor cells secrete higher levels of Th2 pathway cytokines (IL4, IL-5, IL-10, and IL-13), and significantly lower levels of Th1/Th17 cytokines (IL-6, IL12, IL-17A, INF-γ, G-CSF, and TGF-β1), suggesting that the altered pattern of cytokine expression and secretion may enhance UF development via chronic inflammation with the involvement of infiltrating immune cells.54

The link between UF development and early life exposure to xenoestrogen via inflammation has been recently identified in Eker rat animal model.55 The adult Eker rats developmentally exposed to diethylstilbestrol (DES) exhibits significantly higher expression of pro-inflammatory markers (TNF-α, NFkB and IL1β) in myometrium. Concomitantly, the macrophage number is also significantly increased in DES-exposed myometrium in adult stage. Flow cytometry analysis demonstrates that the production of several inflammatory cytokines is increased in DES-MMSCs verse vehicle exposed (VEH)-MMSCs. By RNA- sequencing analysis, some of key pro-inflammatory genes including Pcdh7, Pdpn, Cxcl10, Cd40, Ptger2, and Ereg, exhibits upregulation in MMSCs from myometrium early-life exposed to (DES) verse control (VEH). Subsequently, gene set enrichment analysis on the ChIP-sequencing data demonstrates that an enrichment of H3K4me3 (an active mark for gene transcription) at the promoters of inflammation responsive genes (IRGs) is observed in DES-MSCs as compared to VEH-MMSCs. Furthermore, the increased expression of IRGs in DES-MMSCs is positively correlated with the elevated H3K4me3 epigenetic mark. In addition, the mRNA expression of reprogrammed key cytokine genes encoding CCL-2, CCL-7, CSF-1, which contribute to the recruitment of monocytes/macrophage, exhibits a significant upregulation in DES-MMSCs verse VEH-MMSCs. These studies suggest that developmental exposure to xenoestrogens such as DES alters the inflammatory microenvironment in the myometrium and increases the risk of adult onset of UFs by permanently reprogramming pro-inflammatory genes in MMSCs towards a pro-fibroid epigenomic landscape.55

PRECLINICAL STUDIES OF EPIGENETIC AGENTS

Epigenetic modifiers/agents targeting DNMTs and histone modified enzymes have been widely investigated in preclinical studies of many diseases. Moreover, a variety of studies demonstrate that these epigenetic modifiers suppress and ameliorate varied diseases including immunopathogenesis, tissue damage, pain, bone and cartilage destruction, and cancers, etc. via inflammation32,56,57,58,59,60,61 (Table 1).

The zinc-dependent mammalian histone deacetylase (HDAC) family comprises over 10 enzymes, which have specific and critical functions in development and tissue homeostasis. Increased evidence points to a link between misregulated HDAC activity and many oncologic and non-oncologic diseases. Thus, the development and usage of HDAC inhibitors provide a promising option for therapeutic treatment. Currently, the effect of HDAC inhibitors on suppression of diseases via anti-inflammatory pathway has been widely investigated both in vitro and in vivo. As shown in table 1, most of the epigenetic modifiers targets inflammatory pathway by inhibition of HDAC activity, therefore leading to suppression of diseases via inflammatory pathway. HDAC inhibitors effect that contributes largely to their therapeutic benefits, is achieved through histone deacetylation, chromatin remodeling and transcriptional reprogramming, as well as other unknown or not fully characterized mechanisms.

The Bromodomain and Extra-Terminal Domain (BET) family proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes.62 Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET inhibitors that are capable of targeting BET bromodomains and exhibiting therapeutic effects have been described.63,64,65,66,67,68,69,70 Notably, emerging evidence suggests that BET proteins are involved in pathogenesis of inflammatory diseases62 and BET inhibitors exhibit potent anti-inflammatory effectsin several types of diseases. In the brain of the Alzheimer’s disease animal model, the BET inhibitor JQ1 decreases neuroinflammation with a reduction in the expression of the pro-inflammatory modulators IL-1b, IL-6, TNF-α, CCL2, NOS-2 and PTGS-2 in the brain of mice.71 In addition, BET inhibitors are capable of inhibiting retinal inflammatory disease and inflammatory bowel diseases.72,73

In addition to targeting HDACs and BET proteins, the inhibitors of DNMTs have been widely used in many pre-clinical studies for a variety of diseases, as well as in some clinical application.74,75,76,77,78,79 The approved anti-DNMTdrugs 5-azacitidine (5AC) and 5-aza-2’-deoxyazacytidine (DAC) are in clinical use for the treatment of myelodysplastic syndrome of all types and chronic myelomonocytic leukemia.80 The inflammation related studies in animal model of lung injury demonstrate that inhibition of DNMTs activity, at least in part, augments regulatory T-cells (Tregs) number and function to accelerate repair of experimental lung injury. Mice that received DAC exhibited accelerated resolution of their lung inflammation.81

FUTURE DIRECTIONS AND CONCLUSION

Tumor initiation and disease development via inflammatory pathway are linked with early life exposure to a variety of adverse insults via epigenetic reprogramming, which play an important role in alteration of pro-inflammatory profiling and phenotype. Much more attention is needed to identify epigenetic agents, which exhibit potent anti-inflammatory effect with minimum of side effects. In addition, more studies are needed to evaluate the role of epigenetic-based drugs alone or in combination with other chemical agents in suppressing inflammation as a means of prevention and management of many diseases including UFs.

CONFLICT OF INTEREST

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

ACKNOWLEDGMENTS

This study was supported in part by the National Institutes of Health grants: R01 HD094378, R01 ES028615.

1. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1beta generation. Clin Exp Immunol. 2007; 147(2): 227- 235. doi: 10.1111/j.1365-2249.2006.03261.x

2. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014; 15(11): e493-e503. doi: 10.1016/S1470-2045(14)70263-3

3. Crusz SM, Balkwill FR. Inflammation and cancer: Advances and new agents. Nat Rev Clin Oncol. 2015; 12(10): 584-596. doi: 10.1038/nrclinonc.2015.105

4. Lee H, Abston E, Zhang D, Rai A, Jin Y. Extracellular vesicle: An emerging mediator of intercellular crosstalk in lung inflammation and injury. Front Immunol. 2018; 9: 924. doi: 10.3389/fimmu.2018.00924

5. Kunnumakkara AB, Sailo BL, Banik K, et al. Chronic diseases, inflammation, and spices: How are they linked? J Transl Med. 2018; 16(1): 14. doi: 10.1186/s12967-018-1381-2

6. Leonardi GC, Accardi G, Monastero R, Nicoletti F, Libra M. Ageing: From inflammation to cancer. Immun Ageing. 2018; 15: 1. doi: 10.1186/s12979-017-0112-5

7. Mantovani A. The inflammation - cancer connection. FEBS J. 2018; 285(4): 638-640. doi: 10.1111/febs.14395

8. Martinez BK, White CM. The Emerging role of inflammation in cardiovascular disease. Ann Pharmacother. 2018; 52(8): 801-809. doi: 10.1177/1060028018765939

9. Castaneda S, Gonzalez-Juanatey C, Gonzalez-Gay MA. Inflammation and heart diseases. Curr Pharm Des. 2018; 24(3): 262-280. doi: 10.2174/1381612824666180123102632

10. Wu Y, Dong Y, Duan S, Zhu D, Deng L. Metabolic syndrome, inflammation, and cancer. Mediators Inflamm. 2017; doi: 10.1155/2017/8259356

11. Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011; 1(7): 598-607. doi: 10.1158/2159-8290.CD-11-0214

12. Al-Talabany S, Mordi I, Graeme Houston J, et al. Epicardial adipose tissue is related to arterial stiffness and inflammation in patients with cardiovascular disease and type 2 diabetes. BMC Cardiovasc Disord. 2018; 18(1): 31. doi: 10.1186/s12872-018-0770-z

13. Chen X, Chen X, Xu Y, et al. Association of six CpG-SNPs in the inflammation-related genes with coronary heart disease. Hum Genomics. 2016; 10(2): 21. doi: 10.1186/s40246-016-0067-1

14. Yang Q, Diamond MP, Al-Hendy A. Early life adverse environmental exposures increase the risk of uterine fibroid development: Role of Epigenetic Regulation. Front Pharmacol. 2016; 7: 40. doi: 10.3389/fphar.2016.00040

15. Cook JD, Davis BJ, Cai SL, et al. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A 2005; 102(24): 8644-8649. doi: 10.1073/pnas.0503218102

16. Du Preez A, Leveson J, Zunszain PA, Pariante CM. Inflammatory insults and mental health consequences: Does timing matter when it comes to depression? Psychol Med. 2016; 46(10): 2041- 2057. doi: 10.1017/S0033291716000672

17. Tartaglione AM, Venerosi A, Calamandrei G. Early-life toxic insults and onset of sporadic neurodegenerative diseases-an overview of experimental studies. Curr Top Behav Neurosci. 2016; 29: 231-264. doi: 10.1007/7854_2015_416

18. Spann K, Snape N, Baturcam E, Fantino E. The impact of early-life exposure to air-borne environmental insults on the function of the airway epithelium in asthma. Ann Glob Health. 2016; 82(1): 28-40. doi: 10.1016/j.aogh.2016.01.007

19. Ley D, Desseyn JL, Mischke M, et al. Early-life origin of intestinal inflammatory disorders. Nutr Rev. 2017; 75(3): 175-187. doi: 10.1093/nutrit/nuw061

20. Olvera Alvarez HA, Kubzansky LD, Campen MJ, Slavich GM. Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health. Neurosci Biobehav Rev. 2018; 92: 226- 242. doi: 10.1016/j.neubiorev.2018.06.002

21. Challier JC, Basu S, Bintein T, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta. 2008; 29(3): 274-281. doi: 10.1016/j.placenta.2007.12.010

22. Armitage JA, Poston L, Taylor PD. Developmental origins of obesity and the metabolic syndrome: The role of maternal obesity. Front Horm Res. 2008; 36: 73-84. doi: 10.1159/0000115355

23. Dunn GA, Bale TL. Maternal high-fat diet effects on thirdgeneration female body size via the paternal lineage. Endocrinology. 2011; 152(6): 2228-2236. doi: 10.1210/en.2010-1461

24. Bolton JL, Bilbo SD. Developmental programming of brain and behavior by perinatal diet: Focus on inflammatory mechanisms. Dialogues Clin Neurosci. 2014; 16(3): 307-320. doi: 10.31887/DCNS.2014.16.3/jbolton

25. Dahlgren J, Nilsson C, Jennische E, et al. Prenatal cytokine exposure results in obesity and gender-specific programming. Am J Physiol Endocrinol Metab. 2001; 281(2): E326-E334. doi: 10.1152/ ajpendo.2001.281.2.E326

26. Yang Q, Mas A, Diamond MP, Al-Hendy A. The mechanism and function of epigenetics in uterine leiomyoma development. Reprod Sci. 2016; 23(2): 163-175. doi: 10.1177/1933719115584449

27. Ng GY, Yun-An L, Sobey CG, et al. Epigenetic regulation of inflammation in stroke. Ther Adv Neurol Disord. 2018; 11: 175. doi: 10.1177/1756286418771815

28. Ratay ML, Balmert SC, Bassin EJ, Little SR. Controlled release of an HDAC inhibitor for reduction of inflammation in dry eye disease. Acta Biomater. 2018; 71: 261-270. doi: 10.1016/j. actbio.2018.03.002

29. Tarun A, Antoniades C. The Era of cardiovascular epigenetics: Histone deacetylases and vascular inflammation. Cardiovasc Res.2018; 114(7): 928-930. doi: 10.1093/cvr/cvy099

30. Thankam FG, Boosani CS, Dilisio MF, Agrawal DK. MicroRNAs associated with inflammation in shoulder tendinopathy and glenohumeral arthritis. Mol Cell Biochem. 2018; 437(1-2): 81-97. doi: 10.1007/s11010-017-3097-7

31. Wu XM, Ji KQ, Wang HY, et al. MicroRNA-339-3p alleviates inflammation and edema and suppresses pulmonary microvascular endothelial cell apoptosis in mice with severe acute pancreatitis-associated acute lung injury by regulating Anxa3 via the Akt/ mTOR signaling pathway. J Cell Biochem. 2018; 119(8): 6704-6714. doi: 10.1002/jcb.26859

32. Xia M, Xu H, Dai W, et al. The role of HDAC2 in cigarette smoke-induced airway inflammation in a murine model of asthma and the effect of intervention with roxithromycin. J Asthma. 2018; 55(4): 337-344. doi: 10.1080/02770903.2017.1337788

33. Yang J, Tian B, Brasier AR. Targeting chromatin remodeling in inflammation and fibrosis. Adv Protein Chem Struct Biol. 2017; 107: 1-36. doi: 10.1016/bs.apcsb.2016.11.001

34. Li H, Yao Q, Mariscal AG, et al. Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation. Nat Commun. 2018; 9(1): 1420. doi: 10.1038/s41467-018- 03704-z

35. Lu L, Claud EC. Intrauterine inflammation, epigenetics, and microbiome influences on preterm infant health. Curr Pathobiol Rep. 2018; 6(1): 15-21. doi: 10.1007/s40139-018-0159-9

36. Wang Q, Trevino LS, Wong RL, et al. Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk. Mol Endocrinol. 2016; 30(8): 856-871. doi: 10.1210/me.2015-1310

37. Jorgensen EM, Alderman MH, Taylor HS. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure. FASEB J. 2016; 30(9): 3194-3201. doi: 10.1096/fj.201500089R

38. Yang Q, Al-Hendy A. Developmental environmental exposure alters the epigenetic features of myometrial stem cells. Gynecol Obstet Res. 2016; 3(2): e1-e4. doi: 10.17140/GOROJ-3-e005

39. Monica F, Elisa P, Caterina S, et al. Changes of intestinal microbiota in early life. J Matern Fetal Neonatal Med. 2018; 10: 1-8. doi: 10.1080/14767058.2018.1506760

40. Park CH, Eun CS, Han DS. Intestinal microbiota, chronic inflammation, and colorectal cancer. Intest Res. 2018; 16(3): 338-345. doi: 10.5217/ir.2018.16.3.338

41. Huh JW, Laurer HL, Raghupathi R, Helfaer MA, Saatman KE. Rapid loss and partial recovery of neurofilament immunostaining following focal brain injury in mice. Exp Neurol. 2002, 175(1): 198-208. doi: 10.1006/exnr.2002.7880

42. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004, 7(8): 847- 854. doi: 10.1038/nn1276

43. Sabry M, Al-Hendy A. Medical treatment of uterine leiomyoma. Reprod Sci. 2012, 19(4): 339-353. doi: 10.1177/1933719111432867

44. Pavone D, Clemenza S, Sorbi F, Fambrini M, Petraglia F. Epidemiology and risk factors of uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2018; 46: 3-11. doi: 10.1016/j.bpobgyn.2017.09.004

45. Bulun SE. Uterine fibroids. N Engl J Med. 2013; 369(14): 1344- 55. doi: 10.1056/NEJMra1209993

46. Ono M, Qiang W, Serna VA, et al. Role of stem cells in human uterine leiomyoma growth. PLoS One. 2012; 7(5): e36935. doi: 10.1371/journal.pone.0036935

47. Bulun SE, Moravek MB, Yin P, et al. Uterine leiomyoma stem cells: Linking progesterone to growth. Semin Reprod Med. 2015; 33(5): 357-365. doi: 10.1055/s-0035-1558451

48. Mas A, Nair S, Laknaur A, et al. Stro-1/CD44 as putative human myometrial and fibroid stem cell markers. Fertil Steril. 2015; 104(1): 225-234. doi: 10.1016/j.fertnstert.2015.04.021

49. Mas A, Stone L, O’Connor PM, et al. Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells. 2017, 35(3): 666-678. doi: 10.1002/stem.2519

50. Alam SR, Stirrat C, Spath N, et al. Myocardial inflammation, injury and infarction during on-pump coronary artery bypass graft surgery. J Cardiothorac Surg. 2017; 12(1): 115. doi: 10.1186/ s13019-017-0681-6

51. Prusinski Fernung LE, Al-Hendy A, Yang Q: A preliminary study: Human fibroid stro-1(+)/CD44(+) stem cells isolated from uterine fibroids demonstrate decreased DNA repair and genomic integrity compared to adjacent myometrial stro-1(+)/ CD44(+) cells. Reprod Sci. 2018; doi: 10.1177/1933719118783252

52. Protic O, Toti P, Islam MS, et al. Possible involvement of inflammatory/reparative processes in the development of uterine fibroids. Cell Tissue Res. 2016; 364(2): 415-427. doi: 10.1007/ s00441-015-2324-3

53. Ciebiera M, Wlodarczyk M, Wrzosek M, et al. TNF-alpha serum levels are elevated in women with clinically symptomatic uterine fibroids. Int J Immunopathol Pharmacol. 2018; 32: 2058738418779461. doi: 10.1177/2058738418779461.

54. Orciani M, Caffarini M, Biagini A, et al. Chronic inflammation may enhance leiomyoma development by the involvement of progenitor cells. Stem Cells Int. 2018; doi: 10.1155/2018/1716246

55. Yang Q, Trevino L, EI Andaloussi A, et al. Developmental reprogramming of pro-inflammatory pathway mediates adult onset of uterine fibroids. American Society for Reproductive Medcine. 2018.doi: 10.1016/j.fertnstert.2018.07.1053

56. Sadeghi A, Rostamirad A, Seyyedebrahimi S, Meshkani R. Curcumin ameliorates palmitate-induced inflammation in skeletal muscle cells by regulating JNK/NF-kB pathway and ROS production. Inflammopharmacology. 2018; doi: 10.1007/s10787-018-0466-0

57. Wang J, Zhao L, Wei Z, et al. Inhibition of histone deacetylase reduces lipopolysaccharide-induced-inflammation in primary mammary epithelial cells by regulating ROS-NF-small ka, CyrillicB signaling pathways. Int Immunopharmacol. 2018, 56: 230-234.doi: 10.1016/j.intimp.2018.01.039

58. Xu Y, Liu L. Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-kappaB signaling pathway. Influenza Other Respir Viruses. 2017; 11(5): 457-463. doi: 10.1111/irv.12459

59. Mishra N, Brown DR, Olorenshaw IM, Kammer GM. Trichostatin a reverses skewed expression of CD154, interleukin-10, and interferon-gamma gene and protein expression in lupus T cells. Proc Natl Acad Sci U S A. 2001; 98(5): 2628-2633. doi: 10.1073/ pnas.051507098

60. Yang F, Yang Y, Wang Y, et al. Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain. Sheng Li Xue Bao. 2015; 67(5): 447-454.

61. Heers H, Stanislaw J, Harrelson J, Lee MW. Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer. Eur J Pharmacol. 2018; 835: 61-74. doi: 10.1016/j.ejphar.2018.07.057

62. Hajmirza A, Emadali A, Gauthier A, et al. BET family protein BRD4: An emerging actor in NFkappaB signaling in inflammation and cancer. Biomedicines. 2018; 6(1): E16. doi: 10.3390/biomedicines6010016

63. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014; 54(5): 728- 36. doi: 10.1016/j.molcel.2014.05.016

64. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011; 108(40): 16669-16674. doi: 10.1073/ pnas.1108190108

65. Chatterjee N, Bohmann D. BET-ting on Nrf2: How Nrf2 signaling can influence the therapeutic activities of BET protein inhibitors. Bioessays. 2018, 40(5): e1800007. doi: 10.1002/ bies.201800007

66. Saenz DT, Fiskus W, Manshouri T, et al. BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells. Leukemia. 2017; 31(3): 678-687. doi: 10.1038/leu.2016.260

67. Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011; 478(7370): 529-533.doi: 10.1038/nature10509

68. Lockwood WW, Zejnullahu K, Bradner JE, Varmus H. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci U S A. 2012; 109(47): 19408-19413. doi: 10.1073/pnas.1216363109

69. Bid HK, Kerk S. BET bromodomain inhibitor (JQ1) and tumor angiogenesis. Oncoscience. 2016; 3(11-12): 316-317. doi: 10.18632/oncoscience.326

70. Bid HK, Phelps DA, Xaio L, et al. The bromodomain BET inhibitor JQ1 suppresses tumor angiogenesis in models of childhood sarcoma. Mol Cancer Ther. 2016; 15(5): 1018-1028. doi: 10.1158/1535-7163.MCT-15-0567

71. Magistri M, Velmeshev D, Makhmutova M, et al. The BETbromodomain inhibitor JQ1 reduces inflammation and tau phosphorylation at Ser396 in the brain of the 3xTg model of alzheimer’s disease. Curr Alzheimer Res. 2016; 13(9): 985-995. doi: 10.2174/1567205013666160427101832

72. Eskandarpour M, Alexander R, Adamson P, Calder VL. Pharmacological inhibition of bromodomain proteins suppresses retinal inflammatory disease and downregulates retinal Th17 cells. J Immunol. 2017; 198(3): 1093-1103. doi: 10.4049/jimmu nol.1600735

73. Cheung K, Lu G, Sharma R, et al. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. Proc Natl Acad Sci U S A. 2017; 114(11): 2952-2957. doi: 10.1073/pnas.1615601114

74. Manara MC, Valente S, Cristalli C, et al. A quinoline-based DNA methyltransferase inhibitor as a possible adjuvant in osteosarcoma therapy. Mol Cancer Ther. 2018; 17(9): 1881-1892. doi: 10.1158/15357163.MCT-17-0818

75. Yang J, Tian X, Yang J, et al. 5-Aza-2’-deoxycytidine, a DNA methylation inhibitor, induces cytotoxicity, cell cycle dynamics and alters expression of DNA methyltransferase 1 and 3A in mouse hippocampus-derived neuronal HT22 cells. J Toxicol Environ Health A. 2017; 80(22): 1222-1229. doi: 10.1080/15287394.2017.1367143

76. Andrade AF, Borges KS, Suazo VK, et al. The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma. Invest New Drugs. 2017; 35(1): 26-36. doi: 10.1007/s10637-016-0401-4

77. Shilpi A, Parbin S, Sengupta D, et al. Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer. Chem Biol Interact. 2015; 233: 122-138. doi: 10.1016/j.cbi.2015.03.022

78. Konac E, Varol N, Yilmaz A, Menevse S, Sozen S. DNA methyltransferase inhibitor-mediated apoptosis in the Wnt/ beta-catenin signal pathway in a renal cell carcinoma cell line. Exp Biol Med (Maywood). 2013; 238(9): 1009-1016. doi: 10.1177/1535370213498984

79. Yang QW, Liu S, Tian Y, et al. Methylation-associated silencing of the thrombospondin-1 gene in human neuroblastoma. Cancer Res. 2003; 63(19): 6299-6310.

80. Griffiths EA, Gore SD. DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol. 2008; 45(1): 23-30. doi: 10.1053/j.seminhematol.2007.11.007

81. Singer BD, Mock JR, Aggarwal NR, et al. Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation. Am J Respir Cell Mol Biol. 2015; 52(5): 641-652. doi: 10.1165/rcmb.2014-0327OC

82. Wang J, Hodes GE, Zhang H, et al. Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun. 2018; 9(1): 477. doi: 10.1038/s41467- 017-02794-5

83. Adams KR, Chauhan S, Patel DB, et al. Ubiquitin Conjugation Probed by Inflammation in Myeloid-Derived Suppressor Cell Extracellular Vesicles. J Proteome Res. 2018; 17(1): 315-324. doi: 10.1021/acs.jproteome.7b00585

84. Hammitzsch A, Tallant C, Fedorov O, et al. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci U S A. 2015; 112(34): 10768-10773. doi: 10.1073/pnas.1501956112

85. Thangavel J, Samanta S, Rajasingh S, et al. Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury. J Cell Sci. 2015; 128(16): 3094-3105. doi: 10.1242/jcs.170258

86. Shen J, Wu S, Guo W, et al. Epigenetic regulation of proinflammatory cytokine genes in lipopolysaccharide -stimulated peripheral blood mononuclear cells from broilers. Immunobiology. 2017; 222(2): 308-315. doi: 10.1016/j.imbio.2016.09.009

87. Grabiec AM, Krausz S, de Jager W, et al. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J Immunol. 2010; 184(5): 2718-2728. doi: 10.4049/jimmunol.0901467

88. Joosten LA, Leoni F, Meghji S, Mascagni P. Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol Med. 2011; 17(5-6): 391-396. doi: 10.2119/molmed.2011.00058

89. Leoni F, Fossati G, Lewis EC, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005; 11(1-12): 1-15. doi: 10.2119/2006-00005.Dinarello

90. Leoni F, Zaliani A, Bertolini G, et al. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci U S A. 2002; 99(5): 2995-3000. doi: 10.1073/pnas.052702999

91. Gillespie J, Savic S, Wong C, et al. Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum. 2012; 64(2): 418-422. doi: 10.1002/art.33382

92. Saouaf SJ, Li B, Zhang G, et al. Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis. Exp Mol Pathol. 2009; 87(2): 99-104. doi: 10.1016/j.yexmp.2009.06.003

93. Marquardt JU, Gomez-Quiroz L, Arreguin Camacho LO, et al. Curcumin effectively inhibits oncogenic NF-kappaB signaling and restrains stemness features in liver cancer. J Hepatol. 2015; 63(3): 661-669. doi: 10.1016/j.jhep.2015.04.018

94. Chen Y, Shu W, Chen W, et al. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Basic Clin Pharmacol Toxicol. 2007; 101(6): 427-433. doi: 10.1111/j.1742- 7843.2007.00142.x

95. Wei ZQ, Zhang YH, Ke CZ, et al. Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation. World J Gastroenterol. 2017; 23(34): 6252-6260. doi: 10.3748/wjg.v23.i34.6252

96. Kadiyala CS, Zheng L, Du Y, et al. Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC). J Biol Chem. 2012; 287(31): 25869-25880. doi: 10.1074/jbc.M112.375204

97. Busbee PB, Nagarkatti M, Nagarkatti PS. Natural indoles, indole-3-carbinol and 3,3’-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression. Toxicol Appl Pharmacol. 2014; 274(1): 7-16. doi: 10.1016/j.taap.2013.10.022

98. Nishida K, Komiyama T, Miyazawa S, et al. Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum. 2004; 50(10): 3365-3376. doi: 10.1002/ art.20709

99. Zhang ZY, Schluesener HJ. HDAC inhibitor MS-275 attenuates the inflammatory reaction in rat experimental autoimmune prostatitis. Prostate. 2012; 72(1): 90-99. doi: 10.1002/pros.21410

100. Hogh Kolbaek Kjaer AS, Brinkmann CR, Dinarello CA, et al. The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients. AIDS. 2015; 29(10): 1195-1200. doi: 10.1097/QAD.0000000000000678

101. Qu X, Proll M, Neuhoff C, et al. Sulforaphane epigenetically regulates innate immune responses of porcine monocyte-derived dendritic cells induced with lipopolysaccharide. PLoS One. 2015; 10(3): e0121574. doi: 10.1371/journal.pone.0121574

102. Orecchia A, Scarponi C, Di Felice F, et al. Sirtinol treatment reduces inflammation in human dermal microvascular endothelial cells. PLoS One. 2011; 6(9): e24307. doi: 10.1371/journal. pone.0024307

103. Lugrin J, Ciarlo E, Santos A, et al. The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock. Biochim Biophys Acta. 2013; 1833(6): 1498-1510. doi: 10.1016/j.bbamcr.2013.03.004

104. Cantley MD, Fairlie DP, Bartold PM, et al. Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis. Rheumatology (Oxford). 2015; 54(9): 1713-1723. doi: 10.1093/rheumatology/kev022

105. Zhang ZY, Schluesener HJ. Oral administration of histone deacetylase inhibitor MS-275 ameliorates neuroinflammation and cerebral amyloidosis and improves behavior in a mouse model. J Neuropathol Exp Neurol. 2013; 72(3): 178-185. doi: 10.1097/NEN.0b013e318283114a

106. Zhang ZY, Zhang Z, Schluesener HJ. MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis. Neuroscience. 2010; 169(1): 370- 377. doi: 10.1016/j.neuroscience.2010.04.074

107. Vishwakarma S, Iyer LR, Muley M, et al. Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int Immunopharmacol. 2013; 16(1): 72-78. doi: 10.1016/j.intimp.2013.03.016

LATEST ARTICLES

Laparoscopic Management of Adrenal and Extra-Adrenal

Laparoscopic Management of Adrenal and Extra-Adrenal Pheochromocytoma

Shrenik J. Shah*, Sajid Nurbhai, Rusha Surti, Parixit Malaviya and Pratik Chaudhary

doi.10.17140/UAOJ-7-146

Penile Cancer in the Region of Thies

Penile Cancer in the Region of Thies: Epidemiological, Diagnostic and Therapeutic Aspects

Saint C. N. Kouka*, Tonleu L. Bentefouet, Ngor M. Thiam, Modou Faye, Mbayang Diop, Mouhamed Cisse, Mohamed Jalloh, Aissatou A. Diame, Yoro Diallo and Sylla Cheikhna

doi.10.17140/UAOJ-7-145

Coronavirus Disease-2019 Infection-Associated Glomerular Diseases

Phuong-Chi T. Pham*, Golriz Jafari, Anita Kamarzarian, Vinod K. Valluri, Kulwant Bath, Chau Sally, Nguyen Tuan, Mahalli Joseph, Phuong-Mai T. Pham, Phuong-Anh T. Pham, Son V. Pham and Phuong-Thu T. Pham

doi.10.17140/NPOJ-8-129

West Virginia University Medicine, Wheeling Hospital’s Sepsis Study

Ramya Ramesh*, Jazmin Jatana, Chan Hong, Sathyanarayana Machani, Milind Awale, Stanley Guertal, Catherine Macalister, Heather L. Merkel, Melissa Burkett and Silvia Myndresku

doi. 10.17140/EMOJ-10-173

Yet Another Public Health Threat: A Commentary and Examination of the Extensive Use of Bromazolam

Nelson J. Tiburcio* and Scarlett L. Baker

doi.10.17140/PHOJ-9-167

LATEST ARTICLES