Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans
Bala S.C. Koritala Kenneth I. Porter Osama A. Arshad Rajendra P. Gajula Hugh D. Mitchell Tarana Arman Mugimane G. Manjanatha Justin Teeguarden Hans P.A. Van Dongen
Commentaries by Robert Gorter, MD, PhD.
doi:10.1111/jpi.1272627 February 2021
Circadian disruption has been identified as a risk factor for health disorders such as obesity, cardiovascular disease, and cancer. Although epidemiological studies suggest an increased risk of various cancers associated with circadian misalignment due to night shift work, the underlying mechanisms have yet to be elucidated. We sought to investigate the potential mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased cancer risk in shift workers. In a controlled laboratory study, we investigated the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in circulating leukocytes obtained from healthy young adults during a 24‐hour constant routine protocol following three days of simulated day shift or night shift. The simulated night shift schedule significantly altered the normal circadian rhythmicity of genes involved in cancer hallmark pathways. A DNA repair pathway showed significant enrichment of rhythmic genes following the simulated day shift schedule, but not following the simulated night shift schedule. In functional assessments, we demonstrated that there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift. Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers.
Source: Washington State University / Contact: Hans Van Dongen – Washington State University
My team and I have looked at DNA repair mechanisms and what disrupts DNA repair since the early 1990’s.
Firstly, we could document that practically all cancer patients, who requested to be treated according to the Gorter Model, had a significantly disrupted Circadian Rhythm and a significant lower core body temperature compared to healthy (and nonsmoking) individuals.
Secondly, 4-6 sessions of “fever-range, total-body hyperthermia” could improve circadian rhythm by approximately 80% compared to their baselines.
Thirdly, Viscum album (European mistletoe) improved the restoration of the circadian rhythm as well and improves Natural Killer Cell (NK) function. We found that in 98% of all patients with active cancer had a significantly lower NK activity.
Fourthly, Viscum album improves significantly DNA repair mechanisms which are especially of importance in cancer patients who received chemotherapy earlier: a main reason of the effects of chemotherapy is DNA damage of cancer (and normal) cells.
Fifthly, if night shifts etc. cannot be avoided, like medical staff, power plants, pilots and flight attendants, one could (should) take off and on Viscum album to preventively repair DNA damage.
Improvement of DNA repair in lymphocytes of breast cancer patients treated with Viscum album extract (Iscador®).
Kovacs E, Hajto T, Hostanska K. Improvement of DNA repair in lymphocytes of breast cancer patients treated with Viscum album extract (Iscador). Eur J Cancer. 1991;27(12):1672-6. doi: 10.1016/0277-5379(91)90443-h. PMID: 1782081.
Kovacs, et al. investigated alteration in DNA repair during therapy with an immunomodulator. 14 patients with advanced breast cancer were treated parenterally with Iscador, a watery extract of Viscum album (European mistletoe). As a parameter for measurement of DNA repair the incorporation of (3H) thymidine into DNA of unstimulated lymphocytes after ultra violet light (UV) damage was taken. The DNA repair values in the patients were very low before treatment and on day 1: on average 16% of those in a healthy control population. Values started to increase on day 2 and on days 7-9 were on average 2.7 times higher than before treatment. 12/14 patients showed an improvement in repair. The values of spontaneous DNA synthesis were not altered during the treatment. We suggest that the increase of DNA repair could be due to a stimulation of repair enzymes by lymphokines or cytokines secreted by activated leukocytes or an alteration in the susceptibility to exogenic agents resulting in less damage.
Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective, nonrandomized and randomized matched-pair studies nested within a cohort study
Grossarth-Maticek R, Kiene H, Baumgartner SM, Ziegler R. Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med. 2001 May-Jun;7(3):57-66, 68-72, 74-6 passim. PMID: 11347286.
Context: In anthroposophical medicine, total aqueous extracts of Viscum album (European mistletoe) have been developed since the early 1920’s to treat cancer patients. The oldest such product is Iscador. Although Iscador is regarded as a complementary cancer therapy, it is the most commonly used oncological drug in Germany and Middle Europe at large.
Objective: To determine whether Iscador treatment prolongs survival time of patients with carcinoma of the colon, rectum, or stomach; breast carcinoma with or without axillary or remote metastases; or small cell or non-small-cell bronchogenic carcinoma; and to explore synergies between Iscador treatment and psychosomatic self-regulation.
Design: Prospective nonrandomized and randomized matched-pair studies nested within a cohort study.
Setting: General community in Germany.
Participants: 10,226 cancer patients involved in a prospective long-term epidemiological cohort study, including 1668 patients treated with Iscador and 8475 who had taken neither Iscador nor any other mistletoe product (control patients)..
Results: In the nonrandomized matched-pair study, survival time of patients treated with Iscador was longer for all types of cancer studied. In the pool of 396 matched pairs, mean survival time in the Iscador groups (4.23 years) was roughly 40% longer than in the control groups (3.05 years; P < .001). Synergies between Iscador treatment and self-regulation manifested in a longer survival advantage for Iscador patients with good self-regulation (56% relative to control group; P = .03) than for patients with poor self-regulation. In addition, patients in the treatment group had a better Quality of Life with fewer interventions, like hospitalizations. Results of the 2 randomized matched-pair studies largely confirmed the results of the non-randomized studies.
Conclusion: Iscador (and other aqueous extracts) treatment can achieve a clinically relevant prolongation of survival time of cancer patients and appears to stimulate self-regulation (DNA repair).
Methotrexate-Induced Nephrotoxicity in Rats: Protective Effect of Mistletoe (Viscum album L.) Extract
Sakalli Çetin E · Tetiker H · İlhan Çelik Ö.· Yılmaz N. · Ciğerci I.H.
Complement Med Res 2017;24:364-370
Background: The protective effect of aqueous mistletoe extract (Helixor®, HLX) against methotrexate (MTX)-induced acute oxidative stress and nephrotoxicity in rats was evaluated by histological and biochemical methods as well as the comet assay. Material and Methods: 32 female Wistar albino rats were divided into 4 groups: control group, HLX group (5 mg/kg body weight (bw), days 1-10, intraperitoneally (i.p.)), MTX group (10 mg/kg bw, days 7, 8, and 9, i.p.), and MTX + HLX group (10 mg/kg bw, days 7, 8, and 9, i.p. + 5 mg/kg bw, days 1-10, i.p.). At the end of the experiment, the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), nitric oxide (NO), and myeloperoxidase (MPO) levels were measured, and a histopathological analysis and comet assay were carried out. Results: MTX induced renal oxidative stress and nephrotoxicity in the rats. Pretreatment with HLX significantly improved the renal GSH-Px and SOD activities in the MTX + HLX group compared to the MTX group. The decrease in the NO and MPO levels in the rat groups pretreated with HLX was not significant. The histochemical evaluation revealed that HLX provided significant improvement in the MTX-induced renal degenerative changes, including tubule distension, interstitial inflammation, perirenal inflammation, glomerular congestion, glomerular degeneration, and parenchymal hemorrhage, in the MTX + HLX group compared to the MTX-administered group. According to the comet assay, pretreatment with HLX lowered the MTX-induced DNA damage in endogenous lymphocytes, although not significantly. Conclusion: This study demonstrated that HLX administration markedly reduced the MTX-induced acute oxidative stress and nephrotoxicity in rats through its antioxidant and anti-inflammatory properties.
The in vitro effect of Viscum album (VA) extract on DNA repair of peripheral blood mononuclear cells (PBMC) in cancer patients
Eva Kovacs, et al.
Aqueous Viscum album (VA) extract as an immunomodulator was tested in an in vitro model to investigate DNA repair in damaged peripheral blood mononuclear cells (PBMC) of ten breast cancer patients. The cells were exposed by gamma rays or 4‐hydroxycyclophosphamide (4‐HCy). Two hours after exposure the following were measured, without or with VA extract (1) DNA repair using the alkaline sucrose gradient for the sedimentation of DNA strand breaks, (2) DNA‐gamma‐production in the supernatant of the cultured cells. The VA extract led to an improvement of DNA repair in gamma‐ray or 4‐HCy damaged PBMC and to a significant increase of the IFN‐gamma‐production both in undamaged and in damaged cells.
The results indicate that the VA extract affects positively DNA repair in PBMC damaged by two different agents and suggest that an increased IFN‐gamma‐production may play an important role in the DNA repair process.