Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU2B1DJ)

• DOT Name: Period circadian protein homolog 2 (PER2)
• Synonyms: hPER2; Circadian clock protein PERIOD 2
• Gene Name: PER2
• Related Disease:
  Bipolar disorder
  Matthew-Wood syndrome
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Candidemia
  Cardiovascular disease
  Colorectal carcinoma
  Drug dependence
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Influenza
  Lung cancer
  Lung carcinoma
  Lymphoma
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Pediatric lymphoma
  Rheumatoid arthritis
  Sleep disorder
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Substance withdrawal syndrome
  Gastric cancer
  Methicillin-resistant staphylococci infection
  Advanced sleep phase syndrome
  Acute myelogenous leukaemia
  Advanced sleep phase syndrome 1
  Alcohol dependence
  Coronary atherosclerosis
  Depression
  Myocardial infarction
  Myocardial ischemia
  Obesity
  Pancreatic cancer
  Postpartum depression
  Prostate cancer
  Prostate carcinoma
• UniProt ID: PER2_HUMAN
• PDB ID: 6OF7; 8D7M; 8D7N; 8D7O
• Pfam ID: PF08447 ; PF21353 ; PF12114
• Sequence:
  MNGYAEFPPSPSNPTKEPVEPQPSQVPLQEDVDMSSGSSGHETNENCSTGRDSQGSDCDD
  SGKELGMLVEPPDARQSPDTFSLMMAKSEHNPSTSGCSSDQSSKVDTHKELIKTLKELKV
  HLPADKKAKGKASTLATLKYALRSVKQVKANEEYYQLLMSSEGHPCGADVPSYTVEEMES
  VTSEHIVKNADMFAVAVSLVSGKILYISDQVASIFHCKRDAFSDAKFVEFLAPHDVGVFH
  SFTSPYKLPLWSMCSGADSFTQECMEEKSFFCRVSVRKSHENEIRYHPFRMTPYLVKVRD
  QQGAESQLCCLLLAERVHSGYEAPRIPPEKRIFTTTHTPNCLFQDVDERAVPLLGYLPQD
  LIETPVLVQLHPSDRPLMLAIHKKILQSGGQPFDYSPIRFRARNGEYITLDTSWSSFINP
  WSRKISFIIGRHKVRVGPLNEDVFAAHPCTEEKALHPSIQELTEQIHRLLLQPVPHSGSS
  GYGSLGSNGSHEHLMSQTSSSDSNGHEDSRRRRAEICKNGNKTKNRSHYSHESGEQKKKS
  VTEMQTNPPAEKKAVPAMEKDSLGVSFPEELACKNQPTCSYQQISCLDSVIRYLESCNEA
  ATLKRKCEFPANVPALRSSDKRKATVSPGPHAGEAEPPSRVNSRTGVGTHLTSLALPGKA
  ESVASLTSQCSYSSTIVHVGDKKPQPELEMVEDAASGPESLDCLAGPALACGLSQEKEPF
  KKLGLTKEVLAAHTQKEEQSFLQKFKEIRKLSIFQSHCHYYLQERSKGQPSERTAPGLRN
  TSGIDSPWKKTGKNRKLKSKRVKPRDSSESTGSGGPVSARPPLVGLNATAWSPSDTSQSS
  CPAVPFPAPVPAAYSLPVFPAPGTVAAPPAPPHASFTVPAVPVDLQHQFAVQPPPFPAPL
  APVMAFMLPSYSFPSGTPNLPQAFFPSQPQFPSHPTLTSEMASASQPEFPSRTSIPRQPC
  ACPATRATPPSAMGRASPPLFQSRSSSPLQLNLLQLEEAPEGGTGAMGTTGATETAAVGA
  DCKPGTSRDQQPKAPLTRDEPSDTQNSDALSTSSGLLNLLLNEDLCSASGSAASESLGSG
  SLGCDASPSGAGSSDTSHTSKYFGSIDSSENNHKAKMNTGMEESEHFIKCVLQDPIWLLM
  ADADSSVMMTYQLPSRNLEAVLKEDREKLKLLQKLQPRFTESQKQELREVHQWMQTGGLP
  AAIDVAECVYCENKEKGNICIPYEEDIPSLGLSEVSDTKEDENGSPLNHRIEEQT
• Function: Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndrome and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like BMAL1 or G6PC1. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.
• Tissue Specificity: Widely expressed. Found in heart, brain, placenta, lung, liver, skeleatal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low levels in lung. Isoform 2 is expressed in keratinocytes (at protein level).
• KEGG Pathway:
  Circadian rhythm (hsa04710)
  Circadian entrainment (hsa04713)
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway: Circadian Clock (R-HSA-400253)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[2]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Candidemia	DISVKFN7	Strong	Biomarker	[8]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Drug dependence	DIS9IXRC	Strong	Biomarker	[11]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[14]
Influenza	DIS3PNU3	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[17]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[19]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[20]
Sleep disorder	DIS3JP1U	Strong	Altered Expression	[21]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[23]
Substance withdrawal syndrome	DISTT24U	Strong	Biomarker	[24]
Gastric cancer	DISXGOUK	moderate	Biomarker	[25]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[26]
Advanced sleep phase syndrome	DIS28KRD	Supportive	Autosomal dominant	[27]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[28]
Advanced sleep phase syndrome 1	DISO40XI	Limited	Unknown	[27]
Alcohol dependence	DIS4ZSCO	Limited	Biomarker	[29]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[9]
Depression	DIS3XJ69	Limited	Altered Expression	[30]
Myocardial infarction	DIS655KI	Limited	Biomarker	[31]
Myocardial ischemia	DISFTVXF	Limited	Biomarker	[9]
Obesity	DIS47Y1K	Limited	Genetic Variation	[32]
Pancreatic cancer	DISJC981	Limited	Biomarker	[33]
Postpartum depression	DIS08UKE	Limited	Biomarker	[34]
Prostate cancer	DISF190Y	Limited	Altered Expression	[35]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[35]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Period circadian protein homolog 2 (PER2) affects the response to substance of Methotrexate.	[63]
Ethanol	DMDRQZU	Approved	Period circadian protein homolog 2 (PER2) affects the response to substance of Ethanol.	[64]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Period circadian protein homolog 2 (PER2).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Period circadian protein homolog 2 (PER2).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Period circadian protein homolog 2 (PER2).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Period circadian protein homolog 2 (PER2).	[40]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Period circadian protein homolog 2 (PER2).	[41]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Period circadian protein homolog 2 (PER2).	[42]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Period circadian protein homolog 2 (PER2).	[43]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Period circadian protein homolog 2 (PER2).	[44]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Period circadian protein homolog 2 (PER2).	[45]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Period circadian protein homolog 2 (PER2).	[46]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Period circadian protein homolog 2 (PER2).	[47]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Period circadian protein homolog 2 (PER2).	[48]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Period circadian protein homolog 2 (PER2).	[44]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Period circadian protein homolog 2 (PER2).	[49]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Period circadian protein homolog 2 (PER2).	[50]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Period circadian protein homolog 2 (PER2).	[51]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Period circadian protein homolog 2 (PER2).	[52]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Period circadian protein homolog 2 (PER2).	[46]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Period circadian protein homolog 2 (PER2).	[53]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Period circadian protein homolog 2 (PER2).	[54]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Period circadian protein homolog 2 (PER2).	[56]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Period circadian protein homolog 2 (PER2).	[57]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Period circadian protein homolog 2 (PER2).	[59]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Period circadian protein homolog 2 (PER2).	[60]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Period circadian protein homolog 2 (PER2).	[61]
CGS 21680	DMZ0TGY	Investigative	CGS 21680 decreases the expression of Period circadian protein homolog 2 (PER2).	[62]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Period circadian protein homolog 2 (PER2).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Period circadian protein homolog 2 (PER2).	[55]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Period circadian protein homolog 2 (PER2).	[58]

References

• [1] Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms.Neuropharmacology. 2016 Feb;101:439-48. doi: 10.1016/j.neuropharm.2015.10.017. Epub 2015 Oct 22.
• [2] Patients with resectable pancreatic adenocarcinoma: A 15-years single tertiary cancer center study of laparotomy findings, treatments and outcomes.Surg Oncol. 2018 Dec;27(4):619-624. doi: 10.1016/j.suronc.2018.07.014. Epub 2018 Aug 3.
• [3] A Phase 1 Study to Assess the Relative Bioavailability of Two Capsule Formulations of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma.J Clin Pharmacol. 2018 Jan;58(1):114-121. doi: 10.1002/jcph.987. Epub 2017 Aug 7.
• [4] Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene.J Biol Chem. 2019 Jan 11;294(2):547-558. doi: 10.1074/jbc.RA118.004942. Epub 2018 Nov 14.
• [5] Abnormal circadian locomotor rhythms and Per gene expression in six-month-old triple transgenic mice model of Alzheimer's disease.Neurosci Lett. 2018 May 29;676:13-18. doi: 10.1016/j.neulet.2018.04.008. Epub 2018 Apr 4.
• [6] Impact of adult attention deficit hyperactivity disorder and medication status on sleep/wake behavior and molecular circadian rhythms.Neuropsychopharmacology. 2019 Jun;44(7):1198-1206. doi: 10.1038/s41386-019-0327-6. Epub 2019 Feb 6.
• [7] Analyses of BMAL1 and PER2 Oscillations in a Model of Breast Cancer Progression Reveal Changes With Malignancy.Integr Cancer Ther. 2019 Jan-Dec;18:1534735419836494. doi: 10.1177/1534735419836494.
• [8] Secular trends of candidemia at a Brazilian tertiary care teaching hospital.Braz J Infect Dis. 2018 Jul-Aug;22(4):273-277. doi: 10.1016/j.bjid.2018.07.008. Epub 2018 Aug 16.
• [9] Intense Light-Mediated Circadian Cardioprotection via Transcriptional Reprogramming of the Endothelium.Cell Rep. 2019 Aug 6;28(6):1471-1484.e11. doi: 10.1016/j.celrep.2019.07.020.
• [10] Expression of miR-34a-5p is up-regulated in human colorectal cancer and correlates with survival and clock gene PER2 expression.PLoS One. 2019 Oct 28;14(10):e0224396. doi: 10.1371/journal.pone.0224396. eCollection 2019.
• [11] Abuse potential of 2-(4-iodo-2, 5-dimethoxyphenyl)N-(2-methoxybenzyl)ethanamine (25INBOMe); in vivo and ex vivo approaches.Neurochem Int. 2019 May;125:74-81. doi: 10.1016/j.neuint.2019.02.007. Epub 2019 Feb 13.
• [12] The spectrum of biopsy-proven secondary glomerular diseases: A cross-sectional study in China?"Wang P. Yao J
• [13] The impact of using hepatitis c virus nucleic acid test-positive donor hearts on heart transplant waitlist time and transplant rate.J Heart Lung Transplant. 2019 Nov;38(11):1178-1188. doi: 10.1016/j.healun.2019.08.010. Epub 2019 Aug 14.
• [14] Critical cholangiocarcinogenesis control by cryptochrome clock genes.Int J Cancer. 2017 Jun 1;140(11):2473-2483. doi: 10.1002/ijc.30663. Epub 2017 Mar 16.
• [15] Improving care for pregnant women with suspected influenza: A retrospective study before and after introduction of a rapid molecular assay.PLoS One. 2019 Jun 14;14(6):e0217651. doi: 10.1371/journal.pone.0217651. eCollection 2019.
• [16] Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.BMC Med. 2018 Feb 19;16(1):20. doi: 10.1186/s12916-018-1010-1.
• [17] Long-term survival outcome with tyrosine kinase inhibitors and surgical intervention in patients with metastatic or recurrent gastrointestinal stromal tumors: A 14-year, single-center experience.Cancer Med. 2019 Mar;8(3):1034-1043. doi: 10.1002/cam4.1994. Epub 2019 Jan 28.
• [18] Circadian clock genes and myocardial infarction in patients with type 2 diabetes mellitus.Gene. 2019 Jun 15;701:98-103. doi: 10.1016/j.gene.2019.03.038. Epub 2019 Mar 21.
• [19] Circadian clock gene Per2 downregulation in nonsmall cell lung cancer is associated with tumour progression and metastasis.Oncol Rep. 2018 Nov;40(5):3040-3048. doi: 10.3892/or.2018.6704. Epub 2018 Sep 13.
• [20] PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility.Mol Med Rep. 2017 Jul;16(1):422-428. doi: 10.3892/mmr.2017.6578. Epub 2017 May 11.
• [21] Regulation of Circadian Clock Genes on Sleep Disorders in Traumatic Brain Injury Patients.World Neurosurg. 2019 Oct;130:e475-e486. doi: 10.1016/j.wneu.2019.06.122. Epub 2019 Jun 25.
• [22] Deregulated expression of circadian clock and clock-controlled cell cycle genes in chronic lymphocytic leukemia.Mol Biol Rep. 2014 Jan;41(1):95-103. doi: 10.1007/s11033-013-2841-7. Epub 2013 Nov 5.
• [23] Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer.Int J Oncol. 2018 Jan;52(1):279-287. doi: 10.3892/ijo.2017.4180. Epub 2017 Oct 31.
• [24] Development of morphine-induced tolerance and withdrawal: involvement of the clock gene mPer2.Eur Neuropsychopharmacol. 2010 Jul;20(7):509-17. doi: 10.1016/j.euroneuro.2010.03.006.
• [25] Multi-disciplinary team for early gastric cancer diagnosis improves the detection rate of early gastric cancer.BMC Gastroenterol. 2017 Dec 6;17(1):147. doi: 10.1186/s12876-017-0711-9.
• [26] Clinical outcome of pharmacist-led prospective audit with intervention and feedback after expansion from patients using specific antibiotics to those using whole injectable antibiotics.Eur J Clin Microbiol Infect Dis. 2019 Mar;38(3):593-600. doi: 10.1007/s10096-018-03465-z. Epub 2019 Jan 24.
• [27] An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 2001 Feb 9;291(5506):1040-3. doi: 10.1126/science.1057499.
• [28] Up-regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leukemia.Anticancer Res. 2015 Dec;35(12):6615-22.
• [29] The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice.Addict Biol. 2019 Sep;24(5):946-957. doi: 10.1111/adb.12663. Epub 2018 Aug 9.
• [30] Health services research in patients with breast cancer (CAMISS-prospective): study protocol for an observational prospective study.BMC Cancer. 2018 Jan 8;18(1):54. doi: 10.1186/s12885-017-3926-9.
• [31] Period 2-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction.Hum Gene Ther. 2020 Jan;31(1-2):119-128. doi: 10.1089/hum.2019.146.
• [32] CLOCK, PER2 and BMAL1 DNA methylation: association with obesity and metabolic syndrome characteristics and monounsaturated fat intake.Chronobiol Int. 2012 Nov;29(9):1180-94. doi: 10.3109/07420528.2012.719967. Epub 2012 Sep 24.
• [33] SIRT1 and circadian gene expression in pancreatic ductal adenocarcinoma: Effect of starvation.Chronobiol Int. 2015 May;32(4):497-512. doi: 10.3109/07420528.2014.1003351. Epub 2015 Mar 23.
• [34] The 5-HTTLPR polymorphism modulates the influence on environmental stressors on peripartum depression symptoms.J Affect Disord. 2012 Feb;136(3):1192-7. doi: 10.1016/j.jad.2011.11.042. Epub 2011 Dec 29.
• [35] Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.J Pineal Res. 2010 Aug;49(1):60-8. doi: 10.1111/j.1600-079X.2010.00767.x. Epub 2010 May 27.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [38] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [39] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [42] Inorganic arsenic as an endocrine disruptor: modulation of the glucocorticoid receptor pathway in placental cells via CpG methylation. Chem Res Toxicol. 2019 Mar 18;32(3):493-499.
• [43] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [44] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [45] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [46] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [47] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [48] Influence of the estrous cycle on clock gene expression in reproductive tissues: effects of fluctuating ovarian steroid hormone levels. Steroids. 2010 Mar;75(3):203-12. doi: 10.1016/j.steroids.2010.01.007. Epub 2010 Jan 22.
• [49] Glucocorticoids affect 24 h clock genes expression in human adipose tissue explant cultures. PLoS One. 2012;7(12):e50435. doi: 10.1371/journal.pone.0050435. Epub 2012 Dec 10.
• [50] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [51] Chronic treatment with prednisolone represses the circadian oscillation of clock gene expression in mouse peripheral tissues. Mol Endocrinol. 2006 Mar;20(3):573-83. doi: 10.1210/me.2005-0165. Epub 2005 Nov 3.
• [52] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [53] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [54] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [55] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [56] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [57] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [58] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [59] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [60] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [61] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [62] Adenosine A2A receptor and TNF- regulate the circadian machinery of the human monocytic THP-1 cells. Inflammation. 2013 Feb;36(1):152-62. doi: 10.1007/s10753-012-9530-x.
• [63] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [64] Association of PER2 genotype and stressful life events with alcohol drinking in young adults. PLoS One. 2013;8(3):e59136. doi: 10.1371/journal.pone.0059136. Epub 2013 Mar 22.